Exposure-Response Of Idelalisib, a Novel PI3Kδ Inhibitor, Administered As Monotherapy In The Treatment Of Hematologic Malignancies (2013)

Abstract Background Idelalisib (IDELA) is a potent, competitive PI3Kδ inhibitor currently in Phase 3 clinical development. In numerous Phase 1/2 studies, IDELA alone or in combination with other therapies demonstrated clinical efficacy in patients with various hematologic malignancies (e.g., indolent non-Hodgkin lymphoma [iNHL] and chronic lymphocytic leukemia [CLL]) and overall safety of IDELA has been characterized in these patients. The relationship between IDELA plasma exposures and its inactive circulating metabolite, GS-563117, and clinical efficacy and safety findings were evaluated. Methods IDELA and GS-563117 plasma exposure were generated using population pharmacokinetic (PK) models for IDELA and GS-563117 based on data from several phase 1/2 clinical studies. Efficacy and safety data from 2 clinical studies, a Phase 1 dose ranging study (101-02; 50 mg to 350 mg BID, 150 mg and 300 mg QD) and a Phase 2 study (101-09), were included in the PK/PD analyses. Efficacy endpoints including best overall response rate (BOR), duration of response (DOR), progression free survival (PFS), sum of products of the greatest perpendicular diameters (SPD) of index lesions, and lymph node response rate (LNR) were evaluated against IDELA plasma exposure (AUCtau and Ctau). Safety endpoints evaluated included neutropenia, diarrhea, skin rash, infection, and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation (vs. plasma exposure of IDELA and GS-563117, specifically AUCtau and Cmax). Results Over a wide dose/exposure range in Study 101-02, median SPD response increased with IDELA exposure (Ctau) quartiles, before reaching a plateau at the third quartile (Q3: range ∼280-405 ng/mL), which encompasses the mean IDELA Ctau at 150 mg BID dose (381 [56%] ng/mL). IDELA exposures were less than dose proportional and modestly higher at doses &gt;150 mg BID (eg. Ctau ∼48% higher at 350 mg vs. 150 mg BID). No relationships were observed between the incidence rate (yes/no) of Grade 3 or 4 AST or ALT elevation or the severity (Grade 1 to Grade 4) of elevation over the range of IDELA plasma exposure. Taken together, these data supported the selection of 150 mg BID for further development. No relevant association was observed between IDELA exposure (Ctau: median (Q1, Q3) = 294 (203, 437) ng/mL) vs. any of the efficacy endpoints evaluated in Study 101-09, indicating the absence of exposure-efficacy relationships at 150 mg BID (Table 1). In Study 101-09, no association was observed between IDELA or GS-563117 plasma exposures vs. incidence of neutropenia, diarrhea, rash, infection, or Grade 3 or 4 AST or ALT elevation. Conclusions There were no exposure-response relationships observed for efficacy or safety endpoints at IDELA 150 mg BID, which was selected based on comprehensive exposure-response analyses over a wide dose/exposure range. These data support the use of IDELA 150 mg BID as a monotherapy for treating patients with hematologic malignancies. Disclosures: Jin: Gilead Sciences: Employment, Equity Ownership. Zhou:Gilead Sciences: Employment, Equity Ownership. Fang:Gilead Sciences: Employment, Equity Ownership. Li:Gilead Sciences: Employment, Equity Ownership. Newcomb:Gilead Sciences: Employment, Equity Ownership. Dansey:Gilead: Employment, Equity Ownership. Ramanathan:Gilead Sciences: Employment, Equity Ownership.