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

Sponsors and Collaborators:	Beckman Research Institute National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00641030

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 I

MedlinePlus related topics: Cancer Leukemia, Adult Acute Leukemia, Adult Chronic Leukemia, Childhood

Drug Information available for: Clofarabine Melphalan Sarcolysin Melphalan hydrochloride

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment
Official Title:	A Phase I Study of Clofarabine Plus High Dose Melphalan as a Conditioning Regimen for Allogeneic Transplantation

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Maximum tolerated dose [ Designated as safety issue: Yes ]
Dose-limiting toxicity as assessed by NCI CTCAE v3.0 and the Modified Bearman scale [ Designated as safety issue: Yes ]
Graft failure or rejection [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Efficacy [ Designated as safety issue: No ]
Correlative laboratory studies of engraftment, immune reconstitution, and therapeutic outcomes [ Designated as safety issue: No ]

Estimated Enrollment:	36
Study Start Date:	July 2007
Estimated Primary Completion Date:	July 2010 (Final data collection date for primary outcome measure)

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 -7 to -3 and high-dose melphalan IV over 30 minutes on day -2. 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

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

Locations

United States, California
City of Hope Comprehensive Cancer Center	Recruiting
Duarte, California, United States, 91010-3000
Contact: Joel Conrad 800-826-4673

Sponsors and Collaborators

Beckman Research Institute

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Mark H. Kirschbaum, MD

Beckman Research Institute

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Study ID Numbers:	CDR0000589304, CHNMC-06114
Study First Received:	March 20, 2008
Last Updated:	February 6, 2009
ClinicalTrials.gov Identifier:	NCT00641030 History of Changes
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

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

Study placed in the following topic categories:

Acute Lymphoblastic Leukemia, Childhood
Melphalan
Leukemia, Lymphoid
Immunologic Factors
Precancerous Conditions
Leukemia, Myeloid, Acute
Leukemia
Preleukemia
Acute Myelocytic Leukemia
Acute Myeloid Leukemia, Adult
Neoplasm Metastasis
Congenital Abnormalities
Alkylating Agents
Lymphoma

Acute Lymphoblastic Leukemia
Clofarabine
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immunoproliferative Disorders
Hematologic Diseases
Myelodysplastic Syndromes
Leukemia, Myeloid
Immunosuppressive Agents
Recurrence
Acute Myeloid Leukemia, Childhood
Lymphatic Diseases
Antineoplastic Agents, Alkylating
Lymphoproliferative Disorders
Bone Marrow Diseases

Additional relevant MeSH terms:

Melphalan
Leukemia, Lymphoid
Molecular Mechanisms of Pharmacological Action
Precancerous Conditions
Immunologic Factors
Antineoplastic Agents
Physiological Effects of Drugs
Leukemia, Myeloid, Acute
Leukemia
Preleukemia
Pathologic Processes
Therapeutic Uses
Syndrome
Alkylating Agents
Clofarabine

Immunoproliferative Disorders
Neoplasms by Histologic Type
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Disease
Immune System Diseases
Hematologic Diseases
Myelodysplastic Syndromes
Leukemia, Myeloid
Immunosuppressive Agents
Pharmacologic Actions
Lymphatic Diseases
Neoplasms
Myeloablative Agonists
Antineoplastic Agents, Alkylating
Lymphoproliferative Disorders

ClinicalTrials.gov processed this record on May 06, 2009