A Phase I/II Dose Escalation Trial of Clofarabine, in Addition to Melphalan and Thiotepa as Myeloablative Regimen Followed by an Allogeneic Unmodified Hematopoietic Stem Cell Transplant From HLA-Compatible Related or Unrelated Donors for the Treatment of High Risk and/or Advanced Hematologic Malignancies
- Determine the maximum tolerated dose of clofarabine when administered with melphalan
and thiotepa followed by allogeneic stem cell transplantation in patients with
high-risk and/or advanced hematologic malignancies. (Phase I)
- Determine the 1-year disease-free survival of patients treated with this regimen.
- Determine the efficacy of this regimen, in terms of antileukemic potential and relapse
rate, in these patients.
- Evaluate the incidence and severity of nonhematologic toxicity of this regimen in these
- Evaluate the incidence and severity of graft-versus-host disease in patients treated
with this regimen.
OUTLINE: This is a phase I, dose-escalation study of clofarabine followed by an open-label,
phase II study. Patients are stratified according to HLA-compatible donor type (related vs
- Cytoreductive therapy: Patients receive clofarabine IV over 2 hours once daily on days
-9 to -5, thiotepa IV over 4 hours on day -4, and melphalan IV over 30 minutes once
daily on days -3 and -2.
Cohorts of 3-6 patients receive escalating doses of clofarabine 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.
- Graft-versus-host disease (GVHD) prophylaxis: Patients who undergo bone marrow or
peripheral blood stem cell transplantation receive tacrolimus IV continuously over 24
hours or orally every 8-12 hours beginning on day -3 and methotrexate IV on days 1, 3,
6, and 11. Patients who undergo UCB transplantation receive tacrolimus IV continuously
over 24 hours or orally every 8-12 hours beginning on day -3 and mycophenolate mofetil
(MMF) IV or orally 2 or 3 times daily on days -3 to 45 followed by a taper until day
100 (unless there are signs of acute GVHD). Patients who undergo UCB transplantation
without GVHD continue tacrolimus for 6 months followed by a taper and discontinued 1
year after transplantation.
- Allogeneic hematopoietic stem cell transplantation (HSCT) or allogeneic umbilical cord
blood (UCB) transplantation: Patients undergo allogeneic HSCT (bone marrow or
peripheral blood stem cells) or double UCB transplantation on day 0. Patients also
receive filgrastim (G-CSF) IV or subcutaneously beginning on day 7 and continuing until
blood counts recover.
- Maintenance therapy: Approximately 2 months after transplantation patients with ALL, M4
or M5 AML, and those transplanted with AML in bone marrow relapse receive cytarabine
intrathecally (IT) monthly for up to 5 doses. Patients with a history of CNS leukemia
receive cytarabine IT once monthly during months 2-12 after HSCT.
After completion of study therapy, patients are followed periodically for at least 4 years.
PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Relapse of leukemia
Farid Boulad, MD
Memorial Sloan-Kettering Cancer Center
United States: Institutional Review Board
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