Venetoclax With Obinutuzumab and Magrolimab (VENOM) in Relapsed and Refractory Indolent B-cell Malignancies
A Phase 1 Study of Venetoclax With Obinutuzumab and Magrolimab (VENOM) in Relapsed and Refractory Indolent B-cell Malignancies
2 other identifiers
interventional
11
1 country
1
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_1
Started Dec 2021
Typical duration for phase_1
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
October 22, 2020
CompletedFirst Posted
Study publicly available on registry
October 23, 2020
CompletedStudy Start
First participant enrolled
December 16, 2021
CompletedPrimary Completion
Last participant's last visit for primary outcome
March 29, 2024
CompletedStudy Completion
Last participant's last visit for all outcomes
June 20, 2024
CompletedResults Posted
Study results publicly available
February 4, 2025
CompletedFebruary 4, 2025
January 1, 2025
2.3 years
October 22, 2020
December 17, 2024
January 13, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
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.
4 weeks for Arm 1 and 5 weeks for Arm 2
Secondary Outcomes (6)
Overall Response Rate (ORR) (Complete Response + Partial Response)
From the start of the treatment until disease progression/recurrence, median follow-up of 17.4 months
Duration of Response (DOR)
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)
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
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)
From the start of the treatment until death from any cause, an average of 15.6 months.
- +1 more secondary outcomes
Other Outcomes (1)
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
From the first study intervention, Day 1 through 30 days after the last dose of study agent was administered, an average of 6 months.
Study Arms (4)
Experimental treatment: FL dose expansion
EXPERIMENTALWindow of magrolimab intravenous (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.
Experimental treatment: FL Dose-finding
EXPERIMENTALMagrolimab intravenous (IV) with a 1 mg/kg priming dose followed by 30mg/kg loading and maintenance doses + obinutuzumab IV 1000mg + venetoclax 800mg by mouth (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: Dose-limiting toxicity (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 Dose level (DL (-1) of venetoclax 600mg with magrolimab and obinutuzumab.
Experimental treatment: MZL, MCL, and CLL Dose-finding
EXPERIMENTALMagrolimab intravenous (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: Dose-limiting toxicity (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 Dose level (DL (-1) of venetoclax 200mg with magrolimab and obinutuzumab.
Experimental treatment: mzl, MCL, CLL dose expansion
EXPERIMENTALWindow of magrolimab intravenous (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.
Interventions
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.
Eligibility Criteria
You may qualify if:
- Patients must have a confirmed histologic diagnosis of an indolent cluster of differentiation 20 (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, National Cancer Institute (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
- p deletion
- +29 more criteria
You may not qualify if:
- 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 deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) positive. NOTE: Subjects who are hepatitis B core antibody positive will need to have a negative hepatitis B virus (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 cytochrome P450 (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
- +6 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892, United States
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Dr. Mark J. Roschewski
- Organization
- National Cancer Institute
Study Officials
- PRINCIPAL INVESTIGATOR
Mark J Roschewski, M.D.
National Cancer Institute (NCI)
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- No
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- NIH
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Principal Investigator
Study Record Dates
First Submitted
October 22, 2020
First Posted
October 23, 2020
Study Start
December 16, 2021
Primary Completion
March 29, 2024
Study Completion
June 20, 2024
Last Updated
February 4, 2025
Results First Posted
February 4, 2025
Record last verified: 2025-01
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, ICF
- Time Frame
- Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
- Access Criteria
- Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.
All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).