A phase Ib trial of Bcl-2 inhibitor obatoclax in combination with carboplatin and etoposide for previously untreated patients with extensive-stage small cell lung cancer (ES-SCLC)

Abstract

3576 Background: Obatoclax (Ob) is a small-molecule antagonist of all the Bcl-2 prosurvival proteins. In vitro it enhances the effects of the drugs cisplatin and etoposide. Bcl-2 family proteins are frequently expressed in SCLC, and SCLC cell lines are sensitive to Ob. Methods: This study was designed to find the maximal tolerated doses (MTD) of oOb when given on a 21 day (D) cycle together with carboplatin (AUC 5 D1) and etoposide (100 mg/m2 D1–3), in separate dose escalations using Ob as a 3-hr infusion D1–3 and as a 24-hr infusion D1–3. Eligible patients had ES-SCLC, measurable disease, ≤1 prior therapy, ECOG PS ≤1, and adequate hematological, renal and hepatic function. 3- 6 patients were enrolled into ascending dose cohorts with standard DLT rules evaluating safety in C1 to determine dose escalation. Results: 24 patients were enrolled into 5 dosing cohorts (14 males; median age 67). A total of 66 cycles (C) have been administered to date. There were no DLTs in the initial cohorts using Ob 15 mg over 3 hr or Ob 30 mg over 24 hr. Two DLTs occurred in the Ob 30 mg over 3 hr cohort - both due to myelosuppression in previously treated patients. As a result, the trial was amended to exclude previously treated patients. 5 previously untreated patients receiving Ob 30 over 3 hr had no DLTs. There were no DLTs in the Ob 45 mg over 24 hr cohort but 2 patients in the Ob 24-hr infusion cohorts had infusion pump malfunctions while at home. There were 2 DLTs in the Ob 45 mg over 3 hr cohort (somnolence, euphoria, & disorientation) establishing MTD of Ob 30 mg over 3 hr daily x 3. After C2 the 6 previously untreated patients on Ob 24-hr infusion cohorts had 3 PRs, 1 SD, 1 PD, and 1 Unk; the 2 previously treated patients had PRs. After C2 all 7 previously-untreated patients at 15 or 30 mg in the 3-hr infusion cohorts have PR; the 3 previously treated patients had SD. Conclusions: Ob can be combined with carboplatin and etoposide using either a 3-hr or a 24-hr infusion, and both regimens are associated with high early response rates in ES-SCLC, perhaps due to inhibition of mcl-1. Due to practical issues with the 24-hr infusion arm, the 3-hr 30 mg MTD dose will be utilized in a randomized phase II versus carboplatin and etoposide alone. [Table: see text]