A nonrandomized phase I and biomarker trial of regorafenib in advanced myeloid malignancies.

Autor: How J; Division of Hematology Brigham and Women's Hospital Harvard Medical School Boston Massachusetts USA., Ren S; Department of Data Sciences Dana-Farber Cancer Institute Boston Massachusetts USA., Lombardi-Story J; Department of Medical Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Bergeron M; Department of Medical Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Foster J; Department of Medical Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Amrein PC; Department of Medical Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Brunner AM; Department of Medical Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Fathi AT; Department of Medical Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Hock H; Department of Medical Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Khachatryan A; Department of Radiation Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Kikuchi H; Department of Radiation Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Ng MR; Department of Radiation Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Moran J; Department of Medical Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Narayan R; Department of Medical Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Neuberg D; Department of Data Sciences Dana-Farber Cancer Institute Boston Massachusetts USA., Ramos A; Department of Medical Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Som T; Department of Medical Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Vartanian M; Department of Medical Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Chen YB; Department of Medical Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Duda DG; Department of Radiation Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA., Hobbs GS; Department of Medical Oncology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA.
Jazyk: angličtina
Zdroj: EJHaem [EJHaem] 2022 Mar 06; Vol. 3 (2), pp. 434-442. Date of Electronic Publication: 2022 Mar 06 (Print Publication: 2022).
DOI: 10.1002/jha2.408
Abstrakt: We conducted a single-center, open-label, dose escalation, and expansion phase I trial of the antiangiogenic multikinase inhibitor regorafenib in patients with advanced myeloid neoplasms. We enrolled 16 patients with relapsed/refractory acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), or myelodysplastic syndrome (MDS). A 3 + 3 dose escalation design was used with two planned dose levels (120 or 160 mg daily) and one de-escalation level (80 mg daily). An additional 10 patients were treated on an expansion cohort. The recommended phase two dose of regorafenib was 160 mg daily, with no dose-limiting toxicities. The best overall disease response by International Working Group criteria included one partial and stable disease in 11 patients. Tissue studies indicated no change in Ras/mitogen-activated protein kinase (MAPK) pathway activation in responders. Pharmacodynamic changes in plasma VEGF, PlGF, and sVEGFR2 were detected during treatment. Baseline proinflammatory and angiogenic cytokine levels were not associated with clinical response. Single-agent regorafenib demonstrated an acceptable safety profile in relapsed/refractory myeloid malignancy patients. Most patients achieved stable disease, with modest improvements in cell counts in some MDS patients. Biomarker studies were consistent with on-target effects of regorafenib on angiogenesis. Future studies should investigate the role of regorafenib in combination therapy approaches.
Competing Interests: Amir T. Fathi: Consulting: Foghorn, Amgen, Celgene, BMS, Agios, Novartis, Ipsen, Forma, Abbvie, Genentech, Morphosys, and Takeda. Donna Neuberg: Stock ownership in Madrigal Pharmaceuticals, and received research funding from Pharmacyclics. Yi‐Bin Chen: Consulting: Daiichi, Abbvie, Equilium, Incyte, Jasper, Celularity, and Actinium; clinical trial support: Abbvie, Celgene, BMS, Agios, and Servie; Dan G. Duda received consultant fees from Simcere, Surface Oncology, Sophia Bioscience, Innocoll and BMS, and research grants from Exelixis, BMS, and Surface Oncology. Dan G. Duda's research is supported by National Institutes of Health (NIH) (grant numbers: R01CA260857, R01CA247441, R01CA254351, R03CA256764, and P01CA261669) and Department of Defense PRCRP (grant numbers: #W81XWH‐19‐1‐0284 and W81XWH‐21‐1‐0738). Gabriela Hobbs: Consulting fees from Abbvie, Incyte, Blueprint, Novartis, and Keros; research support from Bayer, Incyte and Constellation; grants: ECOR PSDA Award and ASH‐AMFDP award. The other authors declare no potential conflict of interest. Result of this study has previously been reported as an abstract at the 2020 American Society of Hematology Annual Meeting (Virtual). The funders had no role in data analysis or the preparation of this article.
(© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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