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.
Background: * Indolent B-cell malignancies are associated with frequent disease relapse * Standard frontline therapy includes a monoclonal anti-cluster of differentiation 20 (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 * Cluster of differentiation 47 (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 * Eastern Cooperative Oncology Group (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 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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
11
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.
For follicular lymphoma (FL) patients in dose finding phase, administered orally at a dose of 600mg or 800mg depending on tolerance, daily, cycles 1-12. For MZL (Marginal Zone Lymphoma), MCL (Mantle Cell Lymphoma) or CLL (Chronic Lymphocytic Leukemia) 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.
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.
Premedication with 650mg acetaminophen 30-60 minutes prior to obinutuzumab doses.
Premedication with 25-50mg diphenhydramine 30-60 minutes prior to obinutuzumab doses.
Premedication with 100mg intravenous prednisone/prednisolone 30-60 minutes before obinutuzumab infusion.
Premedication with intravenous methylprednisolone 80mg 30-60 minutes before obinutuzumab infusion.
Screening, baseline, window Cycle -1/pre cycle 1, cycles 6-12; cycles 3-9, end of treatment and follow-up.
Screening, baseline, window Cycle -1/pre cycle 1, cycles 6-12; cycles 3-9, end of treatment and follow-up.
Baseline, Cycle -1, Day 1, window Cycle -1/pre cycle 1, cycles 6-12, end of treatment and follow-up.
Screening, Cycle 7-12, Day 1 and end of treatment.
Screening, Cycle 7-12, Day 1 and end of treatment.
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Number of Grades 3, 4, and/or 5 Dose-limiting Toxicities (DLT) Probably and/or Definitely Related to Triplet Combination Therapy
Incidence of dose limiting toxicities (i.e., grade and frequency) to determine safety and tolerability were measured by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade is 3 is severe. Grade 4 is life threatening, and Grade 5 is death related to adverse event. A DLT is defined as any grade 3 or higher adverse event that is clinically relevant and deemed probably or definitely related to any of the study drugs or to the combination therapy and occurs during the venetoclax dose-finding period. Exceptions are non-hematologic grade 3 nausea, vomiting or diarrhea. Grade 3 fatigue, electrolyte disturbances, magrolimab or obinutuzumab infusion reactions, and/or grade 3 laboratory abnormalities. Hematologic grade 3 neutropenia, thrombocytopenia, anemia and hemolytic anemia. And/or grade 3 or 4 lymphopenia.
Time frame: 4 weeks for Arm 1 and 5 weeks for Arm 2
Overall Response Rate (ORR) (Complete Response + Partial Response)
ORR was determined and reported from individual cohorts and histological diagnosis. ORR was measured by the Lugano response criteria for Follicular Lymphoma, Mantle Cell Lymphoma and Marginal Zone Lymphoma; and the International Workshop on Chronic Lymphocytic Leukemia criteria for Chronic Lymphocytic Leukemia. Complete response is complete resolution of the lesion on imaging. Partial response is 50% or greater reduction in the maximum diameter of the lesion from its original tumor size on imaging. Disease progression is an increase of 50% or more in size of a previously involved site measuring ≥1.5 cm.
Time frame: From the start of the treatment until disease progression/recurrence, median follow-up of 17.4 months
Duration of Response (DOR)
DOR was estimated using Kaplan-Meier curves and reported along with a 95% confidence interval. DOR was measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, death, or, in the absence of progressive disease (PD), date of last assessment. DOR was measured by the Lugano response criteria for Follicular Lymphoma, Mantle Cell Lymphoma and Marginal Zone Lymphoma; and the International Workshop on Chronic Lymphocytic Leukemia criteria for Chronic Lymphocytic Leukemia. Complete response is complete resolution of the lesion on imaging. Partial response is 50% or greater reduction in the maximum diameter of the lesion from its original tumor size on imaging. Disease progression is an increase of 50% or more in size of a previously involved site measuring ≥1.5 cm.
Time frame: From the start of the treatment until time of disease relapse, disease progression, or death, whichever occurs first, an average of 10.9 months.
Event-free Survival (EFS)
EFS was estimated using Kaplan-Meier curves and reported along with a 95% confidence interval. EFS is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, alternative anti-lymphoma therapy including radiation, or death, whichever occurs first, measured by the Lugano response criteria for Follicular Lymphoma, Mantle Cell Lymphoma and Marginal Zone Lymphoma; and the International Workshop on Chronic Lymphocytic Leukemia criteria for Chronic Lymphocytic Leukemia. Disease progression is an increase of 50% or more in size of a previously involved site measuring ≥1.5 cm.
Time frame: From the start of the treatment until time of disease relapse, disease progression, alternative anti-lymphoma therapy including radiation, or death, whichever occurs first, up to 20 months
Progression-free Survival
PFS was estimated using Kaplan-Meier curves and reported along with a 95% confidence interval. PFS is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, or death, whichever occurs first. PFS was measured by the Lugano response criteria for Follicular Lymphoma, Mantle Cell Lymphoma and Marginal Zone Lymphoma; and the International Workshop on Chronic Lymphocytic Leukemia criteria for Chronic Lymphocytic Leukemia. Disease progression is an increase of 50% or more in size of a previously involved site measuring ≥1.5 cm.
Time frame: From the start of the treatment until time of disease relapse, disease progression, or death, whichever occurs first, an average of 13.9 months.
Overall Survival (OS)
OS was estimated using Kaplan-Meier curves and reported along with a 95% confidence interval. OS is defined as the time from study enrollment until death from any cause.
Time frame: From the start of the treatment until death from any cause, an average of 15.6 months.
Percentage of Participants With Chronic Lymphocytic Leukemia (CLL) With Complete Molecular Remission (MRD Negativity)
The percentage of participants who are MRD negative was determined by circulating tumor deoxyribonucleic acid (ctDNA) assay after therapy. Negative is undetectable CLL cells on peripheral blood flow cytometry after end of treatment.
Time frame: From the start of the treatment until disease progression/recurrence, an average of 3.3 months.
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