A Dose-Finding Trial of the Histone Deacetylase Inhibitor MS-275 (NSC 706995) in Combination With 5-Azacitidine (5AC, NSC 102816) in Patients With Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMMoL) and Acute Myeloid Leukemia (AML)
I. Determine the safety and toxicity of MS-275 and azacitidine in patients with
myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia.
II. Determine the maximum tolerated dose and optimal phase II dose of MS-275 when combined
with azacitidine in these patients.
III. Determine, preliminarily, the potential therapeutic activity of this regimen in these
IV. Correlate MS-275 pharmacokinetics with clinical response and laboratory correlative
endpoints in patients treated with this regimen.
OUTLINE: This is a multicenter, dose-escalation study of MS-275. Patients receive
azacitidine subcutaneously on days 1-10 and oral MS-275 on days 3 and 10.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of MS-275 until the maximum tolerated dose
(MTD) is determined. Patients receive adjusted doses of azacitidine based on clinical
response. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients
experience dose-limiting toxicity. Up to 9 additional patients are treated at the MTD.
[Note: Patients who do not achieve hematologic improvement or partial or complete response
but who have stable disease after 4 courses of therapy may receive an additional 4 courses
of therapy at a higher dose than what was originally assigned]
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose of MS-275 in combination with 5-azacitidine, assessed using Common Toxicity Criteria version 3.0
Johns Hopkins University
United States: Food and Drug Administration
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