title: A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors.
abstract: 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.
  
  
  
  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.
  
  
  
  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 treatment-related. 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.
  
  
  
  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. Clin Cancer Res; 22(9); 2146-54. ©2015 AACR.
authors.affiliation: Vanderbilt Ingram Cancer Center, Nashville, Tennessee. laura.goff@Vanderbilt.edu.
authors.forename: Laura W
authors.initials: LW
authors.lastname: Goff
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.affiliation: Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Berlin
authors.affiliation: Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: Filippo G
authors.initials: FG
authors.lastname: de Braud
authors.affiliation: Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Andrej
authors.initials: A
authors.lastname: Lyshchik
authors.affiliation: Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Noberasco
authors.affiliation: Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertolini
authors.affiliation: Pfizer Oncology, Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Carpentieri
authors.affiliation: Pfizer Oncology, Milan, Italy.
authors.forename: Corrado Gallo
authors.initials: CG
authors.lastname: Stampino
authors.affiliation: Pfizer Oncology, Milan, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Abbattista
authors.affiliation: Pfizer Oncology, La Jolla, California.
authors.forename: Erjan
authors.initials: E
authors.lastname: Wang
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Hossein
authors.initials: H
authors.lastname: Borghaei
mesh_terms: D030301:Activin Receptors, Type II / Q000276:immunology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C575087:ascrinvacumab; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II