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Myelodysplastic SyndromesPhase 2NCT00700011

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

A Phase 2 study testing Clofarabine in people with Myelodysplastic Syndromes, run by Texas Oncology Cancer Center at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
Search all trials

Trial summary

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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Myelodysplastic Syndromes
What is being tested?
Clofarabine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
10 participants
Where
1 siteUnited States
Study dates
Mar 2008to Mar 2010
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
Show all 13Show fewer
  • 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.

Who cannot join

  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Texas Oncology Cancer Center

    Amarillo, Texas, 79106

Other trials in United States

About this study

Official title: A Pilot Study of IV Clofarabine for Patients With Myelodysplastic Syndrome Who Have Failed 5-azacytidine

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.

Read the 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

Being tested
Clofarabine
Keywords
Myelodysplastic Syndromes
Medical subject headings
Myelodysplastic Syndromes

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ClofarabineDrug

    Also called Clolar

    10 mg/m2 x 5 days per 4 to 6 week cycles

  • ClofarabineDrug

    Also called Clolar

    5 mg/m2 x 5 days per 4 to 6 week cycles

Study groups in NCT00700011
Study groupRoleWhat they receive
10 mg/m2 groupActive comparatorPatients 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.
Receives: Drug: Clofarabine
5 mg/m2 groupActive comparatorPatients 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.
Receives: Drug: Clofarabine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Improvement in Peripheral Blood Count and Reduction in Number of Transfusions

    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%.

    Measured: 2-3 months

  2. Determine Frequency and Duration of Bone Marrow Responses to IV Clofarabine

    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.

    Measured: 2-3 months

  3. To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above)

    Assess for adverse events in all the patients receiving the Clofarabine at the dose schedules described in the protocol (CTCAE 3.0 used).

    Measured: biweekly for duration of treatment , an average of 3 months

Secondary outcomes (1)

  1. Number of Participants With DNA Hypomethylation During the Study

    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.

    Measured: assessed twice per cycle

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Jun 2008 (estimated)
  2. Study startMar 2008
  3. Primary completionMar 2010
  4. Study completionMar 2010

Why it stopped: poor accrual

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
10 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00700011
Sponsor's protocol ID
iCLO111
Status last verified
Mar 2013
First submitted
17 Jun 2008
Last updated
15 Mar 2013
Data monitoring committee
Yes

Publications

  • Hellstrom-Lindberg E. Update on supportive care and new therapies: immunomodulatory drugs, growth factors and epigenetic-acting agents. Hematology Am Soc Hematol Educ Program. 2005:161-6. doi: 10.1182/asheducation-2005.1.161.

    PubMed 16304375

  • Lim SH, Wang Z, Chiriva-Internati M, Xue Y. Sperm protein 17 is a novel cancer-testis antigen in multiple myeloma. Blood. 2001 Mar 1;97(5):1508-10. doi: 10.1182/blood.v97.5.1508.

    PubMed 11222401

  • Wang Z, Zhang Y, Ramsahoye B, Bowen D, Lim SH. Sp17 gene expression in myeloma cells is regulated by promoter methylation. Br J Cancer. 2004 Oct 18;91(8):1597-603. doi: 10.1038/sj.bjc.6602160.

    PubMed 15381930

  • Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia-Manero G, Giles F, Faderl S, O'Brien S, Jeha S, Davis J, Shaked Z, Craig A, Keating M, Plunkett W, Freireich EJ. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003 Oct 1;102(7):2379-86. doi: 10.1182/blood-2003-03-0925. Epub 2003 Jun 5.

    PubMed 12791647

  • Reichelova V, Liliemark J, Albertioni F. Liquid chromatographic study of acid stability of 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine, 2-chloro-2'-deoxyadenosine and related analogues. J Pharm Biomed Anal. 1995 Apr;13(4-5):711-4. doi: 10.1016/0731-7085(95)01325-f. No abstract available.

    PubMed 9696594

  • Carson DA, Wasson DB, Esparza LM, Carrera CJ, Kipps TJ, Cottam HB. Oral antilymphocyte activity and induction of apoptosis by 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2970-4. doi: 10.1073/pnas.89.7.2970.

    PubMed 1348362

  • Lotfi K, Mansson E, Spasokoukotskaja T, Pettersson B, Liliemark J, Peterson C, Eriksson S, Albertioni F. Biochemical pharmacology and resistance to 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine, a novel analogue of cladribine in human leukemic cells. Clin Cancer Res. 1999 Sep;5(9):2438-44.

    PubMed 10499616

  • Parker WB, Shaddix SC, Chang CH, White EL, Rose LM, Brockman RW, Shortnacy AT, Montgomery JA, Secrist JA 3rd, Bennett LL Jr. Effects of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine on K562 cellular metabolism and the inhibition of human ribonucleotide reductase and DNA polymerases by its 5'-triphosphate. Cancer Res. 1991 May 1;51(9):2386-94.

    PubMed 1707752

  • Genini D, Adachi S, Chao Q, Rose DW, Carrera CJ, Cottam HB, Carson DA, Leoni LM. Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. Blood. 2000 Nov 15;96(10):3537-43.

    PubMed 11071652

  • Kantarjian HM, Gandhi V, Kozuch P, Faderl S, Giles F, Cortes J, O'Brien S, Ibrahim N, Khuri F, Du M, Rios MB, Jeha S, McLaughlin P, Plunkett W, Keating M. Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol. 2003 Mar 15;21(6):1167-73. doi: 10.1200/JCO.2003.04.031.

    PubMed 12637486

  • Faderl S, Gandhi V, O'Brien S, Bonate P, Cortes J, Estey E, Beran M, Wierda W, Garcia-Manero G, Ferrajoli A, Estrov Z, Giles FJ, Du M, Kwari M, Keating M, Plunkett W, Kantarjian H. Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood. 2005 Feb 1;105(3):940-7. doi: 10.1182/blood-2004-05-1933. Epub 2004 Oct 14.

    PubMed 15486072

  • Faderl S, Verstovsek S, Cortes J, Ravandi F, Beran M, Garcia-Manero G, Ferrajoli A, Estrov Z, O'Brien S, Koller C, Giles FJ, Wierda W, Kwari M, Kantarjian HM. Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia (AML) in patients 50 years of age or older. Blood. 2006 Jul 1;108(1):45-51. doi: 10.1182/blood-2005-08-3294. Epub 2006 Jan 10.

    PubMed 16403905

  • Jeha S, Gaynon PS, Razzouk BI, Franklin J, Kadota R, Shen V, Luchtman-Jones L, Rytting M, Bomgaars LR, Rheingold S, Ritchey K, Albano E, Arceci RJ, Goldman S, Griffin T, Altman A, Gordon B, Steinherz L, Weitman S, Steinherz P. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006 Apr 20;24(12):1917-23. doi: 10.1200/JCO.2005.03.8554.

    PubMed 16622268

  • Jeha S, Gandhi V, Chan KW, McDonald L, Ramirez I, Madden R, Rytting M, Brandt M, Keating M, Plunkett W, Kantarjian H. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004 Feb 1;103(3):784-9. doi: 10.1182/blood-2003-06-2122. Epub 2003 Oct 9.

    PubMed 14551141

  • Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25. doi: 10.1182/blood-2005-10-4149. Epub 2006 Apr 11.

    PubMed 16609072

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Clofarabine in people with Myelodysplastic Syndromes, run by Texas Oncology Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 15 Mar 2013. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 9 Jan 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Improvement in Peripheral Blood Count and Reduction in Number of Transfusions (time frame: 2-3 months). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00700011, which also lists 16 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Mar 2013.

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