Only constipation was more frequent in the 223-Ra group. The second phase II trial has been published very recently, in 2012. This randomized, R788 double-blind, phase II study aimed to investigate the dose-response relationship and pain-relieving
effect of 223-Ra in CRPC patients with bone metastases. The primary endpoint was the pain index (according to a visual analog scale [VAS] and analgesic consumption), which was also used to classify patients as responders or non-responders. Between May 2005 and December 2007, a total of 100 patients were randomized to receive different doses of a single injection of 223-Ra (5, 25, 50, or 100 kBq/kg). A statistically significant dose response occurred at week 2 (p = 0.035). At week 8, 40%, 63%, 56%, and 71% of the above dose groups, respectively, selleck chemicals were pain responders (pain index ≤4). Of the responders, 30%, 42%, 44%, and 52% in the above dose groups, respectively, achieved a complete response
(pain index 1) or a marked response (pain index 2). Up to week 8, fewer patients in the high-dose groups required increases in analgesia, compared with the lower-dose groups. Pain responders in all dose groups showed improvement in the Brief Pain Inventory (BPI) functional interference index. On the daily VAS at week 8, pain decreased by a mean of 30, 31, 27, and 29 mm in responders in the above dose groups, respectively. About 97% of patients reported at least one AE. Hematologic events were generally not severe, with slightly greater rates of thrombopenia, leucopenia, and neutropenia in the two highest-dose groups. The most frequent hematologic AEs were anemia (11% of patients) and a hemoglobin decrease (15%). The most frequent non-hematologic AEs were nausea, vomiting, diarrhea, constipation, peripheral edema, and bone pain, with no difference across dose groups. Although survival was not an objective of this trial, the median OS was 50 weeks, which did not differ between dose groups. These two trials suggested efficacy of 223-Ra in
patients with mCRPC, in both symptomatic improvement and prolongation of survival, and with a favorable safety profile. These Adenylyl cyclase findings led to development of the placebo-controlled phase III trial ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer). 4. Phase III Trial (the ALSYMPCA Trial) The results of an interim analysis of the ALSYMPCA phase III trial were presented at the ESMO meeting in 2011 and are yet to be published. This trial enrolled patients with confirmed symptomatic CRPC, with at least two bone metastases and no known visceral metastases, who had previously received chemotherapy with docetaxel or were unfit for docetaxel therapy. Patients were stratified according to ALP levels, previous bisphosphonate use, and prior docetaxel use. The primary endpoint was the OS.