TY - JOUR
T1 - A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma
AU - van den Bent, Martin
AU - Azaro, Analia
AU - De Vos, Filip
AU - Sepulveda, Juan
AU - Yung, W. K.Alfred
AU - Wen, Patrick Y.
AU - Lassman, Andrew B.
AU - Joerger, Markus
AU - Tabatabai, Ghazaleh
AU - Rodon, Jordi
AU - Tiedt, Ralph
AU - Zhao, Sylvia
AU - Kirsilae, Tiina
AU - Cheng, Yi
AU - Vicente, Sergio
AU - Balbin, O. Alejandro
AU - Zhang, Hefei
AU - Wick, Wolfgang
N1 - Funding Information:
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. Acknowledgements
Funding Information:
This study (CINC280X2204) is funded by Novartis Institutes for Biomedical Research (China). The authors would like to acknowledge the assistance of all investigators, clinical trial staff, participants and past and present INC280 EPT members. The authors thank Paul Coyle, Vicki Betts, PhD, Jackie Johnson, PhD, and Gillian Brodie, MSc, of Novartis Ireland Ltd for providing medical writing support/editorial support, which was funded by Novartis Pharma AG, Basel, Switzerland in accordance with Good Publication Practice (GPP3) guidelines ( https://www.ismpp.org/gpp3 ).
Publisher Copyright:
© 2019, The Author(s).
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
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.
KW - Buparlisib
KW - c-Met
KW - Capmatinib
KW - Glioblastoma
KW - INC280
KW - PTEN
UR - https://www.scopus.com/pages/publications/85075939347
U2 - 10.1007/s11060-019-03337-2
DO - 10.1007/s11060-019-03337-2
M3 - Article
C2 - 31776899
AN - SCOPUS:85075939347
SN - 0167-594X
VL - 146
SP - 79
EP - 89
JO - Journal of Neuro-Oncology
JF - Journal of Neuro-Oncology
IS - 1
ER -