KI Intolerance Study: A Phase 2 Study to Assess the Safety and Efficacy of Umbralisib (TGR-1202) in Patients with Chronic Lymphocytic Leukemia (CLL) Who Are Intolerant to Prior BTK or PI3K-δ Inhibitor Therapy

Background: Although kinase inhibitor (KI) therapies such as ibrutinib are generally well tolerated, intolerance is the most common reason for discontinuation in practice (~50%, Mato et al, Blood 2016). KI intolerance is of significance as interruptions ≥ 8 days may shorten overall survival (OS) (Barr et al, Blood 2017). Therefore, patients (pts) who respond to a KI but discontinue due to intolerance represent a pt population with an unmet medical need. In a Ph 1/2 study, 27% of ibrutinib (BTK) intolerant pts treated with the BTK inhibitor acalabrutinib discontinued therapy (Awan et al, ASH 2016), while data suggest that alternate-target KIs can have non-overlapping toxicity profiles. Umbralisib (TGR-1202) is a next generation, highly-specific PI3K-δ inhibitor with nanomolar inhibitory potency. Umbralisib is well-tolerated with a discontinuation rate due to AEs of 8% as demonstrated in an integrated safety analysis of 165 treated pts (Burris et al, ASCO 2016). Methods: We report results of a Phase 2, multicenter study to assess the safety and activity of umbralisib in CLL pts who are KI intolerant, defined as: ≥ 1 grade 3 or ≥ 2 grade 2 non-heme toxicities, ≥ 1 grade 3 neutropenia with infection or fever, and/or ≥ 1 grade 4 heme toxicity leading to KI (BTK and/or PI3K inhibitor) discontinuation. Toxicities must resolve to ≤ grade 1 prior to umbralisib dosing. Prior KI must be discontinued for ≥ 14 days without CLL progression; however, pts could have progressed after 14 days of KI discontinuation. Pts must start umbralisib within 12 mos of discontinuing prior KI. All eligible pts are treated with umbralisib (800mg oral daily) until PD, toxicity, or study conclusion. The primary endpoint is progression-free survival (PFS). Secondary endpoints include ORR, duration of response, time to treatment failure, and umbralisib safety profile. Peripheral blood (PB) samples are collected prior to umbralisib, Cycle 2, and at PD for correlative analyses to identify markers associated with KI intolerance. The trial commenced on 10/1/2016. Results: 22 pts who met study enrollment criteria for KI intolerance were treated as of 7/15/2017. 20 pts were ibrutinib intolerant and 2 were idelalisib intolerant. One idelalisib intolerant pt was deemed ineligible due to Richter transformation discovered 26 days after enrollment but thought present at study entry. Baseline demographics were as follows: median age 66 years (range 53-83), median prior therapies 2 (1-7), 55% female, 64% ECOG 1, stage III-IV (%), bulky disease (45%), del(17p) (14%), del(11q) (27%), IGHV unmutated (59%). Median duration of prior KI exposure was 8 months (range 1-36 months) and median duration from end of KI to start of umbralisib was 2.5 months. 68% experienced progression of CLL within 6 months of first KI discontinuation (prior to enrolling in this study). AEs that led to first KI discontinuation (ibrutinib or idelalisib) are defined in Table 1 . On umbralisib treatment: Grade 3-4 AEs (≥ 10% patients) were limited to neutropenia (23%, n=5) and leukocytosis (14%, n=3, none related to CLL progression). Common Grade 3-4 AE9s associated with other PI3K-δ inhibitors were rare as follows: AST/ALT (0% G 3/4); diarrhea (9% G 3/4); pneumonitis (0%). With a median follow up of 6 months, no pt has discontinued umbralisib due to intolerance, with 1 pt with ongoing clinical benefit discontinuing due to study noncompliance. No pt has experienced a recurrence of an AE on umbralisib that previously led to KI discontinuation (non-overlapping toxicity profile), including common AEs associated with PI3K-δ discontinuation. One pt experienced microscopic lymphocytic colitis possibly infectious or medication-related with grade 3 diarrhea and has been re-challenged with umbralisib. Median PFS has not been reached ( Figure 1 ). Conclusions: Umbralisib is safe and effective in a KI intolerant CLL pt population. These are the first prospective data to confirm that switching from ibrutinib or idelalisib to an alternate PI3K-δ (umbralisib) can result in durable responses in the absence of recurrence of KI intolerance toxicities. These data are indicative of non-overlapping toxicity profiles with an alternate KI. Pre-umbralisib dosing samples are currently being analyzed for BTK, PLC gamma 2 mutations, IGHV mutation status, driver mutations of interest (Notch1, TP53) and CYP-3A4 polymorphisms. Study enrollment is ongoing and additional follow up on study outcomes will be reported. Disclosures Mato: AstraZeneca: Consultancy; Kite: Consultancy; Regeneron: Research Funding; DTRM: Research Funding; Portola: Research Funding; Gilead Sciences, Inc.: Membership on an entity9s Board of Directors or advisory committees; Janssen: Consultancy; Pharmacyclics: Research Funding; TG Therapeutics: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Cheson: AbbVie, Roche-Genentech, Pharmacyclics, Acerta: Consultancy; Acerta, Pharmacyclics, Epizyme, Gilead, Roche, AbbVi: Other: Institution receives research support . Lamanna: Gilead: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Pagel: Actinium Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees. Lansigan: Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy, Research Funding. Barr: Gilead: Consultancy; AbbVie: Consultancy, Research Funding; Celgene: Consultancy; Infinity: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Dorsey: TG Therapeutics, Inc.: Consultancy. Svoboda: Kite: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; BMS: Consultancy, Research Funding; Celgene: Research Funding; Merck: Research Funding. Schuster: Seattle Genetics: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Nordic Nanovector: Consultancy; Celgene: Consultancy, Research Funding. Ujjani: Genentech: Consultancy; Abbvie: Research Funding, Speakers Bureau; Gilead: Consultancy; Pharmacyclics: Consultancy, Research Funding. Paskalis: TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli: TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin: TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss: TG Therapeutics, Inc.: Employment, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees. Brander: Teva Pharmaceuticals, Genentech, AbbVie, Pharmacyclics: Consultancy; AbbVie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Genentech: Consultancy; TG Therapeutics: Consultancy, Membership on an entity9s Board of Directors or advisory committees.