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

October 17, 2019 updated by: National Cancer Institute (NCI)

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)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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]

Study Type

Interventional

Enrollment (Actual)

63

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins University/Sidney Kimmel Cancer Center
    • New York
      • New York, New York, United States, 10065
        • Memorial Sloan Kettering Cancer Center
      • New York, New York, United States, 10029
        • Mount Sinai Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Maximum tolerated dose of MS-275 in combination with 5-azacitidine, assessed using Common Toxicity Criteria version 3.0
Time Frame: 4 weeks
4 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
Response rate measured by IWG criteria
Time Frame: 16 weeks
16 weeks
Optimal dose combination
Time Frame: At study completion
At study completion
Levels of histone acetylation and gene re-expression
Time Frame: 4 weeks
4 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Steven D Gore, Johns Hopkins University/Sidney Kimmel Cancer Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 3, 2004

Primary Completion (Actual)

April 20, 2011

Study Completion (Actual)

February 3, 2014

Study Registration Dates

First Submitted

January 7, 2005

First Submitted That Met QC Criteria

January 7, 2005

First Posted (Estimate)

January 10, 2005

Study Record Updates

Last Update Posted (Actual)

October 18, 2019

Last Update Submitted That Met QC Criteria

October 17, 2019

Last Verified

October 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2009-00071 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • P30CA006973 (U.S. NIH Grant/Contract)
  • U01CA070095 (U.S. NIH Grant/Contract)
  • CDR0000405841
  • J0443 (Other Identifier: Johns Hopkins University/Sidney Kimmel Cancer Center)
  • 6591 (CTEP)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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