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Chronic Myelogenous LeukemiaPhase 1NCT02047149

Evaluating the Safety of Zileuton (Zyflo®) in Combination With Dasatinib (Sprycel®) in Chronic Myelogenous Leukemia

A Phase 1 study testing Zileuton (Zyflo®) Dasatinib (Sprycel®), Dosing with Zileuton/Dasatinib in CML and Daily dosing of Zileuton/Dasatinib in people with Chronic Myelogenous Leukemia, run by University of Massachusetts, Worcester at 1 site in United States.

Terminated

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

Official record
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Trial summary

Prospective nonrandomized phase I study The purpose of this study is to determine safety and efficacy of zileuton when added to dasatinib in patients with chronic myelogenous leukemia (CML). Read more about this study

Who is it for?
Ages 18 to 70 years
Conditions the study is for
Chronic Myelogenous Leukemia
What is being tested?
Zileuton (Zyflo®) Dasatinib (Sprycel®), Dosing with Zileuton/Dasatinib in CML and Daily dosing of Zileuton/Dasatinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
2 participants
Where
1 siteUnited States
Study dates
Jan 2014to Jun 2016
Phase
Phase 1
Are there results?
None posted in the registry

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 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Target Population:
  • 1. Patients with CML with known inadequate response (as appropriate for their CML status) to TKIs or known resistance will be considered for this study
  • Patients who are resistant or not responding adequately to dasatinib as a first line therapy, but are not able or eligible to receive other effective second line treatment can be considered for participation in the study.
  • Age > 18 years
  • ECOG performance status ≤ 2
  • Total bilirubin < 2.0 times the institutional Upper Limit of Normal (ULN)
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  • Hepatic enzymes (AST, ALT ) ≤ 1.5 times the institutional ULN
  • Serum Na, K+, Mg2+, Phosphate and Ca2+>= Lower Limit of Normal (LLN)
  • Serum Creatinine < 2.3 mg/dL
  • PT, PTT all Grade 0-1 3) Ability to take oral medication 4) Concomitant Medications
  • Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy 5) Age and Sex
  • Women of childbearing potential and men of fathering potential must use an adequate method of contraception to avoid pregnancy throughout the study to minimize the risk of pregnancy

Who cannot join

  • Sex and Reproductive Status
  • Women of childbearing potential and men of fathering potential unable or unwilling to use an adequate method of contraception to avoid pregnancy throughout the study to minimize the risk of pregnancy
  • Target Population
  • Patients intolerant of dasatinib.
  • Medical History and Concurrent Diseases
  • History of active malignancy during the past 5 years with the exception of nonmetastatic treated skin cancer (e.g. basal or squamous cell carcinoma ) or stage 0 cervical carcinoma
Show all 35Show fewer
  • Patients known to be HIV-positive
  • Patients with active, uncontrolled infections
  • Concurrent medical condition which may increase the risk of toxicity, including:
  • Pleural or pericardial effusion of any grade
  • Cardiac Conditions:
  • Uncontrolled angina, congestive heart failure or MI within (6 months)
  • Diagnosed congenital long QT syndrome
  • Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)
  • Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec)
  • Severe cardiac dysfunction (NYHA classification III-IV)
  • Severe pulmonary disease
  • History of significant bleeding disorder unrelated to cancer
  • Physical and Laboratory Test Findings
  • Hepatic dysfunction (serum bilirubin ≥ 2 x ULN, and/or ALT ≥ 3 x ULN, and/or AST ≥ 3 x ULN)
  • Renal dysfunction (creatinine ≥ 200 μmol/l or 2.3 mg/dl)
  • Subjects with hypokalemia or hypomagnesemia that cannot be corrected prior to dasatinib administration
  • Allergies and Adverse Drug Reactions
  • Patients with known allergic reaction or intolerance to either dasatinib or zileuton
  • Prohibited Treatments and/or Therapies
  • Category I drugs that are generally accepted to have a risk of causing Torsades de Pointes including:
  • quinidine, procainamide, disopyramide
  • amiodarone, sotalol, ibutilide, dofetilide
  • erythromycin, clarithromycin
  • chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide
  • cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine.
  • Patients requiring anticoagulation with Coumadin
  • Other Exclusion Criteria
  • Prisoners or subjects who are involuntarily incarcerated.
  • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • University of Massachusetts Medical School

    Worcester, Massachusetts, 01655

Other trials in United States

About this study

Official title: Phase I Study to Evaluate the Safety of Zileuton (Zyflo®) in Combination With Dasatinib (Sprycel®) in Patients With Chronic Myelogenous Leukemia

Prospective nonrandomized phase I study

The purpose of this study is to determine safety and efficacy of zileuton when added to dasatinib in patients with chronic myelogenous leukemia (CML).

Read the detailed description

The standard treatment for chronic myelogenous leukemia is therapy with tyrosine kinase inhibitors (TKIs). This treatment can diminish the amount of disease to very low levels that only very sensitive and specialized techniques can measure; it does not, however, provide a cure.

Dr. Shaoguang Li and colleagues at University of Massachusetts have published a unique discovery that the arachidonate 5-lipoxygenase (5-LO) gene (Alox5) is a critical regulator for LSCs in BCR-ABL-induced CML (Chen Y et al. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nature Genetics 41:783-792, 2009). In the absence of Alox5, BCR-ABL failed to induce CML in preclinical studies. While deficiency in Alox5 had no effect on normal hematopoiesis, impairment of the LSCs function through differentiation and cell division of CML LSCs was observed. This defect led to a depletion of LSCs and a failure of CML development. Treatment with a 5-LO inhibitor (zileuton) also impaired the function of LSCs and prolonged survival. These results demonstrate that a specific target gene can be found in cancer stem cells and its inhibition can completely inhibit the function of these stem cells. These findings provide an exciting opportunity to develop the first anti-cancer stem cell therapy for treating CML.

Patients who did not respond or did not tolerate two TKIs will be considered for this study.

Being tested
Zileuton (Zyflo®) Dasatinib (Sprycel®), Dosing with Zileuton/Dasatinib in CML, Daily dosing of Zileuton/Dasatinib, Daily dosing with Zileuton/Dasatinib for CML
Keywords
Myelogenous Leukemia
Medical subject headings
Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Leukemia, Myeloid

What participants receive

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

  • Zileuton (Zyflo®) Dasatinib (Sprycel®)Drug

    To determine the maximum dose of zileuton/dasatinib in subjects with CML

  • Dosing with Zileuton/Dasatinib in CMLDrug

    Also called Zyflo® + Sprycel®

    Three dose levels of daily zileuton will be studied in conjunction with dasatinib to define the MTD

  • Daily dosing of Zileuton/DasatinibDrug

    Also called Zyflo® + Sprycel®

    Three dose levels of daily zileuton will be studied in conjunction with dasatinib to define the MTD

  • Daily dosing with Zileuton/Dasatinib for CMLDrug

    Also called Zyflo®, Sprycel®

    Three dose levels of daily zileuton will be studied in conjunction with dasatinib to define the MTD

Study groups in NCT02047149
Study groupRoleWhat they receive
Zileuton/DasatinibExperimentalzileuton/dasatinib: This is a traditional phase I design. Three dose levels of daily zileuton will be studied in conjunction with dasatinib to define the MTD
Receives: Drug: Zileuton (Zyflo®) Dasatinib (Sprycel®); Drug: Dosing with Zileuton/Dasatinib in CML; Drug: Daily dosing of Zileuton/Dasatinib; Drug: Daily dosing with Zileuton/Dasatinib for CML

What is being measured

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

  1. To determine the maximal tolerated dose (MTD) of zileuton when added to dasatinib in patients with CML

    Measured: 36 mos

Secondary outcomes (1)

  1. To assess the efficacy of zileuton combined with dasatinib in terms of:

    • 5-lipoxygenase (5-LO) blockade in patients
    • The rate of hematological response (where applicable)
    • The rate of complete cytogenetic response (where applicable)
    • The rate of major molecular response (where applicable)
    • Assessment of residual CML stem cells

    Measured: 36 mos

Timeline

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

  1. First posted28 Jan 2014 (estimated)
  2. Study startJan 2014
  3. Primary completionJun 2016
  4. Study completionJun 2016

Why it stopped: Low 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 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
2 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02047149
Sponsor's protocol ID
CA 180-338
Status last verified
Sep 2016
First submitted
24 Jan 2014
Last updated
30 Sep 2016
Results posted
No
Data monitoring committee
Yes

Publications

  • Chen Y, Hu Y, Zhang H, Peng C, Li S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat Genet. 2009 Jul;41(7):783-92. doi: 10.1038/ng.389. Epub 2009 Jun 7.

    PubMed 19503090

  • Shah NP, Kantarjian HM, Kim DW, Rea D, Dorlhiac-Llacer PE, Milone JH, Vela-Ojeda J, Silver RT, Khoury HJ, Charbonnier A, Khoroshko N, Paquette RL, Deininger M, Collins RH, Otero I, Hughes T, Bleickardt E, Strauss L, Francis S, Hochhaus A. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol. 2008 Jul 1;26(19):3204-12. doi: 10.1200/JCO.2007.14.9260. Epub 2008 Jun 9.

    PubMed 18541900

  • Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990 Feb 16;247(4944):824-30. doi: 10.1126/science.2406902.

    PubMed 2406902

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Zileuton (Zyflo®) Dasatinib (Sprycel®), Dosing with Zileuton/Dasatinib in CML and Daily dosing of Zileuton/Dasatinib in people with Chronic Myelogenous Leukemia, run by University of Massachusetts, Worcester 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 12 inclusion and 35 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 30 Sep 2016. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

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

Are results available for this study?

The study was stopped early (reason given: Low accrual). Results are not available in the source record.

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?

To determine the maximal tolerated dose (MTD) of zileuton when added to dasatinib in patients with CML (time frame: 36 mos). 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 NCT02047149, which also lists 3 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 30 Sep 2016.

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