Myelodysplastic Syndrome Clinical Trial
Official title:
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
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.
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.
;
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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