Clinical Trials /

Ibrutinib + Venetoclax in Untreated WM

NCT04273139

Description:

This study evaluates the safety and efficacy of Ibrutinib combined with Venetoclax (IVEN) in the treatment of adults diagnosed with Waldenstrom's macroglobulinemia (WM) cancer with a specific MYD88 gene mutation. This research study involves an experimental drug combination of targeted therapies. The names of the study drugs involved in this study are: - Venetoclax - ibrutinib

Related Conditions:
  • Waldenstrom Macroglobulinemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ibrutinib + Venetoclax in Untreated WM
  • Official Title: Phase II Study on the Combination of Ibrutinib and Venetoclax in Treatment naïve Patients With Waldenström Macroglobulinemia

Clinical Trial IDs

  • ORG STUDY ID: 19-651
  • NCT ID: NCT04273139

Conditions

  • Waldenstrom Macroglobulinemia
  • MYD88 Gene Mutation

Interventions

DrugSynonymsArms
IBRUTINIBImbruvicaIbrutinib and Venetoclax (2 dose ramp up)
VenetoclaxVenclextaIbrutinib and Venetoclax (2 dose ramp up)

Purpose

This study evaluates the safety and efficacy of Ibrutinib combined with Venetoclax (IVEN) in the treatment of adults diagnosed with Waldenstrom's macroglobulinemia (WM) cancer with a specific MYD88 gene mutation. This research study involves an experimental drug combination of targeted therapies. The names of the study drugs involved in this study are: - Venetoclax - ibrutinib

Detailed Description

      -  This research study is a Phase II clinical trial. Phase II clinical trials test the
           safety and effectiveness of an investigational drug to learn whether the drug works in
           treating a specific disease. "Investigational" means that the drug is being studied.

        -  The names of the study drugs involved in this study are:

             -  Venetoclax

             -  ibrutinib

        -  The research study procedures include screening for eligibility and study treatment
           including evaluations and follow up visits.

             -  Participants will be on the research study for up to 2 years on combined venetoclax
                and ibrutinib and 4 years of follow-up .

             -  It is expected that about 50 people will take part in this research study.

        -  The U.S. Food and Drug Administration (FDA) has not approved venetoclax for your
           specific disease but it has been approved for other uses.

           -- Venetoclax is a targeted therapy that blocks BCL-2, a protein that is important for
           the survival of WM cells. Laboratory studies and early clinical data have shown that the
           investigational new agent, venetoclax, may kill cancer cells and may cause tumors to
           shrink.

        -  The U.S. Food and Drug Administration (FDA) has approved ibrutinib as a treatment option
           for this disease.

           --Ibrutinib is a targeted therapy that blocks BTK. It has been FDA approved in chronic
           lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma
           (MCL), marginal zone lymphoma (MZL), chronic graft vs. host disease (cGVHD), and
           Waldenstrom's macroglobulinemia (WM). It is also used in research studies in
           participants with recurrent B-cell lymphoma), diffuse large B-cell lymphoma (DLBCL), and
           prolymphocytic leukemia. In a study of ibrutinib in relapsed/refractory WM patients,
           response rates were high and the treatment was well tolerated.

        -  The U.S. Food and Drug Administration (FDA) has not approved the combination of
           ibrutinib and venetoclax as a treatment for any disease.

        -  The U.S. Food and Drug Administration (FDA) has not approved the MYD88 test. This test
           is investigational.
    

Trial Arms

NameTypeDescriptionInterventions
Ibrutinib and Venetoclax (3 dose ramp up)ExperimentalThe research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. First 12 participants Ibrutinib will be administered at a predetermined dose, once daily for 28 days TLS Prophylaxis (Treatment to reduce risk of tumor lysis syndrome) prior to first dose of venetoclax (and for at least the first 2 weeks of treatment) Venetoclax Cycle 2-24. PO daily, predetermined dosage ramp up during cycle 2.
  • IBRUTINIB
  • Venetoclax
Ibrutinib and Venetoclax (2 dose ramp up)ExperimentalThe research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. Ibrutinib will be administered at a predetermined dose, once daily for 28 days TLS Prophylaxis (Treatment to reduce risk of tumor lysis syndrome) prior to first dose of venetoclax (and for at least the first 2 weeks of treatment) Venetoclax Cycle 2-24. PO daily, predetermined dosage ramp up schedule during cycle 2.
  • IBRUTINIB
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must meet the following criteria on screening examination to be eligible
             to participate. Screening evaluations including consent, physical exam, and laboratory
             assessments will be done within 30 days prior to Cycle 1 Day 1. Bone marrow biopsy &
             aspirate, and CT C/A/P will be done within 90 days prior to Cycle 1 Day 1.

          -  Clinicopathological diagnosis of Waldenström macroglobulinemia [28].

          -  Known tumor expression of mutated MYD88 performed by a CLIA certified laboratory.

          -  Symptomatic disease meeting criteria for treatment using consensus panel criteria from
             the Second International Workshop on Waldenström macroglobulinemia [29].

          -  Participants with symptomatic hyperviscosity (e.g. nosebleeds, headaches, blurred
             vision) must undergo plasmapheresis prior to treatment initiation.

          -  Age ≥ 18 years

          -  ECOG performance status ≤2 (see Appendix A)

          -  Measurable disease, defined as presence of serum immunoglobin M (IgM) with a minimum
             IgM level of >2 times the upper limit of normal of each institution is required

          -  At the time of screening, participants must have acceptable organ and marrow function
             as defined below:

               -  Absolute neutrophil count ≥500/uL (no growth factor permitted)

               -  Platelets ≥50,000/uL (no platelet transfusions permitted)

               -  Hemoglobin ≥ 7 g/dL (transfusions permitted)

               -  Total bilirubin < 1.5 x institutional ULN

               -  AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN

               -  Estimated GFR ≥30 mL/min

          -  Females of childbearing potential (FCBP) must use one reliable form of contraception
             or have complete abstinence from heterosexual intercourse during the following time
             periods related to this study: 1) while participating in the study; and 2) for at
             least 90 days after discontinuation from the study. FCBP must be referred to a
             qualified provider of contraceptive methods if needed. FCBP must have a negative serum
             pregnancy test at screening.

          -  Men must agree to use a latex condom during treatment and for up to 90 days after the
             last dose of ibrutinib or venetoclax during sexual contact with a FCBP

          -  Ability to understand and the willingness to sign a written informed consent document.

          -  Exclusion Criteria

          -  Participants who exhibit any of the following conditions at screening will not be
             eligible for admission into the study:

          -  Participants who have one or more prior systemic therapies for WM.

          -  Participants who are receiving any other investigational agents.

          -  Participants with known CNS lymphoma.

          -  Participants with known history of Human Immunodeficiency Virus (HIV), chronic
             hepatitis B virus (HBV) or hepatitis C (HCV) requiring active treatment. Note:
             Participants with serologic evidence of prior vaccination to HBV (i.e., HBs Ag-, and
             anti-HBs+ and anti-HBC-) and positive anti-HBc from IVIG may participate.

          -  Concurrent administration of medications or foods that are moderate or strong
             inhibitors or inducers of CYP3A within 7 days prior to first dose of study drug.

          -  Participants with chronic liver disease and hepatic impairment meeting Child-Pugh
             class C (Appendix B).

          -  Concurrent administration of warfarin.

          -  Concurrent systemic immunosuppressant therapy within 21 days of the first dose of
             study drug.

          -  Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.

          -  Recent infection requiring systemic treatment that was completed ≤ 14 days before the
             first dose of the study drug.

          -  Known bleeding disorders (e.g., congenital von Willebrand's disease or hemophilia)

          -  History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

          -  Major surgery within 4 weeks of first dose of study drug.

          -  Malabsorption syndrome or other condition that precludes enteral route of
             administration.

          -  Female participants who are pregnant, breastfeeding, or planning to become pregnant
             while enrolled in this study or within 90 days of last dose of study drug.

          -  Male participants who plan to father a child while enrolled in this study or within 90
             days after the last dose of study drug

          -  Participants with known history of alcohol or drug abuse.

          -  Participants with inability to swallow pills.

          -  On any active therapy for other malignancies with the exception of topical therapies
             for basal cell or squamous cell cancers of the skin.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

          -  Participants with a history of non-compliance to medical regimens.

          -  Participants who are unwilling or unable to comply with the protocol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of Very Good Partial Response (VGPR)
Time Frame:24 Months
Safety Issue:
Description:Proportion of patients with VGPR to therapy. (VGPR is >90% reduction in serum IgM from baseline)

Secondary Outcome Measures

Measure:Rate of Complete Response (CR) 6 Cycles
Time Frame:6 Cycles (28 day cycle)
Safety Issue:
Description:Proportion of patients with a complete response after 6 cycles of therapy
Measure:Rate of Complete Response (CR) 12 Cycles
Time Frame:12 Cycles (28 day cycle)
Safety Issue:
Description:Proportion of patients with a complete response after 12 cycles of therapy
Measure:Rate of Complete Response (CR) 24 Cycles
Time Frame:24 Cycles (28 day cycle)
Safety Issue:
Description:Proportion of patients with a complete response after 24 cycles of therapy
Measure:Overall Response 24 Cycles
Time Frame:24 Cycles (28 day cycle)
Safety Issue:
Description:Proportion of patients with minor response (MR) , partial response (PR), very good partial response (VGPR), or complete response (CR) to therapy.
Measure:Rate of VGPR at 30 months
Time Frame:30 Months
Safety Issue:
Description:Proportion of patients with a VGPR at 30 months from beginning therapy.
Measure:Median time to response
Time Frame:12 Months
Safety Issue:
Description:Time from treatment initiation until first response
Measure:Median time to major response
Time Frame:12 Months
Safety Issue:
Description:Time from treatment initiation until partial response or better (>50% reduction in serum IgM)
Measure:median time to VGPR
Time Frame:12 Months
Safety Issue:
Description:Time from treatment initiation until very good partial response (>90% reduction in serum IgM)
Measure:Progression Free Survival (PFS)
Time Frame:24 Months
Safety Issue:
Description:Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase).
Measure:Progression Free Survival (PFS)
Time Frame:36 Months
Safety Issue:
Description:Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase).
Measure:Progression Free Survival (PFS)
Time Frame:48 Months
Safety Issue:
Description:Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase).
Measure:Progression Free Survival (PFS)
Time Frame:60 Months
Safety Issue:
Description:Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase).
Measure:Overall survival
Time Frame:duration of time from start of treatment to time of death or last follow-up up to 72 months
Safety Issue:
Description:Time from initiation of therapy until death
Measure:Time to next treatment
Time Frame:24 Months
Safety Issue:
Description:Time from initiation of IVEN protocol therapy until initiation of new line of therapy.
Measure:Impact of IVEN in the participants' quality of life
Time Frame:24 Months
Safety Issue:
Description:Quality of life questionnaire European Organisation for Research and Treatment of Cancer. Scores range from 0-100 with high scores indicating a better outcome.
Measure:Number of participants with Treatment Related Adverse Events as Assessed (CTCAE) version 5.0
Time Frame:6 Months
Safety Issue:
Description:CTCAE version 5.0
Measure:Impact ofCXCR4 mutations on overall response
Time Frame:12 Months
Safety Issue:
Description:Comparison of response rates between participants with CXCR4 mutations and without CXCR4 mutations

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Waldenstrom Macroglobulinemia
  • ibrutinib
  • venetoclax

Last Updated

February 19, 2020