A MRD‐GUIDED APPROACH FOR THE COMBINATION OF IBRUTINIB TO VENETOCLAX IN RELAPSED/REFRACTORY PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (IMPROVE STUDY)

Abstract

Introduction: The therapeutic armamentarium for chronic lymphocytic leukemia (CLL) has recently gained novel effective agents, based on Bcell receptor signaling inhibition. These agents rarely achieve deep responses in relapsed/refractory (R/R) CLL, and patients with unfavorable characteristics tend to relapse over time. Venetoclax, a highly selective BCL2 inhibitor, demonstrated 80% response rate (5% minimal residual disease ‐MRD‐ negative responses) in R/R CLL, including high risk patients and has recently granted approval by FDA and EMA. Venetoclax combined with anti‐CD20 antibodies improved MRD‐negativity rate, a valuable treatment goal, as it correlates with prolonged progression‐free and overall survival. The optimal combination for venetoclax is still to be defined but in vitro results support the association of venetoclax and ibrutinib to achieve better disease control in CLL and mantle‐cell lymphoma (MCL). Initial results for ibrutinib and venetoclax in R/R MCL documented that both drugs can be used at the standard dose without any relevant unmanageable or unexpected adverse events. Methods: We designed a Phase 2a, multicenter, open‐label uncontrolled study aimed at determining therapeutic benefits of the addition of ibrutinib to venetoclax in patients with R/R CLL based on a MRDguided approach. According to optimal Simon Two‐Stage design (type I standard error 0.05, power 95%), with a null hypothesis of 5% MRD‐negative CR at 12 months, the alternative hypothesis is based on a MRD‐negative CR of 30% with venetoclax and ibrutininib. A total of 31 patients should be enrolled to reach the target of 29 MRD positive patients. An interim analysis is planned after the enrolment of the first 9 MRD positive patients: study will complete the accrual if at least 1/9 patients will obtain a MRD negative CR 12 months after starting Ibrutinib. Results: Venetoclax will be administered as single agent up to 400 mg QD [Ramp‐up period] and continued thereafter. At Cycle 12 Day 1, MRD in the peripheral blood (PB) will be evaluated in patients with CR or PR by flow cytometry (Figure 1). (Figure Presented) All MRD negative subjects (MRD level in the PB <10‐4 in the PB and in the BM) will discontinue venetoclax at the end of Cycle 12. All MRD positive subjects (MRD level in the PB >10‐4) and patients with stable disease without any contraindications to ibrutinib will continue venetoclax and start treatment with ibrutinib at the standard dose for CLL of 420 mg QD. Venetoclax and ibrutinib will be administered until confirmed MRD negativity, unacceptable toxicity or disease progression. In MRD positive responders after 2 years, venetoclax will be interrupted while ibrutinib will be continued as per standard of care. Conclusions: A total of 17 Italian sites will be participating to this trial. The study has been approved by San Raffaele Hospital Ethics Committee on March 9th, 2017. AIFA approval is expected by May 12th, 2017. Recruitment will be open by the first week of June 2017.