Symptoms and General Pathology

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Tretinoin

Azacitidine

Decitabine

Valproic Acid

Antimetabolites

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Keratolytic Agents

Neurotransmitter Agents

Daily for 7 days, Valproic acid (VPA) starting dose 75 mg/m\^2 subcutaneously in combination with 5-azacytidine (5-aza) 50 mg/kg orally; and all-trans retinoic acid (ATRA) 45 mg/m\^2 orally daily (in two divided doses) for 5 days starting on day 3.

Start at 75 mg/m\^2 subcutaneously daily for 7 days.

5-Azacytidine (5-aza)

50 mg/kg daily by mouth for 7 days, same days as 5-aza.

45 mg/m\^2 orally daily (in two divided doses) for 5 days starting on day 3 of the administration of 5-aza and VPA.

All-Trans Retinoic Acid (ATRA)

Guillermo Garcia-Manero, MD

5-aza is a chemotherapy drug with activity in leukemia and myelodysplastic syndromes (MDS). Researchers hope that valproic acid (VPA) and all-trans retinoic acid (ATRA)will increase the effects of 5-aza. The goal of this clinical research study is to find the highest safe dose of valproic acid (VPA) that can be given in combination with 5-azacytidine (5-aza) and all-trans retinoic acid (ATRA) in the treatment of AML and MDS. The safety and effectiveness of this combination therapy will also be studied.

Additional blood and bone marrow samples will be requested. These samples will be used to evaluate the effect of the treatment on leukemic cells. In addition, any leftover blood and bone marrow samples that are collected at the start of the study and during the regularly scheduled evaluations to be sent for research studies. The research studies will examine changes in the blood and bone marrow cells that might help explain the causes of leukemia and MDS and how the combination of 5-aza, VPA, and ATRA works.

Recent studies have shown synergy between demethylating agents and histone deacetylase inhibitors. In my laboratory, we have developed in vitro models using HL-60 and MOLT4 leukemic cells to study the effects of the combination of decitabine (a 5-azacytidine analogue) and valproic acid. Valproic acid is an antiepileptic agent with histone deacetylase inhibitory capacity. These results indicate that the addition of valproic acid to decitabine has an additive effect on growth inhibition, induction of apoptosis, induction of p57KIP2 and p21CIP1 expression independent of cell cycle arrest. These results were dependent on the dose and duration of treatment but not on the sequence used. Based on this data, we developed a phase I/II study of the combination of decitabine and valproic acid (2003-0314) in patients with leukemia that has shown that valproic acid can be safely administered up to doses of 50 mg/kg orally for 10 days in combination with decitabine, and that this combination has significant activity in patients with relapsed/refractory AML and MDS. All-trans retinoic acid (ATRA) is a biological agent that has been shown to induce cell differentiation in leukemia cell lines and has significant clinical activity in acute promyelocytic leukemia with minimal toxicity. In vitro, the combination of ATRA with either a hypomethylating agent or a histone deacetylase inhibitor has been shown to restore ATRA sensitivity in resistant cells. More recently, a German group has reported that the combination of valproic acid and ATRA has activity in patients with MDS and an excellent toxicity profile. 5-azacytidine is a nucleoside analogue with hypomethylating activity that has been shown in a randomized study to benefit patients with MDS, including an improvement in quality of life. Based on this data, this agent was recently approved by the FDA for its use in patients with MDS, and has become the first line agent for patients with MDS that required therapy.

The objectives of the clinical trial are the following:

* To determine the maximal tolerated dose of valproic acid (VPA) in combination with 5-azacytidine (5-aza) and all-trans retinoic acid.
* To determine the clinical activity of the combination of 5-azacytidine, valproic acid and all-trans retinoic acid in patients with AML and MDS.
* To determine the in vivo molecular and biological effects of this combination. These will include analysis of changes in Deoxyribonucleic acid (DNA) methylation, histone modifications, and gene expression.

Phase II 5-Azacytidine Plus VPA Plus ATRA

Phase II Study of the Combination of 5-azacytidine With Valproic Acid and All-trans Retinoic Acid in Patients With High Risk Myelodysplastic Syndrome and Acute Myelogenous Leukemia

Clinical activity of combination defined as: Complete Response (CR), bone marrow with 5% or fewer blasts and peripheral blood count with an absolute neutrophil count of 10\^9/L or more and platelet count of 100x10\^9 or more; Complete response without platelets (CRp), a complete response except for a platelet count less than 100x10\^9 and transfusion independent; and Bone Marrow (BM) Response, bone marrow blast of 5% or less but without meeting the peripheral blood count criteria for (CR) or (CRp).

Celgene Corporation

M.D. Anderson Cancer Center

VPA + 5-aza + ATRA

Age Continuous

Sex: Female, Male

United States

Region of Enrollment

Guillermo Garcia-Manero, MD / Associate Professor

Number of Participants With Response

Overall Study

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Patient takes placebo capsule 3 times a day by mouth for 10 weeks. Patient contacted by phone to assess tolerance and instruction to increase dose. Questionnaires completed at baseline, weeks 2, 6, and 10. Patient given a pill diary to record the time each dose taken. Patient completes daily diary of drainage with the date and amount of fluid drained each day at home. Drained fluid from the day before brought to each clinic visit to give to the research team.

Patients initially receive daily oral VPA 15 mg/kg/day divided in three doses. If patient tolerates the reduced dose for 10 consecutive days, then the VPA dose will increase to 30 mg/kg/day divided into three doses. Patients treated for 10 weeks. Questionnaires completed at baseline, weeks 2, 6, and 10. Patient given a pill diary to record the time each dose taken. Patient completes daily diary of drainage with the date and amount of fluid drained each day at home. Drained fluid from the day before brought to each clinic visit to give to the research team.

Patient takes placebo capsule 3 times a day by mouth for 10 weeks.

Placebo

Patients initially receive daily oral VPA 15 mg/kg/day divided in three doses. If patient tolerates the reduced dose for 10 consecutive days, then the VPA dose will increase to 30 mg/kg/day divided into three doses. Patients treated for 10 weeks.

Valproic Acid (VPA)

Questionnaires completed at baseline, weeks 2, 6, and 10.

Questionnaires

Patient given a pill diary to record the time each dose taken.

Pill Diary

Patient completes daily diary of drainage with the date and amount of fluid drained each day at home. Drained fluid from the day before brought to each clinic visit to give to the research team.

Drainage Diary

Wendy A. Woodward, MD, PHD

The goal of this clinical research study is to learn if receiving valproic acid (VPA) compared to a placebo can reduce the amount of time you will need to have an indwelling pleural catheter compared to the standard of care, which involves using an indwelling pleural catheter alone.

VPA is designed to stop cancer cells from dividing and maturing. This may cause the cancer cells to become less malignant and cause less pleural fluid production.

A placebo is not a drug. It looks like the study drug but is not designed to treat any disease or illness. It is designed to be compared with a study drug to learn if the study drug has any real effect.

Baseline Fluid Collection:

Before receiving the study drug or the placebo, pleural fluid will be drained from your catheter to be compared to fluid collected later in the study.

Study Groups:

You will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups.

Group 1 will take a placebo 3 times a day for 10 weeks while an indwelling pleural catheter drains pleural fluid.

If you are in Group 2, you will take VPA 3 times a day for a total of 10 weeks while an indwelling pleural catheter drains pleural fluid.

Study Drug Administration:

Within 48 hours of collection of baseline fluid, all study participants will take either placebo or VPA capsules 3 times a day by mouth with food. If you tolerate the starting dose well and the study doctor thinks it is in your best interest, your dose level will be doubled. You may be contacted at a later time by telephone to discuss how you are doing with the medicine. If your doctor feels your dose should be doubled, he/she will talk to you about it at this time.

Neither you nor the study staff will know if you are receiving the study drug or the placebo. However, if needed for your safety, the study staff will be able to find out what you are receiving.

You will be given a pill diary to record the time you take each dose. You will need to bring the diary with you to every clinic visit.

The fluid drained from the catheter will be collected and studied to see if the how the VPA is working and how it may affect the time you will need to have an indwelling pleural catheter.

You will also be asked to keep a daily diary of drainage with the date and amount of fluid drained each day at home. You will bring the drained fluid from the day before to each clinic visit to give to the research team. You will be given special containers to store the drained fluid. You will only save fluid from the day before each clinic visit. On the other days you will write down the amount of drained fluid that was collected, then you can throw away the fluid. You must bring the daily drainage diary to each clinic visit.

Study Visits:

At Weeks 2, 6, and 10 while you are receiving the study drug:

* You will have a complete physical exam including weight and vital signs and a medical history.
* You will complete the same questionnaires that you completed at screening.
* Your performance status will be recorded.
* Blood (about 2 tablespoons) will be drawn for routine tests.
* You will have a chest X-ray to check the status of the disease.

At Week 10 only, you will have a computed tomography (CT) scan of the chest to check the status of the disease.

Length of Study:

You will be taken off study after the indwelling pleural catheter has been removed. You will no longer be able to take part in this study if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions. Your active participation in this study will be over after Week 10.

Follow-Up Medical Record Review:

After the 10 week visit the study personnel will continue to review your medical record to learn when the indwelling pleural catheter was removed. Your medical record information will continue to be reviewed for up to 5 years.

This is an investigational study. VPA is FDA approved and commercially available for the treatment of epileptic seizures and mania in bipolar disorder. VPA use in patients using pleural catheters is for research purposes only.

Up to 76 patients will take part in this study. All will be enrolled at MD Anderson.

Study of Valproic Acid (VPA) vs Placebo to Shorten Time of Indwelling Pleural Catheter

Randomized Phase II Double Blind Study of Valproic Acid (VPA) vs Placebo to Shorten Time of Indwelling Pleural Catheter

Primary outcome is time to pleural catheter removal because it is no longer needed to drain the pleura of fluid. Time to catheter removal measured from the date of placement of the catheter to the date it is removed. Cox (1972) proportional hazards regression used to model time to catheter removal as a function of treatment arm, cytology, and lung re-expansion, as well as other potential prognostic factors, including ECOG performance status, number of circulating tumor cells in peripheral blood and in pleural effusion.

Inflammatory Breast Cancer Network Foundation

Of the 3 participants started, only 1 completed with the other 2 withdrawing before treatment 1 withdrew and 1 screen failure. The protocol was terminated early.

Group 1 will take placebo 3 times a day for 10 weeks while an indwelling pleural catheter drains pleural fluid.

Group 1

Group 2 will take valproic acid (VPA) 3 times a day for a total of 10 weeks while an indwelling pleural catheter drains pleural fluid.

Group 2

Total

Age, Categorical

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Dr. Wendy Woodward, PHD/ Professor, Radiation Oncology Department

Study terminated early with single patient leaving low accrual with insufficient data for analysis

Time to Pleural Catheter Removal

Anti-Infective Agents

Cytarabine

Antiviral Agents

Immunosuppressive Agents

Immunologic Factors

5-Azacytidine (5-Aza) 75 mg/m\^2 subcutaneously daily + Valproic Acid (VPA) 50 mg/m\^2 orally daily, each for 7 days

Low-Dose Ara-C 20 mg twice daily subcutaneously for 10 days.

75 mg/m\^2 daily for 7 days (days 1-7) via subcutaneous injection.

5-Azacytidine

20 mg twice daily via subcutaneous injection for 10 days.

Ara-C

Primary Objective:

1. To evaluate whether 5 azacytidine (5-aza)/valproic acid (VPA) or low dose ara-C produces longer event free survival time in patients age \> or = 60 years with untreated Acute Myeloid Leukemia (AML) or high risk Myelodysplastic Syndrome (MDS) who are typically ineligible for, or not placed on, studies of new agents.

Secondary Objective:

1. To evaluate whether pre-treatment methylation/acetylation status in AML/MDS blasts predicts response to either therapy or whether the ability of the 5 azacytidine + valproic acid combination to induce demethylation or acetylation parallels response.

5-aza is a chemotherapy drug with activity in leukemia and MDS. Researchers hope that VPA will increase the effects of 5-aza. Low-dose Cytarabine (ara-C) is considered the standard of care for the treatment of leukemia and MDS in older patients not eligible for other therapies.

Before you can start treatment on this study, you will have what are called "screening tests." These tests will help the doctor decide if you are eligible to take part in the study. You will have blood drawn (about 2 teaspoons) for routine tests. You will also have a bone marrow biopsy and aspiration performed. To collect a bone marrow biopsy/aspirate, an area of the hip or chest bone is numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a large needle. Women who are able to have children must have a negative blood or urine pregnancy test.

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the toss of a coin) to one of two treatment groups. Participants in one group will receive 5-aza and VPA. Participants in the other group will receive ara-C alone. At first, there will be an equal chance of being assigned to either group. As the study goes along, however, the chance of being assigned to the treatment that has worked best so far will increase.

Participants in the 5-aza and VPA group will receive 5-aza as an injection under the skin once a day for 7 days in a row. On these same 7 days, participants in this group will also take VPA by mouth twice a day or 3 times a day based on your weight. Seven (7) days is considered 1 treatment cycle. Both drugs will be taken at the same time. Cycles will be repeated every 4 to 6 weeks.

Participants in the ara-C group will receive ara-c twice a day as an injection under the skin for 10 days (1 cycle). Cycles will be repeated every 4 to 6 weeks.

You will be monitored with routine blood tests (about 1-2 teaspoons each time) 2-3 times a week during this study.

You may receive up to 12 cycles of therapy. You may be taken off study early if the disease gets worse or intolerable side effects occur.

Once you go off study, you will have standard follow-up as is required by your primary physician.

This is an investigational study. 5-aza is approved by the FDA for MDS. VPA is approved by the FDA for epilepsy. Their use together in this study is experimental. Ara-C is approved for acute myelogenous leukemia. About 70 patients will take part in this study. All will be enrolled at M. D. Anderson.

Azacytidine With Valproic Acid Versus Ara-C in Acute Myeloid Leukemia (AML)/ Myelodysplastic Syndrome (MDS) Patients

A Randomized Phase II Study of the Combination of 5-Azacytidine With Valproic Acid (VPA) Versus Low-Dose Ara-C in Patients With AML/MDS Not Eligible for Other Studies

Patient response defined by: Death, Resistant to Therapy \[no major hematologic improvement using International Myelodysplastic Syndromes (MDS) Working Group (Cheson B, Bennett J, Kantarjian H et al, Blood 2006) criteria after a maximum of 4 courses\], or Relapse.

5-Aza + VPA

Low-Dose Cytarabine (Ara-C) 20 mg twice daily subcutaneously for 10 days.

Death

Resistant to Therapy

Relapse

The analysis was per intention to treat. One participant was inevaluable for response.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase II 5-Azacytidine Plus VPA Plus ATRA	NCT00326170	Myelodysplastic... Acute Myelogeno...	5-Azacytidine (... Valproic Acid All-Trans Retin...	3 Years -	M.D. Anderson Cancer Center
Study of Valproic Acid (VPA) vs Placebo to Shorten Time of Indwelling Pleural Catheter	NCT01900730	Breast Cancer	Placebo Valproic Acid (... Questionnaires Pill Diary Drainage Diary	18 Years -	M.D. Anderson Cancer Center
Azacytidine With Valproic Acid Versus Ara-C in Acute Myeloid Leukemia (AML)/ Myelodysplastic Syndrome (MDS) Patients	NCT00382590	Acute Myelogeno... Myelodysplastic... Leukemia	5-Azacytidine Ara-C Valproic Acid (...	60 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for vpa

Every month we try and update this database with for vpa cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for vpa

Every month we try and update this database with for vpa cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for vpa cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.