Venetoclax With Obinutuzumab and Magrolimab (VENOM) in Relapsed and Refractory Indolent B-cell Malignancies

Study Overview
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Brief Summary
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Background: B-cell lymphoma is a cancer of certain white blood cells (called lymphocytes). These cells are found in lymph nodes. The cancer can cause enlargement of the lymph nodes leading to pain and discomfort. Swollen lymph nodes can also press on nearby organs such as liver and kidneys which can affect normal functioning of the organs. Researchers think that a new combination of drugs may be able to help. Objective: To find out if it is safe to give the combination of Magrolimab, Obinutuzumab and Venetoclax to people with B-cell lymphomas. Eligibility: Adults age 18 and older with an indolent B-cell lymphoma whose disease has returned or progressed after other treatment. Indolent B-cell lymphoma for this protocol is defined as having either follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma or marginal zone lymphoma. Design: Participants will be screened under a separate protocol. Participants will have 28-day 'cycles' of treatment. They will take Venetoclax by mouth daily. They will get Obinutuzumab and Magrolimab by intravenous (IV) infusion. Treatment will last for about 8 months. They may be able to have more cycles of treatment if their cancer is responding well. Participants will have physical exams, medical histories, and medicine reviews. Data about how they function in their daily activities will be obtained. They will have blood and urine tests. They may have bone marrow tests. Participants will have imaging scans. These will include computed tomography (CT) and/or magnetic resonance imaging (MRI) scans and positron emission tomography (PET) scans. Participants may give a cheek swab or saliva sample. They may give tumor tissue and bone marrow samples. These samples may be used for gene testing. Participants will have a follow-up visit about 30 days after treatment ends. Then they will have visits every 3 months for the first 2 years, every 6 months for the next 3 years, and then yearly after that.

Detailed Description
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Background: Indolent B-cell malignancies are associated with frequent disease relapse Standard frontline therapy includes a monoclonal anti-CD20 antibody with or without chemotherapy; novel targeted therapies have changed the treatment landscape and are preferred therapy for some patients with high-risk molecular features Targeted therapies given indefinitely add to drug resistance, treatment-emergent toxicities, and non-compliance CD47 is a rational target for indolent B-cell malignancies; CD47 expression is higher in tumor cells than normal B-cells, and blocking CD47 results in phagocytosis of tumor cells Magrolimab is an anti-CD47 monoclonal antibody with activity in refractory indolent lymphomas when combined with rituximab (a first generation anti-CD20 monoclonal antibody) Obinutuzumab is a novel anti-CD20 monoclonal antibody with enhanced binding to the Fc receptor that may improve antibody-dependent cell-mediated cytotoxicity (ADCC), and phagocytosis, when combined with magrolimab We aim to test the safety and efficacy of venetoclax when added to the backbone of magrolimab and obinutuzumab in patients with relapsed or refractory indolent B-cell malignancies Treatment duration will be response-adapted and time-limited in all patients Objective: -To determine the safety of the triplet combination of venetoclax, magrolimab and obinutuzumab in relapsed and refractory indolent B-cell malignancies Eligibility: Follicular lymphoma (FL) (grades 1-2, or 3a), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) with greater than or equal to 2 prior therapies, with at least one of those therapies containing an anti-CD20 monoclonal antibody ECOG performance status 0-2 Adequate bone marrow and organ function Design: Phase 1 study with expansion cohorts of up to 76 patients with relapsed or refractory FL, MZL, MCL or CLL The safety profile of magrolimab, venetoclax, and obinutuzumab will first be determined in a dose-finding phase of up to 24 patients (6-12 patients with FL and 6-12 patients with MZL, MCL or CLL). Patients without dose-limiting toxicity (DLT) will receive an additional 5 cycles (total 6 cycles) of the triplet combination. After dose-finding is completed, expansion cohorts of each histology will first receive magrolimab and obinutuzumab for 2 cycles in a window for translational research. After the window, venetoclax will be added and patients will receive 6 cycles (total 8 cycles) of the triplet combination. Patients who achieve a complete response (CR) (after a total of 6 cycles of the triplet combination) will stop treatment and initiate active monitoring with radiologic imaging and assays for circulating tumor DNA (ctDNA); if these patients relapse, they can be retreated with an 6 additional cycles. Patients who achieve partial response (PR) after 6 cycles of the triplet will continue for an additional 6 cycles; then, will initiate active monitoring.

Official Title
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A Phase 1 Study of Venetoclax With Obinutuzumab and Magrolimab (VENOM) in Relapsed and Refractory Indolent B-cell Malignancies

Conditions
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Follicular Lymphoma, Marginal Zone Lymphoma, Mantle Cell Lymphoma, Chronic Lymphocytic Lymphoma, B-Cell Lymphoma

Intervention / Treatment
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* Drug: Obinutuzumab
* Drug: Venetoclax
* Drug: Magrolimab


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients must have a confirmed histologic diagnosis of an indolent CD20 positive B-cell lymphoma according to the criteria established by the 2016 version of the World Health Organization (WHO) classification system. Lymphomas with any prior CD20 expression (by immunohistochemistry or flow cytometry) will be considered eligible. Diagnosis must be confirmed by Laboratory of Pathology, NCI and the following indolent B-cell lymphomas are included: Follicular lymphoma (FL): must be grade 1-2 or 3a Marginal zone lymphoma (MZL) Mantle cell lymphoma (MCL) Chronic lymphocytic leukemia (CLL) Participant must have relapsed and/or refractory disease, as defined below: FL: relapsed after and/or refractory to at least two (2) prior lines of therapy with at least one of those therapies containing an anti-CD20 monoclonal antibody. NOTE: Participants with FL may be eligible after one (1) prior line of therapy if they have either: Follicular lymphoma international prognostic index (FLIPI) >=2 (120) Disease progression within 24 months of the end of last therapy (POD24) MZL: relapsed after and/or refractory to at least two (2) prior lines of therapy, with at least one containing an anti-CD20 monoclonal antibody. MCL: relapsed after and/or refractory to at least two (2) prior lines of therapy, with at least one containing an anti-CD20 monoclonal antibody. NOTE: Participants with MCL may be eligible after one (1) prior line of therapy if they have either: Blastoid or pleomorphic histology 17p deletion TP53 mutation or deletion Ki67 >=30% Received a BTK inhibitor as first line therapy CLL: relapsed after and/or refractory to at least two (2) prior lines of therapy. Participants with CLL are not required to have had therapy containing anti-CD20. NOTE: Participants with CLL may be eligible after one (1) prior line of therapy if they have either: 17p deletion TP53 mutation or deletion Received both a Bruton s Tyrosine Kinase (BTK) inhibitor AND a B-cell lymphoma 2 (BCL2) inhibitor as first line therapy NOTE: Participants must not have received prior treatment with a CD47 or SIRP targeting agent -Adequate tissue from diagnostic biopsy (archival or fresh) must be available for performance of correlative studies NOTE: Tumor tissue may be from any previously collected tissue and adequacy is at the discretion of the Principal Investigator. If prior tissue is not available, patient must be willing to undergo baseline tissue biopsy (for patients with known or suspected bone marrow involvement, bone marrow may be acceptable tissue per discretion of the investigator). -Patients must have at least evaluable disease as assessed by clinical exam (i.e., palpable lymphadenopathy, measurable skin lesions, etc.), laboratory assessment (i.e., lymphoma involvement of bone marrow or peripheral blood by morphology, cytology or flow cytometry), and/or imaging (measurable lymph nodes or masses on CT or MRI and/or evaluable FDG-avid lesions on PET). Patients may also have measurable disease. NOTE: Patients with known active CNS lymphoma are not eligible. - Age greater than or equal to 18 years NOTE: Because no dosing or adverse event data are currently available on the use of magrolimab in patients <18 years of age, children are excluded from this study ECOG performance status less than or equal to 2 Adequate organ function as evidenced by the following laboratory parameters: Absolute neutrophil count (ANC): greater than or equal to 1,000/mm(3) Platelets: greater than or equal to 50,000/mcL (transfusions permitted) Hemoglobin: greater than or equal to 9 g/dL (transfusions permitted). NOTE: Patients must have required fewer than 2 units of RBC transfusion in the 4 weeks prior to screening. Additional transfusions after screening and prior to enrollment are acceptable. Renal function: Glomerular filtration rate (GFR) greater than or equal to 30 mL/min/1.73 m(2) as estimated by the Modification of Diet in Renal Disease (MDRD) abbreviated formula. If not on target, a 24-hour urine creatinine clearance can be used to directly measure. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): less than or equal to 3.0 x the upper ULN NOTE: Patients with liver involvement with lymphoma less than or equal to 5.0 x ULN -Bilirubin less than or equal to 1.5 X ULN NOTE: Patients with Gilbert's syndrome may have a bilirubin level > 1.5 X ULN, per discretion of the investigator -The effects of the study drugs on the developing human fetus are unknown. For this reason, women of childbearing potential (WOCBP) and men must agree to use effective contraception when sexually active. This applies for the time period between signing of the informed consent form and for the following time frames after the last dose of drug, whichever is later: 90 days after the last dose of magrolimab, 30 days after the last dose of venetoclax, and 18 months after the last dose of obinutuzumab for women and 6 months after the last dose of obinutuzumab for men. Men should refrain also from donating sperm for these same timeframes, and women must also refrain from donating eggs. NOTE: WOCBP is defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal (i.e., amenorrheic for >12 months without alternative medical cause; post-menopausal status in females under 55 years of age should be confirmed with a serum follicle-stimulating hormone [FSH] level within applicable local laboratory reference range for postmenopausal women). Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control (failure rate of less than 1%), e.g., intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner and sexual abstinence. The use of condoms by male patients is required unless the female partner is permanently sterile. Ability of patient to understand and the willingness to sign a written informed consent document Patients with prior autologous or allogeneic stem cell transplantation are potentially eligible if transplanted > 6 months ago, and no active graft-vs-host disease requiring immunosuppressants. EXCLUSION CRITERIA: Concomitant use of any investigational anti-lymphoma treatment Known primary or acquired immunodeficiency syndrome (e.g., HIV) or known infection with human T-cell leukemia virus 1 (HTLV1). NOTE: HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the study drugs. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. In the future, appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. History of hemolytic anemia or autoimmune thrombocytopenia in the 3 months prior to enrollment. Patients with positive Direct Agglutination Test (DAT) but no evidence of clinically active hemolysis are eligible. Hepatitis B surface antigen or hepatitis B DNA PCR positive. NOTE: Subjects who are hepatitis B core antibody positive will need to have a negative HBV DNA PCR result before enrollment. Those with a positive PCR for hepatitis B are excluded. Pregnant or breastfeeding patients. NOTE: Pregnant women are excluded in this study because of the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study drugs, breastfeeding should be discontinued. Requirement to continue on any of the medications that have significant potential for drug-drug interactions with the study regimen. For example, the following: Use of strong CYP3A inhibitors 7 days prior to or at initiation of venetoclax, and during ramp-up phase is contraindicated in patients with MZL, CLL and MCL. For FL patients, use of strong CYP3A inhibitors is contraindicated 7 days prior to and during the first two weeks of venetoclax treatment. Consumption of one or more of the following within 3 days prior to the first dose of any study drug: Grapefruit or grapefruit products Seville oranges including marmalade containing Seville oranges Star fruit Uncontrolled intercurrent illness including, but not limited to the following that may limit interpretation of results or that could increase risk to the patient at the discretion of the investigator: Active hepatitis C infection. NOTE: Subjects who are hepatitis C antibody positive will need to have a negative HCV PCR result before enrollment. Those with a positive PCR for hepatitis C are excluded. Any second malignancy that requires active systemic therapy Known mental or physical illness that would interfere with cooperation with the requirements of the trial or confound the results or interpretation of the results of the trial and, in the opinion of the treating investigator, would make the patient inappropriate for entry into the study Known active infection, or any major infection requiring treatment with IV antibiotics or hospitalization within 4 weeks prior to commencement of the study treatment. Vaccination with a live vaccine less than or equal to 28 days prior to commencement of the study treatment. Inability or unwillingness to swallow a large number of tablets. Known hypersensitivity to any of the study medications or their excipients. History of inflammatory bowel disease (e.g., Crohn s disease or ulcerative colitis). History of malabsorption syndrome felt to be significant enough to interfere with enteral absorption at the discretion of the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental treatment: FL dose expansion<br>Window of magrolimab IV with a 1 mg/kg priming dose followed by 30mg/kg loading and maintenance doses + obinutuzumab IV 1000mg combination for two (2) cycles (28-days each, Cycles -2 and -1), then venetoclax will be added at target dose (dose determined from Arm 1). Triplet combination treatment with magrolimab + obinutuzumab + venetoclax will be 6 cycles (28-days each, Cycles 1-6); further treatment will be response-adapted. | Drug: Obinutuzumab<br>* Administered intravenously, on Days 1, 2, 8 and 15 of Cycle 1 at doses escalating from 100mg - 1000mg then on the first day for all subsequent cycles at 1000mg for dose finding phase. For expansion phase, administered on Days 1, 2, 8 and 15 of Cycle 2 at doses escalating from 100mg - 1000mg then on the first day for all subsequent cycles at 1000mg.<br>Drug: Venetoclax<br>* For FL patients in dose finding phase, administered orally at a dose of 600mg or 800mg depending on tolerance, daily, cycles 1-12. For MZL, MCL or CLL patients in dose finding phase administered at an escalating dose from 20mg-400mg Cycle 1 on days 1-35, and at a dose of 400mg per day for Cycles 2-12. Patients in expansion phase will receive target dose established from dose finding cohorts daily for all 12 cycles.<br>Drug: Magrolimab<br>* Administered intravenously, starting at 1 mg/kg on second day of first cycle then 30mg/kg on days 8, 15 and 22 of cycle 1 and days 1 and 15 of cycles 2-12 for patients in both the dose finding and expansion phases.<br>|
| Experimental: Experimental treatment: FL Dose-finding<br>Magrolimab IV with a 1 mg/kg priming dose followed by 30mg/kg loading and maintenance doses + obinutuzumab IV 1000mg + venetoclax 800mg PO combination administered to 6 patients for six (6) cycles (28-days each, Cycles 1-6); further treatment with additional cycles will be response-adapted. Note: DLT assessment of the magrolimab + obinutuzumab + venetoclax triplet will take place during Cycle 1. If =2 patients experience DLT, an additional 6 patients will be enrolled at DL(-1) of venetoclax 600mg with magrolimab and obinutuzumab. | Drug: Obinutuzumab<br>* Administered intravenously, on Days 1, 2, 8 and 15 of Cycle 1 at doses escalating from 100mg - 1000mg then on the first day for all subsequent cycles at 1000mg for dose finding phase. For expansion phase, administered on Days 1, 2, 8 and 15 of Cycle 2 at doses escalating from 100mg - 1000mg then on the first day for all subsequent cycles at 1000mg.<br>Drug: Venetoclax<br>* For FL patients in dose finding phase, administered orally at a dose of 600mg or 800mg depending on tolerance, daily, cycles 1-12. For MZL, MCL or CLL patients in dose finding phase administered at an escalating dose from 20mg-400mg Cycle 1 on days 1-35, and at a dose of 400mg per day for Cycles 2-12. Patients in expansion phase will receive target dose established from dose finding cohorts daily for all 12 cycles.<br>Drug: Magrolimab<br>* Administered intravenously, starting at 1 mg/kg on second day of first cycle then 30mg/kg on days 8, 15 and 22 of cycle 1 and days 1 and 15 of cycles 2-12 for patients in both the dose finding and expansion phases.<br>|
| Experimental: Experimental treatment: MZL, MCL, and CLL Dose-finding<br>Magrolimab IV with a 1 mg/kg priming dose followed by 30mg/kg loading and maintenance doses + obinutuzumab IV 1000mg + venetoclax ramp-up to target dose of 400mg over 5 weeks (35 days, Cycle 1) administered to 6 patients. Triplet combination of magrolimab + obinutuzumab + venetoclax (target dose, no ramp-up) will continue for five (5) additional cycles (28-days each, Cycles 2-6); further treatment with additional cycles will be response-adapted. Note: DLT assessment of the magrolimab + obinutuzumab + venetoclax triplet will take place during Cycle 1. If =2 patients experience DLT, an additional 6 patients will be enrolled at DL(-1) of venetoclax 200mg with magrolimab and obinutuzumab. | Drug: Obinutuzumab<br>* Administered intravenously, on Days 1, 2, 8 and 15 of Cycle 1 at doses escalating from 100mg - 1000mg then on the first day for all subsequent cycles at 1000mg for dose finding phase. For expansion phase, administered on Days 1, 2, 8 and 15 of Cycle 2 at doses escalating from 100mg - 1000mg then on the first day for all subsequent cycles at 1000mg.<br>Drug: Venetoclax<br>* For FL patients in dose finding phase, administered orally at a dose of 600mg or 800mg depending on tolerance, daily, cycles 1-12. For MZL, MCL or CLL patients in dose finding phase administered at an escalating dose from 20mg-400mg Cycle 1 on days 1-35, and at a dose of 400mg per day for Cycles 2-12. Patients in expansion phase will receive target dose established from dose finding cohorts daily for all 12 cycles.<br>Drug: Magrolimab<br>* Administered intravenously, starting at 1 mg/kg on second day of first cycle then 30mg/kg on days 8, 15 and 22 of cycle 1 and days 1 and 15 of cycles 2-12 for patients in both the dose finding and expansion phases.<br>|
| Experimental: Experimental treatment: mzl, MCL, CLL dose expansion<br>Window of magrolimab IV with a 1 mg/kg priming dose followed by 30mg/kg loading and maintenance doses + obinutuzumab IV 1000mg combination for two (2) cycles (28-day cycles, Cycles -2 and -1), then venetoclax safety ramp-up to target dose (dose determined from Arm 2) over 5 weeks (35-days, Cycle 1). Triplet combination treatment with magrolimab + obinutuzumab + venetoclax (target dose, no ramp-up) will continue for 5 additional cycles (28-days each, Cycles 2-6); further treatment will be response-adapted. | Drug: Obinutuzumab<br>* Administered intravenously, on Days 1, 2, 8 and 15 of Cycle 1 at doses escalating from 100mg - 1000mg then on the first day for all subsequent cycles at 1000mg for dose finding phase. For expansion phase, administered on Days 1, 2, 8 and 15 of Cycle 2 at doses escalating from 100mg - 1000mg then on the first day for all subsequent cycles at 1000mg.<br>Drug: Venetoclax<br>* For FL patients in dose finding phase, administered orally at a dose of 600mg or 800mg depending on tolerance, daily, cycles 1-12. For MZL, MCL or CLL patients in dose finding phase administered at an escalating dose from 20mg-400mg Cycle 1 on days 1-35, and at a dose of 400mg per day for Cycles 2-12. Patients in expansion phase will receive target dose established from dose finding cohorts daily for all 12 cycles.<br>Drug: Magrolimab<br>* Administered intravenously, starting at 1 mg/kg on second day of first cycle then 30mg/kg on days 8, 15 and 22 of cycle 1 and days 1 and 15 of cycles 2-12 for patients in both the dose finding and expansion phases.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | Incidence of adverse events (i.e., grade and frequency) | initiation of study drug until 30 days after last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | Will be determined and reported from individual cohorts and histological diagnosis | From the start of the treatment until disease progression/recurrence | 
| Duration of response | Will be determined and reported along with a 95% confidence interval. | From the start of the treatment until time of disease relapse, disease progression, or death, whichever occurs first | 
| Event-free survival | Will be determined and reported along with a 95% confidence interval. | From the start of the treatment until time of disease relapse, disease progression, alternative anti-lymphoma therapy including radiation, or death, whichever occurs first. | 
| Progression-free survival | Will be determined and reported along with a 95% confidence interval. | From the start of the treatment until time of disease relapse, disease progression, or death, whichever occurs first | 
| Overall survival | Will be determined and reported along with a 95% confidence interval. | From the start of the treatment until death from any cause. | 
| Complete molecular remission (MRD negativity) in CLL patients | Rate of MRD negativity | From the start of the treatment until disease progression/recurrence | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD47, Monoclonal Anti-CD20 Antibody, Follicular Lymphoma, Marginal Zone Lymphoma