Myelodysplastic Syndromes
Conditions
Keywords
de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes
Brief summary
RATIONALE: Drugs used in chemotherapy, such as clofarabine and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Colony-stimulating factors, such as G-CSF, may increase the number of immune cells found in bone marrow or in peripheral blood and may help the immune system recover from the side effects of chemotherapy. Giving clofarabine and cytarabine together with G-CSF may kill more cancer cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of clofarabine and to see how well it works when given together with cytarabine and G-CSF in treating patients with myelodysplastic syndromes.
Detailed description
OBJECTIVES: Primary * 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. Secondary * 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 therapy. 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.
Interventions
BIOLOGICALfilgrastim
subcutaneously one day prior to treatment
DRUGclofarabine
single IV dose over 1 hour daily for 5 days
DRUGcytarabine
subcutaneously daily for 5 days 2-4 hours following the end of the Clofarabine infusion
GENETICmicroarray analysis
Both standard cytogenetic testing and FISH (fluorescent in situ hybridization) are adequate to assess responses.
PROCEDUREbiopsy
bone marrow biopsy
Sponsors
National Cancer Institute (NCI)
University of Nebraska
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
* Confirmed pathologic diagnosis of myelodysplastic syndromes * International Prognostic Scoring System score of intermediate-2 or high-riskFailed or progressed after 1 prior FDA-approved treatment for MDS OR refused the FDA-approved treatment * Not a candidate for intensive or standard chemotherapy or stem cell transplantation, as determined by the treating physician * ECOG performance status 0-2 * Bilirubin ≤ 1.5 times upper limit of normal (ULN) * AST or ALT ≤ 3 times ULN * Creatinine \< 2.0 mg/dL * Fertile patients must use effective contraception
Exclusion criteria
* Not pregnant or nursing * No comorbidity or condition that, in the opinion of the investigator, may interfere with the assessments and procedures of this protocol or that would decrease life expectancy to \< 3 months * No active, serious infection not controlled by oral or IV antibiotics
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of Clofarabine (Phase I) | 7 months | 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). |
| Presence of Hematologic Response (Phase II) | Following phase I, responses must last at least 8 weeks. | These are measured in patients with pretreatment abnormalities defined as: Hemoglobin \< 11 g/dL or transfusion dependence \[erythroid- E\] Platelets less than 100 x 109/L or platelet-transfusion dependence \[platelet- P\] Absolute neutrophil count (ANC) less than 1.0 x 109/L \[neutrophil- N\] Pretreatment baseline measures of cytopenias are averages of at least 2 measurements (not influenced by transfusions)- at least 1 week apart. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assess Quality of Life | 7 months | To assess effects on quality of life of this patient population (questionnaire). |
| Time to Acute Myelooid Leukemia Transformation or Death. | 7months | To assess the time to acute myeloid leukemia transformation or death. |
| Cytogenetic Response Rates | 7 months | To assess cytogenetic response rates. |
| Changes in Flow of Cytometric Patterns. | 7 months | To assess changes in flow cytometric patterns. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment clofarabine: single IV dose over 1 hour daily for 5 days
cytarabine: subcutaneously daily for 5 days 2-4 hours following the end of the Clofarabine infusion
microarray analysis: Both standard cytogenetic testing and FISH (fluorescent in situ hybridization) are adequate to assess responses.
biopsy: bone marrow biopsy | 2 |
| Total | 2 |
Baseline characteristics
| Characteristic | Treatment |
|---|---|
| Age, Continuous | 69 years |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 2 |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 1 / 2 |
Outcome results
Primary
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).
Time frame: 7 months
Population: Not done - Genzyme discontinued Funding
Primary
Presence of Hematologic Response (Phase II)
These are measured in patients with pretreatment abnormalities defined as: Hemoglobin \< 11 g/dL or transfusion dependence \[erythroid- E\] Platelets less than 100 x 109/L or platelet-transfusion dependence \[platelet- P\] Absolute neutrophil count (ANC) less than 1.0 x 109/L \[neutrophil- N\] Pretreatment baseline measures of cytopenias are averages of at least 2 measurements (not influenced by transfusions)- at least 1 week apart.
Time frame: Following phase I, responses must last at least 8 weeks.
Population: The study only enrolled 2 patients of the planned 30. The two patients enrolled did not complete the research as planned and were not evaluable. The study was closed due to lack of funding support. Data were not collected.
Secondary
Assess Quality of Life
To assess effects on quality of life of this patient population (questionnaire).
Time frame: 7 months
Population: Not done - Genzyme discontinued Funding
Secondary
Changes in Flow of Cytometric Patterns.
To assess changes in flow cytometric patterns.
Time frame: 7 months
Population: Not done - Genzyme discontinued Funding
Secondary
Cytogenetic Response Rates
To assess cytogenetic response rates.
Time frame: 7 months
Population: Not done - Genzyme discontinued Funding
Secondary
Time to Acute Myelooid Leukemia Transformation or Death.
To assess the time to acute myeloid leukemia transformation or death.
Time frame: 7months
Population: Not done - Genzyme discontinued Funding