Phase 1–2a dose ranging study of TLK286 (a novel glutathione analog) in combination with docetaxel in platinum-resistant non-small cell lung cancer (NSCLC)
2004; Lippincott Williams & Wilkins; Volume: 22; Issue: 14_suppl Linguagem: Inglês
10.1200/jco.2004.22.90140.7140
ISSN1527-7755
AutoresV. Papadimitrakopoulou, Peter D. Boasberg, Robert Figlin, Ralph Zinner, George R. Blumenschein, Lisa R. King, M.T. Truong, Kashyap Patel, Gail L. Brown, Nadine Hanna,
Tópico(s)Inflammatory mediators and NSAID effects
Resumo7140 Background: TLK286 (Telcyta) is a novel glutathione analog prodrug activated by GST P1–1, which is overexpressed in NSCLC, releasing two electrophilic fragments that induce apoptosis. TLK286 has demonstrated significant single agent activity by RECIST in two Phase 2 NSCLC trials. In preclinical models, TLK286 is not cross resistant to docetaxel and shows synergistic inhibition in MCF-7 cells. Methods: The objectives were to determine the MTD of the TLK286/docetaxel combination and the objective response rate (ORR) by RECIST. NSCLC patients (pts) who had failed prior platinum-based therapy were treated with TLK286 at 500, 750 or 960 mg/m2 and docetaxel at 75 mg/m2 every 3 weeks until tumor progression or unacceptable toxicity. Results: At interim analysis, 30 pts (16 M, 14 F), median age 65 (range 46–80), median ECOG performance status 1, median prior regimens 1.5 (range 1–3) have received 103+ cycles (mean 3.4 cycles/pt, range 1–11). Pts failed prior therapies with: platinum (100%), paclitaxel (70%), pemetrexed (17%), EGFR inhibitors (33%), gemcitabine (10%), others (20%). The MTD of 960/75 mg/m2 of TLK286/docetaxel was well tolerated without dose limiting toxicities. Most common adverse events related to the TLK286/docetaxel combination were: Grade 1–2 fatigue, nausea, vomiting, anorexia, alopecia. Grade 3–4 neutropenia (15%), leukopenia (10%) and fatigue (15%) was seen. Febrile neutropenia occurred as expected with docetaxel in 7%. No cumulative toxicity has been seen. Six PRs (ORR=25%) and 11 SDs (DSR=71%) of 24 evaluable pts at TLK286/docetaxel dose of 960/75 mg/m2 were reported. Conclusions: TLK286/docetaxel combination has been well tolerated and is an active regimen in platinum resistant NSCLC. The recommended TLK286/docetaxel combination dose is 960/75 mg/m2 for future studies in NSCLC, ovarian 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.
Referência(s)