Ibrutinib and Venetoclax in Treating Patients With Chronic Lymphocytic Leukemia After Ibrutinib Resistance

NCT03943342 | Withdrawn Phase 2 DMC FDA Drug

• 2 other identifiers: OSU-18311NCI-2019-02511
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This phase II trial studies how well the combination of ibrutinib and venetoclax works in treating patients with chronic lymphocytic leukemia whose cancer has stopped responding to ibrutinib alone. Both ibrutinib and venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving ibrutinib and venetoclax together after development of ibrutinib resistance may work better than discontinuing ibrutinib and switching to other chemotherapy drugs.

Conditions

Chronic Lymphocytic Leukemia; Loss of Chromosome 17p

Outcome Measures

Primary Outcomes (2)

• Overall response rate (ORR) (intervention cohort)

  Defined as the percentage of patients who have achieved any response better than stable disease after 12 cycles of combination ibrutinib and venetoclax treatment. All eligible patients who take one study dose of venetoclax will be considered evaluable and included in the denominator when calculating the ORR. ORR will be estimated with a 95% exact binomial confidence interval at the response assessment after 12 cycles of combination ibrutinib and venetoclax therapy, and 24 if applicable.

  After 12 cycles of combination therapy, assessed up to 3 years

• Rate of mutation negative status (intervention cohort)

  Rate of mutation negative status will be estimated with a 95% exact binomial confidence interval at the response assessment after 12 cycles of combination ibrutinib and venetoclax therapy, and 24 if applicable.

  After 12 cycles of combination therapy, assessed up to 3 years

Secondary Outcomes (5)

• Incidence of BTK C481S mutations (observation cohort)

  Up to 3 years

• Progression-free survival (PFS) after development of a BTK C481S mutation (observation cohort)

  Up to 3 years

• PFS after adding venetoclax to ibrutinib (intervention cohort)

  Up to 3 years

• Overall survival (OS) after adding venetoclax to ibrutinib (intervention cohort)

  Up to 3 years

• Incidence of adverse events (intervention cohort)

  Up to 3 years

Other Outcomes (5)

• Patient and disease characteristics associated with clinical disease progression (observation cohort)

  Up to 3 years

• Changes in allelic frequency of ibrutinib resistance mutations after their development (observation cohort)

  Up to 3 years

• Changes in allelic frequency of ibrutinib resistance mutations after addition of venetoclax (intervention cohort)

  Up to 3 years

Study Arms (1)

Treatment (venetoclax, ibrutinib)

EXPERIMENTAL

OBSERVATION COHORT: Patients who are taking ibrutinib enter observation cohort and undergo screening every 3 months for development for genetic mutations. If mutations develop, patients undergo increased screening for development of clinical disease progression. Patients who develop clinical disease progression with or without mutations enter the Intervention cohort. INTERVENTION COHORT: Patients receive venetoclax PO daily and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve MRD negative CR after 12 or 24 cycles continue receiving ibrutinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.

Drug: Ibrutinib; Drug: Venetoclax

Interventions

Ibrutinib DRUG

Given PO

Also known as: BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765

Treatment (venetoclax, ibrutinib)

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta

Treatment (venetoclax, ibrutinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of chronic lymphocytic leukemia (CLL) meeting criteria established by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL).
• Currently taking ibrutinib and first took ibrutinib \> 12 months ago.
• At high risk for the development of ibrutinib resistance. Patients are considered at high risk for ibrutinib resistance if they have had \>= 2 prior therapies for CLL prior to ibrutinib and have either del(17p)(13.1) and/or a complex CLL karyotype.
• Able to continue taking ibrutinib.
• Willing to enter the intervention cohort if clinical disease progression as defined by IWCLL 2018 criteria develops.
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2.
• Absolute neutrophil count (ANC) \>= 1000/mm\^3 independent of growth factor support.
• Platelets \>= 100,000/mm\^3 or \>= 50,000/mm\^3 if bone marrow involvement independent of transfusion support in either situation.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3 x upper limit of normal (ULN).
• Total bilirubin =\< 1.5 x ULN unless bilirubin rise is due to Gilbert?s syndrome or of non-hepatic origin.
• Creatinine clearance (CLcr) \>30 ml/min.
• Able to take an absorb pill form oral medications.
• Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug.
• Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin \[beta-hCG\]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study.
• Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.

You may not qualify if:

• Inability to continue taking ibrutinib for any reason.
• Presence of a known ibrutinib resistance mutation as defined.
• Clinical disease progression while taking ibrutinib as defined by IWCLL 2018 criteria.
• Major surgery or a wound that has not fully healed within 4 weeks of randomization.
• Known central nervous system lymphoma.
• Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon).
• Requires chronic treatment with strong CYP3A inhibitors.
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
• Known history of human immunodeficiency virus (HIV) or active hepatitis C virus or active hepatitis B virus infection or any uncontrolled active systemic infection.
• Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator?s opinion, could compromise the subject?s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
• Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.
• History of lymphoma (Richter?s syndrome) unless in complete remission \> 2 years without relapse.
• History of active malignancies other than 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

Sponsors & Collaborators

• Kerry Rogers: lead
• Janssen Research & Development, LLC: collaborator

Related Links

• The Jamesline

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Chromosome 17 deletion

Interventions

ibrutinib; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Kerry A Rogers, MD

  Ohio State University Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 7, 2019
• First Posted: May 9, 2019
• Study Start: March 11, 2020
• Primary Completion: July 20, 2021
• Study Completion: July 20, 2021
• Last Updated: November 5, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share