A Phase I Study of Clofarabine Plus High Dose Melphalan as a Conditioning Regimen for Allogeneic Transplantation
- To determine the maximum tolerated dose and toxicities of clofarabine when administered
with high-dose melphalan as a conditioning regimen in patients undergoing allogeneic
stem cell transplantation for acute myeloid leukemia, acute lymphocytic leukemia, or
- To assess the efficacy of this regimen in facilitating engraftment in these patients.
- To perform correlative laboratory studies of engraftment, immune reconstitution, and
OUTLINE: This is a dose-escalation study of clofarabine. Patients are stratified according
to age (< 18 years vs ≥ 18 years).
- Reduced-intensity conditioning regimen: Patients receive clofarabine IV over 30 minutes
on days -9 to -5 and high-dose melphalan IV over 30 minutes on day -4.
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. At least 6 patients are treated at the MTD.
- Allogeneic stem cell transplantation: Patients undergo allogeneic stem cell
transplantation on day 0.
- Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 10
hours or orally twice daily beginning on day -1 and continuing until day 90-100,
followed by a taper in the absence of GVHD. Patients also receive mycophenolate mofetil
IV or orally twice daily beginning on day 0 and continuing until day 28, followed by a
taper in the absence of GVHD.
Patients undergo blood and/or bone marrow sample collection periodically for correlative
laboratory studies. Samples are examined for markers of immune reconstitution (i.e., CD8+ T
lymphocytes, CD4+ T lymphocytes, NK cells, B cells, and monocytes) by flow cytometry and for
diversity of the reconstituted T-cell repertoire by PCR-based T-cell receptor repertoire
analysis. Samples are also examined for gene expression of hRRM2 and markers of apoptosis
(i.e., Bcl-2, Bid, NFkB2, and Bcl-3) by real-time RT-PCR and for markers of ribonucleotide
reductase inhibition (i.e., dCTP levels in circulating peripheral blood mononuclear cells).
After completion of study therapy, patients are followed periodically for up to 5 years.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose
4 weeks from the start of treatment
Anthony Stein, MD
Beckman Research Institute
United States: Institutional Review Board
|City of Hope Comprehensive Cancer Center||Duarte, California 91010|