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.

Trial registration: ClinicalTrials.gov NCT00429793.

Conflict of interest statement

CONFLICT OF INTEREST

The authors wish to report that there are no conflicts of interest.

Published by Elsevier Inc.

Figures

Figure 1

Kaplan-Meier progression-free survival (PFS) and overall survival (OS) distributions for persistent/recurrent epithelial ovarian cancer or primary peritoneal cancer (A). Kaplan-Meier plots for progression-free survival (PFS)(B) and overall survival (OS)(C) by tumor expression of cyclin D1 categorized as negative or positive, and for progression-free survival by tumor expression of pAKT (D), pmTOR (E), pp70-S6K (F) categorized as negative or positive, or p4E-BP1 (G) categorized as low (<50% positive tumor cells) or positive (≥50% positive tumor cells) following temsirolimus treatment. Suggestive associations were assessed by logrank test with p<0.05.

Figure 1

Kaplan-Meier progression-free survival (PFS) and overall survival (OS) distributions for persistent/recurrent epithelial ovarian cancer or primary peritoneal cancer (A). Kaplan-Meier plots for progression-free survival (PFS)(B) and overall survival (OS)(C) by tumor expression of cyclin D1 categorized as negative or positive, and for progression-free survival by tumor expression of pAKT (D), pmTOR (E), pp70-S6K (F) categorized as negative or positive, or p4E-BP1 (G) categorized as low (<50% positive tumor cells) or positive (≥50% positive tumor cells) following temsirolimus treatment. Suggestive associations were assessed by logrank test with p<0.05.

Figure 2

Kaplan-Meier progression-free survival (PFS) distributions for pre-treatment circulating tumor cells (A), pre-treatment circulating tumor cell (CTC) expression of the apoptotic marker M30 (B) or pre-treatment CTC expression of pS6 (C), or change in CTC counts from pre-cycle 1 to pre-cycle 2 (D) following temsirolimus treatment. Circulating tumor cells (CTC) counts were categorized as negative or positive. M30 and pS6 were categorized as low (<75% positive CTC) or high (≥75% positive CTC). Serial changes in CTC were categorized as stable counts, decreasing counts or increasing counts. Suggestive associations were assessed by logrank test with p<0.05.