Pioglityazone and Imatinib for CML Patients

Study Overview
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Brief Summary
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This project is a Phase II clinical trial that aims at evaluating efficacy and tolerance of the combination of pioglitazone (Actos®) and imatinib mesylate (STI571, CGP57148, Gleevec®) in patients with Chronic Myelogenous Leukemia (CML) in stable major molecular response (i.e. a BCRABL/ABL ratio assessed by RTQ-PCR equal to or lower than 0.1% according to the European Leukemia Net recommendations) after at least 2 years of therapy with imatinib. Imatinib mesylate (Gleevec®) is the gold standard for the treatment of CML in chronic phase (O Brian et al. 2003, Druker et al. 2006). Despite a high efficacy of the drug, CML is not eradicated by imatinib alone in almost any of the patients. Treatment discontinuation in patients treated by imatinib and in complete molecular remission for more than 2 years yield molecular relapses within 6 months in half of the patients,indicating the persistence of CML progenitor cells. STAT5 expression is required for CML stem cell engraftment and expansion in mouse models. STAT5 is the target of the dysregulated activity of BCR-ABL in CML. Recently, Stephane Prost et al. demonstrated that PPAR-γ is a negative regulator of STAT5A and STAT5B gene expression. Data obtained suggest that PPAR-γ agonists may have potential therapeutic value in reversing myeloproliferative disorders. On the basis of our preclinical studies, we went ahead and administered pioglitazone to one patient who suffered from both diabetes type II and CML with residual disease after continuous treatment with Gleevec. The amount of BCR-ABL transcript detected by QPCR decreased dramatically during the first 3 months of combined (Gleevec + ACTOS) therapy to become undetectable thereafter until 9 months post-treatment, the latest time point assessed. This striking anecdotal result now forms the rationale for filing this formal Phase II clinical trial application.

Official Title
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A Study to Assess Efficacy and Safety of Pioglitazone as Add-On Therapy to Imatinib Mesylate in CP-CML Patients in Major Molecular Response

Conditions
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Leukemia, Myeloid, Chronic-Phase

Intervention / Treatment
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* Drug: Add-on therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient aged 18y or more Signed informed consent Patient with Philadelphia chromosome positive chronic phase CML and M BCR-ABL transcript positivity Treatment with imatinib for more than 2 years No dose modification of imatinib within the last 3 months Complete cytogenetic response on the last cytogenetic analysis within the last 12 months Major molecular remission without complete molecular remission ECOG grade 0 to 2 SGOT et SGPT ≤ 2.5 N Bilirubin in serum ≤ 1.5 N Women of childbearing potential (WOCBP) must be using an adequate method of contraception Exclusion Criteria: Participation in another clinical trial with any investigative drug within 30 days prior to study enrollment Prior history of hematopoietic stem cell transplantation (autologous or allogenic) Patient requiring anti-diabetic medication Cardiovascular disease: Stage I to IV congestive heart failure (CHF) as determined by the New York Heart Association (NYHA) classification system for heart failure Myocardial infarction within the previous 6 months Symptomatic cardiac arrhythmia requiring treatment Grade III or IV fluid retention Known osteoporosis with therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACTOS treatment<br>Imatinib mesylate at the same daily dose and pioglitazone as add-on therapy at 30 mg/d during 2 months and then 45 mg/d in the absence of serious adverse events | Drug: Add-on therapy<br>* Pioglitazone therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of patients achieving a complete molecular response (Sensitivity 10-5 or Bcr Abl/Abl ratio < 0.001 %) 24 weeks after the initiation of pioglitazone, confirmed on by a second determination 2 months later. |  | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events |  | 5 years | 
| Duration of the complete molecular response |  | 5 years | 
| The rate of patients achieving a complete molecular response (Sensitivity 10-5 or Bcr-Abl/Abl ratio < 0.001 %) |  | 14 months | 
| Survival |  | 5 years | 
| Progression free survival |  | 5 years |