Pioglityazone and Imatinib for CML Patients

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.

Timeline

Start

2009-12

Primary completion

2012-02

Completion

2016-02

Publications

• Results Rousselot P, Prost S, Guilhot J, Roy L, Etienne G, Legros L, Charbonnier A, Coiteux V, Cony-Makhoul P, Huguet F, Cayssials E, Cayuela JM, Relouzat F, Delord M, Bruzzoni-Giovanelli H, Morisset L, Mahon FX, Guilhot F, Leboulch P; French CML Group. Pioglitazone together with imatinib in chronic myeloid leukemia: A proof of concept study. Cancer. 2017 May 15;123(10):1791-1799. doi: 10.1002/cncr.30490. Epub 2016 Dec 27.

Drugs

Indications