title: A phase 1b, open-label study of trebananib plus bevacizumab or motesanib in patients with solid tumours.
abstract: BACKGROUND
  To examine the angiopoietin pathway inhibitor trebananib IV plus the anti-VEGF agents bevacizumab or motesanib in advanced solid tumours.
  
  
  METHODS
  In this open-label phase 1b study, patients received IV trebananib 3 mg kg-1 QW plus bevacizumab 15 mg kg-1 Q3W (cohort 1) or motesanib orally 75 mg (cohort 2); or trebananib 10 mg kg-1 plus bevacizumab 15 mg kg-1 (cohort 3) or motesanib 125 mg (cohort 4). If <33% of patients had dose-limiting toxicities (DLTs), dose escalation occurred. Endpoints were treatment-related adverse events (AEs) incidence and pharmacokinetics (primary); anti-trebananib antibodies, biomarkers, and tumour response (secondary).
  
  
  RESULTS
  Thirty-six patients received ≥ 1 dose of trebananib (cohorts 1, 2, 3, 4; n = 6, 8, 19, 3). DLT of G3 intestinal perforation and G3 tumor haemorrhage occurred in cohorts 2 and 3, respectively (both n = 1). Across both trebananib plus bevacizumab cohorts, the most common AEs included fatigue (n = 8), diarrhoea (n =4), constipation (n = 3), nausea (n = 3), and epistaxis (n = 3). Three patients across those cohorts had grade ≥ 3 AEs. Across the trebananib plus motesanib cohorts, the most common AEs included hypertension (n = 4), diarrhoea (n = 4), nausea (n = 3), fatigue (n = 3), vomiting (n = 2), and decreased appetite (n = 2). Two patients had grade ≥ 3 AEs. Trebananib did not markedly affect motesanib pharmacokinetics. Across the trebananib plus bevacizumab cohorts, two patients had a partial response; 11 patients had stable disease lasting >6 months. Across the trebananib plus motesanib cohorts, one patient had a partial response; five patients had stable disease lasting >6 months.
  
  
  CONCLUSIONS
  Trebananib IV 3 mg kg-1 or 10 mg kg-1 plus bevacizumab or motesanib in advanced solid tumours may be associated with less severe toxicities relative to those emerging when combining two anti-VEGF agents.
authors.affiliation: Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77230-1402, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.affiliation: Center for Personalized Cancer Therapy and CTO, Division of Hematology and Oncology, UC San Diego Moores Cancer Center, La Jolla, CA 92093-0658, USA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.affiliation: Mulay Educational and Clinical Consulting Associates, Los Angeles, CA 90025, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Mulay
authors.affiliation: Department of Biostatistics, Amgen Inc., Thousand Oaks, CA 91320, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Rasmussen
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, CA 91320, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Wu
authors.affiliation: Department of Molecular Sciences and Computational Biology, Amgen Inc., Thousand Oaks, CA 91320, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Bass
authors.affiliation: Department of Clinical Immunology and Biological Sample Management, Amgen Inc., Thousand Oaks, CA 91320, USA.
authors.forename: Zhandong D
authors.initials: ZD
authors.lastname: Zhong
authors.affiliation: Department of Early Development, Amgen Inc., Thousand Oaks, CA 91320, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Friberg
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, UCLA, Santa Monica, CA 90404, USA.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D009841:Oligonucleotides; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007211:Indoles; D009841:Oligonucleotides; D011993:Recombinant Fusion Proteins; D009536:Niacinamide; D000068258:Bevacizumab; C519562:imetelstat; C551398:trebananib