Clinical Trials /

Venetoclax and Ibrutinib in Treating in Participants With Chronic Lymphocytic Leukemia and Ibrutinib Resistance Mutations

NCT03513562

Description:

This phase II trial studies how well venetoclax and ibrutinib work in treating participants with chronic lymphocytic leukemia and have developed genetic mutations after previously being treated with ibrutinib. Venetoclax and ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Chronic Lymphocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax and Ibrutinib in Treating in Participants With Chronic Lymphocytic Leukemia and Ibrutinib Resistance Mutations
  • Official Title: Phase 2 Study of Venetoclax Added to Ibrutinib to Eliminate Ibrutinib Resistance Mutations in CLL

Clinical Trial IDs

  • ORG STUDY ID: OSU-17387
  • SECONDARY ID: NCI-2018-00410
  • SECONDARY ID: P30CA016058
  • NCT ID: NCT03513562

Conditions

  • Chronic Lymphocytic Leukemia
  • Ibrutinib Resistance

Interventions

DrugSynonymsArms
IbrutinibBTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765Treatment (venetoclax, ibrutinib)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, VenclextaTreatment (venetoclax, ibrutinib)

Purpose

This phase II trial studies how well venetoclax and ibrutinib work in treating participants with chronic lymphocytic leukemia and have developed genetic mutations after previously being treated with ibrutinib. Venetoclax and ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine if the addition of venetoclax to ibrutinib therapy can eliminate ibrutinib
      resistance mutations.

      SECONDARY OBJECTIVES:

      I. Determine the rate of minimal residual disease negative complete remission to combination
      ibrutinib and venetoclax therapy.

      II. Determine progression-free survival after the addition of venetoclax to ibrutinib.

      III. Determine overall survival after the addition of venetoclax to ibrutinib. IV. Describe
      the toxicity profile of venetoclax in combination with ibrutinib in this patient population.

      EXPLORATORY OBJECTIVES I. Describe changes in variant allele frequency (VAF) of known
      ibrutinib resistance mutations after the addition of venetoclax.

      II. Perform BH3 profiling and correlate with response to combination venetoclax and ibrutinib
      therapy.

      III. Determine if increased expression of MCL-1 and BCL-XL is a potential mechanism of
      resistance to venetoclax when given in combination with ibrutinib.

      IV. Determine potential mechanisms of resistance to ibrutinib and venetoclax combination
      treatment by whole exome and ribonucleic acid (RNA) sequencing.

      OUTLINE: This is a dose escalation study of venetoclax.

      Participants receive venetoclax orally (PO) daily on days 1-28 and ibrutinib PO once daily
      (QD) on days 1-28. Treatment repeats every 28 days for up to 12 or 24 courses in the absence
      of disease progression or unacceptable toxicity. Participants with minimal residual disease
      (MRD) negativity after 12 or 24 courses discontinue treatment, while participants with MRD
      positivity continue treatment with venetoclax in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, participants are followed up every 3 months for 2 years
      and then every 6 months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (venetoclax, ibrutinib)ExperimentalParticipants receive venetoclax PO daily on days 1-28 and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 or 24 courses in the absence of disease progression or unacceptable toxicity. Participants with MRD negativity after 12 or 24 courses discontinue treatment, while participants with MRD positivity continue treatment with venetoclax in the absence of disease progression or unacceptable toxicity.
  • Ibrutinib
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of chronic lymphocytic leukemia (CLL) meeting criteria established in the
             World Health Organization (WHO) classification of hematologic disorders or
             International Workshop on Chronic Lymphocytic Leukemia (IWCLL)

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

          -  Currently taking ibrutinib and first took ibrutinib > 3 months ago

          -  Presence of a known ibrutinib resistance mutation at ≥ 4% variant allele frequency OR
             < 4% with two separate measurements at least 4 weeks apart with increasing variant
             allele frequency

          -  Adequate bone marrow function independent of growth factor support at screening unless
             clearly due to marrow involvement by CLL and/or disease-related immune
             thrombocytopenia; if cytopenias are due to disease in the bone marrow any degree of
             cytopenias are allowed; patients with active uncontrolled autoimmune cytopenias are
             excluded

          -  Hemoglobin ≥ 8 g/dL

          -  Absolute neutrophil count (ANC) ≥ 1,000/mm^3

          -  Platelets ≥ 40,000/mm^3

          -  Prothrombin time/partial thromboplastin time (PT/PTT) ≤ 1.5 x upper limit of normal
             (ULN) (unless receiving anticoagulation)

          -  Total bilirubin ≤ 1.5 x ULN (excepting Gilbert's syndrome)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ≤ ULN

          -  Creatinine clearance ≥ 40 mL/min/1.73m^2

               -  Using 24-hour creatinine clearance or modified Cockcroft-Gault equation

          -  All patients must practice a highly effective method of birth control

          -  Able to take an absorb pill form oral medications

          -  Ability to understand and sign a written informed consent

        Exclusion Criteria:

          -  Inability to continue taking ibrutinib for any reason

          -  Treatment with chemotherapy, immunotherapy, radiotherapy, targeted small molecule
             inhibitors, biologic agents, and/or an investigational therapy for 5 half-lives prior
             to first study dose of venetoclax; treatment with a biologic agent, such as a
             monoclonal antibody, for 30 days prior to study treatment; treatment with ibrutinib is
             allowed

          -  Need for anticoagulation with a vitamin K antagonist (warfarin); other anticoagulants
             and antiplatelet agents are allowed

          -  Treatment with a moderate or strong cytochrome P450 3A4 (CYP3A) inhibitor or inducer
             within 7 days prior to first dose of venetoclax or need for treatment with a strong
             CYP3A inhibitor or inducer during the period or the study; patients who have a need
             for treatment with a moderate CYP3A inhibitor or inducer during venetoclax dose
             escalation will also be excluded

          -  Uncontrolled autoimmune hemolytic anemia or thrombocytopenia

          -  History of lymphoma (Richter's syndrome) unless in complete remission > 2 years
             without relapse

          -  Known active involvement of the central nervous system by lymphoma or leukemia

          -  Known infection with the human immunodeficiency (HIV) virus

          -  A cardiovascular disability status of New York Heart Association Class ≥ 2, defined as
             cardiac disease in which patients are comfortable at rest but ordinary physical
             activity results in fatigue, palpitations, dyspnea, or angina pain

          -  Positive hepatitis serology:

               -  Patients with positive serology for hepatitis B defined as positivity for
                  hepatitis B virus surface antigen measurement (HBsAg) or anti-hepatitis B core
                  total antibodies (antiHBc) may be considered for inclusion in the study on a
                  case-by-case basis if they are hepatitis B viral deoxyribonucleic acid (DNA)
                  negative and are willing to undergo ongoing hepatitis B virus (HBV) DNA testing
                  by real-time polymerase chain reaction (PCR) monthly during the study

               -  Patients with positive hepatitis B surface antigen (HBsAg) consistent with prior
                  vaccination to HBV (i.e., hepatitis B immune status/anti-hepatitis B surface
                  antibody [anti-HBs+], anti-HBc-) may participate

               -  Patients suspected to have false positive serologic studies because of
                  intravenous (IV) immunoglobulin administration are potentially eligible without
                  need for further monitoring if they have negative PCR studies for viral DNA/RNA
                  after discussion with the principal investigator

               -  Patients with positive hepatitis C serology are excluded unless they have
                  negative hepatitis C virus (HCV) ribonucleic acid (RNA) testing after receiving
                  HCV-specific treatment and the case is discussed with the principal investigator

          -  Female patients who are pregnant, breast-feeding, or planning to become pregnant

          -  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

          -  History of active malignancies other than chronic lymphocytic leukemia (CLL) within
             the past 3 years prior to study entry, with the exception of:

               -  Adequately treated in situ carcinoma or the cervix or breast

               -  Basal cell or localized squamous cell carcinoma of the skin

               -  Previous malignancy treated with curative therapy and not expected to relapse

          -  Inability to swallow capsules or tablets, or disease significantly affecting
             gastrointestinal function and/or inhibiting small intestine absorption (malabsorption
             syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease,
             etc.)

          -  Prior allogeneic stem cell transplant with day 0 < 12 months prior and/or with chronic
             graft versus host disease (GVHD) requiring current use of immunosuppression; patients
             with prior allogeneic stem cell transplant with day 0 > 12 months prior who do not
             require immunosuppression for GVHD will be eligible
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of mutation negative status after 12 courses of combination therapy of ibrutinib and venetoclax
Time Frame:Up to 3 years
Safety Issue:
Description:The rate of mutation negative status will be the percentage of patients who have negative testing for ibrutinib resistance mutations in the peripheral blood and bone marrow after 12 courses of combination ibrutinib and venetoclax treatment. Mutation negative status is defined as 1% variant allele frequency by the clinical grade test for mutation.

Secondary Outcome Measures

Measure:Rate of minimal residual disease negative complete remission after 12 courses of venetoclax and ibrutinib
Time Frame:Up to 3 years
Safety Issue:
Description:Rate of minimal residual disease negative complete remission estimated with a 95% exact binomial at the response assessment after 12 courses of therapy.
Measure:Progression-free survival after adding venetoclax to ibrutinib
Time Frame:From start date of combination therapy up to 3 years
Safety Issue:
Description:Progression-free survival (PFS) calculated from the start date of combination therapy until the date of clinical disease progression by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria or death from any cause, whichever occurs first. PFS described using the method of Kaplan-Meier. Median PFS reported with 95% confidence interval.
Measure:Overall survival after beginning venetoclax in combination with ibrutinib
Time Frame:From start date of combination therapy up to 3 years
Safety Issue:
Description:Overall survival (OS) calculated from the start date of combination therapy until the date of death from any cause, censoring patients alive at last follow-up. OS described using the method of Kaplan-Meier. Median OS reported with 95% confidence interval.
Measure:Discontinuation rate due to adverse events with combination venetoclax and ibrutinib treatment.
Time Frame:Up to 3 years
Safety Issue:
Description:Safety and tolerability of the combination regimen adverse events are summarized by type, severity and perceived attribution according to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 with the exception of hematologic adverse events

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Ohio State University Comprehensive Cancer Center

Last Updated

May 1, 2018