Temsirolimus With or Without Megestrol Acetate and Tamoxifen Citrate in Treating Patients With Advanced, Persistent, or Recurrent Endometrial Cancer

Study Overview
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Brief Summary
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This randomized phase II trial studies how well temsirolimus with or without megestrol acetate and tamoxifen citrate works in treating patients with endometrial cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment, has returned after a period of improvement, or is persistent. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of endometrial cancer cells. Hormone therapy using megestrol acetate and tamoxifen citrate may fight endometrial cancer by blocking the use of estrogen by the tumor cells. It is not yet known whether temsirolimus is more effective when given alone or together with megestrol acetate and tamoxifen citrate in treating endometrial cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the response rate of patients with advanced, persistent, or recurrent endometrial cancer when treated with each of the arms of the trial; the proposed arms are: Arm #1 temsirolimus intravenously (IV) weekly, Arm #2 megestrol (megestrol acetate)/tamoxifen (tamoxifen citrate) plus temsirolimus IV weekly. II. Time to progression and number of patients remaining on study therapy at 24 weeks. SECONDARY OBJECTIVE: I. To describe the toxicities of each of the arms of the trial when used for patients with advanced/metastatic endometrial cancer. TERTIARY OBJECTIVES: I. Explore whether immunohistochemical expression of hormone receptors (estrogen receptor-alpha, estrogen receptor-beta, progesterone receptors-A, progesterone receptor-B and the alternative estrogen receptor, G protein-coupled estrogen receptor [GPR]-30) or components of the mammalian target of rapamycin (mTOR) signaling pathway (normal and mutant phosphatase and tensin homolog [PTEN], total and phosphorylated v-akt murine thymoma viral oncogene homolog 1 [Akt] as well as total and phosphorylated p70S6 kinase) are associated with treatment, outcome or clinical characteristics. II. Explore whether single nucleotide polymorphisms (SNPs) in the FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1) and regulatory associated protein of mTOR (RAPTOR) genes, mutations in phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), PTEN and paxillin or copy number abnormalities in PTEN and paxillin are associated with treatment, outcome or clinical characteristics. OUTLINE: Patients are randomized to 1 of 2 treatment arms. (Closed to accrual as of 11/22/2010) ARM I: Patients receive temsirolimus IV over 30 minutes once weekly for 6 weeks. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. ARM II (Closed to accrual as of 12/21/2009): Patients receive temsirolimus as in Arm I and megestrol acetate orally (PO) twice daily (BID) for 3 weeks alternating with tamoxifen citrate PO BID for 3 weeks. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 1 year.

Official Title
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A Randomized Phase II Trial of Temsirolimus (NCI-Supplied Agent, NSC # 683864) or the Combination of Hormonal Therapy Plus Temsirolimus in Women With Advanced, Persistent, or Recurrent Endometrial Carcinoma

Conditions
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Endometrial Carcinoma, Recurrent Uterine Corpus Carcinoma, Stage IIIA Uterine Corpus Cancer, Stage IIIB Uterine Corpus Cancer, Stage IIIC1 Uterine Corpus Cancer, Stage IIIC2 Uterine Corpus Cancer, Stage IVA Uterine Corpus Cancer, Stage IVB Uterine Corpus Cancer

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Megestrol Acetate
* Drug: Tamoxifen Citrate
* Drug: Temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed advanced (International Federation of Gynecologists and Obstetricians [FIGO] stage III or IV), persistent, or recurrent endometrial carcinoma, which is not likely to be curable by surgery or radiotherapy; histologic documentation of the recurrence is not required All patients must have measurable disease; measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded); each lesion must be >= 20 mm when measured by conventional techniques, including palpation, plain x-ray, computed tomography (CT), and magnetic resonance imaging (MRI), or >= 10 mm when measured by spiral CT Patients must have at least one target lesion to be used to assess response, as defined by Response Evaluation Criteria In Solid Tumors (RECIST); tumors within a previously irradiated field will be designated as non-target lesions unless progression is documented Prior chemoradiotherapy for a pelvic recurrence is permitted; prior chemotherapy in the adjuvant setting for stage I, II, or III disease is permitted Note: no prior chemotherapy in the setting of stage IV disease is permitted unless the patient was without evidence of disease at the completion of chemotherapy and had at least six months of progression-free survival since the completion of chemotherapy Regardless of circumstances, no more than one prior chemotherapy regimen (including chemoradiotherapy) is permitted Patient must be able to take p.o. medications Performance status must be 0-2 Absolute neutrophil count >= 1,500/mcL Platelets >= 100,000/mcL Total bilirubin within normal institutional limits Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 times institutional upper limit of normal v 3.0 (=< 5 times upper limit of normal [ULN] for subjects with liver metastases) Alkaline phosphatase =< 2.5 times institutional upper limit of normal v 3.0 (=< 5 times ULN for subjects with liver metastases) Creatinine =< 1.5 times normal institutional upper limit of normal Cholesterol =< 350 mg/dL (fasting) Triglycerides =< 400 mg/dL (fasting) Albumin >= 3.0 mg/dL At least 4 weeks must have elapsed since the patient underwent any major surgery (e.g., major: hysterectomy, resection of a lung nodule-minor: a Port-A-Cath placement) Patients who have met the pre-entry requirements Patients must have signed an approved informed consent including Health Insurance Portability and Accountability Act (HIPAA) authorization Exclusion Criteria: Patients with Gynecologic Oncology Group (GOG) performance status of 3 or 4 Patients cannot be receiving enzyme-inducing antiepileptic drugs (EIAEDs; e.g., phenytoin, carbamazepine, phenobarbital) nor any other cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducer such as rifampin or St. John's wort, as these may decrease temsirolimus levels; use of agents that potently inhibit CYP3A (and hence may raise temsirolimus levels), such as ketoconazole, is discouraged, but not specifically prohibited; the appropriateness of use of such agents is left to physician discretion All concomitant medications must be recorded at baseline Patients on maintenance corticosteroids are ineligible with the exception of short term use (fewer than 5 days) Patients known to have congestive heart failure; patients with baseline requirement for oxygen; patients with serious concomitant illness that, in the opinion of the treating physician, will place patient at unreasonable risk from therapy on this protocol Patients with a history of unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE), unless patient is maintained on anticoagulation for the duration of the trial; while the exact definition of provoked is left to the treating physician, a DVT in the setting of pelvic surgery or trauma would be considered provoked Women of child-bearing potential must have a negative pregnancy test prior to treatment on study; breastfeeding should be discontinued if the mother is treated with temsirolimus Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control or abstinence; oral contraceptives [also known as the pill] are not acceptable) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Patients with a concomitant invasive malignancy or a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the past five years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy Patients who have received hormonal therapy or biologic therapy as treatment for endometrial carcinoma Patients who have received chemotherapy directed at metastatic or recurrent endometrial carcinoma
Sexes Eligible for Study
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Female

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (temsirolimus)<br>Patients receive temsirolimus IV over 30 minutes once weekly for 6 weeks. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Temsirolimus<br>* Given IV<br>* Other names: Torisel;|
| Experimental: Arm II (temsirolimus, megestrol acetate, tamoxifen citrate)<br>Patients receive temsirolimus as in Arm I and megestrol acetate PO BID for 3 weeks alternating with tamoxifen citrate PO BID for 3 weeks. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Megestrol Acetate<br>* Given PO<br>* Other names: SC-10363;Drug: Tamoxifen Citrate<br>* Given PO<br>* Other names: Zemide;Drug: Temsirolimus<br>* Given IV<br>* Other names: Torisel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Confirmed Objective Tumor Response Using RECIST Version 1.0 | RECIST 1.0 defines complete response as the disappearance of all target lesions and non-target lesions and no evidence of new lesions documented by two disease assessments at least 4 weeks apart. Partial response is defined as at least a 30% decrease in the sum of longest dimensions (LD) of all target measurable lesions taking as reference the baseline sum of LD. There can be no unequivocal progression of non-target lesions and no new lesions. Documentation by two disease assessments at least 4 weeks apart is required. In the case where the ONLY target lesion is a solitary pelvic mass measured by physical exam, which is not radiographically measurable, a 50% decrease in the LD is required. These patients will have their response classified according to the definitions stated above. Complete and partial responses are included in the objective tumor response rate. | Radiologic tumor evaluations at baseline and every 6 weeks for the first 24 weeks; then repeated every 12 weeks until disease progression. Repeat after treatment discontinuation if patient was taken off study for reasons other than progression. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Overall Survival (OS) | Overall survival is defined as the duration of time from study entry to time of death or the date of last contact. | Every 6 weeks during treatment, then every 3 months for one year. | 
| Duration of Progression-free Survival (PFS) | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions assessed radiographically and 50% increase if the only target lesion is a solitary pelvic mass measured by physical exam, or unequivocal progression of a non-target lesion, or the appearance of new lesions. | Radiologic tumor evaluations at baseline and every six weeks for the first 24 weeks and then repeated every 12 weeks until disease progression. Repeat after treatment discontinuation if patient was taken off study for reasons other than progression. | 
| Incidence of Adverse Effects (Grade 3 or Higher) as Assessed by Common Terminology Criteria for Adverse Events Version 3.0 | Number of participants with a maximum grade of 3 or higher during the treatment period. | Assessed every 6 weeks while on treatment, 30 days after the last cycle of treatment. |