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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

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.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Drug: Venetoclax Drug: Ibrutinib Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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.
Actual Study Start Date : May 1, 2018
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : August 2028


Arm Intervention/treatment
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.
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




Primary Outcome Measures :
  1. Maximum tolerated dose or biologically active dose. [ Time Frame: 1 year or more ]
    Maximum tolerated dose or biologically active dose.


Secondary Outcome Measures :
  1. Treatment-emergent adverse events [ Time Frame: 2 years or more ]
    Treatment-emergent adverse events (description, timing, grade [CTCAE v4.03], severity, seriousness, and relatedness)

  2. 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

  3. 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.

  4. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03422393


Contacts
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Contact: Michael Choi, MD (858) 534-1765 mychoi@ucsd.edu

Locations
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United States, California
UC San Diego Moores Cancer Center Recruiting
La Jolla, California, United States, 92093
Sponsors and Collaborators
Michael Choi
Pharmacyclics LLC.
Investigators
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Principal Investigator: Michael Choi, MD University of California, San Diego

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Responsible Party: Michael Choi, Clinical investigator, University of California, San Diego
ClinicalTrials.gov Identifier: NCT03422393     History of Changes
Other Study ID Numbers: 171613
First Posted: February 5, 2018    Key Record Dates
Last Update Posted: January 25, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Michael Choi, University of California, San Diego:
venetoclax
ibrutinib
high-dose ibrutinib
chronic lymphocytic leukemia
progressive disease
Small Lymphocytic Lymphoma
cancer
Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, B-Cell
Venetoclax
Disease Progression
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease Attributes
Pathologic Processes
Antineoplastic Agents