Sorafenib and Bevacizumab to Treat Ovarian, Fallopian and Peritoneal Cancer

Background:

Sorafenib is an inhibitor of wild-type and mutant proto-oncogene BRaf (B-Raf) and
proto-oncogene c-Raf (c-Raf) kinase isoforms in vitro, but it also inhibits
mitogen-activated protein kinase (p38), proto-oncogene c-kit (c-kit), vascular endothelial
growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor (PDGFR)-Beta affecting
tumor growth as well as possibly promoting apoptosis by events downstream of c-Raf.

Bevacizumab is a humanized immunoglobulin G 1 (IgG1) monoclonal antibody (MAb) that binds
all biologically active isoforms of human vascular endothelial growth factor (vascular
endothelial growth factor (VEGF), or VEGF-A) with high affinity (kd = 1.1nM).

Phase I trial of sorafenib and bevacizumab administered concurrently showed activity of the
combination in patients with refractory ovarian cancer.

Objectives:

Determine the activity and tolerability of the combination bevacizumab and sorafenib in
patients with refractory or recurrent epithelial ovarian, fallopian, or peritoneal cancer in
patients who are bevacizumab-naive or bevacizumab-resistant.

Eligibility:

Adults with histologically documented refractory or recurrent epithelial ovarian, fallopian,
or peritoneal cancer.

Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological
therapy for at least 4 weeks.

Patients must have an Eastern Cooperative Oncology Group (ECOG) of 1 or less.

Patients must have disease that is amenable to biopsy.

Patients must have not been previously treated with bevacizumab or must have progressed on
prior bevacizumab-based therapy.

Design:

Patients will be stratified on entrance to the trial based on their previous exposure to
bevacizumab to either strata A (bevacizumab-naive patients) or strata B (patients previously
treated with bevacizumab).

Patients will receive oral sorafenib 200 mg twice daily 5 out of 7 days each week and
intravenous bevacizumab 5 mg/kg every two weeks.

Tumor biopsies will be obtained from patients before treatment and six weeks into therapy.
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and fludeoxyglucose
18F-positron emission tomography (FDG-PET) will be obtained from patients before treatment,
on day 3 of treatment, and six weeks into therapy.

Patients will be evaluated for response every 8 weeks using the Response Evaluation Criteria
in Solid Tumors (RECIST) criteria.

Approximately 74 patients will be needed to achieve the objectives of the trial.

- ELIGIBILITY CRITERIA:

Histopathologically documented recurrent/refractory epithelial ovarian cancer, primary
peritoneal cancer or fallopian tube cancer from a previous biopsy verified by the
Laboratory of Pathology, National Cancer Institute (NCI).

-Recurrent/refractory disease defined as progression within 6 months of upfront
platinum-containing therapy or progression after subsequent therapy in previously relapsed
patients.

Disease amenable to percutaneous or skin biopsy as determined by an associate investigator
and a member of the interventional team.

Patient willingness to have biopsies performed.

Measurable disease defined as tumor greater than or equal to 1 cm.

Age greater than or equal to 18 years.

Life expectancy of more than 3 months.

Performance status of 0 to 1 according to the Eastern Cooperative Oncology Group (ECOG)
criteria.

Adequate organ function as defined below:

Laboratory Test Required value

- Leukocytes greater than or equal to 3,000/ microliter

- Absolute neutrophil count greater than or equal to 1,200/ microliter

- Platelets greater than or equal to 100,000/ microliter

- Total bilirubin less than or equal to 1.5 times the institutional upper limits of
normal

- Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT) and
alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) less than
or equal to 2.5 times the institutional upper limit of normal

- Creatinine less than or equal to 1.5 mg/dL

OR

- Creatinine clearance greater than or equal to 45 mL/min/1.73 m^2 for patients with
creatinine levels above institutional normal.

- Activated partial thromboplastin time (PTT) less than 1.5 times the institutional
upper limits of normal

- Prothrombin Time (PT)/ International normalized ratio (INR) less than 1.5 times the
institutional upper limits of normal

- Amylase and Lipase Less than institutional upper limits of normal

Patients must have a urine protein/creatinine ratio (UPC) less than 1.0 for enrollment.

No surgery, radiation therapy, chemotherapy, immunotherapy, biotherapy, or hormonal
therapy (exception raloxifene for bone health) within four weeks (6 weeks for mitomycin C,
carboplatin, or nitrosoureas);

No metabolically active complimentary or alternative therapy for at least 1 week, defined
as any ingested or administered chemical substances including herbal medications, but not
including acupuncture, hypnosis, meditation, or other non-chemical treatments.

No monoclonal antibody therapy for at least 6 weeks.

Patients must have recovered from any acute toxicity related to prior therapy, including
surgery. Toxicity should be less than or equal to grade 1 (as defined by Common
Terminology Criteria for Adverse Events (CTCAE v3) or returned to baseline. Peripheral
neuropathy less than or equal to grade 2 will be allowed as this patient population has
universally been treated with platinum-based chemotherapy with residual neuropathy being a
common occurrence.

No other invasive malignancies within the past two years (with the exception of
non-melanoma skin cancers, non-invasive bladder cancer, stage I endometrial cancer or
cervical cancer synchronous to the ovarian cancer diagnosis and cured by surgical
resection).

Ability to understand and sign an informed consent form.

Patients who require hematopoietic growth factor support (e.g. epogen, darbepoetin),
Non-steroidal anti-inflammatory drugs (NSAIDs), and other maintenance medications prior to
study entry will be allowed to continue their supportive therapies.

Ability to tolerate orally administered medications.

Contraception is not a consideration as these patients have all had surgical removal of
their reproductive organs. Pregnant women are excluded from this study because BAY 43-9006
and bevacizumab are agents with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with BAY 43-9006 and/or bevacizumab, breastfeeding
should be discontinued if the mother is treated with BAY 43-9006 and/or bevacizumab.

There is no limit on the number of prior regimens with which a patient has been treated.

Patients who have been treated with bevacizumab previously are eligible for the trial if
they have progressed while on bevacizumab-based therapy.

-Disease progression on bevacizumab therapy will be defined as documented increase in
disease based on imaging while the patient is receiving bevacizumab or within three months
of their last dose of bevacizumab.

Patients must be at least 6 weeks from their last dose of bevacizumab prior to being
enrolled on study.

Patients who have a healed fistula greater than 28 days prior to enrollment are eligible
(refer to section 3.2.15 for patients who have had prior bevacizumab)

EXCLUSION CRITERIA:

Serious non-healing wounds (including wounds healing by secondary intention), acute or
non-healing ulcers, or bone fractures within 3 months of enrollment.

Moderate or massive hemoptysis or surgery within 28 days of enrollment.

Ongoing treatment with any other investigational agents.

Brain metastases

- Patients with central nervous system (CNS) metastases within the past 2 years are
ineligible. Patients who have had CNS disease curatively treated and without
recurrence for 2 years may be eligible. but any CNS disease that has not undergone
curative therapy with radiation, gamma knife, and/or surgical therapy are ineligible.

- CNS imaging will not be mandated for all patients. However, if there is clinical
suspicion of CNS involvement, a contrast computed tomography (CT) or magnetic
resonance imaging (MRI) of the brain will be required.

- Patients with CNS metastases may not be on steroids for the purpose of CNS disease or
edema control.

- Patients with CNS disease must be on an anti-seizure medication and that medication
cannot be a CYPP4503A modulating agent.

Thrombotic or embolic events within the past 6 months such as a cerebrovascular accident
(including transient ischemic attacks), pulmonary embolism, unstable angina, or myocardial
infarction. Fully treated deep vein thrombosis no longer requiring anticoagulation will be
allowed.

Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure (American Heart Association (AHA) Class II
or worse), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
situations that would limit compliance with study requirements.

-Patients with evidence of active infection will become eligible for reconsideration 7
days after completing antibiotic therapy.

Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral
therapy are excluded from the study because of possible pharmacokinetic interactions with
sorafenib, bevacizumab, and/or the combination.

Hypertension defined as systolic blood pressure greater than 150 mmHg or diastolic
pressure greater than 90 mmHg despite optimal medical management.

Therapeutic anticoagulation with coumadin, heparins, or heparinoids.

Evidence of a bleeding diathesis.

History of high grade varices or arteriovenous malformations

Patients previously treated with sorafenib will not be eligible for this trial.

Fistula or bowel obstruction or perforation in the 28 days prior to enrollment.

Patients must not be taking the cytochrome p450 (CYP450) enzyme-inducing drugs phenytoin,
carbamazepine, phenobarbital, St. John's wort, or rifampin.

For patients who have been previously treated with bevacizumab, any severe toxicity
associated with bevacizumab while the patient was being treated with the agent will make
the patient ineligible for the trial. This includes bevacizumab-induced hypertensive
crisis, arterial thromboembolic events (including cardiac ischemia or cerebrovascular
ischemia or other arterial thrombosis), nephrotic syndrome, gastrointestinal perforation,
serious hemorrhage, and fistulas (unless the fistula completely resolved while the patient
was still on bevacizumab or it has been surgically corrected).