KI intolerance study: A phase 2 study to assess the safety and efficacy of TGR-1202 in pts with chronic lymphocytic leukemia (CLL) who are intolerant to prior BTK or PI3K-delta inhibitor therapy

TPS7569 Background: Although kinase inhibitor (KI) therapies, such as ibrutinib, are generally well tolerated, intolerance is the most common reason for discontinuation (d/c) in practice (~50%, Mato et al, Blood 2016). Additionally KI interruptions (≥ 8 days) can shorten OS (Barr et al, ASCO 2015). Fortunately, data suggest that KIs have non-overlapping toxicity profiles. Therefore, pts who d/c KI due to intolerance, with ongoing CLL response, represent an unmet need. TGR-1202 is a next generation, highly-specific PI3K-delta inhibitor with nanomolar inhibitory potency. TGR-1202 is well-tolerated with a d/c rate due to AEs of 8% as demonstrated in an integrated safety analysis of 165 treated pts (Burris et al, ASCO 2016). Methods: A phase 2 investigator initiated study is being conducted to assess the safety and activity of TGR-1202 in CLL pts who are KI intolerant. KI Intolerance is defined as ≥ 1 Gr 3 or ≥ 2 Gr 2 non-heme toxicities, ≥ 1 Gr 3 neutropenia with infection or fever, and/or ≥ 1 Gr 4 heme toxicity leading to KI (BTK and/or PI3K inhibitor) d/c (Table). Toxicities must resolve to ≤ Gr 1 prior to TGR-1202 dosing. Prior KI must be d/c for ≥ 14 days without progression (PD). All eligible pts are treated with TGR-1202 (800mg oral daily) until PD, toxicity or study conclusion. Primary study endpoint is PFS. Secondary endpoints include ORR, duration of response, time to treatment failure and TGR-1202 safety profile. Peripheral blood samples are collected prior to TGR-1202, after 28 days and at PD for correlative analyses to identify markers associated with KI intolerance. The trial commenced 10/1/2016. 55 eligible pts will be enrolled in approximately 12 months with 24 months follow-up. As of 1/2017, 10 study sites are enrolling pts with 10 more to be activated. To date, 10 pts have been enrolled and treated with TGR-1202. Clinical trial information: NCT02742090. [Table: see text]