Allogeneic Hematopoietic Cell Transplantation for Patients With Hematologic Disorders Who Are Undergoing Dose-Adjusted Treatment With A Maximally Intensive Busulfex-Based Therapeutic Regimen
- Phase I Objective: To identify the maximum tolerated dose of continuous infusion IV
busulfan based on blood levels derived from a test dose in conjunction with
fludarabine, ATG and methotrexate plus tacrolimus for GVHD prophylaxis
- Phase II Objective: To determine the one-year disease-free survival (DFS) rate at the
maximum tolerated dose identified during Phase I of the trial (target AUC 6912)
- Determine the overall and disease-free survival of patients treated with this regimen.
- Determine the dose-limiting toxicities of this regimen in these patients.
- Determine the capacity of test dosing of busulfan that would result in the desired area
under the curve concentration exposure of patients receiving a full-dose busulfan
- Determine the incidence of graft-vs-host disease and DNA chimerism between 1 month and
2 years post-transplantation in these patients.
- Compare the overall survival (OS) and disease-free survival (DFS) rates for patients
treated with Campath vs. patients treated with ATG/Methotrexate for GVHD control
OUTLINE: This is a non-randomized, open-label, parallel group study of busulfan. Patients
are stratified according to donor relationship (matched related donor [MRD] vs matched
unrelated donor [MUD]).
- Conditioning regimen: Patients receive fludarabine phosphate IV over 30 minutes on days
-7 to -3 and busulfan IV over 2 hours once within days -15 to -10 and then IV
continuously over 90 hours on days -7 to -4. Patients with a MRD also receive
Methotrexate (MTX) on Days +1, +3, and +6. Patients with a MUD receive ATG on Days -3
and -2 and MTX on Days +1, +3 and +6.
Phase I portion only: Cohorts of 3-6 patients receive escalating doses of busulfan until the
maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at
which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
- Allogeneic peripheral blood stem cell transplantation: Patients undergo allogeneic
peripheral blood stem cell transplantation on day 0. Patients then receive sargramostim
(GM-CSF) subcutaneously beginning on day 5 and continuing until blood counts recover.
- Graft-vs-host disease (GVHD) prophylaxis: Patients receive oral tacrolimus twice daily
on days -1 to 180 or days -1 to 240.
- Donor lymphocyte infusion (DLI): Patients who do not achieve CR, do not have GVHD, and
have been off immunosuppressants for at least 30 days may receive up to 3 DLIs, at
least 8 weeks apart, after completion of tacrolimus.
After the completion of study treatment, patients are followed periodically for up to 5
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
One-year disease-free survival (DFS) rate at the maximum tolerated dose identified during phase I of the trial (target AUC 6912)
One year post-transplant
Thomas C. Shea, MD
UNC Lineberger Comprehensive Cancer Center
United States: Food and Drug Administration
|Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill||Chapel Hill, North Carolina 27599-7570|