Phase I study of PF-03446962, a fully human monoclonal antibody against activin receptor-like kinase-1, in patients with hepatocellular carcinoma

Matteo Simonelli, P. Zucali, A. Santoro, M. B. Thomas, F. G. de Braud, H. Borghaei, J. Berlin, C. S. Denlinger, C. Noberasco, L. Rimassa, T. Y. Kim, P. A. English, A. Abbattista, C. Gallo Stampino, M. Carpentieri, J. A. Williams

Research output: Contribution to journalArticlepeer-review


Background: This expansion cohort of a multicenter, dose-escalation, phase I study (NCT00557856) evaluated safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamic effects of the anti-activin receptor-like kinase-1 (ALK-1) monoclonal antibody PF-03446962 in advanced hepatocellular carcinoma (HCC). Patients and methods: Patients with HCC and disease progression after prior antiangiogenic therapy or intolerance to treatment received PF-03446962 7 mg/kg intravenously biweekly, as recommended in the dose-escalation part of the study. Results: Twenty-four patients received PF-03446962. The most frequent treatment-related adverse events (AEs) were thrombocytopenia (33.3%), asthenia (29.2), and chills (16.7%). Two patients experienced treatment-related telangiectasia, suggesting an in vivo knockout of ALK-1 function through ALK-1 pathway inhibition. Overall, treatment-related grade 3-4 AEs were reported in eight patients (33.3%). Treatment-related grade 3-4 thrombocytopenia was noted in four patients. No complete or partial responses were reported. Twelve (50%) patients achieved stable disease, which lasted ≥12 weeks in seven (29.2%) patients. The median time to progression was 3 months. Biomarker analyses showed higher mean tumor expression of c-tumor mesenchymal-epithelial transition factor and higher mean serum levels of bone morphogenetic protein-9 in patients with disease control (DC) for ≥12 weeks versus patients with disease progression. Conversely, lower mean serum transforming growth factor-β and vascular endothelial growth factor receptor-3 levels were detected in patients with DC versus patients with progression. Conclusions: The observed safety, tolerability, pharmacokinetic profile, and clinical activity support further evaluation of PF-03446962 in patients with HCC and other solid malignancies, as single agent or in combination with other antiangiogenic, chemotherapeutic, or immunotherapeutic agents. Trial registration number: NCT00557856.

Original languageEnglish
Article numbermdw240
Pages (from-to)1782-1787
Number of pages6
JournalAnnals of Oncology
Issue number9
Publication statusPublished - Sep 1 2016


  • Activin-receptor-like kinase-1
  • ALK-1
  • Angiogenesis
  • Hepatocellular carcinoma
  • PF-03446962
  • TGF-β receptor

ASJC Scopus subject areas

  • Hematology
  • Oncology


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