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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)


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndromes, Leukemia, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes, Untreated Adult Acute Myeloid Leukemia

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Trial Information

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)


OBJECTIVES:

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
patients.

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]


Inclusion Criteria:



- Diagnosis of 1 of the following:

- Histologically confirmed myelodysplastic syndromes (MDS) by bone marrow
aspiration and/or biopsy

- International Prognostic Scoring System (IPSS) score of intermediate-1,
intermediate-2, or high

- International Prognostic Scoring System (IPSS) score of intermediate-1,
intermediate-2, or high

- Low IPSS score allowed provided patient has a clinically significant cytopenia
(i.e., absolute neutrophil count < 1,000/mm^3, untransfused hemoglobin < 8 g/dL,
platelet count < 20,000/mm^3, or anemia requiring transfusion)

- Chronic myelomonocytic leukemia

- Acute myeloid leukemia (AML)

- Relapsed or refractory disease

- Untreated AML allowed provided patient meets >= 1 of the following criteria:

- Age 60 and over

- AML arising in the setting of an antecedent hematologic disorder

- High-risk cytogenetic abnormalities

- Medical conditions that may compromise the ability to give cytotoxic
chemotherapy as the primary modality

- Refused cytotoxic chemotherapy

- WBC < 30,000/mm3 for >= 2 weeks before study entry

- Acute promyelocytic leukemia allowed provided patient is in at least second relapse
and has already received treatment regimens containing arsenic trioxide and
isotretinoin

- No clinical evidence of CNS or pulmonary leukostasis or CNS leukemia

- Peformance status:

- Zubrod 0-2

- Life expectancy:

- At least 6 months

- Hematopoietic:

- See Disease Characteristics

- Hemoglobin ≥ 8 g/dL (transfusion allowed)

- No disseminated intravascular coagulation

- Renal:

- Creatinine normal OR

- Creatinine clearance >= 60 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 3 months after study
treatment

- No untreated, active infection

- No other serious or uncontrolled medical condition

- More than 3 weeks since prior hematopoietic growth factors for this malignancy

- At least 3 weeks since prior hydroxyurea (2 weeks for AML patients)

- No concurrent hydroxyurea

- Recovered from all prior therapy

- At least 2 weeks since prior cytotoxic therapy (AML patients)

- More than 3 weeks since other prior therapy for this malignancy

- No other concurrent investigational or commercial agents or therapies for this
malignancy

- No concurrent valproic acid

- Hepatic:

- Bilirubin normal unless due to hemolysis or Gilbert's syndrome

- AST and ALT =< 2.5 times upper limit of normal

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Maximum tolerated dose of MS-275 in combination with 5-azacitidine, assessed using Common Toxicity Criteria version 3.0

Outcome Time Frame:

4 weeks

Safety Issue:

Yes

Principal Investigator

Steven Gore

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00071

NCT ID:

NCT00101179

Start Date:

November 2004

Completion Date:

Related Keywords:

  • Chronic Myelomonocytic Leukemia
  • de Novo Myelodysplastic Syndromes
  • Leukemia
  • Previously Treated Myelodysplastic Syndromes
  • Recurrent Adult Acute Myeloid Leukemia
  • Secondary Acute Myeloid Leukemia
  • Secondary Myelodysplastic Syndromes
  • Untreated Adult Acute Myeloid Leukemia
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute

Name

Location

Johns Hopkins UniversityBaltimore, Maryland  21205