Clinical trial NCT00641030: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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
Lead sponsor: City of Hope Medical Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-03-21
Enrollment: 20
Sex: ALL
Minimum age (years): 1
Maximum age (years): 120
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Maximum tolerated dose
timeFrame: 4 weeks from the start of treatment
measure: Dose-limiting toxicity as assessed by NCI CTCAE v3.0 and the Modified Bearman scale
timeFrame: 4 weeks from the start of treatment
measure: Graft failure or rejection
timeFrame: 35 days post-transplant
Secondary outcomes:
measure: Efficacy
timeFrame: One year post-transplant
measure: Correlative laboratory studies of engraftment, immune reconstitution, and therapeutic outcomes
timeFrame: One year post-transplant
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
Study officials:
affiliation: City of Hope Comprehensive Cancer Center
name: Anthony Stein, MD
role: PRINCIPAL_INVESTIGATOR
References: