Clofarabine and High-Dose Melphalan Followed by Donor Stem Cell Transplant in Patients With Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Myelodysplastic Syndromes
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|ClinicalTrials.gov Identifier: NCT00641030|
Recruitment Status : Completed
First Posted : March 21, 2008
Last Update Posted : July 17, 2012
RATIONALE: Giving chemotherapy, such as clofarabine and melphalan, before a donor stem cell transplant helps stop the growth of cancer or abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.
PURPOSE: This phase I trial is studying the side effects and best dose of clofarabine when given together with high-dose melphalan followed by a donor stem cell transplant in treating patients with acute myeloid leukemia, acute lymphocytic leukemia, or myelodysplastic syndromes.
|Condition or disease||Intervention/treatment||Phase|
|Leukemia Myelodysplastic Syndromes||Drug: clofarabine Drug: melphalan Genetic: gene expression analysis Genetic: reverse transcriptase-polymerase chain reaction Other: flow cytometry Other: laboratory biomarker analysis Procedure: allogeneic hematopoietic stem cell transplantation||Phase 1|
- 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 myelodysplastic syndromes.
- To assess the efficacy of this regimen in facilitating engraftment in these patients.
- To perform correlative laboratory studies of engraftment, immune reconstitution, and therapeutic outcomes.
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||20 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Study of Clofarabine Plus High Dose Melphalan as a Conditioning Regimen for Allogeneic Transplantation|
|Study Start Date :||July 2007|
|Actual Primary Completion Date :||January 2011|
|Actual Study Completion Date :||January 2011|
- Drug: clofarabine
Administered at the appropriate dose level(dose level one = 30 mg/m2, dose level two and three = 40 mg/m2)on days -9 to day -5 from transplant
- Drug: melphalan
Administered at the appropriate dose level (dose level one and two = 100 mg/m2, dose level three = 140 mg/m2) on day -4 from transplant
- Genetic: gene expression analysis
Peripheral blood draw on day -9 and day -4 prior to transplant
- Genetic: reverse transcriptase-polymerase chain reaction
Peripheral blood draw on day -9 and day -4 prior to transplant
- Other: flow cytometry
Bone marrow aspirate and biopsy to confirm diagnosis prior to transplant, day -9 pre-transplant, day 30 post-transplant, day 100 post-transplant, 6 months post-transplant, one year post-transplant, then yearly through year 5 post-transplant
- Other: laboratory biomarker analysis
Peripheral blood draw day -9 or earlier pre-transplant, day 14 post-transplant, day 30 post-transplant, day 60 post-transplant, day 100 post-transplant, 6 months and one year post-transplant.
- Procedure: allogeneic hematopoietic stem cell transplantation
Infusion of allogeneic hematopoietic stem cells on day 0 of transplant
- Maximum tolerated dose [ Time Frame: 4 weeks from the start of treatment ]
- Dose-limiting toxicity as assessed by NCI CTCAE v3.0 and the Modified Bearman scale [ Time Frame: 4 weeks from the start of treatment ]
- Graft failure or rejection [ Time Frame: 35 days post-transplant ]
- Efficacy [ Time Frame: One year post-transplant ]
- Correlative laboratory studies of engraftment, immune reconstitution, and therapeutic outcomes [ Time Frame: One year post-transplant ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00641030
|United States, California|
|City of Hope Comprehensive Cancer Center|
|Duarte, California, United States, 91010-3000|
|Principal Investigator:||Anthony Stein, MD||City of Hope Comprehensive Cancer Center|