A modular phase I study of lenalidomide and paclitaxel in metastatic castration-resistant prostate cancer with prior taxane therapy

Abstract

13545 Background: Thalidomide may enhance the clinical activity of docetaxel and reverse taxane-resistance in prostate cancer. 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 therapy 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 (5mg), 0 (10mg), +1 (15mg), +2 (20mg), +3 (25mg); followed by lenalidomide at the same dose/schedule in combination with weekly intravenous paclitaxel 100mg/m2 on Days 1, 8, 15 every 28 days. A 3+3 dose-escalation design was utilized to assess the maximum tolerated dose, defined as a dose-limiting toxicity (DLT) rate ≥ 0.33 during lead-in and one cycle of combination therapy. Enteric-coated aspirin 81mg and warfarin 2mg was recommended for thromboembolic prophylaxis. Results: See Table. Five patients had therapy discontinued for toxicity between 3–34 weeks Progression-free interval varied from 9–35 weeks (n=5). With lead-in lenalidomide, 1 of 9 evaluable patients had a minor PSA-decline; one patient with lymph-node dominant metastatic disease had a 40% decrease in bulky neck adenopathy followed by progression-free survival of 8 months with combination therapy. Conclusions: The high DLT rates observed with lenalidomide and paclitaxel require exploration of alternate dose-schedules of the combination in the second-line setting of CRPC. Cohort Patients Lenalidomide Paclitaxel DLT DLT [type/grade (G)] 1 3 0mg 100 mg/m2 1 - vomiting, diarrhea: G3 2 3 10mg 100 mg/m2 3 - neutropenia: G 3 - neutropenia: G 3 - chest pain: G 3 3 3 5mg 100 mg/m2 2 - infection/neutropenia: G 3 - dehydration/infection: G 3 4 1 5mg 80 mg/m2 * 1 - pulmonary embolism: G4 * A lower paclitaxel dose-level was studied after a protocol amendment. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer, Onyx Bayer, Onyx Celgene