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Decitabine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00049582
First received: November 12, 2002
Last updated: January 23, 2013
Last verified: January 2013
History of Changes
  Purpose

This phase I trial is studying the side effects and best dose of decitabine in treating patients with myelodysplastic syndromes or acute myeloid leukemia. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die


Condition Intervention Phase
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative
de Novo Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
Previously Treated Myelodysplastic Syndromes
Recurrent Adult Acute Myeloid Leukemia
Secondary Acute Myeloid Leukemia
Secondary Myelodysplastic Syndromes
Untreated Adult Acute Myeloid Leukemia
 Drug: decitabine
Other: laboratory biomarker analysis
Other: pharmacological study
 Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study Of 5-aza-2'-Deoxycytidine (Decitabine) As A Biologic Modifier Of Retinoid Responsive Genes In Patients With High-Risk Myelodysplastic Syndromes And Acute Myelogenous Leukemia (De-novo, Relapsed or Secondary)

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) of decitabine, graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0 [ Time Frame: Up to day 28 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Minimal effective dose of decitabine that will lead to demethylation of deoxyribonucleic acid (DNA) with tolerable toxicity as assessed by RXR gene [ Time Frame: Up to day 28 ] [ Designated as safety issue: No ]
  • Proportion of patients with in-vitro retinoid response [ Time Frame: Up to 8 years ] [ Designated as safety issue: No ]
  • Duration of clinical response [ Time Frame: Up to 8 years ] [ Designated as safety issue: No ]
  • Changes in gene expression, gene methylation and bone marrow aspirate sample measurements [ Time Frame: Up to day 5 ] [ Designated as safety issue: No ]
    The effect on gene expression due to pharmacological exposures (ie retinoic acid receptor [RAR] or retinoid X receptor [RXR]) will be assessed using chi-square tests.


Enrollment: 36
Study Start Date: September 2002
Primary Completion Date: September 2005 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (decitabine)

Patients receive decitabine IV over 3 hours twice daily OR IV over 1 hour once daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of decitabine until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

 Drug: decitabine
Given IV
Other Names:
  • 5-aza-dCyd
  • 5AZA
  • DAC
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

OBJECTIVES:

I. Determine the maximum tolerated dose of decitabine in patients with high-risk myelodysplastic syndromes or acute myeloid leukemia.

II. Determine the minimum effective dose of this drug that produces demethylation of DNA with tolerable toxicity in these patients.

III. Determine the minimum effective dose of this drug that augments in vitro responses to retinoids.

IV. Determine the pharmacokinetics of this drug in these patients. V. Determine the clinical response rate of patients treated with this drug.

OUTLINE: This is a dose-escalation, multicenter study.

Patients receive decitabine IV over 3 hours twice daily OR IV over 1 hour once daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of decitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

PROJECTED ACCRUAL: A maximum of 36 patients will be accrued for this study within 18 months.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • One of the following diagnoses:

    • High-risk myelodysplastic syndromes (MDS)

    • Acute myeloid leukemia (AML)

      • De novo, secondary, or relapsed disease
      • Any number of prior regimens for primary or relapsed disease
  • Ineligible for or refuses aggressive management

  • Measurable disease, defined as:

    • More than 5% blasts in bone marrow of patients with MDS
    • More than 30% blasts in bone marrow of patients with AML
  • Involvement of cerebrospinal fluid allowed
  • Performance status - ECOG 0-2
  • Performance status - Karnofsky 60-100%
  • See Disease Characteristics
  • Bilirubin no greater than 1.25 times upper limit of normal (ULN)
  • AST and/or ALT no greater than 1.25 times ULN
  • Creatinine less than 1.7 mg/dL
  • Creatinine clearance at least 60 mL/min
  • No symptomatic congestive heart failure
  • No unstable angina pectoris
  • No cardiac arrhythmia
  • No ongoing or active infection
  • No other uncontrolled illness that would preclude study participation
  • No psychiatric illness or social situation that would preclude study compliance
  • No prior allergic reactions to compounds of similar chemical or biological composition to decitabine
  • No other active malignancy
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • At least 4 weeks since prior biologic therapy (e.g., interferon, filgrastim [G-CSF], sargramostim [GM-CSF], thrombopoietin, or epoetin alfa)
  • No concurrent hematopoietic growth factors (GM-CSF, thrombopoietin, or epoetin alfa)
  • No concurrent prophylactic G-CSF
  • Prior intrathecal cytarabine allowed for patients with cerebrospinal fluid involvement
  • At least 4 weeks since prior chemotherapy (except low-dose chemotherapy administered to maintain WBC counts) (6 weeks for nitrosoureas or mitomycin) and recovered
  • At least 24 hours since prior hydroxyurea
  • Concurrent intrathecal cytarabine allowed for patients with cerebrospinal fluid involvement
  • No prior radiotherapy greater than 3,000 cGy to marrow-producing areas
  • At least 4 weeks since prior radiotherapy and recovered
  • Prior investigational therapy allowed
  • No other concurrent investigational agents
  • No concurrent combination antiretroviral therapy for HIV-positive patients
  • No other concurrent anticancer therapy
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00049582

Locations
Canada, Ontario
Princess Margaret Hospital Phase 2 Consortium
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Mark Minden Princess Margaret Hospital Phase 2 Consortium
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00049582     History of Changes
Other Study ID Numbers: NCI-2012-02502, PMH-PHL-004, N01CM62203, CDR0000258121
Study First Received: November 12, 2002
Last Updated: January 23, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Congenital Abnormalities
Neoplasms
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Myelodysplastic Syndromes
Preleukemia
Myeloproliferative Disorders
Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
Myelodysplastic-Myeloproliferative Diseases
Neoplasms by Histologic Type
 Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on May 22, 2013