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

Chronic Myelogenous Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01130688
• Other study ID #: UM200905
• Status: Terminated
• Phase: Phase 1
• First received: May 24, 2010
• Last updated: May 26, 2015
• Start date: January 2010
• Est. completion date: December 2014

Study information

• Verified date: January 2013
• Source: University of Massachusetts, Worcester
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: December 2014
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Myelogenous Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Drug:
• Zileuton
Imatinib combined with Zileuton

Locations

Country	Name	City	State
United States	University of Massachusetts Medical School	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
University of Massachusetts, Worcester

Country where clinical trial is conducted

United States, 

References & Publications (2)

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. — View Citation

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, She — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To define toxicity and safety profile of zileuton combined with imatinib in patients with CML		Throughout the study	Yes
Secondary	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	Yes