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Acute Myeloid LeukemiaPhase 2NCT01168219

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

A Phase 2 study testing Allogeneic Hematopoietic Stem Cell Transplantation, Anti-Thymocyte Globulin and Azacitidine in people with Acute Myeloid Leukemia and Adult Acute Megakaryoblastic Leukemia, run by National Cancer Institute (NCI) at 17 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

This phase II clinical trial is studying how well giving busulfan, fludarabine phosphate, and anti-thymocyte 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. Read more about this study

Who is it for?
Ages 18 to 74 years
What is being tested?
Allogeneic Hematopoietic Stem Cell Transplantation, Anti-Thymocyte Globulin and Azacitidine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
68 participants
Where
17 sitesUnited States
Study dates
15 Jul 2010to 1 Feb 2020
Phase
Phase 2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 74 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
Show all 43Show fewer
  • 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

Who cannot join

None listed.

Trial locations and contacts

17 sites in 1 country.

17 sites in 1 country

United States17 sites

  • University of Maryland/Greenebaum Cancer Center

    Baltimore, Maryland, 21201

  • Cooper Hospital University Medical Center

    Camden, New Jersey, 08103

  • UNC Lineberger Comprehensive Cancer Center

    Chapel Hill, North Carolina, 27599

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

  • Christiana Care - Union Hospital

    Elkton, Maryland, 21921

  • University of Iowa/Holden Comprehensive Cancer Center

    Iowa City, Iowa, 52242

  • Northwell Health NCORP

    Lake Success, New York, 11042

  • Northwell Health/Center for Advanced Medicine

    Lake Success, New York, 11042

  • Dartmouth Hitchcock Medical Center

    Lebanon, New Hampshire, 03756

  • Beebe Medical Center

    Lewes, Delaware, 19958

  • North Shore University Hospital

    Manhasset, New York, 11030

  • Mount Sinai Hospital

    New York, New York, 10029

  • NYP/Weill Cornell Medical Center

    New York, New York, 10065

  • Christiana Care Health System-Christiana Hospital

    Newark, Delaware, 19718

  • AdventHealth Orlando

    Orlando, Florida, 32803

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • Wake Forest University Health Sciences

    Winston-Salem, North Carolina, 27157

Other trials in United States

About this study

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

This phase II clinical trial is studying how well giving busulfan, fludarabine phosphate, and anti-thymocyte 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 anti-thymocyte globulin before transplant and giving azacitidine, tacrolimus, and methotrexate after the transplant may stop this from happening.

Read the detailed description

PRIMARY OBJECTIVE:

  1. 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:

  1. 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:

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.

Being tested
Allogeneic Hematopoietic Stem Cell Transplantation, Anti-Thymocyte Globulin, Azacitidine, Busulfan, Fludarabine Phosphate
Medical subject headings
Leukemia, Myeloid, Acute, Leukemia, Megakaryoblastic, Acute, Leukemia, Monocytic, Acute, Leukemia, Myelomonocytic, Acute, Leukemia, Erythroblastic, Acute, Myelodysplastic Syndromes, Anemia, Refractory, with Excess of Blasts

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Allogeneic Hematopoietic Stem Cell TransplantationProcedure or surgery

    Also called Allogeneic, Allogeneic Hematopoietic Cell Transplantation, Allogeneic Stem Cell Transplantation, HSC

    Undergo allogeneic hematopoietic stem cell transplantation

  • Anti-Thymocyte GlobulinBiological

    Also called Antithymocyte Globulin, Antithymocyte Serum, ATG, ATS

    Given IV

  • AzacitidineDrug

    Also called 5 AZC, 5-AC, 5-Azacytidine, 5-AZC

    Given SC or IV

  • BusulfanDrug

    Also called 1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum

    Given IV

  • Fludarabine PhosphateDrug

    Also called 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara

    Given IV

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • MethotrexateDrug

    Also called Abitrexate, Alpha-Methopterin, Amethopterin, Brimexate

    Given IV

  • Pharmacological StudyOther

    Correlative studies

  • TacrolimusDrug

    Also called FK 506, Fujimycin, Hecoria, Prograf

    Given PO or IV

Study groups in NCT01168219
Study groupRoleWhat they receive
Treatment (chemotherapy and transplant)ExperimentalREDUCED-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.
Receives: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Biological: Anti-Thymocyte Globulin; Drug: Azacitidine; Drug: Busulfan; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Methotrexate; Other: Pharmacological Study; Drug: Tacrolimus

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression-free Survival

    Progression-free survival rate (percentage) at 2 and 5 years is defined as the percentage of patients who are alive and progression free at 2 and 5 years from date of transplantation respectively.

    AML progression is defined as:

    • Reappearance of leukemia blast cells in peripheral blood and > 5% blasts in marrow
    • If no circulating blasts, but the marrow contains 5-20% blasts, a repeat bone marrow >= 1 week later with > 5% blasts
    • Development of extramedullary leukemia MDS progression is defined as
    • For patients with <5% bone marrow blasts: ≥50% increase in blasts to >5% blasts
    • For patients with 5-10% bone marrow blasts: ≥50% increase to >10% blasts
    • Any of the following: Reappearance of prior documented characteristic cytogenetic abnormality or refractory cytopenias with unequivocal evidence of dysplasia on bone marrow biopsy/aspirate

    Measured: Up to 5 years

Secondary outcomes (2)

  1. Overall Survival (OS)

    Overall survival rate (percentage) at 2 and 5 years is defined as the percentage of patients who are still alive 2 and 5 years after date of transplantation respectively. Estimated using the Kaplan-Meier product limit estimator.

    Measured: Up to 5 years

  2. 100-day Mortality

    The number of death reported within the first 100 days after transplant.

    Measured: Up to 100 days post-treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Jul 2010 (estimated)
  2. Study start15 Jul 2010
  3. Primary completion14 Nov 2015
  4. Study completion1 Feb 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
68 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01168219
Sponsor's protocol ID
NCI-2011-02053
Other IDs
NCI-2011-02053, CDR0000681025, CALGB-100801, CALGB 100801, CALGB-100801, U10CA180821, U10CA031946
Status last verified
Aug 2022
First submitted
22 Jul 2010
Last updated
4 Aug 2022

Publications

  • Vij R, Le-Rademacher J, Laumann K, Hars V, Owzar K, Shore T, Vasu S, Cashen A, Isola L, Shea T, DeMagalhaes-Silverman M, Hurd D, Meehan K, Beardell F, Devine S. A Phase II Multicenter Study of the Addition of Azacitidine to Reduced-Intensity Conditioning Allogeneic Transplant for High-Risk Myelodysplasia (and Older Patients with Acute Myeloid Leukemia): Results of CALGB 100801 (Alliance). Biol Blood Marrow Transplant. 2019 Oct;25(10):1984-1992. doi: 10.1016/j.bbmt.2019.06.007. Epub 2019 Jun 15.

    PubMed 31212080

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