Clinical Trials /

Venetoclax With High-dose Ibrutinib for CLL Progressing on Single Agent Ibrutinib

NCT03422393

Description:

The purpose of the study is to investigate whether the combination of venetoclax and ibrutinib (administered up to 840 mg per day) might be useful for the treatment of CLL or SLL that is not responding or no longer responding to treatment with ibrutinib alone. The study will evaluate whether this regimen can reduce the amount of cancerous cells in your body. If you agree, you will receive ibrutinib at a dose of up to 840 mg a day by mouth, as well as venetoclax. Although both of these agents are approved by the FDA for the treatment of CLL or SLL, the combination and the dosing schedule of ibrutinib are considered experimental.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax With High-dose Ibrutinib for CLL Progressing on Single Agent Ibrutinib
  • Official Title: A Phase 1 Clinical Trial to Evaluate Venetoclax With High-dose Ibrutinib for the Treatment of Patients With Chronic Lymphocytic Leukemia With Progressive Disease on Single Agent Ibrutinib.

Clinical Trial IDs

  • ORG STUDY ID: 171613
  • NCT ID: NCT03422393

Conditions

  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma

Interventions

DrugSynonymsArms
VenetoclaxVenclextavenetoclax with high-dose ibrutinib
IbrutinibImbruvicavenetoclax with high-dose ibrutinib

Purpose

The purpose of the study is to investigate whether the combination of venetoclax and ibrutinib (administered up to 840 mg per day) might be useful for the treatment of CLL or SLL that is not responding or no longer responding to treatment with ibrutinib alone. The study will evaluate whether this regimen can reduce the amount of cancerous cells in your body. If you agree, you will receive ibrutinib at a dose of up to 840 mg a day by mouth, as well as venetoclax. Although both of these agents are approved by the FDA for the treatment of CLL or SLL, the combination and the dosing schedule of ibrutinib are considered experimental.

Detailed Description

      This is phase 1 study for patients with CLL or small lymphocytic lymphoma (SLL) experiencing
      disease progression on single ibrutinib. This study will evaluate the optimal ibrutinib dose
      (including doses higher than 420 mg) when combined with venetoclax

      During the screening period, patients will continue on ibrutinib at their previous tolerated
      dose, unless required to stop (e.g.: by a preceding clinical trial).

      On cycle 1, day 1, the dose of ibrutinib will be assigned based on the dose cohort. Patients
      in cohort 1 will receive ibrutinib 420 mg PO daily. Patients in cohort 2 will receive
      ibrutinib 560 mg PO daily. Cohort 3 will be 840 mg PO daily.

      On cycle 1, day 1, patients will initiate venetoclax. The dose of venetoclax will ramp-up
      from 20 mg PO daily to 400 mg PO daily over a 5 week period.

      The primary safety endpoint is determination of DLTs during the first 35 days (completion of
      dose ramp up). The primary efficacy endpoint of overall response rate will be assessed on
      approximately Cycle 7, Day 1.

      Rationale: The optimal management of patients that progress on ibrutinib, including those
      with acquired Btk or PLCg2 mutations, is not determined. In other cancers, continued
      treatment with small molecule inhibitors beyond disease progression provides significant
      benefit, with additional agents or adjustments to ablate the resistant subclone. Venetoclax
      is approved for the treatment of patients with CLL, and is well-tolerated and effective in
      high-risk disease, and so is an appropriate agent for this trial.
    

Trial Arms

NameTypeDescriptionInterventions
venetoclax with high-dose ibrutinibExperimentalvenetoclax with high-dose ibrutinib for the treatment of patients with chronic lymphocytic leukemia with progressive disease on single agent ibrutinib.
  • Venetoclax
  • Ibrutinib

Eligibility Criteria

        Inclusion Criteria:

          -  Clinical and phenotypic verification of B cell CLL or SLL and measurable disease.

          -  Prior therapy: Patients must have been receiving single agent ibrutinib therapy at the
             time of disease progression. Patient may have received other therapy in combination
             with ibrutinib earlier in their treatment course.

          -  Women of childbearing potential (not postmenopausal for at least one year or not
             surgically incapable of bearing children) must agree not to become pregnant for the
             duration of the study.

          -  Adequate hematologic, hepatic and renal function

        Exclusion Criteria:

          -  Known CNS lymphoma or leukemia

          -  History of Richter's or prolymphocytic transformation.

          -  Primary ibrutinib resistance

          -  Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenia purpura
             (ITP)

          -  History of major surgery within 4 weeks prior to first dose on this study.

          -  History of prior malignancy, with the exception of adequately treated non-melanoma
             skin cancer, malignancies treated with curative intent and with no evidence of active
             disease for more than 3 years, or adequately treated cervical carcinoma in situ
             without current evidence of disease.

          -  Active clinically significant cardiovascular disease or history of myocardial
             infarction within 6 months of first dose.

          -  Active hepatitis B or C infection.

          -  Known history of infection with human immunodeficiency virus (HIV).

          -  Unable to swallow capsules or disease significantly affecting gastrointestinal
             function.

          -  History of stroke or intracranial hemorrhage within 6 months of first dose.

          -  Requires anticoagulation with warfarin or other Vitamin K antagonists.

          -  Requires treatment with a strong cytochrome P(CYP)450 3A inhibitor.

          -  Pregnant or breast-feeding women

          -  Current infection requiring parenteral antibiotics.

          -  Active, clinically significant hepatic impairment Child-Pugh class B or C according to
             the Child Pugh classification.

          -  Patients who require immediate cytoreduction due to high risk of tumor lysis syndrome
             (ie, absolute lymphocyte count greater than 100k/uL).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose or biologically active dose.
Time Frame:1 year or more
Safety Issue:
Description:Maximum tolerated dose or biologically active dose.

Secondary Outcome Measures

Measure:Treatment-emergent adverse events
Time Frame:2 years or more
Safety Issue:
Description:Treatment-emergent adverse events (description, timing, grade [CTCAE v4.03], severity, seriousness, and relatedness)
Measure:Overall response rate
Time Frame:2 years or more
Safety Issue:
Description:Partial Response, Partial Response with Lymphocytosis, and Complete Response) based on international working group guidelines. Best overall response will be determined
Measure:Progression free survival rate at completion of combination therapy
Time Frame:2 years or more
Safety Issue:
Description:Progression free survival rate at completion of combination therapy, duration of response, as determined by International Working Group in CLL (iwCLL) criteria.
Measure:Stable disease rate
Time Frame:2 years or more
Safety Issue:
Description:Stable disease rate (also based on 2008 iwCLL guidelines), also at the time of primary endpoint response assessment.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Michael Choi

Trial Keywords

  • venetoclax
  • ibrutinib
  • high-dose ibrutinib
  • chronic lymphocytic leukemia
  • progressive disease
  • Small Lymphocytic Lymphoma
  • cancer

Last Updated

January 6, 2020