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Venetoclax With High-dose Ibrutinib for the Treatment of Patients With Chronic Lymphocytic Leukemia With Progressive Disease on Single Agent Ibrutinib

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ClinicalTrials.gov Identifier: NCT03422393
Recruitment Status : Recruiting
First Posted : February 5, 2018
Last Update Posted : January 25, 2019
Sponsor:
Collaborator:
Pharmacyclics LLC.
Information provided by (Responsible Party):
Michael Choi, University of California, San Diego

Tracking Information
First Submitted Date  ICMJE January 30, 2018
First Posted Date  ICMJE February 5, 2018
Last Update Posted Date January 25, 2019
Actual Study Start Date  ICMJE May 1, 2018
Estimated Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 21, 2018)
Maximum tolerated dose or biologically active dose. [ Time Frame: 1 year or more ]
Maximum tolerated dose or biologically active dose.
Original Primary Outcome Measures  ICMJE
 (submitted: January 30, 2018)
Rate of dose limiting toxicities (DLTs) and the maximum tolerated dose or biologically active dose. [ Time Frame: 1 year or more ]
Rate of dose limiting toxicities (DLTs) and the maximum tolerated dose or biologically active dose.
Change History Complete list of historical versions of study NCT03422393 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 30, 2018)
  • Treatment-emergent adverse events [ Time Frame: 2 years or more ]
    Treatment-emergent adverse events (description, timing, grade [CTCAE v4.03], severity, seriousness, and relatedness)
  • Overall response rate [ Time Frame: 2 years or more ]
    Partial Response, Partial Response with Lymphocytosis, and Complete Response) based on international working group guidelines. Best overall response will be determined
  • Progression free survival rate at completion of combination therapy [ Time Frame: 2 years or more ]
    Progression free survival rate at completion of combination therapy, duration of response, as determined by International Working Group in CLL (iwCLL) criteria.
  • Stable disease rate [ Time Frame: 2 years or more ]
    Stable disease rate (also based on 2008 iwCLL guidelines), also at the time of primary endpoint response assessment.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Venetoclax With High-dose Ibrutinib for the Treatment of Patients With Chronic Lymphocytic Leukemia With Progressive Disease on Single Agent Ibrutinib
Official Title  ICMJE 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.
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
Intervention  ICMJE
  • Drug: Venetoclax
    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.
    Other Name: Venclexta
  • Drug: Ibrutinib

    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.

    Other Name: Imbruvica
Study Arms  ICMJE Experimental: venetoclax with high-dose ibrutinib
venetoclax with high-dose ibrutinib for the treatment of patients with chronic lymphocytic leukemia with progressive disease on single agent ibrutinib.
Interventions:
  • Drug: Venetoclax
  • Drug: Ibrutinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 30, 2018)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 2028
Estimated Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Michael Choi, MD (858) 534-1765 mychoi@ucsd.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03422393
Other Study ID Numbers  ICMJE 171613
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Michael Choi, University of California, San Diego
Study Sponsor  ICMJE Michael Choi
Collaborators  ICMJE Pharmacyclics LLC.
Investigators  ICMJE
Principal Investigator: Michael Choi, MD University of California, San Diego
PRS Account University of California, San Diego
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP