title: A phase I dose-escalation study of MEDI-575, a PDGFRα monoclonal antibody, in adults with advanced solid tumors.
abstract: OBJECTIVE
  The purpose of the study was to evaluate safety and determine the maximum tolerated dose (MTD) of MEDI-575, a fully human monoclonal antibody that selectively binds to platelet-derived growth factor receptor-α (PDGFRα), in patients with advanced solid tumors.
  
  
  METHODS
  This phase I multicenter, open-label, single-arm study enrolled adults in a 3 + 3 dose escalation design to receive MEDI-575 (3, 6, 9, 12, or 15 mg/kg) once weekly (QW) until toxicity or disease progression occurred. One 0.5-mg/kg dose was given before the first dose in the 3-mg/kg cohort to determine pharmacokinetics (PK) and pharmacodynamics under unsaturated conditions. After completion of dose escalation in the QW cohorts, patients were enrolled in two additional cohorts and received MEDI-575 25 or 35 mg/kg every 3 weeks (Q3W). Secondary measures included assessments of PK, immunogenicity, and antitumor activity.
  
  
  RESULTS
  A total of 35 patients received MEDI-575 QW (n = 23) or Q3W (n = 12). Most treatment-related adverse events were grade 1 or 2 in severity across all dose levels, with fatigue (n = 12) and nausea (n = 8) being reported most frequently. With no reports of dose-limiting toxicities (DLTs), the MTD was not reached. MEDI-575 exhibited a nonlinear PK profile and increased plasma platelet-derived growth factor-AA levels in a dose-dependent manner with limited immunogenicity. Stable disease was reported as the best tumor response in 9 of 29 evaluable patients; however, no objective responses were reported.
  
  
  CONCLUSIONS
  Administration of MEDI-575 QW or Q3W resulted in a favorable safety profile, including a lack of DLTs, but without evidence of antitumor activity in patients with refractory solid tumors.
authors.affiliation: Sammons Cancer Center, Texas Oncology P.A., 3410 Worth St., Suite 300, Dallas, TX, 75246, USA, Carlos.Becerra@usoncology.com.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Becerra
authors.forename: Paul
authors.initials: P
authors.lastname: Conkling
authors.forename: Nicholas
authors.initials: N
authors.lastname: Vogelzang
authors.forename: Hilary
authors.initials: H
authors.lastname: Wu
authors.forename: Shengyan
authors.initials: S
authors.lastname: Hong
authors.forename: Rajesh
authors.initials: R
authors.lastname: Narwal
authors.forename: Meina
authors.initials: M
authors.lastname: Liang
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Tavakkoli
authors.forename: Naimish
authors.initials: N
authors.lastname: Pandya
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D015331:Cohort Studies; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000276:immunology*; D016019:Survival Analysis; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C000594804:Tovetumab; D020796:Receptor, Platelet-Derived Growth Factor alpha