A Phase II Evaluation of Brivanib (BMS582664, IND #108417) in the Treatment of Persistent or Recurrent Carcinoma of the Cervix (BMS Study CA182-048)

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Patients must have persistent or recurrent squamous cell carcinoma, adenosquamous
carcinoma, adenocarcinoma, or non-squamous cell carcinoma of the cervix with
documented disease progression (disease not amenable to curative therapy)

- Histologic confirmation of the original primary tumor is required via the
pathology report

- All patients must have measurable disease, defined by RECIST 1.1 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 CT, 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

- Patient must have at least one "target lesion" to be used to assess response on this
protocol as defined by RECIST 1.1

- Tumors within a previously irradiated field will be designated as "non-target"
lesions unless progression is documented or a biopsy is obtained to confirm
persistence at least 90 days following completion of radiation therapy

- 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

- Patients must have had one prior systemic chemotherapeutic regimen for management of
advanced, metastatic, or recurrent carcinoma of the cervix

- Chemotherapy administered in conjunction with primary radiation as a
radio-sensitizer is not counted as a systemic chemotherapy regimen

- Adjuvant chemotherapy given following the completion of radiation therapy (or
concurrent chemotherapy and radiation therapy) is not counted as a systemic
chemotherapy regimen for management of advanced, metastatic, or recurrent
disease (e.g.; paclitaxel and carboplatin for up to 4 cycles)

- Patients are allowed to receive, but are not required to receive, one additional
cytotoxic regimen for management of recurrent or persistent disease according to
the following definition:

- Due to the novel nature of biologic compounds, patients are encouraged to
enroll on second-line non-cytotoxic studies prior to receiving additional
cytotoxic therapy

- Patients must have NOT received any non-cytotoxic (biologic or targeted)
agents as part of their primary treatment or for management of recurrent or
persistent disease

- No known brain metastases

PATIENT CHARACTERISTICS:

- Patients who have received one prior regimen must have a GOG performance status of 0,
1, or 2

- Patients who have received two prior regimens must have a GOG performance status
of 0 or 1

- Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl

- Platelets greater than or equal to100,000/mcl

- Hemoglobin > 9 g/dL

- Creatinine less than or equal to 1.5 x institutional upper limit of normal (ULN)

- Urinalysis needs to be assessed at baseline and proteinuria must be less than or
equal to 2+ by dipstick

- If the urine dipstick is > 2+, a 24-hour protein level can be done, as
clinically indicated by the investigator

- The 24-hour protein level must be less than or equal to 3.5 g/24 hours

- AST and ALT less than or equal to 3 x ULN

- Bilirubin less than or equal to 1.5 x ULN

- Alkaline phosphatase less than or equal to 2.5 x ULN

- Albumin greater than or equal to 2.5 g/dL

- PT such that international normalized ratio (INR) is < 1.5 x ULN

- No baseline serum potassium < 3.5 mmol/L (potassium supplementation may be given to
restore the serum potassium above this level prior to entry study)

- Neuropathy (sensory and motor) less than or equal to grade 1

- Patients should be free of active infection requiring antibiotics (with the exception
of uncomplicated UTI)

- Not pregnant or nursing

- Patients of childbearing potential must have a negative serum pregnancy test
performed 48 hours prior to study entry

- Patients must be practicing an effective form of contraception during the study and
for at least 3 months after receiving the final treatment of brivanib

- All patients must have a baseline electrocardiogram completed prior to study entry

- Baseline ECG should be repeated if QTc is found to be > 450 msec

- QTc must NOT be > 450 msec on both ECGs performed during the same visit

- Patients with a history of other invasive malignancies, with the exception of
non-melanoma skin cancer and other specific malignancies, are excluded if there is
any evidence of the other malignancy being present within the last three years

- No gastrointestinal bleeding or any other hemorrhage/bleeding event > grade 3 of the
NCI CTCAE within 30 days prior to study entry

- No poor wound healing, non-healing ulcers, or bone fractures within the last 3 months

- No uncontrolled or significant cardiovascular disease including any of the following:

- Myocardial infarction within 12 months

- Uncontrolled angina within 12 months

- New York Heart Association (NYHA) class III-IV congestive heart failure

- Uncontrolled hypertension despite anti-hypertensive therapy

- BP must be less than or equal to 140/90 at screening

- Patients with a history of hypertension who are receiving treatment with
calcium channel blockers that are CYP3A4 inhibitors should be changed to an
alternative antihypertensive medication before study entry

- History of stroke, TIA, or other CNS ischemic event

- Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers
or digoxin

- Patients must have pre-therapy LVEF testing and have an ejection fraction >
institutional LLN

- Patients with valvular heart disease > grade 2

- No serious uncontrolled medical disorder or active infection that would impair the
ability of the subject to receive protocol therapy or whose control may be
jeopardized by the complications of this therapy

- No pre-existing thyroid abnormality with thyroid function that cannot be maintained
in the normal range with medication

- No hyponatremia (sodium < 130 mEq/L)

- No active/known HIV, hepatitis B, or hepatitis C

- No inability to swallow tablets or untreated malabsorption syndrome

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from effects of recent surgery, radiotherapy, or chemotherapy

- At least 4 weeks must have elapsed from the time of any major surgical procedure

- Any hormonal therapy directed at the malignant tumor must be discontinued at least
one week prior to registration

- Any other prior therapy directed at the malignant tumor, including chemotherapy and
immunologic agents, must be discontinued at least three weeks prior to registration

- Any prior radiation therapy must be completed at least 4 weeks prior to registration

- Patients on therapeutic warfarin anticoagulation are excluded

- Anticoagulation with low molecular weight heparin is allowed provided the
patient's PT is such that international normalized ratio (INR) is < 1.5 x ULN

- No prior therapy with brivanib, anti-vascular, anti-PDGFR (platelet-derived growth
factor receptor), or anti-FGFR (fibroblast growth factor receptor) therapy

- Patients are 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 cervical 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 OTHER
THAN for the treatment of cervical cancer 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

- No patients that are on required chronic anti-platelet therapy (aspirin > 300 mg/day,
or clopidogrel greater than or equal to 75 mg/day)

- Patients may NOT receive amifostine or other protective reagents