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Phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer.

ABSTRACT: BACKGROUND:Radium-223 dichloride (radium-223) is the first targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with bone metastases. This study investigated the efficacy and safety of radium-223 in Japanese patients with symptomatic CRPC and bone metastases. METHODS:In this open-label, multicenter, phase II study, patients with progressive, symptomatic CRPC and bone metastases were treated with radium-223 (55 kBq/kg, intravenously) in a 4-week cycle for six cycles. The primary endpoint was the percent change in total alkaline phosphatase (ALP) from baseline at 12 weeks. Secondary endpoints included the percent ALP change from baseline to end of treatment (EOT), ALP response rates, percent change in prostate-specific antigen (PSA) from baseline to 12 weeks and EOT, PSA response rates, overall survival (OS), and time to symptomatic skeletal events (SSEs). Adverse events were monitored throughout the study period. RESULTS:Of the 49 Japanese patients (median age 74 years), 28 completed all infusions. Mean percent change in total ALP and PSA from baseline to 12 weeks was -19.3 and +97.4%, respectively. One-year OS and SSE-free rate at the end of active follow-up were 78 and 89%, respectively. The ALP response rate was 31%, while the PSA response rate was 6%. Grade 3/4 treatment-emergent adverse events observed in ?10% of patients included decreased lymphocyte count (14%), anemia (14%), anorexia (10%), and bone pain (10%). CONCLUSIONS:Radium-223 is effective and well tolerated in Japanese patients with CRPC and bone metastases. Results were comparable with the Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov NCT01929655.

SUBMITTER: Matsubara N

PROVIDER: S-EPMC5809574 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer.

Matsubara Nobuaki N Nagamori Satsohi S Wakumoto Yoshiaki Y Uemura Hirotsugu H Kimura Go G Yokomizo Akira A Kikukawa Hiroaki H Mizokami Atsushi A Kosaka Takeo T Masumori Naoya N Kawasaki Yoshihide Y Yonese Junji J Nasu Yasutomo Y Fukasawa Satoshi S Sugiyama Takayuki T Kinuya Seigo S Hosono Makoto M Yamaguchi Iku I Tsutsui Hirokazu H Uemura Hiroji H

International journal of clinical oncology 20170802 1

<h4>Background</h4>Radium-223 dichloride (radium-223) is the first targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with bone metastases. This study investigated the efficacy and safety of radium-223 in Japanese patients with symptomatic CRPC and bone metastases.<h4>Methods</h4>In this open-label, multicenter, phase II study, patients with progressive, symptomatic CRPC and bone metastases were treated with radium-223 (55 kBq/kg, intravenously) in a ...[more]

PMID: 28770408

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Project description:BACKGROUND:Radiation therapy with radium-223 dichloride improves overall survival, reduces symptomatic skeletal events in Caucasian patients with castration-resistant prostate cancer (CRPC) and bone metastases, and is well tolerated. We report here the results of the first efficacy and safety study of radium-223 dichloride in a Japanese population. METHODS:In this open-label, uncontrolled, non-randomized, phase I trial, radium-223 dichloride was given to Japanese patients with CRPC and ?2 bone metastases in 4-week cycles. The patients were divided into three cohorts, with cohort 1 and the expansion cohort receiving injections of radium-223 dichloride [55 kBq/kg body weight (BW)] every 4 weeks (Q4W) for up to six injections, and cohort 2 receiving an initial single radium-223 dichloride injection of 110 kBq/kg BW followed by up to five injections of 55 kBq/kg BW Q4W. Safety was determined via adverse event (AE) reporting, and biochemical bone markers were assessed for treatment efficacy. RESULTS:In total 19 patients received at least one dose of radium-223 dichloride and 18 patients experienced at least one treatment-emergent AE (TEAE) of which the most common were anemia, thrombocytopenia, and lymphocytopenia. Serious AEs were reported in three patients but none were drug-related. In the patients of cohort 1 + expansion cohort (55 kBq/kg BW Q4W treatment; n = 16), prostate-specific antigen levels remained stable or slightly increased while the bone alkaline phosphatase (ALP) level significantly decreased. The response rates of bone ALP (?30 and ?50% reductions) were 81.8 and 36.4% at week 12, and 81.3 and 50.0% at the end of treatment. CONCLUSIONS:Radium-223 dichloride was well tolerated in these Japanese patients and, at a dose of 55 kBq/kg BW, efficacy on biomarkers was as expected. The outcomes in Japanese patients were consistent with those reported in other non-Japanese populations. TRIAL REGISTRATION:ClinicalTrials.gov record NCT01565746.

Project description:BackgroundRadium-223 and enzalutamide are approved agents for patients with metastatic castration-resistant prostate cancer (mCRPC). Combining radium-223 and enzalutamide to improve outcomes is of clinical interest due to their differing modes of action and non-overlapping toxicity profiles.MethodsThis phase II study enrolled patients with mCRPC and bone metastases. Patients received six cycles of radium-223 in combination with enzalutamide, followed by enzalutamide alone. The primary endpoint was safety for the combination; secondary endpoints included radiographic/clinical progression-free survival (PFS), PSA PFS, overall survival (OS), change in alkaline phosphatase, patient-reported pain outcomes and skeletal related events.ResultsForty-five patients received the combination treatment: 42 patients (93.3%) received all six cycles. Fourteen patients (31.1%) developed grade 3 or 4 toxicities, most commonly fatigue and neutropaenia. Fractures during the combination period occurred in four patients (8.9%). A further 13 patients (28.9%) developed fractures after completing combination treatment, giving a total of 17 patients (37.8%) who developed a fracture at any time on study. The median time to fracture was greater than 17.2 months [95% confidence interval (CI), 17.2-not estimable]. The median time to PSA progression was 18.1 months (95% CI, 12.68-22.60) and the median time to radiological/clinical progression was 28.0 months (95% CI, 22.54-not reached). At the primary analysis, 19 (42.2%) out of 45 patients had died with a median OS not reached (mean 34.8 months, standard error 1.4).ConclusionIn men with progressive mCRPC and bone metastases, the combination of radium-223 and enzalutamide was tolerable with the majority of patients completing the combination treatment. Bone fractures during the combination period were uncommon; however, we did identify a higher incidence of fractures occurring in patients after completing combination treatment. Bone health agents should be administered and bone health should be closely monitored following treatment with radium-223 and enzalutamide.

Project description:BACKGROUND:Metastasis directed therapy (MDT) for patients with oligometastatic disease is associated with improvements in progression free survival (PFS) and overall survival (OS) compared to systemic therapy alone. Additionally, within a prostate-cancer-specific cohort, MDT is able to forestall initiation of androgen deprivation therapy (ADT) in men with hormone-sensitive, oligometastatic prostate cancer (HSOPCa) compared to observation. While MDT appears to be safe and effective in HSOPCa, a large percentage of men will eventually have disease recurrence. Patterns of failure in HSOPCa demonstrate patients tend to have recurrence in the bone following MDT, raising the question of sub-clinically-apparent osseous disease. Radium-223 dichloride is a radiopharmaceutical with structural similarity to calcium, allowing it to be taken up by bone where it emits alpha particles, and therefore might have utility in the treatment of micrometastatic osseous disease. Therefore, the primary goal of the phase II RAVENS trial is to evaluate the efficacy of MDT?+?radium-223 dichloride in prolonging progression free survival in men with HSOPCa. METHODS:Patients with HSOPCa and 3 or less metastases with at least 1 bone metastasis will be randomized 1:1 to stereotactic ablative radiation (SABR, also known as stereotactic body radiation therapy (SBRT)) alone vs SABR + radium-223 dichloride with a minimization algorithm to balance assignment by institution, primary intervention, prior hormonal therapy, and PSA doubling time. SABR is delivered in one to five fractions and patients in the SABR + radium-223 dichloride arm will receive six infusions of radium-223 dichloride at four-week intervals. The primary end point is progression free survival. The secondary clinical endpoints include toxicity and quality of life assessments, local control at 12?months, locoregional progression, time to distant progression, time to new metastasis, and duration of response. DISCUSSION:The RAVENS trial will be the first described phase II, non-blinded, randomized study to compare SABR +/- radium-223 dichloride in patients with HSOPCa and 3 or less metastases with at least one bone metastasis. The primary hypothesis is that SABR + radium-223 dichloride will increase median progression-free survival from 10?months in the SABR arm to 20?months in the SABR + radium-223 dichloride arm. TRIAL REGISTRATIONS:Clinicaltrials.gov. Identifier: NCT04037358. Date of Registration: July 30, 2019. Date of First Participant Enrolled: August 9, 2019. Date of Last Approved Amendment: October 16, 2019. Protocol Version: Version 5.

Dataset Information

Phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer.

Publications

Phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer.

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