Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by University of Wisconsin, Madison
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Wisconsin, Madison
ClinicalTrials.gov Identifier:
NCT01707004
First received: October 8, 2012
Last updated: July 10, 2014
Last verified: July 2014
  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.


Condition Intervention Phase
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
Drug: decitabine
Drug: fludarabine phosphate
Drug: busulfan
Drug: cyclophosphamide
Drug: tacrolimus
Drug: mycophenolate mofetil
Biological: filgrastim
Radiation: total-body irradiation
Procedure: allogeneic bone marrow transplantation
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Decitabine Followed by Bone Marrow Transplant and High-Dose Cyclophosphamide for the Treatment of Relapsed and Refractory Acute Myeloid Neoplasms

Resource links provided by NLM:


Further study details as provided by University of Wisconsin, Madison:

Primary Outcome Measures:
  • Overall survival [ Time Frame: Day 100 ] [ Designated as safety issue: No ]
    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:
  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    Will be analyzed using KM method.

  • 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 ] [ Designated as safety issue: No ]
    Will be analyzed using KM method, aGVHD grade III-IV will be obtained from the KM estimates along with 95% confidence intervals.

  • Cumulative incidence of chronic GVHD according to BMTCTN [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Will be summarized with a proportion and a 95% confidence interval.

  • Complete remission after transplantation [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
  • Time to relapse/progression [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]

Estimated Enrollment: 20
Study Start Date: May 2013
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (donor bone marrow transplant)

Beginning 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.

Drug: decitabine
Given IV
Other Names:
  • 5-aza-dCyd
  • 5AZA
  • DAC
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: busulfan
Given IV
Other Names:
  • BSF
  • BU
  • Misulfan
  • Mitosan
  • Myeloleukon
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: tacrolimus
Given PO or IV
Other Names:
  • FK 506
  • Prograf
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Biological: filgrastim
Given SC
Other Names:
  • G-CSF
  • Neupogen
Radiation: total-body irradiation
Undergo total-body irradiation
Other Name: TBI
Procedure: allogeneic bone marrow transplantation
Undergo allogeneic bone marrow transplantation
Other Names:
  • bone marrow therapy, allogeneic
  • bone marrow therapy, allogenic
  • transplantation, allogeneic bone marrow
  • transplantation, allogenic bone marrow
Other: laboratory biomarker analysis
Correlative studies

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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)
    • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01707004

Locations
United States, Wisconsin
University of Wisconsin Hospital and Clinics Recruiting
Madison, Wisconsin, United States, 53792
Contact: Mark B. Juckett    608-263-0338    mbj@medicine.wisc.edu   
Principal Investigator: Mark B. Juckett         
Sponsors and Collaborators
University of Wisconsin, Madison
Investigators
Principal Investigator: Mark Juckett University of Wisconsin Hospital and Clinics
  More Information

No publications provided

Responsible Party: University of Wisconsin, Madison
ClinicalTrials.gov Identifier: NCT01707004     History of Changes
Other Study ID Numbers: HO11421, NCI-2012-01325, 2012-0217-CP002, 2012-0217-CP005, HO11421, P30CA014520
Study First Received: October 8, 2012
Last Updated: July 10, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Syndrome
Bone Marrow Diseases
Disease
Hematologic Diseases
Neoplasms
Neoplasms by Histologic Type
Pathologic Processes
Precancerous Conditions
Cyclophosphamide
Decitabine
Fludarabine
Fludarabine phosphate
Mycophenolate mofetil
Mycophenolic Acid
Tacrolimus
Vidarabine
Alkylating Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Antiviral Agents

ClinicalTrials.gov processed this record on November 24, 2014