Pioglityazone and Imatinib for CML Patients

Leukemia, Myeloid, Chronic-Phase Clinical Trial

— ACTIM  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02888964
• Other study ID #: 09/37_ACTIM
• Status: Completed
• Phase: Phase 2
• First received: August 19, 2016
• Last updated: September 7, 2016
• Start date: December 2009
• Est. completion date: February 2016

Study information

• Verified date: September 2016
• Source: Versailles Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Agence Nationale de Sécurité du Médicament et des produits de santéFrance: Committee for the Protection of Personnes
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 27
• Est. completion date: February 2016
• Est. primary completion date: February 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• Add-on therapy
Pioglitazone therapy

Locations

Country	Name	City	State
France	CHR Annecy	Annecy
France	Institut Bergonié	Bordeaux
France	CH Versailles	Le Chesnay
France	CHU Lille	Lille
France	IPC	Marseille
France	CHU archet 1	Nice
France	St Louis	Paris
France	CHU Poitiers	Poitiers
France	CHU Purpan	Toulouse

Sponsors (1)

Lead Sponsor	Collaborator
Versailles Hospital

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Adverse events		5 years	Yes
Secondary	Duration of the complete molecular response		5 years	No
Secondary	The rate of patients achieving a complete molecular response (Sensitivity 10-5 or Bcr-Abl/Abl ratio < 0.001 %)		14 months	No
Secondary	Survival		5 years	No
Secondary	Progression free survival		5 years	No