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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

Phase 2
3 Years
Not Enrolling
Myelodysplastic Syndrome, Acute Myelogenous Leukemia

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Trial Information

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

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.

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)

- 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

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

- 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.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Participants With Response

Outcome Description:

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).

Outcome Time Frame:

Up to 12 cycles of treatment (28 day cycles)

Safety Issue:


Principal Investigator

Guillermo Garcia-Manero, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

July 2005

Completion Date:

December 2007

Related Keywords:

  • Myelodysplastic Syndrome
  • Acute Myelogenous Leukemia
  • 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
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia



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