Pioglityazone and Imatinib for CML Patients (ACTIM)

September 7, 2016 updated by: Philippe ROUSSELOT, Versailles Hospital

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

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.

Study Overview

Status

Completed

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

27

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Annecy, France
        • CHR Annecy
      • Bordeaux, France
        • Institut Bergonié
      • Le Chesnay, France
        • CH Versailles
      • Lille, France
        • CHU Lille
      • Marseille, France
        • IPC
      • Nice, France
        • CHU Archet 1
      • Paris, France
        • St Louis
      • Poitiers, France
        • CHU Poitiers
      • Toulouse, France
        • CHU Purpan

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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:

  1. Patient aged 18y or more
  2. Signed informed consent
  3. Patient with Philadelphia chromosome positive chronic phase CML and M BCR-ABL transcript positivity
  4. Treatment with imatinib for more than 2 years
  5. No dose modification of imatinib within the last 3 months
  6. Complete cytogenetic response on the last cytogenetic analysis within the last 12 months
  7. Major molecular remission without complete molecular remission
  8. ECOG grade 0 to 2
  9. SGOT et SGPT ≤ 2.5 N
  10. Bilirubin in serum ≤ 1.5 N
  11. Women of childbearing potential (WOCBP) must be using an adequate method of contraception

Exclusion Criteria:

  1. Participation in another clinical trial with any investigative drug within 30 days prior to study enrollment
  2. Prior history of hematopoietic stem cell transplantation (autologous or allogenic)
  3. Patient requiring anti-diabetic medication
  4. 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
  5. Grade III or IV fluid retention
  6. Known osteoporosis with therapy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: ACTOS treatment
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
Pioglitazone therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
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.
Time Frame: 26 weeks
26 weeks

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Rousselot Philippe, MD, CH Versailles

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2009

Primary Completion (Actual)

February 1, 2012

Study Completion (Actual)

February 1, 2016

Study Registration Dates

First Submitted

August 19, 2016

First Submitted That Met QC Criteria

August 30, 2016

First Posted (Estimate)

September 5, 2016

Study Record Updates

Last Update Posted (Estimate)

September 8, 2016

Last Update Submitted That Met QC Criteria

September 7, 2016

Last Verified

September 1, 2016

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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