Optimizing obatoclax administration schedule: Safety and efficacy of 3-hour versus 24-hour infusion in combination with carboplatin and etoposide for patients with extensive-stage small cell lung cancer (ES-SCLC).

Abstract

e13531 Background: Previous studies with obatoclax (Ob), a pan-BCL-2 antagonist, identified infusional CNS effects as dose- limiting adverse events (AEs) that occur with greater frequency and intensity with 3-hr versus 24-hr infusions of Ob. This phase I study of Ob used both infusion schedules to compare the safety and efficacy when used in combination with carboplatin (Carb) and etoposide (Et). Methods: As previously reported (ASCO, 2009, Ab 3576) this phase I study evaluated Ob given on a 21-day (D) cycle together with Carb (AUC 5 D1) and Et (100 mg/m2 D1-3), in separate fixed dose escalations using Ob as a 3-hr infusion D1-3 (15 mg, 30 mg and 45 mg) and as a 24-hr infusion D1-3 (30 mg, 45 mg and 60 mg). Eligible patients (pts) had ES-SCLC, measurable disease, ≤1 prior therapy, ECOG PS ≤1, and adequate organ function. 3-6 pts were enrolled into ascending dose cohorts with standard DLT rules. Results: 25 pts were enrolled (14 males; median age 66). 18 pts were previously untreated (12 in 3-hr group; 6 in 24-hour group). Since only chemotherapy-naive pts were to be enrolled in phase II, safety and efficacy data from those pts are presented here. Preliminary safety data indicate that AEs of all grades with >33% difference between the arms were somnolence (83% in 3-hr vs. 0% in 24-hr), euphoric mood (58 vs. 0%), dysguesia (50 vs. 0%), hyponatremia (8 vs. 50%), and chest pain (42 vs. 0%). CNS AEs were generally transient and without sequelae. The RR, PDs during the planned 6 cycles of combination therapy, median PFS, and median OS all demonstrated a trend in favor of the 3-hr infusion arm. Minimum follow-up for all 18 pts is 10.4 months. Conclusions: Although associated with a higher incidence of some (particularly CNS) AEs, Ob 3-hr infusion in combination with Carb and Et showed a trend toward higher RR, PFS, and OS than 24-hour infusion. 3-hr infusions with Carb and Et have been studied further in a randomized, phase II trial in pts with chemotherapy-naïve ES-SCLC which has now completed enrollment. RR % Progression during 6 cycles Median PFS (days) Median OS (days) 3-hr 100 1/12 197 (126-390) 312+* (175-516+) 24-hr 66 2/6 185 (43-224) 198 (80-315+) * Median not reached No significant financial relationships to disclose.