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

被引:35
作者
Morris, Michael J. [1 ,2 ]
Loriot, Yohann [3 ]
Sweeney, Christopher J. [4 ]
Fizazi, Karim [3 ]
Ryan, Charles J. [5 ,6 ,16 ]
Shevrin, Daniel H. [7 ]
Antonarakis, Emmanuel S. [8 ]
Pandit-Taskar, Neeta [9 ]
Deandreis, Desiree [10 ,17 ]
Jacene, Heather A. [11 ,12 ]
Vesselle, Hubert [13 ]
Petrenciuc, Oana [14 ]
Lu, Cindy [14 ]
Carrasquillo, Jorge A. [9 ]
Higano, Celestia S. [15 ]
机构
[1] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA
[2] Weill Cornell Med, New York, NY USA
[3] Univ Paris Saclay, Dept Canc Med, INSERM U981, Gustave Roussy, Villejuif, France
[4] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA
[5] Univ Calif San Francisco, Dept Med, San Francisco, CA USA
[6] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA
[7] NorthShore Univ Hlth Syst, Evanston Hosp, NorthShore Med Grp, Kellogg Canc Ctr, Evanston, IL USA
[8] Johns Hopkins Sch Med, Sydney Kimmel Comprehens Canc Ctr, Baltimore, MD USA
[9] Mem Sloan Kettering Canc Ctr, Dept Radiol, Mol Imaging & Therapy Serv, New York, NY 10065 USA
[10] Univ Paris Sud, Inst Gustave Roussy, Nucl Med & Endocrine Oncol, Villejuif, France
[11] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA
[12] Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA
[13] Univ Washington, Dept Radiol, Div Nucl Med, Seattle, WA 98195 USA
[14] Bayer HealthCare Pharmaceut, Dept Global Clin Dev, Whippany, NJ USA
[15] Univ Washington, Fred Hutchinson Canc Res Ctr, Dept Med, Seattle, WA 98195 USA
[16] Univ Minnesota, Div Hematol Oncol & Transplantat, Minneapolis, MN USA
[17] Univ Turin, Dept Med Sci, Div Nucl Med, Turin, Italy
关键词
Castration-resistant prostate cancer; Radium; 223; dichloride; Docetaxel; Combination treatment; SURVIVAL; MITOXANTRONE; PREDNISONE; RADIATION; RA-223; SR-89;
D O I
10.1016/j.ejca.2019.04.007
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Radium 223 dichloride (radium-223) is an alpha particleeemitting bonedirected 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/m 2 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 x 5 doses, plus docetaxel 60 mg/m(2) q3w x 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. (C) 2019 The Authors. Published by Elsevier Ltd.
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收藏
页码:107 / 116
页数:10
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