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

Purpose 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.

Liquid biopsy in ovarian cancer: recent advances on circulating tumor cells and circulating tumor DNA

“…Fifty four recurrent ovarian cancer patients were recruited and blood specimens were obtained before and after treatment with temsirolimus. No significant association between the presence of CTCs with PFS and OS was reported [31]. Liu et al [29] also used the CellSearch ® system in 78 newly diagnosed and recurrent ovarian cancer patients.…”

Gene therapy for ovarian cancer using carbonyl reductase 1 DNA with a polyamidoamine dendrimer in mouse models

“…The GOG218 and ICON7 studies showed that progression-free survival (PFS) was significantly extended, but there were no significant differences in overall survival (OS). 19,20 Other drugs that have been clinically applied are the multi-targeted tyrosine kinase inhibitor pazopanib, 21 the mammalian target of rapamycin (mTOR) inhibitor temsirolimus, 22 and the angiopoietin inhibitor trebananib. 23 Although these molecularly targeted drugs are effective at extending PFS, no studies have indicated that they significantly extend OS.…”

Targeting mTOR Complexes in Ovarian Cancer

“…Of these, the only study that has published results is the GOG phase II trial of temsirolimus (GOG 170-I). In this trial, temsirolimus monotherapy was evaluated in patients with persistent or recurrent epithelial ovarian or primary peritoneal malignancies [25]. Of the 60 enrolled patients, 54 were eligible for evaluation.…”