Safety and efficacy of crizotinib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: phase Ib GEINO 1402 trial
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- dc.contributor.author Martínez-García, Maria
- dc.contributor.author Velasco, Guillermo
- dc.contributor.author Pineda, Estela
- dc.contributor.author Gil-Gil, Miguel J.
- dc.contributor.author Alameda Quitllet, Francisco
- dc.contributor.author Capellades Font, Jaume
- dc.contributor.author Martín-Soberón, Mari Cruz
- dc.contributor.author López-Valero, Israel
- dc.contributor.author Tovar Ambel, Elena
- dc.contributor.author Foro Arnalot, Palmira
- dc.contributor.author Taus García, Álvaro
- dc.contributor.author Arumí Uría, Montserrat
- dc.contributor.author Hernández-Laín, Aurelio
- dc.contributor.author Sepúlveda-Sánchez, Juan Manuel
- dc.date.accessioned 2023-01-24T08:07:49Z
- dc.date.available 2023-01-24T08:07:49Z
- dc.date.issued 2022
- dc.description.abstract Background: MET-signaling and midkine (ALK ligand) promote glioma cell maintenance and resistance against anticancer therapies. ALK and c-MET inhibition with crizotinib have a preclinical therapeutic rationale to be tested in newly diagnosed GBM. Methods: eligible patients received crizotinib with standard radiotherapy (RT)/temozolomide (TMZ) followed by maintenance with crizotinib. The primary objective was to determine the recommended phase 2 dose (RP2D) in a 3 + 3 dose escalation (DE) strategy and safety evaluation in the expansion cohort (EC). Secondary objectives included progression-free (PFS) and overall survival (OS) and exploratory biomarker analysis. Results: the study enrolled 38 patients. The median age was 52 years (33-76), 44% were male, 44% were MGMT methylated, and three patients had IDH1/2 mutation. In DE, DLTs were reported in 1/6 in the second cohort (250 mg/QD), declaring 250 mg/QD of crizotinib as the RP2D for the EC. In the EC, 9/25 patients (32%) presented grade ≥3 adverse events. The median follow up was 18.7 months (m) and the median PFS was 10.7 m (95% CI, 7.7-13.8), with a 6 m PFS and 12 m PFS of 71.5% and 38.8%, respectively. At the time of this analysis, 1 died without progression and 24 had progressed. The median OS was 22.6 m (95% CI, 14.1-31.1) with a 24 m OS of 44.5%. Molecular biomarkers showed no correlation with efficacy. Conclusions: the addition of crizotinib to standard RT and TMZ for newly diagnosed GBM was safe and the efficacy was encouraging, warranting prospective validation in an adequately powered, randomized controlled study.
- dc.format.mimetype application/pdf
- dc.identifier.citation Martínez-García M, Velasco G, Pineda E, Gil-Gil M, Alameda F, Capellades J, et al. Safety and efficacy of crizotinib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: phase Ib GEINO 1402 trial. Cancers (Basel). 2022 May 12; 14(10): 2393. DOI: 10.3390/cancers14102393
- dc.identifier.doi http://dx.doi.org/10.3390/cancers14102393
- dc.identifier.issn 2072-6694
- dc.identifier.uri http://hdl.handle.net/10230/55419
- dc.language.iso eng
- dc.publisher MDPI
- dc.rights Copyright © 2022 by Martínez-García M, Velasco G, Pineda E, Gil-Gil M, Alameda F, Capellades J, et al. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/
- dc.subject.keyword Crizotinib
- dc.subject.keyword Glioblastoma
- dc.subject.keyword Midkine
- dc.subject.keyword Radiotherapy
- dc.subject.keyword Temozolomide
- dc.title Safety and efficacy of crizotinib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: phase Ib GEINO 1402 trial
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion