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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)79-89
Number of pages11
JournalJournal of neuro-oncology
Volume146
Issue number1
DOIs
StatePublished - Jan 1 2020

Fingerprint

Glioblastoma
Multicenter Studies
Phosphoric Monoester Hydrolases
Maximum Tolerated Dose
Fatigue
NVP-BKM120
Sequence Deletion
Constipation
Lipase
Alanine Transaminase
Glioma
Nausea
Tablets
Capsules
Headache
Transcription Factors

Keywords

  • Buparlisib
  • Capmatinib
  • Glioblastoma
  • INC280
  • PTEN
  • c-Met

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

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; Sepulveda, Juan; Yung, W. K.Alfred; Wen, Patrick Y.; Lassman, Andrew B.; Joerger, Markus; Tabatabai, Ghazaleh; Rodon, Jordi; Tiedt, Ralph; Zhao, Sylvia; Kirsilae, Tiina; Cheng, Yi; Vicente, Sergio; Balbin, O. Alejandro; Zhang, Hefei; Wick, Wolfgang.

In: Journal of neuro-oncology, Vol. 146, No. 1, 01.01.2020, p. 79-89.

Research output: Contribution to journalArticle

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
van den Bent, Martin ; Azaro, Analia ; De Vos, Filip ; Sepulveda, Juan ; Yung, W. K.Alfred ; Wen, Patrick Y. ; Lassman, Andrew B. ; Joerger, Markus ; Tabatabai, Ghazaleh ; Rodon, Jordi ; Tiedt, Ralph ; Zhao, Sylvia ; Kirsilae, Tiina ; Cheng, Yi ; Vicente, Sergio ; Balbin, O. Alejandro ; Zhang, Hefei ; Wick, Wolfgang. / A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma. In: Journal of neuro-oncology. 2020 ; Vol. 146, No. 1. pp. 79-89.
@article{b468502bf8074526ac2f5b1480937bed,
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.",
keywords = "Buparlisib, Capmatinib, Glioblastoma, INC280, PTEN, c-Met",
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",
year = "2020",
month = "1",
day = "1",
doi = "10.1007/s11060-019-03337-2",
language = "English (US)",
volume = "146",
pages = "79--89",
journal = "Journal of Neuro-Oncology",
issn = "0167-594X",
publisher = "Kluwer Academic Publishers",
number = "1",

}

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

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 - Capmatinib

KW - Glioblastoma

KW - INC280

KW - PTEN

KW - c-Met

UR - http://www.scopus.com/inward/record.url?scp=85075939347&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075939347&partnerID=8YFLogxK

U2 - 10.1007/s11060-019-03337-2

DO - 10.1007/s11060-019-03337-2

M3 - Article

C2 - 31776899

AN - SCOPUS:85075939347

VL - 146

SP - 79

EP - 89

JO - Journal of Neuro-Oncology

JF - Journal of Neuro-Oncology

SN - 0167-594X

IS - 1

ER -