Clofarabine for Myelodysplastic Syndrome (MDS) Patients Who Failed Vidaza Treatment (tx)

This study has been terminated.
(poor accrual)
Sponsor:
Collaborator:
Genzyme, a Sanofi Company
Information provided by (Responsible Party):
Seah Lim M.D., Texas Oncology Cancer Center
ClinicalTrials.gov Identifier:
NCT00700011
First received: June 17, 2008
Last updated: March 12, 2013
Last verified: March 2013
  Purpose

The investigators hypothesize that, in addition to its apoptotic effect, clofarabine induces DNA hypomethylation. If the investigators' hypothesis is correct, findings from the present proposal will not only contribute to information relating to the mechanisms of action of clofarabine but also provide the opportunity for combined epigenetic targeting of MDS using clofarabine with either another hypomethylating agent or a histone deacetylase inhibitor.

Clofarabine has demonstrated anti-cancer activity through inhibition of DNA synthesis and repair, induction of apoptosis, and possibly through other mechanisms. Numerous responses have been observed after treatment with clofarabine in heavily pre-treated relapsed/refractory patients with ALL, AML and high risk MDS.

In the present proposal, the investigators will study the clinical and laboratory effects of 2 different dosages of clofarabine in patients who have failed the hypomethylating agent, 5-azacytidine. This study will recruit patients who have received at least six cycles of 5-azacytidine without response or whose disease has progressed or relapsed while on 5-azacytidine. The first cohort of patients will receive clofarabine 10 mg/m2/day for five days and the second cohort of patients 5 mg/m2/day for five days, both every four to six weeks. The investigators will determine the frequency of response to the two dosages of nucleoside analog in this group of patients. Measurement of responses will include improvement in the peripheral blood count, reduction in the blood and platelet transfusion need and eradication of cytogenetically abnormal clones. Successful completion of this study will define the position of clofarabine in MDS in the era of epigenetic targeting.


Condition Intervention Phase
Myelodysplastic Syndromes
Drug: Clofarabine
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study of IV Clofarabine for Patients With Myelodysplastic Syndrome Who Have Failed 5-azacytidine

Resource links provided by NLM:


Further study details as provided by Texas Oncology Cancer Center:

Primary Outcome Measures:
  • Improvement in Peripheral Blood Count and Reduction in Number of Transfusions [ Time Frame: 2-3 months ] [ Designated as safety issue: Yes ]
    Hematologic improvement will be an increased Hemoglobin of 1.5 g/dL or a reduction in the need for PRBC transfusions by at least 4 units over an 8 week period, at least 100% increase and an ANC of >0.5 x 10^9/L and an absolut platelet count increase of >30 x 10^9/L for patients who start at > 20 x 10^9/L, or increase from <20 x 10^9/L to >20 x 10^9/L and by at least 100%.

  • Determine Frequency and Duration of Bone Marrow Responses to IV Clofarabine [ Time Frame: 2-3 months ] [ Designated as safety issue: No ]
    The International Working Group response criteria was used. Complete remission is defined as <5 % marrow blasts without evidence of dysplasia and normalization of the peripheral blood counts, including hemoglobin >11 g/dL, neutrophil count of >1 x 10^9/L. and platelet count of >100 x 10^9/L. Patients must also be transfusion-independent and not require any recombinant erythropoietin. Partial remission (PR) is defined as: satisfying complete remission criteria if abnormal before treatment, except that blasts are reduced by 50% or more compared to pretreatment levels, but still >5 %. Stable disease is defined as: failure to achieve at least a PR but without evidence of disease progression for at least 8 weeks.Progression of disease is defined as: disease progression with worsening cytopenias. Best response of these patients is used in the determination for this outcome below.

  • To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) [ Time Frame: biweekly for duration of treatment , an average of 3 months ] [ Designated as safety issue: Yes ]
    Assess for adverse events in all the patients receiving the Clofarabine at the dose schedules described in the protocol (CTCAE 3.0 used).


Secondary Outcome Measures:
  • Number of Participants With DNA Hypomethylation During the Study [ Time Frame: assessed twice per cycle ] [ Designated as safety issue: Yes ]
    Since we previously observed decreases in DNA methylation in tumor cells after in vitro treatment with Clofarabine, we compared the long interspersednuclear element-1 methylation of genomic DNA obtained from CD3-depletedperipheral blood mononuclear cells between day 1 and day 5 of each cycle of Clofarabine.


Enrollment: 10
Study Start Date: March 2008
Study Completion Date: March 2010
Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 10 mg/m2 group
Patients were treated with Clofarabine 10 mg/m2 daily x 5 days per cycle. Cycles were intended on being every 28 days but this was flexible due to the bone marrow neding to recover from each cycle before strting the next one. Neulasta was given on day 5 of each cycle. Patients were treated until disease progression, or intolerable toxicities.
Drug: Clofarabine
10 mg/m2 x 5 days per 4 to 6 week cycles
Other Name: Clolar
Active Comparator: 5 mg/m2 group
Patients were treated with Clofarabine 5 mg/m2 daily x 5 days per cycle. Cycles were intended on being every 28 days but this was flexible due to the bone marrow neding to recover from each cycle before strting the next one. Neulasta was given on day 5 of each cycle. Patients were treated until disease progression, or intolerable toxicities.
Drug: Clofarabine
5 mg/m2 x 5 days per 4 to 6 week cycles
Other Name: Clolar

Detailed Description:

Study Overview

This study will recruit patients who have received at least six cycles of 5-azacytidine without response or whose disease has progressed or relapsed while on 5-azacytidine. The first cohort of patients will receive clofarabine 10 mg/m2/day for five days and the second cohort of patients 5 mg/m2/day for five days, both every four to six weeks. The investigators will determine the frequency of response to the two dosages of nucleoside analog in this group of patients. Measurement of responses will include improvement in the peripheral blood count, reduction in the blood and platelet transfusion need and eradication of cytogenetically abnormal clones.

  • Primary Objectives

    1. To determine the frequency and duration of peripheral blood responses to IV clofarabine in MDS patients who have failed 5-azacytidine
    2. To determine the frequency and duration of bone marrow responses to IV clofarabine, including CR + PR
  • Secondary Objectives

To determine whether clofarabine exhibits a DNA hypomethylating property

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with MDS of any risk group who have, just immediately prior to being entered into this study, already received at least six cycles of 5-azacytidine and have failed, either due to no response or to disease relapse despite being still on 5-azacytidine, or patients whose MDS has progressed while on 5-azacytidine, irrespective of the number of cycles the patient has received. We have specifically chosen to be very stringent about our patient population in order to address our question of whether clofarabine can be used to salvage patients who have failed 5-azacytidine with only a small patient population, i.e. 10 patients in each cohort.
  • ECOG Performance status of 0 - 2
  • Recombinant erythropoietin is allowed, if the patients are already receiving erythropoietin. G-CSF can be given during the neutropenic stage following therapy since this would not affect evaluation of response because the response will be made based on CBC and bone marrow changes upon recovery from clofarabine.
  • Patients must have been at least four weeks after the last course of 5-azacytidine
  • Age over 18 years
  • Have adequate renal and hepatic functions as indicated by the following laboratory values:

    • Serum creatinine 1.0 mg/dL; if serum creatinine 1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be 60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation where Predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine)-1.154 x (age in years)-0.023 x (0.742 if patient is female) x (1.212 if patient is black)
    • Serum bilirubin ≤1.5 mg/dL × upper limit of normal (ULN)
    • Aspartate transaminase (AST)/alanine transaminase (ALT) 2.5 × ULN
    • Alkaline phosphatase 2.5 × ULN
  • Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide signed informed consent.
  • Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment.
  • Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment.

Exclusion Criteria:

  • Nursing or pregnant women
  • Prior clofarabine therapy
  • Life expectancy of less than 3 months due to other intercurrent illness.
  • Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
  • Use of investigational agents within 30 days or any anticancer therapy within 4 weeks before study entry with the exception of hydroxyurea. The patient must have recovered from all acute toxicities from any previous therapy.
  • Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment.
  • Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
  • Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00700011

Locations
United States, Texas
Texas Oncology Cancer Center
Amarillo, Texas, United States, 79106
Sponsors and Collaborators
Texas Oncology Cancer Center
Genzyme, a Sanofi Company
Investigators
Principal Investigator: Seah Lim, MD Texas Oncology Cancer Center
  More Information

Additional Information:
Publications:

Responsible Party: Seah Lim M.D., Principal Investigator, Texas Oncology Cancer Center
ClinicalTrials.gov Identifier: NCT00700011     History of Changes
Other Study ID Numbers: iCLO111
Study First Received: June 17, 2008
Results First Received: December 6, 2012
Last Updated: March 12, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Texas Oncology Cancer Center:
Myelodysplastic Syndromes

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Syndrome
Bone Marrow Diseases
Disease
Hematologic Diseases
Neoplasms
Pathologic Processes
Precancerous Conditions
Clofarabine
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 22, 2014