PMID- 31776899 OWN - NLM STAT- MEDLINE DCOM- 20200609 LR - 20240422 IS - 1573-7373 (Electronic) IS - 0167-594X (Print) IS - 0167-594X (Linking) VI - 146 IP - 1 DP - 2020 Jan TI - A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma. PG - 79-89 LID - 10.1007/s11060-019-03337-2 [doi] AB - 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. TRIAL REGISTRATION: NCT01870726. FAU - van den Bent, Martin AU - van den Bent M AUID- ORCID: 0000-0001-5710-5127 AD - Erasmus University Medical Center (MC) Cancer Institute, Rotterdam, The Netherlands. m.vandenbent@erasmusmc.nl. FAU - Azaro, Analia AU - Azaro A AD - Molecular Therapeutics Research Unit (UITM), Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. FAU - De Vos, Filip AU - De Vos F AD - University Medical Center Utrecht, Utrecht, The Netherlands. FAU - Sepulveda, Juan AU - Sepulveda J AD - Hospital Universitario, 12 de Octubre, Madrid, Spain. FAU - Yung, W K Alfred AU - Yung WKA AD - MD Anderson Cancer Center, Houston, TX, USA. FAU - Wen, Patrick Y AU - Wen PY AD - Center for Neuro-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. FAU - Lassman, Andrew B AU - Lassman AB AD - Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA. FAU - Joerger, Markus AU - Joerger M AD - Cantonal Hospital, St. Gallen, Switzerland. FAU - Tabatabai, Ghazaleh AU - Tabatabai G AD - Interdisciplinary Division of Neuro-Oncology, Center for CNS Tumors, Comprehensive Cancer Center, University Hospital Tubingen, Hertie Institute for Clinical Brain Research & Eberhard Karls University Tubingen, German Cancer Consortium (DKTK), DKFZ Partner Site Tubingen, Tubingen, Germany. FAU - Rodon, Jordi AU - Rodon J AD - MD Anderson Cancer Center, Houston, TX, USA. FAU - Tiedt, Ralph AU - Tiedt R AD - Novartis Pharma AG, Basel, Switzerland. FAU - Zhao, Sylvia AU - Zhao S AD - Novartis Institutes for Biomedical Research (China), Shanghai, China. FAU - Kirsilae, Tiina AU - Kirsilae T AD - Novartis Pharma AG, Basel, Switzerland. FAU - Cheng, Yi AU - Cheng Y AD - Novartis Institutes for Biomedical Research (China), Shanghai, China. FAU - Vicente, Sergio AU - Vicente S AD - Novartis Pharma AG, Basel, Switzerland. FAU - Balbin, O Alejandro AU - Balbin OA AD - Novartis Institutes for Biomedical Research (United States), Boston, MA, USA. FAU - Zhang, Hefei AU - Zhang H AD - Novartis Institutes for Biomedical Research (China), Shanghai, China. FAU - Wick, Wolfgang AU - Wick W AD - Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), and Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. LA - eng SI - ClinicalTrials.gov/NCT01870726 GR - P30 CA013696/CA/NCI NIH HHS/United States GR - UG1 CA189960/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study DEP - 20191127 PL - United States TA - J Neurooncol JT - Journal of neuro-oncology JID - 8309335 RN - 0 (Aminopyridines) RN - 0 (Benzamides) RN - 0 (Imidazoles) RN - 0 (Morpholines) RN - 0 (NVP-BKM120) RN - 0 (Triazines) RN - EC 2.7.10.1 (MET protein, human) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-met) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (PTEN protein, human) RN - TY34L4F9OZ (capmatinib) SB - IM MH - Adult MH - Aged MH - Aminopyridines/administration & dosage MH - Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics/*therapeutic use MH - Benzamides MH - Brain Neoplasms/*drug therapy/genetics/pathology MH - Female MH - Follow-Up Studies MH - Glioblastoma/*drug therapy/genetics/pathology MH - Humans MH - Imidazoles/administration & dosage MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Morpholines/administration & dosage MH - Neoplasm Recurrence, Local/*drug therapy/genetics/pathology MH - PTEN Phosphohydrolase/genetics MH - Prognosis MH - Proto-Oncogene Proteins c-met/genetics MH - Tissue Distribution MH - Triazines/administration & dosage PMC - PMC6938467 OTO - NOTNLM OT - Buparlisib OT - Capmatinib OT - Glioblastoma OT - INC280 OT - PTEN OT - c-Met COIS- In relation to this presentation, we declare the following, real or perceived conflicts of interest: M. van den Bent has received grants from Abbvie, and honoraria from Cellgene, BMS, Boehringer, AGIOS and VaXIMM. A. Azaro has received consulting fees from Orion Pharmaceuticals and Amcure GmbH. F. De Vos has received financial support for conducting clinical trials from Novartis, BMS, AbbVie and Bioclin. J.M. Sepulveda has received consulting fees from Celgene, Pfizer and Abbvie; he has received research grants from Pfizer and Catalysis. W.K.A. Yung holds stocks in DNATrix; he has received honoraria from DNATrix and Boehringer Ingelheim; he holds patents, royalties and/or intellectual property in, and has participated in a consulting or advisory role for DNATrix; he has received travel and/or accommodation expenses from Boehringer Ingelheim. P. Wen has received grants/research support from Lilly USA, Agios, AstraZeneca, Beigene, Eli Lily, Immunocellular Therapeutics, Kazai, Kadmon, Karyopharm, Merck, Novartis, Oncoceutics, Vascular Biogenics and Vaccines; he has received speaker's bureau fees from Merck; he has received consultant/advisory board fees from Genentech/Roche, Taiho Oncology, Novartis, Agios Pharmaceuticals Inc, Merck, Puma, Abbvie, AstraZeneca, Eli Lilly, GW Pharmaceuticals, Immunomic Therapeutics, Kadmon, Vascular Biogenics, Ziopharm, Monteris and Tocagen. A. Lassman reports grants and non-financial support from Novartis, during the conduct of the study; personal fees and non-financial support from Orbus, grants, personal fees and non-financial support from Karyopharm, personal fees and non-financial support from NW Biotherapeutics, grants and non-financial support from Oncoceutics, personal fees and non-financial support from Agios, personal fees and non-financial support from Celgene, personal fees and non-financial support from Novocure, non-financial support from Tocagen, non-financial support from BMS, grants, personal fees and non-financial support from Kadmon, grants and non-financial support from Genentech/Roche, grants and non-financial support from Amgen, grants and non-financial support from Millenium, non-financial support from Celldex, grants and non-financial support from Pfizer, non-financial support from Keryx/Aeterna Zentaris, grants and non-financial support from VBI Vaccines, grants and non-financial support from Beigene, personal fees from Bioclinica as an expert blinded independent reviewer of clinical and imaging data for a BMS-sponsored trial, personal fees from prIME Oncology, personal fees and non-financial support from Sapience, personal fees from WebMD, personal fees and non-financial support from Physicians' Education Resource, personal fees from Cortice, grants, personal fees and non-financial support from AbbVie, personal fees and non-financial support from Forma, personal fees and non-financial support from Bayer, grants and non-financial support from Global Coalition for Adaptive Research, personal fees and non-financial support from American Society of Clinical Oncology, grants and non-financial support from QED, grants, personal fees and non-financial support from NCI, non-financial support from New York University, grants and non-financial support from NRG Oncology/RTOG-Foundations, grants from UCLA, grants from Northwestern University, grants from James S. McDonnell Foundation, non-financial support from Yale University, non-financial support from Radiological Society of North America, non-financial support from FDA, personal fees from Italian Foundation for Cancer Research, personal fees and non-financial support from Abbott Molecular, and personal fees from Elsevier, outside the submitted work M. Joerger has received grants from BMS and AstraZeneca. G. Tabatabai has served on Advisory Boards for AbbVie and BMS, has received research/travel grants from Medac, Novocure and Roche Diagnostics, and has received speaker;s fees from Meda and Novocure. J. Rodon reports non-financial support and reasonable reimbursement for travel from European Journal of Cancer, Vall d'Hebron Institut of Oncology, Chinese University of Hong Kong, SOLTI, Elsevier, GlaxoSmithKline; receiving consulting and travel fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceutical/Klus Pharma, Spectrum Pharmaceuticals Inc, Pfizer, Roche Pharmaceuticals, Ellipses Pharma (including serving on the scientific advisory board from 2015-present), receiving research funding from Bayer and Novartis, and serving as investigator in clinical trials with Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GlaxoSmithKline, IPSEN and travel fees from ESMO, US Department of Defense, Louissiana State University, Hunstman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute and King Abdullah International Medical Research Center (KAIMRC). R. Tiedt, T. Kirsilae and S. Vicente are employees of Novartis Pharma AG. S. Zhao is an employee of Novartis Institutes for Biomedical Research (China). A. Balbin is an employee of Novartis Institutes for Biomedical Research (US). H. Zhang is an employee of Novartis and holds shares with Novartis. W. Wick receives study support to the institution from Apogenix, Pfizer and Roche. EDAT- 2019/11/30 06:00 MHDA- 2020/06/10 06:00 PMCR- 2019/11/27 CRDT- 2019/11/29 06:00 PHST- 2019/09/10 00:00 [received] PHST- 2019/11/09 00:00 [accepted] PHST- 2019/11/30 06:00 [pubmed] PHST- 2020/06/10 06:00 [medline] PHST- 2019/11/29 06:00 [entrez] PHST- 2019/11/27 00:00 [pmc-release] AID - 10.1007/s11060-019-03337-2 [pii] AID - 3337 [pii] AID - 10.1007/s11060-019-03337-2 [doi] PST - ppublish SO - J Neurooncol. 2020 Jan;146(1):79-89. doi: 10.1007/s11060-019-03337-2. Epub 2019 Nov 27.