Decitabine as Maintenance Therapy After Standard Therapy in Treating Patients With Previously Untreated Acute Myeloid Leukemia

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Brief Title

Decitabine as Maintenance Therapy After Standard Therapy in Treating Patients With Previously Untreated Acute Myeloid Leukemia

Official Title

Phase II Study of Maintenance Therapy With Decitabine (NSC #127716) Following Standard Induction and Cytogenetic Risk-Adapted Intensification in Previously Untreated Patients With AML < 60 Years

Brief Summary

      This phase II trial is studying the side effects and how well decitabine works when given as
      maintenance therapy after standard therapy in treating patients with previously untreated
      acute myeloid leukemia. Drugs used in chemotherapy, such as cytarabine, daunorubicin,
      etoposide, busulfan, and decitabine, work in different ways to stop the growth of cancer
      cells, either by killing the cells or by stopping them from dividing. Giving decitabine as
      maintenance therapy after standard therapy may keep cancer cells from coming back.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the efficacy, feasibility, and toxicities when one year of maintenance
      therapy with decitabine is given to patients < 60 years with untreated acute myeloid leukemia
      (AML) who achieve and maintain first complete remission (CR) following an established
      induction and intensification regimen.

      II. To determine the 1-year disease free survival rate for AML patients in first CR treated
      with maintenance decitabine.

      SECONDARY OBJECTIVES:

      I. To measure biologic response to decitabine in evaluable patients with fusion genes to
      determine eradication of minimal residual disease.

      II. To measure surrogates for deoxyribonucleic acid (DNA) demethylation including
      downregulation of DNA methyltransferase 1 (DNMT1) and induction of fetal hemoglobin.

      III. To examine the significance of gene re expression following ex vivo decitabine exposure
      in primary AML cells taken at the time of diagnosis on clinical outcome and on gene
      expression at the time of relapse after in vivo decitabine exposure.

      IV. To continue to evaluate the effectiveness of a cytogenetically risk-adapted approach for
      consolidation therapy for patients with core binding factor (CBF) or non-CBF AML.

      V. To continue the investigation begun in Cancer and Leukemia Group B (CALGB) 19808 aimed at
      correlation of the rate of relapse and toxicity with intravenous (IV) busulfan
      pharmacokinetics when busulfan and etoposide are used as the preparative regimen for
      autologous stem cell transplantation for AML patients in first CR.

      VI. To correlate outcome measures such as complete response (CR), disease-free survival
      (DFS), event-free survival (EFS), and overall survival (OS), with pretreatment
      characteristics such as age, sex, race, blood counts, morphology, immunophenotype,
      cytogenetics, and molecular features of AML.

      OUTLINE:

      REMISSION INDUCTION THERAPY: Patients receive cytarabine IV over 168 hours on days 1-7 and
      daunorubicin hydrochloride IV over 5-10 minutes and etoposide IV over 2 hours on days 1-3.
      Patients undergo bone marrow biopsy on day 14. Patients with residual leukemia proceed to
      second remission induction therapy. Patients achieving complete remission (CR) proceed to
      intensification therapy.

      SECOND REMISSION INDUCTION THERAPY: Patients receive cytarabine IV over 120 hours on days 1-5
      and daunorubicin hydrochloride IV and etoposide IV over 2 hours on days 1 and 2. Patients
      undergo bone marrow biopsy on day 42. Patients with residual leukemia are removed from the
      study. Patients achieving CR proceed to intensification therapy.

      INTENSIFICATION THERAPY: Patients are stratified and receive intensification therapy
      according to cytogenetic findings (favorable cytogenetics [t(8;21)(q22q22), inv(16)(p13;q22),
      or t(16;16)(p13;q22) by cytogenetic and/or molecular analysis] vs unfavorable cytogenetics
      [all other cytogenetic findings, including normal cytogenetics]).

      FAVORABLE CYTOGENETICS: Within 2-4 weeks after achieving CR, patients receive high-dose
      cytarabine IV over 3 hours twice daily on days 1, 3, and 5.

      Treatment repeats every 28 days for up to 3 courses.

      UNFAVORABLE CYTOGENETICS: Peripheral blood stem cell (PBSC) mobilization: Within 2-4 weeks
      after achieving CR, patients receive etoposide IV over 96 hours and high-dose cytarabine IV
      over 2 hours twice daily on days 1-4 and filgrastim (G-CSF) subcutaneously (SC) once daily
      beginning on day 14 and continuing until blood counts recover. Patients then proceed to
      transplantation.

      PBSC OR BONE MARROW TRANSPLANTATION: Patients receive busulfan IV over 2 hours 4 times daily
      on days -7 to -4 and etoposide IV over 4 hours on day -3. Patients undergo autologous PBSC or
      bone marrow transplantation on day 0 and receive G-CSF SC once daily beginning on day 0 and
      continuing until blood counts recover.

      UNFAVORABLE CYTOGENETICS AND UNABLE TO UNDERGO PBSC TRANSPLANTATION: Within 2-4 weeks after
      achieving CR, patients receive etoposide, high-dose cytarabine, and G-CSF as in unfavorable
      cytogenetics (PBSC mobilization) followed by 2 courses of high-dose cytarabine as in
      favorable genetics.

      MAINTENANCE THERAPY: Within 60-90 days after completion of intensification therapy, patients
      receive decitabine IV over 1 hour on days 1-5. Treatment repeats every 6 weeks for up to 8
      courses.

      After completion of study treatment, patients are followed up every 2 months for 1 year,
      every 6 months for 2 years, and then yearly for 2 years.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Number of Participants Who Completed Maintenance Decitabine.


Condition

Acute Myeloid Leukemia

Intervention

Autologous Bone Marrow Transplantation

Study Arms / Comparison Groups

 Treatment (chemotherapy, PBSC or bone marrow transplantation)
Description:  See Detailed Description.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Procedure

Estimated Enrollment

546

Start Date

November 15, 2006

Completion Date

December 1, 2016

Primary Completion Date

January 31, 2011

Eligibility Criteria

        Inclusion Criteria:

          -  Unequivocal histologic diagnosis of AML (> 20% blasts in the bone marrow based on the
             World Health Organization [WHO] and/or French American British [FAB] classifications),
             excluding M3 (acute promyelocytic leukemia); patients with antecedent myelodysplasia
             are eligible for treatment on this trial only if there were no bone marrow biopsy
             showing myelodysplastic syndrome (MDS) > 3 months prior to enrollment; patients with
             therapy-related AML are eligible if they have been free of their primary disease and
             have not received any chemotherapy for at least 2 years

          -  No prior 5-azacitidine or decitabine therapy

          -  No prior treatment for leukemia or myelodysplastic syndrome with four permissible
             exceptions:

               -  Emergency leukapheresis

               -  Emergency treatment for hyperleukocytosis with hydroxyurea

               -  Cranial radiation therapy (RT) for central nervous system (CNS) leukostasis (one
                  dose only)

               -  Growth factor/cytokine support
      

Gender

All

Ages

15 Years - 59 Years

Accepts Healthy Volunteers

No

Contacts

William Blum, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00416598

Organization ID

NCI-2009-00444

Secondary IDs

NCI-2009-00444

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

William Blum, Principal Investigator, Alliance for Clinical Trials in Oncology


Verification Date

January 2019