Targeted MET Inhibition in Castration-Resistant Prostate Cancer: A Randomized Phase II Study and Biomarker Analysis with Rilotumumab plus Mitoxantrone and Prednisone

To evaluate the efficacy, safety, biomarkers, and pharmacokinetics of rilotumumab, a fully human, monoclonal antibody against hepatocyte growth factor (HGF)/scatter factor, combined with mitoxantrone and prednisone (MP) in patients with castration-resistant prostate cancer (CRPC). This double-blinde...

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Bibliographic Details
Published in:	Clinical cancer research Vol. 19; no. 1; pp. 215 - 224
Main Authors:	RYAN, Charles J, ROSENTHAL, Mark, MIN ZHU, RUI TANG, OLINER, KellyS, YIZHOUJIANG, LOH, Elwyn, DUBEY, Sarita, GERRITSEN, Winald R, NG, Siobhan, ALUMKAL, Joshi, PICUS, Joel, GRAVIS, Gwenaëlle, FIZAZI, Karim, FORGET, Frédéric, MACHIELS, Jean-Pascal, SRINIVAS, Sandy
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 2013
Subjects:	Aged Aged, 80 and over Antibodies, Monoclonal - administration & dosage Antibodies, Monoclonal - pharmacokinetics Antineoplastic agents Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biological and medical sciences Biomarkers, Tumor - metabolism Gynecology. Andrology. Obstetrics Humans Male Male genital diseases Medical sciences Middle Aged Mitoxantrone - administration & dosage Mitoxantrone - pharmacokinetics Molecular Targeted Therapy Nephrology. Urinary tract diseases Orchiectomy Pharmacology. Drug treatments Prednisone - administration & dosage Prednisone - pharmacokinetics Prostatic Neoplasms - drug therapy Prostatic Neoplasms - metabolism Prostatic Neoplasms - mortality Proto-Oncogene Proteins c-met - antagonists & inhibitors Proto-Oncogene Proteins c-met - metabolism Treatment Outcome Tumors Tumors of the urinary system Urinary tract. Prostate gland Antineoplastic agent Prostate disease Targeting Biological marker Monoclonal antibody Target Randomization Castration Phase II trial Inhibition Mitoxantrone Male genital diseases Protooncogene Human Corticosteroid Anthraquinone derivatives Urinary system disease Prednisone Malignant tumor Resistance Alkylating agent Treatment Antimetabolic Analysis C-Onc gene Adrenal hormone Rilotumumab Inhibitor Prostate cancer Cancer
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Summary:	To evaluate the efficacy, safety, biomarkers, and pharmacokinetics of rilotumumab, a fully human, monoclonal antibody against hepatocyte growth factor (HGF)/scatter factor, combined with mitoxantrone and prednisone (MP) in patients with castration-resistant prostate cancer (CRPC). This double-blinded phase II study randomized (1:1:1) patients with progressive, taxane-refractory CRPC to receive MP (12 mg/m(2) i.v. day 1, 5 mg twice a day orally days 1-21, respectively) plus 15 mg/kg rilotumumab, 7.5 mg/kg rilotumumab, or placebo (i.v. day 1) every 3 weeks. The primary endpoint was overall survival (OS). One hundred and forty-four patients were randomized. Median OS was 12.2 versus 11.1 months [HR, 1.10; 80% confidence interval (CI), 0.82-1.48] in the combined rilotumumab versus control arms. Median progression-free survival was 3.0 versus 2.9 months (HR, 1.02; 80% CI, 0.79-1.31). Treatment appeared well tolerated with peripheral edema (24% vs. 8%) being more common with rilotumumab. A trend toward unfavorable OS was observed in patients with high tumor MET expression regardless of treatment. Soluble MET levels increased in all treatment arms. Total HGF levels increased in the rilotumumab arms. Rilotumumab showed linear pharmacokinetics when co-administered with MP. Rilotumumab plus MP had manageable toxicities and showed no efficacy improvements in this estimation study. High tumor MET expression may identify patients with CRPC with poorer prognosis.
ISSN:	1078-0432 1557-3265
DOI:	10.1158/1078-0432.CCR-12-2605