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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

Information source: National Cancer Institute (NCI)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: 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

Intervention: Allogeneic Hematopoietic Stem Cell Transplantation (Procedure); Anti-Thymocyte Globulin (Biological); Azacitidine (Drug); Busulfan (Drug); Fludarabine Phosphate (Drug); Laboratory Biomarker Analysis (Other); Methotrexate (Drug); Pharmacological Study (Other); Tacrolimus (Drug)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Ravi Vij, Principal Investigator, Affiliation: Alliance for Clinical Trials in Oncology


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.

Clinical Details

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 design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Progression-free survival

Secondary outcome:

Overall survival (OS)

Treatment related mortality (TRM)

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.


Minimum age: 18 Years. Maximum age: 74 Years. Gender(s): Both.


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)


- 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


- 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


- 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

Locations and Contacts

Beebe Medical Center, Lewes, Delaware 19958, United States

Christiana Care Health System-Christiana Hospital, Newark, Delaware 19718, United States

Florida Hospital Orlando, Orlando, Florida 32803, United States

University of Iowa/Holden Comprehensive Cancer Center, Iowa City, Iowa 52242, United States

University of Maryland/Greenebaum Cancer Center, Baltimore, Maryland 21201, United States

Union Hospital of Cecil County, Elkton MD, Maryland 21921, United States

Washington University School of Medicine, Saint Louis, Missouri 63110, United States

Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire 03756, United States

Cooper Hospital University Medical Center, Camden, New Jersey 08103, United States

North Shore-LIJ Health System NCORP, Manhasset, New York 11030, United States

Mount Sinai Medical Center, New York, New York 10029, United States

Weill Medical College of Cornell University, New York, New York 10065, United States

University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States

Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, United States

Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, United States

Additional Information

Starting date: July 2010
Last updated: June 3, 2015

Page last updated: August 23, 2015

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