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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

Primary Purpose

Acute Myeloid Leukemia, Adult Acute Megakaryoblastic Leukemia, Adult Acute Monoblastic Leukemia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Allogeneic Hematopoietic Stem Cell Transplantation
Anti-Thymocyte Globulin
Azacitidine
Busulfan
Fludarabine Phosphate
Laboratory Biomarker Analysis
Methotrexate
Pharmacological Study
Tacrolimus
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia

Eligibility Criteria

18 Years - 74 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Beebe Medical Center
  • Christiana Care Health System-Christiana Hospital
  • AdventHealth Orlando
  • University of Iowa/Holden Comprehensive Cancer Center
  • University of Maryland/Greenebaum Cancer Center
  • Christiana Care - Union Hospital
  • Washington University School of Medicine
  • Dartmouth Hitchcock Medical Center
  • Cooper Hospital University Medical Center
  • Northwell Health NCORP
  • Northwell Health/Center for Advanced Medicine
  • North Shore University Hospital
  • Mount Sinai Hospital
  • NYP/Weill Cornell Medical Center
  • UNC Lineberger Comprehensive Cancer Center
  • Wake Forest University Health Sciences
  • Ohio State University Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (chemotherapy and transplant)

Arm Description

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

First Posted
July 22, 2010
Last Updated
August 3, 2022
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01168219
Brief Title
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
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Completed
Study Start Date
July 15, 2010 (Actual)
Primary Completion Date
November 14, 2015 (Actual)
Study Completion Date
February 1, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief 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. 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.
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: 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia, Adult Acute Megakaryoblastic Leukemia, Adult Acute Monoblastic Leukemia, Adult Acute Monocytic Leukemia, 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; q22.1); RUNX1-RUNX1T1, Adult Acute Myeloid Leukemia With t(9;11)(p21.3;q23.3); 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, Myelodysplastic Syndrome, Myelodysplastic Syndrome With Excess Blasts, Recurrent Adult Acute Myeloid Leukemia, Secondary Myelodysplastic Syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
68 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (chemotherapy and transplant)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Procedure
Intervention Name(s)
Allogeneic Hematopoietic Stem Cell Transplantation
Other Intervention Name(s)
Allogeneic, Allogeneic Hematopoietic Cell Transplantation, Allogeneic Stem Cell Transplantation, HSC, HSCT, Stem Cell Transplantation, Allogeneic
Intervention Description
Undergo allogeneic hematopoietic stem cell transplantation
Intervention Type
Biological
Intervention Name(s)
Anti-Thymocyte Globulin
Other Intervention Name(s)
Antithymocyte Globulin, Antithymocyte Serum, ATG, ATS
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Other Intervention Name(s)
5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, Onureg, U-18496, Vidaza
Intervention Description
Given SC or IV
Intervention Type
Drug
Intervention Name(s)
Busulfan
Other Intervention Name(s)
1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
Abitrexate, Alpha-Methopterin, Amethopterin, Brimexate, CL 14377, CL-14377, Emtexate, Emthexat, Emthexate, Farmitrexat, Fauldexato, Folex, Folex PFS, Lantarel, Ledertrexate, Lumexon, Maxtrex, Medsatrexate, Metex, Methoblastin, Methotrexate LPF, Methotrexate Methylaminopterin, Methotrexatum, Metotrexato, Metrotex, Mexate, Mexate-AQ, MTX, Novatrex, Rheumatrex, Texate, Tremetex, Trexeron, Trixilem, WR-19039
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
FK 506, Fujimycin, Hecoria, Prograf, Protopic
Intervention Description
Given PO or IV
Primary Outcome Measure Information:
Title
Progression-free Survival
Description
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
Time Frame
Up to 5 years
Secondary Outcome Measure Information:
Title
Overall Survival (OS)
Description
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.
Time Frame
Up to 5 years
Title
100-day Mortality
Description
The number of death reported within the first 100 days after transplant.
Time Frame
Up to 100 days post-treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
74 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ravi Vij
Organizational Affiliation
Alliance for Clinical Trials in Oncology
Official's Role
Principal Investigator
Facility Information:
Facility Name
Beebe Medical Center
City
Lewes
State/Province
Delaware
ZIP/Postal Code
19958
Country
United States
Facility Name
Christiana Care Health System-Christiana Hospital
City
Newark
State/Province
Delaware
ZIP/Postal Code
19718
Country
United States
Facility Name
AdventHealth Orlando
City
Orlando
State/Province
Florida
ZIP/Postal Code
32803
Country
United States
Facility Name
University of Iowa/Holden Comprehensive Cancer Center
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
University of Maryland/Greenebaum Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Christiana Care - Union Hospital
City
Elkton
State/Province
Maryland
ZIP/Postal Code
21921
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Dartmouth Hitchcock Medical Center
City
Lebanon
State/Province
New Hampshire
ZIP/Postal Code
03756
Country
United States
Facility Name
Cooper Hospital University Medical Center
City
Camden
State/Province
New Jersey
ZIP/Postal Code
08103
Country
United States
Facility Name
Northwell Health NCORP
City
Lake Success
State/Province
New York
ZIP/Postal Code
11042
Country
United States
Facility Name
Northwell Health/Center for Advanced Medicine
City
Lake Success
State/Province
New York
ZIP/Postal Code
11042
Country
United States
Facility Name
North Shore University Hospital
City
Manhasset
State/Province
New York
ZIP/Postal Code
11030
Country
United States
Facility Name
Mount Sinai Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
NYP/Weill Cornell Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
UNC Lineberger Comprehensive Cancer Center
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Facility Name
Wake Forest University Health Sciences
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
31212080
Citation
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.
Results Reference
derived

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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

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