title: Phase 1 study of AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, in combination with chemotherapy in adults with advanced solid tumors.
abstract: OBJECTIVE
  To evaluate the safety, pharmacokinetics, and antitumor activity of AMG 386, an investigational selective angiopoietin 1/2-neutralizing peptibody, in combination with FOLFOX-4 (F), carboplatin/paclitaxel (C/P), or docetaxel (D), in adult patients with advanced solid tumors.
  
  
  METHODS
  Three cohorts of patients (F, n = 6; C/P, n = 8; D, n = 12) received one full cycle of chemotherapy alone during the pretreatment phase, followed by administration of AMG 386 10 mg/kg i.v. weekly in combination with chemotherapy until disease progression or intolerance. Safety and tolerability, tumor response, pharmacokinetic profiles, and biomarkers were assessed.
  
  
  RESULTS
  Twenty-six patients were enrolled; 22 received treatment with AMG 386. No dose-limiting toxicities or grade 3 or 4 adverse events related to AMG 386 were reported. The most common adverse events were diarrhea and hypomagnesemia (n = 3 each). One patient developed grade 2 hypertension and one had grade 1 subconjunctival eye hemorrhage. No neutralizing antibodies to AMG 386 were detected. There were no pharmacokinetic interactions between AMG 386 and F, C/P, or D. One patient receiving AMG 386 plus C/P for bladder cancer refractory to gemcitabine/cisplatin had a complete response at week 8. The remaining best tumor responses were partial response (n = 3, one from each cohort), stable disease > or =8 weeks (n = 13), and progressive disease (n = 1).
  
  
  CONCLUSIONS
  Weekly administration of AMG 386 in combination with three common chemotherapy regimens was well tolerated in patients with advanced solid tumors. No pharmacokinetic interactions between AMG 386 and any of the tested chemotherapy regimens were noted. Promising antitumor activity was observed with all three treatment combinations.
authors.affiliation: Institute for Drug Development, San Antonio, Texas 78229, USA. mita@uthscsa.edu
authors.forename: Alain C
authors.initials: AC
authors.lastname: Mita
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: Monica
authors.initials: M
authors.lastname: Mita
authors.forename: Anthony
authors.initials: A
authors.lastname: Tolcher
authors.forename: Kamalesh
authors.initials: K
authors.lastname: Sankhala
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
authors.forename: Manuel
authors.initials: M
authors.lastname: Valdivieso
authors.forename: Leslie
authors.initials: L
authors.lastname: Wood
authors.forename: Erik
authors.initials: E
authors.lastname: Rasmussen
authors.forename: Yu-Nien
authors.initials: YN
authors.lastname: Sun
authors.forename: Z Don
authors.initials: ZD
authors.lastname: Zhong
authors.forename: Michael B
authors.initials: MB
authors.lastname: Bass
authors.forename: NgocDiep
authors.initials: N
authors.lastname: Le
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
mesh_terms: D000328:Adult; D042683:Angiopoietin-1 / Q000037:antagonists & inhibitors; D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D015507:Drugs, Investigational / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D015507:Drugs, Investigational; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C551398:trebananib