Phase I/II study of TH-302 in combination with pemetrexed in patients with solid tumors including NSCLC.

e13535 Background: TH-302 is a 2-nitroimidazole hypoxia-activated prodrug of the DNA alkylator, bromo-isophosphoramide mustard. In preclinical models, TH-302 was active alone and enhanced the activity of pemetrexed (Pem). A phase I/II study was conducted to establish the safety and tolerability, and investigate the activity of TH-302 in combination with Pem. Methods: This study used standard solid tumor eligibility criteria except patients (pts) could not have received prior Pem. Pts received IV TH-302 on Days 1 and 8 and Pem 500 mg/m2 on day 1 of a 21 day cycle. A standard 3+3 pts design was used with a TH-302 starting dose of 240 mg/m2. Following the determination of the MTD, a dose expansion component enrolled subjects with second-line NSCLC. The objectives of the study were to determine the MTD/RP2D of TH-302 with Pem, and to evaluate the safety, pharmacokinetics (PK), and preliminary efficacy. Results: 29 pts [14M/15F, median age: 61y (range 22 to 86y), ECOG PS 0/1: 16/13] were enrolled at 5 sites and treated at TH-302 doses (mg/m2) of 240 (5 pts), 340 (7), 400 (1), 480 (9) and 575 (7). Primary tumor sites: 9 NSCLC, 4 colorectal, 3 pancreas, 3 HCC, 2 renal, 8 other sites. Treatment is ongoing in 7 pts; 16 pts discontinued prior to Cycle 6 (10 PD, 3 pt/physician decision, 2 clinical deterioration, 1 AE). DLTs were Gr 4 thrombocytopenia and Gr3 oral mucositis and oral candidiasis. Gr 3/4 neutropenia, thrombocytopenia and anemia occurred in 48%, 26% and 15% of pts. Skin and mucosal toxicities occurred in 18 (62%) and 20 (69%) pts, respectively, including four Gr 3 mucosal events (oral mucositis and oral candidiasis). Other common AEs were fatigue (50%) and nausea (46%). Based on DLTs and tolerability a TH-302 RP2D of 400 mg/m2 with Pem 500 mg/m2 was selected. There was no PK interaction between TH-302 and Pem. Best Response: 9 PRs (35%) and 9 SDs (35%) were reported in the 26 evaluable patients including 50% PR and 38% SD in 8 evaluable patients with relapsed/refractory NSCLC. Conclusions: TH-302 may be administered in combination with full dose Pem. Hematologic toxicity was greater than that seen with Pem alone. TH-302-related skin and mucosal toxicities were dose limiting but reversible. Encouraging antitumor activity has been observed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Threshold Pharmaceuticals, Inc. Threshold Pharmaceuticals, Inc. Threshold Pharmaceuticals, Inc. Threshold Pharmaceuticals, Inc.