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Fludarabine and Busulfan Followed by Allogeneic Stem Cell Transplant in Treating Older Patients With Acute Myeloid Leukemia in First Complete Remission

Primary Purpose

Adult Acute Myeloid Leukemia in Remission, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
filgrastim
Anti-Thymocyte Globulin
busulfan
fludarabine phosphate
methotrexate
tacrolimus
Allogeneic Hematopoietic Stem Cell Transplantation
Sponsored by
Alliance for Clinical Trials in Oncology
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Acute Myeloid Leukemia in Remission focused on measuring adult acute myeloid leukemia in remission, secondary acute myeloid leukemia, adult acute monocytic leukemia (M5b), adult acute erythroid leukemia (M6), adult acute megakaryoblastic leukemia (M7), adult acute minimally differentiated myeloid leukemia (M0), adult acute myeloblastic leukemia with maturation (M2), adult acute myeloblastic leukemia without maturation (M1), adult acute myelomonocytic leukemia (M4), adult acute monoblastic leukemia (M5a), adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with 11q23 (MLL) abnormalities

Eligibility Criteria

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

Eligibility Criteria: Patients with acute myeloid leukemia (AML) (excluding French-American-British [FAB] classification system M3) who have achieved a first morphologic complete remission and who meet the criteria below; patients with preceding myelodysplastic syndrome (MDS) or treatment-related AML are eligible; patients with prior central nervous system (CNS) involvement are eligible as long as disease is in remission at transplant; patients with acute leukemia following blast transformation of prior chronic myeloid leukemia (CML) or other myeloproliferative disease are excluded Complete remission (CR) will be defined according to the revised recommendations of the International Working Group (24) as all of the following: Normal bone marrow morphology with < 5% blasts Absolute neutrophil count (ANC) > 1,000/uL, referring to the count needed to confirm that the patient achieved a CR Platelet count > 100,000/uL No extramedullary leukemia No blasts in peripheral blood CR was achieved after one or two (but no more than two) cycles of induction chemotherapy with standard cytotoxic chemotherapy (e.g., cytarabine and an anthracycline) or after no more than four cycles of a hypomethylating agent containing regimen including either 5-azacytidine or decitabine Patients may have received as many as but no more than two cycles of consolidation therapy prior to transplant; any consolidation regimen that does not require transplant can be used; no more than 6 months can elapse from documentation of morphologic CR to transplant; the platelet count does not need to be > 100,000/uL after consolidation, as long as the bone marrow assessment prior to transplant does not show relapse Identification of hematopoietic cell donor >= 4 weeks since prior chemotherapy, radiation therapy, and surgery Performance status 0-2 Diffusion capacity of carbon monoxide (DLCO) > 40% with no symptomatic pulmonary disease Left ventricular ejection fraction (LVEF) by multi gated acquisition scan (MUGA) or echocardiogram (ECHO) >= 30% No uncontrolled diabetes mellitus or active serious infection requiring antibiotics No known hypersensitivity to E. coli-derived products No human immunodeficiency virus (HIV) infection Calculated creatinine clearance >= 40 cc/min Bilirubin < 2 mg/dL * If bilirubin is 2-3 mg/dL, but direct bilirubin is normal then patient will be considered eligible Aspartate aminotransferase (AST) < 3 x upper limit of normal DONOR: HLA-identical sibling (6/6); the donor must be determined to be an human leukocyte antigen (HLA)-identical sibling (6/6) by serologic typing for class (A, B) and low resolution molecular typing for class II (DRB1) DONOR: Matched unrelated donor (10/10); high resolution molecular typing at the following loci is required: HLA-A, -B, -C, -DRB1, and -DQB1 DONOR: the donor must be healthy and must be an acceptable donor as per institutional standards for stem cell donation DONOR: the donor must have no significant cardiopulmonary, renal, endocrine, or hepatic disease DONOR: there is no donor age restriction if the donor is a matched sibling DONOR: syngeneic donors are not eligible

Sites / Locations

  • UCSF Helen Diller Family Comprehensive Cancer Center
  • Tunnell Cancer Center at Beebe Medical Center
  • CCOP - Christiana Care Health Services
  • Greenebaum Cancer Center at University of Maryland Medical Center
  • Union Hospital of Cecil County
  • Massachusetts General Hospital
  • Dana-Farber/Brigham and Women's Cancer Center
  • Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
  • Beth Israel Deaconess Medical Center
  • Masonic Cancer Center at University of Minnesota
  • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
  • Cancer Institute of New Jersey at Cooper - Voorhees
  • Roswell Park Cancer Institute
  • Monter Cancer Center of the North Shore-LIJ Health System
  • CCOP - North Shore University Hospital
  • Don Monti Comprehensive Cancer Center at North Shore University Hospital
  • Long Island Jewish Medical Center
  • New York Weill Cornell Cancer Center at Cornell University
  • Mount Sinai Medical Center
  • Wake Forest University Comprehensive Cancer Center
  • Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (fludarabine, busulfan, allogeneic PBSC)

Arm Description

PREPARATIVE REGIMEN: Patients receive fludarabine IV over 30 minutes on days -7 to -3 and busulfan IV over 2 hours 4 times per day (every 6 hours) on days -4 and -3. GVHD PROPHYLAXIS: Patients receive tacrolimus PO or IV BID on days -2 with taper between days 90-120, and stopping by days 150-180. Patients also receive methotrexate IV on days 1, 3, 6, and 11 and rabbit antithymocyte globulin IV over 4-6 hours on days -4 through -2. ALLOGENEIC PBSC: Patients undergo allogeneic PBSC transplant on day 0. Patients then receive filgrastim SC daily beginning on day 12 and continuing until blood counts recover.

Outcomes

Primary Outcome Measures

2 Year Disease Free Survival In Unrelated Donor Recipient Group
Percentage of participants who were alive and relapse free at 2 years for patients who were matched with an unrelated donor for transplant. The 2 year disease free survival, with 95% confidence interval, was estimated using the Kaplan Meier method. A relapse is defined as any of the following: Reappearance of leukemia blasts cells in peripheral blood >5% blasts in the marrow, not attributable to another cause (e.g., bone marrow regeneration) If there are no circulating blasts, but the marrow contains 5-20% blasts, a repeat bone marrow ≥ 1 week later with >5% blasts is necessary to meet the criteria for relapse The development of extramedullary leukemia or leukemic cells in the cerebral spinal fluid

Secondary Outcome Measures

2 Year DFS for All Patients
Percentage of participants who were alive and relapse free at 2 years for all patients. The 2 year disease free survival, with 95% confidence interval, was estimated using the Kaplan Meier method.
Non-relapse Mortality (NRM)
Percentage of patients who died due to causes other than relapse

Full Information

First Posted
October 3, 2003
Last Updated
May 14, 2018
Sponsor
Alliance for Clinical Trials in Oncology
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00070135
Brief Title
Fludarabine and Busulfan Followed by Allogeneic Stem Cell Transplant in Treating Older Patients With Acute Myeloid Leukemia in First Complete Remission
Official Title
A Phase II Study Of Allogeneic Transplant For Older Patients With AML In First Morphologic Complete Remission Using A Non-Myeloablative Preparative Regimen
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
January 2004 (Actual)
Primary Completion Date
December 2013 (Actual)
Study Completion Date
June 15, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alliance for Clinical Trials in Oncology
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase II trial studies how well fludarabine and busulfan followed by a donor (allogeneic) stem cell transplant work in treating older patients with acute myeloid leukemia that is in first complete remission. Giving low doses of chemotherapy, such as fludarabine and busulfan, before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stops the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Giving tacrolimus, methotrexate, and rabbit antithymocyte globulin before or after the transplant may stop this from happening.
Detailed Description
PRIMARY OBJECTIVES: I. Determine if allogeneic transplantation from a matched sibling or unrelated donor using a non-myeloablative preparative regimen results in a 2-year disease-free survival (DFS) that is better than historical results using standard chemotherapy. SECONDARY OBJECTIVES: I. Determine 2-year actuarial risks of transplant-related mortality, acute and chronic graft-versus-host (GVHD) disease and relapse among patients with acute myeloid leukemia (AML) in first complete remission (CR1) following a non-myeloablative preparative regimen. II. To examine recovery of T and B cell number and function following non-myeloablative stem cell transplant. III. To examine the time course of T, B and myeloid progenitor chimerism following this preparative regimen. IV. To characterize the pharmacokinetics of intravenous busulfan used in a non-myeloablative preparation regimen in AML patients age >= 60 years. OUTLINE: PREPARATIVE REGIMEN: Patients receive fludarabine intravenously (IV) over 30 minutes on days -7 to -3 and busulfan IV over 2 hours 4 times per day (every 6 hours) on days -4 and -3. GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive tacrolimus orally (PO) or IV twice daily (BID) on days -2 with taper between days 90-120, and stopping by days 150-180. Patients also receive methotrexate IV on days 1, 3, 6, and 11 and rabbit antithymocyte globulin IV over 4-6 hours on days -4 through -2. ALLOGENEIC PERIPHERAL BLOOD STEM CELL TRASNPLANTATION (PBSC): Patients undergo allogeneic PBSC transplant on day 0. Patients then receive filgrastim subcutaneously (SC) daily beginning on day 12 and continuing until blood counts recover. Patients are followed monthly for 1 year, every 3 months for 1 year, and then every 6 months for 3 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Acute Myeloid Leukemia in Remission, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
Keywords
adult acute myeloid leukemia in remission, secondary acute myeloid leukemia, adult acute monocytic leukemia (M5b), adult acute erythroid leukemia (M6), adult acute megakaryoblastic leukemia (M7), adult acute minimally differentiated myeloid leukemia (M0), adult acute myeloblastic leukemia with maturation (M2), adult acute myeloblastic leukemia without maturation (M1), adult acute myelomonocytic leukemia (M4), adult acute monoblastic leukemia (M5a), adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with 11q23 (MLL) abnormalities

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Treatment (fludarabine, busulfan, allogeneic PBSC)
Arm Type
Experimental
Arm Description
PREPARATIVE REGIMEN: Patients receive fludarabine IV over 30 minutes on days -7 to -3 and busulfan IV over 2 hours 4 times per day (every 6 hours) on days -4 and -3. GVHD PROPHYLAXIS: Patients receive tacrolimus PO or IV BID on days -2 with taper between days 90-120, and stopping by days 150-180. Patients also receive methotrexate IV on days 1, 3, 6, and 11 and rabbit antithymocyte globulin IV over 4-6 hours on days -4 through -2. ALLOGENEIC PBSC: Patients undergo allogeneic PBSC transplant on day 0. Patients then receive filgrastim SC daily beginning on day 12 and continuing until blood counts recover.
Intervention Type
Biological
Intervention Name(s)
filgrastim
Intervention Description
Given SC
Intervention Type
Biological
Intervention Name(s)
Anti-Thymocyte Globulin
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
busulfan
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
fludarabine phosphate
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
methotrexate
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
tacrolimus
Intervention Description
Given PO or IV
Intervention Type
Procedure
Intervention Name(s)
Allogeneic Hematopoietic Stem Cell Transplantation
Other Intervention Name(s)
HSC, HSCT
Intervention Description
Undergo allogeneic PBSC transplantation
Primary Outcome Measure Information:
Title
2 Year Disease Free Survival In Unrelated Donor Recipient Group
Description
Percentage of participants who were alive and relapse free at 2 years for patients who were matched with an unrelated donor for transplant. The 2 year disease free survival, with 95% confidence interval, was estimated using the Kaplan Meier method. A relapse is defined as any of the following: Reappearance of leukemia blasts cells in peripheral blood >5% blasts in the marrow, not attributable to another cause (e.g., bone marrow regeneration) If there are no circulating blasts, but the marrow contains 5-20% blasts, a repeat bone marrow ≥ 1 week later with >5% blasts is necessary to meet the criteria for relapse The development of extramedullary leukemia or leukemic cells in the cerebral spinal fluid
Time Frame
2 years
Secondary Outcome Measure Information:
Title
2 Year DFS for All Patients
Description
Percentage of participants who were alive and relapse free at 2 years for all patients. The 2 year disease free survival, with 95% confidence interval, was estimated using the Kaplan Meier method.
Time Frame
Up to 2 years
Title
Non-relapse Mortality (NRM)
Description
Percentage of patients who died due to causes other than relapse
Time Frame
Up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
60 Years
Maximum Age & Unit of Time
74 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Eligibility Criteria: Patients with acute myeloid leukemia (AML) (excluding French-American-British [FAB] classification system M3) who have achieved a first morphologic complete remission and who meet the criteria below; patients with preceding myelodysplastic syndrome (MDS) or treatment-related AML are eligible; patients with prior central nervous system (CNS) involvement are eligible as long as disease is in remission at transplant; patients with acute leukemia following blast transformation of prior chronic myeloid leukemia (CML) or other myeloproliferative disease are excluded Complete remission (CR) will be defined according to the revised recommendations of the International Working Group (24) as all of the following: Normal bone marrow morphology with < 5% blasts Absolute neutrophil count (ANC) > 1,000/uL, referring to the count needed to confirm that the patient achieved a CR Platelet count > 100,000/uL No extramedullary leukemia No blasts in peripheral blood CR was achieved after one or two (but no more than two) cycles of induction chemotherapy with standard cytotoxic chemotherapy (e.g., cytarabine and an anthracycline) or after no more than four cycles of a hypomethylating agent containing regimen including either 5-azacytidine or decitabine Patients may have received as many as but no more than two cycles of consolidation therapy prior to transplant; any consolidation regimen that does not require transplant can be used; no more than 6 months can elapse from documentation of morphologic CR to transplant; the platelet count does not need to be > 100,000/uL after consolidation, as long as the bone marrow assessment prior to transplant does not show relapse Identification of hematopoietic cell donor >= 4 weeks since prior chemotherapy, radiation therapy, and surgery Performance status 0-2 Diffusion capacity of carbon monoxide (DLCO) > 40% with no symptomatic pulmonary disease Left ventricular ejection fraction (LVEF) by multi gated acquisition scan (MUGA) or echocardiogram (ECHO) >= 30% No uncontrolled diabetes mellitus or active serious infection requiring antibiotics No known hypersensitivity to E. coli-derived products No human immunodeficiency virus (HIV) infection Calculated creatinine clearance >= 40 cc/min Bilirubin < 2 mg/dL * If bilirubin is 2-3 mg/dL, but direct bilirubin is normal then patient will be considered eligible Aspartate aminotransferase (AST) < 3 x upper limit of normal DONOR: HLA-identical sibling (6/6); the donor must be determined to be an human leukocyte antigen (HLA)-identical sibling (6/6) by serologic typing for class (A, B) and low resolution molecular typing for class II (DRB1) DONOR: Matched unrelated donor (10/10); high resolution molecular typing at the following loci is required: HLA-A, -B, -C, -DRB1, and -DQB1 DONOR: the donor must be healthy and must be an acceptable donor as per institutional standards for stem cell donation DONOR: the donor must have no significant cardiopulmonary, renal, endocrine, or hepatic disease DONOR: there is no donor age restriction if the donor is a matched sibling DONOR: syngeneic donors are not eligible
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Steven M. Devine, MD
Organizational Affiliation
Ohio State University Comprehensive Cancer Center
Official's Role
Study Chair
Facility Information:
Facility Name
UCSF Helen Diller Family Comprehensive Cancer Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Tunnell Cancer Center at Beebe Medical Center
City
Lewes
State/Province
Delaware
ZIP/Postal Code
19958
Country
United States
Facility Name
CCOP - Christiana Care Health Services
City
Newark
State/Province
Delaware
ZIP/Postal Code
19713
Country
United States
Facility Name
Greenebaum Cancer Center at University of Maryland Medical Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Union Hospital of Cecil County
City
Elkton
State/Province
Maryland
ZIP/Postal Code
21921
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Dana-Farber/Brigham and Women's Cancer Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Masonic Cancer Center at University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Cancer Institute of New Jersey at Cooper - Voorhees
City
Voorhees
State/Province
New Jersey
ZIP/Postal Code
08043
Country
United States
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263-0001
Country
United States
Facility Name
Monter Cancer Center of the North Shore-LIJ Health System
City
Lake Success
State/Province
New York
ZIP/Postal Code
11042
Country
United States
Facility Name
CCOP - North Shore University Hospital
City
Manhasset
State/Province
New York
ZIP/Postal Code
11030
Country
United States
Facility Name
Don Monti Comprehensive Cancer Center at North Shore University Hospital
City
Manhasset
State/Province
New York
ZIP/Postal Code
11030
Country
United States
Facility Name
Long Island Jewish Medical Center
City
New Hyde Park
State/Province
New York
ZIP/Postal Code
11040
Country
United States
Facility Name
New York Weill Cornell Cancer Center at Cornell University
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
Mount Sinai Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Wake Forest University Comprehensive Cancer Center
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157-1096
Country
United States
Facility Name
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210-1240
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
26527780
Citation
Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, Champlin RE, Chen YB, Vij R, Slack J, Soiffer RJ, Larson RA, Shea TC, Hars V, Sibley AB, Giralt S, Carter S, Horowitz MM, Linker C, Alyea EP. Phase II Study of Allogeneic Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission Using a Reduced-Intensity Conditioning Regimen: Results From Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. 2015 Dec 10;33(35):4167-75. doi: 10.1200/JCO.2015.62.7273. Epub 2015 Nov 2.
Results Reference
derived

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Fludarabine and Busulfan Followed by Allogeneic Stem Cell Transplant in Treating Older Patients With Acute Myeloid Leukemia in First Complete Remission

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