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Phase II 5-Azacytidine Plus VPA Plus ATRA

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.
ClinicalTrials.gov Identifier: NCT00326170
Recruitment Status : Completed
First Posted : May 16, 2006
Results First Posted : July 11, 2011
Last Update Posted : June 15, 2012
Celgene Corporation
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE May 12, 2006
First Posted Date  ICMJE May 16, 2006
Results First Submitted Date  ICMJE June 6, 2011
Results First Posted Date  ICMJE July 11, 2011
Last Update Posted Date June 15, 2012
Study Start Date  ICMJE July 2005
Actual Primary Completion Date July 2007   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 12, 2012)
Number of Participants With Response [ Time Frame: Up to 12 cycles of treatment (28 day cycles) ]
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).
Original Primary Outcome Measures  ICMJE
 (submitted: May 12, 2006)
Bone marrow aspiration on day 21 (+/- 2 days) and 28 (+/- 2 days) and every 7-14 days thereafter as indicated until remission is documented, then every 1-3 courses.
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: May 12, 2006)
During subsequent courses, complete history and physical, CBC, and chemistries will be performed at least once prior to each course of therapy. Correlative studies will be obtained on days 0, and 7 (all +/- 2 days).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Phase II 5-Azacytidine Plus VPA Plus ATRA
Official Title  ICMJE 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
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.

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.

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 Deoxyribonucleic acid (DNA) methylation, histone modifications, and gene expression.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Myelodysplastic Syndrome
  • Acute Myelogenous Leukemia
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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)
  • Drug: Valproic Acid
  • Drug: All-Trans Retinoic Acid (ATRA)
Publications * 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. doi: 10.1182/blood-2007-03-078576. Epub 2007 Jun 27.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 12, 2012)
Original Enrollment  ICMJE
 (submitted: May 12, 2006)
Actual Study Completion Date  ICMJE December 2007
Actual Primary Completion Date July 2007   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 * 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00326170
Other Study ID Numbers  ICMJE 2004-0799
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party M.D. Anderson Cancer Center
Original Responsible Party Not Provided
Current Study Sponsor  ICMJE M.D. Anderson Cancer Center
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Celgene Corporation
Investigators  ICMJE
Principal Investigator: Guillermo Garcia-Manero, MD M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date June 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP