Phase I/II 5-Azacytidine Plus VPA Plus ATRA - Full Text View

Sponsor:	M.D. Anderson Cancer Center
Collaborator:	Celgene Corporation
Information provided by:	M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:	NCT00326170

Purpose

5-aza is a chemotherapy drug with activity in leukemia and MDS. Researchers hope that VPA and 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.

Condition	Intervention	Phase
Myelodysplastic Syndrome Acute Myelogenous Leukemia	Drug: 5-Azacytidine (5-aza) Drug: Valproic Acid Drug: All-Trans Retinoic Acid (ATRA)	Phase I Phase II

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Historical Control, Single Group Assignment, Safety/Efficacy Study
Official Title:	Phase I/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

Resource links provided by NLM:

MedlinePlus related topics: Cancer Leukemia, Adult Acute Leukemia, Adult Chronic Leukemia, Childhood

Drug Information available for: Divalproex sodium Valproic acid Tretinoin Azacitidine Valproate Sodium

U.S. FDA Resources

Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:

Maximal tolerated dose [ Time Frame: Routine blood tests (about 1-2 teaspoons each time) 2-3 times a week during this study. ] [ Designated as safety issue: Yes ]

Enrollment:	55
Study Start Date:	July 2005
Study Completion Date:	December 2007
Primary Completion Date:	July 2007 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
VPA + 5-aza + ATRA: Experimental Highest safe dose of valproic acid (VPA) given in combination with 5-azacytidine (5-aza) and all-trans retinoic acid (ATRA) in treatment of AML and MDS.	Drug: 5-Azacytidine (5-aza) Start at 75 mg/m^2 subcutaneously daily x 7 days. Drug: Valproic Acid 50 mg/kg daily by mouth for 7 days, same days as 5-aza. 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.

Detailed Description:

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 DNA methylation, histone modifications, and gene expression.

Eligibility

Ages Eligible for Study:	3 Years and older
Genders Eligible for Study:	Both
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 ECOG scale.
Signed informed consent indicating that patients are aware of the investigational nature of this study in keeping with the policies of 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 x 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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00326170

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

Additional Information:

M.D. Anderson's internet website This link exits the ClinicalTrials.gov site

No publications provided by M.D. Anderson Cancer Center

Additional publications automatically indexed to this study by National Clinical Trials Identifier (NCT ID):

Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F, Cortes J, Wierda WG, Ouzounian S, Quezada A, Pierce S, Estey EH, Issa JP, Kantarjian HM, Garcia-Manero G. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007 Oct 1;110(7):2302-8. Epub 2007 Jun 27.

Responsible Party:	UT MD Anderson Cancer Center ( Guillermo Garcia-Manero, MD / Associate Professor )
Study ID Numbers:	2004-0799
Study First Received:	May 12, 2006
Last Updated:	August 3, 2009
ClinicalTrials.gov Identifier:	NCT00326170 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:

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
All-trans retinoic acid
ATRA
Tretinoin
Vesanoid

Additional relevant MeSH terms:

Antimetabolites
Neurotransmitter Agents
Antimetabolites, Antineoplastic
Precancerous Conditions
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Psychotropic Drugs
Leukemia, Myeloid, Acute
Valproic Acid
Keratolytic Agents
Leukemia
Preleukemia
Pathologic Processes
Syndrome

Therapeutic Uses
Azacitidine
Dermatologic Agents
Disease
Neoplasms by Histologic Type
Tranquilizing Agents
Hematologic Diseases
Myelodysplastic Syndromes
Central Nervous System Depressants
Enzyme Inhibitors
Leukemia, Myeloid
Antimanic Agents
Pharmacologic Actions
Neoplasms
GABA Agents

ClinicalTrials.gov processed this record on November 27, 2009