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Differentiation Therapy With Decitabine in Treating Patients With Myelodysplastic Syndrome

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ClinicalTrials.gov Identifier: NCT01165996
Recruitment Status : Completed
First Posted : July 20, 2010
Results First Posted : February 26, 2013
Last Update Posted : March 4, 2019
Sponsor:
Information provided by (Responsible Party):
Case Comprehensive Cancer Center

Tracking Information
First Submitted Date  ICMJE July 14, 2010
First Posted Date  ICMJE July 20, 2010
Results First Submitted Date  ICMJE January 2, 2013
Results First Posted Date  ICMJE February 26, 2013
Last Update Posted Date March 4, 2019
Study Start Date  ICMJE July 2010
Actual Primary Completion Date December 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 21, 2019)
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
Original Primary Outcome Measures  ICMJE
 (submitted: July 19, 2010)
Hematologic Improvement as defined by IWG Criteria for Response in Clinical Trials [ Time Frame: Formal assessment at week 12 for study primary end-point (hematologic improvement). ]
Change History Complete list of historical versions of study NCT01165996 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 21, 2019)
  • 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.
  • 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).
  • 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.
  • 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.
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: July 19, 2010)
  • NCI Common Toxicity Criteria for Adverse Events (CTCAE), Version 4.0 [ Time Frame: Blood counts are CBC with differential and reticulocyte count, every week from week 1-12 then every 2 weeks. Drug dose and schedule is interrupted or modified based on peripheral blood counts as described in detail in 'Dose Modification for Toxicity'. ]
  • Complete hematologic remission, and other measures of response and duration as per IWG criteria [ Time Frame: Protocol treatment will continue for 52 weeks or until disease progression, relapse or failure, whichever comes first. ]
  • Correlation of DNMT1 depletion with clinical response criteria [ Time Frame: D42 (w6), D84, 168, 365 & relapse, Q56 day ]
  • Response by aberrant methylation signature [ Time Frame: Day 84, 168, 365 & relapse, Q56 day ]
  • Correlation of cytogenetic and methylome profile (measured by microarray) with clinical response criteria [ Time Frame: Day 42(cytogenetic), 84, 168, 365 & relapse ]
  • Correlation of CDA genotype and expression with clinical response criteria [ Time Frame: Day 84, 168, 365 & relapse ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Differentiation Therapy With Decitabine in Treating Patients With Myelodysplastic Syndrome
Official Title  ICMJE A Proof of Concept Study of Non-DNA Damaging DNMT1 Depletion Therapy for Myelodysplastic Syndrome
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Chronic Myelomonocytic Leukemia
  • de Novo Myelodysplastic Syndromes
  • Myelodysplastic Syndromes
  • Refractory Anemia
  • Refractory Anemia With Excess Blasts
  • Refractory Anemia With Ringed Sideroblasts
  • Refractory Cytopenia With Multilineage Dysplasia
  • Thrombocytopenia
Intervention  ICMJE
  • Other: flow cytometry
    Correlative studies
  • Other: DNA methylation analysis
    Correlative studies
  • Other: cytogenetic analysis
    Correlative studies
  • Drug: decitabine
    Given subcutaneously
    Other Names:
    • 5-aza-dCyd
    • 5AZA
    • DAC
    • Dacogen
    • deoxyazacytidine
    • dezocitidine
  • Genetic: microarray analysis
    Correlative studies
    Other Name: gene expression profiling
  • Genetic: gene expression analysis
    Correlative studies
  • Other: pharmacological study
    Correlative studies
    Other Name: pharmacological studies
  • Genetic: polymorphism analysis
    Correlative studies
Study Arms  ICMJE Experimental: Arm I: decitabine
INDUCTION PHASE: Patients receive decitabine subcutaneously (SQ) twice weekly for 4 weeks or thrice weekly until achieving bone marrow blasts &lt; 5%. MAINTENANCE PHASE: Patients then receive decitabine SQ twice weekly for up to 52 weeks in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Other: flow cytometry
  • Other: DNA methylation analysis
  • Other: cytogenetic analysis
  • Drug: decitabine
  • Genetic: microarray analysis
  • Genetic: gene expression analysis
  • Other: pharmacological study
  • Genetic: polymorphism analysis
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 19, 2010)
25
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE August 2012
Actual Primary Completion Date December 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01165996
Other Study ID Numbers  ICMJE CASE2908
NCI-2010-00135 ( Other Identifier: NCI/CTRP )
CASE2908 ( Other Identifier: Case Comprehensive Cancer Center )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Case Comprehensive Cancer Center
Study Sponsor  ICMJE Case Comprehensive Cancer Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Yogen Saunthararajah Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Principal Investigator: Brenda Cooper, MD Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
PRS Account Case Comprehensive Cancer Center
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP