Radium-223 in combination with docetaxel in patients with castration-resistant prostate cancer and bone metastases: A phase 1 dose escalation/randomised phase 2a trial Journal Article

   

Authors:	Morris, M. J.; Loriot, Y.; Sweeney, C. J.; Fizazi, K.; Ryan, C. J.; Shevrin, D. H.; Antonarakis, E. S.; Pandit-Taskar, N.; Deandreis, D.; Jacene, H. A.; Vesselle, H.; Petrenciuc, O.; Lu, C.; Carrasquillo, J. A.; Higano, C. S.
Article Title:	Radium-223 in combination with docetaxel in patients with castration-resistant prostate cancer and bone metastases: A phase 1 dose escalation/randomised phase 2a trial
Abstract:	Purpose: Radium 223 dichloride (radium-223)is an alpha particle–emitting bone-directed therapy that prolongs overall survival in men with bone-predominant metastatic castration-resistant prostate cancer (mCRPC). Docetaxel is an antimicrotubule cytotoxic agent that improves survival in mCRPC. We investigated whether combining these potentially cross-sensitising agents to dually target tumour and bone would be safe and effective. Patients and methods: Phase 1 was a dose escalation study to define a recommended phase 2 dose (RP2D)of docetaxel and radium-223. In phase 2a, patients were randomised 2:1 to the recommended combination regimen or docetaxel at a dose of 75 mg/m2 every 3 weeks (q3w). Patients with bone-predominant mCRPC were eligible. End-points were safety, efficacy and treatment-related changes in serum and imaging biomarkers. Results: Twenty patients were enrolled in phase 1; 53 patients were randomised in phase 2a: 36 to combination treatment and 17 to docetaxel alone. The RP2D for the combination was radium-223 55 kBq/kg every six weeks × 5 doses, plus docetaxel 60 mg/m2 q3w × 10 doses. Febrile neutropenia was dose limiting. A higher rate of febrile neutropenia was seen in the docetaxel monotherapy arm (15% vs 0%); the safety profile of the treatment groups was otherwise similar. The combination arm had more durable suppression of prostate-specific antigen (median time to progression, 6.6 vs 4.8 months, respectively), alkaline phosphatase (9 vs 7 months)and osteoblastic bone deposition markers. Conclusions: Radium-223 in combination with docetaxel at the RP2D was well tolerated. Exploratory efficacy data suggested enhanced antitumour activity for the combination relative to docetaxel alone. Comparative studies with end-points of clinical benefit are warranted. ClinicalTrials.gov number: NCT01106352. © 2019 The Authors
Keywords:	adult; cancer survival; clinical article; controlled study; aged; prednisone; constipation; fatigue; neutropenia; cancer combination chemotherapy; diarrhea; drug efficacy; drug safety; monotherapy; treatment duration; bone metastasis; cancer radiotherapy; prostate specific antigen; progression free survival; neutrophil count; phase 2 clinical trial; anemia; leukopenia; nausea; randomized controlled trial; peripheral neuropathy; cohort analysis; bisphosphonic acid derivative; antineoplastic activity; docetaxel; arthralgia; backache; drug dose escalation; dyspnea; febrile neutropenia; lymphocytopenia; alkaline phosphatase; karnofsky performance status; peripheral edema; alkaline phosphatase blood level; phase 1 clinical trial; alopecia; carboxy terminal telopeptide; dysgeusia; castration resistant prostate cancer; abiraterone; decreased appetite; denosumab; sipuleucel t; response evaluation criteria in solid tumors; alkaline phosphatase bone isoenzyme; castration-resistant prostate cancer; enzalutamide; very elderly; radium chloride ra 223; human; male; priority journal; article; combination treatment; radium 223 dichloride; gastrointestinal reflux
Journal Title:	European Journal of Cancer
Volume:	114
ISSN:	0959-8049
Publisher:	Elsevier Inc.
Date Published:	2019-06-01
Start Page:	107
End Page:	116
Language:	English
DOI:	10.1016/j.ejca.2019.04.007
PUBMED:	31082669
PROVIDER:	scopus
PMCID:	PMC7474951
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85065249888&doi=10.1016%2fj.ejca.2019.04.007&partnerID=40&md5=350e0a84193210f6446972d765dfd89a
Notes:	Source: Scopus

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