This randomized phase II trial studies paclitaxel, carboplatin, and bevacizumab or paclitaxel, carboplatin, and temsirolimus or ixabepilone, carboplatin, and bevacizumab to see how well they work in treating patients with stage III, stage IV, or recurrent endometrial cancer. Drugs used in chemotherapy, such as paclitaxel, carboplatin, and ixabepilone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known which treatment regimen is most effective in treating patients with endometrial cancer.

PRIMARY OBJECTIVES:

I. To estimate the hazard of progression or death of each of the three arms relative to that of historical controls in patients with advanced or recurrent endometrial cancer.

SECONDARY OBJECTIVES:

I. To determine the nature, frequency, and maximum degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v)3.0 for each of the three arms.

II. To estimate the distribution of the duration of overall survival for each of the three arms.

III. To estimate the proportion of patients with measurable disease who have confirmed objective tumor responses by treatment.

TERTIARY OBJECTIVES:

I. Explore the associations between select biomarkers and progression-free survival as well as secondary measures of clinical outcome (overall survival, tumor response, or disease status if possible) in the context of histologic cell type and treatment.

IA. Somatic mutations in phosphatase and tensin homolog (PTEN)/ phosphoinositide-3-kinase (PI3K) and RAS pathway members by Sequenom mutational profiling and targeted sequencing of candidate genes.

IB. Microsatellite instability by analysis of five National Cancer Institute consensus microsatellite markers (BAT25, BAT26, D2S2123, D5S346, and D17S250) using the Applied Biosystems (ABI) Prism 3100 Genetic Analyzer.

IC. Copy number alterations (gains or losses) by array comparative genomic hybridization (aCGH).

ID. Tumor expression of PTEN and class III beta-tubulin using immunohistochemistry.

IE. Concentration of vascular endothelial growth factor (VEGF) in pre-cycle 1 plasma using an enzyme-linked immunosorbent assay.

II. Explore the relationship among the various biomarkers by histologic subtype and treatment.

III. Explore which combination of biomarkers and clinical covariates optimally predicts responsiveness and resistance to the three treatment arms.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours, carboplatin IV over 30 minutes, and bevacizumab* IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients undergoing treatment post-surgery (=< 12 weeks) receive bevacizumab beginning on course 2.

ARM II: Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1 and temsirolimus* IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive temsirolimus IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients undergoing treatment post-surgery (=< 12 weeks) receive temsirolimus beginning on course 2.

ARM III: Patients receive ixabepilone IV over 1 hour, carboplatin IV over 30 minutes, and bevacizumab* IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients undergoing treatment post-surgery (=< 12 weeks) receive bevacizumab beginning on course 2.

After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Inclusion Criteria:

• Patients must have measurable stage III, measurable stage IVA, stage IVB (with or without measurable disease) or recurrent (with or without measurable disease) endometrial carcinoma

  • Histologic confirmation of the original primary tumor is required; patients with the following histologic epithelial cell types are eligible: endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.), mucinous adenocarcinoma, squamous cell carcinoma, and transitional cell carcinoma

• Measurable disease is defined by Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1); measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be >= 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes must be >= 15 mm in short axis when measured by CT or MRI

• Patients must have Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2

• Patients must not be eligible for a higher priority GOG protocol, if one exists; in general, this would refer to any active GOG Phase III protocol or Rare Tumor protocol for the same patient population

• Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl equivalent to Common Terminology Criteria (CTCAE v3.0) grade 1

• Platelets greater than or equal to 100,000/mcl

• Creatinine less than or equal to 1.5 times institutional upper limit normal (ULN), CTCAE v3.0 grade 1

• Bilirubin less than or equal to 1.5 x ULN (CTCAE v3.0 grade 1)

• Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) less than or equal to 2.5 x ULN (CTCAE v3.0 grade 1)

• Alkaline phosphatase less than or equal to 2.5 x ULN (CTCAE v3.0 grade 1)

• Urine protein creatinine (UPC) ratio must be < 1.0 gram (gm); if UPC ratio >= 1, collection of 24-hour urine measurement of urine protein is recommended (24-hour urine protein level must be < 1000 mg for patient enrollment)

  • UPC ratio of spot urine is an estimation of the 24 urine protein excretion

    • A UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm

• Prothrombin time (PT) such that international normalized ratio (INR) is =< 1.5 x ULN (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) and a partial thromboplastin time (PTT) =< 1.5 x ULN

• Fasting cholesterol less than 300 mg/dL (CTCAE v3.0 grade 1)

• Fasting triglycerides =< 2.5 x ULN (CTCAE v3.0 grade 1)

• Patients must NOT have received prior chemotherapy or targeted therapy, including chemotherapy used for radiation sensitization for treatment of endometrial carcinoma

• Patients must NOT have received prior therapy with bevacizumab or other VEGF pathway targeted therapy; patients must NOT have received prior therapy with temsirolimus, everolimus, ridaforolimus, sirolimus, or any other PI3K/ v-akt murine thymoma viral oncogene homolog 1 (AKT)/mammalian target of rapamycins (mTor) pathway targeted therapy

• Patients may have receive prior radiation therapy for treatment of endometrial carcinoma; prior radiation therapy may have included pelvic radiation therapy, extended field pelvic/para-aortic radiation therapy, and/or intravaginal brachytherapy; all radiation therapy must be completed at least 4 weeks prior to the first date of study therapy; the prior radiation field, radiation dose, number of fractions and prior radiation start and stop dates must be provided on the Fast Fact Sheet (FFS) at registration

• Patients may have received prior hormonal therapy for treatment of endometrial carcinoma; all hormonal therapy must be discontinued at least one week prior to the first date of study therapy

• Patients must have signed an approved informed consent and authorization permitting release of personal health information

Exclusion Criteria:

• Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, and other specific malignancies as noted below, are excluded if there is any evidence of other malignancy being present within the last three years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy

• Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis OTHER THAN for the treatment of endometrial cancer within the last three years are excluded; prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease

• Patients who have received prior chemotherapy for any abdominal or pelvic tumor within the last three years are excluded; patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease

• Patients with serious, non-healing wound, ulcer, or bone fracture; this includes history of abdominal/pelvic fistula, gastrointestinal perforation or intra-abdominal abscess within 3 months prior to the first date of study therapy; patients with underlying lesions that caused the fistula or perforation in the past that have not been corrected

• Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels

• Patients with history or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, seizures not controlled with standard medical therapy or any brain metastases

• Patients with clinically significant cardiovascular disease; this includes:

  • Uncontrolled hypertension, defined as systolic > 150 mm Hg or diastolic > 90 mm Hg
  • Myocardial infarction or unstable angina within 6 months of the first date of study therapy
  • New York Heart Association (NYHA) class II or greater congestive heart failure
  • History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) or cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with anti-arrhythmic medication)
  • CTCAE grade 2 or greater peripheral vascular disease.
  • History of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months of the first date of study therapy.
  • Aortic aneurysm and/or history of aortic dissection

• Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies

• Patients undergoing invasive procedures as defined below:

  • Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to the first date of bevacizumab or temsirolimus therapy
  • Major surgical procedure anticipated during the course of the study.
  • Minor surgical procedures, fine needle aspirates, or core biopsies within 7 days prior to the first date of study therapy

• Patients with known prior history of interstitial pneumonitis

• Patients with CTCAE v. 3, grade 2 or greater hypoxemia

• Patients with CTCAE v. 3, grade 2 or greater dyspnea

• Patients must not have uncontrolled diabetes, and must not have baseline hemoglobin A1C (HgbA1C) > 8

• Patients with peripheral neuropathy > CTCAE v.3, grade 1

• Patients who are pregnant or nursing