Description:
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.
Title
- Brief Title: Venetoclax With Obinutuzumab and Magrolimab (VENOM) in Relapsed and Refractory Indolent B-cell Malignancies
- Official Title: A Phase 1 Study of Venetoclax With Obinutuzumab and Magrolimab (VENOM) in Relapsed and Refractory Indolent B-cell Malignancies
Clinical Trial IDs
- ORG STUDY ID:
200162
- SECONDARY ID:
20-C-0162
- NCT ID:
NCT04599634
Conditions
- Follicular Lymphoma
- Marginal Zone Lymphoma
- Mantle Cell Lymphoma
- Chronic Lymphocytic Lymphoma
- B-Cell Lymphoma
Interventions
Drug | Synonyms | Arms |
---|
Obinutuzumab | | Experimental treatment: FL Dose-finding |
Venetoclax | | Experimental treatment: FL Dose-finding |
Magrolimab | | Experimental treatment: FL Dose-finding |
Purpose
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
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Experimental treatment: FL Dose-finding | Experimental | 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. | - Obinutuzumab
- Venetoclax
- Magrolimab
|
Experimental treatment: MZL, MCL, and CLL Dose-finding | Experimental | 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. | - Obinutuzumab
- Venetoclax
- Magrolimab
|
Eligibility Criteria
- 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 lymphoma (CLL)
- Relapsed and/or refractory disease that has failed at least two (2) prior lines of
therapy with at least one of those therapies containing an anti-CD20 monoclonal
antibody. Patients must not have received prior treatment with a CD47 or SIRP alpha
targeting agent.
NOTE: Patients with CLL are not required to have had therapy containing anti-CD20.
-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 9.5 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 (SqrRoot) ULN
NOTE: Patients with Gilbert's syndrome may have a bilirubin level > 1.5 (SqrRoot) 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: 120 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.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Safety and tolerability |
Time Frame: | initiation of study drug until 30 days after last dose |
Safety Issue: | |
Description: | Incidence of adverse events (i.e., grade and frequency) |
Secondary Outcome Measures
Measure: | Overall response rate |
Time Frame: | From the start of the treatment until disease progression/recurrence |
Safety Issue: | |
Description: | Will be determined and reported from individual cohorts and histological diagnosis |
Measure: | Duration of response |
Time Frame: | From the start of the treatment until time of disease relapse, disease progression, or death, whichever occurs first |
Safety Issue: | |
Description: | Will be determined and reported along with a 95% confidence interval. |
Measure: | Event-free survival |
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. |
Safety Issue: | |
Description: | Will be determined and reported along with a 95% confidence interval. |
Measure: | Progression-free survival |
Time Frame: | From the start of the treatment until time of disease relapse, disease progression, or death, whichever occurs first |
Safety Issue: | |
Description: | Will be determined and reported along with a 95% confidence interval. |
Measure: | Overall survival |
Time Frame: | From the start of the treatment until death from any cause. |
Safety Issue: | |
Description: | Will be determined and reported along with a 95% confidence interval. |
Measure: | Complete molecular remission (MRD negativity) in CLL patients |
Time Frame: | From the start of the treatment until disease progression/recurrence |
Safety Issue: | |
Description: | Rate of MRD negativity |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Not yet recruiting |
Lead Sponsor: | National Cancer Institute (NCI) |
Trial Keywords
- CD47
- Monoclonal Anti-CD20 Antibody
- Follicular Lymphoma
- Marginal Zone Lymphoma
Last Updated
September 1, 2021