Reduced Intensity Conditioning Versus Myeloablative Conditioning for Acute Myeloid Leukemia or Myelodysplastic Syndrome

This study has been terminated.
(Accrual terminated as recommended by the data and safety monitoring board.)
Sponsor:
Collaborators:
Blood and Marrow Transplant Clinical Trials Network
Information provided by (Responsible Party):
Medical College of Wisconsin
ClinicalTrials.gov Identifier:
NCT01339910
First received: April 20, 2011
Last updated: April 24, 2014
Last verified: April 2014
  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:


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.


Enrollment: 272
Study Start Date: May 2011
Estimated Study Completion Date: November 2017
Estimated Primary Completion Date: December 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:

  1. 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.
  2. 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.

  1. 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).
  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).
  3. 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
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, see Learn About Clinical Studies.

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

  Show 29 Study Locations
Sponsors and Collaborators
Medical College of Wisconsin
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:
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 24, 2014
Health Authority: United States: Federal Government

Keywords provided by Medical College of Wisconsin:
Acute Myelogenous Leukemia
Myelodysplastic Syndrome

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Leukemia
Syndrome
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Disease
Pathologic Processes
Cyclophosphamide
Fludarabine phosphate
Melphalan
Busulfan
Fludarabine
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists

ClinicalTrials.gov processed this record on September 18, 2014