A multicenter phase I study of cabazitaxel, mitoxantrone, and prednisone for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer: A department of defense prostate cancer clinical trials consortium study

Background Cabazitaxel plus prednisone has significant activity in patients with chemotherapy-naïve and pretreated metastatic castration-resistant prostate cancer (mCRPC). Mitoxantrone has antitumor activity in mCRPC and nonoverlapping mechanism of action and toxicity profile. Objective To establish the maximally tolerated dose of the combination of cabazitaxel, mitoxantrone, and prednisone. Methods and materials Patients with chemotherapy-naïve mCRPC were prospectively enrolled in a multicenter phase 1 trial. Cabazitaxel 20 and 25 mg/m² were each evaluated in combination with escalating doses of mitoxantrone (starting dose 4 mg/m²), given with prednisone 5 mg twice daily. Results A total of 25 patients were enrolled, with median age of 67 (range: 51–78) and prostate-specific antigen of 66.8 ng/ml (range: 3–791.2). There were 4 dose-limiting toxicities (febrile neutropenia, n = 3; sepsis, n = 1). The maximally tolerated dose was cabazitaxel 20 mg/m² plus mitoxantrone 12 mg/m². The most common treatment-related grade≥3 related adverse events included neutropenia (n = 8; 32%), febrile neutropenia (n = 5; 20%), and thrombocytopenia (n = 4; 16%). The median number of treatment cycles was 8 (range: 2 to 19+). Decline in prostate-specific antigen to≥50% from baseline was observed in 15 patients (60%). Objective responses were observed in 10/14 (71%) evaluable patients. The median radiographic progression-free survival was 14.5 months (95% CI: 8.0-not reached (NR)), and median overall survival was 23.3 months (95% CI: 14.3-NR). Conclusions The approved single-agent doses of mitoxantrone and cabazitaxel were safely combined. The combination led to durable tumor responses in most patients. Further study of the combination is warranted.