Paclitaxel and Carboplatin With Or Without Sorafenib In The First-Line Treatment Of Patients With Ovarian Cancer

A Randomized Phase II Study of Paclitaxel/Carboplatin With or Without Sorafenib in the First-Line Treatment of Patients With Stage III/IV Epithelial Ovarian Cancer

This trial will compare the efficacy and toxicity of standard first-line chemotherapy alone vs. standard chemotherapy plus sorafenib in patients with stage III/IV ovarian cancer following cytoreductive surgery. Patients with residual large volume disease and/or bowel involvement will be excluded, to minimize the risk of bowel perforation.

All patients must be at least 4 weeks from cytoreductive surgery before starting treatment. Patients will be randomized to receive treatment with either paclitaxel/carboplatin + sorafenib or paclitaxel/carboplatin. Paclitaxel/carboplatin will be repeated every 21 days for a maximum of 6 cycles. Patients with objective response/stable disease after completing 6 courses of chemotherapy will continue sorafenib until disease progression or for a total of 12 months.

- Regimen A:

Paclitaxel 175 mg/m2 1-3 hour IV infusion, Day 1

Carboplatin AUC 6 infused over 20 minutes IV, Day 1

Sorafenib 400mg PO bid

- Regimen B:

Paclitaxel 175mg/m2, 1-3 hour IV infusion, Day 1

Carboplatin AUC 6.0, 20 minute IV infusion, Day 1

Inclusion Criteria:

1. Histologically confirmed, stage III or IV epithelial ovarian carcinoma

2. No previous treatment with chemotherapy or radiation therapy

3. All patients must have undergone cytoreductive surgery, with the

   following results:

   1. No residual tumor nodule > 3cm

   2. No residual tumor involvement of the bowel (ie. invasion into bowel

      wall)

   3. No residual intestinal obstruction

4. Measurable or evaluable disease. Patients with elevated CA-125 levels

   and/or evaluable disease per RECIST criteria are eligible.

5. ECOG performance status 0 or 1.

6. ANC ≥ 1500/µL, platelets ≥ 100,000/µL, hemoglobin ≥ 9.0 g/dL.

7. Total bilirubin ≤ 1.5 x upper limits of normal (ULN), ALT and AST ≤ 2.5 x

   ULN (≤ 5 x ULN for patients with liver metastases)

8. Serum creatinine _ 1.5 x ULN

9. INR < 1.5 or a PT/PTT within normal limits. Patients receiving anticoagulation

   treatment with an agent such as warfarin or heparin may be

   allowed to participate. For patients on warfarin, the INR may be > 1.5,

   and should be measured prior to initiation of sorafenib and monitored at

   least weekly until INR is stable in the desired therapeutic range.

10. Women of childbearing potential must have a negative serum pregnancy

    test performed within 7 days prior to start of treatment.

11. Patients must be able to understand the nature of this study and give

written informed consent.

Exclusion Criteria:

1. Age < 18 years

2. Active cardiac disease, including: A) congestive heart failure > class II

   NYHA , B) unstable angina or onset of angina within last 3 months, C) myocardial infarction within 6 months

3. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

4. Patients with CNS metastases. Patients with neurological symptoms

   must undergo a CT scan/MRI of the brain to exclude brain metastasis.

5. Uncontrolled hypertension defined as systolic blood pressure > 150mmHg or diastolic pressure > 90mmHg, despite optimal medical management

6. Known HIV, chronic hepatitis B or chronic hepatitis C infections

7. Women who are pregnant or lactating. Women of childbearing potential

   must agree to use adequate contraception from time of study entry until

   at least 3 months after the last administration of study drug.

8. Active clinically serious infection (> grade 2)

9. Thrombotic or embolic events such as cerebral vascular accident

   including transient ischemic attacks within the last 6 months.

10. Pulmonary hemorrhage/bleeding event ≥ grade 2 within 4 weeks of

    starting treatment.

11. Any other hemorrhage/bleeding event ≥ grade 3 within 4 weeks of

    starting treatment

12. Serious non-healing wound, ulcer, or bone fracture

13. Evidence of history of bleeding diathesis or coagulopathy

14. Major surgery, open biopsy, or significant traumatic injury within 4 weeks

    of starting treatment.

15. Any condition that impairs the ability to swallow whole pills

16. Patients with any type of malabsorption

17. Known or suspected allergy to any of the agents used in this treatment

18. Use of St. John's Wort or rifampin