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Busulfan, Fludarabine Phosphate, and Anti-Thymocyte Globulin Followed By Donor Stem Cell Transplant and Azacitidine in Treating Patients With High-Risk Myelodysplastic Syndrome and Older Patients With Acute Myeloid Leukemia

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01168219
First received: July 22, 2010
Last updated: November 21, 2014
Last verified: August 2014
  Purpose

This phase II clinical trial is studying how well giving busulfan, fludarabine phosphate, and antithymocyte globulin followed by donor stem cell transplant and azacitidine works in treating patients with high-risk myelodysplastic syndrome and older patients with acute myeloid leukemia. Giving low doses of chemotherapy, such as busulfan and fludarabine phosphate, before a donor stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-vs-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving antithymocyte globulin before transplant and giving azacitidine, tacrolimus, and methotrexate after the transplant may stop this from happening.


Condition Intervention Phase
Adult Acute Megakaryoblastic Leukemia
Adult Acute Monoblastic Leukemia
Adult Acute Monocytic Leukemia
Adult Acute Myeloid Leukemia in Remission
Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11
Adult Acute Myeloid Leukemia With Maturation
Adult Acute Myeloid Leukemia With Minimal Differentiation
Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1
Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL
Adult Acute Myeloid Leukemia Without Maturation
Adult Acute Myelomonocytic Leukemia
Adult Erythroleukemia
Adult Pure Erythroid Leukemia
Alkylating Agent-Related Acute Myeloid Leukemia
de Novo Myelodysplastic Syndrome
Previously Treated Myelodysplastic Syndrome
Recurrent Adult Acute Myeloid Leukemia
Refractory Anemia With Excess Blasts
Secondary Myelodysplastic Syndrome
Untreated Adult Acute Myeloid Leukemia
Drug: Fludarabine Phosphate
Drug: Busulfan
Biological: Anti-Thymocyte Globulin
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Drug: Tacrolimus
Drug: Methotrexate
Drug: Azacitidine
Other: Pharmacological Study
Other: Diagnostic 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: Phase II Study of the Addition of Azacitidine ( NSC#102816) to Reduced-Intensity Conditioning Allogeneic Transplantation for Myelodysplasia (MDS) and Older Patients With AML

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Progression-free survival [ Time Frame: At 2 years ] [ Designated as safety issue: No ]
    Will be estimated using the Kaplan-Meier product limit estimator.


Secondary Outcome Measures:
  • Overall survival (OS) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Estimated using the Kaplan-Meier product limit estimator.

  • Treatment related mortality (TRM) [ Time Frame: Up to 6 months post-treatment ] [ Designated as safety issue: No ]
    TRM is defined as death within the first six months after transplant not secondary to relapse.


Estimated Enrollment: 64
Study Start Date: July 2010
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (chemotherapy and transplant)

REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]).

TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.

GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).

CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.

Drug: Fludarabine Phosphate
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • SH T 586
Drug: Busulfan Biological: Anti-Thymocyte Globulin
Other Names:
  • ATG
  • ATGAM
  • ATS
  • Thymoglobulin
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Other Names:
  • HSC
  • HSCT
Drug: Tacrolimus
Other Names:
  • Advagraf
  • FK 506
Drug: Methotrexate Drug: Azacitidine
Other Names:
  • 5-AC
  • 5-AZC
  • U-18496
Other: Pharmacological Study
Other Name: pharmacological studies
Other: Diagnostic Laboratory Biomarker Analysis

Detailed Description:

PRIMARY OBJECTIVE:

I. To determine if this treatment can improve 2-year progression-free survival (PFS) in patients with high risk myelodysplastic syndrome (MDS) and in patients with acute myeloid leukemia (AML) >= 60 yrs age

SECONDARY OBJECTIVES:

I. To determine the safety and feasibility of using post-transplantation azacitidine.

II. To determine the ability to use pharmacokinetic-directed busulfan to achieve area under the curve (AUC) within 20% of target AUC in > 80% of patients.

III. To determine the rate of grade II-IV and III-IV acute graft-vs-host disease (GVHD).

IV. To determine the incidence of extensive chronic GVHD. V. To determine treatment-related mortality at 100 days and at 1 year. VI. To determine 5-year overall survival.

OUTLINE: This is a multicenter study.

REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]).

TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.

GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus orally (PO) or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).

CONSOLIDATION: Beginning on day 42, patients receive azacitidine subcutaneously (SC) or IV on days 1-5.

Treatment repeats every 4 weeks for 6 courses. Blood and bone marrow samples may be collected periodically for correlative and pharmacokinetic studies.

After completion of study treatment, patients are followed up every 6 months for 5 years.

  Eligibility

Ages Eligible for Study:   18 Years to 74 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Meets one of the following sets of criteria:

    • Myelodysplastic syndromes (MDS):

      • Disease with high-risk features (found either at diagnosis or before initiation of cytotoxic therapy), defined as one of the following:

        • International prognostic scoring system (IPSS) risk >= intermediate-2
        • Refractory anemia with excess blasts by French-American-British (FAB) classification
        • High-risk cytogenetics (either complex or -7)
      • Less than 10% bone marrow blasts as determined by bone marrow biopsy within the past 4 weeks (reduction in marrow blast percentage may be achieved with chemotherapy or other therapy)
      • Less than 75 years old
    • Acute myeloid leukemia (AML):

      • No FAB M3
      • No acute leukemia following blast transformation of prior chronic myelogenous leukemia or other myeloproliferative disease
      • Patients with preceding MDS or treatment-related AML are eligible
      • Prior central nervous system (CNS) involvement is allowed provided the disease is in remission at transplantation
      • Morphologic complete remission (leukemia-free state) is defined as meeting all of the following criteria:

        • Bone marrow blasts < 5% (as determined by bone marrow within the past 4 weeks), but without requirement for normal peripheral blood counts
        • No extramedullary leukemia
        • No blasts in peripheral blood
      • Achieved complete remission (CR) after no more than 2 courses of induction chemotherapy

        • Patients treated with azacitidine or decitabine who achieve a leukemia-free state are eligible (may have required up to 4 courses of therapy to reach this status)
      • Age 60 to 74 years
  • Donors must meet the following criteria:

    • One of the following:

      • HLA-identical sibling (6/6) by serologic typing for class (A, B) and low-resolution molecular typing for class II (DRB1)
      • Matched unrelated donor (8/8) by high-resolution molecular typing at HLA-A, -B, -C, and DRB1
    • No syngeneic donors
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Calculated creatinine clearance ≥ 40 mL/min
  • Bilirubin < 2 mg/dL OR bilirubin 2-3 mg/dL provided direct bilirubin is normal
  • Aspartate aminotransferase (AST) < 3 times upper limit of normal
  • Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% with no symptomatic pulmonary disease
  • Left ventricle ejection fraction (LVEF) >= 30% by echocardiogram (ECHO) or multigated acquisition (MUGA)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No uncontrolled diabetes mellitus or active serious infections
  • No known hypersensitivity to E. coli-derived products, azacitidine, or mannitol
  • No human immunodeficiency virus (HIV) infection or active hepatitis B or C
  • Prior azacitidine or decitabine allowed

    • No patients who progressed from MDS to AML during treatment with azacitidine or decitabine
  • At least 4 weeks since prior deoxyribonucleic acid (DNA)-hypomethylating chemotherapy, radiotherapy, and/or surgery
  • No more than 2 courses of consolidation therapy before transplantation (for patients with AML)

    • Any consolidation regimen that does not require transplantation can be used
    • No more than 6 months from documentation of morphologic CR to transplantation
  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: NCT01168219

Locations
United States, Delaware
Beebe Medical Center
Lewes, Delaware, United States, 19958
Christiana Care Health System-Christiana Hospital
Newark, Delaware, United States, 19718
United States, Florida
Florida Hospital Orlando
Orlando, Florida, United States, 32803
United States, Iowa
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States, 52242
United States, Maryland
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland, United States, 21201
Union Hospital of Cecil County
Elkton MD, Maryland, United States, 21921
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New Hampshire
Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03756
United States, New Jersey
Cooper Hospital University Medical Center
Camden, New Jersey, United States, 08103
United States, New York
North Shore-LIJ Health System CCOP
Manhasset, New York, United States, 11030
Weill Medical College of Cornell University
New York, New York, United States, 10065
Mount Sinai Medical Center
New York, New York, United States, 10029
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27599
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
Columbus, Ohio, United States, 43210
Ohio State University Medical Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Investigators
Principal Investigator: Ravi Vij Cancer and Leukemia Group B
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01168219     History of Changes
Other Study ID Numbers: NCI-2011-02053, NCI-2011-02053, CDR0000681025, CALGB 100801, CALGB-100801, U10CA031946, P30CA014236
Study First Received: July 22, 2010
Last Updated: November 21, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Anemia, Refractory
Anemia, Refractory, with Excess of Blasts
Leukemia
Leukemia, Erythroblastic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Monocytic, Acute
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Myelodysplastic Syndromes
Preleukemia
Syndrome
Anemia
Bone Marrow Diseases
Disease
Hematologic Diseases
Myelodysplastic-Myeloproliferative Diseases
Myeloproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Pathologic Processes
Precancerous Conditions
Antilymphocyte Serum
Azacitidine
Busulfan
Fludarabine
Fludarabine phosphate
Methotrexate
Tacrolimus

ClinicalTrials.gov processed this record on November 23, 2014