A modular Phase i study of lenalidomide and paclitaxel in metastatic castration-resistant prostate cancer following prior taxane therapy

Purpose: Lenalidomide, a highly potent immunomodulatory derivative of thalidomide, potentiates the action of paclitaxel in vitro against prostate cancer cell lines in co-culture with mononuclear cells. A modular Phase I study of lenalidomide and paclitaxel in men with metastatic castration-resistant prostate cancer (CRPC) was conducted to assess PSA kinetics with lead-in lenalidomide and the feasibility of the combination. Methods: Men with metastatic CRPC with prior taxane chemotherapy were planned for single-agent "lead-in" lenalidomide for 21/28 days at dose-levels: -1 (5 mg), 0 (10 mg), +1 (15 mg), +2 (20 mg), +3 (25 mg); followed by lenalidomide at the same dose and schedule in combination with weekly intravenous paclitaxel 100 mg/m² over 3 h on days 1, 8, 15 every 28 days utilizing a 3 + 3 dose-escalation design. Results: Dose-limiting toxicity was observed in 4/6 patients with first-cycle combination therapy at the 10 mg dose-level and 3/6 patients at the 5 mg dose-level of lenalidomide, respectively. These included Grade 3 neutropenia precluding planned paclitaxel therapy (n = 3), grade 3 gastrointestinal toxicity (n = 2), chest pain (n = 1) and pulmonary embolism (n = 1). With lead-in lenalidomide, two patients with lymph-node dominant CRPC had a PSA-decline and regression in lymph node disease, respectively. Two of seven evaluable patients had PSA declines by 50% with combination therapy. Progression-free survival was 13 weeks (range 4-35 weeks). Conclusions: The high dose-limiting toxicity rates observed with lenalidomide and weekly paclitaxel require exploration of alternate dose-schedules of the combination in the second-line setting of CRPC. These early observations suggest distinctive toxicity and efficacy outcomes from thalidomide in combination with paclitaxel.