NCT01165996 · REGISTRY CONDITION SEARCH

Differentiation Therapy With Decitabine in Treating Patients With Myelodysplastic Syndrome

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase: PHASE1, PHASE2
Status at capture: COMPLETED
Registry last update: 2019-03-04

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Number of Patients With Response as Defined by IWG (International Working Group) Criteria for Myelodysplasia

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outcome · POSTED

Number of Patients That Experience > Grade 2 Non-hematologic Toxicity by National Cancer Institute (NCI)/Cancer Therapy Evaluation Program (CTEP) v4 Criteria

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outcome · POSTED

Cytogenetic Response as Per IWG Criteria

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outcome · POSTED

Proportion of Patients With Pharmacodynamic Evidence of Drug Effect.

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outcome · POSTED

Proportion of Patients With Bone Marrow Evidence of Cytotoxicity.

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outcome · POSTED

Proportion of Patients With Bone Marrow Evidence of Terminal Differentiation Response to Therapy.

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outcome · POSTED

Proportion of Patients With Particular Genetic Abnormalities Detected by Whole Exome Sequencing Correlation With Clinical Response

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility 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
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
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.
intervention Names
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
label
Arm I: decitabine
type
EXPERIMENTAL

interventions

arm Group Labels
Arm I: decitabine
description
Correlative studies
name
flow cytometry
type
OTHER
arm Group Labels
Arm I: decitabine
description
Correlative studies
name
DNA methylation analysis
type
OTHER
arm Group Labels
Arm I: decitabine
description
Correlative studies
name
cytogenetic analysis
type
OTHER
arm Group Labels
Arm I: decitabine
description
Given subcutaneously
name
decitabine
other Names
5-aza-dCyd
5AZA
DAC
Dacogen
deoxyazacytidine
dezocitidine
type
DRUG
arm Group Labels
Arm I: decitabine
description
Correlative studies
name
microarray analysis
other Names
gene expression profiling
type
GENETIC
arm Group Labels
Arm I: decitabine
description
Correlative studies
name
gene expression analysis
type
GENETIC
arm Group Labels
Arm I: decitabine
description
Correlative studies
name
pharmacological study
other Names
pharmacological studies
type
OTHER
arm Group Labels
Arm I: decitabine
description
Correlative studies
name
polymorphism analysis
type
GENETIC

Study design

allocation

intervention Model

SINGLE_GROUP

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 25
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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
measure
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).

secondary Outcomes

description
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.
measure
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
description
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).
measure
Cytogenetic Response as Per IWG Criteria
time Frame
at 12 months
description
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.
measure
Proportion of Patients With Pharmacodynamic Evidence of Drug Effect.
time Frame
6 weeks after treatment
description
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.
measure
Proportion of Patients With Bone Marrow Evidence of Cytotoxicity.
time Frame
6 weeks after treatment
description
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
measure
Proportion of Patients With Bone Marrow Evidence of Terminal Differentiation Response to Therapy.
time Frame
6 weeks after treatment
description
Proportion of patients with particular genetic abnormalities, including DNA Methyltransferase 1 (DNMT1) depletion, detected by whole exome sequencing correlation with clinical response
measure
Proportion of Patients With Particular Genetic Abnormalities Detected by Whole Exome Sequencing Correlation With Clinical Response
time Frame
Baseline

Full study description

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.

Source references

references

citation
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25. doi: 10.1182/blood-2005-10-4149. Epub 2006 Apr 11.
pmid
16609072
type
BACKGROUND
citation
Saunthararajah Y, Sekeres M, Advani A, Mahfouz R, Durkin L, Radivoyevitch T, Englehaupt R, Juersivich J, Cooper K, Husseinzadeh H, Przychodzen B, Rump M, Hobson S, Earl M, Sobecks R, Dean R, Reu F, Tiu R, Hamilton B, Copelan E, Lichtin A, Hsi E, Kalaycio M, Maciejewski J. Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes. J Clin Invest. 2015 Mar 2;125(3):1043-55. doi: 10.1172/JCI78789. Epub 2015 Jan 26.
pmid
25621498
type
DERIVED

Source notices and limitations

Discovery and provenance

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Preserved source evidence · Not medical advice