Safety of radium-223 dichloride (Ra-223) with docetaxel (D) in patients with bone metastases from castration-resistant prostate cancer (CRPC): A phase I Prostate Cancer Clinical Trials Consortium Study.

Abstract

5021 Background: Ra-223, a first-in-class α-emitting pharmaceutical, targets bone metastases (mets) with high-energy α-particles of very short range (< 100 µm). D is an approved chemotherapy with demonstrated survival benefit for patients progressing after castrating hormone therapy. We are exploring the hypothesis that simultaneously targeting the tumor and the bone is clinically superior to targeting either alone. We therefore conducted a phase I study of Ra-223 + D in patients with CRPC and bone mets to establish the safety of the combination. Methods: Eligible patients had confirmed symptomatic CRPC with ≥ 2 bone mets and were candidates for treatment with D. Dose escalation followed a 3 + 3 design, with no intrapatient dose escalation or overlapping of cohorts. Patients were to receive 2 combined doses of Ra-223 q6wk + D q3wk (cohort 1: Ra-223/D = 25 kBq/kg /75 mg/m2; cohort 2: Ra-223/D = 25 kBq/kg /60 mg/m2; and cohort 3: Ra-223/D = 50 kBq/kg /60 mg/m2). Dose-limiting toxicity was assessed 6 weeks after first Ra-223 + D injection. Long-term safety data were collected every 3 months after end of study treatment for up to 1 year after start of study treatment. Results: 17 patients were treated, 7 each in cohorts 1 and 3 (1 patient in each cohort discontinued early and was replaced), and 3 in cohort 2. There was no discontinuation or delay of Ra-223 due to adverse events, and so far no reports of long-term toxicity during follow-up. 4 cases of febrile neutropenia occurred during study treatment (12 wk): 3 occurred in cohort 1 (1 was 7 days after first Ra-223 + D, and 2 were in the same subject, both occurring 1 wk after first and second doses of D alone [wk 4 and 10]); 1 occurred in cohort 3, 1 week after second Ra-223 + D (wk 7). Other safety data were as expected based on Ra-223 and D monotherapy data. Conclusions: The phase IIa regimen of Ra-223 + D utilizes a regimen of D 60 mg/m2 q3wk × 10 + Ra-223 50 kBq/kg q6wk × 5. The regimen is currently being explored in a randomized 2:1 open-label expanded safety cohort comparing Ra-223 + D versus D 75 mg/ m2 alone (standard dose). Clinical trial information: NCT01106352.