Azacitidine With Carboplatin and Paclitaxel for Newly Diagnosed Ovarian Cancer

This is a clinical trial for women with newly diagnosed ovarian cancer. The purpose of this study is to determine if the addition of a drug called azacitidine (Vidaza®)when added to carboplatin and paclitaxel will change the genetic material of the tumor so that the chemotherapy drugs work better.

The study will also determine what the maximum tolerated dose of azacitidine that may be safely used in combination with carboplatin and paclitaxel.

Ovarian cancer is a highly chemosensitive tumor with good responses to first line chemotherapy. The problem is the high rate of relapse, especially in advanced disease

Relapses are likely due to the presence of chemoresistant cells that escape from first line platinum and taxane based regimens. Therefore, outcomes may be improved by adding treatment to initial standard therapy that makes resistant cells sensitive to chemotherapy. There are multiple targeted pathways that may achieve this goal. One promising path is epigenetics.

The reasons for this trial are multifold. First, methylation pathways have been proven in tissue models to be integral to ovarian cancer pathogenesis. Second, cisplatin and azacitidine are synergistic, and therefore would be promising in combination to improve ovarian cancer outcomes by combating cisplatin resistance, which is a major cause of ovarian cancer mortality. It has been proven that azacitidine/decitabine reverses platinum resistance. Third, azacitidine has shown tolerable toxicity and promise in clinical trials to date. Ideally, ovarian cancer outcomes are likely to be improved by the addition of treatment that wipes out chemoresistant cells, thus preventing relapse.

This study is a phase I, non-randomized, dose escalation treatment study using azacitidine in combination with intravenous chemotherapy with Paclitaxel and carboplatin.

All patients will receive the chemotherapy drugs Carboplatin and Paclitaxel. Patients will then be randomized to recieve one of three different doses of Azactitidine.

• Drug: Azacitidine
  Azacitidine 20 milligrams per meter squared subcutaneous once daily for 7 days.
• Drug: Azacitidine
  Azacitidine 40 milligrams per meter squared subcutaneous once daily for 7 days.
• Drug: Azacitidine
  Azacitidine 75 milligrams per meter squared subcutaneous once daily for 7 days.

Inclusion Criteria:

• Stage III or IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer
• Appropriately signed and documented informed consent form, with documentation of the informed consent process
• Age more than 18 years old
• ECOG performance status less than or equal to 2
• Life expectancy greater than 12 months
• Adequate baseline bone marrow function: absolute neutrophils count greater than 1500 cells/microliter, platelet count greater than 100,000 cells per microliter
• Adequate liver function: bilirubin than 1.5 times the upper limit of normal. Higher levels of Bilirubin are acceptable if these can be attributed to active hemolysis or ineffective erythropoiesis. Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) levels less than or equal 2 x ULN.
• Adequate renal function: Serum creatinine levels less than or equal to 1.5 times ULN
• Patients must have ascites and be considered not candidates for upfront surgery because of disease bulk (not because of overall health).
• Women of childbearing potential must have a negative serum pregnancy test prior to azacitidine treatment.
• Women of childbearing potential should be advised to avoid becoming pregnant and men should be advised to not father a child while receiving treatment with azacitidine.

Exclusion Criteria:

• Ongoing serious infection
• Neuropathy greater than grade 2 at baseline
• Major surgery within 2 weeks prior to enrollment
• Concurrent investigational treatment, antineoplastic treatment, hormonal treatment, or radiation therapy
• Prior bone marrow transplant
• prior radiation to the pelvis
• radiation therapy for malignancy within the past 5 years
• Other malignancy within the past 5 years except non-melanoma skin cancer.
• Known or suspected hypersensitivity to azacitidine or mannitol
• Pregnant or breast feeding
• Patients with advanced malignant hepatic tumors