Extended phase I trial of the oral pan-Bcl-2 inhibitor AT-101 by multiple dosing schedules in patients with advanced cancers

Abstract

e14537 Background: Over-expression of Bcl-2 family proteins is common in human cancers. Initial trials of the oral, pan-Bcl-2 inhibitor AT-101 showed acute dose limiting toxicity of Gr 3–4 AST/ALT (MTD 40 mg/d) and ileus with prolonged dosing daily (QD) for 21/28 days per cycle (Saleh, NCI/EORTC, 2005; James, ASCO, 2006 and Saleh, ASCO, 2007). MTD in the QD schedule has been previously reported. In this study different dosing schedules of AT-101 were tested in adults with advanced cancers and final results for the pulse dosing schedule of twice a day for three days every other week (b.i.d. x 3d EOW) are being reported. Methods: Serial patient (pt) cohorts received AT-101 at escalating doses of 30–80 mg b.i.d. x 3d EOW. Adverse events (AEs) were graded by the NCI CTCAE v3.0. Efficacy was determined by RECIST. Results: 37 pts have been enrolled. Safety data is available on 34/37 pts. In this b.i.d. x 3d EOW dosing schedule, ileus/small bowel obstruction (SBO) occurred in 3 pts (one at each dose level of 30, 40 and 50 mg) and was the dose limiting toxicity for this schedule. Of note, the SBO that occurred at 30 mg was felt to be unrelated to study agent therefore, 30 mg b.i.d. x 3d EOW was the MTD determined for this schedule. The most common (>50%) grade 1–2 AEs included: nausea, vomiting, diarrhea, fatigue and anorexia. Grade 3–4 AEs occurring in > 2 pts include: nausea, abdominal pain, elevated AST (3 pts each), vomiting, fatigue, dehydration (4 pts each), hypokalemia (5 pts). Stable disease was reported in 13/37 (35%) pts. One pt with NSCLC continues on study with stable disease for 33 cycles and 2 additional pts were on study with stable disease for 18 and 9 cycles. The mean Plasma Cmax was 301 ng/ml (+ 477 ng/ml SD) and mean AUC for 30 mg b.i.d.x3d EOW was 1080 ng*hr/ml (+ 1990 ng/ml SD) with a median peak concentration at 4 hours post dose. Conclusions: Pulse dosing of AT-101 achieved an MTD of 30mg b.i.d. x 3d EOW and is associated with reduced toxicity than continuous daily dosing, and may be preferable in combination regimens. [Table: see text]