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A Proof of Concept Study of Non-DNA Damaging DNMT1 Depletion Therapy for Myelodysplastic Syndrome


Phase 1/Phase 2
18 Years
N/A
Not Enrolling
Both
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

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Trial Information

A Proof of Concept Study of Non-DNA Damaging DNMT1 Depletion Therapy for 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.

Inclusion 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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Patients With Response as Defined by IWG (International Working Group) Criteria for Myelodysplasia

Outcome Description:

The criteria for complete remission (CR) and partial remission (PR) involve specific improvements in marrow and peripheral blood measurements obtained on 2 or more successive assessments. The response parameters in peripheral blood must be maintained for at least 8 weeks. Responses designated as 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 (11 g/dL) 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 classification category than prior to treatment.

Outcome Time Frame:

Formal assessment at week 12 for study primary end-point (hematologic improvement).

Safety Issue:

No

Principal Investigator

Yogen Saunthararajah

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

CASE2908

NCT ID:

NCT01165996

Start Date:

July 2010

Completion Date:

August 2012

Related Keywords:

  • 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
  • previously treated myelodysplastic syndromes
  • secondary myelodysplastic syndromes
  • Anemia
  • Anemia, Refractory
  • Anemia, Refractory, with Excess of Blasts
  • Leukemia
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute
  • Thrombocytopenia

Name

Location
Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center Cleveland, Ohio  44106-5065
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center Cleveland, Ohio  44195