Molecular correlates associated with a phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer—NCIC IND 160

Abstract

3003 Background: PTEN is a tumor suppressor gene and mutations in PTEN causing loss of protein expression/function may play a significant role in the pathogenesis of EC. Loss of PTEN protein expression has been reported in 26–80% of EC and leads to deregulated PI3K/Akt/mTOR signalling which may give neoplastic cells a survival advantage by enhancing angiogenesis, protein translation and cell cycle progression. Inhibition of mTOR, a protein kinase downstream of the PI3K/Akt pathway and target of rapamycins, inhibits proliferation of EC cell lines and formation of EC in PTEN−/+ heterozygous mice. We have evaluated temsirolimus (T) an ester derivative of rapamycin that inhibits mTOR given the frequent loss of PTEN in human EC. Methods: A two stage, phase II study has been conducted to evaluate single agent activity of T in women with recurrent or metastatic EC (chemotherapy naïve, upto 1 prior line of hormonal therapy). Treatment was 25mg i.v. weekly. One cycle is defined as 4 weeks of therapy. Thirty one patients (pts) have been registered; 23 are evaluable for toxicity and 19 for response. Results: Preliminary results have demonstrated encouraging activity and the trial fulfilled predefined criteria for activity. Of 19 pts evaluable for response, 5 have had a confirmed partial response (PR) (26%) and 12 have stable disease (SD) as best response (63%). Two pts had progressive disease (PD) (11%). PTEN, phosphorylated (p) mTOR and p-S6 protein (immunohistochemistry) results are available on 9 pts to date. The preliminary results indicate that responses and stable disease are seen in pts irrespective of PTEN status. Loss of p-mTOR was evident in tumor cells from all pts (range 75–99% loss) and did not correlate with response. Phosphorylated S6 was low in tumor cells in the one pt who had PD (5%), and levels were higher in pts with PR and SD (mean and median 30%). Conclusions: We conclude that Temsirolimus has encouraging single agent activity for in recurrent and metastatic EC, and the findings indicate this is irrespective of PTEN status. We are currently evaluating activity of T in pts previously treated with chemotherapy and molecular correlates in additional specimens. No significant financial relationships to disclose.

Current Treatment of Metastatic Endometrial Cancer

“…The National Cancer Institute of Canada reported a preliminary response rate of 26% in chemotherapynaive endometrial cancer patients treated with temsirolimus, an mTOR inhibitor. 60 Response in this group of patients was not correlated to PTEN status as evaluated by immunohistochemistry. Preliminary studies of other mTOR inhibitors, everolimus and AP2357, have shown clinical responses mainly in the form of stable disease (8 of 15 and 7 of 19 women, respectively).…”

Multiband planar monopole antenna for mobile handsets

“…Oza et al from the National Cancer Institute of Canada evaluated CCI‐779 (temsirolimus; Wyeth Pharmaceuticals, Madison, NJ) in patients with untreated (as first‐line treatment) metastatic or recurrent endometrial cancer 10. Temsirolimus is an mTOR inhibitor available in an intravenous formulation.…”

Targeted therapies in gynecological cancers: a comprehensive review of clinical evidence

“…Temsirolimus, an intravenous mTORC1 inhibitor (25 mg weekly), showed efficacy as monotherapy for advanced and recurrent EC with ORRs of 22-25%. [187][188][189] Ridaforolimus is another intravenous mTORC1 inhibitor, administrated at a dose of 12.5 mg daily for 5 consecutive days every 2 weeks, showing a modest therapeutic efficacy as a single agent. 190 A phase II trial studied the efficacy and tolerability of ridaforolimus in recurrent and advanced EC with an ORR of 8.8% and a SD of 52.9%.…”