Study closed to accrual due unfavorable interim analysis

This multi-institutional phase I/II clinical trial will test the tolerability and efficacy of the combination sorafenib and topotecan in patients with recurrent ovarian cancer, which is platinum-resistant (recurrence within 6 months from completing platinum based therapy) or refractory (progressive disease during platinum based therapy).

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.

Duration of Study

Combined Phase I/Phase II safety data