A safety and schedule seeking trial of Bcl-2 inhibitor obatoclax in previously untreated older patients with acute myeloid leukemia (AML)

Abstract

3579 Background: Obatoclax (Ob) is a small-molecule inhibitor of all Bcl-2 prosurvival proteins. In a previous study a 70 year old patient with untreated AML had a cytogenetic CR 8 days after receiving 20 mg/m2 of Ob over 24 hrs. This study evaluated the single-agent response rate in older patients with previously untreated AML. Methods: A Safety phase to evaluate escalating doses of Ob given by 3-hr infusion was performed. Based on previous results, the dose of 60 mg over 24 hrs was used for the 24-hr infusion arm of the Schedule Seeking phase, in which Ob was administered as either a 3-hr or 24-hr infusion for 3 consecutive days every 2 wks. The endpoint of the Schedule Seeking phase was CR after C2 in 16 randomized patients. Eligibility criteria included age ≥ 70, untreated AML (1 prior Rx allowed in Safety phase), ECOG PS ≤2, adequate renal and hepatic function. PK samples were collected during C1. Results: 18 patients (8 male; median age 82) were enrolled. 2/3 patients enrolled into the 1st cohort (30 mg x 3 days) of the Safety phase had DLT events (ataxia and somnolence). 3 patients enrolled into a 20 mg x 3 days cohort had no DLTs; this dose was used for Schedule Seeking patients receiving 3-hr infusions. In the Schedule Seeking phase, 7 patients were randomized to receive 20 mg by 3-hr infusion and 5 were randomized to receive 60 mg by 24-hr infusion. The most common (>25%) AEs were euphoric mood (50%), ataxia (38%), & somnolence (38%). Efficacy data after C2 show that 3 patients in the 20 mg 3-hr infusion cohort in the Safety phase and 1 at the same dose & schedule in the Schedule Seeking phase had ≥50% decrease in BM blasts after C2, which was not seen in the 60 mg 24-hr infusion cohort. There were no CRs. There was a single death by D28 (24-hr infusion). There were significant differences in PK by infusion schedule. Conclusions: MTD for Ob as a 3-hr infusion administered in older patients with AML on 3 consecutive days is 20 mg/day, and both this regimen and 60 mg as a 24-hr infusion x 3 days were well tolerated. Evidence of biological activity was seen with the 3-hr infusion schedule but not with the 24-hr infusion schedule, suggesting that efficacy may be improved with the 3-hr infusion schedule and may be related to PK differences. [Table: see text]