title: A phase 1b study of trebananib in combination with pegylated liposomal doxorubicin or topotecan in women with recurrent platinum-resistant or partially platinum-sensitive ovarian cancer.
abstract: OBJECTIVE
  To examine the tolerability and antitumor activity of trebananib plus pegylated liposomal doxorubicin (PLD) or topotecan in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer.
  
  
  METHODS
  In this open-label phase 1b study, patients received trebananib 10 mg/kg or 15 mg/kg IV QW plus PLD 50 mg/m(2) (cohorts A1 and A3, respectively) or topotecan 4 mg/m(2) (cohorts B1 and B3, respectively). Endpoints were dose-limiting toxicity (DLT; primary); treatment-emergent adverse events (AEs), overall response rate, anti-trebananib antibodies, and pharmacokinetics (secondary).
  
  
  RESULTS
  103 patients were enrolled. One patient in A1 and B1 had DLTs. Across all cohorts, the most common AEs were nausea, fatigue, and peripheral edema. Across both trebananib plus PLD cohorts (A1/A3), grade 4 AEs were pulmonary embolism, disease progression, and anemia. Two patients had grade 5 intestinal perforation (n=1) and sudden death (n=1). Across both trebananib plus topotecan cohorts (B1/B3), grade 4 AEs were neutropenia, hypokalemia, decreased granulocyte count, chest pain, dyspnea, decreased neutrophil count, and pulmonary embolism. Two patients had grade 5 disease progression. One patient had grade 5 pleural effusion associated with progressive disease. Confirmed objective response rates were 36.0% (A1), 34.8% (A3), 16.7% (B1), and 0.0% (B3). Median progression-free survival duration (months) was 7.4 (A1), 7.1 (A3), 3.5 (B1), and 3.1 (B3), respectively. No drug-drug interactions were apparent.
  
  
  CONCLUSIONS
  Trebananib 10mg/kg and 15 mg/kg IV QW plus PLD or topotecan appear to have acceptable toxicity profiles in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Antitumor activity was evident across all cohorts.
authors.affiliation: University Hospitals Leuven and KU Leuven, Leuven, Belgium.
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
authors.affiliation: Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Schilder
authors.affiliation: Novant Health Oncology Specialists, Winston-Salem, NC, USA.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Pippitt
authors.affiliation: Western Hospital, Footscray, VIC, Australia.
authors.forename: Shirley
authors.initials: S
authors.lastname: Wong
authors.affiliation: Emory University, Atlanta, GA, USA.
authors.forename: Alan N
authors.initials: AN
authors.lastname: Gordon
authors.affiliation: UC Davis Comprehensive Cancer Center, Sacramento, CA, USA.
authors.forename: Sidney
authors.initials: S
authors.lastname: Scudder
authors.affiliation: Centre Hospitalier Universitaire de Liége Sart Tilman, Liège, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Kridelka
authors.affiliation: Sint Augustinus, Antwerpen, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Dirix
authors.affiliation: Virginia Piper Cancer Institute, Minneapolis, MN, USA.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Leach
authors.affiliation: Royal Women's Hospital, Melbourne, VIC, Australia.
authors.forename: Sumitra
authors.initials: S
authors.lastname: Ananda
authors.affiliation: Quintiles, San Diego, CA, USA.
authors.forename: Nuwan
authors.initials: N
authors.lastname: Nanayakkara
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Melara
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Bass
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Litten
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Adewoye
authors.affiliation: H. Lee Moffitt Cancer Center, Tampa, FL, USA. Electronic address: Robert.Wenham@moffitt.org.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Wenham
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017671:Platinum Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D019772:Topotecan / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D017671:Platinum Compounds; D011993:Recombinant Fusion Proteins; D059004:Topoisomerase I Inhibitors; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D019772:Topotecan; D004317:Doxorubicin; C551398:trebananib
keywords: Angiogenesis; Angiopoietins; Combination treatments; Dose-limiting toxicities; Targeted therapy; Tie2 receptor