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

Gynecol Oncol. 2011 Oct;123(1):19-26. doi: 10.1016/j.ygyno.2011.06.022. Epub 2011 Jul 12.

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.

Trial registration: ClinicalTrials.gov NCT00429793.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Ovarian Epithelial
  • Cyclin D1 / biosynthesis
  • Disease-Free Survival
  • Female
  • Humans
  • Middle Aged
  • Neoplasms, Glandular and Epithelial / blood
  • Neoplasms, Glandular and Epithelial / drug therapy*
  • Neoplasms, Glandular and Epithelial / metabolism
  • Neoplasms, Glandular and Epithelial / pathology
  • Neoplastic Cells, Circulating / drug effects*
  • Ovarian Neoplasms / blood
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Peritoneal Neoplasms / blood
  • Peritoneal Neoplasms / drug therapy*
  • Peritoneal Neoplasms / metabolism
  • Peritoneal Neoplasms / pathology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Sirolimus / adverse effects
  • Sirolimus / analogs & derivatives*
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Young Adult

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • CCND1 protein, human
  • Cyclin D1
  • temsirolimus
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Sirolimus

Associated data

  • ClinicalTrials.gov/NCT00429793