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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00101179
First received: January 7, 2005
Last updated: July 18, 2014
Last verified: April 2014
  Purpose

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 Intervention Phase
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
Drug: azacitidine
Drug: entinostat
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: 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)

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose of MS-275 in combination with 5-azacitidine, assessed using Common Toxicity Criteria version 3.0 [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Response rate measured by IWG criteria [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  • Optimal dose combination [ Time Frame: At study completion ] [ Designated as safety issue: No ]
  • Levels of histone acetylation and gene re-expression [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

Enrollment: 56
Study Start Date: November 2004
Primary Completion Date: April 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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-AC
  • 5-azacytidine
  • azacytidine
  • Vidaza
Drug: entinostat
Given orally
Other Names:
  • HDAC inhibitor SNDX-275
  • SNDX-275

Detailed Description:

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]

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00101179

Locations
United States, Maryland
Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
Baltimore, Maryland, United States, 21287
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
Mount Sinai Medical Center
New York, New York, United States, 10029
Sponsors and Collaborators
Investigators
Principal Investigator: Steven Gore Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
  More Information

No publications provided by National Cancer Institute (NCI)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00101179     History of Changes
Other Study ID Numbers: NCI-2009-00071, NCI-2009-00071, CDR0000405841, J0443, J0443, 6591, U01CA070095, P30CA006973
Study First Received: January 7, 2005
Last Updated: July 18, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelomonocytic, Chronic
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Acute
Neoplasms by Histologic Type
Neoplasms
Myelodysplastic-Myeloproliferative Diseases
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Azacitidine
Histone Deacetylase Inhibitors
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on July 22, 2014