A phase I dose-escalation study of pulsatile afatinib in patients with recurrent or progressive brain cancer.

Autor:	Juarez TM; Pacific Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John's Health Center, Neuro-Oncology, Santa Monica, California, USA., Gill JM; Pacific Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John's Health Center, Neuro-Oncology, Santa Monica, California, USA., Heng A; Pacific Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John's Health Center, Neuro-Oncology, Santa Monica, California, USA., Carrillo JA; Pacific Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John's Health Center, Neuro-Oncology, Santa Monica, California, USA., Wagle N; Pacific Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John's Health Center, Neuro-Oncology, Santa Monica, California, USA., Nomura N; Pacific Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John's Health Center, Neuro-Oncology, Santa Monica, California, USA., Nguyen M; Pacific Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John's Health Center, Neuro-Oncology, Santa Monica, California, USA., Truong J; Pacific Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John's Health Center, Neuro-Oncology, Santa Monica, California, USA., Dobrawa L; Pacific Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John's Health Center, Neuro-Oncology, Santa Monica, California, USA., Sivakumar W; Pacific Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John's Health Center, Neurosurgery, Santa Monica, California, USA., Barkhoudarian G; Pacific Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John's Health Center, Neurosurgery, Santa Monica, California, USA., Kelly DF; Pacific Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John's Health Center, Neurosurgery, Santa Monica, California, USA., Kesari S; Pacific Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John's Health Center, Neuro-Oncology, Santa Monica, California, USA.
Jazyk:	angličtina
Zdroj:	Neuro-oncology advances [Neurooncol Adv] 2024 Mar 30; Vol. 6 (1), pp. vdae049. Date of Electronic Publication: 2024 Mar 30 (Print Publication: 2024).
DOI:	10.1093/noajnl/vdae049
Abstrakt:	Background: Afatinib (BIBW2992; Gilotrif®) is a selective and irreversible inhibitor of the epidermal growth factor receptor (ErbB; EGFR) family. It inhibits EGFR, HER2, and HER4 phosphorylation, resulting in tumor growth inhibition and regression. This phase I dose-escalation trial of pulsatile afatinib examined the safety, drug penetration into the central nervous system, preliminary antitumor activity, and recommended phase II dose in patients with progressive or recurrent brain cancers. Methods: Afatinib was taken orally once every 4 days or once every 7 days depending on dose cohort, until disease progression or unacceptable toxicity. Results: A total of 24 patients received the investigational agent and were evaluable for safety analyses, and 21 patients were evaluable for efficacy. Dosing was administered at 80 mg every 4 days, 120 mg every 4 days, 180 mg every 4 days, or 280 mg every 7 days. A recommended phase II dose of pulsatile afatinib was established at 280 mg every 7 days as there were no dose-limiting toxicities in any of the dosing cohorts and all toxicities were deemed manageable. The most common drug-related toxicities were diarrhea, rash, nausea, vomiting, fatigue, stomatitis, pruritus, and limb edema. Out of the 21 patients evaluable for efficacy, 2 patients (9.5%) exhibited partial response based on Response Assessment in Neuro-Oncology criteria and disease stabilization was seen in 3 patients (14.3%). Conclusions: Afatinib taken orally was safe and well-tolerated up to 280 mg every 7 days in brain cancer patients. Competing Interests: SK reports research funding to institutions from AADi, Aivita Biomedical, Inc., Bavarian Nordic, Bayer, Biocept, Blue Earth Diagnostics, Caris MPI, CNS Pharmaceuticals, EpicentRx, Incyte, Lilly, Oblato, Orbus Therapeutics, and Stemedica Cell Technologies; reports stock or other ownership interests in xCures; reports receiving honoraria from Jubilant Biosys and Pyramid Biosciences; and is a consultant/advisory board member for Curtana Pharmaceuticals, Nascent Biotech, Biocept, iCAD, and xCures. JAC reports research funding to institution from Nascent Biotech and Novocure. NW reports research funding to institution from Bavarian Nordic, Bayer, Biocept, Boehringer Ingelheim, Caris MPI, CNS Pharmaceuticals, EpicentRx, Incyte, Novocure, Oblato, Pyramid Biosciences, Stemedica Cell Technologies, xCures, and Xoft. GB is a consultant for Vascular Technologies, Inc. and Cerevasc Inc.; reports payment for expert testimony; is the Data Monitoring Committee Chair for Cerevasc Inc.; and is an executive committee member of the Congress of Neurological Surgeons (CNS) and American Association of Neurological Surgeons (AANS) Tumor Section. DFK reports royalties or licenses from Mizuho, Inc. All other authors declare no competing interests. (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
Databáze:	MEDLINE
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