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 multicenter, open-label, single-arm study

Maxime Luu ,H Devilliers,P Vabres,Victoria Parker ,Agnes Maurer ,Fanny Morice‐Picard ,Marjolijn Duijm-De Carpentier ,Ludovic Martin ,Marc Bardou ,Marie‐Line Jacquemont ,Tristan Mirault ,C Chiavérini ,Mounia El Yousfi ,Marjolaine Willems ,Didier Bessis ,Camille Fleck ,Romaric Loffroy ,Annabel Maruani ,Florence Petit ,Jill Clayton‐Smith ,Alice Phan ,Robert Semple ,Laurence Faivre

doi:10.1038/s41436-021-01290-y

Abstract

ABSTRACTPurposePIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, 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.MethodsPatients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes.ResultsAmong 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 1 mg 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).ConclusionDespite functional improvement, the safety profile of low-dose taselisib precludes its long-term use.

Highlights

PI3KCA-related overgrowth spectrum (PROS) is a group of rare diseases induced by postzygotic activating variants in the PIK3CA gene, encoding of the phosphoinositide-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit alpha
We report on a national multicenter open-label, single-arm, dose escalation phase IB/IIA trial, to evaluate the six-month tolerability of taselisib therapy in PIK3CA-related overgrowth spectrum (PROS) patients aged 16 to 65 years old
Blood and lymphatic inhibitor of the PI3K alpha subunit in patients with PROS. Despite clinical improvements such as pain reduction, cessation of chronic bleeding or improved quality of life (QoL), the negative safety profile makes long-term use of taselisib inappropriate in PROS

Summary

Introduction

PI3KCA-related overgrowth spectrum (PROS) is a group of rare diseases induced by postzygotic activating variants in the PIK3CA gene, encoding of the phosphoinositide-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit alpha. The pathogenic variants produce congenital mosaic tissue overgrowth. The PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway has been a major cancer target, with several candidate inhibitors investigated in oncology trials. Gain-offunction PIK3CA variants in overgrowth syndromes provide a strong rationale for targeted PI3K/AKT/mTOR inhibition as a therapeutic strategy in PROS. Life-threatening complications are uncommon in PROS, which is generally a chronic disease, with the PROS subphenotype largely dependent on the type and location of affected tissue. The dominant concern in PROS is mass effects of overgrowth, which may result in functional impairment, or compression of surrounding unaffected tissue. Invasive debulking surgery has been the mainstay of therapy to date

Objectives

Methods

Results

Conclusion