Intensity-Modulated Radiation Therapy, Cisplatin, and Bevacizumab Followed by Carboplatin and Paclitaxel in Treating Patients Who Have Undergone Surgery for Endometrial Cancer

PRIMARY OBJECTIVE:

I. To assess the treatment-related, grade 3+, non-hematologic adverse-event rate within 90
days from the start of treatment with concurrent intensity-modulated radiotherapy, cisplatin,
and bevacizumab followed by carboplatin and paclitaxel in patients with high-risk endometrial
cancer.

SECONDARY OBJECTIVES:

I. To evaluate treatment-related adverse events occurring within 1 year from the start of
treatment.

II. To evaluate all treatment-related adverse events. III. To evaluate disease-free and
overall survival. IV. To evaluate local, regional, and distant failure.

OUTLINE:

Patients undergo pelvic intensity-modulated radiotherapy (IMRT) once daily, 5 days a week,
for 5 weeks. Patients may also undergo optional nodal boost radiotherapy and/or vaginal
brachytherapy boost. Patients also receive concurrent cisplatin intravenously (IV) over 1
hour on days 1 and 29 and bevacizumab IV over 30-90 minutes on days 1, 15, and 29. Beginning
4-6 weeks after completing IMRT, cisplatin, and bevacizumab, patients receive carboplatin IV
over 1 hour and paclitaxel IV over 3 hours on day 1. Treatment with carboplatin and
paclitaxel repeats every 21 days for 4 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year,
every 6 months for 2 years, and then annually thereafter.

Inclusion Criteria:

- Histologically confirmed endometrial cancer, including 1 of the following cellular
types:

- Endometrioid endometrial adenocarcinoma

- Clear cell carcinoma

- Papillary serous adenocarcinoma

- Adenosquamous cell carcinoma

- Other adenocarcinoma variant

- No carcinosarcoma

- Meets 1 of the following criteria:

- Grade 3 carcinoma with > 50% myometrial invasion (stage IC or IIA) (all papillary
serous or clear cell carcinoma will be considered grade 3)

- Grade 2 or 3 carcinoma with any cervical stromal invasion (stage IIB)

- Known extra-uterine disease confined to the pelvis (stage III or IVA)

- Patients with stage III or IVA disease must have undergone computed
tomography (CT) scan or positron emission tomography (PET)/CT scan of the
abdomen and pelvis within the past 56 days

- Has undergone hysterectomy (i.e., total abdominal, vaginal, robotic-assisted, radical,
or laparoscopic-assisted vaginal hysterectomy) and bilateral salpingo-oophorectomy
within the past 56 days

- No positive common iliac or positive para-aortic nodal disease (defined as lymph nodes
? 2 cm in any dimension on CT scan or biopsy) or positive peritoneal cytology

- No evidence of metastatic extrauterine disease, gross or residual disease (not
including pelvic nodal disease), or distant metastases

- Zubrod performance status 0-1

- Absolute neutrophil count (ANC) ? 1,500/mm^3 (without growth factor support)

- Platelet count ? 100,000/mm^3

- Hemoglobin ? 10 g/dL (transfusion allowed)

- Total bilirubin ? 1.5 times upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ? 2 times ULN

- Serum creatinine ? 1.5 mg/dL

- Urine protein:creatinine ratio ? 0.5 OR urine protein < 1,000 mg on 24-hour urine
collection

- International normalized ratio (INR) < 1.5 (for patients treated with warfarin within
the past 14 days)

- Not nursing

- No neuropathy ? Common Terminology Criteria for Adverse Events (CTCAE) grade 1

- No ototoxicity > CTCAE grade 2

- No serious, active comorbidity, including any of the following:

- Unstable angina and/or New York Heart Association (NYHA) class II-IV congestive
heart failure requiring hospitalization within the past 12 months

- Transmural myocardial infarction within the past 12 months

- Acute bacterial or fungal infection requiring IV antibiotics

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

- Acquired immune deficiency syndrome (AIDS) based upon current Center for Disease
Control (CDC) definition (human immunodeficiency virus [HIV] testing is not
required)

- Active gastrointestinal (GI) ulcers, GI bleeding, inflammatory bowel disease, or
GI obstruction

- Inadequately controlled hypertension, defined as systolic blood pressure (BP) >
150 mm Hg and/or diastolic BP > 90 mm Hg on antihypertensive medications

- Significant vascular disease, including aortic aneurysm, aortic dissection, or
arteriovenous malformation within the past 12 months

- Serious cardiac arrhythmia on medication (well-controlled atrial fibrillation on
medication allowed)

- Serious non-healing wound, ulcer, or bone fracture

- No history of hypertensive crisis or hypertensive encephalopathy

- No stroke/cerebrovascular event within the past 12 months

- No arterial thromboembolic events, including transient ischemic attack or clinically
symptomatic peripheral artery disease within the past 12 months

- No abdominal fistula, GI perforation, or intra-abdominal abscess within the past 6
months

- No other invasive malignancies within the past 3 years other than nonmelanomatous skin
cancer

- No significant trauma within the past 28 days

- No mental status changes or bladder problems that would preclude the ability to comply
with bladder-filling instructions

- No mental or psychiatric illness that would preclude giving informed consent

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

- No prior allergic reaction to bevacizumab, cisplatin, carboplatin, or paclitaxel

- No concurrent erythropoietin, St. John's wort, therapeutic anticoagulants,
aminoglycoside antibiotics, or amifostine

- No prior organ transplantation

- No prior external-beam radiotherapy to the pelvis resulting in overlapping of
radiotherapy fields

- No prior systemic chemotherapy for uterine cancer

- Prior chemotherapy for a different cancer is allowed

- No prior therapy with anti-vascular endothelial growth factor (VEGF) compounds

- More than 28 days since prior major surgical procedure requiring open biopsy incision

- No concurrent surgery (except for vascular access device placement or procedures that
do not require significant incision)

- No concurrent warfarin at doses > 1 mg/day

- Concurrent prophylactic low molecular weight heparin allowed