Clinical Trials /

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

NCT04599634

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.

Related Conditions:
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  • Follicular Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

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

DrugSynonymsArms
ObinutuzumabExperimental treatment: FL Dose-finding
VenetoclaxExperimental treatment: FL Dose-finding
MagrolimabExperimental 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

NameTypeDescriptionInterventions
Experimental treatment: FL Dose-findingExperimentalMagrolimab 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-findingExperimentalMagrolimab 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 or Legally Authorized Representative (LAR) 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.

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

October 27, 2020