Clofarabine, Cytarabine, and G-CSF in Treating Patients With Myelodysplastic Syndromes

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Biological: filgrastim
* Drug: clofarabine
* Drug: cytarabine
* Genetic: microarray analysis
* Procedure: biopsy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>G-CSF 300 μg subcutaneously to begin one day prior to treatment and continued until ANC greater than 1.0 or recovers back to the patients baseline ANC for 3 days in a row subsequent to completion of chemotherapy (SOC) Low-dose Cytarabine 10 mg/m2 subcutaneously daily starting on day 1 for the first 5 consecutive days of the treatment course 2-4 hours following the end of the clofarabine infusion. (SOC) Clofarabine starting at dose level 0. Dose-10 mg/m2 IV over 1 hour daily starting on day 1 for the first 5 consecutive days of the treatment course The G-CSF and cytarabine doses are fixed. The dose of clofarabine is initially fixed. For the subsequent cohort, the dose of clofarabine will be advanced to the next dose level. | Biological: filgrastim<br>* subcutaneously one day prior to treatment<br>* Other names: Neupogen;Drug: clofarabine<br>* single IV dose over 1 hour daily for 5 days<br>* Other names: Clolar;Drug: cytarabine<br>* subcutaneously daily for 5 days 2-4 hours following the end of the Clofarabine infusion<br>* Other names: cytosine arabinoside;Genetic: microarray analysis<br>* Both standard cytogenetic testing and FISH (fluorescent in situ hybridization) are adequate to assess responses.<br>Procedure: biopsy<br>* bone marrow biopsy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 7 months | 
| 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. | Following phase I, responses must last at least 8 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess Quality of Life | To assess effects on quality of life of this patient population (questionnaire). | 7 months | 
| Time to Acute Myelooid Leukemia Transformation or Death. | To assess the time to acute myeloid leukemia transformation or death. | 7months | 
| Cytogenetic Response Rates | To assess cytogenetic response rates. | 7 months | 
| Changes in Flow of Cytometric Patterns. | To assess changes in flow cytometric patterns. | 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes