Targeted MET inhibition in castration-resistant prostate cancer: A randomized phase II study and biomarker analysis with rilotumumab plus mitoxantrone and prednisone

Charles J. Ryan, Mark Rosenthal, Siobhan Ng, Joshi Alumkal, Joel Picus, Gwenaëlle Gravis, Karim Fizazi, Fréd́eric Forget, Jean Pascal Machiels, Sandy Srinivas, Min Zhu, Rui Tang, Kelly S. Oliner, Yizhou Jiang, Elwyn Loh, Sarita Dubey, Winald R. Gerritsen

    Research output: Contribution to journalArticlepeer-review

    55 Scopus citations

    Abstract

    Purpose: 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). Experimental Design: This double-blinded phase II study randomized (1:1:1) patients with progressive, taxane-refractory CRPC to receive MP (12 mg/m2 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). Results: 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. Conclusions: 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.

    Original languageEnglish (US)
    Pages (from-to)215-224
    Number of pages10
    JournalClinical Cancer Research
    Volume19
    Issue number1
    DOIs
    StatePublished - Jan 1 2013

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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