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Differentiation Therapy With Decitabine in Treating Patients With Myelodysplastic Syndrome

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01165996
First received: July 14, 2010
Last updated: February 25, 2013
Last verified: February 2013
  Purpose

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 Intervention 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

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Proof of Concept Study of Non-DNA Damaging DNMT1 Depletion Therapy for Myelodysplastic Syndrome

Resource links provided by NLM:


Further study details as provided by Case Comprehensive Cancer Center:

Primary Outcome Measures:
  • 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). ] [ Designated as safety issue: No ]
    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:
  • 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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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: Day 0, 42, 84 ] [ Designated as safety issue: No ]
    Evidence of pharmacodynamic effect will be correlated with clinical response criteria.

  • Proportion of Patients With Bone Marrow Evidence of Cytotoxicity. [ Time Frame: Day 0, 42, 84 ] [ Designated as safety issue: No ]
    Cytotoxicity will be correlated with clinical response criteria

  • Proportion of Patients With Bone Marrow Evidence of Terminal Differentiation Response to Therapy. [ Time Frame: Day 0,42,84 ] [ Designated as safety issue: No ]
    Bone marrow evidence of terminal differentiation will be correlated with response criteria

  • Proportion of Patients With Particular Genetic Abnormalities Detected by Whole Exome Sequencing Correlation With Clinical Response [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Proportion of patients with particular genetic abnormalities detected by whole exome sequencing correlation with clinical response


Enrollment: 25
Study Start Date: July 2010
Study Completion Date: August 2012
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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: 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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
  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: 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
  More Information

Publications:
Responsible Party: Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01165996     History of Changes
Other Study ID Numbers: CASE2908, NCI-2010-00135, CASE2908
Study First Received: July 14, 2010
Results First Received: January 2, 2013
Last Updated: February 25, 2013
Health Authority: United States: Food and Drug Administration

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

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

ClinicalTrials.gov processed this record on November 27, 2014