title: A randomized, double-blind, dose-finding, multicenter, phase 2 study of radium chloride (Ra 223) in patients with bone metastases and castration-resistant prostate cancer.
abstract: BACKGROUND
  Patients with castration-resistant prostate cancer (CRPC) and bone metastases have an unmet clinical need for effective treatments that improve quality of life and survival with a favorable safety profile.
  
  
  OBJECTIVE
  To prospectively evaluate the efficacy and safety of three different doses of radium chloride (Ra 223) in patients with CRPC and bone metastases.
  
  
  METHODS
  In this phase 2 double-blind multicenter study, 122 patients were randomized to receive three injections of Ra 223 at 6-wk intervals, at doses of 25 kBq/kg (n=41), 50 kBq/kg (n=39), or 80 kBq/kg (n=42). The study compared the proportion of patients in each dose group who had a confirmed decrease of ≥ 50% in baseline prostate-specific antigen (PSA) levels.
  
  
  METHODS
  Efficacy was evaluated using blood samples to measure PSA and other tumor markers, recorded skeletal-related events, and pain assessments. Safety was evaluated using adverse events (AEs), physical examination, and clinical laboratory tests. The Jonckheere-Terpstra test assessed trends between groups.
  
  
  CONCLUSIONS
  The study met its primary end point with a statistically significant dose-response relationship in confirmed ≥ 50% PSA declines for no patients (0%) in the 25-kBq/kg dose group, two patients (6%) in the 50-kBq/kg dose group, and five patients (13%) in the 80-kBq/kg dose group (p=0.0297). A ≥ 50% decrease in bone alkaline phosphatase levels was identified in six patients (16%), 24 patients (67%), and 25 patients (66%) in the 25-, 50-, and 80-kBq/kg dose groups, respectively (p<0.0001). The most common treatment-related AEs (≥ 10%) occurring up to week 24 across all dose groups were diarrhea (21%), nausea (16%), and anemia (14%). No difference in incidence of hematologic events was seen among dose groups. Potential limitations include small patient numbers and differences among dose groups at baseline.
  
  
  CONCLUSIONS
  Ra 223 had a dose-dependent effect on serum markers of CRPC activity, suggesting that control of bone disease with Ra 223 may affect cancer-related outcomes. Ra 223 was well tolerated at all doses.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT00337155.
authors.affiliation: Royal Marsden Hospital, Sutton, UK. chris.parker@rmh.nhs.uk
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Parker
authors.forename: Sarah
authors.initials: S
authors.lastname: Pascoe
authors.forename: Aleš
authors.initials: A
authors.lastname: Chodacki
authors.forename: Joe M
authors.initials: JM
authors.lastname: O'Sullivan
authors.forename: Josep R
authors.initials: JR
authors.lastname: Germá
authors.forename: Charles Gillies
authors.initials: CG
authors.lastname: O'Bryan-Tear
authors.forename: Trond
authors.initials: T
authors.lastname: Haider
authors.forename: Peter
authors.initials: P
authors.lastname: Hoskin
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000532:radiotherapy* / Q000556:secondary; D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood; D000512:Alpha Particles / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000097:blood / Q000532:radiotherapy* / Q000556:secondary; D004307:Dose-Response Relationship, Radiation; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D007610:Kallikreins / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D011868:Radioisotopes / Q000008:administration & dosage; D019275:Radiopharmaceuticals / Q000008:administration & dosage*; D011883:Radium / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D011868:Radioisotopes; D019275:Radiopharmaceuticals; D000469:Alkaline Phosphatase; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; C581106:radium Ra 223 dichloride; D011883:Radium