title: Phase II trial of the mTOR inhibitor, temsirolimus and evaluation of circulating tumor cells and tumor biomarkers in persistent and recurrent epithelial ovarian and primary peritoneal malignancies: a Gynecologic Oncology Group study.
abstract: OBJECTIVE
  Patients with persistent/recurrent epithelial ovarian cancer/primary peritoneal cancer (EOC/PPC) have limited treatment options. AKT and PI3K pathway activation is common in EOC/PPC, resulting in constitutive activation of downstream mTOR. The GOG conducted a phase II evaluation of efficacy and safety for the mTOR inhibitor, temsirolimus in EOC/PPC and explored circulating tumor cells (CTC) and AKT/mTOR/downstream tumor markers.
  
  
  METHODS
  Eligible women with measurable, persistent/recurrent EOC/PPC who had received 1-3 prior regimens were treated with 25mg weekly IV temsirolimus until progression or intolerable toxicity. Primary endpoints were progression-free survival (PFS) ≥6-months, tumor response, and toxicity. CellSearch® system was used to examine CTC, and AKT/mTOR/downstream markers were evaluated by archival tumor immunohistochemistry. Kendall's tau-b correlation coefficient (r) and Cox regression modeling were used to explore marker associations with baseline characteristics and outcome.
  
  
  RESULTS
  Sixty patients were enrolled in a two-stage sequential design. Of 54 eligible and evaluable patients, 24.1% (90% CI 14.9%-38.6%) had PFS ≥6 months (median 3.1 months), 9.3% (90% CI 3.7%-23.4%) experienced a partial response. Grade 3/4 adverse events included metabolic (8), gastrointestinal (8), pain (6), constitutional (5) and pulmonary (4). Suggested associations were between cyclin D1 and PFS ≥6 months, PFS or survival; positive CTC pre-treatment and lack of response; and high CTC expression of M30 and PFS ≥6 months/longer PFS.
  
  
  CONCLUSIONS
  Temsirolimus appears to have modest activity in persistent/recurrent EOC/PPC; however, PFS is just below that required to warrant inclusion in phase III studies in unselected patients. Cyclin D1 as a selection marker and CTC measures merit further study.
authors.affiliation: University of Colorado Denver, Aurora, CO 80045, USA. kian.behbakht@ucdenver.edu
authors.forename: Kian
authors.initials: K
authors.lastname: Behbakht
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sill
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Darcy
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Rubin
authors.forename: Robert S
authors.initials: RS
authors.lastname: Mannel
authors.forename: Steven
authors.initials: S
authors.lastname: Waggoner
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Schilder
authors.forename: Kathy Q
authors.initials: KQ
authors.lastname: Cai
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: R Katherine
authors.initials: RK
authors.lastname: Alpaugh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000077216:Carcinoma, Ovarian Epithelial; D019938:Cyclin D1 / Q000096:biosynthesis; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009360:Neoplastic Cells, Circulating / Q000187:drug effects*; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; D019938:Cyclin D1; C401859:temsirolimus; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus