Reduced Intensity Conditioning Versus Myeloablative Conditioning for Acute Myeloid Leukemia or Myelodysplastic Syndrome (BMT CTN 0901) - Full Text View

Purpose

The study is designed as a Phase III, multicenter trial comparing outcomes after allogeneic hematopoietic stem cell transplantation (HCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) between patients receiving myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC) regimens.

Condition	Intervention	Phase
Leukemia, Myelocytic, Acute	Drug: Fludarabine and Busulfan (Flu/Bu) Drug: Fludarabine and Melphalan (Flu/Mel) Drug: Busulfan and Fludarabine (Bu/Flu) Drug: Busulfan and Cyclophosphamide (Bu/Cy) Drug: Cyclophosphamide and Total Body Irradiation (Cy/TBI)	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Randomized, Multi-Center, Phase III Study of Allogeneic Stem Cell Transplantation Comparing Regimen Intensity in Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia

Resource links provided by NLM:

Genetics Home Reference related topics: familial acute myeloid leukemia with mutated CEBPA

MedlinePlus related topics: Acute Myeloid Leukemia Cancer Flu Leukemia Myelodysplastic Syndromes

Drug Information available for: Cyclophosphamide Busulfan Melphalan Melphalan hydrochloride Fludarabine Fludarabine phosphate

U.S. FDA Resources

Further study details as provided by Medical College of Wisconsin:

Primary Outcome Measures:

Overall Survival [ Time Frame: 18 months ] [ Designated as safety issue: No ]
The primary objective of the trial is to compare 18 month overall survival rates of the two groups of patients starting from the time of randomization to the RIC or MAC arms.

Secondary Outcome Measures:

Disease-Free Survival [ Time Frame: time from randomization to relapse, death, initiation of non-protocol AML or MDS therapy, loss to follow up or end of study whichever comes first ] [ Designated as safety issue: No ]
Disease-free survival will be at different time points. Patients are considered a failure if they die or suffer from disease relapse.
Treatment-related Mortality [ Time Frame: 18 months ] [ Designated as safety issue: No ]
Treatment-related mortality (TRM) is defined as death occurring in a patient from causes other than disease relapse. Individuals who relapse are censored for the event of TRM.
Neutrophil and Platelet Engraftment [ Time Frame: 100 days ] [ Designated as safety issue: No ]
Neutrophil engraftment is defined as achieving an absolute neutrophil count greater than 500 µL for 3 consecutive measurements on different days. The first of the 3 days will be designated the day of neutrophil engraftment. Platelet engraftment is defined as achieving platelet counts greater than 20,000 and 50,000/µL for consecutive measurements over 7 days without requiring platelet transfusions. The first of the 7 days will be designated the day of platelet engraftment. Subjects must not have had platelet transfusions during the preceding 7 days.
Donor Cell Engraftment [ Time Frame: Day 100 and 18 months post transplantation ] [ Designated as safety issue: No ]
Donor cell engraftment will be assessed by donor recipient chimerism studies. For this protocol, mixed chimerism will be defined as the presence of donor cells, as a proportion of the total population of less than 95% in the peripheral blood or bone marrow. Full donor chimerism is defined as greater than 95% donor donor cells. Mixed or full donor chimerism will be evidence of donor engraftment. For this protocol, graft rejection is defined as the inability to detect or loss of detection of greater than 5% donor cells as a proportion of the total population.
Acute GVHD of Grades II-IV and III-IV [ Time Frame: 100 days ] [ Designated as safety issue: No ]
The first day of acute GVHD onset at a certain grade will be used to calculate cumulative incidence curves for that GVHD grade (e.g., if the onset of grade I acute GVHD is on Day 19 post-transplant and onset of grade III is on Day 70 post-transplant, time to grade III is Day 70). This endpoint will be evaluated through 100 days and compared between treatment arms.
Chronic GVHD [ Time Frame: 18 months ] [ Designated as safety issue: No ]
The first day of chronic GVHD onset will be used to calculate cumulative incidence curves. Rates and severity of cGVHD will be compared between treatment arms.
Incidence of Primary Graft Failure [ Time Frame: 28 days ] [ Designated as safety issue: No ]
This is defined by lack of neutrophil engraftment by 28 days. Rates of primary graft failure will be compared between treatment arms.
Incidence of Secondary Graft Failure [ Time Frame: 18 months ] [ Designated as safety issue: No ]
This is defined by initial neutrophil engraftment followed by subsequent decline in neutrophil counts less than 500/µL unresponsive to growth factor therapy. Rates of secondary graft failure will be compared between treatment arms.
Incidence of Toxicities Greater Than Grade 3 [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
All toxicities greater than or equal to Grade 3 will be tabulated by grade for each treatment arm, by type of toxicity as well as the peak grade overall. Toxicity frequencies will be described for each time interval as well as cumulative over time.
Incidence of Infections [ Time Frame: 6, 12, and 18 months post transplant or until death ] [ Designated as safety issue: No ]
The number of infections and the number of patients experiencing infections will be tabulated by type of infection, severity, and time period after transplant. The cumulative incidence of severe, life-threatening, or fatal infections will be compared between the two treatment arms at 6, 12, and 18 months from transplant or until death.
Immune Reconstitution [ Time Frame: Baseline, 100 days, 12 months and 18 months post transplant ] [ Designated as safety issue: No ]
Quantitative assessments of peripheral blood CD3, CD4, CD8, CD19 and CD56 positive lymphocytes will be done through flow cytometric analysis at baseline , 100 days, 12 months and 18 months post transplantation. Results will be tabulated according to time from transplant.
Quality of Life [ Time Frame: Prior to transplant, 100 days, 12 and 18 months or until death ] [ Designated as safety issue: No ]
HQL will be described and compared between the two treatment arms over time. The self report questionnaires will be completed prior to transplantation and subsequently at 100 days, 12, and 18 months from randomization or until death. HQL include: FACT-BMT, SF-36, MDASI and EQ-5D.

Estimated Enrollment:	356
Study Start Date:	May 2011
Estimated Study Completion Date:	November 2017
Estimated Primary Completion Date:	May 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Reduced Intensity Conditioning (RIC) The sequence of (1) fludarabine/busulfan, or (2) fludarabine/melphalan administration in RIC regimens will be done according to institutional standards as long as the prescribed doses are the same as the recommended regimen below: Fludarabine: 30 mg/m^2/day on Days -6 to -2 (total dose of 150 mg/m^2): Busulfan: 4 mg/kg/day PO or 3.2 mg/kg/day,(total dose of 8 mg/kg or 6.4 mg/kg, respectively) on Days -5 to -4. Fludarabine: 30 mg/m^2/day on Days -5 to -2 (total dose of 120 mg/m^2); Melphalan: 140 mg/m^2 on Day -2.	Drug: Fludarabine and Busulfan (Flu/Bu) Fludarabine: 30 mg/m^2/day on Days -6 to -2 (total dose of 150 mg/m^2) Busulfan: 4 mg/kg/day PO or 3.2 mg/kg/day (total dose of 8 mg/kg or 6.4 mg/kg, respectively) on Days -5 to -4. Drug: Fludarabine and Melphalan (Flu/Mel) Fludarabine: 30 mg/m^2/day on Days -5 to -2 (total dose of 120 mg/m^2) Melphalan: 140 mg/m^2 on Day -2
Experimental: Myeloablative Conditioning Regimen (MAC) The sequence of (1) busulfan/fludarabine, (2) busulfan/cyclophosphamide, or (3) cyclophosphamide/total body irradiation administration in MAC regimens will be done according to institutional standards as long as the prescribed doses are the same as the recommended regimen below. Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or mg/m^2/day with Bu Css 900±100 ng/mL (total dose of 16 mg/kg, 12.8 mg/kg or 520 mg/m^2, respectively) on Days -5 to -2 ; Fludarabine: 30 mg/m2/day on Days -5 to -2: Flu (total dose of 120 mg/m^2). Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or 130 mg/m^2/day with Bu Css 900 ± 100 ng/mL (total dose of 16 mg/kg or 12.8 mg/kg or 520 mg/m^2, respectively) on Days -7 to -4; Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg). TBI: 1200-1420 cGy on Days -7 to -4; Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg).	Drug: Busulfan and Fludarabine (Bu/Flu) Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or mg/m^2/day with Bu Css 900±100 ng/mL (total dose of 16 mg/kg, 12.8 mg/kg or 520 mg/m^2, respectively) on Days -5 to -2 Fludarabine: 30 mg/m^2/day on Days -5 to -2: Flu (total dose of 120 mg/m^2) Drug: Busulfan and Cyclophosphamide (Bu/Cy) Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or 130 mg/m^2/day with Bu Css 900 ± 100 ng/mL (total dose of 16 mg/kg or 12.8 mg/kg or 520 mg/m^2, respectively) on Days -7 to -4 Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg) Drug: Cyclophosphamide and Total Body Irradiation (Cy/TBI) TBI: 1200-1420 cGy on Days -7 to -4 Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg)

Arms

Assigned Interventions

Active Comparator: Reduced Intensity Conditioning (RIC)

The sequence of (1) fludarabine/busulfan, or (2) fludarabine/melphalan administration in RIC regimens will be done according to institutional standards as long as the prescribed doses are the same as the recommended regimen below:

Fludarabine: 30 mg/m^2/day on Days -6 to -2 (total dose of 150 mg/m^2): Busulfan: 4 mg/kg/day PO or 3.2 mg/kg/day,(total dose of 8 mg/kg or 6.4 mg/kg, respectively) on Days -5 to -4.
Fludarabine: 30 mg/m^2/day on Days -5 to -2 (total dose of 120 mg/m^2); Melphalan: 140 mg/m^2 on Day -2.

Drug: Fludarabine and Busulfan (Flu/Bu)

Fludarabine: 30 mg/m^2/day on Days -6 to -2 (total dose of 150 mg/m^2)
Busulfan: 4 mg/kg/day PO or 3.2 mg/kg/day (total dose of 8 mg/kg or 6.4 mg/kg, respectively) on Days -5 to -4.

Drug: Fludarabine and Melphalan (Flu/Mel)

Fludarabine: 30 mg/m^2/day on Days -5 to -2 (total dose of 120 mg/m^2)
Melphalan: 140 mg/m^2 on Day -2

Experimental: Myeloablative Conditioning Regimen (MAC)

The sequence of (1) busulfan/fludarabine, (2) busulfan/cyclophosphamide, or (3) cyclophosphamide/total body irradiation administration in MAC regimens will be done according to institutional standards as long as the prescribed doses are the same as the recommended regimen below.

Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or mg/m^2/day with Bu Css 900±100 ng/mL (total dose of 16 mg/kg, 12.8 mg/kg or 520 mg/m^2, respectively) on Days -5 to -2 ; Fludarabine: 30 mg/m2/day on Days -5 to -2: Flu (total dose of 120 mg/m^2).
Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or 130 mg/m^2/day with Bu Css 900 ± 100 ng/mL (total dose of 16 mg/kg or 12.8 mg/kg or 520 mg/m^2, respectively) on Days -7 to -4; Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg).
TBI: 1200-1420 cGy on Days -7 to -4; Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg).

Drug: Busulfan and Fludarabine (Bu/Flu)

Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or mg/m^2/day with Bu Css 900±100 ng/mL (total dose of 16 mg/kg, 12.8 mg/kg or 520 mg/m^2, respectively) on Days -5 to -2
Fludarabine: 30 mg/m^2/day on Days -5 to -2: Flu (total dose of 120 mg/m^2)

Drug: Busulfan and Cyclophosphamide (Bu/Cy)

Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or 130 mg/m^2/day with Bu Css 900 ± 100 ng/mL (total dose of 16 mg/kg or 12.8 mg/kg or 520 mg/m^2, respectively) on Days -7 to -4
Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg)

Drug: Cyclophosphamide and Total Body Irradiation (Cy/TBI)

TBI: 1200-1420 cGy on Days -7 to -4
Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg)

Detailed Description:

Patients randomized to RIC will receive one of two regimen types: the combination of fludarabine (120-180 mg/m^2) and busulfan (less than or equal to 8 mg/kg or IV equivalent) (Flu/Bu) or fludarabine (120-180 mg/m^2) and melphalan (less than 150 mg/m^2) (Flu/Mel). Patient randomized to MAC will receive one of three regimens: busulfan (16 mg/kg oral or 12.8 mg/kg IV equivalent) and cyclophosphamide (120 mg/kg) (Bu/Cy); or, busulfan (16 mg/kg PO or 12.8 mg/kg IV) and fludarabine (120-180 mg/m^2) (Bu/Flu); or, cyclophosphamide (120 mg/kg) and total body irradiation (greater than 1200-1420cGy) (CyTBI). A total of 356 patients (178 to each arm) will be accrued on this study over a period of four years. Patients will be followed for up to 18 months from transplantation.

Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Age equal or less than 65 years old and equal to or greater than 18 years old.
Patients with the diagnosis of MDS or AML with fewer than 5% myeloblasts in the bone marrow and no leukemic myeloblasts in the peripheral blood on morphologic analysis performed within 30 days of start of the conditioning regimen enrollment.
For patients receiving treatment of their MDS or AML prior to transplantation: a)Interval between the start of the most recent cycle of conventional cytotoxic chemotherapy and enrollment must be at least 30 days; b)Interval between completing treatment with a hypomethylating agent or other non-cytotoxic chemotherapy and enrollment must be at least 10 days.
Patients must have a related or unrelated bone marrow or peripheral blood donor who is HLA-matched at 7 or 8 of 8 HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing.
HCT-Specific Comorbidity Index Score (HCT-CI) less than or equal to 4.
Organ function: a) Cardiac function: Ejection fraction greater than or equal to 40%; b) Hepatic function: total bilirubin less than or equal to 2 times the upper limit of normal and ALT and AST less than or equal to 3 times the upper limit of normal.; c)Pulmonary function: DLCO greater than or equal to 40% and FEV1 greater than or equal to 50% (corrected for hemoglobin.
Creatinine clearance greater than or equal to 50mL/min based on the Cockcroft-Gault formula.
Signed informed consent.

Exclusion Criteria:

Prior allograft or prior autograft.
Symptomatic coronary artery disease.
Leukemia involvement in the CNS within 4 weeks of enrollment for patients with a history of prior CNS leukemia involvement (i.e., leukemic blasts previously detected in the cerebral spinal fluid).
Karnofsky Performance Score less than 70.
Patients receiving supplemental oxygen.
Planned use of DLI therapy.
Patients with uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms).
Patients seropositive for the human immunodeficiency virus (HIV).
Patients with prior malignancies, except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent greater than 5 years previously. Cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.
Females who are pregnant or breastfeeding.
Fertile men and women unwilling to use contraceptive techniques during and for 12 months following treatment.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01339910

Contacts

Contact: Mary Horowitz, MD, MS		marymh@mcw.edu
Contact: Sandi Sykes		ssykes@emmes.com

Hide Study Locations

Locations

United States, Arizona
Mayo Clinic Scottsdale	Recruiting
Scottsdale, Arizona, United States, 85259-5499
Contact: Clinical Trials Office 507-538-7623
United States, California
University of California, San Diego Medical Center	Recruiting
La Jolla, California, United States, 92093
Contact: Edward Ball, MD 858-822-6380 tball@ucsd.edu
United States, Florida
University of Florida College of Medicine	Recruiting
Gainesville, Florida, United States, 32610-0277
Contact: John Wingard, MD 352-273-8022 wingarjr@medicine.ufl.edu
H. Lee Moffitt Cancer Center	Recruiting
Tampa, Florida, United States, 33624
Contact: Hugo Fernandez, MD 813-745-7202 hugo.fernandez@moffitt.org
United States, Georgia
Blood and Marrow Transplant Program at Northside Hospital	Recruiting
Atlanta, Georgia, United States, 30342
Contact: Lawrence E Morris, MD 404-255-1930 lemorris@bmtga.com
Emory University	Recruiting
Atlanta, Georgia, United States, 30322
Contact: Edmund Waller, MD, PhD 404-727-4995 ewaller@emory.edu
Contact: Ajay Nooka, MD anooka@emory.edu
United States, Kansas
University of Kansas	Recruiting
Kansas City, Kansas, United States, 66160
Contact: Sunil Abhyankar, MD 913-588-6077 sabhyankar@kumc.edu
United States, Kentucky
University of Kentucky	Recruiting
Lexington, Kentucky, United States, 40536
Contact: Dianna Howard, MD 859-323-1385 Dshowa0@uky.edu
United States, Massachusetts
DFCI, Brigham & Women's Hospital	Not yet recruiting
Boston, Massachusetts, United States, 02114
Contact: Edwin Alyea, MD 617-632-3903 edwin_Alyea@dfci.harvard.edu
Tufts Medical Center	Recruiting
Boston, Massachusetts, United States, 02111
Contact: Hans-Georg Klingemann, MD, PhD 617-636-2520 hklingemann@tufts-nemc.org
United States, Minnesota
University of Minnesota	Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Erica Warlick, MD ewarlick@umn.edu
United States, Nebraska
University of Nebraska Medical Center	Recruiting
Omaha, Nebraska, United States, 68198
Contact: Lori Maness, MD lmaness@unmc.edu
United States, New York
Mount Sinai Medical Center	Recruiting
New York, New York, United States, 10029
Contact: Adriana Malone, MD 212-241-6021 Adriana.malone@mssm.edu
United States, North Carolina
University of North Carolina Hospital at Chapel Hill	Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Thomas Shea, MD 919-966-7746 sheat@med.unc.edu
Duke University Medical Center	Recruiting
Durham, North Carolina, United States, 27705
Contact: Mitchell E Horwitz, MD 919-668-1045 Mitchell.horwitz@duke.edu
United States, Ohio
Jewish Hospital BMT Program	Recruiting
Cincinnati, Ohio, United States, 45236
Contact: Randolph Broun, MD ebroun@ohcmail.com
University Hospitals of Cleveland/Case Western	Recruiting
Cleveland, Ohio, United States, 44106-5061
Contact: Hillard Lazarus, MD 216-844-3629 hillard.lazarus@case.edu
Cleveland Clinic Foundation	Recruiting
Cleveland, Ohio, United States, 44195
Contact: Matthew Kalaycio, MD 216-444-3705 kalaycm@ccf.org
United States, Oklahoma
University of Oklahoma Medical Center	Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: George Selby, MD 405-271-4022 george-selby@ouhsc.edu
United States, Oregon
Oregon Health & Science University	Recruiting
Portland, Oregon, United States, 97239-3098
Contact: Gabrielle Meyers, MD meyersg@ohsu.edu
United States, Pennsylvania
University of Pennsylvania Cancer Center	Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: David Porter, MD 215-662-2867 david.portre@uphs.upenn.edu
United States, Texas
Baylor University Medical Center	Recruiting
Dallas, Texas, United States, 75246
Contact: Edward Agura, MD 214-820-1800 edward.agura@baylorhealth.edu
Baylor College of Medicine/The Methodist Hospital	Recruiting
Houston, Texas, United States, 77030
Contact: George Carrum, MD 713-441-1450 gcarrum@tmhs.org
Texas Transplant Institute	Recruiting
San Antonio, Texas, United States, 78229
Contact: Carlos Bachier, MD 210-575-4238 Carlos.Bachier@MHShealth.com
United States, Utah
Utah BMT/University of Utah Medical School	Recruiting
Salt Lake City, Utah, United States, 84132
Contact: Michael Pulsipher, MD 801-585-3229 michael.pulsipher@hsc.utah.edu
United States, Washington
Fred Hutchinson Cancer Research Center	Recruiting
Seattle, Washington, United States, 98109
Contact: Bart Scott, MD 206-667-1990 bscott@fhcrc.org
United States, West Virginia
West Virginia University Hospital	Recruiting
Morgantown, West Virginia, United States, 26506
Contact: Michael Craig, MD craigm@wvuhealthcare.com
United States, Wisconsin
University of Wisconsin Hospital & Clinics	Recruiting
Madison, Wisconsin, United States, 53792-5156
Contact: Mark Juckett, MD 608-263-0338 mbj@medicine.wisc.edu
Medical College of Wisconsin	Recruiting
Milwaukee, Wisconsin, United States, 53211
Contact: Marcelo Pasquini, MD 414-805-0700 mpasquin@mcw.edu

Sponsors and Collaborators

Medical College of Wisconsin

National Heart, Lung, and Blood Institute (NHLBI)

National Cancer Institute (NCI)

Blood and Marrow Transplant Clinical Trials Network

Investigators

Study Chair:	Bart Scott, MD	Fred Hutchinson Cancer Research Center
Study Chair:	Mitchell Horwitz, MD	Duke University

More Information

Additional Information:

Blood and Marrow Transplant Clinical Trials Network This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Medical College of Wisconsin
ClinicalTrials.gov Identifier:	NCT01339910 History of Changes
Other Study ID Numbers:	709, U01HL069294, U01HL069294-05, 0901
Study First Received:	April 20, 2011
Last Updated:	April 2, 2013
Health Authority:	United States: Federal Government

Keywords provided by Medical College of Wisconsin:

Acute Myelogenous Leukemia
Myelodysplastic Syndrome

Additional relevant MeSH terms:

Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Busulfan
Cyclophosphamide
Melphalan
Fludarabine monophosphate
Fludarabine

Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists
Antirheumatic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents

ClinicalTrials.gov processed this record on May 16, 2013