A Multicenter Study of Ibrutinib Resistance Development and Intervention with Venetoclax in Patients with Chronic Lymphocytic Leukemia

Background:

Ibrutinib (ibr) for the treatment of chronic lymphocytic leukemia (CLL) has improved progression-free survival (PFS) compared to other treatments, especially in high-risk patients (pts). However, resistance occurs and is associated with mutations in the drug binding target (BTK) and its immediate downstream target (PLCg2). These ibr resistance mutations (IRmut) are detectable months prior to developing progressive disease (PD) and predict clinical relapse. Prospectively determining the time from starting ibr to development of IRmut and from IRmut detection to PD will improve our understanding of how to manage these patients.

Venetoclax (ven) is highly effective after ibr and decreases IRmut. Adding ven to ibr for ibr resistance is a rational choice as this combination is safe and effective in CLL. Adding an agent rather than stopping ibr avoids disease flare associated with ibr discontinuation.

This phase 2 study was designed to follow CLL pts taking ibr and at high risk for resistance (observation cohort) and to test ven in combination with ibr for those who develop PD (intervention cohort). This will determine: the incidence of IRmut and PD in this population, the ORR with ibr/ven, and the ability of this combination to eliminate IRmut.

Trial Design and Methods:

This multisite study will open at 4 centers initially. Eligible pts are adults with CLL taking ibr for ≥12 months and at high risk for ibr resistance defined as having ≥2 prior treatments and del(17p)(p13.1) on FISH panel and/or a complex karyotype. Pts with known IRmut or who cannot continue ibr for any reason are excluded.

Enrolled pts enter the observation cohort and are followed every 3 months with a clinic visit, blood counts, and testing for IRmut. Pts who develop IRmut will also have CT scans at their visits to detect PD. Those with IRmut who develop PD by iwCLL 2018 criteria will enter the intervention cohort.

Pts in the intervention cohort will start ven in addition to ibr. Ven will be ramped-up over 5 weeks to a target dose of 400mg. Pts will take combination ibr/ven for 12 cycles of 28 days in length. After 12 cycles they will undergo response assessment and those achieving a complete remission (CR) with no detectable leukemia (uMRD) in both the blood and bone marrow will stop ven and continue ibr alone. Those who do not achieve CR with uMRD will continue ibr/ven until cycle 24 and undergo a second response assessment. If in a CR with uMRD after 24 cycles they continue on ibr alone. If a CR with uMRD is not achieved after 24 cycles patients continue ibr/ven until PD, intolerance, death, or end of study which is 30 months after the last patient enters the intervention cohort (Figure). In the intervention cohort all pts will be tested for IRmut in the blood every 3 months with bone marrow testing at response assessments.

The study has co-primary endpoints of ORR to combination ibr/ven after 12 cycles and the rate of IRmut negative status at that time in the intervention cohort. ORR will be tested first using a single-stage phase 2 design with a null hypothesis that the rate is ≤50% versus the alternative hypothesis that it is ≥75%. Only if the combination is effective in ORR will the rate of IRmut negative status be formally tested. Constraining overall Type I and II errors to 0.10 using this sequential testing strategy, 26 evaluable pts are required and 28 will be accrued.

Secondary endpoints for the intervention cohort are the PFS and overall survival since starting the combination ibr/ven and the incidence and type of adverse events with ibr/ven. Secondary endpoints in the observation cohort are the incidence of IRmut during ibr treatment and the PFS after developing an IRmut.

We estimate that 180 pt-years of follow up for the observation cohort will be needed. The yearly rate of mutation development in this population is approximately 20%, therefore this will identify 36 pts with IRmut. Of those with IRmut, approximately 80% will remain eligible to enter the intervention cohort. Accrual to the observation cohort will stop once 28 pts enter the intervention cohort.

Conclusion:

This multicenter phase 2 trial examines the development of IRmut and clinical resistance to ibr in a cohort of high-risk CLL pts and will determine the efficacy of adding ven to ibr in those who develop PD. We expect to determine the natural course of molecular and clinical ibr resistance in CLL and if adding ven is an effective treatment strategy.

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