Phase I-II trial of TLK286, a novel glutathione analog prodrug, in combination with carboplatin (C) and paclitaxel (P) as first-line treatment for advanced non-small cell lung cancer (NSCLC)

Abstract

7275 Background: TLK286 is a novel glutathione analog prodrug activated by glutathione S-transferase P1–1 that induces apoptosis via the stress response pathway. Pre-clinical data demonstrate that TLK286 is active against tumors that exhibit resistance to C and P and that the triplet TLK286/C/P is synergistic. Methods: The objectives of this phase I-II study are to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and overall response rate (ORR) of TLK286/C/P in chemotherapy-naïve patients (pts) with advanced NSCLC. A cohort-based dose-escalation treatment with planned doses of TLK286 of 400, 500, 750 or 1000 mg/m2 combined with standard doses of C (AUC 6) and P (200 mg/m2) intravenously every 3 weeks until tumor progression or unacceptable toxicity is ongoing. DLTs are assessed on day 21 and are defined as any ≥ grade 3 non-hematologic toxicity or ≥ grade 4 hematologic toxicity persisting to day 21. If ≥ 2 pts have a DLT within a dose level, that level will be the MTD and will be further examined in the phase II portion. Tumor response is assessed for each pt after every 2 treatments. Results: At interim analysis, 9 pts (4 M, 5 F), median age 63 (range 43–74), have been treated at 3 dose levels and have received 32 cycles (median 4 cycles/pt, range 2–6). No DLTs have been observed. The MTD has not been reached. The most common toxicities observed have been grade 1–2 alopecia, anemia, thrombocytopenia and myalgias. 2 pts had grade 3–4 neutropenia that resolved before the next cycle was due. No febrile neutropenia or unexpected toxicities were seen. Significant anti-tumor activity was observed in the first 8 pts with 5 partial responses, 2 stable disease, and 1 progression (ORR=63%). Conclusions: The combination of TLK286/C/P has been well tolerated and has shown clinical activity in advanced NSCLC pts. Accrual continues at the 1000mg/m2 dose level, and expansion of the MTD into a phase II study to further assess the efficacy of the combination will be performed. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Telik Telik Telik