A Multicenter Study of Ibrutinib Resistance Development and Intervention With Venetoclax (Phase II)
A Multicenter Study of Ibrutinib Resistance Development and Intervention With Venetoclax (Phase II)
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.
PRIMARY OBJECTIVES:
I. Overall response rate to combination ibrutinib and venetoclax after 12 cycles (intervention cohort).
II. Rate of mutation negative status after 12 cycles of combination venetoclax and ibrutinib (intervention cohort ).
SECONDARY OBJECTIVES:
I. Incidence of BTK C481S mutations during ibrutinib treatment (observation cohort).
II. Progression-free survival after development of a BTK C481S mutation (observation cohort).
III. Progression-free and overall survival after adding venetoclax to ibrutinib (intervention cohort).
IV. Type and incidence of adverse events during combination ibrutinib and venetoclax treatment in this patient population (intervention cohort).
EXPLORATORY OBJECTIVES:
I. Determine patient and disease characteristics associated with clinical disease progression in a univariable and multivariable analysis (observation cohort).
II. Determine the changes in the allelic frequency of ibrutinib resistance mutations after their development (observation cohort) and after venetoclax is added (intervention cohort).
III. Determine novel resistance mechanisms to ibrutinib and ibrutinib/venetoclax combination therapy by whole exome and ribonucleic acid (RNA) sequencing at baseline and clinical relapse.
IV. Perform BH3 profiling and correlate with response to combination venetoclax and ibrutinib therapy.
OUTLINE: This is a dose-escalation study of venetoclax.
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 orally (PO) daily and ibrutinib PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve minimal residual disease (MRD) negative complete remission (CR) after 12 or 24 cycles continue receiving ibrutinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months thereafter.
Inclusion Criteria:
Exclusion Criteria:
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:
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.
Patients in the observation cohort who develop clinical disease progression and do NOT have a known ibrutinib resistance mutation will be taken off study and may not enter the intervention cohort.