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

Phase I Study to Evaluate the Safety of Zileuton (Zyflo) in Combination With Imatinib Mesylate (Gleevec) in Patients With Chronic Myelogenous Leukemia

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.

Study Overview

• Status: Terminated
• Conditions: Chronic Myelogenous Leukemia
• Intervention / Treatment: Drug: Zileuton

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.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: single arm of experimental drug combination	Drug: Zileuton; Imatinib combined with Zileuton; Other Names: Zyflo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To define toxicity and safety profile of zileuton combined with imatinib in patients with CML	Throughout the study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the efficacy of zileuton combined with imatinib in terms of (See Description)	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	Throughout the study

Collaborators and Investigators

• Sponsor: University of Massachusetts, Worcester
• Investigators: Principal Investigator: Jan Cerny, MD, PhD, University of Massachusetts, Worcester

Publications and helpful links

General 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.
• Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA; IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006 Dec 7;355(23):2408-17. doi: 10.1056/NEJMoa062867.

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: May 24, 2010
• First Submitted That Met QC Criteria: May 25, 2010
• First Posted (Estimate): May 26, 2010

Study Record Updates

• Last Update Posted (Estimate): May 27, 2015
• Last Update Submitted That Met QC Criteria: May 26, 2015
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: Leukemia; myeloproliferative neoplasm; Zileuton
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Leukotriene Antagonists; Hormone Antagonists; Lipoxygenase Inhibitors; Zileuton
• Other Study ID Numbers: UM200905