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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| ClinicalTrials.gov Identifier: NCT01168219 |
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Recruitment Status :
Active, not recruiting
First Posted : July 23, 2010
Results First Posted : April 3, 2018
Last Update Posted : December 15, 2021
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| 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 | 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 | Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 68 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (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 |
| Actual Study Start Date : | July 15, 2010 |
| Actual Primary Completion Date : | November 15, 2015 |
| Arm | Intervention/treatment |
|---|---|
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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. |
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic hematopoietic stem cell transplantation
Other Names:
Biological: Anti-Thymocyte Globulin Given IV
Other Names:
Drug: Azacitidine Given SC or IV
Other Names:
Drug: Busulfan Given IV
Other Names:
Drug: Fludarabine Phosphate Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Methotrexate Given IV
Other Names:
Other: Pharmacological Study Correlative studies Drug: Tacrolimus Given PO or IV
Other Names:
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- Progression-free Survival [ Time Frame: Up to 5 years ]
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
- Overall Survival (OS) [ Time Frame: Up to 5 years ]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 [ Time Frame: Up to 100 days post-treatment ]The number of death reported within the first 100 days after transplant.
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, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years to 74 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
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Meets one of the following sets of criteria:
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Myelodysplastic syndromes (MDS):
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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
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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
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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
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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
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Donors must meet the following criteria:
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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
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- 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
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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
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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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01168219
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| Principal Investigator: | Ravi Vij | Alliance for Clinical Trials in Oncology |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT01168219 |
| Other Study ID Numbers: |
NCI-2011-02053 NCI-2011-02053 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) CDR0000681025 CALGB-100801 CALGB 100801 ( Other Identifier: Alliance for Clinical Trials in Oncology ) CALGB-100801 ( Other Identifier: CTEP ) U10CA180821 ( U.S. NIH Grant/Contract ) U10CA031946 ( U.S. NIH Grant/Contract ) |
| First Posted: | July 23, 2010 Key Record Dates |
| Results First Posted: | April 3, 2018 |
| Last Update Posted: | December 15, 2021 |
| Last Verified: | December 2021 |
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Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Preleukemia Leukemia, Monocytic, Acute Leukemia, Myelomonocytic, Acute Leukemia, Megakaryoblastic, Acute Leukemia, Erythroblastic, Acute Myelodysplastic Syndromes Anemia, Refractory, with Excess of Blasts Syndrome Disease Pathologic Processes Neoplasms by Histologic Type Neoplasms |
Bone Marrow Diseases Hematologic Diseases Precancerous Conditions Myeloproliferative Disorders Anemia, Refractory Anemia Methotrexate Fludarabine phosphate Azacitidine Fludarabine Busulfan Tacrolimus Antilymphocyte Serum Abortifacient Agents, Nonsteroidal Abortifacient Agents |