title: Phase I dose-escalation study of MEDI-573, a bispecific, antiligand monoclonal antibody against IGFI and IGFII, in patients with advanced solid tumors.
abstract: OBJECTIVE
  This phase I, multicenter, open-label, single-arm, dose-escalation, and dose-expansion study evaluated the safety, tolerability, and antitumor activity of MEDI-573 in adults with advanced solid tumors refractory to standard therapy or for which no standard therapy exists.
  
  
  METHODS
  Patients received MEDI-573 in 1 of 5 cohorts (0.5, 1.5, 5, 10, or 15 mg/kg) dosed weekly or 1 of 2 cohorts (30 or 45 mg/kg) dosed every 3 weeks. Primary end points included the MEDI-573 safety profile, maximum tolerated dose (MTD), and optimal biologic dose (OBD). Secondary end points included MEDI-573 pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor activity.
  
  
  RESULTS
  In total, 43 patients (20 with urothelial cancer) received MEDI-573. No dose-limiting toxicities were identified, and only 1 patient experienced hyperglycemia related to treatment. Elevations in levels of insulin and/or growth hormone were not observed. Adverse events observed in >10% of patients included fatigue, anorexia, nausea, diarrhea, and anemia. PK evaluation demonstrated that levels of MEDI-573 increased with dose at all dose levels tested. At doses >5 mg/kg, circulating levels of insulin-like growth factor (IGF)-I and IGFII were fully suppressed. Of 39 patients evaluable for response, none experienced partial or complete response and 13 had stable disease as best response.
  
  
  CONCLUSIONS
  The MTD of MEDI-573 was not reached. The OBD was 5 mg/kg weekly or 30 or 45 mg/kg every 3 weeks. MEDI-573 showed preliminary antitumor activity in a heavily pretreated population and had a favorable tolerability profile, with no notable perturbations in metabolic homeostasis.
authors.affiliation: Mayo Clinic, Rochester, Minnesota. haluska.paul@mayo.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
authors.affiliation: Mayo Clinic, Jacksonville, Florida.
authors.forename: Michael
authors.initials: M
authors.lastname: Menefee
authors.affiliation: Fox Chase Cancer Center, Temple Health, Philadelphia, Pennsylvania.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Plimack
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosenberg
authors.affiliation: Mayo Clinic, Scottsdale, Arizona.
authors.forename: Donald
authors.initials: D
authors.lastname: Northfelt
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Theresa
authors.initials: T
authors.lastname: LaVallee
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Li
authors.initials: L
authors.lastname: Shi
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Xiang-Qing
authors.initials: XQ
authors.lastname: Yu
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Burke
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Huang
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Jaiqi
authors.initials: J
authors.lastname: Huang
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Jaye
authors.initials: J
authors.lastname: Viner
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: McDevitt
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Detroit, Missouri.
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
mesh_terms: D000368:Aged; D018033:Antibodies, Bispecific / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors; D007335:Insulin-Like Growth Factor II / Q000037:antagonists & inhibitors; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II