Safety and efficacy of low-dose PI3K inhibitor taselisib in adult patients with CLOVES and KLIPPEL TRENAUNAY SYNDROME (KTS): the TOTEM trial, a phase 1/2 multicentre, open-label, single-arm study

Maxime Luu, Pierre Vabres, Herve Devilliers, Romaric Loffroy, A Phan, L. Martin, Fanny Morice-Picard, F. Petit, M Willems, Didier Bessis, Marie-Line Jacquemont, A. Maruani, Christine Chiaverini, T. Mirault, J. Clayton-Smith, M. Carpentier, C Fleck, A Maurer, M Yousfi, Victoria E R ParkerRobert K Semple, Marc Bardou, Laurence Faivre

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signalling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low dose taselisib, a selective class I PI3K-inhibitor, in PROS patients.
Methods: Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multi-centre, open-label single arm trial (Six patients at 1mg/day of taselisib, then 24 at 2mg/day).
The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of i) tissue volume at affected and unaffected sites, both clinically and on imaging, ii) cutaneous vascular outcomes when relevant, iii) biologic parameters, iv) quality of life and v) patient-reported outcomes.
Results: Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1mg cohort (n=6). No significant reduction in affected tissue volume was observed (mean -4.2%; p=0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement).
Conclusion: Despite functional improvement, the safety profile of low-dose taselisib precludes its longterm use.
Original languageEnglish
JournalGenetics in Medicine
DOIs
Publication statusPublished - 12 Aug 2021

Keywords

  • clinical trial
  • PIK3CA
  • Overgrowth syndrome
  • mosaic
  • taselisib
  • PROS treatment

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