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Clinical Trial
. 2014 Mar;132(3):585-92.
doi: 10.1016/j.ygyno.2014.01.015. Epub 2014 Jan 20.

Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: a gynecologic oncology group study

Gini F Fleming  1 , Virginia L Filiaci  2 , Brandon Marzullo  2 , Richard J Zaino  3 , Susan A Davidson  4 , Michael Pearl  5 , Vicky Makker  6 , James J Burke 2nd  7 , Susan L Zweizig  8 , Linda Van Le  9 , Parviz Hanjani  10 , Gordon Downey  11 , Joan L Walker  12 , Henry D Reyes  13 , Kimberly K Leslie  13
Affiliations
Clinical Trial

Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: a gynecologic oncology group study

Gini F Fleming et al. Gynecol Oncol. 2014 Mar.

Abstract

Objectives: To determine the response, toxicities, and progression free survival of a regimen of temsirolimus with or without hormonal therapy in the treatment of advanced, or recurrent endometrial carcinoma.

Background: Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy.

Methods: We performed a randomized phase II trial of intravenous temsirolimus 25mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma.

Results: There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT) and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total of 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded.

Conclusions: Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy.

Keywords: Endometrial cancer; Hormonal therapy; Megestrol acetate; Tamoxifen; Temsirolimus.

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Conflict of interest statement

CONFLICT OF INTEREST

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

Figures

Figure 2
Figure 2
Figure 2a. PFS and OS by arm Figure 2b. PFS and OS by prior therapy
Figure 3
Figure 3
Figure 3a. OS by pAKT Figure 3b OS by ER
Figure 4
Figure 4
Immunohistochemistry for PTEN and pAKT Immunostaining for PTEN and pAKT in the same tumor, demonstrating the expected inverse correlation between loss of PTEN and activation of AKT.
See this image and copyright information in PMC

References

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    1. Fleming GF, Brunetto VL, Cella D, Look KY, Reid GC, Munkarah AR, et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol. 2004;22:2159–66. - PubMed
    1. Weigelt B, Banerjee S. Molecular targets and targeted therapeutics in endometrial cancer. Curr Opin Oncol. 2012;24:554. - PubMed

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