Official Title: “Phase I/II Trial of Sequential Azacitidine and Valproic Acid Plus Carboplatin in the Treatment of Patients With Platinum Resistant Epithelial Ovarian Cancer”

Primary Objectives:

1. To determine acceptable dosages of valproic acid and carboplatin in a regimen of sequential azacitidine and valproic acid plus carboplatin in the treatment of patients with advanced solid tumor during the phase 1 part.

2. To assess objective response rates in platinum resistant epithelial ovarian cancer patients treated with sequential azacitidine and valproic acid plus carboplatin during the phase 2 part.

3. To determine whether DNA methylation, and histone H3 and H4 acetylation of tumor tissue and peripheral blood monocytes are able to predict objective responses.

Secondary Objectives:

1. To describe toxicity profile.

2. To assess progression-free survival.

3. To assess overall survival.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study

Study Primary Completion Date: August 2012

The Study Drugs:

Researchers want to see if the combination of azacitidine, carboplatin, and valproic may work better together to control advanced cancer.

Azacitidine is designed to activate (turn on) certain genes in cancer cells whose job is to fight tumors, which may also make azacitidine work better with other anti-tumor drugs.

Carboplatin is designed to block the growth of cancer cells by stopping cell division, which may cause the cells to die.

Valproic Acid is an anti-seizure medication that may also have cancer-fighting abilities.

This drug may be able to activate tumor-fighting genes, causing cancer cells to die.

Screening Tests:

Before you can start treatment on this study, you will have what are called screening tests.

The below tests/procedures (to be done within 28 days before the start of treatment) will help the study doctor decide if you are eligible to take part in this study. - You will have a computed tomography (CT) scan or a magnetic resonance imaging (MRI) scan to measure the size and locations of the cancer. - You will have a chest x-ray. - You will have an electrocardiogram (ECG -- a test to measure the electrical activity of the heart). - You will have a physical exam, including measurement your vital signs (heart rate, breathing rate, temperature, and blood pressure), height, and weight. - You will have a routine urine test. - Your medical history will be recorded. - Women who are able to have children must have a negative blood (about 1 teaspoon) pregnancy test.

Phase 1 (Dose Escalation) and Phase 2 (Treatment):

Participants will be enrolled on phase 1 of the study in groups of 3. Each group will receive a different combination of the study drugs. If the first group of 3 tolerates the study drug combination well, the next group of 3 will be enrolled, and their dose(s) of carboplatin and/or valproic acid will be higher than the last group. Each new group will get a higher dose of carboplatin and/or valproic acid. If 1 of the 3 participants has a serious side effect at a certain dose level, 3 more participants may be added at that dose level to check the safety of the combination. If no more participants at that dose level have serious side effects, the next dose level will be tested. However, if a second participant has a serious side effect, then the dose level before that one will be considered the maximum tolerated dose (MTD). Once the MTD is found, participants will be enrolled on Phase 2 of the study.

Participants enrolled on phase 2 will be given the MTD level of the study drug combination.

Participants on both phases will have the same treatment schedule and study tests performed.

The only difference between phase 1 and phase 2 is the dose level of the study drug combination being given. The phase you are enrolled on will depend on when you enroll in the study.

Study Treatment:

If you are found to be eligible to take part in this study, you will begin receiving the study treatment on a 28-day treatment cycle.

On day 1 of each cycle, you will receive an injection of azacitidine just under the skin or by vein over 30 minutes once a day for 5 days in a row.

On day 3 and Day 10 of each cycle, you will receive carboplatin by vein over 60 minutes.

On days 5-11 of each cycle, you will take valproic acid by mouth once a day with or without food.

On day 12 of each cycle, you may receive an injection of NeulastaTM (pegfilgrastim) just under the skin, depending on whether the study doctor thinks it is needed to help boost your white blood cell count.

On days 13-28 of each cycle, you will have a rest period from the study drugs before you begin a new 28-day cycle of treatment.

Study Visits:

At certain time points, you will have the following tests/procedure performed during study visits:

On day 5 and Day 11 of cycles 1-3, you will have about 1 tablespoon of blood drawn before treatment for molecular marker studies. These tests will be performed to look for a link between your genetic characteristics and how you respond to the study drug treatment.

Within the last 72 hours (3 days) of each cycle, you will have blood drawn (about 1 tablespoon) and urine collected for routine tests. After the start of each cycle, you will have blood drawn (about 1 tablespoon) once weekly for routine tests.

Within 7 days before starting each new cycle, you will be evaluated to see if you may be experiencing any side effects.

After the end of the first cycle and then every 2 cycles (about every 8 weeks), you will have an x-ray and either a CT scan or an MRI scan to re-evaluate the cancer.

Length of Study:

You will continue to receive treatment on this study, as long as the disease does not get worse and you do not experience any intolerable side effects.

End-of-Treatment Visit:

Once treatment has ended for any reason, you will come back for an end-of-treatment visit to have the following tests/procedures performed: - You will have a complete physical exam. - You will have urine collected and blood drawn (about 1 tablespoon) for routine tests. - You may have a CT scan or an MRI scan to remeasure and re-evaluate the cancer.

Follow-Up:

The disease status will be followed-up for as long as possible after you complete treatment on this study. You will either be contacted by phone or asked to come to the clinic for a routine visit once every 8 weeks. You will have a CT or MRI scan once every 12 weeks (or until another anticancer therapy has been started) to re-evaluate the cancer. If you receive a phone call, it should last about 5-10 minutes each time.

This is an investigational study. Both of the study drugs are FDA approved and commercially available. Azacitidine is FDA approved to treat myelodysplasia. Carboplatin is FDA approved to treat ovarian cancer and other types of cancer. Valproic acid is FDA approved as an anti-seizure medication. At this time, their use together in this study is being used for research purposes only.

Up to 50 patients will take part in this study. All will be enrolled at M. D. Anderson.

Intervention(s) in this Clinical Trial

• Drug: Azacitidine
  • 75 mg/m^2 Subcutaneous Injection or IV Daily x 5 Days
• Drug: Valproic Acid
  • 40 mg/kg PO Daily x 7 days
• Drug: Carboplatin
  • AUC 2 IV Daily Over 60 Minutes

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Azacitidine + Valproic Acid + Carboplatin

Primary Measures

• To find out if giving azacitidine with valproic acid plus carboplatin can help control advanced cancer.
  • Time Frame: 5 Years
    Safety Issue?: Yes

Inclusion Criteria:

• 1. Patient has histologically or cytologically confirmed diagnosis of advanced solid tumor (that has progressed following standard therapy or for whom, in the opinion of the investigator, no standard effective therapy is available) during the phase I study. Only patients who have platinum resistant epithelial carcinoma of the ovary, fallopian tube or primary peritoneal carcinoma are enrolled onto the phase II study.
• According to standard GOG criteria platinum resistant is defined to have had a disease-free interval of shorter than 6 months following platinum treatment.
• 2. Patient has measurable or evaluable disease by radiological imaging techniques with documented progression within 1 month before study entry or disease that has not responded to treatment. (Pleural effusions, ascites, osseous metastasis, elevation of tumor marker and lesions located in previously irradiated areas are not considered measurable).
• 3. Patient is willing to comply with study procedures to have blood collections for correlative studies.
• 4. Patient has an ECOG performance status of 0-2.
• 5. Patient must be informed of the investigational nature of this study and must sign and give written IRB approved informed consent in accordance with institutional guidelines.
• 6. If patient is of child-bearing potential, she or he has agreed to practice an effective method of birth control during the study and up to 3 months after the last treatment.
• 7. Patient has adequate liver and renal function: serum albumin =/>3.0 g/dL; serum bilirubin =/<2.0 mg/dL; ALT=/<3x upper limit of normal (uln); and serum creatinine =/<
• 2.0 mg/dL or a calculated creatinine clearance of at least 40 ml/min.
• 8. Patient has adequate bone marrow reserve. ANC=/>1,500/ul, Platelet count
• =/>100,000/ul, and Hemoglobin =/>9.0g/dL.

Exclusion Criteria:

• 1. Any concurrent chemotherapy.
• 2. Underlying medical condition that might be aggravated by treatment or that cannot be controlled, such as active uncontrolled serious infection and cardiac dysfunction.
• 3. Medical and psychiatric problems of sufficient severity to limit full compliance with the study or expose patients to undue risk.
• 4. Known hypersensitivity to azacitidine, valproic acid, carboplatin or their analogs.
• 5. Failure to recover from any prior surgery within 4 weeks of study entry.
• 6. Pregnant or lactating.
• 7. Any treatment specific for tumor control within 3 weeks of dosing with study drugs (within 2 weeks if given weekly or within 6 weeks for nitrosoureas or mitomycin C) or failure to recover from the toxic effect of any of these therapies prior to study entry. Any investigational drug within 30 days of first day of dosing.
• 8. Any signs of intestinal obstruction interfering with nutrition or oral intake.
• 9. History of CNS metastasis unless the patient has had surgery or radiation, and does not require oral or intravenous corticosteroids or anticonvulsants.
• 10. Advanced malignant hepatic tumors that are defined as the total hepatic metastases more than 25% of hepatic parenchyma.
• 11. History of high dose chemotherapy for ovarian cancer in phase II study. High dose chemotherapy is defined as the intensity and/or the density of a chemotherapeutic agent that are beyond standard of care for ovarian cancer treatment.
• 12. History of prior malignancy except for adequately treated carcinoma in situ of the uterine cervix, basal cell or squamous cell skin cancer, or other cancer for which the patient has been disease free for at least two years in phase II study.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: M.D. Anderson Cancer Center

Overall Clinical Trial Officials and Contacts

Siqing Fu, MD, PhD Principal Investigator U.T.M.D. Anderson Cancer Center  

Overall Contact: Siqing Fu, MD, PhD 713-792-9669 

Information obtained from ClinicalTrials.gov on January 08, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00529022

Study ID Number: 2007-0030

ClinicalTrials.gov Identifier: NCT00529022

Health Authority: United States: Institutional Review Board

The University of Texas M.D.Anderson Cancer Center