Efficacy, safety, pharmacokinetics and pharmacodynamics of SAR245409 (voxtalisib, XL765), an orally administered phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor: a phase 1 expansion cohort in patients with relapsed or refractory lymphoma

Abstract

The maximum tolerated dose of SAR245409 (voxtalisib), a pan-class I phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, was determined in a phase 1 dose-escalation study in advanced solid tumors. We report safety, pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of SAR245409 capsules 50 mg twice daily in an expansion cohort of 16 patients with relapsed/refractory lymphoma. The most common treatment-related adverse events (AEs) were nausea (31.3%) and diarrhea (25.0%). The most common grade 3/4 treatment-related AE was increased alanine aminotransferase (12.5%). PK results were consistent with solid tumors, confirming a relatively short steady-state half-life (mean 4.61 h). Among 12 evaluable patients, one complete response and two partial responses were achieved in patients with and without PI3K/mTOR pathway alterations. In a patient with mantle cell lymphoma achieving PR, SAR245409 was associated with significant inhibition of PI3K/mTOR and extracellular signal-related kinase (ERK) pathways. Preliminary efficacy warrants further evaluation of SAR245409 in lymphoma.

Keywords::

• PI3K
• mTOR
• pharmacokinetics
• pharmacodynamics
• lymphoma
• signaling therapies

Acknowledgements

The authors would like to thank Christelle Castell, Bin Wu, Colette Dib, Giliane Buzenet, Joanne Lager and Thibaud de Gallier (Sanofi), Adrianne Kelly, Kevin Rockich (formerly Sanofi), Christoph Lengauer (Blueprint Medicines) and Art De Cillis, Anushka deCosta, Rajana Bautista, Valentina Vysotskaia and Douglas Laird (Exelixis). This study was funded by Sanofi and Exelixis. The authors received editorial support from Simone Blagg of MediTech Media Ltd, funded by Sanofi.

Potential conflict of interest

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Supplementary material available online

Methods, and tables and figure showing further results.