OncoTrials - мониторинг клинических исследований

Описание

This phase of the protocol (protocol part B), seeks to evaluate the new formulation in healthy normal volunteers to confirm the new formulation provides comparable human dosimetry to which was seen and published in protocol part A. Additionally, the new formulation will be studied utilizing an expanded patient population to include patients with confirmed diagnosis of multiple myeloma (MM), low-grade lymphoma, or MM and lymphoma patients who are status post bone marrow transplant (BMT) with negative imaging and suspected recurrence.

Критерии включения

• Healthy Volunteer:
• * Adult 18 years of age or older
• * Able to give informed consent.
• * Able to comprehend and willing to follow instructions for study procedures as called for by the protocol
• * Capable of lying still and supine within the PET/CT scanner for up to 75 minutes.
• * No illicit drug use or other inhaled drug use (including pharmacologic agents and illicit drugs) within the past year per self-reporting mechanisms.
• * No history of claustrophobia or other condition that has previously or would interfere with completion of protocol specified imaging sessions.
• * Not currently pregnant or nursing: Subject must be surgically sterile (has had a documented bilateral oophorectomy and/or documented hysterectomy), post-menopausal (cessation of menses for more than 1 year), non-lactating, or of childbearing potential for whom a urine pregnancy test (with the test performed within the 24 hour period immediately prior to administration of 64Cu-LLP2A) is negative.
• Inclusion Criteria Hematological Malignancy:
• * Clinical or pathologically defined MM or lymphoma including both newly diagnosed, relapsed or refractory disease:
• * Multiple Myeloma defined in accordance with the International Myeloma Working Group criteria
• * Low-grade lymphoma, including the following subtypes: follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia
• * Adult 18 years of age or older and able to provide informed consent
• * Capable of lying still and supine within the PET/CT scanner for up to 75 minutes.
• * No history of claustrophobia or other condition that has previously or would interfere with completion of protocol specified imaging sessions
• * Not currently pregnant or nursing: Subject must be surgically sterile (has had a documented bilateral oophorectomy and/or documented hysterectomy), post-menopausal (cessation of menses for more than 1 year), non-lactating, or of childbearing potential for whom a urine pregnancy test (with the test performed within the 24 hour period immediately prior to administration of 64Cu-LLP2A) is negative
• * Patients participating in imaging or therapeutic trials with investigational agents are eligible to participate

Критерии исключения

Описание

To assess the efficacy and safety of mosunetuzumab combined with zanubrutinib in patients with relapsed or refractory MZL.

Критерии включения

• Histologically diagnosed marginal zone lymphoma (any subtypes) Low grade lymphoma unclassifiable is also eligible Have received at least 1 prior treatment including CD20 monoclonal antibody Stage II, III or IV disease Age ≥18 years. Because no dosing or adverse event data are currently available on the use of mosunetuzumab and zanubrutinib combination in patients /<18 years of age, children are excluded from this study.
• Performance status ≤2 on the ECOG scale (≤3 if due to lymphoma) Requiring systemic therapy assessed by investigator based on tumor size, symptoms and/or GELF criteria42 A nodal or extranodal (except spleen) mass /> 7 cm in its greater diameter At least 3 nodal or extranodal sites ≥ 3 cm in diameter Presence of at least one B symptom Fever (/>38 ℃), night sweats, weight loss /> 10% in the past 6 months Symptomatic splenomegaly (or size />13cm) Impending organ compression or involvement (ureteral, orbital, gastrointestinal) Any of the following cytopenias due to bone marrow involvement of lymphoma Hemoglobin ≤ 10 g/dL Platelets ≤ 100 x 109/L Absolute neutrophil count (ANC) /< 1.5x109/L Pleural effusion or ascites LDH /> ULN or β2 microglobulin /> ULN Bi-dimensionally measurable disease, with at least one nodal lesion ≥ 1.5 cm or one extra-nodal lesion /> 1 cm in longest diameter by CT, PET/CT, and/or MRI Subjects with splenic MZL who do not meet the radiographically measurable disease criteria are eligible for participation is spleen is enlarged over 16 cm and MZL is histologically confirmed by bone marrow biopsy or peripheral blood flow cytometry Subjects with EMZL such as skin of conjunctival EMZL who do not meet the radiographically measurable disease criteria are eligible for participation if at least one of the skin lesions is histologically confirmed as MZL and measures ≥1.5 cm in diameter
• Patients must have adequate organ and marrow function as defined below:
• Total bilirubin ≤ 1.5 institutional ULN, unless consistent with Gilbert`s (ratio between total and direct bilirubin /> 5) AST (SGOT) and ALT (SGPT) ≤ 3 x institutional ULN Alkaline phosphatase /< 2.5 ULN Creatinine clearance ≥ 40 ml/min calculated by modified Cockcroft-Gault formula Blood counts below if without lymphoma cause for cytopenia Hemoglobin ≥ 8 g/dL Platelets ≥ 75 x 109/L Absolute neutrophil count (ANC) ≥ 1.0x109/L/* /*Growth factor permitted during screening Blood counts below if cytopenia are due to lymphoma (such as bone marrow involvement or splenomegaly) Hemoglobin ≥ 6 g/dL (no transfusion within 7 days prior to treatment) Platelets ≥ 50 x 109/L Absolute neutrophil count (ANC) ≥ 0.5x109/L All subjects must Have an understanding that the study drug could have a potential teratogenic risk.
• Agree to refrain from donating blood while on study treatment, during dose interruptions and for at least 28 days following the last dose of study treatment.
• Agree not to share study medication with another person. Sign an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.
• Females must agree to abstain from breastfeeding during study participation and for at least 12 months after treatment discontinuation.
• Females of childbearing potential (FCBP§) must:
• Have one negative pregnancy tests via serum or urine prior to starting study therapy.
• Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice. Otherwise, she must agree to use, and be able to comply with two forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption 28 days prior to starting mosunetuzumab, during the study treatment (including dose interruptions), and for at least 3 months after the completion of treatment.
• Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. 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.
• Male subjects must:
• A male subject who is sexually active with a female with reproductive potential must agree to use a barrier method of birth control, eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ suppository (including dose interruptions), even if they have undergone a successful vasectomy, from the time of signing consent and for at least 3 months after the completion of treatment. A male subject must agree not to donate sperm or semen, while taking treatment, during breaks (dose interruptions), and for at least 3 months after the completion of treatment.
• Sign an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.
• The investigator is responsible for: ensuring that the patient understands the potential risks and benefits of participating in the study; ensuring that informed consent is given by each patient, this includes obtaining the appropriate signatures and dates on the informed consent document prior to the performance of any study procedures and prior to the administration of study treatment; answering any questions the patient may have throughout the study and sharing in a timely manner any new information that may be relevant to the patient`s willingness to continue his or her participant in the trial. Subjects will undergo a brief physical exam including a brief exam to determine cognitive review. No one without capacity to personally consent will be enrolled. Patients have medical decision-making capacity if they can demonstrate understanding of the situation, appreciation of the consequences of their decision, and reasoning in their thought process, and if they can communicate their wishes.
• A determination of lack of decision-making capacity shall be made after an appropriate medical evaluation that concludes there is little or no likelihood that the participant will regain decision-making capacity in a reasonable period of time.
• §A FCBP is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).

Критерии исключения

• Known active central nervous system lymphoma or leptomeningeal disease. Treatment with any chemotherapeutic agent, or treatment with any other anti-lymphoma agent (investigational or otherwise) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to first investigational agent administration.
• Any prior history of other malignancy besides B-NHL, unless the patient has been free of disease for ≥ 3 years and felt to be at low risk for recurrence by the treating physician, except:
• Adequately treated localized skin cancer without evidence of disease. Adequately treated cervical carcinoma in situ without evidence of disease. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator`s opinion, could compromise the subject`s safety, interfere with the absorption or metabolism of lenalidomide capsules, or put the study outcomes at undue risk.
• Uncontrolled human immunodeficiency virus (HIV), or active Hepatitis C Virus, or active Hepatitis B Virus infection, or any uncontrolled active significant infection, including suspected or confirmed JC virus infection and SARS-CoV2.
• Patients with inactive hepatitis B infection must adhere to hepatitis B reactivation prophylaxis unless contraindicated. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded. Subjects with a history of Hepatitis C who received antiviral treatment are eligible as long as PCR is negative.
• History of immunodeficiency (with the exception of hypogammaglobulinemia) or concurrent systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc., or chronic administration glucocorticoid equivalent of />10mg/day of prednisone) within 28 days of the first dose of study drug with exception of steroid used for IV contrast allergy. In addition, use of inhaled, topical, intranasal corticosteroids or local steroid injection (eg, intra- articular injection) is permitted.
• Requires chronic treatment with strong CYP3A inhibitors (List in Table 1). However, patients can be eligible after discontinuation of the perpetrator and a sufficient washout period of 7-days or 5 half-lives, whichever is longer. Patients also can be potentially eligible with dose reduction of zanubrutinib through the discussion with primary investigator and medical monitor.
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study Significant screening electrocardiogram (ECG) abnormalities including 2nd degree atrioventricular (AV) block, type II AV block, or 3rd degree block.
• Active bleeding or known bleeding diathesis (e.g., von Willebrand`s disease) or hemophilia History of stroke or intracranial hemorrhage within 6 months prior to study entry.
• Lactating or pregnant subjects. Administration of any investigational agent within 28 days of first dose of study drug.
• Patients who have undergone major surgery within 28 days or minor surgery within 3 days of first dose of study drug.
• Patients taking corticosteroids during the last 4 weeks, unless administered at a dose equivalent to /< 10 mg/day prednisone (over these 4 weeks).
• Known or suspected chronic active Epstein-Barr virus (CAEBV) infection Administration of a live, attenuated vaccine within 4 weeks before first mosunetuzumab administration or anticipation that such a live, attenuated vaccine will be required during the study Prior solid organ transplantation Prior allogeneic stem cell transplant (autologous stem cell transplants are allowed if conducted at least 100 days prior to C1D1.) Contraindication to tocilizumab Patients who have difficulty with or are unable to swallow oral medication, or have disease significantly affecting gastrointestinal function that would limit absorption of oral medication.
• Patients who have an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• Patients who have a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

Observational, non-interventional, retrospective, multicentre study focusing on efficacy and safety of zanubrutinib in daily clinical practice in patients with relapsed/refractory (R/R) marginal zone lymphoma.

Критерии включения

• 1. Histologically confirmed diagnosis of relapsed/refractory marginal zone lymphoma
• 2. Patients who received at least one dose of zanubrutinib under the Named patient program (D.M. 7 Sep 2017), between January 2021 and October 2023 3) Age≥18 at start of zanubrutinib therapy. 4) Signature of written informed consent to study participation and personal data processing.

Критерии исключения

• 1) relapsed/refractory marginal zone lymphoma patients who received zanubrutinib in a clinical trial context.

Описание

This is a purely retrospective and observational monocentric study

Критерии включения

• 1. Marginal zone lymphoma patients who were diagnosed and treated in our Hospital between December 2012 and December 2018.
• 2. Age ≥ 18 years at enrolment.
• 3. Written informed consent (if applicable)

Критерии исключения

• * none

Описание

The purpose of this clinical trial is to learn if the drugs Pirtobrutinib and Rituximab are effective for the treatment of newly diagnosed marginal zone lymphoma.

Критерии включения

• * Subjects aged ≥ 18 years.
• * ECOG Performance Status ≤ 2.
• * Histologically confirmed marginal zone lymphoma, including splenic, nodal, and extranodal sub-types per the enrolling institution.
• * Subjects must have an indication for treatment.
• * No prior systemic therapy for MZL except for the following:
• * Prior antibiotic therapy for H. pylori, C. psittaci, and B. burgdorferi
• * Prior antiviral therapy for HCV
• ---Note: Subjects are eligible if they had a prior splenectomy or other local surgical treatment or local radiation therapy without systemic therapy and now require their first ever systemic therapy. In the event of the receipt of radiation therapy, the minimum washout period is 14 days
• * Subjects with gastric MALT lymphoma must be H. pylori negative or have failed a trial of H. pylori eradication
• * Subjects with localized MALT lymphoma must be ineligible for, have refused or failed radiation therapy (washout period of 14 days)
• * Adequate organ function as defined as:
• * Hematologic:
• * Absolute neutrophil count ≥ 750 cells/mm3 (≥ 0.75 x 10/^9/L) independent of G-CSF support, unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case ANC of 500 cells/mm3 (0.5 x 10/^9/L) is permissible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow
• * Platelet count ≥ 50,000/mm3 (≥50 x 10/^9/L) independent of transfusion support unless there is documented bone marrow involvement in which case platelet count of ≥30,000 cells/mm3 (≥30 x 10/^9/L) is permissible. Subjects must be responsive to transfusion support if given for thrombocytopenia and subjects refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow.
• * Note: The platelet count threshold in the current study (≥50,000 cells/mm/^3 or ≥50 x 10/^9/L) is lower than normal threshold (≥75,000 cells/mm/^3 or ≥75 x 10/^9/L) as the majority of MZL subjects have lower than normal platelets due to splenomegaly and or autoimmune phenomena (which are related to the underlying lymphoma) and hence the lower than normal platelet count threshold for study entry
• * Hemoglobin ≥ 8 g/dL independent of transfusion support unless there is documented bone marrow involvement or splenomegaly with ensuing cytopenia in which case hemoglobin of ≥7 g/dL (≥70 g/L) is permissible. Subjects must be responsive to transfusion support if given for anemia and subjects refractory to transfusion support are not eligible. Also, there should be no evidence of myelodysplasia or hypoplastic bone marrow.
• * Hepatic:
• ----Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN)
• -----Subjects with liver involvement will be allowed to enroll with total bilirubin ≤3 x ULN
• * AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN ----Subjects with liver metastases will be allowed to enroll with AST and ALT levels ≤ 5 x ULN.
• * Renal: Estimated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula:
• * aPPT or PT or INR ≤ 1.5 X ULN
• * Life expectancy of />3 months, in the opinion of the investigator
• * For female subjects: Negative pregnancy test or evidence of post-menopausal status. The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
• * Women /< 50 years of age:
• ---Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
• * Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution; or
• * Underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• * Women ≥ 50 years of age:
• * Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
• * Had radiation-induced menopause with last menses />1 year ago; or
• * Had chemotherapy-induced menopause with last menses />1 year ago; or
• * Underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).
• * Female subjects of childbearing potential and male subjects with a sexual partner of childbearing potential must agree to use a highly effective method of contraception as described in Section 5.3.1.
• * Subjects may not plan to become pregnant or breastfeed within 1 month of the last dose of pirtobrutinib or 12 months following the last rituximab infusion
• * Ability to swallow oral tablets.
• * Subjects or their legal representatives must be able to read, understand, and provide informed consent to participate in the trial.

Критерии исключения

• * Subjects requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
• * Receipt of live-virus vaccines within 28 days prior to the initiation of study treatment or need for live-virus vaccines at any time during study treatment
• * Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug.
• * History of bleeding diathesis
• * Major surgery 4 weeks prior to starting study drug or who have not fully recovered from major surgery.
• * The diagnosis of another malignancy which is, in the opinion of the investigator, likely to negatively impact study participation or subject safety.
• * Subjects with CNS involvement
• * Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:
• * Cardiovascular disorders:
• * Grade 3 NYHA functional classification system of heart failure, uncontrolled or symptomatic arrhythmias ---Unstable angina pectoris or acute coronary syndrome within 2 months of first dose.
• ---History of myocardial infarction within 3 months prior to the first dose of study treatment
• ---Stroke or intracranial hemorrhage within 6 months prior to the first dose of study treatment.
• * QTc prolongation defined as a QTcF /> 470 ms. ----Correction of suspected drug induced QTcF prolongation can be attempted at the investigator`s discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
• * Correction for underlying bundle branch block (BBB) allowed .
• * Left ventricular ejection fraction /< 40% within 12 months prior to the first dose of study treatment.
• * Note: Subjects with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
• * Any other condition that would, in the Investigator`s judgment, contraindicate the subject`s participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, /[subjects may not receive the drug through a feeding tube/], etc.)
• * Known HIV infection.
• * Active hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis C.
• * Note: Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody /[anti-HBc/] and absence of HBsAg) are eligible, if HBV DNA PCR is negative. Subjects with positive anti-HBc and negative HBV DNA should be on prophylactic nucleo(t)side analogue therapy to prevent reactivation with serial HBV DNA PCR monitoring per section 6.6.9.
• Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• * Known active cytomegalovirus (CMV) infection
• * Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia /[AIHA/], idiopathic thrombocytopenic purpura /[ITP/]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts
• * Medical, psychiatric, cognitive, or other conditions that may compromise the subject`s ability to understand the subject information, give informed consent, comply with the study protocol or complete the study.
• * Known prior severe hypersensitivity to investigational product (IP) or any component in its formulations (NCI CTCAE v5.0 Grade ≥ 3).

Описание

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

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

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

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

Критерии включения

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

Критерии исключения

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

Описание

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

Критерии включения

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

Критерии исключения

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