TY - JOUR
T1 - Targeted MET inhibition in castration-resistant prostate cancer
T2 - A randomized phase II study and biomarker analysis with rilotumumab plus mitoxantrone and prednisone
AU - Ryan, Charles J.
AU - Rosenthal, Mark
AU - Ng, Siobhan
AU - Alumkal, Joshi
AU - Picus, Joel
AU - Gravis, Gwenaëlle
AU - Fizazi, Karim
AU - Forget, Fréd́eric
AU - Machiels, Jean Pascal
AU - Srinivas, Sandy
AU - Zhu, Min
AU - Tang, Rui
AU - Oliner, Kelly S.
AU - Jiang, Yizhou
AU - Loh, Elwyn
AU - Dubey, Sarita
AU - Gerritsen, Winald R.
PY - 2013/1/1
Y1 - 2013/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84871962904&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-12-2605
DO - 10.1158/1078-0432.CCR-12-2605
M3 - Article
C2 - 23136195
AN - SCOPUS:84871962904
SN - 1078-0432
VL - 19
SP - 215
EP - 224
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -