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

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.

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