Vicente Gabarda, Sergio, Tiedt, Ralph, Zhao, Sylvia, Myers, Andrea and Kirsilae, Tiina A phase Ib/II, open-label, multicenter study of INC280 in combination with buparlisib in adult patients with recurrent glioblastoma.

Abstract

Title: A phase Ib/II, open-label, multicenter study of INC280 in combination with buparlisib in adult patients with recurrent glioblastoma

Authors: Martin J. van den Bent1, Analia Azaro2, Filip Y.F.L. de Vos3, Juan Manuel Sepulveda4, W.K. Alfred Yung5, Patrick Wen6, Andrew B. Lassman7, Markus Joerger8, Ghazaleh Tabatabai9, Jordi Rodon5, Ralph Tiedt10, Sylvia Zhao11, Tiina Kirsilae10, Sergio Vicente10, Andrea Myers11, Wolfgang Wick12
1. Erasmus University Medical Center, Rotterdam, The Netherlands
2. Vall d'Hebron University Hospital, Barcelona, Spain
3. UMC Utrecht, Utrecht, The Netherlands
4. Hospital Universitario 12 De Octubre, Madrid, Spain
5. MD Anderson Cancer Center, Houston, Texas, USA
6. Dana Farber Cancer Institute, Boston, Massachusetts, USA
7. Columbia U. Medical Center, New York, New York, USA
8. Kantonsspital St. Gallen, St. Gallen, Switzerland
9. Universitätsklinikum Tübingen & Eberhard Karls University Tübingen, Tübingen, Germany
10. Novartis Pharma AG, Basel, Switzerland
11. Novartis Institutes for Biomedical Research (China), Shanghai, China
12. University of Heidelberg, Heidelberg, Germany

Keywords: Glioblastoma (GBM), c-MET inhibitor, capmatinib (INC280), PI3K inhibitor, buparlisib (BKM120)

Background: c-MET and PI3K pathways are dysregulated in GBM and can drive cancer growth in pre-clinical models. INC280 (capmatinib) is an oral, small molecule inhibitor of c-MET; buparlisib (BKM120) is an oral, pan-class I PI3K inhibitor. A phase Ib/II study was designed to evaluate capmatinib + buparlisib in patients with recurrent GBM (NCT01870726).

Methods: Key objectives were to estimate MTD/RP2D (phase Ib); to characterize safety/tolerability and PK (phase Ib/II); and estimate anti-tumor activity (phase II) of capmatinib + buparlisib. Key eligibility criteria were: age ≥ 18 years; ECOG PS ≤ 2 and recurrent GBM [RANO criteria] following ≤ 2 prior systemic therapies. For the phase Ib part PTEN mutations or homozygous deletion was required. Based on phase Ib results, the phase II was amended into a single agent arm of capmatinib 400 mg tablet BID in patients with c-MET amplification. Blood and tumor specimens were collected for PK and molecular analyses.

Results: Thirty-three patients were enrolled in six phase Ib dose cohorts of capmatinib + buparlisib. MTD was identified at capmatinib 300 mg BID + buparlisib 80 mg QD. RP2D was not declared due to: poor tolerability, a drug-drug interaction resulting in low buparlisib exposure, and lack of efficacy. The capmatinib + buparlisib phase II arm was not opened. In the capmatinib monotherapy arm, 10 patients (median age 48 years; 70% women, 90% Caucasian) were enrolled. The most common capmatinib-related AEs were nausea (20%) and fatigue (20%). Three patients had stable disease as best response (RANO). Molecular analyses are ongoing.
Conclusions: The MTD of capmatinib 300 mg BID + buparlisib 80 mg QD was identified, below both single agent RP2Ds. No efficacy was observed with this combination in PTEN altered GBM. In this small study, capmatibnib was well-tolerated but displayed no clear evidence of anti-tumor activity in c-MET altered GBM.

Item Type:	Article
Date Deposited:	11 Jan 2020 00:45
Last Modified:	11 Jan 2020 00:45
URI:	https://oak.novartis.com/id/eprint/33296