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
| العنوان: | 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 |
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| المؤلفون: | Marc Bardou, Pierre Vabres, Laurence Faivre, Annabel Maruani, Victoria E R Parker, A. Phan, Christine Chiaverini, L. Martin, Jill Clayton-Smith, C. Fleck, Maxime Luu, Tristan Mirault, Fanny Morice-Picard, M. Carpentier, Marie-Line Jacquemont, Hervé Devilliers, Marjolaine Willems, A. Maurer, Romaric Loffroy, Didier Bessis, Florence Petit, Robert K. Semple, M. Yousfi |
| المساهمون: | Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de Référence des Maladies Génétiques à Expression Cutanée (MAGEC), Service de médecine interne et maladies systémiques (SOC 2) [CHU de Dijon], Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Institute of Applied Physics [Bern] (IAP), University of Bern, CHU Bordeaux [Bordeaux], Centre de Référence Maladies Rares Anomalies du Développement et Syndromes Malformatifs Nord, Centre Hospitalier Universitaire de Lille (CHU de Lille), Hôpital Lapeyronie [Montpellier] (CHU), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), MethodS in Patients-centered outcomes and HEalth ResEarch (SPHERE), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre national de référence des maladies vasculaires rares, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Manchester [Manchester], CHU Dijon, AstraZeneca [Cambridge, UK], University of Edinburgh, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement |
| المصدر: | Genetics in Medicine Genetics in Medicine, Nature Publishing Group, 2021, ⟨10.1038/s41436-021-01290-y⟩ Luu, M, Vabres, P, Devilliers, H, Loffroy, R, Phan, A, Martin, L, Morice-Picard, F, Petit, F, Willems, M, Bessis, D, Jacquemont, M-L, Maruani, A, Chiaverini, C, Mirault, T, Clayton-Smith, J, Carpentier, M, Fleck, C, Maurer, A, Yousfi, M, Parker, V E R, Semple, R K, Bardou, M & Faivre, L 2021, ' 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 ', Genetics in Medicine . https://doi.org/10.1038/s41436-021-01290-yTest |
| بيانات النشر: | Elsevier BV, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Adult, Klippel-Trenaunay-Weber Syndrome, medicine.medical_specialty, Klippel-Trenaunay syndrome, Syzygium, [SDV]Life Sciences [q-bio], Population, Overgrowth syndrome, Article, Phosphatidylinositol 3-Kinases, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Internal medicine, taselisib, medicine, Humans, education, Adverse effect, Genetics (clinical), education.field_of_study, business.industry, Imidazoles, clinical trial, PIK3CA, medicine.disease, 3. Good health, Clinical trial, Oxazepines, Tolerability, 030220 oncology & carcinogenesis, Mutation, Cohort, Quality of Life, mosaic, business, PROS treatment |
| الوصف: | International audience; ABSTRACT Purpose PIK3CA 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. Methods Patients 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. 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 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). Conclusion Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use. |
| وصف الملف: | application/pdf |
| تدمد: | 1098-3600 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2cb35a651c9d3e22a4c1a05d557c9a14Test https://doi.org/10.1038/s41436-021-01290-yTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2cb35a651c9d3e22a4c1a05d557c9a14 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10983600 |
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