Background: TLK286 (T) is a novel glutathione analog prodrug activated by glutathione S-transferase P1-1 that induces apoptosis via the stress response pathway. TCP is a synergistic regimen in vitro and T has shown single agent activity in NSCLC. Methods: Patients (Pts) with Stage IIIB or IV NSCLC, all histologic subtypes, CNS lesions and prior neoadjuvant or adjuvant therapy were allowed. Pts were evaluated in groups with T at 500, 750 and 1000 mg/m2 with P at 200 mg/m2 and C at AUC 6 every 3 weeks. Pts were treated until tumor progression or unacceptable toxicity. After completion of 6 cycles, responding pts could continue on T maintenance therapy. Objectives were to determine the safety, objective response rate (ORR) by RECIST, time to tumor progression (TTP), and select the optimal TCP dosing regimen. Results: A total of 122 pts were treated, with T at 500 (N=50), 750 (N=51), and 1000 mg/m2 (N=21). A total of 522 cycles of TCP were given, median # cycles/pt =6 (range 1-24); 170 cycles of T maintenance therapy were given. The most common toxicities were Grade 1-2 anemia, neutropenia, thrombocytopenia, nausea, vomiting, fatigue and alopecia. Febrile neutropenia was observed in 7 of 522 cycles (0.1%). Grade 4 toxicities were primarily hematologic with neutropenia at 20%, 35% and 29.6% and thrombocytopenia at 0%, 6% and 9.5% at doses of 500, 750 and 1000 mg/m2 of TCP respectively. Hematologic toxicity was effectively managed with dose reductions and growth factor support as required. There were no cumulative toxicities. ORR was 38.6% (95% CI 24.4-54.5), 32.6% (95% CI 19.5-48), and 40% (95% CI 19.1-63.9) at the three dose levels respectively; overall median TTP estimate was 5.43 months. Conclusions: The combination of TCP is well tolerated at all 3 dose levels and has significant clinical activity in pts with Stage IIIB or IV NSCLC. Phase 3 studies of the active TCP regimen are planned.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA