Preliminary Results of a Phase Ib Study of Duvelisib in Combination with FCR (dFCR) in Previously Untreated, Younger Patients with CLL

Background: FCR remains the gold standard for the initial treatment of younger patients with CLL, yet only about 20% of patients will achieve complete response (CR) with minimal residual disease (MRD) negativity in the bone marrow (BM), which is likely a prerequisite for cure. Duvelisib (formerly IPI-145) is a delta/gamma PI3K inhibitor with promising efficacy in relapsed/refractory CLL. We report on the preliminary results of an investigator-initiated, phase Ib study of duvelisib plus FCR (dFCR) as upfront treatment for younger patients with CLL.

Methods: A standard 3 + 3 phase I design included 2 dose levels of duvelisib (25 mg daily (starting level) and 25 mg bid). The primary objectives were to determine the RP2D and toxicities. Secondary objectives included efficacy by IW-CLL criteria, including the rate of CR with BM MRD-negativity at final re-staging. Duvelisib monotherapy was given for 1 week, with FCR started on day 8. Up to 6 cycles of FCR were given with continuous duvelisib, and responders could then continue on duvelisib monotherapy for up to 2 years of maintenance. Eligibility criteria included: age ≤ 65, requiring treatment by IW-CLL criteria, ECOG PS ≤1, and adequate organ function. Toxicity evaluations were performed by CTCAE v4.03/IW-CLL, and response evaluations occurred after 3 cycles, 2 months after final FCR, and q6 months thereafter. MRD was assessed by four-color flow cytometry (sensitivity of 10^-4).

Results: As of July 27, 2015, 12 patients were accrued, with 6 patients each at duvelisib 25 mg daily and 25 mg bid. The median age at enrollment was 57 (range 46-65). Unmutated IGHV was present in 8/12 (66.7%), ZAP-70 was positive in 6/12 (50%), 2 patients had del(11q), and 1 patient had del(17p). The only DLT was gr3 febrile neutropenia at 25 mg qd (n=1). Hematologic toxicity included neutropenia (67%; 50% gr 3-4), thrombocytopenia (25%; 17% gr 3-4), and anemia (17%, no gr 3-4). All grade non-hematologic toxicities included nausea (83%), fever (50%), diarrhea, anorexia, and fatigue (42% each), transaminitis, pruritus, and vomiting (25% each). SAEs included pneumonia (n=4, including 2 cases of PCP), Gr 3 transaminitis (n=2), and Gr 3 febrile neutropenia, diarrhea, pruritus, and CMV infection (n=1 each). The ORR was 100% (n=9 evaluable at final re-staging 2 months post FCR), with 33% achieving CR (n=2) or CRi (n=1), and 67% achieving PR. Five of the 7 patients with PR had residual lymph nodes < 2.5 cm in long axis by CT imaging. The rate of MRD-negativity in the BM was 8/9 (89%). The median follow-up is 8.7 months, and all 9 patients who completed chemotherapy are now on duvelisib maintenance. A phase II expansion cohort at 25 mg bid of duvelisib recently opened, and updated results will be presented on all patients.

Discussion: The RP2D of duvelisib given with FCR is 25 mg bid. The toxicities with dFCR are manageable and comparable to historical toxicities observed with duvelisib and FCR individually. Although the ORR and CR rates are also similar to FCR alone, the 89% rate of BM MRD negativity with dFCR is substantially higher. Most patients who achieved PR with MRD-negativity have small residual nodes and will be monitored for conversion to CR while on duvelisib maintenance. dFCR is a feasible regimen for the initial therapy of younger, fit patients with CLL, and the promising preliminary efficacy data warrant further exploration in a phase II expansion cohort (NCT02158091), which is now ongoing.