Brivanib Alaninate in Treating Patients With Persistent or Recurrent Cervical Cancer

PRIMARY OBJECTIVES:

I. To estimate the proportion of patients with persistent or recurrent cervical cancer, who
survive progression-free for at least 6 months and the proportion of patients who have
objective tumor response (complete or partial), treated with brivanib (brivanib alaninate).

II. To determine the nature and degree of toxicity of brivanib in this cohort of patients.

SECONDARY OBJECTIVES:

I. To estimate the progression-free survival (PFS) and overall survival (OS) of patients with
persistent or recurrent cervical cancer treated with brivanib.

TERTIARY OBJECTIVES:

I. To obtain the serum expression levels of surrogate markers of brivanib effects including
angiogenic factors (vascular endothelial growth factor [VEGF] and basic fibroblast growth
factor [bFGF]) and markers of endothelial damage (E-selectin, vascular cell adhesion molecule
1 [VCAM-1], and (intercellular adhesion molecule 1 [ICAM-1]). (exploratory) II. To determine
whether these marker expression levels alone or in combination are associated with response,
PFS, or overall survival. (exploratory)

OUTLINE:

Patients receive brivanib alaninate orally (PO) once daily (QD) on days 1-28. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

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 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 Response Evaluation Criteria In
Solid Tumors (RECIST 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

- 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 Gynecologic Oncology Group (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 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

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

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

- 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

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

- Patients must have had one prior systemic chemotherapeutic regimen for management of
advanced, metastatic, or recurrent carcinoma of the cervix; chemotherapy administered
concurrent with primary radiation (e.g.; weekly cisplatin) is not counted as a
systemic chemotherapy regimen for management of advanced, metastatic, or recurrent
disease; 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

- 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

- Non-cytotoxic (biologic or targeted) agents include (but are not limited to)
monoclonal antibodies, cytokines, and small-molecule inhibitors of signal
transduction

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

- Platelets greater than or equal to 100,000/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

- Bilirubin less than or equal to 1.5 x ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal
to 3 x ULN

- Alkaline phosphatase less than or equal to 2.5 x ULN

- Albumin greater than or equal to 2.5 g/dl

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

- Prothrombin time (PT) such that international normalized ratio (INR) is =< 1.5 x ULN;
patients on therapeutic warfarin are excluded from trial, anticoagulation with low
molecular weight heparin is allowed

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

- Patients of childbearing potential must have a negative serum pregnancy test performed
48 hours prior to study entry and 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 electrocardiogram (ECG) should be repeated if corrected QT interval
(QTc) is found to be > 450 msec; QTc must NOT be > 450 msec on both ECGs
performed during the same visit

Exclusion Criteria:

- Patients who have had prior therapy with brivanib or anti-vascular, anti-PDGFR
(platelet-derived growth factor receptor) or anti-FGFR (fibroblast growth factor
receptor) therapy

- 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; 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 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

- Patients that are on required chronic anti-platelet therapy (aspirin > 300 mg/day, or
clopidogrel greater than or equal to 75 mg/day)

- Patients with gastrointestinal bleeding or any other hemorrhage/bleeding event >=
grade 3 of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse
Events (CTCAE) within 30 days prior to study entry

- Patients with a history of poor wound healing, non-healing ulcers, or bone fractures
within the last 3 months

- Patients with uncontrolled or significant cardiovascular disease including any of the
following:

- Myocardial infarction within 12 months

- Uncontrolled angina within 12 months

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

- Uncontrolled hypertension despite anti-hypertensive therapy

- Blood pressure (BP) must be less than or equal to 140/90 at screening

- Subjects with a history of hypertension who are receiving treatment with
calcium channel blockers that are cytochrome P450 family 3, subfamily A,
polypeptide 4 (CYP3A4) inhibitors should be changed to an alternative
antihypertensive medication before study entry

- History of stroke, transient ischemic attack (TIA), or other central nervous
system (CNS) ischemic event

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

- Patients must have pre-therapy left ventricular ejection fraction (LVEF) testing
and have an ejection fraction >= institutional lower limit of normal (LLN)

- Patients with valvular heart disease >= grade 2

- Patients with a serious uncontrolled medical disorder or active infection which would
impair the ability of the subject to receive protocol therapy or whose control may be
jeopardized by the complications of this therapy

- Pre-existing thyroid abnormality with thyroid function that cannot be maintained in
the normal range with medication

- Patients with hyponatremia (sodium < 130 mEq/L)

- Patients with active/known human immunodeficiency virus (HIV), hepatitis B, or
hepatitis C; HIV-positive subjects on combination antiretroviral therapy are
ineligible

- Patients with known brain metastases

- Patients who are pregnant or nursing

- Patients with inability to swallow tablets or untreated malabsorption syndrome

- Patients with baseline serum potassium < 3.5 mmol/L (potassium supplementation may be
given to restore the serum potassium above this level prior to entry study)

- Patients on therapeutic warfarin anticoagulation are excluded

- Patients converted to anticoagulation with low molecular weight heparin will be
allowed provided the patient?s PT is such that INR is =< 1.5 x ULN