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

Huanwen Chen; John Kuhn; Kathleen R Lamborn; Lauren E Abrey; Lisa M DeAngelis; Frank Lieberman; H Ian Robins; Susan M Chang; W K Alfred Yung; Jan Drappatz; Minesh P Mehta; Victor A Levin; Kenneth Aldape; Janet E Dancey; John J Wright; Michael D Prados; Timothy F Cloughesy; Patrick Y Wen; Mark R Gilbert

doi:10.1093/noajnl/vdaa124

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

Neurooncol Adv. 2020 Sep 17;2(1):vdaa124. doi: 10.1093/noajnl/vdaa124. eCollection 2020 Jan-Dec.

Authors

Huanwen Chen¹, John Kuhn², Kathleen R Lamborn³, Lauren E Abrey⁴, Lisa M DeAngelis⁴, Frank Lieberman⁵, H Ian Robins⁶, Susan M Chang³, W K Alfred Yung⁷, Jan Drappatz⁵, Minesh P Mehta⁸, Victor A Levin⁷, Kenneth Aldape⁹, Janet E Dancey¹⁰, John J Wright¹¹, Michael D Prados³, Timothy F Cloughesy¹², Patrick Y Wen¹³, Mark R Gilbert¹

Affiliations

¹ Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
² Division of Pharmacology, University of Texas, San Antonio, Texas, USA.
³ Department of Neurological Surgery, University of California, San Francisco, California, USA.
⁴ Memorial Sloan Kettering Cancer Center, New York, New York, USA.
⁵ Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
⁶ Departments of Medicine, Human Oncology, and Neurology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
⁷ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁸ Department of Radiation Oncology, Miami Cancer Institute, Miami, Florida, USA.
⁹ Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
¹⁰ Queen's University, Kingston, Ontario, Canada.
¹¹ Investigational Drug Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
¹² Department of Neurology, University of California, Los Angeles, Los Angeles, California, USA.
¹³ Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

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.

Keywords: erlotinib; glioblastoma; molecular therapy; novel trial design; sorafenib.

Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology 2020.

Abstract

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