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A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma Azaro Pedrazzoli, Analía Beatriz De Vos, Filip Sepúlveda, Juan Manuel Yung, W. K. Alfred Wen, Patrick Y. van den Bent, Martin Institut Català de la Salut [van den Bent M] Erasmus University Medical Center (MC) Cancer Institute, Rotterdam, The Netherlands. [Azaro A] Unitat d’Investigació de Teràpia Molecular, Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [De Vos F] University Medical Center Utrecht, Utrecht, The Netherlands. [Sepulveda J] Hospital Universitario, 12 de Octubre, Madrid, Spain. [Yung WKA] MD Anderson Cancer Center, Houston, TX, USA. [Wen PY] Center for Neuro-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA Vall d'Hebron Barcelona Hospital Campus Glioblastoma multiforme Cervell - Càncer - Quimioteràpia DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Glioma::Astrocytoma::Glioblastoma ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols DISEASES::Neoplasms::Neoplastic Processes::Neoplasm Recurrence, Local ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::neoplasias neuroepiteliales::glioma::astrocitoma::glioblastoma TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada ENFERMEDADES::neoplasias::procesos neoplásicos::recurrencia neoplásica local Buparlisib; Capmatinib; Glioblastoma Buparlisib; Capmatinib; Glioblastoma Buparlisib; Capmatinib; Glioblastoma Purpose To estimate the maximum tolerated dose (MTD) and/or identify the recommended Phase II dose (RP2D) for combined INC280 and buparlisib in patients with recurrent glioblastoma with homozygous phosphatase and tensin homolog (PTEN) deletion, mutation or protein loss. Methods This multicenter, open-label, Phase Ib/II study included adult patients with glioblastoma with mesenchymal-epithelial transcription factor (c-Met) amplification. In Phase Ib, patients received INC280 as capsules or tablets in combination with buparlisib. In Phase II, patients received INC280 only. Response was assessed centrally using Response Assessment in Neuro-Oncology response criteria for high-grade gliomas. All adverse events (AEs) were recorded and graded. Results 33 patients entered Phase Ib, 32 with altered PTEN. RP2D was not declared due to potential drug–drug interactions, which may have resulted in lack of efficacy; thus, Phase II, including 10 patients, was continued with INC280 monotherapy only. Best response was stable disease in 30% of patients. In the selected patient population, enrollment was halted due to limited activity with INC280 monotherapy. In Phase Ib, the most common treatment-related AEs were fatigue (36.4%), nausea (30.3%) and increased alanine aminotransferase (30.3%). MTD was identified at INC280 Tab 300 mg twice daily + buparlisib 80 mg once daily. In Phase II, the most common AEs were headache (40.0%), constipation (30.0%), fatigue (30.0%) and increased lipase (30.0%). Conclusion The combination of INC280/buparlisib resulted in no clear activity in patients with recurrent PTEN-deficient glioblastoma. More stringent molecular selection strategies might produce better outcomes. This study is funded by Novartis Institutes for Biomedical Research (China). A.B. Lassman was supported in part by grants P30CA013696 and UG1CA189960 from the NCI. 2021-10-22T11:40:36Z 2021-10-22T11:40:36Z 2020-01 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion van den Bent M, Azaro A, De Vos F, Sepulveda J, Yung WKA, Wen PY, et al. A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma. J Neurooncol. 2020 Jan;146:79–89. 1573-7373 https://hdl.handle.net/11351/6452 10.1007/s11060-019-03337-2 31776899 000500801900001 http://hdl.handle.net/11351/6452 eng Journal of Neuro-Oncology;146 https://doi.org/10.1007/s11060-019-03337-2 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf application/pdf Springer Scientia