Clinical trial NCT01165996: Differentiation Therapy With Decitabine in Treating Patients With Myelodysplastic Syndrome
Official title: A Proof of Concept Study of Non-DNA Damaging DNMT1 Depletion Therapy for Myelodysplastic Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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
Keywords: previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
Lead sponsor: Case Comprehensive Cancer Center
Sponsor class: OTHER
First posted: 2010-07-20
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of Patients With Response as Defined by IWG (International Working Group) Criteria for Myelodysplasia
timeFrame: Formal assessment at week 12 for study primary end-point (hematologic improvement).
Secondary outcomes:
measure: Number of Patients That Experience > Grade 2 Non-hematologic Toxicity by National Cancer Institute (NCI)/Cancer Therapy Evaluation Program (CTEP) v4 Criteria
timeFrame: up to 12 months of treatment
measure: Cytogenetic Response as Per IWG Criteria
timeFrame: at 12 months
measure: Proportion of Patients With Pharmacodynamic Evidence of Drug Effect.
timeFrame: 6 weeks after treatment
measure: Proportion of Patients With Bone Marrow Evidence of Cytotoxicity.
timeFrame: 6 weeks after treatment
measure: Proportion of Patients With Bone Marrow Evidence of Terminal Differentiation Response to Therapy.
timeFrame: 6 weeks after treatment
measure: Proportion of Patients With Particular Genetic Abnormalities Detected by Whole Exome Sequencing Correlation With Clinical Response
timeFrame: Baseline
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
state: Ohio
Study officials:
affiliation: Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
name: Yogen Saunthararajah
role: PRINCIPAL_INVESTIGATOR
affiliation: Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
name: Brenda Cooper, MD
role: PRINCIPAL_INVESTIGATOR
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.
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.