Safety of Zileuton (Zyflo) in Combination With Imatinib Mesylate (Gleevec) in CML.

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
Jan Cerny, University of Massachusetts, Worcester
ClinicalTrials.gov Identifier:
NCT01130688
First received: May 24, 2010
Last updated: January 8, 2013
Last verified: January 2013
  Purpose

The leukemic stem cells (LSCs) are cells that self- renew and give rise to leukemia. Eradication of LSC is required for cure. In chronic myelogenous leukemia (CML) LSCs are not eradicated by imatinib (Gleevec) alone. Recent discovery by Dr. Shaoguang Li at University of Massachusetts indicates that the LSCs can be targeted by a new drug zileuton (Chen et al. Nature Genetics 2009; 41:783-792). Zileuton (approved for asthma) will be tested in a combination with Gleevec. This combination has not been used previously to treat leukemia.

This is a Phase I study. The goal of this research is to evaluate the safety of the standard anti-cancer drug imatinib and experimental drug zileuton.


Condition Intervention Phase
Chronic Myelogenous Leukemia
Drug: Zileuton
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study to Evaluate the Safety of Zileuton (Zyflo) in Combination With Imatinib Mesylate (Gleevec) in Patients With Chronic Myelogenous Leukemia

Resource links provided by NLM:


Further study details as provided by University of Massachusetts, Worcester:

Primary Outcome Measures:
  • To define toxicity and safety profile of zileuton combined with imatinib in patients with CML [ Time Frame: Throughout the study ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To assess the efficacy of zileuton combined with imatinib in terms of (See Description) [ Time Frame: Throughout the study ] [ Designated as safety issue: Yes ]
    • Level of 5-lipoxygenase (5-LO) blockade
    • The rate of complete hematological response
    • The rate of complete cytogenetic response
    • The rate of major molecular response


Estimated Enrollment: 18
Study Start Date: January 2010
Estimated Study Completion Date: December 2014
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: single arm of experimental drug combination Drug: Zileuton
Imatinib combined with Zileuton
Other Name: Zyflo

Detailed Description:

More than twenty two thousand people live with chronic myelogenous leukemia in the United States and more than five thousand people are expected to be diagnosed this year. The majority of patients with this disease are diagnosed in what is called the chronic phase. The standard treatment for this phase of the disease is therapy with a medication called imatinib. 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.

  Eligibility

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

Inclusion Criteria:

  • Patients with CML in chronic phase (patients already on imatinib)
  • Presence of Philadelphia chromosome or bcr-abl rearrangement
  • Age ≥ 18 years
  • ECOG performance status ≤ 2
  • Written informed consent

Exclusion Criteria:

  • 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)
  • Severe cardiac dysfunction (NYHA classification III-IV)
  • Severe pulmonary or neurologic disease
  • Pregnant or lactating females
  • Patients with a history of active malignancy during the past 5 years with the exception of nonmetastatic skin cancer (e.g. treated squamous or basal cell carcinoma) or stage 0 cervical carcinoma
  • Patients known to be HIV-positive
  • Patients with active, uncontrolled infections
  • Male and female patients of reproductive potential who are not practicing effective means of contraception
  • Patients with known allergic reaction or intolerance to either imatinib or zileuton
  • Patients requiring anticoagulation therapy with coumadin
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01130688

Locations
United States, Massachusetts
University of Massachusetts Medical School
Worcester, Massachusetts, United States, 01655
Sponsors and Collaborators
University of Massachusetts, Worcester
Investigators
Principal Investigator: Jan Cerny, MD, PhD University of Massachusetts, Worcester
  More Information

Publications:
Responsible Party: Jan Cerny, Principal Investigator, University of Massachusetts, Worcester
ClinicalTrials.gov Identifier: NCT01130688     History of Changes
Other Study ID Numbers: UM200905
Study First Received: May 24, 2010
Last Updated: January 8, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by University of Massachusetts, Worcester:
Leukemia
Zileuton
myeloproliferative neoplasm

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Zileuton
Imatinib
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Lipoxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Leukotriene Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Central Nervous System Agents
Antineoplastic Agents
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on August 19, 2014