Differentiation Therapy With Decitabine in Treating Patients With Myelodysplastic Syndrome

February 21, 2019 updated by: Case Comprehensive Cancer Center

A Proof of Concept Study of Non-DNA Damaging DNMT1 Depletion Therapy for Myelodysplastic Syndrome

RATIONALE: Decitabine may help myelodysplastic cells become more like normal stem cells. PURPOSE: This clinical trial studies differentiation therapy with decitabine in treating patients with myelodysplastic syndrome.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. Demonstrate that differentiation therapy with DNMT1 depleting but non-DNA damaging doses of decitabine is efficacious and can be administered weekly for > = 12 months. SECONDARY OBJECTIVES: I. Assess safety of the regimen.

II. Retrospectively compare study and standard regimen clinical responses. III. Assess the ability of a pharmacodynamic assay that measures DNMT1 depletion in peripheral blood white blood cells to predict clinical responses to decitabine.

IV. Assess PCR for aberrant methylation signature as an early marker of relapse. V. Identify biologic features of MDS that correlate with response to decitabine, thereby facilitating future patient selection.

VI. In cases of relapse or resistance, assess the role of the enzyme CDA in altering decitabine metabolism and preventing DNMT1 depletion.

OUTLINE:

INDUCTION PHASE: Patients receive decitabine subcutaneously (SC) twice weekly for 4 weeks or thrice weekly until achieving bone marrow blasts < 5%.

MAINTENANCE PHASE: Patients then receive decitabine SC twice weekly for up to 52 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically.

Study Type

Interventional

Enrollment (Actual)

25

Phase

  • Phase 2
  • 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
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center
      • Cleveland, Ohio, United States, 44106
        • Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

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

  • MDS classified by hematopathology review as WHO categories refractory anemia (RA) or refractory cytopenia with multi-lineage dysplasia (RCMD) or refractory anemia with ring sideroblasts (RARS) or refractory anemia with excess blasts (RAEB1 or RAEB2) or chronic myelo-monocytic leukemia (CMML1 or CMML2)
  • Symptomatic anemia OR thrombocytopenia with a platelet count of < 100 x 10^9/L OR transfusion dependence for red-cells OR transfusion dependence for platelets OR absolute neutrophil count < 1 x 10^9/L

Exclusion

  • MDS of the WHO sub-types RA or RCMD with sole 5q- abnormality on cytogenetics unless failed lenalidomide (Revlimid) therapy
  • Previous treatment with decitabine
  • Untreated erythropoietin deficiency defined as an erythropoietin level of < 200 IU/L and erythropoietin replacement therapy for < 8 weeks (erythropoietin deficiency until corrected)
  • Uncontrolled infection
  • Severe sepsis or septic shock
  • Current pregnancy or breast feeding
  • The patient is of childbearing age, and is unwilling to use contraception and has not had a tubal ligation, hysterectomy, or vasectomy , or their partner is also unwilling to use an acceptable method of contraception as determined by the investigator
  • Not able to give informed consent
  • Altered mental status or seizure disorder
  • ALT > 300 IU; or albumin < 2.0 mg/dL
  • Creatinine > 2.5 mg/dl and creatinine clearance < 60ml/min
  • B12, folate, or iron deficient, until corrected
  • NYHA class III/IV status
  • ECOG performance status > 2
  • HIV positive or history of seropositivity for HIV
  • Transformation to acute leukemia ( >= 20% myelo-blasts in marrow aspirate)
  • Any experimental agents other than the study drug decitabine

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: decitabine
INDUCTION PHASE: Patients receive decitabine subcutaneously (SQ) twice weekly for 4 weeks or thrice weekly until achieving bone marrow blasts < 5%. MAINTENANCE PHASE: Patients then receive decitabine SQ twice weekly for up to 52 weeks in the absence of disease progression or unacceptable toxicity.
Other: flow cytometry
Correlative studies
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies
Genetic: microarray analysis
Correlative studies
Other Names:
  • gene expression profiling
Genetic: polymorphism analysis
Correlative studies
Genetic: gene expression analysis
Correlative studies
Other: DNA methylation analysis
Correlative studies
Other: cytogenetic analysis
Correlative studies
Drug: decitabine
Given subcutaneously
Other Names:
  • Dacogen
  • DAC
  • 5-aza-dCyd
  • 5AZA
  • deoxyazacytidine
  • dezocitidine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Patients With Response as Defined by IWG (International Working Group) Criteria for Myelodysplasia
Time Frame: Formal assessment at week 12 for study primary end-point (hematologic improvement).
Complete Response (CR) include less than 5% marrow blasts without evidence of dysplasia and normalization of peripheral blood counts, including a hemoglobin level of 110 g/L or more, a neutrophil count of 1.5 × 109/L or more, and a platelet count of 100 × 109/L or more. For PR, patients must demonstrate all CR criteria if abnormal before treatment except that marrow blasts should decrease by 50% or more compared with pretreatment levels, or patients may demonstrate a less-advanced MDS disease category than prior to treatment. Stable disease (SD) is defined by failure to achieve at least a partial response but no evidence of progression. Disease progression (DP) includes at least 50% decrease from maximum remission in granulocytes or platelets, reduction in hemoglobin by greater than or equal to 2g/dL, or transfusion dependence. Hematologic improvement (HI) includes hemoglobin increase by at least 1.5g/dL, reduction in transfusions, increase of platelets, increase of neutrophil count
Formal assessment at week 12 for study primary end-point (hematologic improvement).

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Patients That Experience > Grade 2 Non-hematologic Toxicity by National Cancer Institute (NCI)/Cancer Therapy Evaluation Program (CTEP) v4 Criteria
Time Frame: up to 12 months of treatment
Incidence of treatment-emergent adverse events (AEs) will be presented in tables that include causality, seriousness, severity/grade, and whether the AE resulted in death or discontinuation of treatment, Laboratory data will be summarized in tables that show changes from pre-treatment values and frequencies of abnormal values. Descriptive statistics will also be provided.
up to 12 months of treatment
Cytogenetic Response as Per IWG Criteria
Time Frame: at 12 months
Described as the number of patients with a major cytogenetic response (refers to disappearance of a cytogenetic abnormality) or a minor cytogenetic response (50% or more reduction of abnormal metaphases).
at 12 months
Proportion of Patients With Pharmacodynamic Evidence of Drug Effect.
Time Frame: 6 weeks after treatment
Evidence of pharmacodynamic effect will be correlated with clinical response criteria. The pharmacodynamic effect of treatment is defined as the number of participants that had depletion DNMT1 with minimal DNA damage and cytotoxicity.
6 weeks after treatment
Proportion of Patients With Bone Marrow Evidence of Cytotoxicity.
Time Frame: 6 weeks after treatment
Cytotoxicity is the ability to destroy cells. This will be measured by taking bone marrow samples and measuring the damage to cells. The level of cell destruction will be correlated with clinical response criteria.
6 weeks after treatment
Proportion of Patients With Bone Marrow Evidence of Terminal Differentiation Response to Therapy.
Time Frame: 6 weeks after treatment
Number of participants who, after therapy, had more of the differentiated types of blood (red cells, platelets, and white cells) compared to abnormal bone marrow cells than before therapy
6 weeks after treatment
Proportion of Patients With Particular Genetic Abnormalities Detected by Whole Exome Sequencing Correlation With Clinical Response
Time Frame: Baseline
Proportion of patients with particular genetic abnormalities, including DNA Methyltransferase 1 (DNMT1) depletion, detected by whole exome sequencing correlation with clinical response
Baseline

Collaborators and Investigators

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

Sponsor

Case Comprehensive Cancer Center

Investigators

  • Principal Investigator: Yogen Saunthararajah, Cleveland Clinic Taussig Cancer institute, Case Comprehensive 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

July 1, 2010

Primary Completion (Actual)

December 1, 2011

Study Completion (Actual)

August 1, 2012

Study Registration Dates

First Submitted

July 14, 2010

First Submitted That Met QC Criteria

July 19, 2010

First Posted (Estimate)

July 20, 2010

Study Record Updates

Last Update Posted (Actual)

March 4, 2019

Last Update Submitted That Met QC Criteria

February 21, 2019

Last Verified

February 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CASE2908 (Other Identifier: Case Comprehensive Cancer Center)
  • NCI-2010-00135 (Other Identifier: NCI/CTRP)

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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