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

Primary Purpose

Leukemia, Myelodysplastic Syndromes

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
clofarabine
melphalan
gene expression analysis
reverse transcriptase-polymerase chain reaction
flow cytometry
laboratory biomarker analysis
allogeneic hematopoietic stem cell transplantation
Sponsored by
City of Hope Medical Center
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia focused on measuring 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

Eligibility Criteria

1 Year - 120 Years (Child, Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • City of Hope Comprehensive Cancer Center

Outcomes

Primary Outcome Measures

Maximum tolerated dose
Dose-limiting toxicity as assessed by NCI CTCAE v3.0 and the Modified Bearman scale
Graft failure or rejection

Secondary Outcome Measures

Efficacy
Correlative laboratory studies of engraftment, immune reconstitution, and therapeutic outcomes

Full Information

First Posted
March 20, 2008
Last Updated
June 14, 2023
Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00641030
Brief Title
Clofarabine and High-Dose Melphalan Followed by Donor Stem Cell Transplant in Patients With Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Myelodysplastic Syndromes
Official Title
A Phase I Study of Clofarabine Plus High Dose Melphalan as a Conditioning Regimen for Allogeneic Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Completed
Study Start Date
July 2007 (undefined)
Primary Completion Date
January 2011 (Actual)
Study Completion Date
January 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myelodysplastic Syndromes
Keywords
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
clofarabine
Intervention Description
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
Intervention Name(s)
melphalan
Intervention Description
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
Genetic
Intervention Name(s)
gene expression analysis
Intervention Description
Peripheral blood draw on day -9 and day -4 prior to transplant
Intervention Type
Genetic
Intervention Name(s)
reverse transcriptase-polymerase chain reaction
Intervention Description
Peripheral blood draw on day -9 and day -4 prior to transplant
Intervention Type
Other
Intervention Name(s)
flow cytometry
Intervention Description
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
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
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
Procedure
Intervention Name(s)
allogeneic hematopoietic stem cell transplantation
Intervention Description
Infusion of allogeneic hematopoietic stem cells on day 0 of transplant
Primary Outcome Measure Information:
Title
Maximum tolerated dose
Time Frame
4 weeks from the start of treatment
Title
Dose-limiting toxicity as assessed by NCI CTCAE v3.0 and the Modified Bearman scale
Time Frame
4 weeks from the start of treatment
Title
Graft failure or rejection
Time Frame
35 days post-transplant
Secondary Outcome Measure Information:
Title
Efficacy
Time Frame
One year post-transplant
Title
Correlative laboratory studies of engraftment, immune reconstitution, and therapeutic outcomes
Time Frame
One year post-transplant

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
120 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anthony Stein, MD
Organizational Affiliation
City of Hope Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Comprehensive Cancer Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010-3000
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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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