title: Phase I study of PF-03446962, a fully human monoclonal antibody against activin receptor-like kinase-1, in patients with hepatocellular carcinoma.
abstract: 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 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  NCT00557856.
authors.affiliation: Humanitas Clinical and Research Center, Humanitas Cancer Center, Rozzano, Milano, Italy matteo.simonelli@cancercenter.humanitas.it.
authors.forename: M
authors.initials: M
authors.lastname: Simonelli
authors.affiliation: Humanitas Clinical and Research Center, Humanitas Cancer Center, Rozzano, Milano, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Zucali
authors.affiliation: Humanitas Clinical and Research Center, Humanitas Cancer Center, Rozzano, Milano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Division of Hematology/Oncology, Medical University of South Carolina, Charleston, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Thomas
authors.affiliation: Department of Medical Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: F G
authors.initials: FG
authors.lastname: de Braud
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia.
authors.forename: H
authors.initials: H
authors.lastname: Borghaei
authors.affiliation: Department of Gastrointestinal Oncology, Vanderbilt University, Nashville, USA.
authors.forename: J
authors.initials: J
authors.lastname: Berlin
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia.
authors.forename: C S
authors.initials: CS
authors.lastname: Denlinger
authors.affiliation: Department of Medical Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Noberasco
authors.affiliation: Humanitas Clinical and Research Center, Humanitas Cancer Center, Rozzano, Milano, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Rimassa
authors.affiliation: Department of Medical Oncology/Hematology, Seoul National Hospital, Seoul, Republic of Korea.
authors.forename: T-Y
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Pfizer Oncology, La Jolla, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: English
authors.affiliation: Pfizer Oncology, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Abbattista
authors.affiliation: Pfizer Oncology, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Gallo Stampino
authors.affiliation: Pfizer Oncology, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Carpentieri
authors.affiliation: Pfizer Oncology, La Jolla, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Williams
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors / Q000276:immunology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; C575087:ascrinvacumab; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II
keywords: ALK-1; PF-03446962; TGF-β receptor; activin-receptor-like kinase-1; angiogenesis; hepatocellular carcinoma