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

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

Kian Behbakht  1 , Michael W Sill, Kathleen M Darcy, Stephen C Rubin, Robert S Mannel, Steven Waggoner, Russell J Schilder, Kathy Q Cai, Andrew K Godwin, R Katherine Alpaugh
Affiliations
Clinical Trial

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

Kian Behbakht et al. Gynecol Oncol. 2011 Oct.

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.

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Conflict of interest statement

CONFLICT OF INTEREST

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

Figures

Figure 1
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
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
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.
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