Actr-74. a Phase Ib/ii, Open-label, Multicenter Study of Capmatinib (inc280) Alone and in Combination With Buparlisib (bkm120) in Adult Patients With Recurrent Glioblastoma
Year: 2017
Type: article
Study design: Clinical Trial
Abstract: c-MET and PI3K pathways are dysregulated in GBM and can drive cancer growth in pre-clinical models. INC280 is a small molecule inhibitor of c-MET; BKM120 is a pan-class I PI3K inhibitor. A phase Ib/II study was designed to evaluate INC280+BKM120 in patients with recurrent GBM (NCT01870726). Key objectives were to estimate the MTD/RP2D of INC280+BKM120 and to characterize safety/tolerability, pharmacokinetics (PK), and anti-tumor activity of INC280+BKM120 and INC280 alone. Key eligibility criteria were: age ≥ 18 years; ECOG PS ≤ 2, and recurrent GBM (RANO criteria) following ≤ 2 prior systemic therapies, including VEGF inhibitors. For inclusion in phase Ib, mutation/homozygous deletion of PTEN, a suppressor of PI3K signals, was required (irrespective of c-MET status). For phase II with INC280 alone, c-MET amplification (GCN > 5) was required. Blood and tumor specimens were collected for PK and molecular analyses. Thirty-three patients were enrolled in six phase Ib dose cohorts of INC280+BKM120. DLTs were nausea, personality change, and elevated transaminases. MTD was identified at INC280 300 mg BID + BKM120 80 mg QD. RP2D was not declared due to: poor tolerability; a drug-drug interaction resulting in low BKM120 exposure; and no strong evidence of activity. The INC280+BKM120 phase II arm was not opened. In the INC280 monotherapy arm, 10 patients (median age 48 years; 70% women, 90% Caucasian) were enrolled. The most common INC280-related AEs (all grades) were nausea and fatigue. Three patients had stable disease as best response (RANO). Molecular analyses are ongoing. The MTD of INC280 300 mg BID + BKM120 80 mg QD was identified, with both doses below the single agent RP2Ds. Limited efficacy was observed with the combination in PTEN altered GBM. INC280 alone was well-tolerated but displayed no clear evidence of anti-tumor activity in heavily pre-treated GBM with c-MET alteration.
Source: Neuro-Oncology
Institutions: Erasmus MC, Vall d'Hebron Hospital Universitari, University Medical Center Utrecht, Hospital Universitario 12 De Octubre, The University of Texas MD Anderson Cancer Center, Dana-Farber/Harvard Cancer Center, Columbia University Irving Medical Center, Kantonsspital St. Gallen, Universitätsklinikum Tübingen, University of Tübingen, Novartis (Switzerland), Novartis (China), German Cancer Research Center, Heidelberg University, University Hospital Heidelberg, National Center for Tumor Diseases, Deutsches Konsortium für Translationale Krebsforschung
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2768023881