ClinicalTrials.gov
ClinicalTrials.gov Menu

Differentiation Therapy With Decitabine in Treating Patients With Myelodysplastic Syndrome

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01165996
Recruitment Status : Completed
First Posted : July 20, 2010
Results First Posted : February 26, 2013
Last Update Posted : March 1, 2013
Sponsor:
Information provided by (Responsible Party):
Case Comprehensive Cancer Center

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.

Condition or disease Intervention/treatment Phase
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 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 Phase 1 Phase 2

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  (Clinical Trial)
Actual Enrollment : 25 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Proof of Concept Study of Non-DNA Damaging DNMT1 Depletion Therapy for Myelodysplastic Syndrome
Study Start Date : July 2010
Actual Primary Completion Date : December 2011
Actual Study Completion Date : August 2012


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 &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.
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




Primary Outcome Measures :
  1. 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). ]
    The criteria for complete remission (CR) and partial remission (PR) involve specific improvements in marrow and peripheral blood measurements obtained on 2 or more successive assessments. The response parameters in peripheral blood must be maintained for at least 8 weeks. Responses designated as 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 (11 g/dL) 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 classification category than prior to treatment.


Secondary Outcome Measures :
  1. 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.

  2. 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).

  3. Proportion of Patients With Pharmacodynamic Evidence of Drug Effect. [ Time Frame: Day 0, 42, 84 ]
    Evidence of pharmacodynamic effect will be correlated with clinical response criteria.

  4. Proportion of Patients With Bone Marrow Evidence of Cytotoxicity. [ Time Frame: Day 0, 42, 84 ]
    Cytotoxicity will be correlated with clinical response criteria

  5. Proportion of Patients With Bone Marrow Evidence of Terminal Differentiation Response to Therapy. [ Time Frame: Day 0,42,84 ]
    Bone marrow evidence of terminal differentiation will be correlated with response criteria

  6. 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 detected by whole exome sequencing correlation with clinical response



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01165996


Locations
United States, Ohio
Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44106
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44195
Sponsors and Collaborators
Case Comprehensive Cancer Center
Investigators
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

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01165996     History of Changes
Other Study ID Numbers: CASE2908
NCI-2010-00135 ( Other Identifier: NCI/CTRP )
CASE2908 ( Other Identifier: Case Comprehensive Cancer Center )
First Posted: July 20, 2010    Key Record Dates
Results First Posted: February 26, 2013
Last Update Posted: March 1, 2013
Last Verified: February 2013

Keywords provided by Case Comprehensive Cancer Center:
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes

Additional relevant MeSH terms:
Syndrome
Anemia
Myelodysplastic Syndromes
Preleukemia
Thrombocytopenia
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Anemia, Refractory
Anemia, Refractory, with Excess of Blasts
Disease
Pathologic Processes
Hematologic Diseases
Bone Marrow Diseases
Precancerous Conditions
Neoplasms
Blood Platelet Disorders
Leukemia, Myeloid
Leukemia
Neoplasms by Histologic Type
Myelodysplastic-Myeloproliferative Diseases
Decitabine
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors