POEM STUDY: A Phase IIa Trial in Endometrial Carcinoma With Temsirolimus

Study Overview
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Brief Summary
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Type of Application: Clinical trial of new indication. Experimental drug: The study dose of temsirolimus will be 25 mg administered intravenously, infused over a 30- to 60-minute period once weekly for 28 days (Total doses: 4 doses). Temsirolimus is a selective inhibitor of mTOR (mammalian target of rapamycin). Pharmacotherapeutic group: Protein Kinase Inhibitors; ATC code: L01X E09. Primary Objective: To identify in tumor samples future biomarkers associated with a short term exposure to temsirolimus. This is an exploratory clinical study. No efficacy objectives are included in this clinical trial. Secondary Objectives: To estimate the tolerability for all temsirolimus-treated patients throughout the study and up to 28 days after the last dose of temsirolimus. To correlate observed changes with the different type of endometrial carcinoma (type I and type II), with regard to proteins related to mTOR (p4EBP1, pS6K1, c-MYC, cyclin D, p27, BAD, p53, Bcl-2 PTEN, pAKT, mTOR), To estimate the potential predictive value of some biomarkers (immunostaining for PTEN, pAKT, mTOR), relevant mutations in PTEN, PI3KCA, k-RAS, CTNNB1, and microsatellite instability status. To estimate the prognostic value of Ki67 expression after short-term presurgical therapy exposure To collect data about the differences in expression profile, assessed by RNA microarrays

Official Title
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A Phase IIa Pharmacokinetic-pharmacodynamic Study to Confirm the Inhibitory Effect of Temsirolimus, Targeting the mTOR Pathway in Endometrial Carcinoma

Conditions
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Carcinoma, Endometrioid, mTOR Protein

Intervention / Treatment
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* Drug: Temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically-confirmed endometrial cancer Stage I - II (grade 1, 2 or 3), candidates for surgery as the primary treatment Age ≥ 18 years WHO performance status ≤ 2 Adequate bone marrow function Adequate liver function Adequate renal function Fasting serum cholesterol ≤300 mg/dL or ≤7.75 mmol/L and fasting triglycerides ≤ 2.5 x ULN Signed informed consent Exclusion Criteria: Subjects who have received prior anticancer therapies for the current endometrial cancer Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery or patients that may require major surgery during the course of the study Prior treatment with any investigational drug within the preceding 4 weeks Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period Uncontrolled brain or leptomeningeal metastases Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study Patients with an active, bleeding diathesis Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods Patients who have received prior treatment with an mTOR inhibitor Patients with a known hypersensitivity to rapamycine derivates or to its excipients History of noncompliance to medical regimens Patients unwilling to or unable to comply with the study protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Temsirolimus<br>25 mg administered intravenously, infused over a 30- to 60-minute period once weekly for 28 days (Total doses: 4 doses). | Drug: Temsirolimus<br> <br> * Other names: Torisel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the mTOR inhibitor effects of temsirolimus directly on endometrial tumor tissue after four weeks of therapy. | To evaluate the mTOR inhibitor effects, assessed by level 4EBP1 and S6K1, of temsirolimus directly on endometrial tumor tissue after four weeks of therapy. | 1 month after last dose of the last patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate if mTOR inhibition is associated with changes in tumor-tissue | To evaluate if mTOR inhibition is associated with changes in tumor-tissue: Signal transduction: AKT and PTEN c-MYC, cyclin D activity Proliferation index analysis: p53, p27, BAD, Bcl-2 and ki-67 | 1 month after the surgery of the last patient | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetic, pharmacodynamic, Carcinoma, Endometrioid, mTOR protein, temsirolimus, torisel, biological marker, phase II