Differentiation Therapy With Decitabine in Treating Patients With Myelodysplastic Syndrome

• Sponsor: Case Comprehensive Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01165996
• Collaborator: (none)
• Enrollment: 25
• Locations: 2
• Arm: 1
• Duration (Months): 25
• Patients Per Site: 12.5
• Patients Per Site Per Month: 0.5

Study Details

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.

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:

1. 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.

2. 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.

3. 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.

4. 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 Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: N/A
• 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: Jul 1, 2010
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Aug 1, 2012

Arms and Interventions

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 < 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 Names: gene expression profiling ; Genetic: gene expression analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies ; Genetic: polymorphism analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

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

   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

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 [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 [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. [6 weeks after treatment]

   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.

4. Proportion of Patients With Bone Marrow Evidence of Cytotoxicity. [6 weeks after treatment]

   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.

5. Proportion of Patients With Bone Marrow Evidence of Terminal Differentiation Response to Therapy. [6 weeks after treatment]

   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. Proportion of Patients With Particular Genetic Abnormalities Detected by Whole Exome Sequencing Correlation With Clinical Response [Baseline]

   Proportion of patients with particular genetic abnormalities, including DNA Methyltransferase 1 (DNMT1) depletion, detected by whole exome sequencing correlation with clinical response

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106
2	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

Study Documents (Full-Text)

None provided.

More Information

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.

• Responsible Party: Case Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT01165996
• Other Study ID Numbers: CASE2908; NCI-2010-00135; CASE2908
• First Posted: Jul 20, 2010
• Last Update Posted: Mar 4, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by Case Comprehensive Cancer Center: previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes
• Additional relevant MeSH terms: Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Anemia; Myelodysplastic Syndromes; Thrombocytopenia; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Syndrome; Decitabine; Azacitidine

Study Results

Participant Flow

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

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

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 Participants	25
Age, Customized (participants) [Number]
40-49 years	1 4%
50-59 years	1 4%
60-69 years	8 32%
70-79 years	9 36%
80-89 years	6 24%
Sex: Female, Male (Count of Participants)
Female	11 44%
Male	14 56%
Region of Enrollment (participants) [Number]
United States	25 100%

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.
Measure Participants	25
Hematologic Improvement	7 28%
Complete Remission	4 16%
Partial Remission	0 0%
Stable Disease	9 36%
Disease Progression	5 20%

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.
Measure Participants	25
Number [participants]	16 64%

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.
Measure Participants	11
complete cytogenetic remission	5 20%
partial cytogenetic remission	2 8%
no cytogenetic remission	4 16%

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
Measure Participants	25
Number [participants]	25 100%

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
Measure Participants	11
Complete cytogenetic remission	5 20%
Partial cytogenetic remission	2 8%

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
Measure Participants	25
Number [participants]	11 44%

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
Measure Participants	25
Number [participants]	4 16%

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 (%)	# Events
Total	3/25 (12%)
Serious Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	15/25 (60%)
Blood and lymphatic system disorders
Febrile neutropenia	10/25 (40%)	17
Neutropenic Fever	2/25 (8%)	4
General disorders
Death	3/25 (12%)	3
fever	1/25 (4%)	1
Left Sided Chest Pain	1/25 (4%)	1
Infections and infestations
bacterial infection	2/25 (8%)	2
Sepsis	1/25 (4%)	1
Tooth Extraction	1/25 (4%)	1
Urinary tract infection	1/25 (4%)	1
Metabolism and nutrition disorders
Dehydration	1/25 (4%)	1
Nervous system disorders
Headache	1/25 (4%)	1
Renal and urinary disorders
Hematuria	1/25 (4%)	1
Respiratory, thoracic and mediastinal disorders
aspiration pneumonia	1/25 (4%)	1
Skin and subcutaneous tissue disorders
Furuncle on left groin area	1/25 (4%)	1
Vascular disorders
Acute Left Popliteal DVT	1/25 (4%)	1
Hypertension	1/25 (4%)	2
Hypotension	1/25 (4%)	1
Orthostasis	1/25 (4%)	2
Orthostatic Hypotension	1/25 (4%)	1
Other (Not Including Serious) Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.