Phase I/II study of sorafenib in combination with erlotinib for recurrent glioblastoma as part of a 3-arm sequential accrual clinical trial: NABTC 05-02 Journal Article

   

Authors:	Chen, H.; Kuhn, J.; Lamborn, K. R.; Abrey, L. E.; DeAngelis, L. M.; Lieberman, F.; Robins, H. I.; Chang, S. M.; Yung, W. K. A.; Drappatz, J.; Mehta, M. P.; Levin, V. A.; Aldape, K.; Dancey, J. E.; Wright, J. J.; Prados, M. D.; Cloughesy, T. F.; Wen, P. Y.; Gilbert, M. R.
Article Title:	Phase I/II study of sorafenib in combination with erlotinib for recurrent glioblastoma as part of a 3-arm sequential accrual clinical trial: NABTC 05-02
Abstract:	Background: Receptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) and their downstream signaling pathways such as the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway play important roles in glioblastoma (GBM). This study investigated the safety, pharmacokinetics, and efficacy of sorafenib (Ras/Raf/MAPK inhibitor) in combination with erlotinib (EGFR inhibitor) for treatment of recurrent GBMs. Methods: Patients with recurrent GBM were eligible. A novel sequential accrual trial design was used, where patients were sequentially accrued into separate treatment arms in phase I and phase II investigations to optimize recruitment efficiency. In phase I, a standard 3 + 3 format was used to identify dose-limiting toxicities (DLTs), determine maximum tolerated dose (MTD), and investigate pharmacokinetics. Phase II followed a 2-stage design with the primary endpoint being 6-month progression-free survival (PFS6). Results: Sixteen patients were recruited for phase I, and the MTD was determined to be sorafenib 200 mg twice daily and erlotinib 100 mg once daily. DLTs include Grade 3 hypertension, Grade 3 elevated liver transaminases, and Grade 4 elevated lipase. While erlotinib did not affect sorafenib levels, sorafenib reduced erlotinib levels. In phase II, 3 of 19 stage 1 participants were progression free at 6 months. This did not meet the predetermined efficacy endpoint, and the trial was terminated. Conclusion: This study identified the MTD and DLTs for sorafenib and erlotinib combination therapy for recurrent GBMs; however, efficacy data did not meet the primary endpoint. This study also demonstrates the feasibility of a novel sequential accrual clinical trial design that optimizes patient recruitment for multiarm studies, which is particularly effective for multicenter clinical trials. © 2020 Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology 2020.
Keywords:	sorafenib; erlotinib; glioblastoma; molecular therapy; novel trial design
Journal Title:	Neuro-Oncology Advances
Volume:	2
Issue:	1
ISSN:	2632-2498
Publisher:	Oxford University Press
Date Published:	2020-01-01
Start Page:	vdaa124
Language:	English
DOI:	10.1093/noajnl/vdaa124
PROVIDER:	scopus
PMCID:	PMC7668489
PUBMED:	33235994
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85120410562&doi=10.1093%2fnoajnl%2fvdaa124&partnerID=40&md5=24560423468e60941f0bcf5782761b77
Notes:	Article -- Source: Scopus

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