A phase I/IIa study of the safety and efficacy of radium-223 chloride (Ra-223) with docetaxel (D) for castration-resistant prostate cancer (CRPC) patients with bone metastases.

Abstract

TPS4694 Background: Ra-223is a first-in-class alpha-pharmaceutical that targets bone metastases (mets) with high energy alpha-particles of short range (< 100 μm). In the ALSYMPCA trial, Ra-223 plus best standard of care (BSC) significantly improved OS vs placebo plus BSC in CRPC patients (pts) with bone mets (Parker et al. ECCO/ESMO 2011), and was shown to have an excellent safety profile. Since D is an approved chemotherapy with demonstrated survival benefit for pts progressing after castrating hormone therapy, it is logical to explore combining Ra-223 plus D in pts with CRPC and bone mets. This study is being conducted in the Prostate Cancer Clinical Trials Consortium with an aim to establish the safe dose of Ra-223 and D when used in combination in pts with bone mets with CRPC. Methods: This ongoing phase I/IIa trial (NCT01106352) is enrolling pts with bone mets from CRPC intended for treatment with D. D naïve pts are preferred, although up to 10 previous infusions of D are acceptable if D was well tolerated and the patient is in good condition and fulfills all eligibility criteria at study entry. Phase I dose-escalation study: minimum of 9 pts (max. 18 pts) will be included if no dose limiting toxicity (DLT) is observed. Dose escalation will follow a ‘3+3’ design, with no intra-patient dose escalation or overlapping of cohorts permitted. Ra-223 doses are 25 or 50 kBq/kg, with number of Ra-223 injections (inj) (2, 4, 5, or 10) and interval between inj (3 or 6 wks) varying by escalation schema; D doses are 60 or 75 mg/m2 q3wk. DLT will be assessed when 6 wks post-inj safety data are available after 1st Ra-223 +D inj. Phase IIa open-label expanded safety study: pts will be randomized 2:1 to the recommended dose of Ra‑223 to be used with D or to treatment with D alone (approx. 42 pts will be included). Primary endpoint is to assess safety of combining Ra-223 with D. Exploratory efficacy endpoints for the open-label expanded safety portion of the study include change in disease-related biomarkers, time to 1st radiological or clinical progression, CTC and pain assessment. Enrollment in dose-escalation portion of the study is complete; expanded safety cohort to begin enrolling in March 2012.