title: A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041).
abstract: BACKGROUND
  There is crosstalk between the ANG-Tie2 and the PI3K/Akt/mTOR pathways. Combined ANG1/2 and mTOR blockade may have additive anti-cancer activity. The combination of trebananib, an inhibitor of ANG1/2-Tie2 interaction, with temsirolimus was evaluated in patients with advanced solid tumors to determine tolerability, maximum tolerated dose (MTD), and preliminary antitumor activity.
  
  
  METHODS
  Patients were enrolled using 3 + 3 design, and were given intravenous trebananib and temsirolimus on Day 1, 8, 15 and 22 of a 28-day cycle. Dose limiting toxicities (DLTs) were evaluated during cycle 1. Peripheral blood was collected for evaluation of Tie2-expressing monocytes (TEMs) and thymidine phosphorylase (TP). Sparse pharmacokinetic (PK) sampling for trebananib drug levels was performed on Day 1 and 8 of cycle 2.
  
  
  RESULTS
  Twenty-one patients were enrolled, 6 at dose level (DL) 1, 7 at DL -1, and 8 at DL -2. No effect of temsirolimus on trebananib PK was observed. The most common treatment-related adverse events (AEs) were: fatigue (81 %), edema (62 %), anorexia (57 %), nausea (52 %), rash (43 %) and mucositis (43 %). The most common grade ≥ 3 AEs included lymphopenia (28 %) and fatigue (28 %). The MTD was exceeded at DL-2. Of 18 response evaluable patients, 1 partial response was observed (ER+/HER2-/PIK3CA mutant breast cancer) and 4 patients had prolonged SD ≥ 24 weeks. No correlation with clinical benefit was observed with change in number TEMs or TP expression in TEMs with treatment.
  
  
  CONCLUSIONS
  The MTD was exceeded at trebananib 10 mg/kg weekly and temsirolimus 20 mg weekly, with frequent overlapping toxicities including fatigue, edema, and anorexia.
authors.affiliation: Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Joanne W
authors.initials: JW
authors.lastname: Chiu
authors.affiliation: Juravinski Cancer Centre and Escarpment Cancer Research Institute, Hamilton, ON, Canada.
authors.forename: Sebastien J
authors.initials: SJ
authors.lastname: Hotte
authors.affiliation: British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Christian K
authors.initials: CK
authors.lastname: Kollmannsberger
authors.affiliation: British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Renouf
authors.affiliation: Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Cescon
authors.affiliation: Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Hedley
authors.affiliation: Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Sue
authors.initials: S
authors.lastname: Chow
authors.affiliation: National Cancer Institute, Cancer Therapy Evaluation Program, Rockville, MD, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Moscow
authors.affiliation: Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Meghan
authors.initials: M
authors.lastname: Perry
authors.affiliation: Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Diaz-Padilla
authors.affiliation: Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Tan
authors.affiliation: Juravinski Cancer Centre and Escarpment Cancer Research Institute, Hamilton, ON, Canada.
authors.forename: Hal
authors.initials: H
authors.lastname: Hirte
authors.affiliation: Juravinski Cancer Centre and Escarpment Cancer Research Institute, Hamilton, ON, Canada.
authors.forename: Elaine
authors.initials: E
authors.lastname: McWhirter
authors.affiliation: National Cancer Institute, Cancer Therapy Evaluation Program, Rockville, MD, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Chen
authors.affiliation: Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.affiliation: Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 2M9, Canada. philippe.bedard@uhn.ca.|Department of Medicine, University of Toronto, Toronto, ON, Canada. philippe.bedard@uhn.ca.
authors.forename: Philippe L
authors.initials: PL
authors.lastname: Bedard
mesh_terms: D000328:Adult; D000368:Aged; D000855:Anorexia / Q000139:chemically induced / Q000453:epidemiology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D004487:Edema / Q000139:chemically induced / Q000453:epidemiology; D005221:Fatigue / Q000139:chemically induced / Q000453:epidemiology; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D016896:Treatment Outcome
chemical_list: D011993:Recombinant Fusion Proteins; C401859:temsirolimus; D020123:Sirolimus; C551398:trebananib
keywords: AMG386; Combination therapy; Phase 1; Temsirolimus; Trebananib