A Dose Escalation Phase I/II Study of Clofarabine Plus Cytarabine With Growth Factor Priming in Patients Who Are Not Felt to be Candidates for More Aggressive Treatment, With Int-2 and High-Risk MDS
- To determine the maximum tolerated dose (MTD) of clofarabine when administered with
low-dose cytarabine and filgrastim (G-CSF) in patients with intermediate-2 or high-risk
myelodysplastic syndromes (MDS).
- To evaluate efficacy as measured by hematologic response rates in patients who are
treated with this novel combination of drugs and who are not candidates for more
intensive treatment for intermediate-2 and high-risk MDS.
- To assess effects on quality of life of this patient population.
- To assess the time to acute myeloid leukemia transformation or death.
- To assess cytogenetic response rates.
- To assess changes in flow cytometric patterns.
OUTLINE: This is a phase I, nonrandomized, dose-escalation study of clofarabine followed by
a phase II study.
- Phase I: Patients receive clofarabine IV over 1 hour and low-dose cytarabine
subcutaneously (SC) on days 1-5. Patients also receive filgrastim (G-CSF) SC beginning
1 day prior to the start of chemotherapy and continuing through completion of
chemotherapy until blood counts recover. Treatment repeats every 6 weeks for up to 10
courses in the absence of disease progression or unacceptable toxicity.
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.
- Phase II: Patients receive clofarabine at the MTD, cytarabine, and G-CSF as in phase I.
Quality of life is assessed at baseline, prior to course 4, and after completion of study
Patients undergo bone marrow biopsy at baseline and prior to courses 3, 6, and 8 for
evaluation of treatment response. Bone marrow samples are analyzed for myeloblast phenotypic
expression profiles, which include the following parameters: percentage of CD34-positive
myeloblasts; antigen expression density of CD13, CD34, CD45, and CD117; and aberrant
myeloblast expression of CD4, CD11c, CD15, and CD56.
Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose of clofarabine (phase I)
Maximum Tolerated Dose (MTD) is defined to be the dose cohort below which 2 out of 6 patients experience dose limiting toxicities or the highest dose cohort, if 2 limiting toxicities are not observed at any dose cohort. These will be presented as actual rates. Dose limiting toxicity (DLT) will be defined according to oncology standards based on NCI CTC version 2 grading criteria (DLT = > grade 3 non-hematological toxicity or any > 4 hematological toxicity that persists for more than 4 weeks and in the opinion of the investigator is felt not to be due to disease).
When/if 2 out of 6 patients experience dose limiting toxicity (DLT based on NCI CTC version 2 grading criteria)
Lori J. Maness, MD
University of Nebraska
United States: Food and Drug Administration
|UNMC Eppley Cancer Center at the University of Nebraska Medical Center||Omaha, Nebraska 68198-7680|