Phase 1–2a study of TLK286 (a novel glutathione analog) in combination with carboplatin in platinum refractory or resistant (≥ 3rd line) ovarian cancer

Abstract

5060 Background: TLK286 (Telcyta) is a novel glutathione analog prodrug activated by GST P1–1, which is overexpressed in ovarian cancer, releasing two electrophilic fragments that induce apoptosis. In vitro, TLK286 is not cross resistant to carboplatin and has shown synergistic inhibition in OVCAR3 cells. TLK286 has demonstrated significant single agent activity in two Phase 2 trials in ovarian cancer. Methods: Platinum refractory or resistant ovarian cancer patients (pts) were treated at doses of 500, 750 or 960 mg/m2 of TLK286 in combination with carboplatin (AUC 5) every 4 weeks until tumor progression or unacceptable toxicity. The objectives were to determine the MTD of the combination, and objective response rate (ORR) by RECIST. Results: At interim analysis, 8 pts median age 56 (range 49–68), prior chemotherapy regimens median 3.5 (range 2–5) have received 44+ cycles (median 4 cycles, range 3–11+). All pts have failed paclitaxel and platinum (platinum resistant 63%, refractory 25%) and additional therapies: Doxil (63%), gemcitabine (25%), topotecan (38%) and others (75%). Most common adverse events (AEs) related to TLK286/carboplatin are Grade 1–2 fatigue (5 pts), nausea (8), vomiting (3), neutropenia (3), leukopenia (7). Grade 3 fatigue, vomiting and leukopenia were reported in 1 pt, thrombocytopenia in 3 pts and neutropenia in 5 pts. No Grade 4 AEs or dose limiting toxicities were observed. One CR (13%), 4 PRs (50%) and 3 SDs (38%) are shown (ORR=63% and DSR=100%). Conclusions: TLK286 at 50% of the single agent dose (500 mg/m2) in combination with carboplatin (AUC 5) shows enhanced efficacy with ORR of 63% and DSR of 100% in platinum refractory or resistant (≥ 3rd line) ovarian cancer pts. Further pt follow-up and dose escalation continues. The TLK286/carboplatin combination is an active regimen for future studies in ovarian, NSCLC and breast cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Telik, Inc. Telik, Inc. Telik, Inc. Telik, Inc. Telik, Inc.