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

Ann Oncol. 2016 Sep;27(9):1782-7. doi: 10.1093/annonc/mdw240. Epub 2016 Jun 20.


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.

Keywords: ALK-1; PF-03446962; TGF-β receptor; activin-receptor-like kinase-1; angiogenesis; hepatocellular carcinoma.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Activin Receptors, Type II / antagonists & inhibitors
  • Activin Receptors, Type II / immunology*
  • Adult
  • Aged
  • Aged, 80 and over
  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / adverse effects
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / pharmacokinetics
  • Antibodies, Monoclonal, Humanized
  • Biomarkers, Tumor / antagonists & inhibitors
  • Biomarkers, Tumor / immunology
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / pathology
  • Drug Administration Schedule
  • Drug-Related Side Effects and Adverse Reactions / pathology
  • Female
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / immunology
  • Liver Neoplasms / pathology
  • Male
  • Middle Aged
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects


  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Biomarkers, Tumor
  • Protein Kinase Inhibitors
  • ascrinvacumab
  • ACVRL1 protein, human
  • Activin Receptors, Type II

Associated data