Phase I 5-Azacytidine Plus VPA Plus ATRA

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Myelodysplastic Syndrome; Acute Myelogenous Leukemia	Drug: 5-Azacytidine (5-aza); Drug: Valproic Acid; Drug: All-Trans Retinoic Acid (ATRA)	Phase 1

Detailed Description:

Participants receive 5-aza as an injection under the skin once a day for 7 days. This will be repeated every 3-8 weeks depending on blood counts and how well bone marrow is recovering. This is defined as 1 treatment cycle. Also during each cycle, participant will take VPA by mouth for 7 days and ATRA by mouth for 5 days. VPA will be given on the same days as 5-aza. ATRA will start on Day 3.

In the Phase I portion of the study, the dose of VPA will be increased in each new group of participants until the highest safe dose is found. A minimum of 3 participants and a maximum of 10 will be treated at each dose level.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	21 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase I 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
Study Start Date :	July 2005
Actual Primary Completion Date :	July 2007
Actual Study Completion Date :	December 2007

Arms and Interventions

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Arm

Intervention/treatment

Experimental: VPA + 5-aza + ATRA; 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.

Drug: 5-Azacytidine (5-aza); Start at 75 mg/m^2 subcutaneously daily for 7 days.; Other Names: Azacitidine; 5-azacytidine; 5-AZC; Vidaza; AZA-CR; Ladakamycin; NSC-102816 Drug: Valproic Acid; 50 mg/kg daily by mouth for 7 days, same days as 5-aza.; Other Name: Depakene Drug: All-Trans Retinoic Acid (ATRA); 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.; Other Names: Tretinoin (oral); Vesanoid

Outcome Measures

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Primary Outcome Measures :

1. Maximal tolerated dose (MTD) of valproic acid (VPA) in combination with 5-azacytidine (5-aza) and all-trans retinoic acid (ATRA) [ Time Frame: 28 day cycle ]
   MTD defined as the dose level below where either 0 dose limiting toxicities (DLTs) out of the first 3 participants, or 1 DLT in the first 3 participants, and 0 DLTs in following additional 3 participants of a cohort. The MTD designation will apply to cycle 1 (28 day cycle). Routine blood tests (about 1-2 teaspoons each time) 2-3 times a week.

Eligibility Criteria

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Ages Eligible for Study:	3 Years and older (Child, Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Patients with refractory or relapsed: acute myelogenous leukemia (AML), and myelodysplastic syndrome (MDS) (bone marrow blasts > or = 10%) are eligible.
• Untreated patients older than 60 years of age with AML or MDS (bone marrow blasts > or = 10%) who refuse or are not eligible for front-line chemotherapy, are eligible.
• Performance status of < or = 2 by the Eastern Cooperative Oncology Group (ECOG) scale.
• Signed informed consent indicating that patients are aware of the investigational nature of this study in keeping with the policies of University of Texas M D Anderson Cancer Center (UTMDACC).
• Age > 2 years. Valproic acid has been associated with a higher rate of severe liver toxicity in children younger than 2 years.
• Patients must have been off chemotherapy for 2 weeks prior to entering this study and recovered from the toxic effects of that therapy, unless there is evidence of rapidly progressive disease. Use of hydroxyurea for patients with rapidly proliferative disease is allowed for the first two weeks on therapy.
• Adequate liver function (bilirubin of < 2mg/dL, SGPT < 3 * Upper Limits of Normal (ULN)) and renal function (creatinine < 2mg/dL).
• Women of childbearing potential must practice contraception. Men and women must continue birth control for the duration of the trial.
• Patients with relapsed /refractory disease with inv16, t(8;21) or t(15;17) are eligible.

Exclusion Criteria:

• Nursing and pregnant females are excluded.
• Patients with active and uncontrolled infections are excluded.
• Patients already receiving valproic acid or receiving other anticonvulsants will be excluded.
• Untreated patients younger than 60 years will not be candidates for this study.
• Patients with untreated disease inv16, t(8;21) or t(15;17) will be excluded.

Contacts and Locations

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Locations

United States, Texas
The University of Texas M.D. Anderson Cancer Center
Houston, Texas, United States, 77030

Sponsors and Collaborators

M.D. Anderson Cancer Center

Celgene Corporation

Investigators

Principal Investigator:	Guillermo Garcia-Manero, MD	M.D. Anderson Cancer Center

More Information

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Additional Information:

M.D. Anderson's internet website 

Responsible Party:	M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:	NCT01575691 History of Changes
Other Study ID Numbers:	2004-0799 Phase I
First Posted:	April 11, 2012
Last Update Posted:	April 11, 2012
Last Verified:	April 2012

Keywords provided by M.D. Anderson Cancer Center:

All-trans retinoic acid; Tretinoin; Vesanoid; Combination Chemotherapy; MDS; High-Risk Myelodysplastic Syndrome; AML; Acute myelogenous leukemia; valproic acid; VPA	Depakene; 5-azacytidine; 5-aza; Azacitidine; 5-AZC; Vidaza; AZA-CR; Ladakamycin; NSC-102816; ATRA

Additional relevant MeSH terms:

Tretinoin; Syndrome; Leukemia; Myelodysplastic Syndromes; Preleukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Disease; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Azacitidine	Valproic Acid; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Enzyme Inhibitors; Anticonvulsants; GABA Agents; Neurotransmitter Agents; Physiological Effects of Drugs; Antimanic Agents; Tranquilizing Agents; Central Nervous System Depressants; Psychotropic Drugs; Keratolytic Agents