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

NCT ID: NCT01130688

Last Updated: 2015-05-27

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 2 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-01-31
• Study Completion Date: 2014-12-31

Brief 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.

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.

Conditions

Chronic Myelogenous Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

single arm of experimental drug combination

Group Type: EXPERIMENTAL

Zileuton

Intervention Type: DRUG

Imatinib combined with Zileuton

Interventions

Zileuton

Imatinib combined with Zileuton

Intervention Type: DRUG

Other Intervention Names

Zyflo

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Massachusetts, Worcester

OTHER

Sponsor Role: lead

Responsible Party

Jan Cerny

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jan Cerny, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Massachusetts, Worcester

Locations

University of Massachusetts Medical School

Worcester, Massachusetts, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 19503090 (View on PubMed)

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.

Reference Type: RESULT

PMID: 17151364 (View on PubMed)

Other Identifiers

UM200905

Identifier Type: -

Identifier Source: org_study_id