title: Phase 1, open-label study of MEDI-547 in patients with relapsed or refractory solid tumors.
abstract: BACKGROUND
  Targeting the cell-surface receptor EphA2, which is highly expressed in some solid tumors, is a novel approach for cancer therapy. We aimed to evaluate the safety profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of MEDI-547, an antibody drug conjugate composed of the cytotoxic drug auristatin (toxin) linked to a human anti-EphA2 monoclonal antibody (1C1), in patients with solid tumors relapsed/refractory to standard therapy.
  
  
  METHODS
  In this phase 1, open-label study with planned dose-escalation and dose-expansion cohorts, patients received a 1-h intravenous infusion of MEDI-547 (0.08 mg/kg) every 3 weeks.
  
  
  RESULTS
  Six patients received 0.08 mg/kg; all discontinued treatment. Dose escalation was not pursued. The study was stopped before cohort 2 enrollment due to treatment-related bleeding and coagulation events (hemorrhage-related, n = 3; epistaxis, n = 2). Therefore, lower doses were not explored and an MTD could not be selected. The most frequently reported treatment-related adverse events (AEs) were increased liver enzymes, decreased hemoglobin, decreased appetite, and epistaxis. Three patients (50%) experienced treatment-related serious AEs, including conjunctival hemorrhage, pain (led to study drug discontinuation), liver disorder, and hemorrhage. Best response included progressive disease (n = 5; 83.3%) and stable disease (n = 1; 16.7%). Minimal or no dissociation of toxin from 1C1 conjugate occurred in the blood. Serum MEDI-547 concentrations decreased rapidly, ~70% by 3 days post-dose. No accumulation of MEDI-547 was observed at 0.08 mg/kg upon administration of a second dose 3 weeks following dose 1.
  
  
  CONCLUSIONS
  The safety profile of MEDI-547 does not support further clinical investigation in patients with advanced solid tumors.
authors.affiliation: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 12 N226, Bethesda, MD 20892-1906, USA. annunzic@mail.nih.gov
authors.forename: Christina M
authors.initials: CM
authors.lastname: Annunziata
authors.forename: Elise C
authors.initials: EC
authors.lastname: Kohn
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Houston
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.forename: Manuela
authors.initials: M
authors.lastname: Buzoianu
authors.forename: Gabriel
authors.initials: G
authors.lastname: Robbie
authors.forename: Robert
authors.initials: R
authors.lastname: Lechleider
mesh_terms: D000368:Aged; D062365:Aminobenzoates / Q000008:administration & dosage* / Q000009:adverse effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019008:Drug Resistance, Neoplasm; D004844:Epistaxis / Q000139:chemically induced; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D036104:Receptor, EphA2 / Q000276:immunology
chemical_list: D062365:Aminobenzoates; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C582519:MEDI-547; D036104:Receptor, EphA2