Sorafenib + Topotecan for Platinum-Resistant Recurrent Ovarian Cancer

OUTLINE: This is a multi-center study.

- Topotecan: 4mg/m2 weekly, 3 weeks on and one week off.

- Sorafenib: Assigned cohort dose for phase I (up to 12 patients) Maximum tolerated dose
for phase II (21 total patients)

Cycles will consist of 4 weeks (28 days) with disease evaluations every 8 weeks.

Non-PD and acceptable toxicity: Patients will continue protocol therapy PD or unacceptable
toxicity: Patients will discontinue protocol therapy

ECOG performance status 0-1

Life expectancy: Three (3) months

Hematopoietic:

- White blood cell count (WBC) > 3 K/mm3

- Hemoglobin (Hgb) > 9 g/dL

- Platelets > 100 K/mm3

- Absolute neutrophil count (ANC) > 1.5 K/mm3

- INR < 1.5 or a PTT within normal limits. NOTE: Patients receiving anti-coagulation
treatment with an agent such as warfarin or heparin may be allowed to participate.

- No evidence or history of bleeding diathesis or coagulopathy.

Hepatic:

- Bilirubin < 1.5 x ULN

- Aspartate aminotransferase (AST, SGOT) < 2.5 x ULN

- Alanine aminotransferase (ALT, SGPT) < 2.5 x ULN

- Alkaline phosphate < 2.5 x ULN

Renal:

- Creatinine < 1.5 x ULN

Cardiovascular:

- No history of myocardial infarction or angina pectoris or angina equivalent within 6
months prior to registration for protocol therapy (the patient may not be on
anti-anginal or anti-arrhythmic medications), or have uncontrolled hypertension or
congestive heart failure > class II NYHA

Pulmonary:

- No thrombolic or embolic events such as a cerebrovascular accident, including transient
ischemic attacks within the past 6 months.

- No pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 28 days prior to
registration for protocol therapy.

- No non-pulmonary hemorrhage/bleeding event > CTCAE Grade 3 within 28 days prior to
registration for protocol therapy.

Inclusion Criteria:

- Have histologically-confirmed epithelial ovarian cancer, primary peritoneal
carcinomatosis or fallopian tube cancer. Enrollment of patients with clear cell
histology is encouraged.

- Have measurable disease according to RECIST or detectable disease by 1) CA-125 at
least twice the ULN within 14 days prior to registration for protocol therapy; 2)
Ascites and/or pleural effusion attributed to tumor; 3) solid and/or cystic
abnormalities on radiographic imaging that do not meet RECIST definitions for target
lesions.

- Have failed at least one prior platinum based chemotherapeutic regimen.

- No more than 3 prior treatment regimens for epithelial ovarian cancer.

- Prior radiation therapy is allowed to < 25% of the bone marrow.

- Be at least 4 weeks since last anti-cancer treatment, radiation or surgery at the
time of registration for protocol therapy.

- No active cancer in addition to the epithelial ovarian cancer within the last 5
years, with the exception of: superficial skin cancer (basal cell or squamous cell
skin carcinoma; carcinoma in situ of the cervix; Stage I endometrial cancer with less
than 50% invasion of the myometrium, or other adequately treated Stage I or II cancer
in complete remission.

- Age > 18 years at the time of consent

- Written informed consent and HIPAA authorization for release of personal health
information.

- Females of childbearing potential must be willing to use an effective method of
contraception (hormonal or barrier method of birth control; abstinence) from the time
consent is signed until 90 days after treatment discontinuation

- Females of childbearing potential must have a negative pregnancy test within 7 days
prior to being registered for protocol therapy.

Exclusion Criteria:

- No known or suspected allergy to sorafenib or any agent given in the course of this
trial.

- No prior treatment with anti-angiogenesis therapy.

- No active CNS metastases.

- No treatment with any investigational agent within 30 days prior to being registered
for protocol therapy.

- No concurrent combination anti-retroviral therapy for the treatment of
immunodeficiency.

- No clinically significant infections requiring antibiotic treatment.

- No evidence of bowel obstruction, malabsorption, or other contraindication to oral
medication.

- No serious non-healing wound, ulcer, or bone fracture.

- No major surgery, open biopsy or significant traumatic injury within 28 days of
registration for protocol therapy.

- No use of St. John's Wort or rifampin (rifampicin) while on protocol therapy.

- No condition that impairs patient's ability to swallow whole pills.