Vorinostat in Combination With Azacitidine in Patients With Newly-Diagnosed Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Study Overview
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Brief Summary
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The goal of this clinical research study is to learn if the combination of azacitidine and vorinostat can help to control AML or MDS better than azacitidine alone. The safety of this drug combination will also be studied.

Detailed Description
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The Study Drugs: Azacitidine is designed to block certain genes in cancer cells whose job is to stop the function of the tumor-fighting genes. By blocking the bad genes, the tumor-fighting genes may be able to work better. Vorinostat is designed to cause chemical changes in different groups of proteins that are attached to DNA (the genetic material of cells), which may slow the growth of cancer cells or cause the cancer cells to die. Study Groups: If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 groups. If you are in Group 1, you will receive azacitidine and vorinostat. If you are in Group 2, you will receive azacitidine alone. For the first 40 patients, you will have an equal chance of being in either group. After the first 40 patients, you will have a higher chance of being assigned to a group based on the results from previous participants. Study Drug Administration: On Days 1-5 of every cycle, you will receive azacitidine by vein over 15-30 minutes. If you are in Group 1, you will also take vorinostat by mouth 3 times a day with food on Days 1-5 of every cycle. If you cannot take vorinostat by mouth during a cycle, you will receive only azacitidine during that cycle. You will begin taking vorinostat by mouth again when you are able. Your dose of study drugs may be lowered if you experience side effects. You may receive a drug such as ondansetron before each dose of azacitidine to prevent nausea and vomiting. If you have diarrhea, you will take a drug such as Imodium (loperamide) to prevent diarrhea. Study Visits: Once a week of Cycle 1, the following tests and procedures will be performed: Your complete medical history will be recorded. You will have a physical exam. You will be asked if you have experienced any intolerable side effects. Blood (about 1-2 tablespoons) will be drawn for routine tests. On Day 28 of Cycle 1 (+/- 3 days), you will have bone marrow aspiration to check the status of the disease. To collect a bone marrow aspirate, an area of the hip is numbed with anesthetic, and a small amount of bone marrow is withdrawn through a large needle. If the doctor thinks it is needed, you will have extra bone marrow aspirations during the later cycles to check the status of the disease. One (1) time each cycle of Cycles 2 and beyond, the following tests and procedures will be performed: Your complete medical history will be recorded. You will have a physical exam. You will be asked if you have experienced any intolerable side effects. If the doctor thinks it is needed, blood (about 2 tablespoons) will be drawn for routine tests. Length of Study: You will be on active study for up to 12 cycles (about 12-18 months). You will be taken off study if the disease gets worse or you experience intolerable side effects. This is an investigational study. Vorinostat is FDA approved and commercially available for the treatment of cutaneous T-cell lymphoma. Azacitidine is FDA approved commercially available for the treatment of MDS. The combination of these drugs for use in patients with intermediate-1 or higher risk MDS and AML is investigational. Up to 80 participants will take part in this study. All will be enrolled at MD Anderson.

Official Title
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A Phase 2 Trial of Vorinostat in Combination With Azacitidine in Patients With Newly-Diagnosed Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS) Who Are Ineligible for Other Leukemia Protocols

Conditions
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Leukemia

Intervention / Treatment
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* Drug: Vorinostat
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with newly diagnosed AML or MDS (Intermediate 1 or higher risk) Patient must have at least one of the following: a. Creatinine >/= 2 mg/dL; b. total Bilirubin >/= 2 mg/dL; c.ECOG Performance Status equal to 3 or 4; and d. is ineligible for participation on a protocol of higher priority Patients must provide written informed consent. Patients must be age > 18 years due to lack of safety information with these agents in children. Patient agrees to: 1) Use 2 adequate methods of contraception to prevent pregnancy (either 2 barrier methods or a barrier method plus a hormonal contraceptive method) or 2) abstain from heterosexual activity throughout the study starting with Visit 1. Female patients of childbearing potential should have a negative pregnancy test (serum) within 72 hrs. of study enrollment. Exclusion Criteria: Patients must not have the favorable cytogenetic abnormalities of inv (16), t (16;16), t (8;21), or t (15;17). Patients receiving any anti-leukemic therapy with the exception of Hydroxyurea prior to study enrollment. Prior growth factor therapy is acceptable. Hydroxyurea could be used at the discretion of the treating physician. A single or a two day dose of cytarabine (up to 3 g/m^2) for emergency use is allowed as prior therapy. Patient has a prior history of treatment with HDAC inhibitors. Patients who have received valproic acid (VPA) for the treatment of seizures may be enrolled on this study, but must not have received VPA within 30 days of study enrollment. Patient is unable to take and/or tolerate oral medications on a continuous basis, examples include patients on a ventilator, or have altered mental status that precludes safe oral route of administration. Patient has active hepatitis A, B, or C infection. Patient is pregnant or breast-feeding. Patient has a known allergy or hypersensitivity to any component of vorinostat or azacitidine. History of any psychiatric condition that might impair the patient's ability to understand or to comply with the requirements of the study or to provide informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vorinostat with Azacitidine<br>ARM A: Azacitidine 75 mg/m^2/day by vein over 15 - 30 minutes daily for 5 days (Days 1 - 5). Vorinostat 200 mg by mouth three time a day with food for 5 days (Days 1 - 5). Courses repeated every 3 to 8 weeks. | Drug: Vorinostat<br>* 200 mg by mouth three (3) times per day with food for 5 days (Days 1 - 5)<br>* Other names: Zolinza;Drug: Azacitidine<br>* 75 mg/m^2/day given intravenously over 15 - 30 minutes daily for 5 days (Days 1 - 5)<br>* Other names: NSC-102816;|
| Experimental: Azacitidine<br>ARM B: Azacitidine 75 mg/m^2 /day by vein over 15 - 30 minutes daily for 5 days (Days 1 - 5). Courses repeated every 3 to 8 weeks. | Drug: Azacitidine<br>* 75 mg/m^2/day given intravenously over 15 - 30 minutes daily for 5 days (Days 1 - 5)<br>* Other names: NSC-102816;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival at Day 60 | Assessment of survival for outcome done on 60 days following therapy and includes participants alive for at least 60 days. Survival is calculated from start of therapy until death from any cause. | Phase I, Baseline to 60 days following first treatment. | 
| Response Rate | Number of participants with Complete Response (CR) in AML requiring disappearance of all signs and symptoms related to disease, normalization of peripheral counts (absolute neutrophil count 10^9/L or more, platelet count 100 x 10^9/L or more), and a marrow with 5% or less marrow blasts; a hematologic improvement (HI) defined as a CR except for a platelet count increase by 50% to above 30 x 10^9/L. For MDS, the International Working Group criteria used to assess response. | 12-18 Months | 
| Survival at Day 60 | Assessment of survival for outcome done on 60 days following therapy and includes participants alive for at least 60 days. Survival is calculated from start of therapy until death from any cause. | Phase II, Baseline to 60 days following first treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Acute Myelogenous Leukemia, AML, Myelodysplastic Syndrome, MDS, Vorinostat, SAHA, Suberoylanilide Hydroxamic Acid, MSK-390, Zolinza, Azacitidine, 5-Azacitidine, 5-Aza, Vidaza, 5-AZC, AZA-CR, Ladakamycin, NSC-102816