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

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    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

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    Mitoxantrone
    Castration
    Prednisone
    Prostatic Neoplasms
    Biomarkers
    Hepatocyte Growth Factor
    Survival
    Pharmacokinetics
    Confidence Intervals
    rilotumumab
    Disease-Free Survival
    Edema
    Neoplasms
    Research Design
    Therapeutics
    Monoclonal Antibodies
    Placebos
    Safety

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    Targeted MET inhibition in castration-resistant prostate cancer : A randomized phase II study and biomarker analysis with rilotumumab plus mitoxantrone and prednisone. / Ryan, Charles J.; Rosenthal, Mark; Ng, Siobhan; Alumkal, Joshi; Picus, Joel; Gravis, Gwenaëlle; Fizazi, Karim; Forget, Fréd́eric; Machiels, Jean Pascal; Srinivas, Sandy; Zhu, Min; Tang, Rui; Oliner, Kelly S.; Jiang, Yizhou; Loh, Elwyn; Dubey, Sarita; Gerritsen, Winald R.

    In: Clinical Cancer Research, Vol. 19, No. 1, 01.01.2013, p. 215-224.

    Research output: Contribution to journalArticle

    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 2013, 'Targeted MET inhibition in castration-resistant prostate cancer: A randomized phase II study and biomarker analysis with rilotumumab plus mitoxantrone and prednisone', Clinical Cancer Research, vol. 19, no. 1, pp. 215-224. https://doi.org/10.1158/1078-0432.CCR-12-2605
    Ryan, Charles J. ; Rosenthal, Mark ; Ng, Siobhan ; Alumkal, Joshi ; Picus, Joel ; Gravis, Gwenaëlle ; Fizazi, Karim ; Forget, Fréd́eric ; Machiels, Jean Pascal ; Srinivas, Sandy ; Zhu, Min ; Tang, Rui ; Oliner, Kelly S. ; Jiang, Yizhou ; Loh, Elwyn ; Dubey, Sarita ; Gerritsen, Winald R. / Targeted MET inhibition in castration-resistant prostate cancer : A randomized phase II study and biomarker analysis with rilotumumab plus mitoxantrone and prednisone. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 1. pp. 215-224.
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    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.",
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    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.

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    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.

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