title: Phase 1/2 study of atrasentan combined with pegylated liposomal doxorubicin in platinum-resistant recurrent ovarian cancer.
abstract: BACKGROUND
  Ovarian cancer overexpresses ET-1, and in vitro studies have shown that ET-1 confers resistance to anthracycline-containing chemotherapy. Atrasentan has been developed as an oral selective endothelin-A receptor antagonist. The objective of the study was to investigate the feasibility and toxicity of adding increasing doses of atrasentan (to a maximum of 10 mg/d) and liposomal doxorubicin in patients with progressive ovarian cancer, refractory for platinum and paclitaxel.
  
  
  METHODS
  Patients with platinum-resistant ovarian cancer were treated with pegylated liposomal doxorubicin (PLD) 50 mg/m(2) on day 1 (and repeated every 4 weeks) in combination with escalating doses of atrasentan once daily. The starting dose was 2.5 mg and escalated in cohorts of three patients from 5 to 10 mg.
  
  
  RESULTS
  Twenty-six patients (mean age = 60 years, range = 42-74 years) were treated at the three dose levels. Atrasentan could be safely administered in combination at a dose of 10 mg. All patients were evaluable for toxicity, and 19 patients, included in the phase 2 period, were evaluable for response. Adverse events included nausea, vomiting, mucositis, skin toxicity, and rhinitis. Clinical cardiac toxicity, intensively monitored, was not observed, although two patients had a decrease in cardiac ejection fraction. Three objective responses were observed and another six patients had stable disease with a median time to progression of 14 weeks and an overall survival of 13.1 months.
  
  
  CONCLUSIONS
  The addition of atrasentan to standard dose PLD in platinum-resistant ovarian cancer is feasible with some suggestion of prolonged survival.
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht Cancer Center, Utrecht, The Netherlands. P.O.Witteveen@umcutrecht.nl
authors.forename: Petronella O
authors.initials: PO
authors.lastname: Witteveen
authors.forename: Koen J C
authors.initials: KJ
authors.lastname: van der Mijn
authors.forename: Maartje
authors.initials: M
authors.lastname: Los
authors.forename: Roelien H
authors.initials: RH
authors.lastname: Kronemeijer
authors.forename: Gerard
authors.initials: G
authors.lastname: Groenewegen
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
mesh_terms: D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000077868:Atrasentan; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010984:Platinum / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects; D016019:Survival Analysis; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D011759:Pyrrolidines; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D010984:Platinum; D004317:Doxorubicin; D000077868:Atrasentan