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

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ClinicalTrials.gov Identifier: NCT00503880
Recruitment Status : Terminated (Genzyme discontinued Funding)
First Posted : July 19, 2007
Results First Posted : April 13, 2018
Last Update Posted : April 13, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Lori Maness Harris, MD, University of Nebraska

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.


Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes Biological: filgrastim Drug: clofarabine Drug: cytarabine Genetic: microarray analysis Procedure: biopsy Phase 1 Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : May 2007
Actual Primary Completion Date : October 2009
Actual Study Completion Date : October 2009

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: Treatment
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
subcutaneously one day prior to treatment
Drug: clofarabine
single IV dose over 1 hour daily for 5 days
Drug: cytarabine
subcutaneously daily for 5 days 2-4 hours following the end of the Clofarabine infusion
Genetic: microarray analysis
Both standard cytogenetic testing and FISH (fluorescent in situ hybridization) are adequate to assess responses.
Procedure: biopsy
bone marrow biopsy



Primary Outcome Measures :
  1. Maximum Tolerated Dose of Clofarabine (Phase I) [ Time Frame: 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).

  2. Presence of Hematologic Response (Phase II) [ Time Frame: 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 Outcome Measures :
  1. Quality of Life [ Time Frame: 7 months ]
    To assess effects on quality of life of this patient population.

  2. Time to Acute Myelooid Leukemia Transformation or Death. [ Time Frame: 7months ]
    To assess the time to acute myeloid leukemia transformation or death.

  3. Cytogenetic Response Rates [ Time Frame: 7 months ]
    To assess cytogenetic response rates.

  4. Changes in Flow of Cytometric Patterns. [ Time Frame: 7 months ]
    To assess changes in flow cytometric patterns.



Information from the National Library of Medicine

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Ages Eligible for Study:   19 Years to 120 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Confirmed pathologic diagnosis of myelodysplastic syndromes
  • International Prognostic Scoring System score of intermediate-2 or high-risk
  • Failed 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

PATIENT CHARACTERISTICS:

  • 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
  • Not pregnant or nursing
  • Fertile patients must use effective contraception
  • 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

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00503880


Locations
United States, Nebraska
UNMC Eppley Cancer Center at the University of Nebraska Medical Center
Omaha, Nebraska, United States, 68198-6805
Sponsors and Collaborators
University of Nebraska
National Cancer Institute (NCI)
Investigators
Principal Investigator: Lori J. Maness, MD University of Nebraska

Responsible Party: Lori Maness Harris, MD, UNMC Principal Investigator, University of Nebraska
ClinicalTrials.gov Identifier: NCT00503880     History of Changes
Other Study ID Numbers: 032-07
P30CA036727 ( U.S. NIH Grant/Contract )
UNMC-03207
UNMC 032-07
First Posted: July 19, 2007    Key Record Dates
Results First Posted: April 13, 2018
Last Update Posted: April 13, 2018
Last Verified: April 2018

Keywords provided by Lori Maness Harris, MD, University of Nebraska:
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes

Additional relevant MeSH terms:
Syndrome
Myelodysplastic Syndromes
Preleukemia
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Cytarabine
Clofarabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs