Differentiation Therapy With Decitabine in Treating Patients With Myelodysplastic Syndrome

• 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: Case Comprehensive Cancer Center
• Information provided by (Responsible Party): Case Comprehensive Cancer Center

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: 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
• 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
• Enrollment: 25

Participant Flow

Recruitment Details	Patients were recruited from medical clinic between July 2010 and September 2011.
Pre-assignment Details

Arm/Group Title	Arm I: Decitabine 0.2mg/kg
Arm/Group 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.
Period Title: Overall Study
Started	25
Induction Phase	25
Maintenance Phase	23
Completed	23
Not Completed	2
Reason Not Completed
Death	1
Physician Decision	1

Baseline Characteristics

Arm/Group Title		Arm I: Decitabine 0.2mg/kg
Arm/Group 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.
Overall Number of Baseline Participants		25
Baseline Analysis Population Description		[Not Specified]
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	25 participants
40-49 years		1
50-59 years		1
60-69 years		8
70-79 years		9
80-89 years		6
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	25 participants
	Female	11 44.0%
	Male	14 56.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	25 participants
		25

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Response as Defined by IWG (International Working Group) Criteria for Myelodysplasia
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
Time Frame	Formal assessment at week 12 for study primary end-point (hematologic improvement).

Outcome Measure Data

Analysis Population Description

All patients enrolled and that received any treatment.

Arm/Group Title	Arm I: Decitabine 0.2mg/kg
Arm/Group 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.
Overall Number of Participants Analyzed	25
Measure Type: Number; Unit of Measure: participants
Hematologic Improvement	7
Complete Remission	4
Partial Remission	0
Stable Disease	9
Disease Progression	5

2. Secondary Outcome

Title	Number of Patients That Experience > Grade 2 Non-hematologic Toxicity by National Cancer Institute (NCI)/Cancer Therapy Evaluation Program (CTEP) v4 Criteria
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.
Time Frame	up to 12 months of treatment

Outcome Measure Data

Analysis Population Description

All patients that received treatment.

Arm/Group Title	Arm I: Decitabine 0.2mg/kg
Arm/Group 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.
Overall Number of Participants Analyzed	25
Measure Type: Number; Unit of Measure: participants
	16

3. Secondary Outcome

Title	Cytogenetic Response as Per IWG Criteria
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).
Time Frame	at 12 months

Outcome Measure Data

Analysis Population Description

Patients that had cytogenetic abnormalities at baseline and were evaluable with follow-up metaphase karyotyping.

Arm/Group Title	Arm I: Decitabine 0.2mg/kg
Arm/Group 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.
Overall Number of Participants Analyzed	11
Measure Type: Number; Unit of Measure: participants
complete cytogenetic remission	5
partial cytogenetic remission	2
no cytogenetic remission	4

4. Secondary Outcome

Title	Proportion of Patients With Pharmacodynamic Evidence of Drug Effect.
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.
Time Frame	6 weeks after treatment

Outcome Measure Data

Analysis Population Description

All subjects that had treatment with DNMT1 depletion.

Arm/Group Title	Arm I: Decitabine 0.2mg/kg
Arm/Group 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. flow cytometry: Correlative studies DNA methylation analysis: Correlative studies cytogenetic analysis: Correlative studies decitabine: Given subcutaneously microarray analysis: Correlative studies gene expression analysis: Correlative studies pharmacological study: Correlative studies polymorphism analysis: Correlative studies
Overall Number of Participants Analyzed	25
Measure Type: Number; Unit of Measure: participants
	25

5. Secondary Outcome

Title	Proportion of Patients With Bone Marrow Evidence of Cytotoxicity.
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.
Time Frame	6 weeks after treatment

Outcome Measure Data

Analysis Population Description

Patients with chromosomal abnormalities which were evaluable for follow-up karyotyping

Arm/Group Title	Arm I: Decitabine 0.2mg/kg
Arm/Group 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. flow cytometry: Correlative studies DNA methylation analysis: Correlative studies cytogenetic analysis: Correlative studies decitabine: Given subcutaneously microarray analysis: Correlative studies gene expression analysis: Correlative studies pharmacological study: Correlative studies polymorphism analysis: Correlative studies
Overall Number of Participants Analyzed	11
Measure Type: Number; Unit of Measure: participants
Complete cytogenetic remission	5
Partial cytogenetic remission	2

6. Secondary Outcome

Title	Proportion of Patients With Bone Marrow Evidence of Terminal Differentiation Response to Therapy.
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
Time Frame	6 weeks after treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I: Decitabine 0.2mg/kg
Arm/Group 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. flow cytometry: Correlative studies DNA methylation analysis: Correlative studies cytogenetic analysis: Correlative studies decitabine: Given subcutaneously microarray analysis: Correlative studies gene expression analysis: Correlative studies pharmacological study: Correlative studies polymorphism analysis: Correlative studies
Overall Number of Participants Analyzed	25
Measure Type: Number; Unit of Measure: participants
	11

7. Secondary Outcome

Title	Proportion of Patients With Particular Genetic Abnormalities Detected by Whole Exome Sequencing Correlation With Clinical Response
Description	Proportion of patients with particular genetic abnormalities, including DNA Methyltransferase 1 (DNMT1) depletion, detected by whole exome sequencing correlation with clinical response
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I: Decitabine 0.2mg/kg
Arm/Group 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. flow cytometry: Correlative studies DNA methylation analysis: Correlative studies cytogenetic analysis: Correlative studies decitabine: Given subcutaneously microarray analysis: Correlative studies gene expression analysis: Correlative studies pharmacological study: Correlative studies polymorphism analysis: Correlative studies
Overall Number of Participants Analyzed	25
Measure Type: Number; Unit of Measure: participants
	4

Adverse Events

Time Frame	Data collected from on treatment to completion of treatment over a 1 year period.
Adverse Event Reporting Description	Only grade 3 and above AEs were collected and all submitted as SAEs.
Arm/Group Title	Arm I
Arm/Group 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.
All-Cause Mortality
	Arm I
	Affected / at Risk (%)
Total	3/25 (12.00%)
Serious Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	15/25 (60.00%)
Blood and lymphatic system disorders
Febrile neutropenia * 1	10/25 (40.00%)	17
Neutropenic Fever * 1	2/25 (8.00%)	4
General disorders
Death * 1	3/25 (12.00%)	3
fever * 1	1/25 (4.00%)	1
Left Sided Chest Pain * 1	1/25 (4.00%)	1
Infections and infestations
bacterial infection * 1	2/25 (8.00%)	2
Sepsis * 1	1/25 (4.00%)	1
Tooth Extraction * 1	1/25 (4.00%)	1
Urinary tract infection * 1	1/25 (4.00%)	1
Metabolism and nutrition disorders
Dehydration * 1	1/25 (4.00%)	1
Nervous system disorders
Headache * 1	1/25 (4.00%)	1
Renal and urinary disorders
Hematuria * 1	1/25 (4.00%)	1
Respiratory, thoracic and mediastinal disorders
aspiration pneumonia * 1	1/25 (4.00%)	1
Skin and subcutaneous tissue disorders
Furuncle on left groin area * 1	1/25 (4.00%)	1
Vascular disorders
Acute Left Popliteal DVT * 1	1/25 (4.00%)	1
Hypertension * 1	1/25 (4.00%)	2
Hypotension * 1	1/25 (4.00%)	1
Orthostasis * 1	1/25 (4.00%)	2
Orthostatic Hypotension * 1	1/25 (4.00%)	1
1 Term from vocabulary, CTCAE (4.0); * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Arm I
	Affected / at Risk (%)	# Events
Total	0/0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Yogen Saunthararajah, MD
• Organization: Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
• Phone: 216-444-8170
• EMail: saunthy@ccf.org

Publications:

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. Epub 2006 Apr 11.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Case Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT01165996
• Other Study ID Numbers: CASE2908; NCI-2010-00135 ( Other Identifier: NCI/CTRP ); CASE2908 ( Other Identifier: Case Comprehensive Cancer Center )
• First Submitted: July 14, 2010
• First Posted: July 20, 2010
• Results First Submitted: January 2, 2013
• Results First Posted: February 26, 2013
• Last Update Posted: March 4, 2019