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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT00641030
First received: March 20, 2008
Last updated: July 16, 2012
Last verified: July 2012
  Purpose

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 Intervention 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

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Clofarabine Plus High Dose Melphalan as a Conditioning Regimen for Allogeneic Transplantation

Resource links provided by NLM:


Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:
  • Maximum tolerated dose [ Time Frame: 4 weeks from the start of treatment ] [ Designated as safety issue: Yes ]
  • Dose-limiting toxicity as assessed by NCI CTCAE v3.0 and the Modified Bearman scale [ Time Frame: 4 weeks from the start of treatment ] [ Designated as safety issue: Yes ]
  • Graft failure or rejection [ Time Frame: 35 days post-transplant ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Efficacy [ Time Frame: One year post-transplant ] [ Designated as safety issue: No ]
  • Correlative laboratory studies of engraftment, immune reconstitution, and therapeutic outcomes [ Time Frame: One year post-transplant ] [ Designated as safety issue: No ]

Enrollment: 20
Study Start Date: July 2007
Study Completion Date: January 2011
Primary Completion Date: January 2011 (Final data collection date for primary outcome measure)
Intervention Details:
    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
    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
    Genetic: gene expression analysis
    Peripheral blood draw on day -9 and day -4 prior to transplant
    Genetic: 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
    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.
    Procedure: allogeneic hematopoietic stem cell transplantation
    Infusion of allogeneic hematopoietic stem cells on day 0 of transplant
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.

  Eligibility

Ages Eligible for Study:   1 Year and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00641030

Locations
United States, California
City of Hope Comprehensive Cancer Center
Duarte, California, United States, 91010-3000
Sponsors and Collaborators
City of Hope Medical Center
Investigators
Principal Investigator: Anthony Stein, MD Beckman Research Institute
  More Information

Additional Information:
No publications provided

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT00641030     History of Changes
Other Study ID Numbers: 06114, P30CA033572, CHNMC-06114, CDR0000589304
Study First Received: March 20, 2008
Last Updated: July 16, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by City of Hope Medical Center:
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

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Preleukemia
Syndrome
Bone Marrow Diseases
Disease
Hematologic Diseases
Immune System Diseases
Immunoproliferative Disorders
Leukemia, Lymphoid
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Pathologic Processes
Precancerous Conditions
Clofarabine
Melphalan
Alkylating Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists

ClinicalTrials.gov processed this record on October 29, 2014