A PHASE 2 STUDY TO ASSESS THE SAFETY AND EFFICACY OF UMBRALISIB IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) WHO ARE INTOLERANT TO PRIOR BTK OR PI3K DELTA INHIBITOR THERAPY (2019)

Introduction: Although kinase inhibitor (KI) therapies are generally well tolerated, intolerance is the most common reason for discontinuation (~50% discontinuations; Mato et al 2017). Therefore, patients (pts) who discontinue a KI due to intolerance represent an unmet medical need. Umbralisib (TGR-1202, Umbra) is a novel, highly-specific PI3Kδ inhibitor which is active and well tolerated in pts with CLL. This phase 2 trial evaluates the safety/efficacy of Umbra in CLL pts who are intolerant to prior BTK or PI3Kδ inhibitor therapy. Methods: KI intolerant is defined as: ≥ 1 GR 3 or ≥ 2 GR 2 non-heme tox, ≥ 1 GR 3 neutropenia with infection or fever, and/or ≥ 1 GR 4 heme tox leading to KI discontinuation. Prior KI must be discontinued for ≥ 14 days without CLL progression. Pts must start Umbra within 12 mos of prior KI. All pts treated with Umbra (800 mg oral daily) until progression, toxicity, or study conclusion. Primary endpoint is progression-free survival (PFS). Secondary endpoints include time to treatment failure as compared to prior KI therapy and characterization of Umbra safety profile. Peripheral blood samples are being collected for correlative analyses to identify markers associated with KI intolerance. Results: 51 pts were enrolled (44 BTK & 7 PI3Kδ intolerant). Baseline demographics include: med age 70 yrs (range 48-96), med prior therapies 2 (1-7), del17p and/or TP53 (24%), del11q (18%), IGHV unmutated (57%), BTK mut or PLCg2 mut (8%). 76% required tx within 6 mos of prior KI discontinuation. Most common AEs leading to prior KI discontinuation were: rash (14 events), arthralgia, A-Fib/Cardiac, (9 events each), diarrhea/colitis, bleeding/hemorrhage (6 events each). 50 pts were evaluable for efficacy. Median PFS is 23.5 mos (95% CI 16.6-not estimable, Fig 1). As of the cut-off date, 58% of pts have been on Umbra for a longer duration than their prior KI. Most common (≥ 5%) GR ≥3 AEs while on Umbra (all causality) were: neutropenia (14%), thrombocytopenia (10%), diarrhea (8%), hypophosphatemia, pneumonia (6% each). Six pts (12%) discontinued Umbra due to an AE (pneumonitis (2), pneumonia, rash, dermatitis, pancreatitis). Four pts had recurrence of an AE that led to prior KI intolerance, however 3/4 recurrences did not result in dose-modification. No prior PI3K treated patients (n = 7) had a recurrence of AE that led to PI3K discontinuation including the 3 pts with colitis. Four pts (8%) had dose reductions (headache, hematologic, AST/ALT and colitis) and were successfully re-challenged. Keywords: BTK inhibitors; chronic lymphocytic leukemia (CLL); PI3K/AKT/mTOR. Disclosures: Mato, A: Consultant Advisory Role: Genentech, TG Therapeutics, PCYC, Loxo, Abbvie, Sunesis, Celgene, Verastem, Astra-Zeneca; Research Funding: TG Therapeutics, PCYC, Loxo, Abbvie, Sunesis, Regeneron, J and J. Pagel, J: Consultant Advisory Role: TG Therapeutics, Inc.; Research Funding: TG Therapeutics, Inc. Barr, P: Consultant Advisory Role: TG Therapeutics, Inc.; Research Funding: TG Therapeutics, Inc. Skarbnik, A: Consultant Advisory Role: Abbvie, Pharmacyclics, Janssen, Genentech; Honoraria: Verastem, Abbvie, Pharmacyclics, Janssen, Jazz, Gilead, Seattle Genetics, Genentech; Research Funding: BMS. Svoboda, J: Consultant Advisory Role: Seattle Genetics, BMS, Kite, Kyowa, Astra-Zeneca; Research Funding: Seattle Genetics, BMS, Merck, Celgene, Pharmacyclics, TG Therapeutics, Novartis. Paskalis, D: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Sportelli, P: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Miskin, H: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Weiss, M: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Brander, D: Consultant Advisory Role: TG Therapeutics, Inc.