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

NCT ID: NCT00641030

Last Updated: 2023-06-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-07-31
• Study Completion Date: 2011-01-31

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.

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.

Conditions

Leukemia; Myelodysplastic Syndromes

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Interventions

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

Intervention Type: 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

Intervention Type: DRUG

gene expression analysis

Peripheral blood draw on day -9 and day -4 prior to transplant

Intervention Type: GENETIC

reverse transcriptase-polymerase chain reaction

Peripheral blood draw on day -9 and day -4 prior to transplant

Intervention Type: GENETIC

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

Intervention Type: 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.

Intervention Type: OTHER

allogeneic hematopoietic stem cell transplantation

Infusion of allogeneic hematopoietic stem cells on day 0 of transplant

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• 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

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 120 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

City of Hope Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Anthony Stein, MD

Role: PRINCIPAL_INVESTIGATOR

City of Hope Comprehensive Cancer Center

Locations

City of Hope Comprehensive Cancer Center

Duarte, California, United States

Countries

United States

Other Identifiers

P30CA033572

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CHNMC-06114

Identifier Type: -

Identifier Source: secondary_id

CDR0000589304

Identifier Type: REGISTRY

Identifier Source: secondary_id

06114

Identifier Type: -

Identifier Source: org_study_id