Phase I 5-Azacytidine Plus VPA Plus ATRA

This study has been completed.

Sponsor:

ClinicalTrials.gov Identifier:

NCT01575691

First Posted: April 11, 2012

Last Update Posted: April 11, 2012

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.

Collaborator:

Celgene Corporation

Information provided by (Responsible Party):

M.D. Anderson Cancer Center

Purpose

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	Intervention	Phase
Myelodysplastic Syndrome Acute Myelogenous Leukemia	Drug: 5-Azacytidine (5-aza) Drug: Valproic Acid Drug: All-Trans Retinoic Acid (ATRA)	Phase 1


Study Type:	Interventional
Study Design:	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

Resource links provided by NLM:

Genetics Home Reference related topics: core binding factor acute myeloid leukemia cytogenetically normal acute myeloid leukemia familial acute myeloid leukemia with mutated CEBPA

MedlinePlus related topics: Leukemia Myelodysplastic Syndromes

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

Genetic and Rare Diseases Information Center resources: Myeloid Leukemia Acute Myeloid Leukemia Acute Non Lymphoblastic Leukemia Myelodysplastic Syndromes

U.S. FDA Resources

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

Primary Outcome Measures:

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.


Enrollment:	21
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
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

Arms

Assigned Interventions

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

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.

Eligibility

Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01575691

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


Responsible Party:	M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:	NCT01575691 History of Changes
Other Study ID Numbers:	2004-0799 Phase I
First Submitted:	April 9, 2012
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

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