title: A phase I trial of oral ridaforolimus (AP23573; MK-8669) in combination with bevacizumab for patients with advanced cancers.
abstract: OBJECTIVE
  This phase I dose-escalation study was designed to evaluate the combination of the mammalian target of rapamycin inhibitor ridaforolimus with the vascular endothelial growth factor inhibitor bevacizumab.
  
  
  METHODS
  Seventeen adult patients with refractory advanced solid tumours received oral ridaforolimus (30 or 40 mg) once daily for 5 days per week (QDx5/wk) combined with intravenous bevacizumab (10 mg/kg every 2 weeks [Q2wk] or 15 mg/kg every 3 weeks [Q3wk]). Patients were evaluated for dose-limiting toxicities, safety and anti-tumour activity.
  
  
  RESULTS
  A 40 mg dose of ridaforolimus with either bevacizumab dosing schedule was the recommended phase II dose. No dose-limiting toxicities were reported; the most common drug-related adverse events were mucosal inflammation and anorexia. Seven patients, with clinical features that included primary tumour of the abdominal origin (colorectal, pancreatic or gynaecological cancers) and previous abdominal radiotherapy, reported serious adverse events related to bowel perforations. There were no objective responses, but 65% of patients had a best response of stable disease.
  
  
  CONCLUSIONS
  Oral ridaforolimus (40 mg QDx5/wk) is feasible to combine with standard doses of bevacizumab, although careful patient selection would be needed to mitigate the risk of bowel perforation-related adverse events. Combination therapy produced prolonged stable disease in several heavily pretreated patients.
authors.affiliation: Mary Crowley Cancer Research Centers, Clinical Research, Dallas, TX 75201, USA. jnemunaitis@marycrowley.org
authors.forename: J
authors.initials: J
authors.lastname: Nemunaitis
authors.forename: H S
authors.initials: HS
authors.lastname: Hochster
authors.forename: S
authors.initials: S
authors.lastname: Lustgarten
authors.forename: R
authors.initials: R
authors.lastname: Rhodes
authors.forename: S
authors.initials: S
authors.lastname: Ebbinghaus
authors.forename: C D
authors.initials: CD
authors.lastname: Turner
authors.forename: P F
authors.initials: PF
authors.lastname: Dodion
authors.forename: M M
authors.initials: MM
authors.lastname: Mita
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; 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; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; C515074:ridaforolimus; D020123:Sirolimus