Paclitaxel, Carboplatin, and Bevacizumab or Paclitaxel, Carboplatin, and Temsirolimus or Ixabepilone, Carboplatin, and Bevacizumab in Treating Patients With Stage III, Stage IV, 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