Targeted MET inhibition in castration-resistant prostate cancer: A randomized phase 2 study and biomarker analysis with Rilotumumab plus Mitoxantrone and Prednisone.

Ryan CJ, Rosenthal M, Ng S, Alumkal J, Picus J, Gravis G, Fizazi K, Forget F, Machiels JP, Srinivas S, Zhu M, Tang R, Oliner KS, Jiang Y, Loh E, Dubey S, Gerritsen WR.
Journal   Clin Cancer Res.
Species  
Analytes Measured   HGF , Met
Matrix Tested   Plasma
Year   2012
Volume  
Page Numbers  
Application   Angiogenesis and Vascular
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 2 study randomized (1:1:1) patients with progressive, taxane-refractory CRPC to receive MP (12 mg/m2 IV day 1, 5 mg BID orally days 1-21, respectively) plus rilotumumab 15 mg/kg, rilotumumab 7.5 mg/kg, or placebo (IV day 1) every 3 weeks. The primary endpoint was overall survival (OS).

RESULTS: 142 patients were randomized. Median OS was 12.2 versus 11.1 months (HR, 1.10; 80% 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% versus 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 CRPC patients with poorer prognosis.

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