Phase I/II study of exisulind and gemcitabine in patients with recurrent advanced non-small cell lung cancer (NSCLC)

Abstract

7103 Background: Exisulind is an oral selective apoptotic antineoplastic drug which inhibits the cyclic GMP phosphodiesterase. The combination of exisulind and gemcitabine produced an additive anti-tumor effect in preclinical studies. The objectives of this study were to determine the maximally tolerated dose (MTD) (Phase I) and clinical efficacy (Phase II) of this combination in patients (pts) with recurrent advanced NSCLC. Methods: In phase I, exisulind was escalated in 3 dose levels (from 125mg BID up to 250mg BID) in combination with a fixed dose of gemcitabine 1250mg/m2 IV days 1 and 8 of a 3 week cycle. Plan for phase II is to accrue 24 pts (95% power to detect a 50% increase in TTP from 3 months to 4.5 months with the level of significance of 0.1). Eligibility: Disease recurrence of more than 3 months from completion of first-line therapy, only one prior chemotherapy regimen, PS 0–1. Results: To date, 33 pts (24men, 9 women) have been enrolled; 15 in phase I and 18 in phase II. Median age was 65. 30% had PS 0, 70% had PS 1. 60% had distant metastasis. All pts received platinum-based doublets as first-line therapy, of which 94% were third-generation regimens. Phase I: Six pts were entered to dose level 1, 3 in dose level 2 and 6 in dose level 3. Of 14 evaluable pts, 1 achieved PR, while 4 had SD after 6 cycles of treatment. The regimen was well tolerated (MTD not reached) with grade 3 fatigue and grade 3 constipation being DLTs (1 patient each). Myelotoxicities were mild. Phase II (ongoing): Dose level 3 was chosen for testing. Of 18 pts, 7 have died, 11 survived including 4 who are still on treatment. PR was seen in 2/18 pts, SD in 10/18. Toxicities included G3/4 leukopenia in 4 pts (22 %), G3/4 neutropenia 7 (39 %), G3 neutropenic infection 1 (6%), G3 anemia 2 (11 %), G3 thrombocytopenia 3 (17 %), G3 transaminases 3 (17 %). As of 8/03, of 32 evaluable pts enrolled in both phase I/II, disease was controlled in 17 pts (53%) including 3 with PR (9 %) and 14 with SD (44 %). Median and one year survival was 10 months and 40% (standard error 13%) in phase I. Conclusions: The study regimen is well tolerated and the phase I results are promising. Phase II is still ongoing; survival and TTP will be updated. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly