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

Acute Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01168219
• Other study ID #: NCI-2011-02053
• Secondary ID: NCI-2011-02053CD
• Status: Completed
• Phase: Phase 2
• Start date: July 15, 2010
• Est. completion date: February 1, 2020

Study information

• Verified date: August 2022
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 68
• Est. completion date: February 1, 2020
• Est. primary completion date: November 14, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 74 Years

Eligibility

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

Related Conditions & MeSH terms

• 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
• Anemia, Refractory, with Excess of Blasts
• de Novo Myelodysplastic Syndrome
• Leukemia
• Leukemia, Erythroblastic, Acute
• Leukemia, Megakaryoblastic, Acute
• Leukemia, Monocytic, Acute
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Acute
• Myelodysplastic Syndrome
• Myelodysplastic Syndrome With Excess Blasts
• Myelodysplastic Syndromes
• Preleukemia
• Recurrent Adult Acute Myeloid Leukemia
• Secondary Myelodysplastic Syndrome
• Syndrome

Intervention

Procedure:
• Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic hematopoietic stem cell transplantation

Biological:
• Anti-Thymocyte Globulin
Given IV

Drug:
• Azacitidine
Given SC or IV
• Busulfan
Given IV
• Fludarabine Phosphate
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Methotrexate
Given IV

Other:
• Pharmacological Study
Correlative studies

Drug:
• Tacrolimus
Given PO or IV

Locations

Country	Name	City	State
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Cooper Hospital University Medical Center	Camden	New Jersey
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Christiana Care - Union Hospital	Elkton	Maryland
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	Northwell Health NCORP	Lake Success	New York
United States	Northwell Health/Center for Advanced Medicine	Lake Success	New York
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	Beebe Medical Center	Lewes	Delaware
United States	North Shore University Hospital	Manhasset	New York
United States	Mount Sinai Hospital	New York	New York
United States	NYP/Weill Cornell Medical Center	New York	New York
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	AdventHealth Orlando	Orlando	Florida
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Up to 5 years
Secondary	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.	Up to 5 years
Secondary	100-day Mortality	The number of death reported within the first 100 days after transplant.	Up to 100 days post-treatment