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| ID | Type | Description | Link |
|---|---|---|---|
| NCI-2010-00135 | Other Identifier | NCI/CTRP | |
| CASE2908 | Other Identifier | Case Comprehensive Cancer Center |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm I: decitabine | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| flow cytometry | Other | Correlative studies |
| |
| DNA methylation analysis |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Patients With Response as Defined by IWG (International Working Group) Criteria for Myelodysplasia | 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). |
| 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 | 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. |
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Inclusion
Exclusion
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| Name | Affiliation | Role |
|---|---|---|
| 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 | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center | Cleveland | Ohio | 44106 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 16609072 | Background | 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. | |
| 25621498 |
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Patients were recruited from medical clinic between July 2010 and September 2011.
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| ID | Title | Description |
|---|---|---|
| FG000 | Arm I: Decitabine 0.2mg/kg | 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. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Other |
Correlative studies |
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| cytogenetic analysis | Other | Correlative studies |
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| decitabine | Drug | Given subcutaneously |
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| microarray analysis | Genetic | Correlative studies |
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| gene expression analysis | Genetic | Correlative studies |
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| pharmacological study | Other | Correlative studies |
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| polymorphism analysis | Genetic | Correlative studies |
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| up to 12 months of treatment |
| Cytogenetic Response as Per IWG Criteria | 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. | 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. | 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. | 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 | Proportion of patients with particular genetic abnormalities, including DNA Methyltransferase 1 (DNMT1) depletion, detected by whole exome sequencing correlation with clinical response | Baseline |
| Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center | Cleveland | Ohio | 44195 | United States |
| Derived |
| 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. |
| Induction Phase |
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| Maintenance Phase |
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| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Arm I: Decitabine 0.2mg/kg | 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. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Number | participants |
| ||||||||||||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||||||||||||
| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Patients With Response as Defined by IWG (International Working Group) Criteria for Myelodysplasia | 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 | All patients enrolled and that received any treatment. | Posted | Number | participants | Formal assessment at week 12 for study primary end-point (hematologic improvement). |
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| Secondary | Number of Patients That Experience > Grade 2 Non-hematologic Toxicity by National Cancer Institute (NCI)/Cancer Therapy Evaluation Program (CTEP) v4 Criteria | 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. | All patients that received treatment. | Posted | Number | participants | up to 12 months of treatment |
|
| |||||||||||||||||||||||||||||||||||||
| Secondary | Cytogenetic Response as Per IWG Criteria | 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). | Patients that had cytogenetic abnormalities at baseline and were evaluable with follow-up metaphase karyotyping. | Posted | Number | participants | at 12 months |
|
| |||||||||||||||||||||||||||||||||||||
| Secondary | Proportion of Patients With Pharmacodynamic Evidence of Drug Effect. | 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. | All subjects that had treatment with DNMT1 depletion. | Posted | Number | participants | 6 weeks after treatment |
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| |||||||||||||||||||||||||||||||||||||
| Secondary | Proportion of Patients With Bone Marrow Evidence of Cytotoxicity. | 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. | Patients with chromosomal abnormalities which were evaluable for follow-up karyotyping | Posted | Number | participants | 6 weeks after treatment |
|
| |||||||||||||||||||||||||||||||||||||
| Secondary | Proportion of Patients With Bone Marrow Evidence of Terminal Differentiation Response to Therapy. | 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 | Posted | Number | participants | 6 weeks after treatment |
|
| ||||||||||||||||||||||||||||||||||||||
| Secondary | Proportion of Patients With Particular Genetic Abnormalities Detected by Whole Exome Sequencing Correlation With Clinical Response | Proportion of patients with particular genetic abnormalities, including DNA Methyltransferase 1 (DNMT1) depletion, detected by whole exome sequencing correlation with clinical response | Posted | Number | participants | Baseline |
|
|
Data collected from on treatment to completion of treatment over a 1 year period.
Only grade 3 and above AEs were collected and all submitted as SAEs.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Arm I | 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. | 3 | 25 | 15 | 25 | 0 | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute Left Popliteal DVT | Vascular disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| aspiration pneumonia | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| bacterial infection | Infections and infestations | CTCAE (4.0) | Non-systematic Assessment |
| |
| Dehydration | Metabolism and nutrition disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Death | General disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Febrile neutropenia | Blood and lymphatic system disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| fever | General disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Furuncle on left groin area | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Headache | Nervous system disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Hematuria | Renal and urinary disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Hypertension | Vascular disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Hypotension | Vascular disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Left Sided Chest Pain | General disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Neutropenic Fever | Blood and lymphatic system disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Orthostasis | Vascular disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Orthostatic Hypotension | Vascular disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Sepsis | Infections and infestations | CTCAE (4.0) | Non-systematic Assessment |
| |
| Tooth Extraction | Infections and infestations | CTCAE (4.0) | Non-systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | CTCAE (4.0) | Non-systematic Assessment |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Yogen Saunthararajah, MD | Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center | 216-444-8170 | saunthy@ccf.org |
| ID | Term |
|---|---|
| D015477 | Leukemia, Myelomonocytic, Chronic |
| D009190 | Myelodysplastic Syndromes |
| D000753 | Anemia, Refractory |
| D000754 | Anemia, Refractory, with Excess of Blasts |
| D013921 | Thrombocytopenia |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D054437 | Myelodysplastic-Myeloproliferative Diseases |
| D001855 | Bone Marrow Diseases |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D000740 | Anemia |
| D001791 | Blood Platelet Disorders |
| D000095542 | Cytopenia |
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| ID | Term |
|---|---|
| D005434 | Flow Cytometry |
| D019175 | DNA Methylation |
| D020732 | Cytogenetic Analysis |
| D000077209 | Decitabine |
| D046228 | Microarray Analysis |
| D020869 | Gene Expression Profiling |
| D054458 | Amplified Fragment Length Polymorphism Analysis |
| ID | Term |
|---|---|
| D002469 | Cell Separation |
| D003584 | Cytological Techniques |
| D019411 | Clinical Laboratory Techniques |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D003592 | Cytophotometry |
| D005470 | Fluorometry |
| D008163 | Luminescent Measurements |
| D010783 | Photometry |
| D002623 | Chemistry Techniques, Analytical |
| D008919 | Investigative Techniques |
| D008745 | Methylation |
| D000478 | Alkylation |
| D001669 | Biochemical Phenomena |
| D055598 | Chemical Phenomena |
| D008660 | Metabolism |
| D055614 | Genetic Phenomena |
| D005821 | Genetic Techniques |
| D001374 | Azacitidine |
| D001372 | Aza Compounds |
| D009930 | Organic Chemicals |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D012263 | Ribonucleosides |
| D046208 | Microchip Analytical Procedures |
| D016172 | DNA Fingerprinting |
| D016133 | Polymerase Chain Reaction |
| D021141 | Nucleic Acid Amplification Techniques |
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| Title | Measurements |
|---|---|
|
| 70-79 years |
|
| 80-89 years |
|
| Title | Measurements |
|---|---|
|
| Stable Disease |
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| Disease Progression |
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