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

Phase 1
1 Year
Not Enrolling
Leukemia, Myelodysplastic Syndromes

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Trial Information

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
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.

Inclusion Criteria


- 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


- 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

- 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

- No active cytomegalovirus (CMV) or fungal disease

- HIV negative


- 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

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose

Outcome Time Frame:

4 weeks from the start of treatment

Safety Issue:


Principal Investigator

Anthony Stein, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Beckman Research Institute


United States: Institutional Review Board

Study ID:




Start Date:

July 2007

Completion Date:

January 2011

Related Keywords:

  • Leukemia
  • Myelodysplastic Syndromes
  • de novo myelodysplastic syndromes
  • previously treated myelodysplastic syndromes
  • secondary myelodysplastic syndromes
  • adult acute lymphoblastic leukemia in remission
  • adult acute myeloid leukemia with 11q23 (MLL) abnormalities
  • adult acute myeloid leukemia with inv(16)(p13;q22)
  • adult acute myeloid leukemia with t(15;17)(q22;q12)
  • adult acute myeloid leukemia with t(16;16)(p13;q22)
  • adult acute myeloid leukemia with t(8;21)(q22;q22)
  • adult acute myeloid leukemia in remission
  • recurrent adult acute myeloid leukemia
  • childhood acute myeloid leukemia in remission
  • recurrent childhood acute myeloid leukemia
  • secondary acute myeloid leukemia
  • childhood myelodysplastic syndromes
  • recurrent adult acute lymphoblastic leukemia
  • recurrent childhood acute lymphoblastic leukemia
  • childhood acute lymphoblastic leukemia in remission
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia



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