Ridaforolimus in Treating Patients With Recurrent Metastatic and/or Locally Advanced Endometrial Cancer

Study Overview
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Brief Summary
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RATIONALE: Ridaforolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. PURPOSE: This phase II trial is studying the side effects of ridaforolimus and to see how well it works in treating patients with recurrent metastatic and/or locally advanced endometrial cancer.

Detailed Description
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OBJECTIVES: To assess the efficacy, in terms of objective response rate, of ridaforolimus, in patients with recurrent metastatic and/or locally advanced endometrial cancer. To assess the adverse events, time to progression, and response duration of this drug in these patients. To correlate objective tumor response with PTEN expression and other potential markers in primary tumor tissue from these patients. OUTLINE: This is a multicenter study. Patients receive oral ridaforolimus once daily on days 1-5 for 4 weeks. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Archived tumor tissue samples (paraffin block or unstained slides) are analyzed for PTEN gene expression and other mTOR pathway elements to explore possible markers of response or non-progression by immunohistochemistry. After completion of study treatment, patients are followed at 4 weeks and then every 3 months thereafter.

Official Title
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A Phase II Study of Ridaforolimus in Patients With Metastatic And/Or Locally Advanced Recurrent Endometrial Cancer

Conditions
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Endometrial Cancer

Intervention / Treatment
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* Drug: ridaforolimus
* Genetic: gene expression analysis
* Other: immunohistochemistry staining method
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed endometrial cancer, including any 1 of the following subtypes: Adenocarcinoma Papillary serous Papillary Villoglandular Mucinous Clear cell Endometrioid Adenosquamous carcinoma Recurrent or metastatic and/or locally advanced disease Incurable disease by standard therapies Clinically and/or radiologically documented disease within the past 28 days (35 days if negative), defined as ≥ 1 unidimensionally measurable disease site meeting 1 of the following criteria: At least 20 mm by x-ray or physical exam At least 10 mm by spiral CT scan At least 20 mm by non-spiral CT scan Available tumor tissue (paraffin block or unstained slides) from primary tumor No uterine sarcoma (leiomyosarcoma), mixed müllerian tumor (MMT), and/or adenosarcoma No known brain metastases Clinical suspicion of CNS involvement requires a head CT scan PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy ≥ 12 weeks Granulocyte count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Bilirubin ≤ upper limit of normal (ULN) ALT and AST ≤ 2.5 times ULN Creatinine ≤ 1.25 times ULN OR creatinine clearance ≥ 50 mL/min Fasting serum cholesterol ≤ 9.0 mmol/L Fasting triglycerides ≤ 4.56 mmol/L Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Accessible for treatment and follow up (e.g., 1 ½ hours driving distance from participating center) No upper gastrointestinal or other condition that would impair swallowing or absorption of oral medication No serious illness or medical condition that would not permit the patient to be managed according to the protocol, including, but not limited to, any of the following: History of significant neurologic or psychiatric disorder (e.g., uncontrolled psychotic disorders) that would impair the ability to obtain consent or limit compliance with study requirements Active uncontrolled or serious infection Active peptic ulcer disease Myocardial infarction within the past 6 months, congestive heart failure (even if medically controlled), unstable angina, active cardiomyopathy, unstable ventricular arrhythmia, or uncontrolled hypertension Pulmonary disease requiring oxygen HIV infection or other immune deficiency Other medical conditions that might be aggravated by study treatment No history of other malignancies, except adequately treated nonmelanoma skin cancer, curatively treated carcinoma in situ of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years No known hypersensitivity to the study drug or its components PRIOR CONCURRENT THERAPY: At least 7 days since prior hormonal therapy (progestational or aromatase inhibitor) as either adjuvant therapy or for treatment of metastatic disease At least 21 days since prior major surgery and recovered At least 28 days since prior radiotherapy and recovered Prior low-dose palliative radiotherapy allowed At least 4 months since prior adjuvant chemotherapy No prior mTOR inhibitors No prior or concurrent chemotherapy for metastatic or recurrent disease More than 7 days since prior and no concurrent CYP3A4 inhibitors including, but not limited to, any of the following: Azole antifungals (i.e., ketoconazole, itraconazole, miconazole, fluconazole) HIV protease inhibitors (i.e., indinavir, saquinavir, ritonavir, atazanavir, nelfinavir) Clarithromycin Verapamil Erythromycin Delavirdine Diltiazem Nefazodone Telithromycin More than 12 days since prior and no concurrent CYP3A4 inducers including, but not limited to, any of the following: Rifampin Phenytoin Rifabutin St. John's wort Carbamazepine Efavirenz Phenobarbital Tipranavir At least 14 days since prior and no concurrent investigational drugs or anticancer therapy (e.g., immunotherapy, biological response modifiers [excluding hematopoietic growth factors], and systemic hormonal therapy) No concurrent CYP3A4 substrates

Ages Eligible for Study
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Minimum Age: 18 Years

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ridaforolimus<br>oral ridaforolimus 40 mg days 1-5 each week (once daily for 5 consecutive days every week; cycle arbitrarily defined as a 4 week period) | Drug: ridaforolimus<br>* oral ridaforolimus 40 mg days 1-5 each week (once daily for 5 consecutive days every week; cycle arbitrarily defined as a 4 week period)<br>Genetic: gene expression analysis<br> <br> Other: immunohistochemistry staining method<br> <br> Other: laboratory biomarker analysis<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response measured by RECIST criteria | After every second cycle | every 8 weeks | 
| Adverse events | Adverse events will be monitored and assessed from the time of the first dose with overall results being assessed at final analysis. | 4 years | 
| Time to progression |  | 4 years | 
| Correlation between objective tumor response with PTEN expression and other potential markers | will be assessed overall at the time of completion of therapy and final analysis. | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response duration | After progression with overall results assessed at final analysis | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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endometrial adenocarcinoma, endometrial adenosquamous cell carcinoma, endometrial clear cell carcinoma, endometrial papillary carcinoma, recurrent endometrial carcinoma, stage III endometrial carcinoma, stage IV endometrial carcinoma