MS-275 and Azacitidine in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00101179

Collaborator

(none)

Enrollment

Locations

Arm

111

Actual Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

MS-275 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving MS-275 together with azacitidine may kill more cancer cells. This phase I trial is studying the side effects and best dose of MS-275 when given together with azacitidine in treating patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia de Novo Myelodysplastic Syndrome Leukemia Myelodysplastic Syndrome Recurrent Adult Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Secondary Myelodysplastic Syndrome	Drug: Azacitidine Drug: Entinostat	Phase 1

Detailed Description

OBJECTIVES:

Determine the safety and toxicity of MS-275 and azacitidine in patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia.
Determine the maximum tolerated dose and optimal phase II dose of MS-275 when combined with azacitidine in these patients.
Determine, preliminarily, the potential therapeutic activity of this regimen in these patients.
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]

Study Design

Study Type:

Interventional

Actual Enrollment :

63 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Actual Study Start Date :

Nov 3, 2004

Actual Primary Completion Date :

Apr 20, 2011

Actual Study Completion Date :

Feb 3, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I 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.	Drug: Azacitidine Given SC Other Names: 5 AZC 5-AC 5-Azacytidine 5-AZC Azacytidine Azacytidine, 5- Ladakamycin Mylosar U-18496 Vidaza Drug: Entinostat Given orally Other Names: HDAC inhibitor SNDX-275 MS 27-275 MS-275 SNDX-275

Arm

Intervention/Treatment

Experimental: Arm I

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.

Drug: Azacitidine

Given SC

Other Names:

5 AZC

5-AC

5-Azacytidine

5-AZC

Azacytidine

Azacytidine, 5-

Ladakamycin

Mylosar

U-18496

Vidaza

Drug: Entinostat

Given orally

Other Names:

HDAC inhibitor SNDX-275

MS 27-275

MS-275

SNDX-275

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose of MS-275 in combination with 5-azacitidine, assessed using Common Toxicity Criteria version 3.0 [4 weeks]

Secondary Outcome Measures

Response rate measured by IWG criteria [16 weeks]
Optimal dose combination [At study completion]
Levels of histone acetylation and gene re-expression [4 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
2	Mount Sinai Hospital	New York	New York	United States	10029
3	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065