A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma

Martin van den Bent; Analia Azaro; Filip De Vos; Juan Sepulveda; W. K.Alfred Yung; Patrick Y. Wen; Andrew B. Lassman; Markus Joerger; Ghazaleh Tabatabai; Jordi Rodon; Ralph Tiedt; Sylvia Zhao; Tiina Kirsilae; Yi Cheng; Sergio Vicente; O. Alejandro Balbin; Hefei Zhang; Wolfgang Wick

doi:10.1007/s11060-019-03337-2

A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma

Martin van den Bent^*, Analia Azaro, Filip De Vos, Juan Sepulveda, W. K.Alfred Yung, Patrick Y. Wen, Andrew B. Lassman, Markus Joerger, Ghazaleh Tabatabai, Jordi Rodon, Ralph Tiedt, Sylvia Zhao, Tiina Kirsilae, Yi Cheng, Sergio Vicente, O. Alejandro Balbin, Hefei Zhang, Wolfgang Wick

^*Corresponding author for this work

Neurology

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Abstract

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.

Original language	English
Pages (from-to)	79-89
Number of pages	11
Journal	Journal of Neuro-Oncology
Volume	146
Issue number	1
DOIs	https://doi.org/10.1007/s11060-019-03337-2
Publication status	Published - Jan 2020

Bibliographical note

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).

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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 glioblastomaFinal published version, 0.98 MBLicence: CC BY

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van den Bent, M., Azaro, A., De Vos, F., Sepulveda, J., Yung, W. K. A., Wen, P. Y., Lassman, A. B., Joerger, M., Tabatabai, G., Rodon, J., Tiedt, R., Zhao, S., Kirsilae, T., Cheng, Y., Vicente, S., Balbin, O. A., Zhang, H., & Wick, W. (2020). A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma. Journal of Neuro-Oncology, 146(1), 79-89. https://doi.org/10.1007/s11060-019-03337-2

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title = "A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma",

abstract = "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.",

author = "\{van den Bent\}, Martin and Analia Azaro and \{De Vos\}, Filip and Juan Sepulveda and Yung, \{W. K.Alfred\} and Wen, \{Patrick Y.\} and Lassman, \{Andrew B.\} and Markus Joerger and Ghazaleh Tabatabai and Jordi Rodon and Ralph Tiedt and Sylvia Zhao and Tiina Kirsilae and Yi Cheng and Sergio Vicente and Balbin, \{O. Alejandro\} and Hefei Zhang and Wolfgang Wick",

note = "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: {\textcopyright} 2019, The Author(s).",

year = "2020",

month = jan,

doi = "10.1007/s11060-019-03337-2",

language = "English",

volume = "146",

pages = "79--89",

journal = "Journal of Neuro-Oncology",

issn = "0167-594X",

publisher = "Springer",

number = "1",

}

van den Bent, M, Azaro, A, De Vos, F, Sepulveda, J, Yung, WKA, Wen, PY, Lassman, AB, Joerger, M, Tabatabai, G, Rodon, J, Tiedt, R, Zhao, S, Kirsilae, T, Cheng, Y, Vicente, S, Balbin, OA, Zhang, H & Wick, W 2020, 'A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma', Journal of Neuro-Oncology, vol. 146, no. 1, pp. 79-89. https://doi.org/10.1007/s11060-019-03337-2

A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma. / van den Bent, Martin; Azaro, Analia; De Vos, Filip et al.
In: Journal of Neuro-Oncology, Vol. 146, No. 1, 01.2020, p. 79-89.

Research output: Contribution to journal › Article › Academic › peer-review

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

Y1 - 2020/1

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.

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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

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