Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 5 of 318 for:    IBRUTINIB

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03513562
Recruitment Status : Recruiting
First Posted : May 1, 2018
Last Update Posted : March 28, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Kerry Rogers, Ohio State University Comprehensive Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Ibrutinib Resistance Drug: Ibrutinib Other: Laboratory Biomarker Analysis Drug: Venetoclax Phase 2

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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Study of Venetoclax Added to Ibrutinib to Eliminate Ibrutinib Resistance Mutations in CLL
Actual Study Start Date : February 27, 2019
Estimated Primary Completion Date : February 28, 2021
Estimated Study Completion Date : February 28, 2021


Arm Intervention/treatment
Experimental: Treatment (venetoclax, ibrutinib)
Participants 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.
Drug: Ibrutinib
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta




Primary Outcome Measures :
  1. Rate of mutation negative status after 12 courses of combination therapy of ibrutinib and venetoclax [ Time Frame: Up to 3 years ]
    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 :
  1. Rate of minimal residual disease negative complete remission after 12 courses of venetoclax and ibrutinib [ Time Frame: Up to 3 years ]
    Rate of minimal residual disease negative complete remission estimated with a 95% exact binomial at the response assessment after 12 courses of therapy.

  2. Progression-free survival after adding venetoclax to ibrutinib [ Time Frame: From start date of combination therapy up to 3 years ]
    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.

  3. Overall survival after beginning venetoclax in combination with ibrutinib [ Time Frame: From start date of combination therapy up to 3 years ]
    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.

  4. Discontinuation rate due to adverse events with combination venetoclax and ibrutinib treatment. [ Time Frame: Up to 3 years ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

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): NCT03513562


Contacts
Layout table for location contacts
Contact: The Ohio State University Comprehensive Cancer Center 800-293-5066 OSUCCCClinicaltrials@osumc.edu
Contact: Jennifer Zvosec 614-685-7099 jennifer.zvosec@osumc.edu

Locations
Layout table for location information
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Kerry A. Rogers, MD    614-366-9338    kerry.rogers@osumc.edu   
Principal Investigator: Kerry A. Rogers, MD         
Sponsors and Collaborators
Ohio State University Comprehensive Cancer Center
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Kerry Rogers, MD Ohio State University Comprehensive Cancer Center

Additional Information:
Layout table for additonal information
Responsible Party: Kerry Rogers, Principal Investigator, Ohio State University Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT03513562     History of Changes
Other Study ID Numbers: OSU-17387
NCI-2018-00410 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
P30CA016058 ( U.S. NIH Grant/Contract )
First Posted: May 1, 2018    Key Record Dates
Last Update Posted: March 28, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Venetoclax
Antineoplastic Agents