OncoTrials - мониторинг клинических исследований

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. 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.
• * At high risk for CNS relapse 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.
• * Will 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 participation, and for 6 months after completion of study participation (for women) and 12 months after completion of study participation (for men). Should a woman become pregnant or suspect she is pregnant while participating in this study 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.
• * Diagnosis of primary CNS lymphoma.
• * Diagnosis of secondary CNS involvement at baseline.
• * 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 of study entry.

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 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

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

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

This research study involves assessing the impact of emapalumab as preventative management of CAR-T related cytokine release syndrome in participants with Non-Hodgkin`s lymphoma (NHL).

The research study involves the following study interventions:

* Fludarabine and cyclophosphamide (Lymphodepleting Chemotherapy)
* Axicabtagene Ciloleucel
* Emapalumab

Критерии включения

• * Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. Or adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
• * At least 1 measurable lesion per Lugano at time of screening.
• * At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy however steroids only require a 7-day washout.
• * At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy at the time the subject is planned for leukapheresis (e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists, etc).
• * Age 18 or older
• * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• * Adequate renal, hepatic, pulmonary and cardiac function defined as:
• * ANC ≥1000/uL
• * Platelet count ≥50,000/uL
• * Absolute lymphocyte count ≥100/uL
• * Creatinine clearance (as estimated by Cockcroft Gault or CKD-EPI) ≥ 30 mL/min
• * Serum ALT/AST ≤2.5 per institutional ULN
• * Total bilirubin ≤1.5 mg/dl, except in subjects with Gilbert`s syndrome.
• * Cardiac ejection fraction ≥ 40%, no clinically significant pericardial effusion, and no clinically significant ECG findings
• * Baseline oxygen saturation />92% on room air.
• * Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential).
• * Ability to understand and the willingness to sign a written informed consent document.

Критерии исключения

• * History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years.
• * History of Richter`s transformation of CLL.
• * Autologous stem cell transplant within 6 weeks of planned axicabtagene ciloleucel infusion.
• * History of allogeneic stem cell transplantation.
• * Presence of uncontrolled fungal, bacterial, viral, or other infection at time of screening.
• * Known history of acute or chronic active hepatitis B or C infection. Subjects with history of hepatitis infection must have cleared their infection as determined by standard serological and genetic testing per current Infectious Diseases Society of America (IDSA) guidelines.
• * Patients should also be negative for latent Tb, CMV (NAT), EBV (NAT) and adenovirus (NAT) by PCR testing.
• * No evidence of active CNS disease regardless of prior CNS history.
• * History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage within 6 months of enrollment.
• * History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment.
• * History of symptomatic pulmonary embolism within 3 months of enrollment; ongoing anticoagulation is allowed if beyond 3 months.
• * Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.
• * History of allergic reactions or severe immediate hypersensitivity reaction to any of the agents used in this study or compounds of similar chemical or biologic composition.
• * Females who are pregnant or breastfeeding or female or male participants who are not willing to practice birth control from the time of consent through 6 months after the completion of axicabtagene ciloleucel
• * In the investigators judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation.
• * History of autoimmune disease requiring ongoing systemic immunosuppression. Steroids are allowed up to 5mg predinosine-equivalent for adrenal insufficiency.
• * Patients anticipated to require canakinumab, JAK inhibitors, TNF inhibitors, and tocilizumab for non-CAR-T management of baseline autoimmune/inflammatory disease at the time of emapalumab initiation.
• * Receipt of a BCG vaccine within 12 weeks prior to Screening.
• * Receipt of a live or attenuated live (other than BCG) vaccine within 4 weeks prior to screeing.
• * Participants who are receiving any other investigational agents for this condition.

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 Phase 2 global, multi-center, open-label study to assess the efficacy, safety and tolerability of AZD0486 monotherapy in adult participants with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) who have received at least two prior lines of therapies. The study has 2 Modules: Module 1 for FL and Module 2 for DLBCL.

Критерии включения

• 1. Key Inclusion Criteria:
• * Aged 18 to 80 years old
• * Histologically confirmed relapsed refractory FL (Module 1) and DLBCL (Module 2) after at least 2 prior lines of therapy
• * ECOG performance status 0 to 2
• * Locally confirmed CD-19 expression in lymphoma cells after progression from last CD 19 directed therapy
• * FDG-avid disease with at least one bi-dimensionally measurable nodal lesion (defined as /> 1.5 cm in its longest dimension), or extranodal lesion (defined as /> 1.0 cm in its longest dimension)
• * Adequate hematological function: ANC ≥ 1000/mm3, platelets
• * 75,000/mm3, hemoglobin ≥ 9 g/dL. Transfusion and/or growth factor are allowed but counts must be stable for at least 72 hours afterwards prior to screening
• * Adequate liver function: total bilirubin /<1.5x ULN, AST/ALT ≤ 3xULN Note: Patients with documented history of Gilbert`s Syndrome and in whom total bilirubin elevations are accompanied by elevated indirect bilirubin are eligible)
• * Adequate renal function: creatinine clearance (CrCl) of ≥ 45 mL/min
• The above is a summary, other inclusion criteria details may apply.
• 2.

Критерии исключения

• * Diagnosis of CLL, Burkitt lymphoma, or Richter`s transformation
• * Active CNS involvement by B-NHL
• * Leukemic presentation of B-NHL
• * History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson`s disease, cerebellar disease, organic brain syndrome, or psychosis
• * Prior therapy with T-cell engager (TCE) within 8 weeks, CAR T- cell therapy or autologous Hematopoietic Stem Cell Transplantation (HSCT) within 12 weeks, or prior allogeneic HSCT within 24 weeks of first dose of AZD0486
• * Requires chronic immunosuppressive therapy
• * Unresolved non hematological AEs ≥ Grade 2 from prior therapies; history of ≥ Grade 3 CRS or neurotoxicity from prior CAR-T or TCE therapy
• * History of major cardiac abnormalities.
• * If female, participant must not be pregnant or breastfeeding.
• The above is a summary, other exclusion criteria details may apply.

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 goal of this study is to evaluate the efficacy of HMPL-760 in combination with R-GemOx versus placebo in combination with R-GemOx in patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL).

Критерии включения

• 1. Sign the Informed consent form(ICF) and be able to follow the requirements of study protocol;
• 2. Age ≥18 years;
• 3. Eastern Cooperative Oncology Group (ECOG) performance status between 0 and 2;
• 4. Histopathologically confirmed diagnosis of DLBCL;
• 5. The investigator judges that the patient`s current condition requires further treatment;
• 6. Patients should have at least one bi-dimensionally measurable lesion;
• 7. Expected survival is more than 12 weeks

Критерии исключения

• 1. Patients with known primary or secondary central nervous system lymphoma (CNSL) or the presence of clinical symptoms suggestive of CNSL;
• 2. Women who are pregnant (positive pregnancy test during the screening period) or breastfeeding;
• 3. Organ insufficiency;
• 4. Currently known history of liver disease, including cirrhosis, alcoholic liver, known active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV):
• 5. History of significant organ bleeding, including gastrointestinal bleeding, hematencephalon, haemoptysis, etc., within 8 weeks prior to the first dose of study drug;
• 6. Known risk of bleeding, such as coagulation factor deficiency, vascular hemophilia; or the patient is receiving vitamin K antagonist (warfarin);
• 7. Toxicities from prior anticancer therapy not resolved to Grade ≤ 1 (except for alopecia and decreased appetite);
• 8. Clinically significant active infection

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

The objective of this study is to evaluate the efficacy and safety of the Glofitamab bridging ASCT regimen in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and to provide better clinical benefits to these patients.

Критерии включения

• 1. Patients with diffuse large B-cell lymphoma (DLBCL) confirmed by histopathology/cytology using the 2022 World Health Organization (WHO) Classification of Diseases;
• 2. Patients with R/R DLBCL who have received at least two lines of systemic treatment;
• 3. Age range: 18-70 years old, male or female not limited;
• 4. When the disease recurs or is difficult to treat, there are assessable lesions (lymph node diameter ≥ 1.0cm; or skin lesions assessable by physical examination);
• 5. Expected lifespan/>3 months;
• 6. No previous transplantation treatment has been performed;
• 7. ECOG score 0-1 points;
• 8. Appropriate organ function:
• Cardiac function: ejection fraction ≥ 50%, asymptomatic arrhythmia; Liver function: alanine aminotransferase and aspartate aminotransferase ≤ 2 times the upper limit of normal, total bilirubin/<2 times the upper limit of normal; Renal function: serum creatinine clearance rate ≥ 80 mL/min, creatinine/<160 umol/l; Pulmonary function: Without oxygen inhalation, SPO2/>90%, FEV1, FVC, and DLCO ≥ 50% predicted values;
• 9. Adequate bone marrow reserve is defined as:
• Hemoglobin ≥ 9g/dL, Platelet count ≥ 70 × 10 /^ 9/L, The absolute value of neutrophils is ≥ 1.0 × 10 /^ 9/L, If accompanied by bone marrow invasion, platelet count ≥ 50 × 10 /^ 9/L, absolute neutrophil count ≥ 0.75 × 10 /^ 9/L, The number of CD34+cells is ≥ 2.0 × 109/kg.
• 10. The patient has the ability to understand and is willing to provide written informed consent.
• 11. Subjects with fertility or potential for fertility must be willing to undergo contraception from the date of registration in this study until the study follow-up period.

Критерии исключения

• -1) Previously underwent autologous hematopoietic stem cell transplantation; 2) HIV infection and/or active hepatitis B or C; 3) Uncontrolled active infections; 4) Severe liver and kidney dysfunction (alanine aminotransferase, bilirubin, creatinine/>3 times the upper limit of normal); 5) Existence of organic heart disease or severe arrhythmia, leading to clinical symptoms or abnormal heart function (NYHA functional class ≥ 2); 6) Simultaneously present other tumors that require treatment or intervention; 7) Previous or current history of vascular embolism; 8) Pregnant or lactating women; 9) In a state of severe immune suppression; 10) Other psychological conditions that hinder patients from participating in research or signing informed consent forms.
• 11) According to the researcher`s assessment, it is unlikely that the subjects will complete all the required study visits or procedures, including follow-up visits, or meet the requirements for participation in the study.

Описание

A Prospective Clinical Study of the Combination Therapy of Obutinib or Decitabine with Rituximab, Cyclophosphamide, and Prednisone for the Primary Treatment of Elderly Patients with newly Diagnosed Diffuse Large B-cell Lymphoma

Критерии включения

• 1. Individuals aged 65 years or older who are intolerant to chemotherapy, regardless of gender;
• 2. ECOG 0-1； IPI score ≤ 3 points;
• 3. Expected survival period of more than 3 months;
• 4. DLBCL diagnosed by tissue biopsy pathology;
• 5. No contraindications for chemotherapy (blood and physiological examination results within 7 days), absolute neutrophil count ≥ 1.0 × 10 /^ 9/L, PLT ≥ 75 × 10 /^ 9/L, hemoglobin ≥ 80g/L (excluding patients with lymphoma bone marrow infiltration);
• 6. According to the RECIST criteria, there must be at least one measurable lesion. For intranodal lesions, it is defined as: long diameter ≥ 1.5cm and short diameter ≥ 1.0cm; For extranodal lesions, the length and diameter should be ≥ 1.0cm;
• 7. Liver function: TBIL ≤ 1.5 × ULN; ALT or AST ≤ 2.5 × ULN; Non bone invasive patients with alkaline phosphatase ≤ 3 × ULN;
• 8. Renal function: serum creatinine ≤ 1.5 × ULN;
• 9. No other serious illnesses that conflict with this plan;
• 10. Excluding other major illnesses, the heart function is normal;
• 11. There are no other related treatments including traditional Chinese medicine (anti-tumor effects), immunotherapy, or biologic therapy (except for treatment of bone metastasis and other symptoms);
• 12. The subjects voluntarily participate in the clinical trial, sign an informed consent form, and cooperate with follow-up;
• 13. During this treatment period, if other anti-tumor drugs are not used simultaneously, bisphosphonates can be used for bone metastasis treatment and other symptomatic treatments

Критерии исключения

• 1. Clear patients with neurological or psychiatric disorders, including dementia or seizures, a history of abuse of psychotropic drugs that cannot be quit, or other substantial lesions that may increase central neurotoxicity;
• 2. Individuals who are currently participating in other clinical trials or have participated in other clinical studies within the first 4 weeks of enrollment (excluding those who have not received treatment);
• 3. Systemic autoimmune diseases or immunodeficiency;
• 4. Refusing to collect blood samples;
• 5. Allergic to any medication in the plan;
• 6. Pregnant and lactating women;
• 7. Major diseases that can cause experimental interference and uncontrolled active infections;
• 8. Primary or secondary central tumors;
• 9. Chemotherapy contraindications;
• 10. Within 28 days of using Rituximab/Obutinib/Compound Cyclophosphamide Tablets/Azacitidine;
• 11. Researchers believe that it is not suitable for inclusion;
• 12. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infections (excluding nail bed skin fungal infections) or any major systemic infection requiring intravenous antibiotic treatment or hospitalization within the 4 weeks prior to enrollment (excluding tumor fever);
• 13. Apply other anti-tumor treatments (such as radiotherapy, chemotherapy, hormone therapy, biotherapy, immunotherapy);
• 14. Other serious diseases that may restrict the subjects from participating in the test, such as uncontrollable diabetes; Severe heart failure (NYHA grade II or above); Acute coronary syndrome has occurred within the past 6 months; Coronary revascularization such as stent implantation, coronary artery bypass surgery, and other heart and large vessel related surgeries within the past 6 months; Severe arrhythmias include frequent premature ventricular contractions, ventricular tachycardia, rapid atrial fibrillation/flutter, and severe bradycardia. Uncontrolled hypertension: systolic blood pressure/>150mmHg, diastolic blood pressure/>100mmHg. Gastric ulcer (determined by researchers to have a risk of perforation); Active autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren`s syndrome, autoimmune thrombocytopenia, etc.); Severe respiratory diseases (such as obstructive pulmonary disease and history of bronchospasm), etc;
• 15. Individuals with bloodthirsty cell syndrome;
• 16. Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) is positive and the detection of hepatitis B virus (HBV) DNA titer in peripheral blood is not within the normal reference value range; Individuals with positive hepatitis C virus (HCV) antibodies and positive hepatitis C virus (HCV) RNA in peripheral blood; Individuals who are HIV antibody positive; Individuals who test positive for Cytomegalovirus (CMV) DNA; Individuals who test positive for syphilis.

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

To prospectively evaluate the efficacy and safety of large fraction radiation therapy combined with granulocyte-macrophage colony-stimulating factor, lenalidomide, and glofitamab monoclonal antibody in the treatment of refractory relapsed diffuse large B-cell lymphoma patients

Критерии включения

• 1. Written informed consent must be obtained before any trial-related procedures are implemented.
• 2. Participants must be aged 18 or older, of any gender, with an expected survival period of more than 3 months.
• 3. ECOG PS score must be between 0-3.
• 4. Participants must have histopathologically confirmed diffuse large B-cell lymphoma.
• 5. Patients who have failed first-line standard treatment due to primary resistance, short-term progression (within 1 year after the end of treatment), and second-line standard treatment.
• 6. Participants must not have received bispecific antibody therapy in the past.
• 7. B-cell non-Hodgkin`s lymphoma must have at least one measurable lesion according to RECIST1.1 criteria.
• 8. Participants must have sufficient organ function, meeting the following:
• laboratory criteria: (1) Total bilirubin ≤1.5× upper limit of normal (ULN); (2) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5× ULN; (3) Blood creatinine ≤1.5× ULN and creatinine clearance rate (calculated using the Cockcroft-Gault formula) ≥60 ml/min; (4) Good coagulation function, defined as an international normalized ratio (INR) or prothrombin time (PT) ≤1.5 times ULN.
• 9. For women of childbearing potential, a urine or serum pregnancy test must be conducted within 3 days before the first administration of the study drug (Day 1 of Cycle 1) and the results must be negative. If the results of the urine pregnancy test cannot be confirmed as negative, a blood pregnancy test is required. Non-childbearing women are defined as those who have been menopausal for at least 1 year, or who have undergone surgical sterilization or hysterectomy.
• 10. If there is a risk of pregnancy, all participants (both male and female) must use contraception with an annual failure rate of less than 1% throughout the treatment period and for 120 days after the last administration of the study drug (or 180 days after the last chemotherapy administration).

Критерии исключения

• 1. B-cell non-Hodgkin`s lymphoma with loss of CD20 expression.
• 2. Acute or chronic active Hepatitis B or C infection, Hepatitis B virus (HBV) DNA/>2000IU/ml or 104 copies/ml; Hepatitis C virus (HCV) RNA/>103 copies/ml; simultaneous positivity for Hepatitis B surface antigen (HbsAg) and anti-HCV antibody.
• 3. Participants with central nervous system metastasis can be included if they are asymptomatic or if their disease is controlled and stable for ≥4 weeks after treatment for any symptoms.
• 4. Participants have received anti-hematologic malignancy treatment within 2 weeks before the start of treatment or within 5 half-lives of the drug, whichever is longer.
• 5. Bone marrow insufficiency defined by platelet count /<30 x 109/L or absolute neutrophil count /<1.0 x 109/L.
• 6. Participants with clinically significant pulmonary disease, including (1) participants with chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) /<50% of the predicted normal value. Note that participants suspected of having COPD need to undergo an FEV1 test, and if FEV1/<50% of the predicted normal value, the participant must be excluded. (2) Participants with moderate or severe persistent asthma in the past 2 years, or currently have any category of uncontrolled asthma. (Note that participants currently with controlled intermittent asthma or controlled mild persistent asthma can participate in this study).
• 7. Uncontrolled hypertension, with systolic blood pressure />150mmHg or diastolic blood pressure />90mmHg after optimal medical treatment, history of hypertensive crisis or hypertensive encephalopathy.
• 8. Symptomatic congestive heart failure (New York Heart Association class II-IV). Symptomatic or poorly controlled arrhythmias. History of congenital long QT syndrome or a corrected QTc />500ms (calculated using the Fridericia method) at screening.
• 9. Large fraction radiation therapy received within 4 weeks prior to the first treatment. For patients who received radiation therapy more than 4 weeks before the first treatment, all the following conditions must be met to be included: there are currently no radiation-related toxic reactions, no need to take glucocorticoids, excluding radiation pneumonia, radiation hepatitis, radiation enteritis, etc.
• 10. Patients who have difficulty swallowing oral medications.
• 11. Past and current history of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, drug-related pneumonia, severe impairment of lung function, and other lung diseases.
• 12. Human immunodeficiency virus (HIV) infection (HIV 1/2 antibody positive), known syphilis infection.
• 13. Presence of unhealed wounds, fractures, gastric and duodenal ulcers, persistent fecal occult blood positivity, ulcerative colitis, etc., or other conditions that the investigator determines may cause gastrointestinal bleeding or perforation.
• 14. Active or poorly controlled severe infection. Severe infection within 4 weeks before the first administration, including but not limited to hospitalization for complications of infection, sepsis, or severe pneumonia.
• 15. Major surgical treatment or significant traumatic injury received within 4 weeks before the first administration.
• 16. Traditional Chinese medicine with anti-tumor indications received within 2 weeks before the first administration.
• 17. Known allergy to any component of bispecific antibodies or GM-CSF formulations.
• 18. Treatment in another clinical trial within 4 weeks before the first administration.
• 19. Pregnant or breastfeeding female patients.
• 20. Presence of any active autoimmune disease or history of autoimmune disease (such as but not limited to: autoimmune hepatitis, interstitial pneumonia, enteritis, vasculitis, nephritis; participants who need bronchodilators for medical intervention for asthma cannot be included); but the following patients are allowed to participate: vitiligo, psoriasis, alopecia, well-controlled type I diabetes that does not require systemic treatment, and hypothyroidism with normal thyroid function through replacement therapy.
• 21. Other acute or chronic diseases, mental illnesses, or abnormal laboratory test values that may lead to the following results: increase the risk associated with study participation or administration of the study drug, or interfere with the interpretation of study results, and according to the investigator`s judgment, the patient is deemed ineligible to participate in this study.

Описание

This is a prospective, single-arm, multicenter, phase II clinical trial to evaluate the efficacy and safety of orelabrutinib combined with the R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) regimen as first-line treatment in CD5-positive diffuse large B-cell lymphoma (DLBCL) patients.

Критерии включения

• 1. Subjects fully understand and voluntarily participate in this study and sign informed consent.
• 2. Aged ≥18 years, both male and female.
• 3. Pathologically confirmed CD5-positive 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 0-2.
• 6. Expected survival ≥3 months.
• 7. Sufficient bone marrow, liver, and kidney function.

Критерии исключения

• 1. DLBCL combined with other types of lymphoma. Transformed DLBCL.
• 2. DLBCL with central nervous system invasion.
• 3. The patients had previously received BTK inhibitors.
• 4. The patients have contraindications to any drug in the combined treatment.
• 5. Patients with the infection of human immunodeficiency virus (HIV) and/or acquired immunodeficiency syndrome.
• 6. Inability to swallow tablets, presence of malabsorption syndrome, or any other gastrointestinal disease or dysfunction that may affect the absorption of the study drug.
• 7. Pregnant and lactating women, and subjects of childbearing age who do not want to use contraception.
• 8. Mentally ill persons or persons unable to obtain informed consent.
• 9. The investigators think that the patient is not suitable for the study.

Описание

This study investigates the feasibility and efficacy of epcoritamab treatment before CAR T cells. This study also investigates if, when patients have residual lymphoma after CAR T cells, epcoritamab can help to effectively treat that lymphoma.

Критерии включения

• * Age /> 18 years
• * Subject must be able and willing to provide informed consent. In the case where the patient is incapacitated or not otherwise capable, a legally authorized representative (or decision maker when there is not an advanced directive in place) must be willing to provide informed consent on behalf of the patient.
• * Able to comply with the study protocol, in the investigator`s judgment
• * ECOG PS of 0 - 2
• * Pathology report confirming eligible diagnosis
• * Documented CD20+ tumor cells on most recent biopsy
• * Patients will have failed to respond to frontline standard of care therapy containing an anthracycline and anti-CD20 antibody
• * Patients will be eligible and consent to be treated with a "commercially available" anti-CD19, 4-1BB, CD3zeta CAR-T cell therapy or anti-CD19, CD28, CD3zeta CAR T cell therapy (for example, tisagenlecleucel, lisocabtagene maraleucel, or axicabtagene maraleucel)
• * Patients must have a PET/CT scan (preferred), diagnostic CT scan, or MRI with at least one bi-dimensionally measurable lesion (≥ 1.5 cm for nodal lesions or ≥ 1cm for extra-nodal lesions in largest dimension by low-dose computerized tomography /[CT/] scan with FDG-uptake ≥ liver)
• * Adequate laboratory studies
• * Resolution of toxicities from prior therapy to a grade that does not contraindicate trial participation in the opinion of the investigator
• * Ability and willingness to take proper contraceptive precautions

Критерии исключения

• * Inability or unwillingness of the patient or legally authorized representative (or decision-maker when there is not an advanced directive in place) to provide informed consent.
• * Prior solid organ transplantation
• * Primary central nervous system (CNS) lymphoma or active secondary CNS involvement by lymphoma at screening as confirmed by magnetic resonance imaging (MRI)/computed tomography (CT) scan (brain) or, if clinically indicated, by lumbar puncture.
• * History of autoimmune disease or other diseases resulting in permanent immunosuppression or requiring chronic immunosuppressive therapy (see Exclusion Criteria 5a), with the following exceptions:
• 1. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone
• 2. Patients with a history of lymphoma-related immune thrombocytopenic purpura or autoimmune hemolytic anemia in remission may be eligible for this study if approved by the Regulatory Sponsor and Principal Investigator
• 3. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
• i. Rash must cover /< 10% of body surface area ii. Disease is well controlled at baseline and requires only low-potency topical corticosteroid iii. No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or corticosteroids (/> 20 mg/day prednisone or equivalent for /> 2 weeks) within the previous 3 months d. rheumatoid arthritis or similar autoimmune/rheumatic conditions
• * Systemic immunosuppressive medications (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents). However, the following are permitted:
• 1. If receiving glucocorticoid treatment at screening, must be a maximum daily dose of prednisone 10 mg (or equivalent) and a total of no more than 140 mg over the last 14 days prior to the first dose of epcoritamab, unless for disease control.
• 2. Patients who received a single dose of a systemic immunosuppressant medications (e.g., single dose of dexamethasone for nausea or B symptoms) may be enrolled
• 3. The use of inhaled corticosteroids is permitted
• 4. The use of mineralocorticoids for management of orthostatic hypotension is permitted
• 5. The use of physiologic doses of corticosteroids (/< 20 mg/day of prednisone or equivalent) for uses such as management of adrenal insufficiency is permitted
• * Known past or current malignancy, other than inclusion diagnoses, except for:
• 1. Cervical carcinoma of Stage 1B or less.
• 2. Adequately resected, non-metastatic basal cell or squamous cell skin carcinoma.
• 3. Non-invasive, superficial bladder cancer.
• 4. Prostate cancer with a current PSA level /<0.1 ng/mL.
• 5. Patients with a malignancy that has been treated with curative intent will also be enrolled if that malignancy is in remission prior to first dose of epcoritamab
• * Known clinically significant cardiovascular disease
• * Patients with the following active infection(s) could have increased risks for toxicity if treated with bispecific antibody therapy, thus patient will be excluded if:
• 1. Positive serologic or PCR test results for acute or chronic HBV infection. Patients whose HBV infection status cannot be determined by serologic test results (www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf) must be negative for HBV by PCR to be eligible for study participation. Patients with a history of hepatitis B who are negative for HBV by PCR, will not be excluded but will be placed on suppressive antiviral therapy
• 2. Acute or chronic HCV infection. Patients who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation. Patients with a history of hepatitis C who have been adequately treated (negative PCR) will not be excluded.
• 3. Positive serologic or RT-PCR test results for HIV infection.
• * Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major documented infection requiring treatment with IV antibiotics or hospitalization within 2 weeks of enrollment. Empiric or prophylactic antibiotics administered during neutropenia or neutropenic fever without microbiologic evidence of infection do not exclude patients.
• * Clinically significant pulmonary disease (e.g., bronchospasm and/or obstructive pulmonary disease) that requires chronic oxygen or corticosteroid use /> 20 mg mg/day prednisone or equivalent
• * Uncontrolled seizure disorder
• * Exposure to live or live attenuated vaccine within 4 weeks prior to signing ICF
• * Pregnancy or breast feeding
• * Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator`s judgment, precludes the patient`s safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results

Описание

B-cell Lymphoma is an aggressive and rare cancer of a type of immune cells (a white blood cell responsible for fighting infections). This study will assess how safe and effective epcoritamab plus lenalidomide (E-Len) is compared to rituximab plus gemcitabine and oxaliplatin (R-GemOx) )in treating adult participants with relapsed or refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL). Adverse events and change in disease condition will be assessed.

Epcoritamab is an investigational drug being developed for the treatment of DLBCL. Study doctors put the participants in 1 of 2 groups, called treatment arms. Each group receives a different treatment. Around 320 adult participants with R/R DLBCL will be enrolled in approximately 165 sites across the world.

Participants in arm A will receive subcutaneous (SC) injections of epcoritamab plus oral lenalidomide capsules (E-Len) for up to 12 cycles (each cycle is 28 days). Participants "in arm B will receive intrav... (IV) infused R-GemOx for up to 4 cycles (each cycle is 28 days)

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 a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

Критерии включения

• * Eastern Cooperative Oncology Group Performance status score of 0 to 2.
• * Histologically confirmed CD20+ Diffuse Large B-Cell Lymphoma (DLBCL) and documented in the most recent and representative pathology report, inclusive of the following according to the World Health Organization (WHO) 2022 as per the protocol.
• * Must have relapsed or refractory (R/R) disease and have been previously treated with at least 1 line of systemic antineoplastic therapy including anti-CD20 mAb-containing combination chemotherapy since DLBCL diagnosis.
• * . Participant must meet at least 1 of the following criteria:
• * Failed prior autologous stem cell transplant (ASCT), defined as relapsed after ASCT or been refractory to ASCT.
• * Not be considered a candidate for ASCT due to age, performance status, comorbidities and/or insufficient response to prior treatment, or have refused ASCT.
• * Be ineligible for or unable to receive chimeric antigen receptor T-cell (CAR-T) meeting at least 1 of the following criteria:
• * Unable to receive CAR-T therapy due to fitness and/or comorbidity.
• * Lymphocyte apheresis failure.
• * Unwilling to receive CAR-T therapy.
• * Unable to receive CAR-T therapy due to financial, geographic, insurance, access, and/or manufacturing constraints.
• * Relapsed/progressed after having achieved at least a Partial Response (PR) or Complete Response (CR) while on prior CAR-T therapy.
• * Must have measurable disease.
• * Life expectancy /> 3 months on standard of care treatment at the time of enrolling in the study

Критерии исключения

• * Current evidence of primary central nervous system (CNS) lymphoma or known CNS involvement by lymphoma including leptomeningeal disease, at screening.
• * History of prior treatment with a bispecific antibody targeting CD3 and CD20 or prior treatment with rituximab plus gemcitabine and oxaliplatin (R-GemOx) or gemcitabine and oxaliplatin (GemOx).
• * Documented refractoriness to lenalidomide.

Описание

Patients treated for DLBCL are at high risk of developing AICD. This adverse event is characterized by irreversible damage to the heart muscle with a loss of cardiomyocytes and subsequent decline in cardiac pumping capacity. Thereby patients treated for this malignancy are at double the risk of developing symptomatic heart failure / cardiomyopathy when compared to the general population. This corresponds to a cumulative incidence of 5-10% within 5-years after receiving R-CHOP. In the elderly, an incidence of 26% has been reported after 8-years of follow-up. Among patients who die in complete remission, heart failure has been described to be one of the most important causes of death. ANTICIPATE aims to evaluate if dexrazoxane can prevent AICD in DLBCL patients and identify those at highest risk of AICD. Of all patients treated with anthracyclines in a first-line setting, DLBCL patients were chosen for this trial for two primary reasons. Firstly, these patients have a favourable oncological prognosis with a 5-year relative survival in the Netherlands of 64-78% in those aged 18-74 years increasing the importance of preventing long-term toxicity. Secondly, the cumulative anthracycline dose used for the treatment of DLBCL is higher than the dose used in breast cancer. The cumulative anthracycline dose is the most important risk factor for AICD known.

Критерии включения

• 1. Untreated patients with a confirmed histologic diagnosis of CD20+ DLBCL according to WHO classification 2022:
• * DLBCL, not otherwise specified (NOS)
• * High-grade B-cell lymphoma NOS
• * High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 translocation when DA-EPOCH-R is not an option. R2- CHOP is allowed.
• * Follicular lymphoma
• * T-cell/histiocyte-rich B cell lymphoma (THRBCL)
• Note: Transformed, previously untreated lymphoma is allowed.
• Note: 5-day treatment of dexamethasone 15 mg/day or prednisone 100 mg/day or local radiotherapy in order to control life-threatening/invalidating tumor related symptoms is allowed.
• Note: It is allowed to start with a first cycle of R-CHOP21 pending the FISH results.
• 2. Planned treatment with 6 R-CHOP21. The following regimens are also allowed:
• * Treatment with reversed R-CHOP21
• * Treatment with R2-CHOP21 (6 R-CHOP21 + lenalidomide 15 mg day 1-14) in case of double hit lymphoma
• * Two additional administrations of rituximab after 6 cycles of R-CHOP21
• * High dosis MTX and/or MTX-it for CNS prophylaxis
• 3. Ann Abor stages II-IV and stage I if the treatment plan is 6 R-CHOP21 in case of bulky disease (defined as a ≥10 cm mass);
• 4. Age ≥ 18 years;
• 5. WHO performance status ≤ 2, WHO 3 performance status is allowed when considered directly related to the DLBCL;
• 6. Negative pregnancy test at study entry for women of childbearing potential;
• 7. Female patient is either post-menopausal for at least 1 year before the screening visit or surgically sterile or if of childbearing potential, agrees to practice two effective methods of contraception, at the same time, from the time of signing the informed consent through at least 12 months after the last dose of protocol treatment, or agrees to completely abstain from heterosexual intercourse;
• 8. Male patient, even if surgically sterilized, (i.e., status post vasectomy) agrees to practice effective barrier contraception during the entire study period and through 12 months after the last dose of protocol treatment, or agrees to completely abstain from heterosexual intercourse;
• 9. Patient is able to adhere to the study visit schedule and other protocol requirements;
• 10. Written informed consent.

Критерии исключения

• 1. Any of the following B-cell lymphomas according to WHO classification 2022:
• o Central Nervous System involvement by DLBCL;
• Note: high CNS-IPI is allowed
• * Testicular DLBCL;
• * Primary mediastinal B-cell lymphoma;
• * Epstein-Barr virus (EBV) post-transplant lymphoproliferative disorder;
• 2. Any prior malignancy or present malignancy other than DLBCL that required or requires systemic therapy. Prior surgery or local radiotherapy is allowed in case the heart has not been exposed.
• 3. Patients requiring treatment with mini-R-CHOP
• 4. Pre-existing cardiac disease including:
• * LVEF /<50% measured with echocardiography (2D or 3D)
• * Symptomatic heart failure (NYHA ≥II) or hospitalization for heart failure in the last year;
• * Refractory anginal symptoms
• * Cardiac arrhythmias not controlled with optimal medical treatment, in case of atrial fibrillation the ventricular response needs to be /<110/min;
• * Significant valvular dysfunction on echocardiography;
• * Non-ischemic cardiomyopathy
• 5. Non-diagnostic/poor transthoracic echocardiography imaging quality at baseline;
• 6. Severe pulmonary dysfunction defined as breathlessness at rest (COPD GOLD III or IV), unless clearly related to DLBCL;
• 7. Severe neurological or psychiatric disease;
• 8. Inadequate hematological function (absolute Neutrophil Count (ANC) /<1.0x109/L or platelets /<75x109/L), unless clearly related to DLBCL;
• 9. Significant hepatic dysfunction (serum bilirubin or transaminases ≥ 3 times the upper limit of normal) unless related to lymphoma infiltration of the liver;
• 10. Active hepatitis B or C infection (serology testing is required at screening). Patients positive for hepatitis B surface antigen (HBsAg) regardless of antibody status or HBsAg negative but anti-HBc positive are only eligible if HBV-PCR is negative and patients are protected with lamuvidine or entecavir. Patients with positive hepatitis C serology are only eligible if HCV-(RNA) is confirmed negative;
• 11. Significant renal dysfunction (creatinine clearance /< 30 ml/min after rehydration) or requiring dialysis;
• 12. Active uncontrolled fungal, bacterial and/or viral infection;
• 13. Patient known to be HIV-positive;
• 14. Breast-feeding female patients;
• 15. Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule;
• 16. Participation in another clinical trial with anti-cancer therapy or a cardiovascular drug.

Описание

Substudy 01A is part of a platform study. The purpose of this study is to assess the efficacy and safety of zilovertamab vedotin in pediatric participants with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL)/Burkitt lymphoma, or neuroblastoma and in pediatric and young adult participants with Ewing sarcoma.

Критерии включения

• The main inclusion and exclusion criteria include but are not limited to the following:
• Inclusion Criteria:
• * For hematological malignancies: Confirmed diagnosis of B-precursor B-ALL or DLBCL/Burkitt lymphoma according to World Health Organization (WHO) classification of neoplasms of the lymphoid tissues.
• * For solid tumor malignancies: Histologically confirmed diagnosis of neuroblastoma or Ewing sarcoma.

Критерии исключения

• * History of solid organ transplant.
• * Clinically significant (ie, active) cardiovascular disease.
• * Known history of liver cirrhosis.
• * Ongoing Grade />1 peripheral neuropathy.
• * Demyelinating form of Charcot-Marie-Tooth disease.
• * Diagnosed with Down syndrome.
• * Ongoing graft-versus-host disease (GVHD) of any grade or receiving systemic GVHD treatment or prophylaxis.
• * History of human immunodeficiency virus (HIV) infection.
• * Contraindication or hypersensitivity to any of the study intervention components.
• * Received prior radiotherapy within 4 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities.
• * Ongoing, chronic corticosteroid therapy (exceeding 10 mg daily of prednisone equivalent). Prednisone equivalent dosing must have been stable for at least 4 weeks before Cycle 1 Day 1 (C1D1).
• * Received a strong cytochrome P450 3A4 (CYP3A4) inhibitor within 7 days or a strong CYP3A4 inducer within 14 days before the start of study intervention or expected requirement for chronic use of a strong CYP3A4 inhibitor or inducer during the study intervention period and for 30 days after the last dose of study intervention
• * Received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention (except for prophylactic intrathecal chemotherapy and/or cytoreductive therapy with steroids/hydroxyurea.
• * Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
• * Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
• * Known additional malignancy that is progressing or has required active treatment within the past 1 year.
• * Active infection requiring systemic therapy.
• * Known history of Hepatitis B or known active Hepatitis C virus infection.
• * Participants who have not adequately recovered from major surgery or have ongoing surgical complications.

Описание

This is a prospective, single-arm, open study to observe the efficacy and safety of the CART-SCB regimen (Clinical Regimen for the Prospective Study of Autologous Hematopoietic Stem Cell Boost for the Improvement of Bone Marrow Suppression in Patients with High-Risk Immunohematologic Toxicity Lymphoma After Chimeric Antigen Receptor T (CAR-T)-Cell Immunotherapy Therapy) . After the patient has completed CAR-T therapy, if the patient has unrelieved hematologic toxicity, consider infusing a reserve of stem cells; if myelosuppression has not been significantly relieved, stem cell infusion can be performed again.

Критерии включения

• * 18 years of age or older and gender-neutral;
• * Diagnosis of B-cell non-Hodgkin lymphoma confirmed histologically or cytologically according to World Health Organization 2016 criteria;
• * Prior CAR-T cell immunotherapy;
• * Patients who are at high risk according to the CAR-HEMATOTOX score prior to leukapheresis; or patients who are clinically considered potentially at high risk for hematologic toxicity following immunotherapy (including age ≥60 years; or Eastern Cooperative Oncology Group (ECOG) Performance Status≥ 2 points; or number of prior lines of therapy ≥ 2, etc.);
• * Myelosuppression as determined by the investigator has occurred after CAR-T therapy;
• * Have a storage of stem cell;
• * Stable lymphoma disease status (final investigator-assessed efficacy CR/PR);
• * Bone marrow biopsy to rule out hemophilia/infection/bone marrow infiltration;
• * Adequate organ function;
• * Able to provide written informed consent (ICF) and able to understand and agree to comply with the study requirements and assessment schedule;
• * Patients of childbearing potential must be willing to use highly effective contraception for the duration of the study, and for 120 days after the last dose of treatment.

Критерии исключения

• * History of allogeneic hematopoietic stem cell transplantation;
• * History of epilepsy, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease involving the central nervous system;
• * Presence of or current concurrent other malignancies within the past 2 years, with the exception of cured carcinoma in situ of the uterine cervix, non-melanoma skin cancers, and superficial bladder tumors (Ta (non-invasive tumors), Tis (carcinoma in situ), and T1 (tumors infiltrating the basement membrane));
• * Suffering from severe cardiovascular disease: grade II or greater myocardial ischemia or myocardial infarction, poorly controlled arrhythmias; grade III-IV cardiac insufficiency according to New York Heart Association (NYHA) criteria, or cardiac ultrasound suggestive of a left ventricular ejection fraction (LVEF) /<50%;
• * Allergy to any investigational drug or excipient;
• * Presence of any active autoimmune disease (including, but not limited to: autoimmune hepatitis, interstitial pneumonitis, uveitis, enteritis, hepatitis, pituitary gland inflammation, vasculitis, nephritis, hyperthyroidism, hypothyroidism), or known history of allograft transplantation, or patients with prolonged and heavy use of hormones or use of other immune-modulating agents or other patients who, as assessed by the Investigator Patients who are considered to have an impact on study treatment;
• * Have an active infection;
• * History of uncontrolled systemic disease, including diabetes mellitus, hypertension, and acute pulmonary disease;
• * Known human immunodeficiency virus (HIV) infection;
• * Presence of an underlying medical condition or alcohol/substance abuse or dependence that is not conducive to the administration of study medication, or that may interfere with the interpretation of results, or that puts the patient at high risk for developing treatment complications;
• * End-organ damage due to autoimmune disease (e.g., Crohns disease, rheumatoid arthritis, systemic lupus erythematosus) within the past 2 years, or the need for systemic immunosuppression or other systemic disease-control medications.

Описание

This is a prospective, multicenter, single-arm, open phase II study to explore the efficacy and safety of Zanubrutinib in combination with Polatuzumab Vedotin, bendamustine, and rituximab (Polo-ZBR) in subjects with relapsed/refractory diffuse large B-cell lymphoma. Subjects with relapsed/refractory DLBCL who met the inclusion/exclusion criteria were screened and treated with 4 courses of Pola-ZBR regimen after signing informed consent. Subjects achieving PR or CR were consolidated with autologous transplantation consolidation or the original regimen for 2 additional courses, and then given Zanubrutinib maintenance therapy for 1 year. The final follow-up was observed until 2 years after enrollment.

Критерии включения

• * Aged between 18 and 75 (inclusive);
• * For patients with DLBCL confirmed by histopathology (which needs to be confirmed by specimens after this or past recurrence), the following DLBCL histology will be considered eligible for study enrollment:
• DLBCL, NOS(includes GCB type and ABC type); T-cell rich large B-cell lymphoma; High-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangement; High-grade B-cell lymphoma, NOS; Primary mediastinal (thymus) large B-cell lymphoma; EB virus positive DLBCL, NOS;HHV-8 positive DLBCL, NOS;
• * Relapsed refractory patients, defined as those who had no response after first-line treatment (including immunochemotherapy, chemotherapy or hematopoietic stem cell transplantation) or relapsed or refractory after remission;
• * There is at least one two-dimensional measurable lesion with a short diameter ≥1.0cm;
• * Estimated survival time ≥3 months;
• * The patient is informed and agrees to the program;
• * ECOG score 0-2 points;
• * Those who understand the procedure and content of the experiment, voluntarily participate in the study and sign the informed consent;
• * Patients can follow up on schedule, communicate well with researchers and complete the trial according to the trial regulations;
• * Confirm negative pregnancy test of female patients of childbearing age within 7 days before administration; Women and men in the reproductive period must agree to use medically recognized effective contraception throughout the treatment period and for 6 months after the end of the trial.

Критерии исключения

• * Active bleeding within 4 weeks prior to initial administration or anticoagulant therapy such as warfarin or vitamin K antagonists during the study period, or a tendency to bleed (such as esophageal varicose veins at risk of bleeding, locally active ulcerative lesions) or a clotting disorder deemed by the investigator;
• * Surgical procedures have been performed within 6 weeks prior to the signing of the informed consent for the first dose of the trial drug, but tests for diagnostic purposes are not considered surgical procedures, and the insertion of a vascular access device will be exempt from this exclusion criteria;
• * History of stroke and intracranial hemorrhage within 6 months before the first administration, except intracranial hemorrhage after surgery;
• * Those who cannot stop or adjust moderate or strong CYP3A inhibitors;
• * Have received organ transplantation or allogeneic stem cell transplantation;
• * Previous or concurrent history of other malignant tumors;
• * Chronic or currently active infectious diseases requiring systemic antibiotic, antifungal, or antiviral treatment (except EBV infections);
• * Accompanied by uncontrolled cardiovascular and cerebrovascular diseases, thrombotic diseases, connective tissue diseases and other diseases. Those who were not considered suitable for inclusion by the researchers;
• * Laboratory test value at screening (unless due to lymphoma) : Leukocyte count /< 3.5×109/L, neutrophils /<1.5×109/L, platelets /<80×109/L, hemoglobin /<100g/L, ALT or AST were 2.5 times higher than the upper limit of normal, bilirubin was 1.5 times higher than the upper limit of normal, creatinine level was 1.5 times higher than the upper limit of normal;
• * HbsAg positive patients need to check HBV-DNA /< 104 to be enrolled. In addition, if HBsAg is negative but HBcAb is positive (regardless of HBsAb status), HBV-DNA testing is also required, and HBV-DNA results /< 104 are required to be enrolled and continue treatment and monitoring of HBV-DNA. Patients with HCV antibody positive were required to check HCV-RNA quantitative DNA /< 103 to be enrolled;
• * HIV antibody, treponema pallidum antibody positive;
• * Pregnant or lactating women;
• * Those who have a history of drug use or drug abuse upon inquiry;
• * Patient communication, understanding and cooperation are not enough, or compliance is poor, and it cannot be guaranteed that the program is carried out according to the requirements;
• * Known allergy to the investigational drug or its related ingredients;
• * Patients with past or current lymphoma central invasion;
• * The patient is unable to swallow the capsule or has a disease or condition that severely affects gastrointestinal function, such as malabsorption syndrome, removal of the stomach or small intestine, or complete intestinal obstruction;
• * Patients who could not stop using any other antitumor drugs within 2 weeks prior to medication in this study;
• * Participants considered unsuitable for this clinical trial due to various other reasons.

Описание

This first-in-human (FIH) trial is designed to assess the safety, feasibility and preliminary efficacy of a single intravenous (IV) dose of SynKIR-310 administered to participants with relapsed/refractory B-NHL.

Критерии включения

• * Adult 18 years of age and older.
• * Histologically confirmed diagnosis of B-NHL before enrollment.
• * Must have received prior CAR T or were unwilling/unable to receive prior CAR T.
• * Must have refractory or relapsed disease after receiving 2 prior lines of therapies.
• * If relapsed/refractory post-auto-SCT, then must have undergone auto-SCT at least 6 months prior to enrollment.
• * If relapsed/refractory disease after allogeneic stem cell transplant (allo SCT) then must have undergone allo-SCT at least 6 months prior to enrollment and without evidence of graft versus host disease.
• * Measurable disease at time of enrollment: At least one measurable lesion per Lugano Response Criteria (Cheson et al., 2014).
• * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

Критерии исключения

• * Previously treated with any investigational agent within 30 days prior to screening.
• * Adequately treated non-melanoma skin cancer such as basal cell or squamous cell carcinoma
• * Carcinoma-in-situ (e.g., cervix, bladder, breast) treated curatively and without evidence of recurrence for at least 3 years prior to enrollment.
• * Any other malignancy which has been completely treated and remains in complete remission for ≥ 5 years prior to enrollment. Completely treated prostate cancer with prostate-specific antigen (PSA) level /< 1.0 may also be permitted.
• * Known immunodeficiency disease.
• * History or presence of active or clinically relevant primary central nervous system (CNS) disorder, such as seizure, encephalopathy, cerebrovascular ischemia/hemorrhage, cerebellar disease, or any autoimmune disease with CNS involvement. For primary CNS disorders that have recovered or are in remission, participants without recurrence within 2 years of planned study enrollment may be included.
• * Uncontrolled hypertension, history of myocarditis or congestive heart failure, unstable angina, serious uncontrolled cardiac arrhythmia, or myocardial infarction within 6 months prior to study entry.
• * Any active uncontrolled systemic fungal, bacterial or viral infection.
• Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Описание

The goal of this phase 2 trial is to test the safety and efficacy of zanubrutinib and lenalidomide as maintenance therapy in patients with DLBCL.

Критерии включения

• * Pathologically confirmed Diffuse Large B Cell Lymphoma according World Health Organization (WHO) classification;
• * Patient is ≥ 18 years of age at the time of signing the informed consent form (ICF).
• * Patient must understand and voluntarily sign an ICF prior to any study-specific assessments/procedures being conducted;
• * Patient is willing and able to adhere to the study visit schedule and other protocol requirements;
• * Patient has recieved complete remission and has completed planed courses of chemotherapy
• * Meet the following lab criteria: Absolute Neutrophil Count (ANC) ≥ 1,5 x 10/^9/L (≥ 1 x 10/^9/L if bone marrow (BM) involvement by lymphoma)；Platelet ≥ 75 x 10/^9/L (≥ 50 x 10/^9/L if BM involvement by lymphoma)； Hemoglobin ≥ 8 g/dL. Anticipated life expectancy at least 3 months

Критерии исключения

• * Active or uncontrolled infections requiring systemic treatment within 14 days before enrollment;
• * Any instability of systemic disease, including but not limited to severe cardiac, liver, kidney, or metabolic disease need therapy;
• * Pregnant or lactating women

Описание

This phase I trial tests the safety, side effects, and best dose of genetically engineered cells called EGFRt/19-28z/IL-12 CAR T cells, and to see how they work in treating patients with hematologic malignancies that makes a protein called CD19 (CD19-positive) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Chimeric Antigen Receptor (CAR) T-cell Therapy is a type of treatment in which a patient`s T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient`s blood. Then the gene for a special receptor that binds to a certain protein on the patient`s cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. To improve the effectiveness of the modified T cells and to help the immune system fight cancer cells better, the modified T cells given in this study will include a gene that makes the T cells produce a cytokine (a molecule involved in signaling within the immune system) called interleukin-12 (IL-12). The researchers think that IL-12 may improve the effectiveness of the modified T cells, and it may also strengthen the immune system to fight cancer. Giving EGFRt/19-28z/IL-12 CAR T cells may be safe and tolerable in treating patients with relapsed or refractory CD19+ hematologic malignancies.

Критерии включения

• * Patients with relapsed refractory B Cell malignancies which commonly express CD-19.
• * Eligible disease subtypes include the following:
• * Patients with diffuse large B-cell lymphoma (de novo or diffuse large B-cell lymphoma /[DLBCL/] transformed from an indolent lymphoma (follicular lymphoma, chronic lymphocytic leukemia) or high grade B-cell Lymphoma (HGBL):
• * Relapsed or refractory DLBCL or high-grade B-cell lymphoma (HGBL) following 2 or more prior chemoimmunotherapy regimens containing an anthracycline and CD20-directed therapy following diagnosis of de novo DLBCL/HGBL or DLBCL arising from indolent lymphoma and requiring further treatment.
• * Relapse following a single prior chemoimmunotherapy regimen containing an anthracycline and CD20-directed therapy following diagnosis of de novo DLBCL/HGBL or DLBCL arising from indolent lymphoma and considered ineligible for high dose chemotherapy and autologous stem cell rescue as determined by the investigator.
• * Patients must have at least one fludeoxyglucose F-18 (FDG)-avid (PET-avid) measurable lesion.
• * Biopsy confirmation of relapsed or refractory DLBCL is required.
• * Chronic lymphocytic leukemia after 2 lines of therapy including a BTKi (bruton tyrosine kinase inhibitor).
• * Mantle cell lymphoma after 2 lines of therapy. Patients must have previously received chemoimmunotherapy and a prior BTK inhibitor.
• * Follicular lymphoma after 2 lines of therapy.
• * For cohort 1A specifically, patients must additionally have received a prior CD19-targeted CAR T-cell therapy or not have an indication for a Food and Drug Administration (FDA)-approved commercial CD19-targeted CAR T-cell therapy. This will include patients with relapsed/refractory DLBCL, FL, CLL and MCL.
• * For cohorts other than cohort 1A (and if needed, cohort -1), patients with an indication for an FDA approved commercial CD19-targeted CAR T-cell therapy are eligible following an informed consent discussion that reviews the risks and benefits of the FDA-approved commercial CD19-targeted CAR T-cell therapy vs the investigational product.
• * Prior CD19-targeted therapies, including CAR T-cell therapy, does not exclude participation; however, CD19 expression by immunohistochemical staining or flow cytometry must be confirmed prior to enrollment for patients who have received such therapies.
• * Age ≥ 18 years of age.
• * Creatinine Clearance /> 30 mL/min (Cockroft-Gault equation).
• * Direct bilirubin ≤ 2.0 mg/dL (unless related to disease).
• * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN) (unless related to disease).
• * Adequate pulmonary function as assessed by ≥ 90% oxygen saturation on room air by pulse oximetry.
• * Have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• * Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Patients of childbearing age should use effective contraception while on this study and continue for 1 year after all treatment is finished.
• * Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure.

Критерии исключения

• * Pregnant or lactating patients.
• * Impaired cardiac function (left ventricular ejection fraction /[LVEF/] /< 40%) as assessed by ECHO or MUGA scan during screening.
• * Patients with active graft versus host disease following allogeneic hematopoietic cell transplantation requiring systemic T cell suppressive therapy are ineligible.
• * Patients with active autoimmune disease requiring systemic T cell suppressive therapy are ineligible.
• * Patients with following cardiac conditions will be excluded:
• * New York Heart Association (NYHA) stage III or IV congestive heart failure.
• * Myocardial infarction ≤ 6 months prior to enrollment.
• * Any history of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration.
• * Patients with HIV are ineligible.
• * Patients with active hepatitis B infection (as manifest by either detectable hepatitis B virus deoxyribonucleic acid /[DNA/] by polymerase chain reaction /[PCR/] and/or positivity for hepatitis B surface antigen) are ineligible.
• * Patients with active hepatitis C infection (as manifest by detectable hepatitis C virus ribonucleic acid /[RNA/] by PCR) are ineligible. Patients with detectable antibodies to hepatitis C virus will be screened by PCR for evidence of active infection.
• * Patients with uncontrolled systemic fungal, bacterial, viral or other infection are ineligible.
• * 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.
• * Patients with history or presence of clinically significant neurological disorders such as epilepsy, generalized seizure disorder, severe brain injuries are ineligible.
• * Patients with primary central nervous system (CNS) disease are ineligible.
• * Unwilling or unable to follow protocol requirements.
• * Any other condition/issue which, in the opinion of the treating physician, would make the patient ineligible for the study.

Описание

The purpose of this study is to evaluate the safety and preliminary efficacy of ATA3219 in participants with relapsed/refractory (R/R) B-cell non-Hodgkin Lymphoma (NHL).

Критерии включения

• * Histologically confirmed, R/R, B-cell NHL according to the 2022 revision of the World Health Organization classification of lymphoid neoplasms /[Alaggio 2022/] defined as any of the following:
• 1. LBCL
• 2. FL Grade 3b
• 3. MCL
• * The following criteria apply for details of prior treatment/therapy: R/R to at least 2 lines of therapy; if the most recent line of therapy was autologous hematologic cell transplant (HCT), relapse within 12 months of the transplant.
• * Measurable disease by scan (diagnostic positron emission tomography-positive and/or computed tomography-measurable) as per Lugano Classification /[Cheson 2014/]. Magnetic resonance imaging may be used when computed tomography with contrast is contraindicated or when mandated by local practice.
• * If sufficient archival material is not available from the latest relapse, a new tumor biopsy is required any time during screening, prior to conditioning chemotherapy.
• * Participants who have received prior CD19-directed therapy as the prior line of therapy:
• 1. must have achieved either a CR or partial response as a best response and maintained the response for ≥ 3 months after receiving CD19-directed treatment, and
• 2. must still have CD19+ disease as determined by a local laboratory.
• * Eastern Cooperative Oncology Group performance status ≤ 2
• * Adequate organ function
• * Written informed consent as per protocol.
• * Participants are able to commit to the inpatient portion of the study, encompassing conditioning (if per the institution`s standard practice), and frequent monitoring during Days 1-15, as well as remain within 1 hour travel time of the clinical site for 28 days after each infusion.

Критерии исключения

• * History of a human immunodeficiency virus infection or acute or chronic active hepatitis B or C infection.
• * History or presence of clinically relevant central nervous system (CNS) pathology.
• * Unresolved Grade 1-2 Immune effector cell-associated neurotoxicity syndrome (ICANS) or experienced Grade 3-4 ICANS from prior chimeric antigen receptor T-cell.
• * Unresolved graft-versus-host disease (GvHD) or Grade 3-4 acute GvHD from any prior therapy or moderate to severe chronic GvHD from any prior therapy.
• * History of any one of the following cardiovascular conditions: class III or IV heart failure as defined by the New York Heart Association /[The Criteria Committee of the New York Heart Association 1994/], cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically meaningful cardiac disease, within the past 6 months of study informed consent.
• * History of malignancies, other than R/R NHL, unless the participant has been disease-free for ≥ 1 year (certain noninvasive malignancies are allowed).
• * Active primary, CNS-only, or systemic plus CNS involvement by lymphoma, unless the CNS involvement has been effectively treated.
• * Active autoimmune disorders or inflammatory conditions that require systemic immunosuppressive therapies, including therapeutic doses of steroids.
• * Has received prior allogeneic HCT or prior solid organ transplant.
• * Systemic bacterial, viral, fungal, or other infection that is untreated or unresponsive to appropriate treatment (or requires IV antibiotics at enrollment); participants must be afebrile for ≥ 48 hours. Prophylactic antibiotics, antivirals, and antifungals are permitted.
• * Concurrent serious uncontrolled or unresolved medical condition, including any laboratory abnormality or psychiatric illness.
• * The following therapies within defined periods prior to the conditioning regimen: therapeutic doses of corticosteroids (/> 0.5 mg/kg/day of prednisone or equivalent), lymphodepleting chemotherapeutic agents, live attenuated vaccines, prior systemic cancer therapy, investigational agents, including approved drugs being used off label, autologous HCT, donor lymphocyte infusions, radiation, alemtuzumab.
• * Female who is breastfeeding or pregnant.
• * Inability or unwillingness to comply with study procedures.
• * Unwilling to use protocol specified contraceptive methods.
• * Life expectancy of ≤ 8 weeks.
• * For participants being considered for retreatment: had a DLT with prior ATA3219 dose.

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,