title: Phase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199).
abstract: OBJECTIVE
  HPV infection has been associated with deregulation of the PI3K-Akt-mTOR pathway in invasive cervical carcinomas. This 2-stage phase II study assessed the activity of the mTOR inhibitor, temsirolimus, in patients with measurable metastatic and/or locally advanced, recurrent carcinoma of the cervix.
  
  
  METHODS
  Temsirolimus 25mg i.v. was administered weekly in 4 week cycles. One response among the first 18 patients was required to proceed to the second stage of accrual. Correlative molecular studies were performed on archival tumor tissue.
  
  
  RESULTS
  Thirty-eight patients were enrolled. Thirty-seven patients were evaluable for toxicity and 33 for response. One patient experienced a partial response (3.0%). Nineteen patients had stable disease (57.6%) [median duration 6.5 months (range 2.4-12.0mo)]. The 6-month progression free survival rate was 28% (95% CI: 14-43%). The median progression free survival was 3.52 months [95% CI (1.81-4.70)]. Adverse effects were mild-moderate in most cases and similar to other temsirolimus studies. No toxicity>grade 3 was observed. Assessment of PTEN and PIK3CA by IHC, copy number analyses and PTEN promoter methylation status did not reveal subsets associated with disease stability.
  
  
  CONCLUSIONS
  Single agent temsirolimus has modest activity in cervical carcinoma with about two-thirds of patients exhibiting stable disease. Molecular markers for treatment benefit remain to be identified.
authors.affiliation: BC Cancer Agency, Vancouver Clinic, Vancouver, BC, Canada. atinker@bccancer.bc.ca
authors.forename: A V
authors.initials: AV
authors.lastname: Tinker
authors.forename: S
authors.initials: S
authors.lastname: Ellard
authors.forename: S
authors.initials: S
authors.lastname: Welch
authors.forename: F
authors.initials: F
authors.lastname: Moens
authors.forename: G
authors.initials: G
authors.lastname: Allo
authors.forename: M S
authors.initials: MS
authors.lastname: Tsao
authors.forename: J
authors.initials: J
authors.lastname: Squire
authors.forename: D
authors.initials: D
authors.lastname: Tu
authors.forename: E A
authors.initials: EA
authors.lastname: Eisenhauer
authors.forename: H
authors.initials: H
authors.lastname: MacKay
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D058534:Class I Phosphatidylinositol 3-Kinases; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D051059:PTEN Phosphohydrolase / Q000032:analysis; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000401:mortality
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C401859:temsirolimus; C484760:PIK3CA protein, human; C494929:PTEN protein, human
keywords: Cervical cancer systemic therapy; Phase II trial; Temsirolimus; mTOR pathway