A Three Arm Randomized Phase II Study of Paclitaxel/Carboplatin/Bevacizumab (NSC#704865, IND#7921), Paclitaxel/Carboplatin/Temsirolimus (NSC#683864, IND#61010) and Ixabepilone (NSC#710428, IND#59699) / Carboplatin/Bevacizumab as Initial Therapy for Measurable Stage III or IVA, Stage IVB, or Recurrent Endometrial Cancer

Inclusion Criteria:

- Histologically confirmed endometrial carcinoma, including any of the following
epithelial 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

- Stage III, IVA-B, or recurrent disease

- Refractory to curative or established therapy

- Measurable disease*, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by
chest x-ray or ≥ 10 mm by CT scan, MRI, or caliper measurement by clinical exam

- Lymph nodes must be ≥ 15 mm in short axis by CT scan or MRI

- No history or evidence of CNS disease, including primary brain tumor, seizures not
controlled with standard medical therapy, or any brain metastases

- Not eligible for a higher priority GOG protocol (any active GOG phase III protocol or
rare tumor protocol), if one exists

- GOG performance status 0-2

- ANC ≥ 1,500/mm³

- Platelets ≥ 100,000/mm³

- Creatinine ≤ 1.5 times upper limit of normal (ULN)

- Bilirubin ≤ 1.5 times ULN

- SGOT and SGPT ≤ 2.5 times ULN

- Alkaline phosphatase ≤ 2.5 times ULN

- Urine protein:creatinine ratio < 1.0 g OR < 1,000 mg by 24-hour urine collection

- INR and PTT ≤ 1.5 times ULN

- Fasting cholesterol < 300 mg/dL

- Fasting triglycerides ≤ 2.5 times ULN

- Not pregnant or nursing

- Negative pregnancy test

- No other invasive malignancies within the past 3 years, except nonmelanoma skin
cancer

- No serious, non-healing wound, ulcer, or bone fracture, including history of
abdominal/pelvic fistula, gastrointestinal perforation, or intraabdominal abscess
within the past 3 months

- No uncorrected underlying lesions that caused the fistula or perforation

- No active bleeding or pathologic conditions that carry high risk of bleeding, such as
known bleeding disorder, coagulopathy, or tumor involving major vessels

- No clinically significant cardiovascular disease, including any of the following:

- Uncontrolled hypertension, defined as systolic BP > 150 mm Hg or diastolic BP >
90 mm Hg

- Myocardial infarction or unstable angina within the past 6 months

- NYHA class II-IV congestive heart failure

- History of serious ventricular arrhythmia (i.e., ventricular tachycardia or
ventricular fibrillation), or cardiac arrhythmias requiring anti-arrhythmic
medications

- Atrial fibrillation that is well controlled with anti-arrhythmic medication
allowed

- Peripheral vascular disease ≥ CTCAE grade 2

- History of cerebrovascular accident (stroke), transient ischemic attack, or
subarachnoid hemorrhage within the past 6 months

- Aortic aneurysm and/or history of aortic dissection

- No known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human or humanized antibodies

- No significant traumatic injury within the past 28 days

- No known history of interstitial pneumonitis

- No hypoxemia ≥ grade 2 by CTCAE v.3

- No dyspnea ≥ grade 2 by CTCAE v.3

- No uncontrolled diabetes or baseline hemoglobin A1C > 8%

- No peripheral neuropathy > grade 1 by CTCAE v.3

- At least 4 weeks since prior radiation therapy (RT) for treatment of endometrial
carcinoma allowed, including pelvic RT, extended field pelvic/para-aortic RT, and/or
intravaginal brachytherapy

- More than 3 years since prior RT to any portion of the abdominal cavity or
pelvis, other than for the treatment of endometrial cancer

- More than 3 years since prior RT for localized cancer of the breast, head and
neck, or skin and no metastatic or recurrent disease

- At least 1 week since prior hormonal therapy for treatment of endometrial carcinoma

- More than 28 days since prior and no concurrent major surgical procedure or open
biopsy

- More than 7 days since prior minor surgical procedures, fine-needle aspirates, or
core biopsies

- No prior chemotherapy or target therapy (e.g., bevacizumab or other VEGF pathway
targeted therapy, temsirolimus, everolimus, ridaforolimus, sirolimus, or any other
PI3K/AKT/mTor pathway targeted therapy), including chemotherapy used for radiation
sensitization, for treatment of endometrial carcinoma

- More than 3 years since prior chemotherapy for any abdominal or pelvic tumor

- More than 3 years since prior adjuvant chemotherapy for localized breast cancer
and no metastatic or recurrent disease

- No prior cancer treatment that contraindicates this protocol therapy

- No concurrent treatment with potent CYP3A4 inhibitors and agents that have CYP3A4
induction potential (arms II and III)

- No concurrent sunitinib malate during temsirolimus treatment (arm II)

- No concurrent amifostine or other protective agents