UPDATED RESULTS OF A MULTICENTER PHASE I/IB STUDY OF TGR‐1202 IN COMBINATION WITH IBRUTINIB IN PATIENTS WITH RELAPSED OR REFRACTORY MCL OR CLL (2017)

Introduction: The depth and durability of response to ibrutinib in patients (pts) with relapsed/refractory (R/R) MCL and high risk CLL is limited. TGR-1202 is a novel oral PI3K-δ specific inhibitor designed to have less toxicity than other PI3K inhibitors. We hypothesized that combined PI3K/BTK blockade with TGR-1202 and ibrutinib would be tolerable and efficacious in R/R MCL and CLL. Methods: This is an ongoing phase I/Ib investigator-initiated trial with primary endpoints of recommended phase 2 dose (RP2D) and safety/tolerability. Secondary endpoints include ORR and CR rates, PFS, and OS. Pts receive daily ibrutinib (560 mg MCL, 420 mg CLL) and TGR-1202. TGR-1202 doses from 400 mg to 800 mg were evaluated in a standard 3 + 3 design. Pts continue both drugs until progression or unacceptable toxicity. Eligibility criteria: ≥1 prior therapy, ECOG PS ≤2, and adequate hematologic and organ function. Prior PI3K/BTK inhibitors were allowed. Lugano Classification (MCL) and IW-CLL criteria were used to evaluate efficacy. Results: Thirty-three pts have enrolled on study, including 15 MCL and 18 CLL pts. The median age at enrollment was 67 yrs. (range 48-83). The median number of prior therapies was 3 for MCL (range 2-5, including 4 with prior autoSCT) and 2 for CLL (range 1-6). In CLL pts, del(17p) was present in 4/17 (24%), del (11q) in 7/17 (41%), and unmutated IGHV in 11/17 (65%). In phase I, no DLTs occurred in either arm, and the RP2D of TGR-1202 for both MCL and CLL was 800 mg. In a combined safety analysis of both arms (n = 33), hematologic toxicity included neutropenia (36%, 12% gr3/4), thrombocytopenia (21%, 3% gr3), and anemia (21%, 3% gr3). All grade non-hematologic toxicities in >10% of pts included: nausea (36%, all gr1/2), fatigue (33%, all gr1/2), diarrhea (33%, all gr1/2), and dizziness (24%, all gr1). Transaminitis (all gr1) was observed in 7/33 (21%) pts. SAEs included 2 pts each with: gr3/4 lipase elevation, gr3 hypophosphatemia, CNS aspergillus infection, and atrial fibrillation, and 1 pt each with: adrenal insufficiency (gr3), influenza A infection (gr4), C. difficile infection (gr4), and sudden death of uncertain cause. Two pts had dose reduction of TGR-1202 (dizziness, nausea), and 3 pts had dose-reduction of ibrutinib (atrial fibrillation, palpitations, vitreous hemorrhage). In MCL, with a median time on study of 10.9 mo. (range 1.1-19.8 mo.), the ORR is 85% (11/13), including 1 CR. In CLL, with a median time on study of 11 mo. (range 0.1-23.5 mo.), the ORR is 89% (16/18), with 1 pt achieving iwCLL CR, and 1 pt with radiographic CR. The 1 year PFS and OS for MCL are 37% and 52%, and for CLL both are 94%. Conclusions: TGR-1202 plus ibrutinib is well-tolerated in pts with R/R MCL and CLL, with no DLTs observed and a RP2D of TGR-1202 800 mg daily. Preliminary efficacy data suggest a high response rate in both diseases. Phase Ib expansion cohorts continue to accrue in this ongoing study (NCT 02268851). Keywords: chronic lymphocytic leukemia (CLL); ibrutinib; mantle cell lymphoma (MCL).