title: Phase II study of bevacizumab and temsirolimus combination therapy for recurrent glioblastoma multiforme.
abstract: BACKGROUND
  Bevacizumab combined with chemotherapy has recently shown promising efficacy in recurrent high-grade glioma. Phosphatase and tensin homolog (PTEN) mutation in glioblastoma multiforme (GBM) patients causes abnormally high activity of the pathways of Phosphatidylinositide 3-kinases (PI3K), Protein Kinase B (AKT), and the mammalian target of rapamycin (mTOR) and is associated with unfavorable prognosis. Temsirolimus, an mTOR inhibitor, has been well-tolerated in monotherapy, but with limited effects. The combination of temsirolimus and antibodies to vascular endothelial factor (VEGF) has not yet been investigated, but with the hypothesis that temsirolimus might provide complimentary therapeutic benefit in combination with bevacizumab, we included patients with progressive GBM after bevacizumab in an open phase II study.
  
  
  METHODS
  Adult patients with GBM recurrence after standard temozolomide chemoradiotherapy and bevacizumab-containing second-line therapy, received temsirolimus (25 mg i.v.) on days 1 and 8 and bevacizumab (10 mg/kg) on day 8, every two weeks. Assessments were performed every eight weeks. Blood samples for biomarkers were collected weekly for the first eight weeks and at progression. The primary end-point was median progression-free survival (PFS) and secondary end-points were radiographic response, overall survival (OS), and safety of the bevacizumab-temsirolimus combination.
  
  
  RESULTS
  Thirteen patients were included, whereof three went off-study during the first four weeks and were replaced. The trial was terminated at 13 patients, according to the planned two-stage design, because 0/10 patients obtained partial remission (PR). Two out of 10 patients obtained radiological stable disease (SD). The median PFS survival was eight weeks, and OS was 15 weeks. One patient had an serious adverse event (SAE) with a hypersensitive reaction to temsirolimus; overall, side-effects were mild, and the most common grade III side-effect was hypercholesterolaemia (4/10). Other grade III side-effects included hypertriglyceridaemia (1/10), thrombocytopenia (1/10), infection (1/10), hypertension (1/10), and hyperglycemia (1/10).
  
  
  CONCLUSIONS
  Temsirolimus can be safely administered in combination with bevacizumab. This study failed to detect activity of such a combination in patients with progressive GBM beyond bevacizumab therapy.
authors.affiliation: Department of Oncology, Rigshospitalet, Copenhagen, Denmark. ulrik.lassen@rh.regionh.dk
authors.forename: Ulrik
authors.initials: U
authors.lastname: Lassen
authors.forename: Morten
authors.initials: M
authors.lastname: Sorensen
authors.forename: Tine Bernhardtsen
authors.initials: TB
authors.lastname: Gaziel
authors.forename: Benedikte
authors.initials: B
authors.lastname: Hasselbalch
authors.forename: Hans Skovgaard
authors.initials: HS
authors.lastname: Poulsen
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D015996:Survival Rate; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; C401859:temsirolimus; D020123:Sirolimus