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.

Autor:	Chen H; Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Kuhn J; Division of Pharmacology, University of Texas, San Antonio, Texas, USA., Lamborn KR; Department of Neurological Surgery, University of California, San Francisco, California, USA., Abrey LE; Memorial Sloan Kettering Cancer Center, New York, New York, USA., DeAngelis LM; Memorial Sloan Kettering Cancer Center, New York, New York, USA., Lieberman F; Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA., Robins HI; Departments of Medicine, Human Oncology, and Neurology, University of Wisconsin-Madison, Madison, Wisconsin, USA., Chang SM; Department of Neurological Surgery, University of California, San Francisco, California, USA., Yung WKA; Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Drappatz J; Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA., Mehta MP; Department of Radiation Oncology, Miami Cancer Institute, Miami, Florida, USA., Levin VA; Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Aldape K; Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Dancey JE; Queen's University, Kingston, Ontario, Canada., Wright JJ; Investigational Drug Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Prados MD; Department of Neurological Surgery, University of California, San Francisco, California, USA., Cloughesy TF; Department of Neurology, University of California, Los Angeles, Los Angeles, California, USA., Wen PY; Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Gilbert MR; Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Jazyk:	angličtina
Zdroj:	Neuro-oncology advances [Neurooncol Adv] 2020 Sep 17; Vol. 2 (1), pp. vdaa124. Date of Electronic Publication: 2020 Sep 17 (Print Publication: 2020).
DOI:	10.1093/noajnl/vdaa124
Abstrakt:	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. (Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology 2020.)
Databáze:	MEDLINE
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