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 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:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• 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: July 2010
• Actual Primary Completion Date: December 2011
• Actual Study Completion Date: August 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 Name: gene expression profiling; Genetic: gene expression analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Name: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: 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

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

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:

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 Posted: July 20, 2010
• Results First Posted: February 26, 2013
• Last Update Posted: March 4, 2019
• Last Verified: February 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; Disease; Pathologic Processes; Hematologic Diseases; Bone Marrow Diseases; Precancerous Conditions; Neoplasms; Blood Platelet Disorders; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Myelodysplastic-Myeloproliferative Diseases; Decitabine; Azacitidine; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Enzyme Inhibitors