A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors

Laura W. Goff, Roger B. Cohen, Jordan D. Berlin, Filippo De Braud, Andrej Lyshchik, Cristina Noberasco, Francesco Bertolini, M. Carpentieri, C. G. Stampino, A. Daniele Abbattista, Erjan Wang, Hossein Borghaei

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Abstract

Purpose: Objectives of this dose-finding study were to determine the MTD and recommended phase II dose (RP2D) of the first-in-class anti-activin receptor-like kinase 1 (ALK-1) monoclonal antibody PF-03446962, and assess safety and antitumor activity in patients with advanced solid tumors. Experimental Design: This open-label, multicenter study was based on a 3+3 design. PF-03446962 was administered biweekly by intravenous infusion, at doses ranging from 0.5 to 15 mg/kg. Results: Forty-four patients received treatment with PF-03446962. Dose-limiting toxicities observed during dose escalation included grade 3 increased amylase, grade 3/4 increased lipase, and grade 3/4 thrombocytopenia. The MTD was determined to be 10 mg/kg. The RP2D was set at 7 mg/kg for patients with advanced solid tumors, based on the observed safety, pharmacokinetics, and antitumor activity. The most-frequent treatment-related, all-grade adverse events included thrombocytopenia (20.5%), fatigue (15.9%), and nausea, increased amylase, and increased lipase (each 11.4%). Treatment-related telangiectasia was noted in 7% of patients, suggesting in vivo inhibition of the ALK-1 pathway. None of the deaths was deemed to be treatmentrelated. Three (6.8%) patients with advanced hepatocellular carcinoma, renal cell carcinoma, or non-small cell lung cancer achieved a partial response, and 12 (27.3%) patients had stable disease, across dose levels. Contrast-enhanced ultrasound analysis of tumor vascularity showed reduction in tumor perfusion in 2 patients with stable disease following treatment with PF-03446962. Conclusions: The clinical activity demonstrated in this study points to PF-03446962 as a novel approach to antiangiogenic therapy, with manageable safety profile and single-agent, antitumor activity in patients with advanced solid tumors.

Original languageEnglish
Pages (from-to)2146-2154
Number of pages9
JournalClinical Cancer Research
Volume22
Issue number9
DOIs
Publication statusPublished - May 1 2016

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Goff, L. W., Cohen, R. B., Berlin, J. D., De Braud, F., Lyshchik, A., Noberasco, C., Bertolini, F., Carpentieri, M., Stampino, C. G., Abbattista, A. D., Wang, E., & Borghaei, H. (2016). A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors. Clinical Cancer Research, 22(9), 2146-2154. https://doi.org/10.1158/1078-0432.CCR-15-1622