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Decitabine and Total-Body Irradiation Followed By Donor Bone Marrow Transplant and Cyclophosphamide in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

NCT01707004

Description:

This phase II trial studies how well decitabine and total-body irradiation followed by donor bone marrow transplant and cyclophosphamide works in treating patients with relapsed or refractory acute myeloid leukemia. Giving decitabine and total-body irradiation before a donor bone marrow transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving decitabine and total-body irradiation before the transplant together with high-dose cyclophosphamide, tacrolimus, and mycophenolate mofetil after the transplant may stop this from happening.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
  • Myeloproliferative Neoplasm
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Decitabine and Total-Body Irradiation Followed By Donor Bone Marrow Transplant and Cyclophosphamide in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
  • Official Title: Decitabine Followed by Bone Marrow Transplant and High-Dose Cyclophosphamide for the Treatment of Relapsed and Refractory Acute Myeloid Neoplasms

Clinical Trial IDs

  • ORG STUDY ID: HO11421
  • SECONDARY ID: NCI-2012-01325
  • SECONDARY ID: 2012-0217
  • SECONDARY ID: 2017-0116
  • SECONDARY ID: P30CA014520
  • NCT ID: NCT01707004

Conditions

  • Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
  • Adult Acute Myeloid Leukemia in Remission
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • 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)
  • de Novo Myelodysplastic Syndromes
  • Previously Treated Myelodysplastic Syndromes
  • Recurrent Adult Acute Myeloid Leukemia
  • Secondary Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
decitabine5-aza-dCyd, 5AZA, DACTreatment (donor bone marrow transplant)
fludarabine phosphate2-F-ara-AMP, Beneflur, FludaraTreatment (donor bone marrow transplant)
busulfanBSF, BU, Misulfan, Mitosan, MyeloleukonTreatment (donor bone marrow transplant)
cyclophosphamideCPM, CTX, Cytoxan, Endoxan, EndoxanaTreatment (donor bone marrow transplant)
tacrolimusFK 506, PrografTreatment (donor bone marrow transplant)
mycophenolate mofetilCellcept, MMFTreatment (donor bone marrow transplant)
filgrastimG-CSF, NeupogenTreatment (donor bone marrow transplant)

Purpose

This phase II trial studies how well decitabine and total-body irradiation followed by donor bone marrow transplant and cyclophosphamide works in treating patients with relapsed or refractory acute myeloid leukemia. Giving decitabine and total-body irradiation before a donor bone marrow transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving decitabine and total-body irradiation before the transplant together with high-dose cyclophosphamide, tacrolimus, and mycophenolate mofetil after the transplant may stop this from happening.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine overall survival at 100 days after transplantation following decitabine and a
      bone marrow transplant using a donor that is at least partially-matched and a myeloablative
      preparative regimen with post-transplantation cyclophosphamide for graft-versus-host disease
      (GVHD) prophylaxis.

      SECONDARY OBJECTIVES:

      I. Patients enrolled in this study will also be followed for the following endpoints:
      neutrophil and platelet recovery, graft failure, acute graft-versus-host disease (GVHD),
      chronic GVHD, incidence of infection, treatment-related mortality, time to
      relapse/progression, overall survival, and progression-free survival.

      OUTLINE:

      Beginning between days -29 and -22, patients receive decitabine intravenously (IV) over 1
      hour daily for 10 days, fludarabine phosphate IV over 30 minutes on days -5 to -2, and
      busulfan IV over 3 hours on days -5 to -2.

      PREPARATIVE REGIMEN: Patients undergo total-body irradiation twice daily (BID) on day -1.

      TRANSPLANT: Patients undergo allogeneic bone marrow transplant on day 0.

      GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 2 hours on days 3 and 4,
      tacrolimus orally (PO) BID or IV continuously on days 5-180, mycophenolate mofetil PO three
      times daily (TID) on days 5-35 and filgrastim subcutaneously (SC) beginning day 5 until
      absolute neutrophil count (ANC) >= 1,000/mm^3 for 3 consecutive days.

      After completion of study treatment, patients are followed up at 6 months and 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (donor bone marrow transplant)ExperimentalBeginning between days -29 and -22, patients receive decitabine IV over 1 hour daily for 10 days, fludarabine phosphate IV over 30 minutes on days -5 to -2, and busulfan IV over 3 hours on days -5 to -2. PREPARATIVE REGIMEN: Patients undergo total-body irradiation BID on day -1. TRANSPLANT: Patients undergo allogeneic bone marrow transplant on day 0. GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 2 hours on days 3 and 4, tacrolimus PO BID or IV continuously on days 5-180, mycophenolate mofetil PO TID on days 5-35, and filgrastim SC beginning day 5 until ANC >= 1,000/mm^3 for 3 consecutive days.
  • decitabine
  • fludarabine phosphate
  • busulfan
  • cyclophosphamide
  • tacrolimus
  • mycophenolate mofetil
  • filgrastim

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must meet one of two disease criteria:

               -  Acute myelogenous leukemia within one of the following categories:

                    -  Primary induction failure (PIF): patients who have not achieved a complete
                       remission following initial diagnosis and after at least two induction
                       cycles of chemotherapy consisting of cytarabine and an anthracycline or
                       high-dose cytarabine

                    -  Relapsed AML: Patients are defined as having relapsed disease if they
                       entered a complete remission confirmed with a bone marrow biopsy following
                       initial treatment, and then were found to have morphological or cytogenetic
                       evidence of recurrent disease on a subsequent bone marrow exam

                    -  Any complete remission (CR)2 or greater: CR must be defined using a bone
                       marrow exam taken at least 21 days since the last chemotherapy (including a
                       methyltransferase inhibitor), and may include CRp (morphologic CR without
                       peripheral platelet recovery)

                    -  CR1 with high-risk features: includes patients with treatment-related AML,
                       secondary AML (following myelodysplastic syndrome [MDS] or
                       myeloproliferative neoplasms [MPN]), high-risk cytogenetic or molecular
                       phenotype (by National Comprehensive Cancer Network [NCCN] criteria)

                    -  Untreated AML (> 20% blasts on a bone marrow) arising from a previous
                       confirmed diagnosis of MDS or MPN (excluding BCR-ABL positive diseases).

               -  Myelodysplastic syndromes within one of the following categories:

                    -  High-risk MDS at diagnosis as defined by the International Prognostic
                       Scoring System (IPSS) or World Health Organization (WHO) classification
                       based Prognostic Scoring System (WPSS)

                    -  Transfusion dependent MDS (either red blood cells [RBC] or platelet
                       dependent) without a hematologic response to at least 4 months of MTI
                       therapy; hematological response is defined as transfusion independence for
                       two or more months

                    -  Progressive MDS following at least 4 months of MTI therapy; progression is
                       defined as resumption of transfusion dependence after at least two months of
                       transfusion independence OR increase of marrow blasts by 50% from
                       pretreatment OR overall blasts over 10% of marrow cells at any time after
                       treatment

          -  Available related donor that is at least an allele level haplotype-match at human
             leukocyte antigen (HLA)- A, B, C, DRB1 and DPB1 loci (DPB1 matching according to the
             "permissive - non-permissive" dichotomy as stated by University of Wisconsin [UW]
             Histocompatibility Laboratory); a minimum match of 5/10 loci is required; an unrelated
             donor search is not required for a patient to be eligible for this protocol

          -  Karnofsky score of 60% or better (requires occasional assistance, but is able to care
             for most of his/her needs)

          -  Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for hemoglobin >
             40%; and forced expiratory volume in one second (FEV1) > 50%

          -  Ejection fraction (EF) >= 50% and no uncontrolled angina, symptomatic ventricular
             arrhythmias, or electrocardiogram (ECG) evidence of active ischemia

          -  Serum creatinine within normal range for age, or if serum creatinine outside normal
             range, then renal function (estimated glomerular filtration rate [GFR] by modification
             of diet in renal disease [MDRD] formula) > 40 mL/min/1.73 m^2

          -  Women of child bearing potential must have a negative pregnancy test within 14 days
             prior to study registration and agree to use adequate birth control during study
             treatment

          -  Voluntary written consent

          -  Patients must be 28 days from the end of the last induction course or at least 14 days
             from completion of previous methyltransferase inhibitor therapy (azacitidine or
             decitabine) at the time of registration

          -  DONOR: Donors must be at least HLA-haploidentical first degree relatives of the
             patients; eligible donors include biological parents, siblings, half-siblings or
             children

          -  DONOR: Age >= 18 years and =< 60 years

          -  DONOR: Donors must meet the selection criteria prior to the start of the recipient's
             pre-transplant conditioning regimen as defined by the Foundation for the Accreditation
             of Cell Therapy (FACT) and will be screened according to the American Association of
             Blood Banks (AABB) guidelines and UW Bone Marrow Transplant (BMT) program standard
             operating procedure (SOP)

        Exclusion Criteria:

          -  Active central nervous system (CNS) leukemia within two weeks of registration;
             patients with a history of CNS leukemia must have adequate treatment as defined by at
             least two negative spinal fluid assessments separated by at least one week; patients
             who have received cranial radiation therapy (XRT) must still be eligible to receive
             total body irradiation to 4 Gy

          -  New or active infection as determined by fever, unexplained pulmonary infiltrate or
             sinusitis on radiographic assessment; infections diagnosed within 4 weeks of
             registration must be determined to be controlled or resolving prior to treatment

          -  Active human immunodeficiency virus (HIV), hepatitis A, B or C infection

          -  Allergy or hypersensitivity to agents used within the treatment protocol

          -  DONOR: Recipient derived anti-donor high-titer (> 3000 MFI) HLA antibody as determined
             by Luminex assay

          -  DONOR: Not suitable for donation according to UW BMT program donor selection SOP
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival
Time Frame:Day 100
Safety Issue:
Description:Will be analyzed using Kaplan-Meier (KM) method, and OS will be obtained from the KM estimates along with 95% confidence intervals.

Secondary Outcome Measures

Measure:Neutrophil recovery defined as achieving an absolute neutrophil count (ANC) greater than or equal to 500/ul for three consecutive measurements on different days
Time Frame:Up to 1 year
Safety Issue:
Description:Will be summarized with mean and standard deviation or median and interquartile range, and the change will be tested using a one-sample paired t-test at a two-tailed significance level of 0.05.
Measure:Platelet recovery defined as the first day of a platelet count greater than 20,000/mm^3 with no platelet transfusions in the preceding 7 days
Time Frame:Up to 1 year
Safety Issue:
Description:Will be summarized with mean and standard deviation or median and interquartile range, and the change will be tested using a one-sample paired t-test at a two-tailed significance level of 0.05.
Measure:Primary graft failure defined as less than 5% donor chimerism in the cluster of differentiation (CD)3 and CD33 selected cell populations at any time after transplantation
Time Frame:Day 30
Safety Issue:
Description:Will be analyzed using KM method.
Measure:Cumulative incidence of grade III-IV acute GVHD determined by the standard bone marrow transplant (BMT) Clinical Trials Network criteria (BMTCTN)
Time Frame:Day 100
Safety Issue:
Description:Will be analyzed using KM method, aGVHD grade III-IV will be obtained from the KM estimates along with 95% confidence intervals.
Measure:Cumulative incidence of chronic GVHD according to BMTCTN
Time Frame:Up to 1 year
Safety Issue:
Description:Will be summarized with a proportion and a 95% confidence interval.
Measure:Complete remission after transplantation
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Time to relapse/progression
Time Frame:Up to 1 year
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:University of Wisconsin, Madison

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