TY - JOUR
T1 - 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
T2 - A Gynecologic Oncology Group study
AU - Behbakht, Kian
AU - Sill, Michael W.
AU - Darcy, Kathleen M.
AU - Rubin, Stephen C.
AU - Mannel, Robert S.
AU - Waggoner, Steven
AU - Schilder, Russell J.
AU - Cai, Kathy Q.
AU - Godwin, Andrew K.
AU - Alpaugh, R. Katherine
N1 - Funding Information:
Temsirolimus was provided by the Cancer Therapy Evaluation Program of the National Cancer Institute (NCI-CTEP). The study involves original work which was presented in part at the 41st Annual Meeting of the Society of Gynecologic Oncologists, San Francisco, CA, March 13–17, 2010.
Funding Information:
This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office (CA 27469), the GOG Tissue Bank (CA 27469 and CA 11479), the GOG Statistical and Data Center (CA 37517), to AKG (CA 140323 and Ovarian Cancer Research Fund) and the Ovarian Cancer SPORE at FCCC/U Penn (P50 CA083638).
PY - 2011/10
Y1 - 2011/10
N2 - 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 25 mg 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.
AB - 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 25 mg 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.
KW - AKT/PI3K pathway
KW - Circulating tumor cells
KW - Ovarian clinical trial
KW - mTOR inhibitor
UR - http://www.scopus.com/inward/record.url?scp=80052588957&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2011.06.022
DO - 10.1016/j.ygyno.2011.06.022
M3 - Article
C2 - 21752435
AN - SCOPUS:80052588957
SN - 0090-8258
VL - 123
SP - 19
EP - 26
JO - Gynecologic Oncology
JF - Gynecologic Oncology
IS - 1
ER -