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

Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00641030
• Other study ID #: 06114
• Secondary ID: P30CA033572CHNMC
• Status: Completed
• Phase: Phase 1
• Start date: July 2007
• Est. completion date: January 2011

Study information

• Verified date: June 2023
• Source: City of Hope Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: January 2011
• Est. primary completion date: January 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 120 Years

Eligibility

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

Related Conditions & MeSH terms

• Leukemia
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

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
• 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
• 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
• 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

Locations

Country	Name	City	State
United States	City of Hope Comprehensive Cancer Center	Duarte	California

Sponsors (2)

Lead Sponsor	Collaborator
City of Hope Medical Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose		4 weeks from the start of treatment
Primary	Dose-limiting toxicity as assessed by NCI CTCAE v3.0 and the Modified Bearman scale		4 weeks from the start of treatment
Primary	Graft failure or rejection		35 days post-transplant
Secondary	Efficacy		One year post-transplant
Secondary	Correlative laboratory studies of engraftment, immune reconstitution, and therapeutic outcomes		One year post-transplant