Phase 1b study defining the optimal dosing combinations of the mTOR inhibitor AP23573 and Paclitaxel (PTX)

Abstract

3509 Background: AP23573 is a novel mTOR inhibitor with demonstrated anti-tumor activity in clinical trials. In vitro, AP23573 exhibits at least additive anti-proliferative activity in combination with a variety of agents including taxanes. This trial studied the combination of AP23573 and paclitaxel (PTX) in patients with advanced solid tumors. Methods: This was a modified, sequential (3+3) dose finding study with starting doses of 25 mg AP23573 i.v. and 80 mg/m2 PTX i.v. as Dose Level 1 (DL1) on days 1, 8 and 15 of a 28 day cycle. Doses of either drug were adjusted in successive cohorts. Blood samples and skin biopsies were collected for pharmacokinetic (PK) and pharmacodynamic (PD) studies. Dose limiting toxicity definitions included neutrophils <500/μL; thrombocytopenia = Grade 3 (CTC), any non- hematologic toxicities = Grade 2; missing 2 consecutive doses due to any toxicity. For PK and PD analysis, AP23573 and PTX were administered one day apart at the start of Cycle 1, reversing the sequence at Day 8. Results: Enrollment is complete and 29 patients with a variety of tumors (sarcoma, pancreatic, H&N, melanoma, thymoma) have been treated. Grade 3 thrombocytopenia and Grade 2 mouth sores were seen at DL1 as well as missed doses due to moderate (Grade 2) neutropenia. Adverse events include mouth sores and fatigue which were mild and reversible. Available PK data for AP23573 and PTX suggest no interaction. PD analysis in peripheral blood mononuclear cells demonstrates no interference by PTX on mTOR inhibition by AP23573. PD data in skin biopsies are forthcoming. Both 12.5 mg AP23573/80mg/m2 PTX and 37.5mg AP23573/60mg/m2 PTX are maximal dose combinations that appear to be well tolerated. Activity has been observed at multiple AP23573 mg/PTX mg/m2 dose levels (25/60, 12.5/80, 25/80). Five patients have been on study for >4 cycles, including 2 patients with partial responses (H&N and pancreatic). Conclusions: Combined therapy with AP23573 and PTX is safe. It is notable that evidence of anti-tumor activity was observed at modest doses of each drug when in combination. Combinations of these agents at both doses cited would be recommended for evaluation in trials examining efficacy in specific tumors. No significant financial relationships to disclose.