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.
Interventional
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Number of Participants With Response
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).
Up to 12 cycles of treatment (28 day cycles)
No
Guillermo Garcia-Manero, MD
Principal Investigator
M.D. Anderson Cancer Center
United States: Food and Drug Administration
2004-0799
NCT00326170
July 2005
December 2007
Name | Location |
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The University of Texas M.D. Anderson Cancer Center | Houston, Texas |