Clofarabine and High-Dose Melphalan Followed by Donor Stem Cell Transplant in Patients With Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Myelodysplastic Syndromes

Sponsor

City of Hope Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT00641030

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

42.1

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Detailed Description

OBJECTIVES:

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 Design

Study Type:

Interventional

Actual Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Study of Clofarabine Plus High Dose Melphalan as a Conditioning Regimen for Allogeneic Transplantation

Study Start Date :

Jul 1, 2007

Actual Primary Completion Date :

Jan 1, 2011

Actual Study Completion Date :

Jan 1, 2011

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose [4 weeks from the start of treatment]
Dose-limiting toxicity as assessed by NCI CTCAE v3.0 and the Modified Bearman scale [4 weeks from the start of treatment]
Graft failure or rejection [35 days post-transplant]

Secondary Outcome Measures

Efficacy [One year post-transplant]
Correlative laboratory studies of engraftment, immune reconstitution, and therapeutic outcomes [One year post-transplant]

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Diagnosis of one of the following:
Acute myeloid leukemia
Acute lymphocytic leukemia
Myelodysplastic syndromes
Disease meets 1 of the following criteria:
In first complete remission (CR)
In second CR
In relapse
No more than 50% blasts in bone marrow
Not deemed eligible for standard transplantation regimens by the attending physician, or at high risk for relapse
No suspected or proven CNS leukemia
HLA-matched (6/6) sibling donor available

PATIENT CHARACTERISTICS:

Karnofsky performance status 50-100%
Glomerular filtration rate (pediatric patients) or creatinine clearance ≥ 60 mL/min OR serum creatinine < 1.5 times upper limit of normal (ULN)
Serum bilirubin ≤ 2.0 mg/dL
AST and ALT ≤ 2.5 times ULN
LVEF ≥ 50% by ECHO or MUGA scan
DLCO or FEV_1 ≥ 40% predicted
Not pregnant
Negative pregnancy test
No concurrent uncontrolled illness including, but not limited to, any of the following:
Ongoing, active, or poorly controlled infection
Symptomatic congestive heart failure
Unstable angina pectoris
Cardiac arrhythmia
Poorly controlled pulmonary disease
Psychiatric illness/social situation that would limit compliance with study requirement
No active cytomegalovirus (CMV) or fungal disease
HIV negative

PRIOR CONCURRENT THERAPY:

Recovered from prior intensive chemotherapy (pediatric patients)
At least 100 days since prior autologous stem cell transplantation
At least 100 days since prior radiotherapy administered as part of a transplantation conditioning regimen
At least 4 weeks since prior chemotherapy
At least 24 hours since prior hydroxyurea for blast count control