Activity of TGR-1202, a novel once-daily PI3Kδ inhibitor, in patients with relapsed or refractory hematologic malignancies.

2513 Background: TGR-1202 is a novel, next generation PI3Kδ inhibitor. Preliminary data from an ongoing Ph I study of TGR-1202 demonstrated clinical activity in patients (pts) with advanced hematologic malignancies. Herein we present updated results from this Phase I, first in human study of TGR-1202. Methods: TGR-1202 is administered orally daily following a 3+3 dose escalation design. Previously treated pts with an ECOG PS < 2 and confirmed diagnosis of B-cell non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or other lymphoproliferative disorders are eligible. Endpoints include safety, PK/PD, and efficacy. Results: 27 pts have been enrolled to date across 7 dose levels: 50, 100, 200, 400, 800, 1200, and 1800 mg QD. 74% male, ECOG 0/1: 33%/67%, median age of 59 yrs (range: 28-82), median 3 (range: 1-14) prior treatment regimens, and 40% were refractory to prior treatment. Evaluable pts include 7 indolent NHL (iNHL), 11 CLL/SLL, 4 Hodgkin’s lymphoma (HL), 2 mantle cell lymphoma (MCL), 1 each of lymphoplasmacytic lymphoma, DLBCL, and atypical hairy cell leukemia. TGR-1202 was well tolerated. Gr≥3 AE’s in >5% of patients were limited to: dyspnea (7%), neutropenia (15%), rash (7%), and thrombocytopenia (7%). Two DLTs were observed: 1 Gr. 3 rash at 800 mg (pt rechallenged with no recurrence), and 1 Gr. 3 hypokalemia at 1800 mg (pt discontinued due to non-compliance). Notably, no hepatotoxicity has been observed to date. Of the 27 enrolled, 23 were evaluable for efficacy. A significant dose-response relationship was observed. Of the 13 pts treated at < 800 mg QD who completed 2 cycles of treatment, 7 achieved SD. Of 10 pts treated at ≥ 800 mg QD: 4/6 CLL pts (67%) achieved a nodal PR, 1/3 Hodgkin’s pts (33%) achieved a PR. Nodal reductions occurred rapidly in patients with CLL and were accompanied by marked lymphocytosis. Conclusions: TGR-1202 is well tolerated in pts with rel/ref hematologic malignancies with no reported hepatic toxicity and signs of clinical activity at doses ≥ 800 mg QD. Enrollment continues in expansion cohorts and at higher dose cohorts. Updated safety, efficacy, PK, and PD data will be presented. Clinical trial information: NCT01767766.