title: Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept, an activin receptor-like kinase-1 ligand trap, in patients with advanced cancer.
abstract: OBJECTIVE
  The angiogenesis inhibitor dalantercept (formerly ACE-041) is a soluble form of activin receptor-like kinase-1 (ALK1) that prevents activation of endogenous ALK1 by bone morphogenetic protein-9 (BMP9) and BMP10 and exhibits antitumor activity in preclinical models. This first-in-human study of dalantercept evaluated its safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity in adults with advanced solid tumors.
  
  
  METHODS
  Patients in dose-escalating cohorts received dalantercept subcutaneously at one of seven dose levels (0.1-4.8 mg/kg) every 3 weeks until disease progression. Patients in an expansion cohort received dalantercept at 0.8 or 1.6 mg/kg every 3 weeks until disease progression.
  
  
  RESULTS
  In 37 patients receiving dalantercept, the most common treatment-related adverse events were peripheral edema, fatigue, and anemia. Edema and fluid retention were dose-limiting toxicities and responded to diuretic therapy. No clinically significant, treatment-related hypertension, proteinuria, gross hemorrhage, or gastrointestinal perforations were observed. One patient with refractory squamous cell cancer of the head and neck had a partial response, and 13 patients had stable disease according to RECISTv1.1, eight of whom had prolonged periods (≥12 weeks) of stable disease. Correlative pharmacodynamic markers included tumor metabolic activity and tumor blood flow, which decreased from baseline in 63% and 82% of evaluable patients, respectively, and telangiectasia in eight patients.
  
  
  CONCLUSIONS
  Dalantercept was well-tolerated at doses up to 1.6 mg/kg, with a safety profile distinct from inhibitors of the VEGF pathway. Dalantercept displayed promising antitumor activity in patients with advanced refractory cancer, and multiple phase II studies are underway.
authors.affiliation: Authors' Affiliations: Sarah Cannon Research Institute, Nashville, Tennessee; Pinnacle Oncology Hematology, Scottsdale, Arizona; Duke University Medical Center, Durham, North Carolina; Huntsman Cancer Institute, Salt Lake City, Utah; and Acceleron Pharma, Cambridge, Massachusetts.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.forename: David S
authors.initials: DS
authors.lastname: Mendelson
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Blobe
authors.forename: Neeraj
authors.initials: N
authors.lastname: Agarwal
authors.forename: Carolyn H
authors.initials: CH
authors.lastname: Condon
authors.forename: Dawn
authors.initials: D
authors.lastname: Wilson
authors.forename: Amelia E
authors.initials: AE
authors.lastname: Pearsall
authors.forename: Yijun
authors.initials: Y
authors.lastname: Yang
authors.forename: Ty
authors.initials: T
authors.lastname: McClure
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Attie
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Sherman
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
mesh_terms: D030301:Activin Receptors, Type II / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology* / Q000627:therapeutic use*; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D049268:Positron-Emission Tomography; D011993:Recombinant Fusion Proteins / Q000494:pharmacology* / Q000627:therapeutic use*; D013684:Telangiectasis / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007141:Immunoglobulin Fc Fragments; D008024:Ligands; D011993:Recombinant Fusion Proteins; D019788:Fluorodeoxyglucose F18; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II; C000591618:ALK1-Fc fusion protein, human