Bevacizumab and Temsirolimus in Treating Patients With Recurrent or Persistent Endometrial Cancer

Study Overview
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Brief Summary
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This phase II trial is studying the side effects of giving bevacizumab together with temsirolimus and to see how well it works in treating patients with recurrent or persistent endometrial cancer. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for their growth. Giving bevacizumab together with temsirolimus may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the activity of bevacizumab and temsirolimus, in terms of 6-month progression-free survival (PFS) and objective tumor response, in patients with recurrent or persistent endometrial cancer. II. To determine the nature and degree of toxicity of this regimen in these patients. SECONDARY OBJECTIVES: I. To determine the duration of PFS and overall survival of patients treated with this regimen. II. To determine the effects of prognostic factors (i.e., performance status, histological subtype, and grade) in patients treated with this regimen. TERTIARY OBJECTIVES: I. To compare the proportion of patients with objective tumor response and PFS at 6 months receiving the combination of bevacizumab and temsirolimus with those for the single agents bevacizumab and temsirolimus using historical controls. OUTLINE: This is a multicenter study. Patients receive bevacizumab IV on days 1 and 15 and temsirolimus IV on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed every 3 months for 2 years, then every 6 months for 3 years, for a total of 5 years.

Official Title
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A Phase II Evaluation of Combination Bevacizumab (NCI-Supplied Agent: NSC #70486) and Temsirolimus (CCI-779, NCI-Supplied Agent, NSC #683864) in the Treatment of Recurrent or Persistent Endometrial Carcinoma

Conditions
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Recurrent Endometrial Carcinoma

Intervention / Treatment
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* Biological: bevacizumab
* Drug: temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed endometrial carcinoma (from primary tumor) including any of the following cell types: Endometrioid adenocarcinoma Serous adenocarcinoma Undifferentiated carcinoma Clear cell adenocarcinoma Mixed epithelial carcinoma Adenocarcinoma not otherwise specified Mucinous adenocarcinoma Squamous cell carcinoma Transitional cell carcinoma Mesonephric carcinoma Recurrent or persistent disease that is refractory to curative therapy or established treatments Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan Must have ≥ 1 target lesion to assess response as defined by RECIST Tumors within a previously irradiated field are designated as non-target lesions in the absence of documented disease progression or a biopsy to confirm persistence for ≥ 90 days after completion of radiotherapy Must have received 1 prior chemotherapeutic regimen for management of endometrial carcinoma May have received 1 additional cytotoxic regimen for management of this disease Not eligible for a higher priority Gynecologic Oncology Group (GOG) protocol, including any active GOG Phase III protocol for patients with endometrial carcinoma No history or evidence of CNS disease, including primary brain tumor or any brain metastases upon physical examination GOG performance status (PS) 0-2 (for patients who have received 1 prior regimen) OR PS 0-1 (for patients who have received 2 prior regimens) ANC ≥ 1,500/mcL Platelet count ≥ 100,000/mcL Creatinine ≤ 1.5 times upper limit of normal (ULN) Bilirubin ≤ 1.5 times ULN SGOT ≤ 2.5 times ULN Alkaline phosphatase ≤ 2.5 times ULN Urine protein:creatinine ratio < 1.0 OR urine protein < 1,000 mg by 24-hour urine collection INR ≤ 1.5 OR in-range INR between 2 and 3 if patient is on a stable dose of therapeutic warfarin PTT ≤ 1.5 times ULN Fasting cholesterol < 350 mg/dL Fasting triglycerides < 400 mg/dL Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Seizures allowed provided they are controlled with standard medical therapy No active infection requiring antibiotics, except uncomplicated urinary tract infection No active bleeding or pathologic conditions that carry high risk of bleeding, (e.g., known bleeding disorder, coagulopathy, or tumor involving major vessels) No serious, non-healing wound, ulcer, or bone fracture, including abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 3 months No prior underlying lesions that caused the fistula or perforation that have not been corrected No prior interstitial pneumonitis No clinically significant cardiovascular disease, including any of the following: Uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg or diastolic BP > 90 mm Hg Myocardial infarction or unstable angina within the past 6 months New York Heart Association class II-IV congestive heart failure Serious cardiac arrhythmia requiring medication Peripheral vascular disease ≥ grade 2 No cerebrovascular accident, transient ischemic attack, or subarachnoid hemorrhage within the past 6 months No uncontrolled diabetes Hemoglobin A1C < 10 No other invasive malignancies within the past 5 years, except nonmelanoma skin cancer and other specific malignancies (e.g., localized breast, head and neck, or skin cancer that completed treatment > 3 years prior to study and remain disease-free) No significant traumatic injury within the past 28 days No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies Concurrent prophylactic or therapeutic anticoagulation* (e.g., warfarin) allowed Recovered from recent surgery, radiotherapy, or chemotherapy No prior bevacizumab or other VEGF pathway-targeted therapy No prior temsirolimus, everolimus, deforolimus, sirolimus, or any other mTor/PI3K pathway-targeted therapy No prior non-cytotoxic chemotherapy for management of this disease, except hormonal therapy At least 1 week since prior hormonal therapy directed at the malignant tumor No prior therapy that contraindicates this protocol therapy No prior radiotherapy to any portion of the abdominal cavity or pelvis within the past 5 years, except treatment of endometrial cancer Prior radiotherapy for localized cancer of the breast, head and neck, or skin is allowed, provided it was completed > 3 years prior to study entry and patient remains free of recurrent or metastatic disease No prior chemotherapy for any abdominal or pelvic tumor within the past 5 years, except treatment of endometrial cancer Prior adjuvant chemotherapy for localized breast cancer allowed, provided it was completed > 3 years prior to study entry and the patient remains free of recurrent or metastatic disease Prior treatment with an anthracycline (i.e., doxorubicin and/or liposomal doxorubicin) allowed provided ejection fraction < 50% More than 28 days since prior major surgery or open biopsy More than 7 days since minor surgical procedures, fine needle aspirates, or core biopsies At least 3 weeks since prior therapy directed at the malignant tumor, including immunologic agents No concurrent major surgery No concurrent prophylactic filgrastim (G-CSF) or thrombopoietic agents No concurrent amifostine or other protective reagents

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: Treatment (bevacizumab, temsirolimus)<br>Patients receive bevacizumab IV on days 1 and 15 and temsirolimus IV on days 1, 8, 15, and 22. | Biological: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;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 |
| --- | --- | --- |
| Tumor Response | Complete and Partial Tumor Response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 | Scans are done while patient is on study therapy every other cycle for the first 6 months; then every 3 cycles thereafter; and at any other time if clinically indicated based on symptoms or physical signs suggestive of progressive disease | 
| Progression-free Survival at 6 Months | Percentage of patients who are progression-free 6 months after study entry. Progression-Free Survival is the period from study entry until disease progression, death or date of last contact. | Every other cycle for 6 months | 
| Frequency and Severity of Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 |  | Every cycle and 30 days after the last treatment, an average of 5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival | Progression-Free Survival is the period from study entry until disease progression, death or date of last contact. | Scans are done while patient is on study therapy every other cycle for the first 6 months; then every 3 cycles thereafter; and at any other time if clinically indicated based on symptoms or physical signs suggestive of progressive disease. | 
| Overall Survival | The observed length of life from entry into the study to death or the date of last contact. | From entry into the study to death or the date of last contact, up to 5 years | 
| Complete and Partial Tumor Response by RECIST 1.0 by Performance Status | Complete and Partial Tumor Response by RECIST 1.0 | Scans are done while patient is on study therapy every other cycle for the first 6 months; then every 3 cycles thereafter; and at any other time if clinically indicated based on symptoms or physical signs suggestive of progressive disease | 
| Progression-free Survival at 6 Months by Performance Status | Percentage of patients who are progression-free 6 months after study entry. Progression-Free Survival is the period from study entry until disease progression, death or date of last contact. | Every other cycle for 6 months | 
| Complete and Partial Tumor Response by RECIST 1.0 by Histologic Type | Complete and Partial Tumor Response by RECIST 1.0 | Scans are done while patient is on study therapy every other cycle for the first 6 months; then every 3 cycles thereafter; and at any other time if clinically indicated based on symptoms or physical signs suggestive of progressive disease | 
| Progression-free Survival at 6 Months by Histologic Type | Percentage of patients who are progression-free 6 months after study entry. Progression-Free Survival is the period from study entry until disease progression, death or date of last contact. | Every other cycle for 6 months | 
| Complete and Partial Tumor Response by RECIST 1.0 by Tumor Grade | Complete and Partial Tumor Response by RECIST 1.0 | Scans are done while patient is on study therapy every other cycle for the first 6 months; then every 3 cycles thereafter; and at any other time if clinically indicated based on symptoms or physical signs suggestive of progressive disease | 
| Progression-free Survival at 6 Months by Tumor Grade | Percentage of patients who are progression-free 6 months after study entry. Progression-Free Survival is the period from study entry until disease progression, death or date of last contact. | Every other cycle for 6 months |