OncoTrials - мониторинг клинических исследований

Описание

This is a Phase Ib in adult patients with relapsed or refractory EBV-positive DLBCL using daily oral dosing of VK-2019 in three dose escalation cohorts: 600 mg/day, 1200 mg/day, 1800 mg/day for 28 days (cycle), until progression or toxicity.

Критерии включения

• 4.1 Inclusion Criteria
• 1. Informed consent obtained prior to any protocol mandated assessment.
• 2. Age ≥ 18 years.
• 3. Patient must have relapsed or refractory EBV-positive DLBCL after a minimum of 2 prior regimens of systemic therapy.
• 4. Patient must have exhausted all available standard of care treatment options that could potentially provide clinical benefit.
• 5. Toxicities related to prior therapy must have returned to Grade 1 or less, or if chronic must be stable. Peripheral neuropathy must be Grade 2 or less
• 6. Prior anti-cancer treatment must have been completed greater than 2 weeks prior to study day 1.
• 7. Patients must have measurable disease, as defined by IWG 2007 criteria.
• 8. ECOG performance status score of ≤2
• 9. Adequate organ function as defined by the following criteria:
• 1. Absolute neutrophil count /> 1,500/microl (stable off any growth factor within 1 week of study drug administration)
• 2. Hemoglobin /> 9 g/dL (transfusion to achieve this level is permitted)
• 3. Platelet count /> 75,000/microl (transfusion to achieve this level is NOT permitted)
• 4. Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN);
• 5. Total serum bilirubin ≤ 1.5 x ULN;
• 6. Creatinine clearance≥ 60 ml/min as calculated per Cockcroft and Gault equation.
• 7. Urinary protein /< 2+ by dipstick. If dipstick ≥ 2+, then a 24-hour urine collection can be done, and the patient may enter only if urinary protein is /< 1 g/24 hour;
• 10. Sexually active patients will agree to utilize birth control method during the study and for 18 weeks after the study is concluded, using effective birth control methods as defined in https://www.cdc.gov/reproductivehealth/unintendedpregnancy/pdf/contraceptive_methods_508.pdf. See Protocol Appendix C.
• 11. Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.
• 4.2 Exclusion Criteria
• 1. Patients with severe or active symptomatic cardiopulmonary diseases (unstable angina and/or congestive heart failure or peripheral vascular disease within the last 12 months; chronic obstructive pulmonary disease exacerbation other respiratory illness requiring hospitalization) or clinically significant psychiatric disorders; patents with effectively treated conditions (e.g. stenting for CAD) are eligible.
• 2. Patients with metastatic disease with active central nervous system (CNS) involvement, defined as parenchymal brain or leptomeningeal involvement.
• 3. Concurrent administration of herbal preparations.
• 4. A serious uncontrolled medical disorder or active infection which would impair the ability of the subject to receive protocol therapy or whose control may be jeopardized by the complications of this therapy.
• 5. Patients currently taking drugs that inhibit or induce OATP1B1 or OATP1B3 within 5 half- lives of that agent. Examples are included in Appendix B.
• 6. Patients currently taking drugs that are proton pump inhibitors (PPIs) within 5 half- lives of that agent. Examples are included in Appendix B.
• 7. Patients who have received a prior organ allograft or allogeneic bone marrow transplant are eligible but must have no evidence of active GVHD and be off immunosuppressive drugs.
• 8. Current non-prescription drug or alcohol dependence;
• 9. For all female patients, pregnancy or breastfeeding.
• 10. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrollment.
• 11. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, or in the judgment of the investigator would make the patient inappropriate for entry into the study.
• 12. Patients with corrected QT by Fridericia`s formula (QTcF) of />470 ms are excluded.
• 13. Patients with Post-Transplant Lymphoproliferative Disease (PTLD) are excluded.

Критерии исключения

Описание

Patients who undergo allogeneic stem cell transplantation lose previously acquired immunity and are routinely revaccinated against many infectious diseases. For several reasons, these patients have a long-term immune deficiency due to the transplant itself (lack of immune reconstitution) and due to possible complications, primarily GvHD and its treatment. The risk of secondary malignancy in the long-term following an allogeneic bone marrow transplant is greatly increased, and secondary cancer cases account for a significant proportion of late deaths in both women and men after transplantation. Some of these secondary cancers are associated with HPV. The risk of cervical cancer has been reported to be 13 times increased compared to a healthy population.

Therefore in this trial, the aim is to study immune response (antigen-specific antibody response) after vaccination with 9-valent HPV vaccine (Gardasil 9®) in adult women and men (up to and including 45 years of age) who have undergone allogeneic stem cell transplantation. In this trial, the sponsor will compare "early" (start 9 months after tx) with "late" (start 15 months after tx) vaccination.

Критерии включения

• * Recipient of AlloSCT from related or unrelated donor.
• * Adults (men and women) ≥18 years up to and including 45 years of age for vaccination.
• * Patients can be included regardless of prior HPV vaccination prior to transplantation

Критерии исключения

• * Severe thrombocytopenia (under 50 x 10/^9) not allowing intramuscular injection
• * Severe acute GvHD grade III-IV.
• * Extensive chronic GvHD requiring treatment with prednisone doses above 0.7 mg/kg/day plus at least two other systemic treatments against GvHD (for example ruxolitinib or photopheresis).
• * Prednisone doses above 1mg/kg/day at study start.
• * Treatment with rituximab 6 months before start of vaccination. Doses given later (unusual) do not require exclusion.
• * Treatment within 3 months before start of vaccination with iv or sc immunoglobulin.
• * Pregnancy, pregnancy desire or active pregnancy planning during time vaccine is given and up to three months after last vaccine dose.
• * Treatment with blood thinning medication contraindicating intramuscular injection
• * Allergy against Gardasil 9

Описание

This is a prospective, multicenter, single-arm clinical study designed to evaluate the efficacy and safety of Polatuzumab Vedotin combined with Rituximab, Gemcitabine, and Oxaliplatin (Pola-R-GemOx) as salvage therapy for relapsed/refractory Diffuse Large B-Cell Lymphoma (DLBCL) patients ineligible for autologous transplantation.

Критерии включения

• -
• Participants must meet all of the following criteria to participate in the study:
• 1. Age ≥18 years old;
• 2. ineligible for autologous transplantation;
• 3. Sign the Informed Consent Form (ICF);
• 4. CD79b-positive DLBCL confirmed by pathology (including transformed DLBCL, PMBL, HGBCL);
• 5. Patients must have received adequate first-line treatment and only first-line treatment, with
• * Anti-CD20 monoclonal antibodies (unless the investigator determines that the tumor is CD20-negative)
• * Chemotherapy regimens containing anthracyclines
• 6. Recurrent or refractory diseases after first-line immunochemotherapy:
• * Refractory disease is defined as not having a complete response to first-line therapy (except for patients who are intolerant to first-line therapy)
• * Recurrent disease is defined as disease recurrence after complete response to first-line treatment
• 7. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2, with an expected survival of more than 12 weeks.
• 8. Have at least one measurable two-dimensional lesion identified by clinical examination, CT scan or MRI: ① lymph node />1.5cm; ② Other non-lymph node lesions ≥1.0cm;
• 9. The main tissues and organs function well:
• Hematological function: absolute granulocyte count ≥ 1,000/mm3, platelet count ≥ 75,000/mm3; Liver function: ALT/AST /< 3 times upper limit of normal (ULN) and total bilirubin ≤1.5× upper limit of normal (ULN) (/< 5 times ULN in patients with Gilbert syndrome, cholestasis due to hilar compression adenopathy, biliary obstruction due to liver involvement or lymphoma); Renal function: creatinine clearance /> 30 mL/min, creatinine ≤1.5× upper limit of normal (ULN) Lung function: indoor oxygen saturation ≥95%; Cardiac function: no obvious cardiac insufficiency or cardiovascular disease; 10. Fertile patients must be willing to use highly effective contraception during the study period and for 120 days after the last dose of treatment.

Критерии исключения

• -
• Subjects who meet any of the following criteria are not eligible to participate in this study:
• 1. Subjects with any factor that may affect their ability to comply with the protocol, as determined by the investigator, including uncontrollable medical, psychological, family, social, or geographical conditions, or those unwilling or unable to follow the procedures required by the study protocol.
• 2. Known human immunodeficiency virus (HIV) infection or immunoassay positive；
• 3. Viral infections that cannot be controlled by antiviral drugs, such as active herpes virus infection, acute or chronic active hepatitis B, acute or chronic active hepatitis C, etc. (Note: chronic HBV carriers or inactive HBsAg positive subjects with HBV-DNA lower than the lower limit of detection can be enrolled, requiring clinical evaluation and preventive antiviral therapy if appropriate; HCV antibody negative can be enrolled, HCV antibody positive patients need to test HCV-RNA, if negative can be enrolled)
• 4. Patients with uncontrolled lymphomas with CNS infiltration (CNS disease diagnosed at initial diagnosis is allowed, provided complete remission of CNS disease is achieved and maintained and no CNS disease is present at recurrence);
• 5. Patients who have previously received oxaliplatin or gemcitabine treatment;
• 6. Pregnant or lactating patients;
• 7. Other concurrent serious illness or medical condition that would prevent participation in the study

Описание

This study is a single-arm, open label, non-randomized, phase 2 trial of zanubrutinib in patients with diffuse large B-cell lymphoma (DLBCL) who have an MYD88 L265P mutation, a CD79B mutation, a NOTCH1 truncation, or who are CD5+ by immunohistochemistry (IHC).

Критерии включения

• * Patients must have a documented pathologic diagnosis of DLBCL at any stage.
• * Must have documented MYD88 L265P, CD79B, or NOTCH1 truncation mutation or be CD5+ by IHC.
• * Age ≥18 years on the day of signing the informed consent form.
• * Patients must have measurable disease on Positron Emission Tomography-Computed Tomography scan (CT/PET) imaging.
• * Patient must have received no more than one cycle of R-CHOP prior to enrollment. Length of time between first R-CHOP treatment and planned 2nd R-CHOP treatment should vary by no more than 21 days ± 3 days.
• * Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2.
• * Adequate bone marrow function as defined by:
• * Absolute neutrophil count (ANC) ≥1000/mm3, except for patients with bone marrow involvement in which ANC must be ≥500/mm3.
• * Platelet ≥75,000/mm3, except for patients with bone marrow involvement in which the platelet count must be ≥30,000/mm3.
• * Hemoglobin ≥7 g/dL, after transfusion if necessary
• * Adequate organ function defined as:
• * Creatinine clearance ≥30 mL/min as estimated by the Cockcroft-Gault equation.
• * Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase ≤2.5 × upper limit of normal (ULN).
• * Serum total bilirubin ≤3 x ULN (except patients with Gilberts syndrome 3g/dl).
• * Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment.
• * Women of childbearing potential and men must agree to use one of the following highly effective forms of birth control during the treatment and for 1 month following completion of study treatment for women and for 1 week following completion of study treatment for men.
• * combined (estrogen and progestogen containing) hormonal contraception:
• * oral
• * intravaginal
• * transdermal
• * progestogen-only hormonal contraception associated with inhibition of ovulation
• * oral
• * injectable
• * implantable
• * intrauterine device (IUD)
• * intrauterine hormone-releasing system (IUS)
• * bilateral tubal occlusion
• * vasectomized partner
• * heterosexual abstinence
• * Patients must not have any known allergies, hypersensitivity or intolerance to corticosteroids or monoclonal antibodies.
• * Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments.

Критерии исключения

• * Patients with high grade B-cell lymphoma with myelocytomatosis oncogene (MYC) and BCL-2 and/or BCL6 rearrangements.
• * Patients with brain metastasis.
• * Patients with peripheral neuropathy CTCAE grade ≥2.
• * Any uncontrolled or clinically significant cardiovascular disease including the following:
• * Myocardial infarction within 6 months before screening.
• * Unstable angina within 3 months before screening.
• * New York Heart Association class III or IV congestive heart failure.
• * History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes).
• * Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score 6 prostate cancer.
• * History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention.
• * History of stroke or intracranial hemorrhage within 6 months before first dose of study drug.
• * Severe or debilitating pulmonary disease in the opinion of the treating investigator.
• * Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
• * Active fungal, bacterial and/or viral infection requiring systemic therapy.
• * Underlying medical conditions that, in the investigator`s opinion, will render the administration of study drug hazardous or obscure the interpretation of toxicity or AEs.
• * Active infection with HIV, or serologic status reflecting active hepatitis B or C infection as follows:
• * Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (/< 20 IU), and if they are willing to undergo monitoring every 4 weeks for HBV reactivation.
• * Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable.
• * Major surgery within 4 weeks of the first dose of study drug.
• * Pregnant or lactating women.
• * Left ventricular ejection fraction (LVEF) /<55% on screening echocardiogram.
• * Vaccination or requirement for vaccination with a live vaccine within 28 days prior to the first dose of study drug or at any time during planned study treatment.
• * Hypersensitivity to zanubrutinib, rituximab, cyclophosphamide, doxorubicin, vincristine, or prednisone.
• * Requires ongoing treatment with a strong CYP3A inducer (Table 3).
• * Concurrent participation in another therapeutic clinical trial.
• * Active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia (eg, idiopathic thrombocytopenia purpura).
• * Requires ongoing treatment with warfarin or warfarin derivatives.

Описание

This study evaluates the feasibility and safety of a novel method for comparing the effectiveness of hypofractionated versus hyperfractionated radiation therapy in participants with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) undergoing T-cell redirection therapies (CAR T-cell therapy or bispecific antibodies).

Критерии включения

• 1. Provision of signed and dated informed consent form.
• 2. Stated willingness to comply with all study procedures and availability for the duration of the study.
• 3. Adult aged 18 years or older.
• 4. Histologically confirmed diagnosis of R/R DLBCL with tumor size greater than or equal to 5 cm in its greatest dimension with plan for CAR T or BsAb therapy at Yale New Haven Hospital.
• 5. ECOG performance status 0 to 3.
• 6. Ability to present for twice daily (M-F) fractionated radiation therapy, without contraindications for radiotherapy as determined by the treating radiation oncologist.
• 7. Women of childbearing potential must have a negative serum or urine pregnancy test at screening and at time of radiation treatment planning, per standard of care and departmental standard operating procedure. Participants must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through safety follow-up. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the participants and their understanding confirmed.

Критерии исключения

• Participants who meet any of the following criteria will be disqualified from entering the study:
• 1. Participants who are pregnant or currently breastfeeding.
• a. Females who have undergone surgical sterilization or who have been postmenopausal for at least 12 months are not considered to be of childbearing potential.
• 2. Participants with history of prior radiation exposure for research purposes within the past year, such that participation in this study would place them over the FDA limits for annual radiation exposure.
• 3. Participants who are unable to safely receive FDG PET tracer.
• 4. Any condition that would, in the investigator`s judgment, interfere with full participation in the study and attending required study visits (if outpatient); pose a significant risk to the participant; or interfere with interpretation of study data.
• 5. Participants who would not be anticipated to derive any clinical benefit from bridging radiotherapy, are unable to participate in twice daily radiotherapy, or have clinical contraindications to radiation therapy per treating investigator.

Описание

The purpose of this study is to learn about the effects of a new study medicine called PF-08046032, when taken alone and when taken with another medicine called sasanlimab, for the treatment of advanced cancers. The effects are studied in adult participants with certain types of lymphomas or solid tumors that are advanced or metastatic (spread to other parts of the body).

The study has three parts:

* Part A will test PF-08046032 alone at increasing dose levels in participants with certain lymphomas (cancer that begins in cells of the immune system) and in participants with certain solid tumors whose disease has worsened on or after standard treatments.
* Part B will test PF-08046032 (at selected doses) and sasanlimab in participants with certain solid tumors, including those whose disease has worsened on or after standard treatments as well as participants before receiving standard treatments.
* Part C will further test the combination of PF-08046032 and sasanlimab in participants with specific types of solid tumors based on the results from Part A and Part B of the study.

All participants will receive the study drug PF-08046032. Only participants in Part B and Part C of the study will also receive sasanlimab. PF-08046032 will be given as an intravenous (IV) infusion, which means it will be injected directly into a vein. Sasanlimab will be given as a subcutaneous injection, which means it will be injected under the skin.

Критерии включения

• 1. Histological or cytological diagnosis of metastatic or unresectable malignancy:
• * Part A1: Participants with lymphomas (cHL, PTCL, large B-cell lymphoma) who have progressed on/after standard therapies
• * Part A2: Participants with solid tumors (NSCLC, HNSCC, melanoma, or other limited tumor types) who have progressed on or following prior immune checkpoint inhibitor if indicated and available
• * Part B: Participants with solid tumors who have either progressed on/after prior immune checkpoint inhibitor, or who have not received prior immune checkpoint inhibitor therapy
• * Part C: Participants with selected tumor type who have not received systemic anticancer treatment for the tumor type (including prior immune checkpoint inhibitor
• 2. Measurable disease as defined by Lugano Classification for lymphomas or RECIST 1.1 for solid tumors
• 3. Able to provide tumor tissue(s) as defined by the protocol depending on the Part of the study at enrollment
• 4. ECOG Performance Status score 0 or 1

Критерии исключения

• 1. Ongoing peripheral neuropathy
• 2. History of significant immune-mediated adverse event considered related to prior immune-modulatory therapy
• 3. Known or suspected active autoimmune disease

Описание

This study is developed by the investigator and is a, phase I, single arm, clinical trial that will enroll subjects with untreated diffuse large B-cell lymphoma (DLCBL) at high risk for poor outcome. The types of treatments given will be shared with participants.

The aims are:

1. To assess the safety and how well the participants tolerate the treatment
2. Assess the response of the tumor to treatment to estimate complete response
3. Assess the response of the tumor to treatment to estimate progression-free survival

Критерии включения

• 1. Men and women 18 years of age or older.
• 2. Pathologically proven diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS).
• - Patients with Diffuse large B-cell lymphoma/ high grade B-cell lymphoma with MYC and BCL2 rearrangements are allowed.
• 3. No prior systemic therapy for lymphoma.
• 4. Subject has provided informed consent.
• 5. Subject is willing and able to comply with clinic visits and procedure outlined in the study protocol.
• 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• 7. Life expectancy of ≥3 months.
• 8. Ann Arbor stage II-IV
• 9. National Comprehensive Cancer Network - International Prognostic Index (NCCN-IPI) risk score of ≥ 2
• 10. Measurable disease, meaning at least 1 lymph node or other lymphomatous lesion with a long axis of ≥1.5 cm by CT imaging, and at least one FDG-avid lesion by FDG-PET scan.
• 11. Left ventricular ejection fraction of at least 45% by either echocardiography or radionucleotide angiography.
• 12. Ability to swallow oral tablets without difficulty.
• 13. All subjects with preserved reproductive potential must agree to practice abstinence or employ contraceptive measures for the duration of treatment and for 10 months (if female) or 7 months (if male) following final dosing. All male subjects are considered to have reproductive potential.
• Female subjects of reproductive potential are those who:
• i) are not at least 50 years old and have no menses for 24 consecutive months; or ii) have not been rendered surgically sterile (having undergone hysterectomy and/or bilateral salpingo-oophorectomy).
• Female subjects of reproductive potential must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin (hCG) within 7 days of first day of drug dosing.
• 14. Meet the following clinical laboratory requirements:
• * Creatinine clearance ≥30 ml/min by Cockcroft-Gault formula;
• * Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (unless indirect bilirubin is elevated due to Gilbert`s syndrome or hemolysis);
• * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)≤ 3 × ULN;
• * Platelet count ≥ 50,000/µL, with or without transfusion support;
• * ANC ≥ 1000/µL, with or without chronic granulocyte growth factor support;
• * Hemoglobin ≥8 g/dL, with or without transfusion support.

Критерии исключения

• 1. Allergy or intolerance to roflumilast.
• 2. Allergy or intolerance to loncastuximab
• 3. Any active malignancy other than DLBCL
• 4. Current participation in another interventional clinical study
• 5. Prior allogeneic bone marrow transplant within 12 months of screening date.
• 6. Prior autologous stem cell transplant within 6 months of screening date.
• 7. Immunotherapy, chemotherapy, radiotherapy, or investigational therapy within 6 months prior to drug dosing.
• 8. Active central nervous system (CNS) involvement by lymphoma, including untreated symptomatic epidural disease.
• 9. Active uncontrolled infection.
• 10. Poorly controlled depressive symptoms and/ or currently under management for depression that is poorly controlled.
• 11. Significant disease or medical conditions, as assessed by the Investigator and Sponsor, that would substantially increase the riskbenefit ratio of participating in the study. This includes, but is not limited to, acute myocardial nfarction within the last 6 months, unstable angina, uncontrolled diabetes mellitus, significant active infections, and congestive heart failure New York Heart Association Class III-IV.
• 12. Second malignancy, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer, or other malignancies for which subjects are not on active anti-cancer therapies and have had no evidence of active malignancy for at least 1 year.
• 13. History of major surgery within 3 weeks or minor surgery within 1 week of roflumilast administration. Major surgery includes, for example, any open or laparoscopic entry into a body cavity, or operative repair of fracture; minor surgery includes, for example, open surgical biopsy of palpable/superficial lymph node, or placement of vascular access device.
• 14. Other medical or psychiatric illnesses or organ dysfunction, which in the opinion of the investigator, would either compromise the subject`s safety or interfere with the evaluation of the safety of the study agent.
• 15. Corrected QT interval (QTc) prolongation (defined as a QTc />450 ms for males and />470 ms for females -Fridericia`s correction-) or other clinically significant ECG abnormalities as assessed by the investigator.
• 16. Baseline serum troponin above the upper limit of normal.
• 17. Baseline serum BNP above the age-adjusted upper limit of normal.
• 18. Baseline amylase above the upper limit of normal.
• 19. Subjects known to be HIV-positive must not have multi-drug resistant HIV infection, CD4 counts /< 150/µl or other concurrent AIDS-defining conditions. Serologic screening for HIV is required within the 6 months prior to study enrollment.
• 20. Subjects positive for Hepatitis B surface antigen (HBsAg) or Hepatitis C-virus ribonucleic acid (HCV RNA), unless both AST and ALT≤1.25 x ULN and there is no known history of chronic active hepatitis.
• Serologic screening for hepatitis B and C testing is required within the 6 months prior to study enrollment.
• 21. Subjects with moderate or severe liver impairment, as defined by a Child-Pugh class of B or C.
• 22. Women who are pregnant or breastfeeding.
• 23. Current use of any of the following medications: boceprevir, carbamazepine, ciprofloxacin, cobicistat, conivaptan, enzalutamide, fluvoxamine, itraconazole, ketoconazole, mitotane, phenytoin, posaconazole, rifampin, ritonavir, St. John`s Wort, telaprevir, voriconazole, or zafirlukast.
• 24. Current use of non-nucleoside reverse transcriptase inhibitors (NNRTI) including efavirenz, rilpivirine, etravirine, delavirdine, nevirapine, and lersivirine.

Описание

This is a multicenter, randomized, open-label, phase 3 clinical study to evaluate the efficacy of SHR-A1912 combined with R-GemOx in relapsed refractory diffuse large B-cell lymphoma.

Критерии включения

• 1. Histologically confirmed diffuse large B-cell lymphoma (DLBCL).
• 2. Have received ≥1 line of systemic antitumor therapy.
• 3. At least one bi-dimensionally measurable lesion.
• 4. Expected survival of at least 3 months.
• 5. Age ≥18 years old and under 80 years old.
• 6. The patients voluntarily participated in the study, signed informed consent, had good compliance and were willing to cooperate with follow-up.

Критерии исключения

• 1. Central nervous system lymphoma involvement.
• 2. Primary mediastinal (thymus) large B-cell lymphoma.
• 3. Patients who have only one prior line therapy and are candidates for stem cell transplantation.
• 4. A history of immunodeficiency.
• 5. A history of severe cardiovascular disease.
• 6. A history of other malignancies within 5 years prior to administration of the first dose.

Описание

To explore the efficacy and safety of TQB2825 injection combined immunochemotherapy in subjects with untreated or R/R DLBCL.

The efficacy evaluation indicators are objective response rate (ORR), complete response rate (CR rate),progression free survival (PFS), duration of response (DOR) and overall survival(OS).

The safety evaluation indicators are dose-limiting toxicity (DLT) , maximum tolerated dose (MTD)and recommended phase II dose (RP2D).

Критерии включения

• * Subjects voluntarily participate in this study, sign the informed consent form, and have good compliance;
• * Age 18 to under 80 years old (calculated from the date of signing the informed consent form);
• * Eastern Cooperative Oncology Group (ECOG) score of 0 to 2;
• * Life expectancy greater than 12 weeks;
• * In the dose expansion phase, previously untreated patients with International Prognostic Index (IPI) scores of 2-5;
• * A confirmed diagnosis of diffuse large B-cell lymphoma or grade 3b follicular lymphoma, in accordance with the 2022 World Health Organization (WHO) diagnostic criteria, based on histology or cytology (including diffuse large B-cell lymphoma-not otherwise specified and transformed from indolent lymphomas, not allowing for the following types or components: double-hit, triple-hit, or high-grade B-cell lymphoma-not otherwise specified, mediastinal large B-cell lymphoma, T/histiocyte-rich large B-cell lymphoma, human herpesvirus 8 (HHV8)-positive/primary effusion lymphoma, Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma, Burkitt`s lymphoma, and Hodgkin`s lymphoma, etc.);
• * Immunophenotypic analysis shows that the tumor is CD20 positive;
• * Previous treatment meets the following criteria:
• 1. Combined with R-CHOP patients: previously untreated diffuse large B-cell lymphoma patients, allowing for corticosteroid pre-treatment (with or without vincristine) or non-curative palliative local radiotherapy.
• 2. Combined with GemOx patients: patients with diffuse large B-cell lymphoma who have received at least one line of systemic treatment (including at least one line with CD20 monoclonal antibody) and are not suitable for hematopoietic stem cell transplantation or have failed treatment after transplantation or relapsed, and whose disease progressed during the most recent treatment or relapsed after completion of treatment or confirmed no objective response after adequate treatment.
• * According to the 2014 Lugano criteria, there is at least one measurable lesion, i.e., lymph node lesions with a long diameter />15 mm or extranodal lesions with a long diameter />10 mm based on CT cross-sectional imaging; Positron emission tomography (PET)-computed tomography (CT) scan shows PET positivity;
• * Laboratory tests meet the following criteria (not corrected with blood transfusion or hematopoietic growth factors within 14 days before screening):
• 1. Hemoglobin (HGB) ≥80g/L;
• 2. Absolute neutrophil count (NEUT) ≥1.0×10∧9/L;
• 3. Platelet count (PLT) ≥ 75×10∧9/L (if accompanied by bone marrow invasion, platelets ≥50×10∧9/L).
• 4. Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN);
• 5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 ULN. If accompanied by liver metastasis, then ALT and AST ≤ 5 ULN;
• 6. Serum creatinine (CR) ≤ 1.5 ULN or estimated glomerular filtration rate ≥50 ml/min by the Cockcroft-Gault formula.
• 7. Prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤ 1.5×ULN (not on anticoagulant therapy);
• * Women of childbearing age must agree to use effective contraceptive measures during the study and for 12 months after the study ends, with a negative serum or urine pregnancy test within 7 days before study enrollment; men must agree to use effective contraceptive measures during the study and for 12 months after the study ends.

Критерии исключения

• * The subject has had or currently has other malignant tumors that occurred within 5 years before the first dose of the study drug. The following two situations are eligible for enrollment: other malignant tumors that have been treated with single surgery and have achieved continuous 5 years of disease-free survival (DFS); cured carcinoma in situ of the cervix, non-melanoma skin cancer, and superficial bladder tumors /[Ta (non-invasive tumors), Tis (carcinoma in situ), and T1 (tumors infiltrating the basement membrane)/];
• * Adverse reactions from previous treatments have not recovered to a Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade score of ≤1, except for grade 2 alopecia, non-clinically significant and asymptomatic laboratory abnormalities, and hypothyroidism stabilized with hormone replacement therapy, which are deemed to have no safety risks by the investigator;
• * Received major surgical treatment, significant traumatic injury within 4 weeks before the first dose, or expected to undergo major surgery during the study treatment period, or has long-term unhealed wounds or fractures;
• * Any subject with bleeding or bleeding events ≥CTC AE grade 3 within 4 weeks before the first dose;
• * A history of arterial/venous thrombotic events within 6 months before the first dose, such as cerebrovascular accidents (including transient ischemic attacks), deep vein thrombosis, and pulmonary embolism, or any other history of serious thromboembolism (thrombosis from implanted venous access ports or catheters, or superficial vein thrombosis is not considered "serious" thromboembolism);
• * Clinically significant uncontrollable pleural effusion requiring repeated drainage, ascites, moderate or greater pericardial effusion;
• * Decompensated cirrhosis (Child-Pugh liver function rating of B or C) and active hepatitis (hepatitis B reference: positive HBsAg, and positive hepatitis B virus (HBV) DNA or detection value exceeding the lower limit of detection; hepatitis C reference: positive HCV antibody, and positive hepatitis C virus (HCV) RNA or detection value exceeding the lower limit of detection); Note: Subjects with hepatitis B who are positive for HBsAg, regardless of whether their HBV DNA is detectable, must continue antiviral treatment (nucleoside analogs recommended) and regularly monitor HBV DNA; for subjects with hepatitis B who are positive for HBcAb but negative for HBsAg, regular monitoring of HBV DNA is required, and prophylactic antiviral treatment is recommended; for hepatitis C subjects, regular monitoring of HCV RNA is required.
• * Pulmonary diseases, including any of the following conditions:
• 1. Past or present non-infectious pneumonia requiring treatment with corticosteroids (including but not limited to acute respiratory distress syndrome, acute hypersensitivity pneumonia, drug-related pneumonia, bronchospasm, acute interstitial pneumonia, idiopathic pulmonary interstitial fibrosis, etc.);
• 2. Past or present chronic obstructive pulmonary disease (COPD), and forced expiratory volume in one second (FEV1) /<60% (predicted value);
• * Brain or mental abnormalities, including any of the following conditions:
• 1. A history of substance abuse that cannot be quit;
• 2. Accompanying or past central nervous system disease history, including epileptic seizures, hemorrhagic/ischemic stroke, severe brain injury, dementia, Parkinson`s disease, cerebellar disease, paralysis, aphasia, mental illness, consciousness disturbance, unexplained coma, neuropathy, organic brain syndrome, etc.;
• 3. Brain MRI evidence indicating inflammatory lesions and/or vasculitis;
• 4. Cerebrovascular accidents, cerebral infarction, etc., within 6 months before the first dose;
• * Major cardiovascular diseases, including any of the following conditions:
• 1. Heart failure of more than grade II according to the New York Heart Association (NYHA) standards or cardiac ultrasound examination: Left ventricular ejection fraction (LVEF) /<50%;
• 2. A history of clinically significant ventricular arrhythmias (such as sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes ventricular tachycardia) or arrhythmias requiring continuous antiarrhythmic drug treatment;
• 3. A history of myocardial infarction, serious arrhythmias, unstable angina, etc., within 6 months before the first dose;
• 4. The Fridericia-corrected QT interval (QTcF) is />450 milliseconds (msec) for males and />470 msec for females (if QTc is abnormal, it can be measured three times continuously with an interval of more than 2 minutes, and the average value can be taken);
• 5. A history or family history of congenital long QT syndrome;
• 6. Hypertension that cannot be controlled with a combination of two drugs (at least two measurement results are systolic pressure ≥160 mmHg, diastolic pressure ≥100 mmHg);
• * Active or uncontrolled infections (≥CTC AE grade 2 infections), including bacterial, fungal, or viral infections (including but not limited to active pneumonia, syphilis, tuberculosis, and Coronavirus disease 2019 (COVID-19), etc. During the screening period, Polymerase chain reaction (PCR) testing or two antigen tests for COVID-19 must be performed (with an interval of at least 24 hours), and the test results must be negative to be eligible. Subjects who do not meet the COVID-19 infection eligibility criteria must fail the screening, and can only be re-screened under the following conditions: asymptomatic subjects at least 10 days after the first positive test result, or symptomatic subjects at least 10 days after the onset of symptoms);
• * Renal failure requiring hemodialysis or peritoneal dialysis, history of nephrotic syndrome;
• * A history of immunodeficiency, including HIV positivity or other acquired or congenital immunodeficiency diseases;
• * Having or having had autoimmune diseases that require treatment, subjects receiving stable replacement therapy for hypothyroidism, and type 1 diabetes can be enrolled.
• * Prepared for or having received organ transplantation, or having obvious host-graft reactions, or having received allogeneic hematopoietic stem cell transplantation in the past;
• * Need for systemic immunosuppressive treatment, including but not limited to: use of cyclosporine, tacrolimus, etc., within 4 weeks before the first dose, receiving high-dose glucocorticoid therapy (prednisone />30 mg/day or equivalent dose of other glucocorticoids), or receiving any other immunosuppressive treatment. Subjects receiving inhaled or local corticosteroid treatment, or those who have been receiving a stable dose of prednisone /<10 mg/day or equivalent dose of other glucocorticoids for systemic treatment for at least 4 weeks before the first dose, or those receiving prophylactic medication to prevent infusion reactions before the administration of the trial medication can be enrolled;
• * Known or suspected history of hemophagocytic lymphohistiocytosis (HLH);
• * For relapsed/refractory patients, previous anti-tumor treatments:
• 1. Received chemotherapy, immunotherapy, monoclonal antibody treatment within 4 weeks before the first dose, radiotherapy or small molecule targeted drugs within 2 weeks, or still within the 5 half-lives of the drug (the shortest appearing time shall prevail), the washout period is calculated from the end of the last treatment;
• 2. Received traditional Chinese medicine (including Compound Eschar Capsules, Kangai Injection, Kanglaite Capsules/Injection, Aidi Injection, Yanzaizi Oil Injection/Capsules, Xiaocaiping Tablets/Injection, Huachansu Capsules, etc.) with anti-tumor indications approved by the National Medical Products Administration (NMPA) in the drug instructions within 2 weeks before the first dose;
• 3. Previously used other antibody drugs targeting both CD3 and CD20;
• 4. Received Chimeric antigen receptor T (CAR-T) treatment or other immune cell therapy, or autologous hematopoietic stem cell transplantation (auto-HSCT) within 3 months before the first dose;
• 5. Previously received R-GemOx or GemOx treatment;
• * Known allergies to excipient components of the study drug.
• * Participated in and used other anti-tumor clinical trial drugs within 4 weeks or 5 half-lives before the first dose.
• * In the judgment of the investigator, there are situations that seriously endanger the safety of the subject or affect the subject`s completion of the study.

Описание

This study is being done to determine the safety, efficacy and tolerability of a single 50 mCi dose of 131I-Apamistamab given prior to CAR-T cell infusion in patients with Relapsed or refractory (R/R) Diffuse large B-cell lymphoma (DLBCL).

Критерии включения

• 1. Patients with diffuse large B-cell lymphoma (de novo or DLBCL transformed from an indolent lymphoma (follicular lymphoma, chronic lymphocytic leukemia /[Richter syndrome/]) or high-grade B-cell lymphoma (HGBL): ("DLBCL patients")
• * Defined as relapsed or refractory DLBCL or high-grade B-cell lymphoma (HGBL) following at least one or more prior chemoimmunotherapy regimen (with at least one course including an anthracycline and CD20-directed therapy) following diagnosis of de novo DLBCL/HGBL or DLBCL arising from indolent lymphoma and requiring further treatment and deemed to be candidates for standard of care CAR-T therapy. This includes patients with primary refractory disease (failure to achieve complete response (CR) to first-line therapy), relapsed disease within 12 months of first line chemoimmunotherapy or relapsed/refractory disease after 2 or more prior lines of systemic therapy.
• * Patients must have at least one FDG-avid (PET-avid) measurable lesion.
• * Relapsed or refractory disease must be confirmed with a repeat biopsy within the last 12 months.
• * For patients who have received treatment for confirmed relapsed or refractory disease otherwise meeting criteria 1.i.-1.iii. as above within 6 weeks of study enrollment, active disease does not need to be re-confirmed or present immediately prior to Screening 1 (Section 5.2) for the patient to be eligible for leukapheresis. However, detectable evidence of residual malignancy must be present at Screening 2 (Section 5.3) for the patient to be eligible for 131I-Apamistamab and CAR T-cell therapy.
• 2. Age ≥ 18 years of age
• 3. Creatinine clearance ≥50 mL/min as calculated by the Cockroft-Gault formula.
• 4. Total bilirubin ≤1.5x upper limit of normal , AST and ALT ≤3x upper limit of normal (ULN), unless liver dysfunction is thought to be related to underlying malignancy or secondary to Gilbert`s disease in which case the direct bilirubin should be ≤3.0 mg/dL, and AST and ALT ≤5x ULN.
• 5. Adequate pulmonary function as assessed by ≥92% oxygen saturation on room air or per institutional guidelines.
• 6. Thyroid function tests (TSH, FT4) ≤2x upper limit of normal (ULN)
• 7. Adequate bone marrow function meeting the following criteria as defined below, without requiring blood product or granulocyte-colony stimulating factor support in the 7 days prior to screening and start of 131I-Apamistamab treatment.
• 1. Absolute neutrophil count ≥1.0k/µL,
• 2. Platelets ≥50k/µL,
• 3. Hemoglobin ≥8g/dL.
• 8. Performance status: ECOG performance status 0-2.
• 9. All men, as well as women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control, and/or abstinence) prior to study entry, and for the duration of study treatment, and for 30 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
• * Has not undergone a hysterectomy or bilateral oophorectomy; or
• * Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
• 10. Ability to understand and the willingness to sign a written informed consent.
• 11. For patients undergoing bridging therapy after leukapheresis and prior to 131I-Apamistamab infusion a repeat PET/CT scan will be performed 10-14 days prior to the 131I-Apamistamab infusion. They will also be required to meet additional inclusion criteria as written within specific sections of the protocol within 10-14 days prior to the planned infusion of 131I-Apamistamab. This will be considered eligibility Screening 2 and will be approved by the Sponsor-Investigator.

Критерии исключения

• 1. Pregnant or lactating patients.
• 2. Impaired cardiac function (LVEF /<40%) as assessed by echocardiogram or MUGA scan.
• 3. Patients with active graft versus host disease following allogeneic hematopoietic cell transplantation requiring systemic T-cell suppressive therapy are ineligible.
• 4. Patients with active autoimmune disease requiring systemic T-cell suppressive therapy are ineligible.
• 5. Patients with the following cardiac conditions will be excluded:
• 1. New York Heart Association (NYHA) stage III or IV congestive heart failure
• 2. Myocardial infarction ≤6 months prior to enrollment
• 3. Any history of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration.
• 6. Have current or prior positive test results for human immunodeficiency virus (HIV) or hepatitis B (HBV) or C (HCV), with the following exceptions:
• 1. Patients who have positive HBV test results due to having been previously vaccinated against hepatitis B, as evidenced by negative hepatitis B surface antigen (HbsAg), negative anti- hepatitis B core protein (HBc) and positive antibody to the HbsAg (anti-HBs) are not excluded.
• 2. Patients who have antibodies to HCV or who have hepatitis B core antibody, with undetectable viremia by PCR, and with adequate organ function as defined in the protocol, are not excluded.
• 7. Patients with uncontrolled systemic fungal, bacterial, viral, or other infections are ineligible.
• 8. Patients with any concurrent active malignancies as defined by malignancies requiring any therapy other than expectant observation or hormonal therapy, with the exception of squamous and basal cell carcinoma of skin.
• 9. Patients with history or presence of clinically significant neurological disorders such as epilepsy, generalized seizure disorder, severe brain injuries are ineligible.
• 10. Any other issue which, in the opinion of the treating physician, would make the patient ineligible for the study.
• 11. Patients with circulating human anti-mouse antibodies (HAMA) to BC8
• 12. Patients with prior history of treatment with radiopharmaceuticals for any indication.
• 13. Patients with a history of external beam radiation therapy except for treatment of cutaneous lesions and localized prostate cancer.
• 14. Patients with QTcF />470mSec on EKG

Описание

Researchers are looking for ways to treat germinal center B-cell-like diffuse large B-cell lymphoma (GCB DLBCL). DLBCL is a fast-growing blood cancer that affects B-cells. GCB is a type of DLBCL that affects young B-cells that are still maturing.

The goal of this study is to learn if more people who receive zilovertamab vedotin (MK-2140) and R-CHP have the cancer respond (go away) than those who receive polatuzumab vedotin and R-CHP.

Критерии включения

• The main inclusion criteria include but are not limited to the following:
• * Has histologically confirmed diagnosis of germinal center B-cell (GCB) subtype of diffuse large B-cell lymphoma (DLBCL), by prior biopsy, according to the World Health Organization (WHO) classification of neoplasms of the hematopoietic and lymphoid tissues.
• * Has positron emission tomography (PET) positive disease at screening, defined as 4 to 5 on the Lugano 5-point scale.
• * Has received no prior treatment for their DLBCL.
• * Human immunodeficiency virus (HIV) infected participants must have well controlled HIV on antiretroviral therapy (ART).
• * Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy and have undetectable HBV viral load prior to randomization.
• * Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening.

Критерии исключения

• The main exclusion criteria include but are not limited to the following:
• * Has a history of transformation of indolent disease to DLBCL.
• * Has received a diagnosis of primary mediastinal B-cell lymphoma (PMBCL) or Grey zone lymphoma.
• * Has Ann Arbor Stage I DLBCL.
• * Has clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (/<6 months prior to enrollment), myocardial infarction (/<6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class ≥II), or serious cardiac arrhythmia requiring medication.
• * Has clinically significant pericardial or pleural effusion.
• * Has ongoing Grade />1 peripheral neuropathy.
• * Has a demyelinating form of Charcot-Marie-Tooth disease.
• * HIV-infected participants with a history of Kaposi`s sarcoma and/or Multicentric Castleman`s Disease.
• * Has ongoing corticosteroid therapy.
• * Known additional malignancy that is progressing or has required active treatment within the past 2 years.
• * Known active central nervous system (CNS) lymphoma.
• * Has active autoimmune disease that has required systemic treatment in the past 2 years.
• * Has active infection requiring systemic therapy.
• * Has active HBV (defined as HBsAg positive and detectable HBV deoxyribonucleic acid (DNA)) and HCV (defined as anti-HCV antibody positive and detectable HCV ribonucleic acid (RNA)) infection.
• * Has history of stem cell/solid organ transplant.

Описание

This is a Phase I, prospective, dose-finding study to evaluate the safety, persistence, and clinical activity of GF-CART01 in subjects aged 18-70 with relapsed or refractory (R/R) B-cell hematological malignancies and failure of two-line or more standard chemotherapies or auto-hematopoietic stem cell transplantation (HSCT).This study is a traditional 3+3 dose-escalation design to observe dose-limiting toxicity (DLT), establish the maximum tolerated dose(MTD)/recommended phase 2 doses (RP2D), and preliminary efficacy of GF-CART01. RP2D may equal to or lower than MTD

Критерии включения

• 1. Subjects must be of age ≥ 18 years and ≤ 70 years
• 2. Subjects or their legal guardians must volunteer to participate in the study and sign the informed consent
• 3. Histologically confirmed diagnosis of Diffuse Large B-Cell Lymphoma - Not Otherwise Specified (DLBCL-NOS), follicular lymphoma (FL), Primary Mediastinal Large B-cell Lymphoma (PMBCL), or High-Grade B-Cell Lymphoma (HGBCL) per the world health organization (WHO) Classification Criteria for Lymphoma (2022)
• 4. Tumor cell surface expression of CD19 (+) and/or CD20 (+) by flow cytometry or immunohistochemistry staining
• 5. Relapsed, progressive or refractory disease (defined as have not achieved a complete response) after ≥ two lines of systemic therapy, including anti-CD20 antibody and anthracycline and/or Relapsed, progressive or refractory disease ( defined as have not achieved a complete response) after auto-HSCT
• 6. Subjects have any accessible PET-positive lesion or measurable CT-positive lesion per Lugano 2014 criteria
• 7. Adequate hematologic function: absolute neutrophil count (ANC) /> 1,000/μL, absolute lymphocyte count (ALC) /> 300/μL, platelet count ≥ 75,000/μL, hemoglobin ≥ 8.0 g/dL
• 8. Adequate hepatic function: alanine aminotransferase (ALT) ≤ 5 times upper limit of normal (ULN), aspartate transaminase (AST) ≤ 5 times ULN, total bilirubin ≤ 1.5 times ULN
• 9. Adequate renal function: blood estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2 (calculated by Modification of Diet in Renal Disease (MDRD) equation)
• 10. Adequate cardiac function: echocardiogram or multigated blood pool analysis (MUGA) shows left ventricular ejection fraction (LVEF) ≥ 50%; and no clinically significant electrocardiogram (ECG) findings
• 11. Adequate pulmonary function: no active infection in the lungs, blood oxygen saturation in indoor air ≥ 92%
• 12. No clinically significant pleural effusion determined by the investigators
• 13. Estimated survival time ≥ 3 months
• 14. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
• 15. Willingness and ability to comply with protocol-stated requirements, instructions, and restrictions in the investigator`s judgement

Критерии исключения

• 1. Previously treated with any CAR T cell product or allogenic hematopoietic stem cell transplant (HSCT)
• 2. Known or suspected allergy, hypersensitivity, or intolerance to any ingredients of the investigational product (IP)
• 3. Known medical history or possible risk for taking contrast agent(s) for positron emission tomography (PET) and/or computed tomography (CT) scan
• 4. Received any other investigational product, cell therapy, or gene therapy within 12 weeks prior to the leukapheresis
• 5. Received any tyrosine kinase inhibitor within 2 weeks prior to the leukapheresis
• 6. Received any systemic steroid, immunotherapy (such as immune checkpoint inhibitors, T- cell transfer therapies, monoclonal antibodies), or chemotherapy within 4 weeks prior to the leukapheresis
• 7. Received any live vaccine from 2 weeks prior to the leukapheresis
• 8. Subjects with human immunodeficiency virus (HIV), syphilis, Hepatitis B or C infection: HIV-1 and HIV-2 antibody positive, syphilis antibody positive, both hepatitis B virus (HBV) DNA and hepatitis B core (HBc) antibody positive, or hepatitis C virus (HCV) antibody positive
• 9. Subjects with atrial or ventricular involvement by B-cell malignancies
• 10. Subjects with tumor mass requiring urgent treatment within 8 weeks prior to the leukapheresis, such as ileus, tumor lysis syndrome, or vascular compression
• 11. Subjects with severe disease or other uncontrolled diseases, such as coronary heart disease, angina pectoris, myocardial infarction, arrhythmia (urgent intervention indicated, life- threatening consequences, or hemodynamic compromise), cardiac angioplasty or stenting, unstable angina, cerebral thrombosis, cerebral hemorrhage, hypertension (systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg)
• 12. Unstable pulmonary embolism, deep venous embolism, or other major arterial/venous thromboembolism events that occurred within 6 weeks prior to the leukapheresis. If subjects receive anticoagulant therapy, the treatment dose and frequency must be stable for more than 14 weeks prior to the leukapheresis
• 13. History of craniocerebral trauma, disturbance of consciousness, epilepsy, cerebrovascular ischemia, cerebrovascular hemorrhagic diseases, dementia, cerebellar disease, or any autoimmune disease with central nervous system (CNS) involvement
• 14. Female subject of childbearing potential who: a. Has positive pregnancy test result; or b. Is lactating
• 15. Female subjects of childbearing potential, or male subject with female spouse/partner of childbearing potential, who refuses to adopt at least one form of birth control from the date of signing informed consent to 12 months after GF-CART01 infusion. Acceptable forms of birth control include: a. Established use of oral, injected or implanted hormonal methods of contraception b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) c. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps)
• 16. Any following situations that the investigators believe are not suitable for this trial and/or may increase the risk for subjects or interfere with the results of the study a. With severe active infections (except simple urinary tract infection and bacterial pharyngitis) b. With active central nervous system involvement by lymphoma, malignant cells in cerebrospinal fluid c. History of brain metastasis d. With uncontrolled malignancies e. Any toxicities due to prior therapy f. With any uncontrolled illness or a history of any illness

Описание

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and rare cancer of a type of immune cells (a white blood cell responsible for fighting infections) and the most common type of non-Hodgkin lymphoma. Follicular Lymphoma (FL) is a slow-growing type of non-Hodgkin lymphoma. The purpose of this study is to assess the real-world effectiveness of subcutaneous epcoritamab in adult participants with advanced DLBCL and FL.

Epcoritamab is an investigational drug being developed for treating participants with DLBCL and FL. Approximately 700 participants will be enrolled in approximately 80 sites across 12-20 countries globally.

Participants will receive epcoritamab as prescribed by their physician in accordance with local country label. Participants will be followed for up to 3 years.

There is expected to be no additional burden for participants in this trial. Participants will attend regular visits during the study at a hospital or clinic according to their routine clinical practice.

Критерии включения

• * Participants who are scheduled to be treated with epcoritamab for Treatment after two or more prior lines of therapy 3L+ diffuse large B-cell lymphoma ((D)LBCL) or 3L+ Follicular lymphoma (FL).
• * Treatment with epcoritamab should be administered in accordance with the approved local label in the participating country.
• * The decision to treat the participant should have been made by the clinician prior to, and independently of any decision to approach the participant to participate in this study.

Критерии исключения

• * Any condition included in the contraindications section of the approved local epcoritamab label in the participating country.
• * Participation in a concurrent interventional clinical trial (not including non-interventional/ observational study, PMOS, or registry participation) from enrollment and throughout the study.

Описание

This is a phase ll study of participants with untreated diffuse large B Cell lymphoma (DLBCL).

Критерии включения

• 1. Men and women ≥ 18 years of age deemed eligible for treatment with full-dose Pola- R-CHP and possible treatment with glofitamab by the qualified investigator.
• 2. Histologic diagnosis of DLBCL and variants according to the WHO 201613 or WHO 202254 classification including DLBCL non-organ-specific (NOS), Germinal centre B-cell type, activated B-cell type, T-cell/histiocyte-rich large B-cell lymphoma, Epstein-Barr Virus (EBV) + DLBCL, Primary mediastinal/thymic large B-cell lymphoma, High grade B-cell lymphoma with myelocytomatosis oncogene (MYC) and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) rearrangements, High grade B cell lymphoma NOS including lymphomas transformed from previously untreated indolent lymphomas.
• 3. Previously untreated DLBCL with the following exceptions: (a) prior radiotherapy for palliation (not localized), (b) up to 7 days of corticosteroids (prednisone 100mg/day equivalent).
• 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
• 5. Presence of at least one radiologically measurable nodal or extranodal mass. A measurable nodal mass must have a longest diameter ≥1.5 cm. A measurable extranodal mass should have a longest diameter ≥1.0 cm.16
• 6. Left ventricular ejection fraction (LVEF) ≥ 50%, as determined on cardiac multiple- gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO)
• 7. Women of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and up to 18 months after the last dose of or protocol therapy. Men who are sexually active must use highly effective methods of contraception during treatment and up to 6 months after the last dose of protocol therapy. Men require an agreement to remain abstinent (ie, refrain from heterosexual intercourse) or use a condom, and an agreement to refrain from donating sperm. Periodic abstinence and withdrawal are not acceptable methods of contraception. Fertility preservation options should be discussed. Examples of highly effective contraceptive methods include an agreement to remain abstinent (ie, refrain from heterosexual intercourse), bilateral tubal ligation, male sterilization, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
• 8. Willing and able to participate in all required evaluations and procedures in this study.
• 9. Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained by the patient or legally acceptable representative before any study-specific procedures are performed.

Критерии исключения

• 1. Current/past history of central nervous system (CNS) lymphoma.
• 2. Prior exposure to any anthracycline, rituximab or cluster of differentiation 3 (CD3) targeted bispecific antibody.
• 3. Prior malignancy (or any other malignancy requiring active treatment), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for ≥ 2 years or which will not limit survival to /< 5 years. Subjects receiving adjuvant hormonal therapy for early breast or prostate cancer are eligible.
• 4. Significant or extensive cardiovascular disease such as New York Heart Association Class III or IV cardiac disease or Objective Assessment Class C or D, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study.
• 5. Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including diabetes mellitus, history of relevant pulmonary disorders (bronchospasm, obstructive pulmonary disease), and known autoimmune diseases.
• 6. Patients with a known or suspected history of hemophagocytic lymphohistiocytosis (HLH)
• 7. History of illicit drug or alcohol abuse within 12 months prior to screening, in the Investigator`s judgment.
• 8. Known active infection, or reactivation of a latent infection, whether bacterial, viral (including, but not limited to, EBV, cytomegalovirus (CMV), hepatitis B, hepatitis C, and human immunodeficiency virus (HIV), fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics (for IV antibiotics this pertains to completion of last course of antibiotic treatment) within 4 weeks of dosing. Individuals with a positive HIV test at screening are eligible provided they are stable on antiretroviral therapy, have a cluster of differentiation 4 (CD4) count ≥ 200/μL, and have an undetectable viral load. HIV positive patients should be monitored per local/institutional standards while receiving study treatment.
• 9. Known history of drug-specific hypersensitivity or anaphylaxis to study drugs (glofitamab and individual components of Pola-R-CHP), including grade III or greater allergic reactions to any monoclonal antibody.
• 10. Known Type I hypersensitivity or anaphylactic reactions to murine proteins, Chinese Hamster Ovary (CHO) cell proteins, or to any component of Rituximab
• 11. Current history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease. Patients with a history of stroke who have not experienced a stroke or transient ischemic attack within the past 2 years and have no residual neurological deficient, as judged by the investigator, are allowed.
• 12. Active autoimmune disease which is not well controlled by therapy:
• * Participants with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone may be eligible. Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
• * Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
• * Participants with active autoimmune disease with dermatologic manifestations are eligible for the study.
• * Participants with a history of autoimmune hepatitis, systemic lupus erythematosus, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome, multiple sclerosis, or glomerulonephritis will be excluded.
• * Participants with a history of immune thrombocytopenic purpura, autoimmune hemolytic anemia, Guillain-Barré syndrome, myasthenia gravis, myositis, rheumatoid arthritis, vasculitis, or other autoimmune disease will be excluded unless they have not required systemic therapy in the last 12 months
• 13. Major surgical procedure within 4 weeks of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
• 14. Administration of a live, attenuated vaccine within 4 weeks before study treatment infusion on Cycle 1/Day 1 or anticipation that such a live, attenuated vaccine will be required during the study. Live vaccines during the study and until participants` B- cells recover, are prohibited. Note: Influenza vaccination should be given during influenza season only. Participants must not receive live, attenuated influenza vaccine (e.g., FluMist) at any time during the study treatment period).
• 15. Use of any of the prohibited therapies including: investigational or unlicensed/unapproved agents; biologic agents (e.g., bevacizumab, erlotinib); immunotherapy/radio-immunotherapy; radiotherapy (with the exception of limited field palliative radiotherapy for bone pain or for soft tissue lesions after consultation with the Sponsor); chemotherapy (apart from Pola-R-CHP per protocol); hormone therapy (other than contraceptives, hormone-replacement therapy, or megestrol acetate); chronic use of steroids (inhaled, topical or systemic)
• 16. Positive test results for hepatitis B virus (HBV) infection (defined as positive B surface antigen /[HBsAg/] serology). Patients with occult or prior HBV infection (defined as negative HBsAg and positive hepatitis B core antibody /[HBcAb/]) may be included if HBV DNA is undetectable, provided that they are willing to undergo DNA testing on Day 1 of every cycle and every three months for at least 12 months after the last cycle of study treatment and appropriate antiviral therapy.
• 17. Positive test results for hepatitis C virus (HCV) antibody. Patients who are positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
• 18. Absolute Neutrophil Count (ANC) /<1.0 x109/L (subjects with bone marrow involvement by lymphoma are eligible regardless of ANC).
• 19. Hemoglobin (Hgb) ≤ 9 g/dL
• 20. Platelets /<50 x109/L (subjects with bone marrow involvement by lymphoma are eligible regardless of platelet count)
• 21. Total serum bilirubin />2 times the upper limit of normal (or /<3 times for Gilbert`s disease or documented hepatic involvement by lymphoma), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) />3 times the upper limit of normal (or />5 times for documented hepatic involvement by lymphoma)
• 22. Creatinine clearance /<30 mL/min.
• 23. Prothrombin time (PT)/ international normalized ratio (INR) />2 times the upper limit of normal in the absence of anticoagulants or partial thromboplastin time (PTT) />2 times the upper limit of normal in the absence of anticoagulants.
• 24. Breastfeeding or pregnant, or intending to become pregnant during the study or within 12 months after the final dose of Pola-R-CHP, 3 months after the final dose of tocilizumab (if applicable), or 2 months after the final dose of glofitamab. WOCBP must have a serum pregnancy test done a maximum of 7 days prior to treatment initiation and a negative result must be documented prior to recruitment.
• 25. Concurrent participation in another therapeutic clinical trial.
• 26. Any other diseases, metabolic dysfunction, physical examination finding, or clinical
• 27. Laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug.
• 28. Current Grade /> 1 peripheral neuropathy by clinical examination or demyelinating form of Charcot Marie Tooth disease.
• 29. Known history of progressive multifocal leukoencephalopathy.
• 30. Positive severe acute respiratory syndrome (SARS-CoV-2) test within 7 days prior to enrollment. Rapid antigen test result is also acceptable.
• 31. Known or suspected chronic active Epstein-Barr viral infection.

Описание

This phase II trial tests the effectiveness of golcadomide and rituximab as bridging treatment before chimeric antigen receptor (CAR) T-cell therapy in patients with aggressive B-cell non-Hodgkin lymphoma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Patients that are able to receive CAR T-cell therapy have a potential for cure, however, many will not be qualified to receive therapy due to relapse. Bridging therapy is therapy intended to transition a patient from one therapy or medication to another or maintain their health or status until they are a candidate for a therapy or have decided on a therapy. Golcadomide may help block the formation, growth or spread of cancer cells. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Giving golcadomide and rituximab as bridging therapy before CAR T-cell therapy may kill more tumor cells and may improve the chance of proceeding to CAR T-cell therapy in patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma.

Критерии включения

• * Age ≥ 18 years
• * Confirmed pathology diagnosis according to 2016 World Health Organization (WHO) classification including patients with diseases listed below with relapsed, progressive and/or refractory disease (Cheson et al. 2014) following treatment with one or two prior lines of standard therapy, no more than two lines of therapy are permitted:
• * Diffuse large B-cell lymphoma not otherwise specified (NOS) including:
• * Transformed lymphoma
• * Germinal center B-cell type
• * Activated B-cell type
• * High-grade B-cell lymphoma (HGBCL), NOS
• * High grade B-cell lymphoma with MYC and BCL2 translocation
• * Primary mediastinal (thymic) large B-cell lymphoma
• * Grade 3B follicular lymphoma
• * T-cell/histiocyte-rich large B-cell lymphoma
• * Large B-cell lymphoma with IRF4 rearrangement
• * Primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type
• * Epstein-Barr virus (EBV) positive DLBCL, NOS
• * DLBCL associated with chronic inflammation
• * Intravascular large B-cell lymphoma
• * ALK positive large B-cell lymphoma
• * NOTE: Richters transformation patients are excluded
• * Measurable disease by PET-CT with at least one lymph node or other type of lesion that has a size /> 1.5 cm in the transverse diameter, as defined by Lugano classification
• * NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease; Disease that is measurable by physical examination only is not eligible
• * Patient is potentially eligible for CAR-T therapy as determined by treating physician
• * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
• * Hemoglobin /> 7.0 g/dL (obtained ≤ 14 days prior to registration)
• * Absolute neutrophil count (ANC) ≥ 1000/mcL (obtained ≤ 14 days prior to registration); growth factor support allowed at physician discretion
• * Platelet count ≥ 75,000/mcL (obtained ≤ 14 days prior to registration)
• * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained ≤ 14 days prior to registration); if total bilirubin is /> 1.5 ULN, direct bilirubin must be normal
• * Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2.5 x ULN (≤ 5 x ULN if there is evidence of parenchymal liver involvement with lymphoma) (obtained ≤ 14 days prior to registration)
• * Calculated creatinine clearance ≥ 45 ml/min using the Cockcroft-Gault formula (obtained ≤ 14 days prior to registration)
• * Have 2 negative pregnancy tests as verified by the investigator prior to starting CC-99282:
• * A negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at screening (between 10 to 14 days prior to cycle 1 day 1)
• * A negative serum or urine pregnancy test (investigator`s discretion) within 24 hours prior to cycle 1 day 1 of study treatment
• * Provide written informed consent
• * Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
• * Subjects must agree not to donate blood while receiving golcadomide, during dose interruptions and for ≥ 28 days following the last dose of golcadomide

Критерии исключения

• * Any of the following because this study involves an investigational agent that has known genotoxic, mutagenic, and teratogenic effects:
• * Pregnant persons
• * Nursing persons
• * Persons of childbearing potential (and persons able to father a child) who are unwilling to employ adequate contraception
• * Persons of childbearing potential (PCBP) unwilling to use two reliable forms of contraception simultaneously or to practice complete abstinence (true abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence /[e.g., calendar, ovulation, symptothermal or postovulation methods/] and withdrawal are not acceptable methods of contraception) from heterosexual contact during the following time periods related to this study:
• * For ≥ 28 days before starting treatment, during treatment and dose interruptions, and for ≥ 28 days after the last dose of golcadomide
• * Examples of highly effective methods of contraception:
• * Intrauterine device (IUD)
• * Hormonal (birth control pills, injections, implants, levonorgestrel-releasing intrauterine system /[IUS/], medroxyprogesterone acetate depot injections, ovulation inhibitory
• * Progesterone-only pills /[e.g., desogestrel/])
• * Tubal ligation
• * Partner`s vasectomy
• * Examples of additional effective methods:
• * Male condom
• * Diaphragm
• * Cervical cap
• * Persons who can father a child unwilling to practice complete abstinence (true abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence /[e.g., calendar, ovulation, symptothermal or post-ovulation methods/] and withdrawal are not acceptable methods of contraception.) or unwilling to use a condom during sexual contact with a pregnant person or a PCBP during treatment and dose interruptions, and for /> 28 days following the last dose of golcadomide, even if they have undergone a successful vasectomy
• * Persons who can father a child and are unwilling to refrain from donating semen or sperm while receiving golcadomide, during dose interruptions, or for ≥ 28 days following the last dose of golcadomide
• * Life expectancy /< 3 months
• * Any of the following prior therapies:
• * Any prior CAR-T or other T-cell targeting treatment (approved or investigational) ≤ 4 weeks prior to registration
• * Any prior systemic anti-cancer treatment (approved or investigational) ≤ 5 half-lives or 4 weeks prior to registration, whichever is shorter
• * Exception: Monoclonal and bispecific antibodies is acceptable
• * Prior therapy with golcadomide ≤ 4 weeks prior to registration
• * Prior autologous stem cell transplantation (SCT) ≤ 3 months prior to registration. If subject had autologous SCT /> 3 months prior to the start of registration, any treatment-related toxicity is unresolved (grade /> 1)
• * Major surgery ≤ 3 weeks prior to registration
• * Chemotherapy ≤ 2 weeks prior to registration
• * Concomitant radiation therapy; local palliative radiotherapy is permitted
• * Co-morbid systemic illnesses or other severe concurrent disease or cancer which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
• * Impaired cardiac function or clinically significant cardiac diseases including, but not limited to:
• * Symptomatic congestive heart failure
• * History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
• * Unstable angina pectoris
• * Cardiac arrhythmia
• * Uncontrolled intercurrent non-cardiac illness including, but not limited to:
• * Ongoing or active infection
• * Psychiatric illness/social situations
• * Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy (such as interstitial lung disease or chronic obstructive pulmonary disease /[COPD/])
• * Any other conditions that would limit compliance with study requirements
• * Subject had prior allogeneic SCT with either standard or reduced intensity conditioning ≤ 6 months prior to registration. If subject had prior allogeneic SCT /> 6 months prior to registration, any treatment-related toxicity is unresolved (grade />1)
• * Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy, as there is currently no safety data in HIV positive patients
• * Subject has known chronic active hepatitis B or C virus (HBV/HCV) infection
• * Exception: Patients with HBV and an undetectable viral load who are on suppressive therapy and/or those with HCV and an undetectable viral load are allowed
• * Concurrent administration of strong or moderate CYP3A4/5 inhibitors and inducers within 14 days or 5 half-lives, whichever is longer before the study treatment administration
• * Receiving any other investigational agent which would be considered as a treatment for lymphoma.
• * Exception: Corticosteroids are allowed
• * Active second malignancy requiring treatment that would interfere with the assessment of the response of the primary cancer or interpretation of the safety of this protocol therapy
• * History of deep venous thrombosis/embolism, threatening thromboembolism or known thrombophilia. Patients with a history of deep vein thrombosis (DVT)/pulmonary embolism (PE) or thrombophilia may still participate if they are willing to be on full anticoagulation during treatment. Full anticoagulation is defined as Warfarin, factor X inhibitors, or low molecular weight heparin at therapeutic doses. The rationale for this requirement is that golcadomide therapy is associated with an increased risk of thrombosis. Patients with no history of DVT/PE or thrombophilia are not required to take anticoagulation and/or anti-platelet prophylaxis
• * NOTE: If a patient develops a thrombotic event, they must be able and willing to receive anticoagulation therapy with aspirin 81-325 mg daily prophylaxis, low molecular weight heparin, factor X inhibitors or Warfarin. This is due to an increased risk of thrombosis in patients treated with golcadomide without prophylaxis
• * Live COVID-19 vaccine administered ≤ 28 days prior to registration

Описание

This is a prospective, randomized, controlled, multicenter, phase II clinical trial to evaluate the efficacy and safety of R-CMOP versus R-CHOP in the initial treatment of low-risk and medium-risk diffuse large B-cell lymphoma (DLBCL).

Критерии включения

• 1. Aged ≥18,≤80 years, both male and female.
• 2. Pathologically confirmed DLBCL
• 3. No prior treatment for DLBCL.
• 4. There must be at least one measurable or evaluable lesion that meets the evaluation criteria for Lugano 2014 lymphoma.
• 5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-
• 6. Expected survival ≥3 months.
• 7. International Prognostic Index (IPI) ≤ 2
• 8. Sufficient bone marrow, liver, and kidney function.

Критерии исключения

• 1. Other types of LBCL:Primary Cutaneous Diffuse Large B-cell Lymphoma (Leg Type), Primary Mediastinal (Thymic) Large B-cell Lymphoma, Lymphomatoid Granulomatosis, ALK-positive Diffuse Large B-cell Lymphoma, Plasmablastic Lymphoma, Intravascular Large B-cell Lymphoma, T-cell/Histiocyte-rich Large B-cell Lymphoma, and others.
• 2. Transformed DLBCL.
• 3. Patients with central nervous system involvement, or those who require high-dose methotrexate for prevention.
• 4. The patients had previously received antitumor therapy.
• 5. Patients with the infection of human immunodeficiency virus (HIV) and/or acquired immunodeficiency syndrome.
• 6. Pregnant and lactating women and subjects of childbearing age who do not want to use contraception.
• 7. Mentally ill persons or persons unable to obtain informed consent.
• 8. The investigators think that the patient is not suitable for the study.

Описание

The goal of this clinical trial is to evaluate the efficacy and safety of early secondary infusion of CD19 CAR T-cell therapy in adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), guided by ctDNA monitoring. The main questions it aims to answer are:

1. Efficacy: Does early secondary CAR-T infusion improve the 3-month complete remission (CR) rate and long-term survival outcomes (e.g., 1-year PFS, OS)?
2. Safety: What are the adverse events associated with secondary CAR-T infusion, such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity (ICANS), and infections?

This is a single-arm, single-center, prospective study. All participants will receive:

* Leukapheresis to collect T cells for CAR-T manufacturing.
* Preconditioning chemotherapy (fludarabine and cyclophosphamide) to prepare the body for CAR-T infusion.
* Two CD19 CAR-T infusions: The first infusion (2×10⁶ cells/kg) followed by a second infusion (same dose) if ctDNA remains positive when PET/CT shows CR or PET/CT shows PR within 60 days post-first infusion.

Participants will undergo:

* Frequent hospital monitoring for ≥14 days post-infusion to manage potential toxicities.
* Regular follow-ups (e.g., blood tests, ctDNA analysis, PET/CT scans) at scheduled intervals up to 12 months.
* Continuous safety assessments, including CRS grading, neurological evaluations, and infection monitoring.

Критерии включения

• 1. Age ≥18 years, regardless of gender.
• 2. Life expectancy />12 weeks.
• 3. ECOG performance status 0-2.
• 4. Histologically or cytologically confirmed B-cell non-Hodgkin lymphoma per WHO 2016 classification, including:
• Diffuse large B-cell lymphoma (DLBCL) Primary mediastinal large B-cell lymphoma (PMBCL) Transformed follicular lymphoma (TFL) High-grade B-cell lymphoma (HGBCL).
• 5. Relapsed/refractory disease, defined as:
• ≥1 prior relapse, Failure to achieve partial response (PR) after 2-3 cycles of first-line therapy, Failure to achieve complete response (CR) after 4-6 cycles of first-line therapy, Primary refractory disease, Secondary refractory disease, Disease progression following last line of therapy.
• 6. Adequate venous access for leukapheresis, with:
• Hemoglobin ≥80 g/L, Absolute neutrophil count ≥1.0 ×10⁹/L, Platelet count ≥75 ×10⁹/L, OR parameters not meeting above thresholds but deemed acceptable for mononuclear cell collection per investigator`s judgment.
• 7. ≥1 measurable lesion per Lugano 2014 response criteria.
• 8. Organ function requirements:
• Renal: Serum creatinine ≤2×ULN OR creatinine clearance ≥40 mL/min (Cockcroft-Gault formula).
• Cardiopulmonary:
• Left ventricular ejection fraction (LVEF) />50%, Baseline oxygen saturation />92% on room air.
• Hepatic:
• Total bilirubin ≤2×ULN (≤5×ULN in Gilbert syndrome), ALT/AST ≤3×ULN (≤5×ULN in patients with hepatic involvement).
• 9. Negative serum pregnancy test for women of childbearing potential (WOCBP). Postmenopausal (≥2 years since last menses) or surgically sterilized women are exempt.
• 10. Within 60 days post-axi-cel:
• Persistent ctDNA(+) or ctDNA(-→+) under CR or PET/CT-confirmed PR

Критерии исключения

• 1. History of malignancies other than DLBCL, PMBCL, TFL, or HGBCL within 5 years prior to screening, except:
• Adequately treated carcinoma in situ of the cervix, Basal cell or squamous cell carcinoma of the skin, Localized prostate cancer after definitive resection, Ductal carcinoma in situ of the breast after curative surgery, Thyroid cancer after radical treatment.
• 2. Unstable systemic diseases, including but not limited to:
• Active infections (excluding localized infections), Unstable angina, Cerebrovascular accident or transient ischemic attack (within 6 months prior to screening), Myocardial infarction (within 6 months prior to screening), Congestive heart failure (NYHA Class ≥III), Severe arrhythmia requiring pharmacologic management, Hepatic, renal, or metabolic disorders.
• 3. Conditions affecting informed consent or protocol compliance:
• Physical or psychological disorders impairing the ability to provide written informed consent, Inability or unwillingness to comply with study requirements.
• 4. Grade ≥3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) following prior axi-cel therapy.
• 5. Active, uncontrolled serious infections.
• 6. Uncontrolled active comorbidities that preclude study participation.
• 7. Other conditions deemed by the investigator to confer unacceptable risk or render the patient ineligible.

Описание

The purpose of this study is to assess the preliminary efficacy of TQB2825 in combination with chemotherapy in subjects with diffuse large B-cell lymphoma.

Критерии включения

• * The subjects voluntarily participate in this study, sign the informed consent form, and have good compliance;
• * Age ≥18 years (calculated from the date of informed consent);
• * Eastern Cooperative Oncology Group (ECOG) score 0 /~ 2 points;
• * Expected survival greater than 12 weeks;
• * Histological or cytological diagnosis of diffuse large B-cell lymphoma in accordance with the World Health Organization (WHO) diagnostic criteria in 2022;
• * Pathological diagnosis results containing CD20 positive expression and Myc rearrangement negative after anti-CD20 treatment must be provided;
• * Subjects with relapsed or refractory diffuse large B-cell lymphoma who have received at least 1 line of systemic therapy;
• * Not suitable for hematopoietic stem cell transplantation;
• * According to the Lugano criteria in 2014, there is at least one measurable lesion, that is, the long diameter of lymph node lesions /> 15 mm or extranodal lesions /> 10 mm according to CT cross-sectional images; Positron emission tomography - computerized tomography (PET-CT) scan shows PET positive;
• * Laboratory tests meet specific criteria;
• * Adopt effective contraceptive measures

Критерии исключения

• * Subjects who had or currently had other malignant tumors within 5 years prior to the first dose;
• * Previous or current involvement or suspected involvement of the central nervous system by lymphoma;
• * Failure to recover from adverse reactions to Common Terminology Criteria for Adverse Events version 5.0 (CTCAEv5.0) criteria ≤ grade 1 from previous treatment;
• * History of previous anti-tumor treatment:
• 1. previous use of other antibody drugs targeting CD3 and CD20 at the same time;
• 2. received Chimeric Antigen Receptor T-Cell Immunotherapy (CAR-T) therapy, or other immune cell therapy, or autologous hematopoietic stem cell transplantation (auto-HSCT) within 3 months before the first dose;
• 3. previous treatment with R-GemOx or GemOx;
• 4. received chemotherapy, immunotherapy, monoclonal antibody therapy 4 times before the first dose, 2 times received radiotherapy or small molecule targeted drugs, or subjects who are still within 5 half-lives of the drug, the washout period is calculated from the end time of treatment;
• 5. received treatment with Chinese patent medicines with clear anti-tumor indications in the package insert of National Medical Products Administration (NMPA)-approved drugs 2 times before the first dose;
• * Subjects who have undergone major surgical treatment, significant traumatic injury, or expected major surgery during the study treatment period within 4 weeks prior to the first use of medication, or have long-term untreated wounds or fractures;
• * Subjects who experience any bleeding or bleeding events ≥ Common Terminology Criteria Adverse Event (CTC AE) grade 3 within 4 weeks prior to the first administration;
• * Hyperactive/venous thrombotic events within 6 months prior to first dose,Such as cerebrovascular accident (including transient ischemic attack), deep venous thrombosis and pulmonary embolism or any other history of severe thromboembolism;
• * Clinically significant uncontrolled pleural effusion, ascites and more than moderate pericardial effusion requiring repeated drainage;
• * Decompensated cirrhosis (Child-Pugh class B or C liver function) and active hepatitis;
• * Pulmonary disease, including any of the following: 1) with or without current pneumonitis requiring corticosteroid therapy; 2) with or suspected chronic obstructive pulmonary disease (COPD), and forced expiratory volume in 1 second (FEV1) /< 60% (predicted);
• * Brain or mental disorders;
• * Have major cardiovascular disease;
• * Active or uncontrolled infection (≥ CTCAE grade 2 infection), including bacterial, fungal or viral infections including but not limited to active pneumonia, syphilis and tuberculosis.
• * Unexplained fever /> 38.5℃ during screening or before the first dose;
• * Renal failure requiring hemodialysis or peritoneal dialysis, previous history of nephrotic syndrome;
• * History of immunodeficiency, including HIV-positive or other acquired, congenital immunodeficiency diseases;
• * Have or have had prior autoimmune disease requiring treatment.
• * Prepare to undergo or have previously received organ transplantation, or have a significant host transplant response, or have previously received allogeneic hematopoietic stem cell transplantation; 19、Need to receive systemic immunosuppressive therapy;
• * Known or suspected history of hemophagocytic syndrome (HLH);
• * Known hypersensitivity to excipient components of the study drug.
• * Subjects who participated in other anti-tumor clinical trials within 4 or 5 half-lives before the first dose.
• * Any condition that, in the judgment of the investigator, would jeopardize the safety of the subject or prevent the subject from completing the study.

Описание

This phase Ib/II trial evaluates the safety, optimal dose, and efficacy of the combination of epcoritamab and ibrutinib in treating patients with aggressive B-cell non-Hodgkin lymphoma that has come back (relapsed) or responded to previous treatment (refractory). Epcoritamab, a bispecific antibody, binds to two different types of receptors (proteins present on the cell surface) at the same time. The two receptors that epcoritamab binds to are called CD3 and CD20. CD3 is found on T cells, which are important cells of the immune system that help fight cancer and infections. CD20 is found on the surface of most types of aggressive B-cell non-Hodgkin lymphoma cells. By binding to both CD3 and CD20, epcoritamab brings the two cells close together so the T cells can fight and kill the lymphoma B cells. Ibrutinib, a Bruton`s tyrosine kinase (BTK) inhibitor, binds to a protein on B cells, a type of white blood cell from which the lymphoma developed. By doing this it decreases the ability of the lymphoma B cells to survive and grow. Ibrutinib may also improve the health (or fitness) of T cells thus making epcoritamab safer and/or more effective.

Критерии включения

• * One of the following CD20+ B-cell non-Hodgkin lymphoma subtypes (note, documentation of CD20 positivity by flow cytometry and/or immunohistochemistry is based on any representative pathology report)
• * Diffuse large B-cell lymphoma (DLBCL), including DLBCL, not otherwise specified (NOS); T-cell/histiocyte-rich large B-cell lymphoma; and Epstein-Barr virus-positive DLBCL, NOS
• * High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit lymphoma) or HGBL, NOS
• * Primary mediastinal B-cell lymphoma (PMBCL)
• * Follicular lymphoma, grade 3b (also known as follicular large B-cell lymphoma in the 5th edition of World Health Organization /[WHO/] classification of lymphoid neoplasms)
• * Patients with previously diagnosed indolent lymphoma (follicular lymphoma or marginal zone lymphoma but not lymphoplasmacytic lymphoma or small lymphocytic lymphoma/chronic lymphocytic leukemia) who have transformed to any of the above lymphoma subtypes are eligible
• * Patients must have relapsed or refractory aggressive B-cell lymphoma and received prior treatment with an anthracycline in combination with an anti-CD20 monoclonal antibody:
• * ≥ 2 prior systemic lymphoma treatments OR
• * ≥ 1 prior systemic lymphoma treatment in patients with high-risk disease defined as primary refractory or relapsed within 12 months of completing anthracycline-based frontline treatment who are ineligible for chimeric antigen receptor (CAR) T cells per the treating physician. The reason for CAR T-cell treatment ineligibility should be documented
• * Prior treatment with a BTK inhibitor is allowed if stopped due to lymphoma progression or treatment completion but not intolerance
• * Prior treatment with autologous stem cell transplant (ASCT) is allowed if ≥ 100 days prior to enrollment
• * Prior treatment with CAR T cells is allowed if ≥ 30 days prior to enrollment
• * Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of ibrutinib or epcoritamab in patients /< 18 years of age, children are excluded from this study
• * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• * Measurable disease (defined as /> 1.5 cm in diameter) or at least one PET fludeoxyglucose F-18 (FDG) avid area of disease
• * Absolute neutrophil count (ANC) ≥ 1,000/mcL
• * Platelet count ≥ 75,000/mcL. Platelet count ≥ 50,000/mcL is allowed in case of bone marrow involvement and/or splenomegaly
• * Hemoglobin ≥ 8 g/dL
• * Transfusion and/or growth factor support within 7 days (or 14 days in case of long-acting growth factors such as pegylated granulocyte colony-stimulating factor /[G-CSF/]) of enrollment to meet these requirements is not permitted
• * Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN) (unless due to Gilbert`s disease or hemolysis in which case bilirubin must be /< 3 x ULN)
• * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase /[SGOT/]) /< 3 x institutional ULN
• * Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase /[SGPT/]) /< 3 x institutional ULN
• * Creatinine clearance /> 45 mL/min calculated by Cockcroft-Gault. Patients on dialysis are not eligible
• * The effects of ibrutinib and epcoritamab on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) 2 weeks before initiation of treatment, for the duration of study participation and for 12 months after completing treatment. Should a woman become pregnant or suspect that she is pregnant while she or her partner is participating in this study, she should inform the treating physician immediately. Men must agree to refrain from sperm donation for at least 12 months after the last dose of epcoritamab
• * Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin /[β-hCG/]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study
• * Patients must have the ability to understand and the willingness to sign a written informed consent document and Health Insurance Portability and Accountability Act (HIPAA) consent document. Voluntary written consent must be given before the performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care

Критерии исключения

• * Prior therapy with a bispecific antibody targeting CD3 and CD20
• * Prior lymphoma therapy should be completed greater than two weeks before the start of protocol therapy, except for corticosteroids used for palliation of symptoms
• * Patients who require immediate cytoreductive therapy for their lymphoma per the treating physician`s assessment are ineligible
• * Patients with a history of allogeneic stem cell transplantation are excluded unless the transplant was /> 180 days before the first scheduled dose of ibrutinib AND the patient does not have evidence of active acute or chronic graft versus host disease AND the patient must not have taken immunosuppressive medications associated with the transplant for at least 1 month before the first scheduled dose of ibrutinib
• * Ongoing systemic treatment with a strong CYP3A inhibitor or inducer. Treatment with any strong CYP3A inhibitor or inducer needs to be stopped for 5 half-lives prior to starting treatment on trial
• * Major surgery within 4 weeks before the start of treatment other than surgery performed for lymphoma diagnosis
• * Known active central nervous system (CNS) involvement by lymphoma. Patients who are enrolled and subsequently identified to have pathologic confirmation of CNS involvement by lymphoma may be continued on the study at the discretion of the principal investigator
• * Active uncontrolled infection or infection requiring intravenous (IV) antibiotic therapy for /> 2 consecutive days within 2 weeks prior to the first dose of study drug
• * Evidence of current uncontrolled or symptomatic cardiovascular conditions, including, uncontrolled cardiac arrhythmias, history of or symptomatic congestive heart failure (New York Heart Association /[NYHA/] class III or greater), unstable angina, or myocardial infarction within the past 6 months. Poorly controlled or clinically significant atherosclerotic vascular disease including angioplasty, cardiac or vascular stenting within 6 months of enrollment
• * Known liver cirrhosis with moderate to severe hepatic impairment (Child-Pugh class B or C)
• * Clinically significant pulmonary disease or history of bronchospasm requiring intubation, or clinically significant active interstitial lung disease or pneumonitis
• * History of cerebrovascular accident or transient ischemic attack within the 6 months before day 1, cycle 1 of treatment
• * Any prior history of intracranial hemorrhage
• * Clinically significant known bleeding diatheses or platelet dysfunction disorders.
• * Receiving treatment with coumadin/warfarin
• * Known gastrointestinal disease or gastrointestinal procedure that will significantly interfere with the oral absorption or tolerance of ibrutinib including the inability to swallow pills/capsules
• * Any serious medical or psychiatric illness that could, in the investigator`s opinion, potentially interfere with the completion of treatment according to this protocol
• * Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
• * Prior solid organ transplant
• * History of other malignancies that could affect compliance with the protocol or interpretation of results in the opinion of the investigator
• * Participation in other interventional clinical trials, including those with other investigational agents not included in this trial, within 21 days of the first scheduled dose of ibrutinib (cycle 1 day -7)
• * Known history of HIV, active hepatitis C infection (HCV ribonucleic acid /[RNA/] polymerase chain reaction /[PCR/]-positive) and/or active hepatitis B infections (HBV DNA PCR-positive). If hepatitis B core (HBc) antibody is positive, the patient must be evaluated for the presence of HBV DNA by PCR. If HCV antibody is positive, the patient must be evaluated for the presence of HCV RNA by PCR. Patients with positive HBc antibody and negative HBV DNA by PCR are eligible. Patients with positive HCV antibody and negative HCV RNA by PCR are eligible
• * Pregnant or breastfeeding women are excluded from this study. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with ibrutinib or epcoritamab, breastfeeding should be discontinued if the mother is treated with ibrutinib or epcoritamab
• * Patients with ongoing clinically significant grade ≥ 2 toxicity from prior therapy

Описание

This study evaluates immune responses after CAR-T therapy to find out if CAR-T therapy reduces the effectiveness of the vaccines (vaccine immunity) against diseases such as measles, mumps and rubella, among others in patients with multiple myeloma and non-Hodgkin lymphoma.

Критерии включения

• * /* Willingness to provide written informed consent before any study-specific procedures or activities are performed
• * Age ≥ 18 years of age, at the time of consent
• * Documented, histologically or cytologically confirmed diagnosis of multiple myeloma (MM), diffuse large B cell lymphoma (DLBCL),follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL), or primary mediastinal B cell lymphoma (PMBL). All number of prior lines of therapy are allowed
• * History of prior vaccination against common VPD
• * Approved by managing physician for CAR-T therapy, with preparative conditioning planned within the next 90 days
• * Approved by managing physician for revaccination against Streptococcus pneumoniae or tetanus

Критерии исключения

• * /* Ongoing use of immunosuppressive agents or plans for immunosuppressive therapy that would interfere with interpretation of study endpoints
• * Uncontrolled, intercurrent illness including, but not limited to, systemic infection, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements or make the study procedures unadvisable

Описание

An open-label, single-arm, single-center, phase II clinical trial to evaluate the feasibility, efficacy and safety of Glofitamab Combination with chidamide in patients with recurrent/refractory diffuse large B-cell lymphoma.

Критерии включения

• - To be eligible for enrollment in this study, a subject must meet all of the following criteria:
• 1. Signed informed consent
• 2. Age ≥ 18 years at the time of informed consent
• 3. Patients must be willing and able to comply with protocol-specified hospitalization requirements following administration of Glofitamab. Patients must also be willing to comply with all study-related procedures.
• 4. Histologically confirmed DLBCL, including any of the following 2016 WHO Lymphocytes Neoplasm classifications (Swerdlow et al. 2016) Diagnosis: DLBCL-NOS, HGBCL, PMBCL and FL transformed DLBCL (trFL)
• - A pathology report (if available) from the initial histopathological diagnosis must be provided. Patients with trFL must also provide a pathology report (if available) at the time of disease transformation. Results of all tissue tests performed at initial diagnosis should be provided, including but not limited to tests to assess cellular origin, BCL2, and MYC abnormalities (if performed).
• 5. Patients must have relapsed or Cap following at least two prior lines of systemic therapy (including at least one prior regimen containing anthracene Treatment failure and at least one prior regimen containing anti-CD20 targeted therapy).
• * Patients may have received Autologous haematopoietic stem cell transplant (HSCT) prior to recruitment; consolidative autologous HSCT after Chemotherapy will be counted as a line of therapy.
• * CAR T cells plus bridging were counted as a treatment line.
• * Local therapies (e.g., radiotherapy) will not be considered as treatment lines.
• 6. Patients must have measurable disease: at least one bidimensionally measurable Lymphadenopathy, defined as /> 1.5 cm in the longest diameter; or at least one bidimensionally measurable extranodal lesion, defined as /> 1.0 cm in the longest diameter.
• 7. Verify availability of Neoplasm tissues, unless not available per investigator assessment. Freshly collected Biopsy specimens are preferred. Representative Neoplasm tissue specimens or unstained serial sections are acceptable.
• 8. Eastern Cooperative Neoplasm Group (ECOG) performance status of 0 or 1
• 9. Life expectancy (as assessed by the investigator) ≥ 12 weeks
• 10. Carcinoma due to prior anti Adverse event therapy must have resolved to ≤ grade 1 (except Alopecia and Hyporexia).
• 11. Adequate liver function
• * Bilirubin total ≤ 1.5 x upper limit of normal (ULN); patients with documented history of Gilbert`s syndrome: Bilirubin total ≤ 3 x ULN with elevated indirect Bilirubin;
• * AST/ALT ≤ 3 × ULN
• 12. Adequate hematological function:
• * Neutrophil count ≥ 1.5 x 109 cells/L (1.500/μL);
• * Platelet count ≥ 75,000/μL (and no Platelet transfusion within 14 days before Gpt administration on Day 1 of Cycle 1);
• * Haemoglobin ≥ 10.0 g/dL (6.2 mmol/L); no Transfusion within 21 days prior to Gpt dosing on Cycle 1 Day 1
• 13. Adequate renal function: Serum creatinine ≤ 1.5 × ULN or Creatinine clearance ≥ 50 mL/min calculated according to the C OC kroft Gault formula (see Appendix 14) (patients whose renal function is not adequately reflected by Serum creatinine levels as judged by the investigator)
• 14. Negative serum Pregnancy test within 7 days prior to study treatment for women of childbearing potential. Amenorrhoea is not required for women of non-childbearing potential who are post-menopausal (≥ 12 months of non-therapeutic Surgery) or Pregnancy test sterilized (absence of ovaries and/or uterus). For women of childbearing potential: Agree to remain abstinent (avoid heterosexual intercourse) or to take Contraception measures.
• 15. For men: Agree to remain abstinent (avoid heterosexual intercourse) or practice Contraception

Критерии исключения

• Any subject who meets any of the following criteria should not be enrolled in the study:
• 1. Inability to comply with protocol-specified hospitalization and restrictions
• 2. Richter`s transformation
• 3. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other Infection (excluding Nail bed infection fungal) at study entry or any major Infection (as evaluated by the investigators) within 4 weeks prior to first study treatment Contacts and Locations
• 4. Suspected or Latent tuberculosis disease (confirmed by positive IFNγ release assay)
• 5. Positive test result for Chronic hepatitis B virus (HBV) Infection (defined as positive Hepatitis B surface antigen /[HBsAg/] serology).
• - Patients with occult or previous HBV Infection (defined as HBsAg negative and Hepatitis B core antibody /[HBcAb/] positive) may be included if HBV DNA is undetectable, provided they are willing to undergo HBV DNA testing monthly during study treatment (or on Day 1 of each cycle) and monthly for at least 12 months after the last cycle, and are willing to receive appropriate antiviral therapy.
• 6. Positive Hepatitis C virus (HCV) Antibody test
• - Patients with HCV Polymerase chain reaction are eligible only if the PCR (Antibody positive) is negative for HCV RNA.
• 7. Known HIV seropositive status
• - For patients with unknown HIV status, HIV testing will be performed at screening if required by local regulations.
• 8. Known or suspected chronic active Epstein-Barr Viral infection
• 9. Known or suspected history of Haemophagocytic lymphohistiocytosis (H LH)
• 10. Pregnancy or lactating, or planning to Pregnancy during treatment and for at least 3 months after the last dose of Gpt or within 2 months after the last dose of Glofitamab
• 11. A history of treatment-emergent Immunization related Immunization associated with prior Adverse event treatment agents as follows:
• * Grade 3 Adverse event, except for Grade 3 endocrinopathy managed with alternative therapy
• * Grade 1-2 Adverse event that did not return to baseline after Therapy cessation
• 12. Documented refractory to Obinutuzumab monotherapy
• 13. Active autoimmune disease requiring treatment requires investigator assessment of Immunization
• 14. Evidence of significant, uncontrolled concomitant disease that could affect adherence to the study protocol or interpretation of results, including Immunization, relevant Lung disorder history (Bronchospasm, Obstruction Pneumopathy), and known autoimmune Diabetes mellitus
• 15. History of severe Allergy or Allergic reaction to monoclonal antibody therapy (or recombinant antibody-associated fusion Protein)
• 16. History of confirmed progressive multifocal Leukoencephalopathy (PML)
• 17. Current or past history of CNS Lymphoma
• 18. Current or past history of CNS disease such as Stroke, Epilepsy, CNS Vasculitis, or neurodegenerative disease
• 19. Another invasive Neoplasm malignant within the last 2 years (except Basal cell carcinoma and Neoplasm with a low likelihood of recurrence)
• 20. Serious or extensive Angina unstable such as New York Heart disorder Association Class III or IV or objectively assessed Class C or D Cardiac disorder, Myocardial infarction within the last 6 months, unstable Arrhythmia, or Cardiovascular disorder
• 21. Administration of a live attenuated vaccine within 4 weeks prior to Gpt infusion, or anticipated need for a live attenuated vaccine during the study. ( Note: Flu vaccination should only be administered during the Flu season. Patients must not receive live attenuated Flu vaccine at any time during study treatment.)
• 22. Systemic Tumour necrosis agents (including but not limited to Cap Phosphorus amide, thiazolyl Purines, methotrexate, thalidomide, and anti Ammonia factor agents) within 2 weeks prior to Gpt infusions
• * Corticosteroid therapy with ≤ 25 mg/day prednisone or equivalent is allowed.
• * Inhaled and topical steroids are allowed.
• 23. History of illicit drugs or Alcohol abuse within 12 months prior to screening, as judged by the investigators.
• 24. Any other disease, metabolic dysfunction, Physical examination result, or clinical lab result reasonably suspecting a disease or condition that contraindicates the use of an investigational drug
• 25. Investigators should review the Vaccination status of potential study patients considered for this study and follow local disease control and prevention guidelines for vaccination of any other non-live vaccinated adults aiming to prevent infectious diseases prior to the study.
• 26. Any mental or Cognitive disorder that would limit the understanding, conduct, and compliance with the informed consent form;
• 27. Pregnancy or lactating females, or females or male partners planning to Pregnancy during the study;
• 28. Other situations that the investigators consider Discomfort to be eligible for this trial

Описание

This is a phase I, interventional, single arm, open label, treatment study designed to evaluate the safety and efficacy of LV20.19 CAR -T cells with pirtobrutinib bridging and maintenance in adult patients with B cell malignancies that have failed prior therapies.

Критерии включения

• To facilitate rapid start of pirtobrutinib, there will be separate inclusion/exclusion for pirtobrutinib and LV20.19 CAR T-cells in addition to the general inclusion as outlined below.
• General inclusion criteria for trial:
• 1. Patients must be aged ≥18 years and /<81 years with relapsed or refractory B-cell non-Hodgkin Lymphoma (NHL).
• 2. Diagnosis of relapsed or refractory B-cell NHL including Follicular Lymphoma, Marginal Zone Lymphoma (splenic, nodal, extranodal), Mantle Cell Lymphoma, Burkitt Lymphoma and DLBCL with associated subtypes (aggressive B-cell lymphoma, high grade B-cell lymphoma, T-cell/histocyte rich B-cell lymphoma, primary mediastinal B-cell lymphoma, Epstein-Barr virus-positive (EBV)+ diffuse large B-cell lymphoma, transformed lymphoma such as transformed follicular or marginal zone, and Richter`s transformation).
• 3. Disease specific criteria as follows:
• 1. DLBCL and associated subtypes (listed above)
• i. Must have received Rituximab or another cluster of differentiation 20 (CD20) antibody with combination anthracycline based chemotherapy regimen and have ONE of the following:
• <!-- -->
• 1. Primary refractory lymphoma or early relapse ≤6 months after one line of therapy.
• 2. For relapse />6.00 months, failure of two different chemotherapy regimens appropriate for their disease and be ineligible to receive autologous transplant.
• ii. Relapse post-autologous transplant. iii. Relapse post-allogeneic transplant. iv. Relapse post-CAR T-cell therapy (maximum 2 patients allowed with this designation).
• b. Mantle Cell Lymphoma
• i. Must have received Rituximab or another CD 20 antibody with one chemotherapy regimen appropriate for this disease (bendamustine or cytarabine, or anthracycline based treatment) and have ONE of the following:
• 1. Relapsed disease after two lines of cytotoxic chemotherapy including administration of anti-CD20 antibody.
• 2. Progressive disease after ≥second line BTK inhibitor.
• 3. Relapse post-autologous transplant.
• 4. Relapse post-allogeneic transplant.
• c. Marginal Zone Lymphoma and Follicular Lymphoma
• i. Must have received Rituximab or another CD20 antibody with chemotherapy regimen appropriate for the disease and have ONE of the following:
• <!-- -->
• 1. Relapsed disease after two lines of therapy including administration of anti-CD20 antibody.
• 2. Relapse post-autologous transplant.
• 3. Relapse post-allogeneic transplant.
• d. Burkitt`s Lymphoma
• i. Must have received Rituximab or another CD20 antibody in combination with anthracycline based chemotherapy regimen and have ONE of the following:
• <!-- -->
• 1. Primary refractory lymphoma.
• 2. Relapse within 6 months.
• 3. For relapse />6 months, failure of two different chemotherapy regimens appropriate for their disease and be ineligible to receive autologous transplant.
• i. Relapse post-autologous transplant. ii. Relapse post-allogeneic transplant.
• 4. Able to provide written informed consent.
• 5. Negative urine or serum pregnancy test in females of childbearing potential at screening.
• 6. Willingness of women of reproductive potential and their partners to observe highly effective birth control methods for duration of treatment and for 1 month following the last dose if study treatment.
• 7. Karnofsky performance score ≥70.
• 8. Expected survival />12 weeks.
• 9. Patient has demonstrated compliance with prior therapies.
• 10. Able to take oral medications.
• 11. Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x upper limit of normal (ULN).
• 12. Patients are required to have the following washout periods prior to planned Cycle 1 Day 1 (C1D1). In addition, prior treatment-related adverse events (AEs) must have recovered to Grade ≤ 1 with the exception of alopecia and Grade 2 peripheral neuropathy.
• 1. Targeted agents, investigational agents, therapeutic monoclonal antibodies or cytotoxic chemotherapy: 5 half-lives or 2 weeks, whichever is shorter.
• 2. immunoconjugated antibody treatment within 10 weeks prior to randomization.
• 3. broad field radiation (≥ 30% of the bone marrow or whole brain radiotherapy) must be completed 14 days prior to study enrollment.
• 4. palliative limited field radiation must be completed 7 days prior to study enrollment.
• Inclusion Criteria to START Pirtobrutinib Bridging:
• 1. Absolute neutrophil count (ANC) ≥1000 with no G-CSF within 7 days or pegylated G-CSF within 14 days unless patient has biopsy proven bone marrow involvement.
• 2. Platelets≥50,000 with no transfusion within 7 days unless patient has biopsy proven bone marrow involvement.
• 3. Hemoglobin ≥8g/dL (≥80 g/L) /[blood transfusions are allowable to reach this goal/].
• 4. Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine transaminase (ALT) /<3 x upper limit of normal (ULN) or /< 5 x ULN with documented liver involvement; serum bilirubin /<1.5 x ULN or /<3 x ULN with documented liver involvement , or considered not clinically significant as per the clinical PIs discretion (e.g. Gilbert`s or indirect hyperbilirubinemia) or felt to be due to underlying disease.
• 5. Adequate renal function, defined as creatinine clearance≥50 ml/min.
• 1. No IV hydration within 24 hours of eligibility.
• 2. No dialysis dependent renal failure.
• Inclusion criteria for Pirtobrutinib Maintenance (part B)
• 1. Recovery of neutrophils count after CAR T-cell infusion with ANC ≥1000/dL without G-CSF within the last 7 days.
• 2. Recovery of platelet count after CAR T-cell infusion with platelet count ≥50,000/dL.
• 3. Adequate hepatic function, defined as back to baseline or AST and ALT /<3 x upper limit of normal (ULN); serum bilirubin and alkaline phosphatase /<3 x ULN, or considered not clinically significant as per the clinical PI`s discretion (e.g., Gilbert`s or indirect hyperbilirubinemia) or felt to be due to underlying disease.
• 4. Adequate renal function, defined as creatinine clearance≥40 ml/min.
• 5. Evidence of response or stable disease (complete response/partial response/stable disease) at day 28 after CAR T-cell therapy.
• Inclusion Criteria for Apheresis and LV20.19 CAR T-cells:
• 1. Active Measurable disease must be documented within 4 weeks of lymphodepletion start defined as nodal lesions greater than 15 mm in the long axis or extranodal lesions />10 mm in long and short axis OR bone marrow involvement that is biopsy proven for B-cell NHL.
• 2. Absolute cluster of differentiation (CD) 3 count≥50 mm/^3.
• 3. MRI brain and Lumbar Puncture with cerebrospinal fluid (CSF) analysis by cytology and flow cytometry without evidence of central nervous system (CNS) involvement ONLY in patients with history of CNS involvement or clinical suspicion at the time of enrollment.
• 4. Adequate cardiac function as indicated by New York Heart Association (NYHA) classification I or II AND left ventricular ejection fraction of ≥45% (by echocardiogram (ECHO) or MUGA) and adequate pulmonary function as indicated by room air oxygen saturation of ≥92%.
• 5. No contraindication to central line access.
• 6. ANC≥1000 with no pegylated G-CSF within 14 days unless patient has biopsy proven bone marrow involvement.
• 7. Platelets≥50,000 with no transfusion within 72 hours unless patient has biopsy proven bone marrow involvement.
• 8. Adequate hepatic function, defined as AST and ALT /<3 x upper limit of normal (ULN); serum bilirubin and alkaline phosphatase /<3 x ULN, or considered not clinically significant as per the clinical PIs discretion (e.g. Gilbert`s or indirect hyperbilirubinemia) or felt to be due to underlying disease.
• 9. Adequate renal function, defined as creatinine clearance≥50 ml/min. a. No IV hydration within 24 hours of eligibility. b. No dialysis dependent renal failure.

Критерии исключения

• A potential subject who meets any of the following exclusion criteria is ineligible to participate in the study.
• 1. Positive beta-human chorionic gonadotropin (HCG) in female of child-bearing potential or plan to become pregnant during the study or within 1 month of the last dose of study treatment and women who are current lactating or plan to breastfeed during the study or within 1 week of the last dose of study treatment.
• 2. Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:
• 1. HBV: Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before randomization. Patients who are hepatitis B PCR positive will be excluded.
• 2. Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before randomization. Patients who are hepatitis C RNA positive will be excluded.
• 3. Known active cytomegalovirus (CMV) infection (Unknown or negative status are eligible).
• 4. History of significant autoimmune disease OR active, uncontrolled autoimmune phenomenon requiring steroid therapy defined as />20 mg of prednisone or equivalent daily.
• 5. Presence of ≥ grade 3 non-hematologic toxicities as per CTCAE version 5.0 from any previous treatment unless it is felt to be due to underlying disease.
• 6. Concurrent use of investigational therapeutic agents or enrollment on another therapeutic clinical trial at any institution. Minimum of 14 days or 5 half-lives of the drug (whichever is shorter) washout prior to apheresis.
• 7. Refusal to participate in the long-term follow-up protocol.
• 8. Patients with active CNS involvement by malignancy on MRI or by lumbar puncture.
• 1. Patients with prior CNS disease that has been effectively treated will be eligible providing treatment was />4 weeks before enrollment and a remission documented within 8 weeks of planned CAR-T cell infusion by MRI brain and CSF analysis.
• 9. Previous recipients of allogeneic hematopoietic stem cell transplantation (AHCT) are excluded if they are /<100 days post-transplant, have evidence of active graft-versus-host-disease (GVHD) of any grade, or are currently on immunosuppression.
• 10. Prior allogeneic CAR T-cell therapy /<100 days from prior CAR T-cell treatment.
• 11. Previous recipients of autologous CAR-T cell therapy directed at either cluster of differentiation 19 (CD19) or CD20 are excluded if they are /<100 days post prior CAR-T cell treatment (does not include re-enrollment) or have />5% residual circulating CAR-T as measured by flow cytometry using a CD19 CAR detection reagent (Miltenyi Biotec).
• a. Patients with prior CAR-T treatment against CD19 or CD20 must have repeat biopsy post-CAR-T cell therapy confirming a minimum of 5% CD19 or CD20 positivity by immunohistochemistry or flow cytometry.
• 12. Anti-CD20 antibody treatment within 4 weeks of cell infusion.
• 13. Anti-CD19 antibody treatment within 4 weeks of cell infusion.
• 14. Cytotoxic chemotherapy treatment within 14 days or steroid treatment (other than replacement dose steroids) within 7 days prior to apheresis collection for CAR-T cells.
• 15. No other oral chemotherapeutic agents or antibody directed treatment after starting pirtobrutinib other than steroids or radiation to a single site in a palliative fashion.
• 16. Patients post solid organ transplant who develop high grade lymphomas or leukemias.
• 17. Concurrent active malignancy other than basal or squamous cell carcinomas of the skin (underlying low-grade lymphoma chronic lymphocytic leukemia/Follicular lymphoma (FL) / Marginal zone lymphoma (MZL) is allowable in patients with transformed large cell lymphoma/Richter`s.
• 18. Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor.
• 19. History of stroke or intracranial hemorrhage within 6 months of randomization.
• 20. Significant cardiovascular disease defined as myocardial infarction within 6 months of randomization, congestive heart failure with ejection fraction /<30%, active unstable angina, QT prolongation (QTcF)/>470 msec on ECG.
• 21. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug.
• 22. Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
• 23. Patients who had surgery within 4 weeks prior to randomization.
• 24. Patients who have received vaccination with live vaccine within 28 days prior to randomization.
• 25. Patients with known hypersensitivity to any of the excipients of pirtobrutinib.
• Special Criteria Regarding Fertility and Contraception
• Female subjects of reproductive potential (women who have reached menarche or women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or have not undergone a sterilization procedure /[hysterectomy or bilateral oophorectomy/]) must have a negative serum or urine pregnancy test performed at screening.
• Due to the high-risk level of this study, while enrolled, all subjects must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization). Additionally, if participating in sexual activity that could lead to pregnancy, the study subject must agree to use reliable and double barrier methods of contraception during the follow-up period of the protocol.
• Acceptable birth control includes a combination of two of the following methods:
• • Combined estrogen and progestin containing hormonal contraception associated with inhibition of ovulation given orally, intravaginally, or transdermally
• • Progestin-only hormonal contraception associated with inhibition of ovulation given orally, by injection, or by implant
• • Intrauterine device (IUD)
• • Intrauterine hormone-releasing system (IUS)
• • Vasectomized partner
• • Sexual abstinence: considered a highly effective method only if defined as refraining from heterosexual intercourse during an entire period of risk associated with the study treatment. The reliability of sexual abstinence will be evaluated in relation to the duration of the study and to the usual lifestyles of the patient.
• • Female sterilization
• • Fallopian tube implants (if confirmed by hysterosalpingogram) Oocyte donation is prohibited during the duration of participation on this protocol and for 1 month after the last dose of study drug.
• Subjects who are not of reproductive potential (women who are premenarche or have been post-menopausal for at least 24 consecutive months which is non-therapy induced or have undergone hysterectomy tubal ligation, salpingectomy, and/or bilateral oophorectomy or men who have documented azoospermia) are eligible without requiring the use of contraception.

Описание

This study aims to observe and explore the efficacy and safety of Rituximab-Methotrexate-Temozolomide-Thiotepa (RMTT) regimen as first-line therapy for primary central nervous system diffuse large B-cell lymphomas(PCNS DLBCL)

Критерии включения

• * Patients voluntarily joined the study, signed the informed consent, and had good compliance;
• * Patients with 18 Years to 75 Years(at the time of signing the informed consent); Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score: 0-3;
• * Patients with histopathologically confirmed newly diagnosed primary central nervous system diffuse large B-cell lymphoma, and there were intracranial evaluable lesions (long diameter greater than 1.5cm, short diameter greater than 1cm);
• * Patients who have not received any systemic therapy, except those who use hormones to control complications
• * Expected survival of more than 3 months.
• * Female patients of reproductive age should agree that birth control (such as intrauterine device, birth control pills, or condoms) must be used during the study period and for six months after completion; Having a negative serum pregnancy test within 7 days prior to study enrollment, and must be non-lactating; Male patients should agree to use contraception during the study period and for six months after the end of the study.

Критерии исключения

• * Patients who have previously received antitumor therapy or targeted therapy
• * Patients who have undergone major surgery within the past 3 weeks .
• * Presence of severe or uncontrolled comorbid conditions including, but not limited to, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina, active peptic ulcer disease, or severe hemorrhagic disorders such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring transfusion or other medical interventions.
• * Any active infection requiring systemic antimicrobial therapy within 14 days before starting study treatment, including, but not limited to, bacterial, fungal, and viral infections.
• * Patients who are pregnant or breastfeeding.
• * Current participation in other clinical studies, or initiation of study drugs administration less than 4 weeks after completion of previous clinical study treatment.
• * Patients with concomitant diseases that, in the investigator`s judgment, may seriously endanger patients` safety or may interfere with the completion of the study, or are deemed unsuitable for inclusion for other reasons.

Описание

This is a prospective, observational, multicenter, cohort study with 400 newly treated DLBCL patients. To evaluate the clinical efficacy and safety of tucidinostat in the real-world treatment of primary diffuse large B-cell lymphoma

Критерии включения

• * 1. Age ≥18 years old, male or female;
• * 2. No previous treatment for DLBCL, including chemotherapy, targeted therapy and immunotherapy;
• * 3. DEL /[Diffuse large B-cell lymphoma with double expression of MYC and BCL2 (immunohistochemical MYC≥40%, BCL2≥50%)/] was confirmed by pathology; Or non-double expression but at least one of the following:;
• 1. TP53 or other epigenetic gene mutations (as in: ACTB, BCL6, BCOR, CREBBP, EP300, EZH2, HIST1H1C, HIST1H1E, HIST1H2BK, HIST2H2AB, IRF4, KMT2A, KMT2C, KMT2D, MYC, MYD88, NSD2, RAG1, SETD1B SF3B1, SIN3A, TBL1XR1, TET2, TOX, TP53, TRIP12, TRRAP, UBE2A)
• 2. MYC and BCL2 double hit
• * 4. Plan to receive or are receiving a treatment regimen containing tucidinostat (if it is permitted to start using tucidinostat after obtaining specific test results due to pending genetic sequencing results);
• * 5. Voluntarily sign informed consent.

Критерии исключения

• * 1. Patients currently enrolled or planning to participate in any interventional clinical trial;
• * 2. The expected survival time is less than 6 months;
• * 3. There are any other reasons that the investigators believe are not suitable for patients to participate in this study.

Описание

The main goal of this trial is to study the frequency and severity of cytokine release syndrome (CRS) in participants with diffuse large B-cell lymphoma (DLBCL) who are using a combination of glofitamab + gemcitabine + oxaliplatin (Glofit-GemOx) followed by glofitamab-only treatment.

Критерии включения

• * Histologically confirmed DLBCL, not otherwise specified (NOS)
• * R/R disease, defined as: relapsed = disease that has recurred following a response that lasted />/= 6 months after completion of the last line of therapy; refractory = disease that did not respond to or that progressed /< 6 months after completion of the last line of therapy
• * At least one line of prior systemic therapy
• * Participants who have failed only one prior line of therapy must not be a candidate for high-dose chemotherapy followed by autologous stem cell transplant (ASCT)
• * At least one bi-dimensionally measurable (/> 1.5 cm) nodal lesion, or one bi-dimensionally measurable (/> 1 cm) extranodal lesion, as measured on CT scan
• * Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2
• * Adequate hematologic and renal function

Критерии исключения

• * Prior enrollment in Study GO41943 (NCT04313608), GO41944 (STARGLO; NCT04408638), or Study GO44900 (NCT06624085)
• * Participant has failed only one prior line of therapy and is a candidate for stem cell transplantation
• * History of transformation of indolent disease to DLBCL
• * High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, and high-grade B-cell lymphoma NOS, as defined by 2016 WHO guidelines
• * Primary mediastinal B-cell lymphoma
• * History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies (or recombinant antibody-related fusion proteins) or known sensitivity or allergy to murine products
• * Contraindication to obinutuzumab, gemcitabine or oxaliplatin, or tocilizumab
• * Prior treatment with glofitamab or other bispecific antibodies targeting both CD20 and CD3
• * Prior treatment with gemcitabine or oxaliplatin
• * Peripheral neuropathy or paresthesia assessed to be Grade />/= 2 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 at enrollment
• * Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational agent for the purposes of treating cancer within 2 weeks prior to first study treatment
• * Treatment with monoclonal antibodies for the purposes of treating cancer within 4 weeks prior to first study treatment
• * Primary or secondary CNS lymphoma at the time of recruitment or history of central nervous system (CNS) lymphoma
• * Prior CNS involvement that has been definitively treated and confirmed via magnetic resonance imaging (MRI) or cerebrospinal fluid analysis to be in complete remission is permissible
• * Current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease
• * History of other primary malignancy, with exceptions defined by the protocol
• * Significant or extensive cardiovascular disease
• * Significant pulmonary disease (including moderate or severe obstructive pulmonary disease)
• * Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or any major episode of infection (as evaluated by the investigator) within 4 weeks prior to the first study treatment
• * Positive for: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); tuberculosis; hepatitis B virus (HBV); hepatitis C virus (HCV); chronic active Epstein-Barr viral infection
• * Known or suspected history of hemophagocytic lymphohistiocytosis (HLH) or progressive multifocal leukoencephalopathy
• * Adverse events from prior anti-cancer therapy that have not resolved to Grade 1 or better (with the exception of alopecia and anorexia)
• * Administration of a live, attenuated vaccine within 4 weeks before first study treatment administration or anticipation that such a live, attenuated vaccine will be required during the study
• * Prior solid organ transplantation or prior allogenic stem cell transplant
• * Active autoimmune disease requiring treatment
• * Prior treatment with systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor agents), within 4 weeks prior to first dose of study treatment
• * Ongoing systemic corticosteroid use which, in the opinion of the investigator, puts the participant at increased risk of steroid-related iatrogenic adrenal insufficiency
• * Recent major surgery (within 4 weeks before the first study treatment) other than for diagnosis
• * Clinically significant history of cirrhotic liver disease
• * Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the participant at high-risk from treatment complications
• * Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 18 months after the final dose of study treatment

Описание

The researchers are doing this study to find out if the study treatment is an effective treatment that causes few or mild side effects in people with diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), or transformed lymphoma. The treatment being tested in this study is glofitamab, polatuzumab, and obinutuzumab in combination with standard treatment (the combination of rituximab, cyclophosphamide, doxorubicin, and prednisone, or R-miniCHP).

Критерии включения

• 1. Age 65-79 years with a fitness assessment of unfit or frail per simplified GA (Appendix 1, www.filinf.it/epi)
• 2. Age ≥80 years with any fitness level
• 3. Pathologically confirmed DLBCL, HGBCL or transformed lymphoma
• 4. No prior systemic anti-lymphoma therapy (prednisone/equivalent up to 100 mg daily x 7 days is permissible)
• 5. Ann Arbor Stage 2 bulky, 3 or 4 disease (Appendix 1)
• 6. Any IPI score (Appendix 1)
• 7. Anthracycline eligible: LVEF ≥ 45% by echocardiogram or MUGA scan.
• 8. Must have at least one bi-dimensionally measurable lesion (/>1.5 cm in its largest dimension for nodal lesions, or />1.0 cm in its largest dimension for extranodal lesions by computerized tomography /[CT/] scan or MRI)
• 9. Eastern Cooperative Oncology Group performance status ≤ 2 (Appendix 1)
• 10. Must have adequate organ and marrow status:
• 1. Absolute neutrophil count (ANC) ≥1,000/mm3 or ≥500/mm3 if due to disease involvement in the bone marrow
• 2. Platelet count ≥50,000 cells/mm3 or ≥25,000/mm3 if due to disease involvement in the bone marrow
• 3. Patients who do not meet criteria for bone marrow function due to marrow involvement of lymphoma and/or other disease-related cytopenias (e.g., immune thrombocytopenia) may be enrolled into the study after discussion with, and confirmation by the PI.
• 4. Serum creatinine ≤ULN OR estimated Creatinine Clearance (CrCl) ≥30 mL/min (Cockcroft-Gault formula or other institutional standard methods)
• 5. Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤3 x upper limit of normal (ULN)
• 6. Total bilirubin ≤ 1.5 x ULN (≤3 if due to Gilbert`s syndrome or liver involvement by the lymphoma
• 7. Patients who do not meet criteria for liver function due to liver involvement of lymphoma may be enrolled into the study after discussion with, and confirmation by the PI.
• 11. Negative HIV test at screening, with the following exception: Individuals with a positive HIV test at screening are eligible provided, prior to enrollment, they are stable on antiretroviral therapy, have a CD4 count ≥200/µL, and have an undetectable viral load.
• 12. Signed Informed Consent Form(s)
• 13. Ability to comply with all the study-related procedures, in the investigator`s judgement
• 14. Female patients who are not of child bearing potential (i.e., who are postmenopausal or surgically sterile). For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agree to refrain from donating sperm, as defined below: With a female partner of childbearing potential or pregnant female partners, male participants must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of /< 1% per year during the treatment period and for at least 6 months after pretreatment with obinutuzumab, 6 months after the last dose of polatuzumab, 160 days after the last dose of rituximab, 2 months after the final dose of glofitamab or 2 months after the last dose of tocilizumab (as applicable), whichever is longer. Male participants must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.

Критерии исключения

• 1. Prior systemic anti-lymphoma therapy (localized radiation, steroids and antibiotics are permitted)
• 2. Prior solid organ transplantation
• 3. Prior allogeneic stem cell transplantation
• 4. Active CNS involvement
• 5. Uncontrolled HIV or active HBV or HCV infection (controlled HIV with undetectable viral load and previously treated HBV and HCV are allowed) 5.1 Participants with occult or prior hepatitis B infection (defined as positive total hepatitis B core antibody and negative HBsAg) may be included if hepatitis B virus (HBV) DNA is undetectable at the time of screening. Such participants must be willing to undergo HBV DNA testing on Day 1 of every cycle and every 3 months for at least 12 months after the final cycle of study treatment and appropriate antiviral therapy as indicated.
• 5.2 Participants positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
• 6. Uncontrolled active systemic infection
• 7. Major surgery within 4 weeks of the first dose of study drug (exceptions may be allowed after discussion with PI if patient has fully recovered from procedure and antilymphoma therapy is urgently needed)
• 8. Significant or extensive history of cardiovascular disease such as New York Heart Association Class III or IV cardiac disease or Objective Assessment Class C or D, myocardial infarction within the last 3 months prior to the start of Cycle 1, unstable arrhythmias, or unstable angina.
• 9. Uncontrolled autoimmune disorder
• 10. A history of confirmed progressive multifocal leukoencephalopathy
• 11. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator`s opinion, could compromise the subject`s safety or risk study outcomes
• 12. Inability to comply with all the study-related procedures, in the investigator`s judgement.
• 13. Contraindication to any of the individual components of polatuzumab, R-miniCHP and glofitamab or history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
• 14. Prior treatment with systemic immunotherapeutic agents, including but not limited to, radio-immuno-conjugates, antibody-drug conjugates, immune/cytokines and monoclonal antibodies (mAbs) (e.g., anti-cytotoxic T lymphocyte associated protein 4, anti-PD-1, and anti-PD-L1) within 4 weeks or five half-lives of the drug, whichever is shorter 15. Prior use of any monoclonal antibody for the purposes of treating cancer within 3 months of the start of Cycle 1
• 15. Prior use of any monoclonal antibody for the purposes of treating cancer within 3 months of the start of Cycle 1
• 16. Any investigational therapy for the purposes of treating cancer within 28 days prior to the start of Cycle 1
• 17. Prior radiotherapy to the mediastinal/pericardial region. Radiotherapy to non-target lesion sites will be permitted.
• 18. Corticosteroid use /> 50 mg/day of prednisone or equivalent, for purposes other than lymphoma symptom control 18.1 Participants receiving corticosteroid treatment with ≤ 50 mg/day of prednisone or equivalent for reasons other than lymphoma symptom control (e.g., rheumatoid arthritis) must be documented to be on a stable dose of at least 4 weeks duration prior to the start of cycle 18.2 Corticosteroid therapy for control of cancer symptoms or side effects of prior treatment (e.g., nausea or B-symptoms) is permitted.
• 18.3 The use of inhaled corticosteroids is permitted. 18.4 The use of mineralocorticoids for management of orthostatic hypotension is permitted.
• 18.5 The use of physiologic doses of corticosteroids for management of adrenal insufficiency is permitted.
• 19. Participants who require lymphoma symptom control during screening may receive steroids in the following manner: - Up to 100 mg of prednisone PO (or equivalent steroids) per day for up to 7 days are allowed. Prednisone dose is at the discretion of the treating physician, provided that the dose is within the above specified dosage range. - As part of the pre-phase treatment, vincristine or rituximab may not be administered.
• 20. History of other malignancy that could affect compliance with the protocol or interpretation of results:
• 20.1 Participants with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix at any time prior to the study are eligible.
• 20.2 Participants with any malignancy appropriately treated with curative intent and the malignancy has been in remission without treatment for ≥ 2 years prior to enrollment are eligible.
• 20.3 Participants with low-grade, early-stage prostate cancer (Gleason score 6 or below, Stage 1 or 2) with no requirement for therapy at any time prior to study are eligible.
• 20.4 Patients with other concomitant malignancies may be eligible after discussion with, and confirmation by the PI
• 21. Live, attenuated vaccine within 4 weeks before study treatment infusion on Day 1 of Cycle 1 or anticipation that such a live, attenuated vaccine will be required during the study. Live vaccines during the study and until participants B cells recover, are prohibited.
• 21.1 Influenza vaccination should be given during influenza season only. Participants must not receive live, attenuated influenza vaccine at any time during the study treatment period.

Описание

This is a multicenter, randomized, controlled, open-label Phase III clinical trial, aimed at evaluating the efficacy and safety of BEBT-908 combined with rituximab (R) compared to investigator-selected standard chemotherapy regimens /[Standard of Care (SOC)/] /[i.e., rituximab-gemcitabine-oxaliplatin (R-GemOx) or rituximab-ifosfamide-carboplatin-etoposide (R-ICE)/] for the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL).

Критерии включения

• 1. The subject has been fully informed and is willing to sign the Informed Consent Form (ICF).
• 2. Age is ≥18 years and ≤75 years, both men and women are eligible.
• 3. Pathologically diagnosed as diffuse large B-cell lymphoma according to the 2022 World Health Organization classification, confirmed by central pathology review (Patients who relapse after more than one year need to undergo tissue biopsy again to confirm the pathological diagnosis.).
• 4. Measurable lesions /[The criteria for measurable lesions are: the longest diameter of lymph node lesions measured by enhanced Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) is greater than 15 mm, and the longest diameter of extranodal lesions is greater than 10 mm./] assessed by Positron Emission Tomography/Computed Tomography (PET-CT) and Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) according to the Lugano 2014 criteria .
• 5. Must have relapsed or refractory diffuse large B-cell lymphoma after at least one systemic therapy /[Salvage chemotherapy and immunotherapy after stem cell transplantation will be considered as first-line systemic treatment; maintenance therapy will not be counted as a separate line of systemic treatment; local radiotherapy for diffuse large B-cell lymphoma (DLBCL) aimed at cure will not be counted as first-line systemic treatment; patients who do not achieve PR after four cycles of first-line treatment are eligible for the study; patients who do not achieve PR after two cycles of second-line or higher treatment are eligible for the study. Primary refractory DLBCL patients are defined as those who have no response during first-line treatment or relapse within six months after the end of treatment, and they will be allowed to participate in the study. Patients who relapse within 12 months after stem cell transplantation are also eligible for inclusion. Refractory DLBCL patients are those who do not achieve response after adequate front-line treatment (at least four cycles of first-line chemotherapy, or at least two cycles of subsequent treatment), or who progress during previous first-line treatment, or who progress within six months (less than six months) after achieving response to previous adequate front-line treatment, or who relapse within 12 months after achieving response to stem cell transplantation. Relapsed DLBCL patients are those who relapse six months or more after achieving response to previous adequate front-line treatment, or who relapse 12 months or more after achieving response to stem cell transplantation./], and at least one systemic therapy must include CD20 antibody.
• 6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2.
• 7. Expected survival />12 weeks.
• 8. Organ function levels must meet the following requirements:
• Peripheral blood:
• 1. Absolute neutrophil count (ANC) ≥1.0×10/^9/L;
• 2. Hemoglobin (HGB) ≥80g/L;
• 3. Platelet count (PLT) ≥100×10/^9/L;
• Liver and kidney function:
• 1. Serum total bilirubin ≤1.5×Upper Limit of Normal (ULN) (for patients with Gilbert syndrome, total bilirubin /<3.0×ULN with direct bilirubin within normal range);
• 2. Serum creatinine /<1.5×ULN;
• 3. Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) ≤2.5×ULN (≤5×ULN if there is liver involvement).

Критерии исключения

• 1. Known severe allergy to the study drug or any of its excipients;
• 2. Due to the potential genotoxicity, mutagenicity, and teratogenicity of the study drug, the following subjects should be excluded:
• 1. Men and women who have not undergone in vitro preservation of sperm or oocytes and plan to have children within 5 years, unless subsequent studies confirm reproductive safety;
• 2. Pregnant or breastfeeding women;
• 3. Primary central nervous system lymphoma;
• 4. DLBCL with active central nervous system brain metastases or meningeal involvement at the time of screening;
• 5. Other active malignant tumors that require treatment and may interfere with the study.
• 6. Treatment history before the trial:
• 1. Received other small molecule targeted drug therapy within 2 weeks before enrollment;
• 2. Previously received BEBT-908 or R-ICE and R-GemOx therapy before enrollment;
• 3. Underwent autologous hematopoietic stem cell transplantation within 3 months before enrollment;
• 4. Received radiotherapy that affects the evaluation of the efficacy of this study within 3 months before enrollment, or local supportive radiotherapy that affects the subject`s bone marrow function;
• 5. Underwent myelosuppressive chemotherapy or biological therapy within 3 weeks before enrollment;
• 6. Used traditional Chinese medicine and patent medicine with antitumor effects within 2 weeks before enrollment;
• 7. Underwent major surgery (Referring to the Level 3 and Level 4 surgeries as stipulated in the "Administrative Measures for the Clinical Application of Medical Technologies" implemented on May 1, 2009.) other than tumor biopsy within 4 weeks before enrollment, or the side effects of the surgery have not yet stabilized;
• 8. Received any hematopoietic cell colony-stimulating factor therapy (such as granulocyte colony-stimulating factor G-CSF, granulocyte-macrophage colony-stimulating factor GM-CSF) or thrombopoietin TPO therapy (Subjects who have started receiving erythropoiesis-stimulating agents or darbepoetin within 2 weeks prior to enrollment are eligible for inclusion.) within 2 weeks before enrollment;
• 9. Received prednisone />10mg per day (or other equivalent doses of glucocorticoids) within 7 days before enrollment /[If used for the treatment of diseases other than lymphoma, such as rheumatoid arthritis, polymyalgia rheumatica, adrenal insufficiency, or asthma, subjects may receive a stable dose of up to 10 mg per day of prednisone (or an equivalent dose of other glucocorticoids)./];
• 10. Underwent chimeric antigen receptor T cell immunotherapy (CAR-T therapy) within 3 months before enrollment.
• 7. After the previous treatment (chemotherapy or biological therapy), there are persistent Grade 2 or higher /[Common Terminology Criteria for Adverse Events (CTCAE) V5.0 criteria/] toxicities that have not stabilized at the time of enrollment (alopecia excluded);
• 8. There is an active clinical severe infection of Grade 2 or higher (CTCAE V5.0 criteria);
• 9. Co-morbid conditions:
• 1. Poorly controlled diabetes mellitus /[with a random blood glucose level ≥11.1 mmol/L or Glycosylated Hemoglobin, Type A1C (HbA1c) ≥8.5% despite hypoglycemic treatment/];
• 2. Severe pulmonary disease (CTCAE V5.0 Grade III-IV);
• 3. Severe cardiac disease /[Including any of the following: left ventricular ejection fraction (LVEF) /<50% detected by cardiac radionuclide scan /[Multigated Acquisition (MUGA)/] or echocardiogram (ECHO); Fridericia-corrected QT value (QTcF interval) />450ms for males and /> 470ms for females (QTcF formula); unstable angina; symptomatic pericarditis; myocardial infarction within the past 6 months with persistent elevation of cardiac enzymes or persistent regional left ventricular wall abnormalities recorded during LVEF measurement; history of congestive heart failure (New York Heart Association Class III-IV), or history of cardiomyopathy./].
• 4. Significant renal or hepatic dysfunction;
• 5. Uncontrolled active hepatitis B, hepatitis C, syphilis (individuals with both specific and non-specific syphilis antibodies positive), and active Epstein-Barr virus infection /[The following active infections with clinical significance, including hepatitis B (HBV), hepatitis C (HCV), and syphilis. Active hepatitis B is defined as: hepatitis B surface antigen (HBsAg) or hepatitis B e antigen (HBeAg) or hepatitis B core antibody positive, and HBV DNA ≥ 2000 IU/ml (approximately equal to 10/^4 copies/ml), hepatitis B surface antigen (HBsAg) or hepatitis B e antigen (HBeAg) positive, HBV DNA /< 2000 IU/ml, according to the requirements of infectious disease control, the subject should continue to take antiviral drug treatment); active hepatitis C is defined as: HCV RNA above the upper limit of detection; positive syphilis spirochete antibody test, should be tested for non-specific syphilis spirochete antibodies /[Rapid Plasma Reagin Test (PRP) or Toluidine Red Unheated Serum Test (TRUST)/], the latter is negative and the subject is judged by the researcher to have been infected with syphilis in the past but has been cured can be included; current EB virus infection refers to EB virus serological detection of Epstein-Barr Virus Capsid Antigen Immunoglobulin M (VCA-IgM), Epstein-Barr Virus Early Antigen Immunoglobulin G (EA-IgG) positive or EB virus DNA test positive./];
• 6. Known positive for human immunodeficiency virus (HIV);
• 7. History of mental illness, family history of mental illness, or mood disorders as judged by the investigator or psychiatrist /[Including a medical history of depressive episodes, bipolar disorder (Type I or II), obsessive-compulsive disorder, schizophrenia, suicide attempts or suicidal ideation, or thoughts of killing (immediate risk of harming others), and anxiety levels above Grade 3./], and deemed unsuitable for enrollment by the investigator;
• 8. Need for concomitant anticoagulant or antiplatelet therapy during the study period;
• 9. Uncontrolled hypertension (systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg);
• 10. Severe internal medical conditions with a risk of major bleeding or a history of major bleeding.
• 10. Concurrent use of drugs that may cause QT interval prolongation or torsades de pointes;
• 11. Within 4 weeks prior to enrollment, currently receiving or requiring treatment with strong inhibitors or inducers of cytochrome P450 (CYP) 3A4 isoenzyme after enrollment (Within 4 weeks prior to enrollment and during the study period, subjects must not receive treatment with strong inhibitors or inducers of the cytochrome P450 (CYP) 3A4 isoenzyme. However, concurrent treatment with moderate or weak CYP3A4 inhibitors is permitted.);
• 12. Within 4 weeks prior to enrollment, participated in other clinical trials and used investigational drugs;
• 13. Any unstable condition or situation that may jeopardize the subject`s safety and compliance with the study as judged by the investigator;
• 14. Subjects deemed unsuitable for treatment with this protocol by the investigator.

Описание

A serious consequence of systemic diffuse large B-cell lymphoma (DLBCL) is secondary central nervous system (CNS) relapse, which occurs in approximately 5% of all patients. Many CNS relapses occur within the first year after completion of frontline treatment and are associated with significantly increased mortality; thus, it is important to tailor frontline treatment to provide prophylaxis against CNS relapse in those patients who are determined to be high-risk.

Autologous stem cell transplantation (ASCT) is standard of care for patients with DLBCL who relapse one year or more after first remission, and it has been shown to improve progression-free survival for patients with primary CNS lymphoma.

The four-drug BEAM regimen (carmustine, etoposide, cytarabine, and melphalan) is the preferred conditioning regimen for DLBCL patients undergoing ASCT; however, patients with primary CNS lymphoma receive thiotepa plus carmustine as their conditioning regimen due to its better CNS penetration.

This study tests the hypothesis that consolidation thiotepa/carmustine ASCT in first complete remission will reduce the risk of CNS relapse in transplant-eligible patients with DLBCL with no prior CNS disease at high risk of secondary CNS recurrence.

Критерии включения

• * Newly diagnosed diffuse large B-cell lymphoma, large B-cell lymphoma transformed from underlying indolent lymphoma, or high-grade B-cell lymphoma. Patients with secondary CNS lymphoma are eligible.
• * At high risk for CNS relapse prior to start of induction as defined by at least one of the criteria below:
• * CNS-IPI ≥ 4
• * Kidney or adrenal involvement
• * Testicular involvement
• * Double hit lymphoma as defined by containing translocations of MYC gene together with rearrangement of BCL2 and/or BCL6.
• * Bone marrow involvement
• * Myocardium involvement
• * CNS adjacent
• * Secondary CNS involvement
• * Intend to receive a full course (6 cycles) of curative-intent anthracycline-based induction treatment and has not yet received more than 2 cycles at the time of screening. Can receive induction chemotherapy outside of Siteman if still compliant with study eligibility, laboratory studies, lumbar punctures, imaging, and other events.
• * Eligible for autologous stem cell transplant as determined by the treating physician.
• * Ages 18 to 75.
• * ECOG performance status ≤ 2.
• * Thiotepa and carmustine can cause fetal harm when administered to a pregnant person. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study treatment, and for 6 months following receipt of thiotepa and/or carmustine (for women) and 12 months following receipt of thiotepa and/or carmustine (or 3 months following receipt of carmustine if discontinuing before thiotepa) (for men). Should a woman become pregnant or suspect she is pregnant during treatment or within 6 months of the last dose of either thiotepa or carmustine or should a man suspect he has fathered a child, s/he must inform the treating physician immediately.
• * Ability to understand and willingness to sign an IRB-approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants if patient is otherwise unable to sign for themselves or unable to understand consent document

Критерии исключения

• * Relapsed or refractory diffuse large B-cell lymphoma or high-grade B-cell lymphoma. Prior treatment for underlying indolent lymphoma is permitted.
• * Diagnosis of primary CNS lymphoma.
• * Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen as determined by the PI. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial.
• * Currently receiving any other investigational agents.
• * A history of allergic reactions attributed to compounds of similar chemical or biologic composition to thiotepa, carmustine, or other agents used in the study.
• * Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days prior to start of induction (for people enrolling prior to induction) or within 7 days of enrollment (for people enrolling after the start of induction).

Описание

The objective of exploring the application of CHiR is to evaluate its therapeutic efficacy and safety in newly diagnosed elderly patients with diffuse large B-cell lymphoma (DLBCL) aged 70 and above, and to investigate the genetic subtypes that may benefit from CHiR. The primary endpoint is the complete remission rate (CRR) at the end of 8 cycles.

Критерии включения

• ：
• 1. Age ≥ 70 years;
• 2. ECOG score of 0-3;
• 3. Rated as unfit or frail on the simplified geriatric assessment (sGA);
• 4. Histologically confirmed CD20-positive diffuse large B-cell lymphoma (diagnostic criteria according to WHO 2016), excluding transformed type 2 DLBCL;
• 5. Immunohistochemically confirmed positive expression of MYC and BCL2 (MYC ≥ 40%, BCL2 ≥ 50% by immunohistochemistry);
• 6. Previously untreated patients;
• 7. Cardiac, hepatic, and renal function: creatinine /< 2 times the upper limit of normal (ULN); ALT (alanine aminotransferase)/AST (aspartate aminotransferase) /< 2.5 ULN; total bilirubin /< 2 ULN;
• 8. At least one measurable lesion;
• 9. Unable to tolerate standard CHOP regimen chemotherapy or unwilling to receive chemotherapy;
• 10. Adequate understanding and voluntary signing of the informed consent form. Exclusion Criteria：
• 1.Patients with central nervous system involvement at the time of onset; 2.Known human immunodeficiency virus (HIV) infection; 3.Pregnant or lactating women; 4.Other tumors requiring treatment; 5.Uncontrollable active infection; 6.Active hepatitis with HBV-DNA copy number not controlled within 2/*1000/mL despite antiviral treatment; 7.Inability to understand, comply with the study protocol, or sign the informed consent form.

Критерии исключения

Описание

This study is a multi-center, global, open-label, Phase 1b/2 clinical study, and it will be conducted at multiple study sites in several countries, including Japan, Korea, and Singapore, to reveal the safety, tolerability, dose limiting toxicity (DLT), maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D), pharmacokinetics (PK), and preliminary efficacy of BCV in patients with relapsed or refractory lymphoma and to assess the efficacy and safety of Brincidofovir (SyB V-1901, BCV) in patients with relapsed or refractory Extranodal Natural Killer/T-cell Lymphoma (ENKL).

This study consists of 2 parts and will enroll a total (maximum) of 43 male and female participants who meet the eligibility criteria (Phase 1b part: Up to 18 participants /[3 to 6 participants in each of the 3 cohorts/], Phase 2 part: 25 participants).

Критерии включения

• * Patients who are histopathologically diagnosed with ENKL based on the World Health Organization (WHO) Classification of Malignant Lymphoma 5th Edition (WHO-HAEM5) (can be enrolled in the Phase 1b part and the Phase 2 part) or patients diagnosed with EBV-positive nodal T- and NK-cell lymphoma (EBV + nTNKCL), nodal T-follicular helper cell lymphoma (nTFHcL) (including angioimmunoblastic T-cell lymphoma (AITL) as defined in the WHO Classification, 4th Edition), peripheral T-cell lymphoma not otherwise specified (PTCL, NOS), anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL) (e.g., DLBCL, NOS), or adult T-Cell Leukemia Lymphoma (ATLL) (can only be enrolled in the Phase 1b part)
• * Patients with relapsed or refractory lymphoma and previously treated with systemic chemotherapy (history of multidrug chemotherapy including L-asparaginase such as SMILE therapy for ENKL is mandatory) who are ineligible for other systemic therapies
• * Patients with the following Eastern Cooperative Oncology Group (ECOG) Performance Status (PS):
• * Phase 1b part: 0-1
• * Phase 2 part: 0-2

Критерии исключения

• * Patients with another active malignant tumor requiring treatment
• * Patients with NCI-CTCAE Grade 2 or higher diarrhea (increase of 4 or more bowel movements per day compared to usual number of bowel movements) within 7 days prior to starting the first dose of BCV
• * Graft-Versus-Host Disease (GVHD) patients requiring immunosuppressive agents
• * Patients with a history of Cidofovir intolerance
• * Patients with a history of being diagnosed with cirrhosis

Описание

This phase Ib trial tests the safety and effectiveness of epcoritamab in treating patients with post-transplant lymphoproliferative disorder (PTLD) that has come back after a period of improvement (relapsed) or has not responded to previous treatment (refractory). Epcoritamab, a bispecific antibody, binds to a protein called CD3, which is found on T cells (a type of white blood cell). It also binds to a protein called CD20, which is found on B cells (another type of white blood cell) and some lymphoma cells. This may help the immune system kill cancer cells. Giving epcoritamab may be safe and effective in treating patients with relapsed or refractory B-cell PTLD.

Критерии включения

• * Written informed consent obtained to participate in the study and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information to the sponsor, sites, and relevant study organizations.
• * Age ≥ 18 years at the time of consent.
• * Karnofsky scale ≥ 50% or Eastern Cooperative Oncology Group (ECOG) ≤ 2.
• * Histological evidence of B-cell PTLD (any histologic subtype) following solid organ transplantation; expresses CD20; with or without EBV association.
• * Treatment failure of immunosuppression reduction (ISR). NOTE: if ISR was deemed not feasible by treating physician, ISR treatment failure may be waived.
• * Treatment failure of rituximab or rituximab plus any concurrent or sequentially administered chemotherapy regimen.
• * Measurable disease of /> 1.5 cm in diameter and/or bone marrow involvement.
• * Subjects having undergone heart, lung, liver, kidney, pancreas, small intestine transplantation or a combination of the organ transplantations mentioned.
• * HIV infection is allowed if viral load is undetectable at time of enrollment, CD4+ count /> 200 cells/uL, and subject remains on anti-viral therapy.
• * Resolution of toxicities from prior therapy to a grade that does not contraindicate trial participation in the opinion of the investigator.
• * Expected survival greater than 60 days.
• * Absolute neutrophil count 1.0 ≥ x 10/^9/L.
• * Platelets 50 ≥ x 10/^9/L.
• * Creatinine clearance (mL/min) ≥ 30 mL/min - Cockcroft-Gault Equation.
• * Note: Hematology and other lab parameters that are ≤ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy.
• * Bilirubin ≤ 3.0 x upper limit of normal (ULN). Subjects with Gilbert`s syndrome may be enrolled despite a total bilirubin level /> 3.0 mg/dL if their conjugated bilirubin is ≤ 3.0 × ULN).
• * Note: Hematology and other lab parameters that are ≤ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy.
• * Aspartate aminotransferase (AST) ≤ 3.0 x ULN.
• * Note: Hematology and other lab parameters that are ≤ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy.
• * Alanine aminotransferase (ALT) ≤ 3.0 x ULN.
• * Note: Hematology and other lab parameters that are ≤ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy.
• * Females of childbearing potential must have a negative serum pregnancy test within 3 days prior to registration. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. Documentation of postmenopausal status must be provided.
• * Females of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 12 months after treatment the last dose of epcoritamab. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method or an intrauterine device.
• * Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 12 months after the last dose of epcoritamab.
• * Subjects with prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the experimental regimen are eligible for the trial.
• * Subject is willing and able to comply with study procedures based on the judgement of the investigator or protocol designee.

Критерии исключения

• * Uncontrolled active (symptomatic) infection. Patients requiring systemic therapy are eligible if the infection is deemed controlled by the investigator.
• * Post-transplant lymphoproliferative disorder following stem cell transplantation for hematologic malignancies or nonmalignant conditions.
• * Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study and lactating females must agree to not breastfeed while taking study drug).
• * Subjects with central nervous system (CNS) involvement by PTLD.
• * Seizure disorder requiring therapy (such as steroids or anti-epileptics).
• * Uncontrolled concomitant illness including, but not limited to, symptomatic congestive heart failure (New York Heart Association (NYHA) Class III or IV), unstable angina pectoris, myocardial infarction within 1 month prior to enrollment, uncontrolled cardiac arrhythmias, uncontrolled seizures, or severe non-compensated hypertension (systolic blood pressure /> 180mmHg or diastolic blood pressure /> 120mmHg).
• * History of progressive multifocal leukoencephalopathy.
• * Active Hepatitis B infection or Hepatitis C infection with positive viral polymerase chain reaction (PCR) from the blood. Subjects with active Hepatitis B infection and undetectable viral PCR from the blood will be allowed with concurrent use of entecavir suppression. Subjects with history of Hepatitis C infection (undetectable viral PCR) are allowed.
• * Electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant.
• * Any condition, including the presence of laboratory values which is deemed by the clinician to place the subject at an unacceptable risk or confounds the ability to interpret the data from this study.
• * Live virus vaccines must not be administered within 28 days of the start of study treatment.
• * Any investigational treatments must have been completed at least 4 weeks or 5 half-lives, whichever is shorter, prior to the start of study treatment. Investigational antibody therapies are not included in this requirement.

Описание

This is a phase I dose-finding trial of an autologous CD22 targeting chimeric antigen receptor (CAR)-T cell product, called CLIC-2201, for participants with relapsed/refractory B cell malignancies. In the proposed trial, eligible enrolled participants will undergo leukapheresis for autologous T cell collection to enable CLIC-2201 manufacturing, followed by lymphodepletion with cyclophosphamide and fludarabine, then intravenous infusion of the autologous CLIC-2201 product. The trial will use the 3+3 design to escalate or de-escalate the dose level of CLIC-2201 administered. Participants will be monitored for safety and tolerability up to day 365 following CLIC-2201 infusion.

The primary objective is to evaluate the safety and tolerability of CLIC-2201 and estimate the maximum tolerated dose (MTD) of CLIC-2201 in B-cell malignancies.

The secondary objectives are to evaluate the (i) feasibility; (ii) anti-tumour activity of CLIC-2201; (iii) and characterize the pharmacokinetic (PK) profile of CLIC-2201.

Exploratory objectives will include: i) characterizing the cellular and humoral immune responses against CLIC-2201 up to 1 year following infusion of CLIC-2201; (ii) characterizing the phenotype and gene expression profile of CLIC-2201 cells; (iii) evaluating immune and tumour cells at baseline and relapse for biomarkers of response or toxicity; (iv) evaluating serum cytokines, circulating tumour DNA (ctDNA) and B cell aplasia as biomarkers of clinical outcomes; and (v) assessing the quality of life.

Критерии включения

• in Cohort A:
• Participants must meet the following criteria to be enrolled on the trial:
• 1. Participants in the cohort A must be 18 years of age or older of age at time of informed consent.
• 2. Participants must provide written informed consent. The investigator is responsible for obtaining written informed assent/consent for the subject after adequate explanation of the study design, anticipated benefits and the potential risks. Subjects should sign the most current REB approved assent/consent prior to any study specific activity or procedure is performed. (Sites will follow their REB board requirements for consenting).
• 3. Participants must have a relapsed or refractory B cell lymphoma, including one of the following:
• 1. diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS),
• 2. high grade B cell lymphoma NOS,
• 3. high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,
• 4. primary mediastinal large B-cell lymphoma (PMBCL),
• 5. aggressive B cell lymphoma transformed from an indolent lymphoma,
• 6. mantle cell lymphoma (MCL),
• 4. Participants must have refractory or relapsed disease, defined as one of the following:
• 1. Relapse or refractory disease after at least 2 lines of therapy, OR
• 2. Any relapse after autologous or allogeneic hematopoietic cell transplantation (HCT), OR
• 3. Any relapse after CAR-T cell therapy.
• 5. Participants must have adequate organ function at enrolment, defined as:
• 1. Left ventricular ejection fraction (LVEF) ≥40%,
• 2. Creatinine clearance using Cockcroft-Gault of /> 30 mL/min, AND
• 3. ALP/ALT /< 5X upper limit of normal (ULN), conjugated bilirubin /< 2X ULN, and no evidence or history of liver cirrhosis.
• 6. Participants must have Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 or Karnofsky Score ≥50%.
• 7. Females of child-bearing potential and sexually active males must agree to use a highly effective contraception method (see section 5.4) through to at least one year following administration of the CLIC-2201 product.
• 8. Participants with accessible disease, willingness to undergo a tumour biopsy at enrolment. For participants with a recent (within 3 months) tumor biopsy, access to the archival biopsy is acceptable.
• Inclusion Criteria in Cohort B:
• 1. Participants in the cohort B must be between 1-21 years of age at the time of consent.
• 2. Parent or legal guardian of the participant signed the informed consent and the participant`s assent/consent is obtained (if applicable). The investigator is responsible for obtaining written informed assent/consent for the subject or legally acceptable representative (e.g. parent, legal guardian) after adequate explanation of the study design, anticipated benefits and the potential risks. Subjects should sign the most current REB approved assent/consent prior to any study specific activity or procedure is performed. (Sites will follow their REB board requirements for consenting).
• 3. Participants must have a relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL).
• 4. Participants must have refractory or relapsed disease, defined as one of the following:
• 1. Relapse or refractory disease after at least 2 lines of therapy, OR
• 2. Any relapse after autologous or allogeneic hematopoietic cell transplantation (HCT), OR
• 3. Any relapse after CAR-T cell therapy.
• 5. Participants in cohort B and/or those who have received CD22 targeted therapy must have documentation of CD22 tumour expression within the 6 months prior to study screening, and after any prior CD22 directed therapy (if applicable).
• 6. Participants must have adequate organ function at enrolment, defined as:
• 1. Left ventricular ejection fraction (LVEF) ≥45%,
• 2. Creatinine clearance using Cockcroft-Gault or Schwartz equation of /> 30 mL/min, AND
• 3. ALP/ALT /< 5X upper limit of normal (ULN), conjugated bilirubin /< 2X ULN, and no evidence or history of liver cirrhosis.
• 7. Participants must have a Karnofsky or Lansky Score ≥50%.
• 8. Participants in reproductive age must agree to use a highly effective contraception method (see section 5.4) through to at least one year following administration of the CLIC-2201 product.
• 9. Participants willingness to undergo a bone marrow biopsy at enrolment.

Критерии исключения

• 1. Any uncontrolled or serious active infection at the time of enrolment.
• 2. Active autoimmune disease requiring immunosuppressive therapy within 4 weeks of enrolment.
• 3. Live vaccine ≤6 weeks prior to enrolment
• 4. Active Graft Versus Host Disease (GVHD) requiring systemic immunosuppressive therapy within 4 weeks of enrolment.
• 5. Treatment with any of the following in the specified time period before leukapheresis:
• 1. Allogeneic HCT within 3 months,
• 2. Autologous HCT within 3 months,
• 3. CD19 CAR-T cell infusion within 3 months,
• 4. Donor lymphocyte infusion (DLI) within 3 months,
• 5. Bendamustine within the last 6 months,
• 6. Any investigational agent within 30 days or 5 half-lives (whichever is shorter),
• 7. Systemic administration of therapeutic dose corticosteroids (/>20 mg/day prednisone or equivalent for adults and ≥ 12 mg/m2/day for paediatric participants) within 7 days prior to leukapheresis.
• 8. Immunosuppressive therapies (i.e., calcineurin inhibitors, methotrexate, mycophenolate, rapamycin) within 4 weeks.
• 9. Oral chemotherapy agents (i.e., venetoclax) within 5 half-lives. An exception to this is that bruton tyrosine kinase (BTK) inhibitors like ibrutinib can be continued in participants with mantle cell lymphoma throughout the trial period.
• 6. Other concurrent malignancy or a prior malignancy treated within the past 2 years, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
• 7. Concomitant genetic syndrome associated with bone marrow failure such as Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure or immunodeficiency syndrome.
• 8. Active (confirmed by PCR) hepatitis B or hepatitis C at time of screening confirmed by PCR.
• 9. Any Human Immunodeficiency Virus (HIV) infection at time of screening.
• 10. Hypersensitivity to fludarabine or cyclophosphamide.
• 11. Any allergy to gentamycin or its derivatives
• 12. Pregnant or nursing participants.

Описание

To explore the application of HiR (Zebtorizumab, Lenalidomide) + X (targeted drug) guided by NGS molecular typing, the aim is to assess the therapeutic efficacy and safety in newly diagnosed unfit or frail elderly patients with DLBCL aged ≥70 years, and to investigate the genetic subtypes that may benefit from HiR-X.

Критерии включения

• 1. Age ≥ 70 years;
• 2. ECOG score 0-3;
• 3. Rated as "unfit" or "frail" on the simplified geriatric assessment (sGA);
• 4. Histologically confirmed CD20-positive diffuse large B-cell lymphoma /[diagnostic criteria according to WHO 2016/], excluding transformed type 2 DLBCL;
• 5. Previously untreated, newly diagnosed patients;
• 6. Cardiac, hepatic, and renal function: creatinine /< 2 times the upper limit of normal (ULN); ALT (alanine aminotransferase) / AST (aspartate aminotransferase) /< 2.5 x ULN; total bilirubin /< 2 x ULN;
• 7. At least one measurable lesion;
• 8. Intolerance to standard CHOP chemotherapy regimen or unwillingness to receive chemotherapy;
• 9. Sufficient understanding and voluntary signing of the informed consent form.

Критерии исключения

• 1. Patients with central nervous system involvement at the onset of the disease;
• 2. Known human immunodeficiency virus (HIV) infection;
• 3. Pregnant or lactating women;
• 4. Other tumors requiring treatment;
• 5. Uncontrolled active infection;
• 6. Active hepatitis with HBV-DNA copy number unable to be controlled within 2000/mL despite antiviral treatment;
• 7. Individuals who cannot understand, comply with the study protocol, or sign the informed consent form.

Описание

The purpose of this study is to evaluate if zilovertamab vedotin with standard treatment can help people live longer without the cancer growing or spreading than people who receive standard treatment alone.

Критерии включения

• * Has histologically confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL), by prior biopsy, based on local testing according to the WHO classification of neoplasms of the hematopoietic and lymphoid tissues
• * Has positron emission tomography (PET) positive disease at screening, defined as 4 to 5 on the Lugano 5-point scale
• * Has received no prior treatment for their DLBCL
• * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 assessed within 7 days before randomization
• * Has an ejection fraction ≥45% as determined by either echocardiogram (ECHO) or multigated acquisition (MUGA)
• * Human immunodeficiency virus (HIV) infected participants must have well controlled HIV on antiretroviral therapy (ART)
• * Who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy and have undetectable HBV viral load prior to randomization
• * Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening

Критерии исключения

• * Has a history of transformation of indolent disease to DLBCL
• * Has received a diagnosis of primary mediastinal B-cell lymphoma (PMBCL) or Grey zone lymphoma
• * Has Ann Arbor Stage I DLBCL
• * Has clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (/<6 months prior to enrollment), myocardial infarction (/<6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class ≥II), or serious cardiac arrhythmia requiring medication
• * Has clinically significant pericardial or pleural effusion
• * Has ongoing Grade />1 peripheral neuropathy
• * Has a demyelinating form of Charcot-Marie-Tooth disease
• * HIV-infected participants with a history of Kaposi`s sarcoma and/or Multicentric Castleman`s Disease
• * Has ongoing corticosteroid therapy
• * Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed
• * Known additional malignancy that is progressing or has required active treatment within the past 2 years
• * Known active central nervous system (CNS) lymphoma
• * Has active autoimmune disease that has required systemic treatment in the past 2 years
• * Has active infection requiring systemic therapy
• * Has concurrent active HBV (defined as HBsAg positive and detectable HBV DNA) and HCV (defined as anti-HCV antibody positive and detectable HCV ribonucleic acid (RNA)) infection
• * Has history of allogeneic tissue/solid organ transplant

Описание

The purpose of this study is to find out how many people with B-cell lymphoma who are at high risk for central nervous system/CNS relapse test positive for cerebral spinal fluid/CSF ctDNA but test negative for CNS involvement using standard tests. The study will also look at how often CNS relapse happens in people with and without detected CSF ctDNA.

Критерии включения

• * Signed Informed Consent.
• * Ability and willingness to comply with the requirements of the study protocol.
• * Age ≥ 18 years old.
• * Diagnosis of the following histologies according to the 2016 WHO Classification for Mature Lymphoid Neoplasms81 along with a specific high-risk criteria for CNS relapse if indicated as certain diagnoses in of themselves are high-risk alone:
• 1. Diffuse Large B-cell Lymphoma (DLBCL) with CNS IPI score ≥ 4.
• 2. Stage III/IV High Grade B-cell lymphoma (HGBCL) with MYC, BCL2, and/or BCL6 translocations
• 3. Primary DLBCL of Breast
• 4. Primary DLBCL of Testis
• 5. Primary Cutaneous DLBCL, Leg Type
• 6. Intravascular Large B-cell Lymphoma
• 7. Stage III/IV HIV-associated DLBCL
• 8. Double expressor DLBCL (co-expression of MYC ≥ 40% and BCL2 ≥ 50% without translocations) with a CNS IPI score ≥ 3
• 9. DLBCL with the following extranodal involvement AND CNS IPI score ≥ 3
• i. Adrenal ii. Breast iii. Bone Marrow with pathological overt morphological involvement iv. Epidural/Paraspinal v. Nasal/parasinus with local invasion such as bone destruction vi. Renal viii. Uterine
• * Transformed DLBCL from any indolent B-cell lymphoma is permitted (as long as there is no prior history of CNS involvement).
• * Planned to receive standard chemoimmunotherapy.
• * Patient is able to undergo lumbar puncture without any contraindications which include but are not limited to altered mental status, increased intracranial pressure due to any CNS lesion (mass, abscess), overlying skin infection at the site of LP, inability to safely access CSF due to lymphomatous involvement (i.e. epidural mass), or inability to hold antiplatelet or anticoagulation safely for the procedure to be performed.
• * No systemic therapy prior to study enrollment for an aggressive B-cell lymphoma is permitted. Treatment for a history of indolent lymphoma is permitted. Systemic corticosteroids are permitted (must be ≤7 days and tapered down to prednisone ≤ 20 mg oral/day or steroid equivalent by first day of anthracycline treatment). Clinical exceptions in regards to steroid management can be made after discussion with PI.
• * ECOG performance status of 0 to 2.

Критерии исключения

• * Active systemic therapy for another malignancy (other than indolent B-cell lymphoma) within 2 years; local/regional therapy with curative intent such as surgical resection or localized radiation within 2 years of treatment is permitted.
• * Active concurrent malignancy with the exception of basal cell or localized squamous cell skin carcinoma, localized prostate cancer, or other localized carcinomas such as carcinoma in situ of cervix, breast, or bladder.
• * Any uncontrolled illness that in the opinion of the investigator would preclude administration of curative intent chemoimmunotherapy (e.g. significant active infections, hypertension, angina, arrhythmias, pulmonary disease, or autoimmune dysfunction).
• * Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 2 weeks prior to Cycle 1, Day 1.
• * Psychiatric illness or social situations that would limit the patient`s ability to tolerate and/or comply with study requirements.

Описание

This is a prospective, single-arm, open-label phase II clinical trial that evaluates the efficacy and safety of CR-CHOP regimen combined with different targeted drugs based on different molecular subtypes in newly diagnosed DEL patients.

Критерии включения

• * 1. Histologically confirmed diffuse large B-cell lymphoma with CD20 positive;
• * 2. MYC and BCL2 are expressed simultaneously, WHO immunohistochemical standards: MYC≥40%, BCL2 ≥50%;
• * 3. Age ≥ 18 years old, ≦75 years old;
• * 4. ECOG physical status score of 0, 1 or 2;
• * 5. No previous history of malignant tumors; No other tumors occurred simultaneously;
• * 6. Patients judged by the investigator to have a life expectancy of at least 6 months;
• * 7. The patient or his legal representative must provide written informed consent prior to any research special examination or procedure;
• * 8. International prognostic Index (IPI) />1 score.

Критерии исключения

• * 1. Have previously received systemic or local treatment including chemotherapy;
• * 2. Previously received autologous stem cell transplantation;
• * 3. Previous history of other malignant tumors, except skin basal cell carcinoma and cervical carcinoma in situ;
• * 4. Accompanied by uncontrolled cardiovascular and cerebrovascular diseases, coagulation disorders, connective tissue diseases, serious infectious diseases and other diseases;
• * 5. Primary central nervous system lymphoma;
• * 6. Left ventricular ejection fraction ≤ 50%;
• * 7. Laboratory test values at the time of screening (unless due to lymphoma): A. Neutrophils /<1.5/*109/L; B. Platelet /<75/*109/L; C. ALT or AST were 2 times higher than the upper limit of normal, AKP and bilirubin were 1.5 times higher than the upper limit of normal; D. Creatinine levels higher than 1.5 times the upper limit of normal;
• * 8. Other concurrent and uncontrolled medical conditions that the investigator believes will affect patient participation in the study;
• * 9. Patients with mental illness or other patients known or suspected to be unable to fully comply with the study protocol;
• * 10. Pregnant or lactating women;
• * 11. People living with HIV;
• * 12. Patients with positive HbsAg test results need to undergo HBV DNA test, and can be enrolled before turning negative. In addition, if the HBsAg test result is negative, but the HBcAb test is positive (regardless of the HBsAb status), HBV DNA test should also be performed. If the result is positive, the treatment should also be negative before admission.

Описание

The purpose of this study is to 1) determine whether it is feasible to measure circulating tumor DNA (ctDNA) in real-time during standard treatment for newly diagnosed diffuse large B-cell lymphoma (DLBCL), and 2) evaluate the outcomes of participants with undetectable ctDNA in the middle of treatment who receive a shortened course of chemotherapy.

There are no investigational drug agents to be administered in this study. The investigational assay, phased variant enrichment and detection sequencing (PhasED-seq) will be used to guide de-escalation of standard-of-care therapy for newly diagnosed DLBCL.

The PhasED-seq assay has not yet been approved by the Food and Drug Administration (FDA).

Критерии включения

• 1. Patients with newly diagnosed, histologically confirmed CD20+ DLBCL
• * Stage II-IV disease
• * Planned for anthracycline-based therapy with standard dosed R-CHOP or R-pola- CHP without consolidative radiation
• * Measurable disease on cross sectional imaging ≥ 1.5 cm in longest diameter and measurable in two perpendicular dimensions, with at least one corresponding hypermetabolic lesion by Lugano classification on baseline FDG PET/CT or CT with intravenous contrast of the chest, abdomen, and pelvis if FDG PET/CT not available.
• 2. Age 18 years or older at time of screening
• 3. Subject/legal representative willing and able to provide written informed consent
• 4. Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for duration of study participation
• 5. Organ function as assessed by laboratory and cardiac function testing and Eastern Cooperative Oncology Group (ECOG) performance status in appropriate range for receipt of R-CHOP or R-pola-CHP at standard dose as per treating physician

Критерии исключения

• 1. Previous treatment for diffuse large B-cell lymphoma, except as outlined below:
• * Up to 14 days of corticosteroids for the relief of lymphoma-related symptoms
• * A dose of pre-phase vincristine or rituximab
• * One cycle of R-chemotherapy (including but not limited to R-CHOP, R-pola-CHP, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab /[DA-EPOCH-R) that has not started more than 28 days prior to consent
• * Intrathecal chemotherapy for central nervous system (CNS) prophylaxis
• * Radiation therapy for the treatment or prevention of spinal cord compression that has not started more than 28 days prior to enrollment
• 2. Simultaneous participation in other treatment clinical protocol
• 3. Planned anti-lymphoma therapies beyond R-CHOP or R-pola-CHP:
• * Consolidative radiation to any baseline sites of disease
• * Planned high-dose intravenous methotrexate for central nervous system (CNS) lymphoma prophylaxis (both mid-cycle and EOT excluded)
• * Any number of doses of intrathecal chemotherapy for CNS lymphoma prophylaxis are allowed
• 4. Transformed indolent lymphoma (including follicular lymphoma, marginal zone lymphoma, or lymphoplasmacytic lymphoma) or grade IIIB follicular lymphoma
• 5. Known CNS involvement by lymphoma. R-CHOP and R-pola- CHP are insufficient to treat CNS disease.
• 6. Any disease characteristics that would make R-CHOP or R-pola-CHP without radiation insufficient therapy at the discretion of the treating physician
• * High-grade B-cell lymphoma with rearrangement of MYC and BCL2, primary mediastinal B-cell lymphoma, and HIV-associated lymphomas are excluded
• 7. Richter transformation of chronic lymphocytic leukemia
• 8. Pregnancy and/or nursing period. R-CHOP and R-pola-CHP may cause fetal harm or birth defects, and effects of exposure in the breastfed infant are unknown.
• * A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "childbearing potential"
• * Women of childbearing potential are eligible if a negative serum or urine beta human chorionic gonadotropin pregnancy test is documented within 28 days of screening, and they must agree to us an effective contraception method during systemic treatment
• * Men who have partners of childbearing potential must agree to use an effective contraceptive method during systemic treatment
• * In addition to routine contraceptive methods, "acceptable contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen.
• 9. Uncontrolled active systemic infection
• * Patients with a positive hepatitis B virus (HBV) core antibody and negative HBV surface antigen consistent with prior HBV exposure must be willing to take appropriate anti-viral prophylaxis.
• * Patients with evidence of chronic HBV infection must have undetectable HBV viral load on the most recent test results obtained within the last year and received suppressive therapy.
• * Participants with a history of hepatitis C virus (HCV) infection must have an undetectable viral load. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 28 days prior to consent.
• 10. Active second malignancy unless in remission and with life expectancy /> 2 years with exception of patients diagnosed with basal cell or squamous cell carcinoma of the skin or carcinoma "in situ" of the cervix or breast who are eligible even if diagnosed within 2 years. If patients have another malignancy that was treated within the last 2 years, such patients may be enrolled, if the likelihood of requiring systemic therapy for this other malignancy within 2 years is less than 10%, as determined by an expert in that particular malignancy at CUIMC, and after consultation with the Principal Investigator. Hormone therapy for treated prostate and breast cancer is allowed.
• 11. Known hypersensitivity to any component of R-CHOP or R-pola-CHP

Описание

Non-Hodgkin`s lymphoma (NHL) is a cancer that arises from the transformation of normal B and T lymphocytes (white blood cells). The purpose of this study is to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of ABBV-291 in adult participants in relapsed or refractory (R/R) NHL, including but not limited to diffuse large b-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL). Adverse events will be assessed.

ABBV-291 is an investigational drug being developed for the treatment of NHL. This study will include a dose escalation phase to determine the maximum administered dose (MAD)/Maximum tolerated dose (MTD) of ABBV-291 and a dose expansion/optimization phase to determine the change in disease activity in participants with R/R NHL. Approximately 165 adult participants with multiple NHL subtypes will be enrolled in the study in sites world wide

In the dose escalation phase of the study participants will receive escalating Intravenously (IV) infused doses of ABBV-291, until the MAD/MTD is determined. In the dose expansion/optimization phase of the study participants receive IV infused ABBV-291, as part of the approximately 74 month study duration.

There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at an approved institution (hospital or clinic). The effect of the treatment will be frequently checked by medical assessments, blood tests, and side effects.

Критерии включения

• * For dose escalation (Part 1) only: Participants must have documented diagnosis of B-cell malignancies including (but not limited to) the following, with histology based on criteria established by the World Health Organization (WHO), and measurable disease requiring treatment:
• * Mantle cell lymphoma (MCL);
• * Marginal zone lymphoma (MZL);
• * Waldenstrom macroglobulinemia (WM);
• * Diffuse large b-cell lymphoma (DLBCL) (including: germinal center B-cell type, activated B-cell type, primary cutaneous DLBCL /[leg type/], Epstein-Barr virus-positive (EBV+) DLBCL /[not otherwise specified/], DLBCL associated with chronic inflammation, human herpesvirus 8-positive /[HHV8+/] DLBCL /[not otherwise specified/], B cell lymphoma /[unclassifiable/] with features intermediate between DLBCL and classical Hodgkin lymphoma, high-grade B-cell lymphoma /[not otherwise specified/], high-grade B-cell lymphoma /[with MYC (avian myelocytomatosis viral oncogene homolog) and BCL2 and/or BCL6 rearrangements/], DLBCL arising from follicular lymphoma /[FL/] /[transformed FL/]);
• * FL Grades 1 to 3B;
• * For dose expansion (Part 2) only: Participants must have documented diagnosis of one of the following B-cell malignancies, with histology based on criteria established by the WHO, and measurable disease requiring treatment:
• * Part 2a only: DLBCL (including: germinal center B-cell type, activated B-cell type, primary cutaneous DLBCL /[leg type/], EBV+ DLBCL /[not otherwise specified/], DLBCL associated with chronic inflammation, HHV8+ DLBCL /[not otherwise specified/], B-cell lymphoma /[unclassifiable/] with features intermediate between DLBCL and classical Hodgkin lymphoma, high-grade B-cell lymphoma /[not otherwise specified/], high-grade B-cell lymphoma /[with MYC and BCL2 and/or BCL6 rearrangements/], DLBCL arising from FL /[transformed FL/]);
• * Part 2b only: FL Grades 1 to 3B;
• * Part 2c only: Mantle cell lymphoma;
• * For all participants (Parts 1 and 2):
• * Must be considered relapsed or refractory to, or intolerant of, at least 2 or more prior lines of therapy known to provide a clinical benefit for their condition, and for whom there is no appropriate locally available therapy known to provide clinical benefit (e.g., standard chemotherapy or autologous stem cell transplantation /[ASCT/]).
• * Indolent non-Hodkin`s lymphoma (NHL) participants must meet relevant disease specific requirements for treatment (e.g., National Comprehensive Cancer Network /[NCCN/], Groupe d`Etude des Lymphomes Folliculaires /[GELF/]).
• * History of allogeneic stem cell transplantation must be stable off of immunosuppression for at least 3 months.
• * For participants enrolled in backfill cohorts or at dose levels previously cleared, subjects must provide consent to an on-treatment fresh tumor biopsy from the same tumor lesion as the baseline tumor tissue. This requirement may be waived at the discretion of the contract research organization (CRO) Medical Monitor if collecting a biopsy would place the subject at risk of harm or would require a technically complicated procedure based on tumor location as assessed by the investigator or could hinder a subject`s ability to participate in the study.
• * Previously treated with a CD79b-targeting therapy (e.g., CD79b monoclonal antibody) a core or excision tumor biopsy subsequent to the most recent CD79b-targeting therapy must be collected. Tumor biopsy requirements may be modified by Sponsor during the study. This requirement may be waived at the discretion of the contract research organization (CRO) Medical Monitor if collecting a biopsy would place the subject at risk of harm or would require a technically complicated procedure based on tumor location as assessed by the investigator or could hinder a subject`s ability to participate in the study.
• * CD79b expression status will be assessed in all participants.
• * Have an eastern cooperative oncology group (ECOG) Performance Status of 0 or 1.
• * Laboratory values meeting the criteria in the protocol within the screening period prior to the first dose of study drug (if multiple samples are drawn within the screening period, the sample/result immediately prior to Cycle 1 Day 1 is applicable).
• * Availability of representative baseline tumor tissue (most recent archived tumor tissue or fresh biopsy collected during screening phase) suitable for immunohistochemistry (IHC) testing. This requirement may be waived at the discretion of the CRO Medical Monitor if collecting a biopsy at screening would place the participant at risk of harm or would require a technically complicated procedure based on tumor location as assessed by the investigator or could hinder a participant`s ability to participate in the study.

Критерии исключения

• * History of interstitial lung disease (ILD) or pneumonitis that required treatment with systemic steroids, or any evidence of active ILD or pneumonitis.
• * Treatment with any of the following:
• * Anticancer therapy including chemotherapy, radiotherapy, small molecule, investigational, and biologic agents within 14 days (or at least 5 half-lives, whichever is shorter), prior to the first dose of the study treatment;
• * CD79b-directed agents (e.g., CD79b monoclonal antibody therapy) within 4 weeks (or at least 5 half-lives, whichever is shorter) prior to the first dose of study treatment.
• * Prior treatment with an antibody drug conjugate that consists of a topoisomerase I inhibitor.

Описание

This is a Phase 1/2, first-in-human, open-label, dose-escalating trial designed to assess the safety and efficacy of VNX-101 in patients with relapsed or refractory CD19-positive hematologic malignancies.

Критерии включения

• * Age: Part 1: 18-90 years of age, Part 2: 13-90 years of age
• * Relapsed or refractory CD-19 positive leukemia or lymphoma as defined in the protocol
• * CD19-positive expression
• * AAV specified capsid total antibody /<1:400
• * Protocol-specified ranges for renal, liver, cardiac and pulmonary function
• * Protocol-specified ranges for hematology parameters

Критерии исключения

• * Hepatoxicity (AST or ALT /> 2x upper limit of normal)
• * History of thrombotic microangiopathy or cardiomyopathy, or evidence of sensory neuropathy
• * Pregnant or nursing (lactating) women
• * Acute Graft versus Host Disease (GvHD): Grade 2-4 or chronic GvHD of any grade
• * History of hypersensitivity to corticosteroids or history of corticosteroid-related toxicity
• * Chemotherapy given within the protocol-specified discontinuation timelines
• Other Inclusion/Exclusion criteria to be applied per protocol.

Описание

This is an open-label, randomized (1:1), multi-center trial of epcoritamab (GEN3013; DuoBody®-CD3xCD20) versus prespecified investigator`s choice of chemotherapy in patients with relapsed, refractory diffuse large B-Cell Lymphoma

Критерии включения

• Main Inclusion Criteria:
• Relapsed or refractory disease and previously treated with at least 1 line of systemic antineoplastic therapy including anti-CD20 mAb-containing combination chemotherapy since lymphoma diagnosis
• One of the confirmed histologies below with CD20-positivity:
• DLBCL, NOS, including de novo or histologically transformed from FL
• "Double-hit" or "triple-hit" DLBCL (technically classified in WHO 2016 as HGBCL, with MYC and BCL2 and/or BCL6 translocations), including de novo or histologically transformed from FL
• FL Grade 3B
• ECOG PS score of 0-2
• Failed previous HDT-ASCT or not eligible for HDT-ASCT at screening
• Patients must have detectable disease by PET scan and measurable by CT scan or MRI
• Acceptable renal and liver function
• Life expectancy >2 months on SOC treatment

Критерии исключения

• Main Exclusion Criteria:
• Primary CNS tumor or known CNS involvement
• Any prior therapy with a bispecific antibody targeting CD3 and CD20
• Major surgery within 4 weeks prior to randomization
• Chemotherapy and other non-investigational antineoplastic agents (except CD20 mAbs) within 4 weeks or 5 half-lives (whichever is shorter) prior to randomization
• Any investigational drug within 4 weeks or 5 half-lives, whichever is longer, prior to randomization
• ASCT within 100 days of randomization
• Treatment with CAR-T therapy within 100 days prior to randomization
• Seizure disorder requiring anti-epileptic therapy
• Clinically significant cardiac disease,