Total Marrow Irradiation and Myeloablative Chemotherapy Followed By Double Umbilical Cord Blood Transplantation In Patients With High Risk Hematological Malignancies
- Determine the maximum tolerated dose of total marrow irradiation (TMI) delivered by
image-guided tomographic intensity-modulated radiotherapy when administered in
combination with myeloablative chemotherapy in patients undergoing double umbilical
cord blood (UCB) transplantation for refractory acute leukemia.
- Determine the incidence of engraftment (defined as achievement of neutrophil count >
500/uL at 42 days after transplantation).
- Determine the incidence of platelet engraftment at 6 months and at 1 year after
- Evaluate the incidence of complete donor chimerism and the relative contribution of
each UCB unit to donor engraftment within the first 100 days after transplantation.
- Determine the incidence of transplantation-related mortality (TRM) at 6 months after
treatment with a TMI-containing myeloablative conditioning regimen.
- Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease
(GVHD) at 100 days after transplantation.
- Determine the incidence of chronic GVHD at 1 year after transplantation.
- Determine the incidence of relapse at 1 year after transplantation.
- Determine the survival and disease-free survival at 1 and 2 years after
- Assess the durability of remission based on presence of rapid early response (defined
by clearance of leukemic blasts from the bone marrow at 21 days after transplantation).
OUTLINE: This is a dose-escalation study of total marrow irradiation (TMI).
- Myeloablative conditioning regimen: Patients receive fludarabine phosphate IV over 1
hour once daily for 3 days between days -12 and -6 and cyclophosphamide IV once daily
for 2 days between days -11 and -6. Patients undergo TMI once daily for 4-8 days
between days -8 and -1.
- Donor umbilical cord blood (UCB) transplantation: Patients undergo single-unit or
double-unit donor UCB transplantation on day 0. Patients receive filgrastim (G-CSF) IV
or subcutaneously once daily beginning on day 1 and continuing until blood counts
- Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2
hours or orally 2-3 times daily beginning on day -3 and continuing until day 100,
followed by a taper until day 180, in the absence of GVHD. Patients also receive
mycophenolate mofetil IV or orally 2-3 times daily beginning on day -3 and continuing
until day 30 (or 7 days after engraftment), in the absence of acute GVHD.
Patients are followed periodically for up to 2 years after transplantation.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose (MTD) of total marrow irradiation (TMI)
Maximum tolerated dose (MTD) is the highest dose of a drug or treatment that does not cause unacceptable side effects. The MTD of TMI will be determined by using the modified Continual Reassessment Method (CRM). The goal of this CRM will be to identify 1 of the 5 dose levels which corresponds to the desired maximum toxicity rate of <=15%.
Michael R. Verneris, MD
Masonic Cancer Center, University of Minnesota
United States: Food and Drug Administration
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