A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas.

Autor:	Desai PB; Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, Ohio., Karve AS; Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, Ohio., Zawit M; Department of Internal Medicine, Division of Hematology/Oncology, University of Cincinnati, Cincinnati, Ohio., Arora P; Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, Ohio., Dave N; Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, Ohio., Awosika J; National Institute of Health, Bethesda, Maryland., Li N; Division of Oncology, University of Texas Health Science Center at Houston, Houston, Texas., Fuhrman B; University of Cincinnati Cancer Center, Cincinnati, Ohio., Medvedovic M; Department of Environmental and Public Health Sciences, University of Cincinnati, Cincinnati, Ohio., Sallans L; Department of Chemistry, University of Cincinnati, Cincinnati, Ohio., Kendler A; Department of Pathology, University of Cincinnati, Cincinnati, Ohio., DasGupta B; Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio., Plas D; Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio., Curry R; CTI, Covington, Kentucky., Zuccarello M; Department of Neurosurgery, University of Cincinnati, Cincinnati, Ohio., Chaudhary R; Department of Internal Medicine, Division of Hematology/Oncology, University of Cincinnati, Cincinnati, Ohio., Sengupta S; Department of Neurology & Neurosurgery & the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina., Wise-Draper TM; Department of Internal Medicine, Division of Hematology/Oncology, University of Cincinnati, Cincinnati, Ohio.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 May 15; Vol. 30 (10), pp. 2068-2077.
DOI:	10.1158/1078-0432.CCR-23-3341
Abstrakt:	Purpose: High-grade gliomas (HGG) carry a poor prognosis, with glioblastoma accounting for almost 50% of primary brain malignancies in the elderly. Unfortunately, despite the use of multiple treatment modalities, the prognosis remains poor in this population. Our preclinical studies suggest that the presence of aromatase expression, encoded by CYP19A1, is significantly upregulated in HGGs. Remarkably, we find that letrozole (LTZ), an FDA-approved aromatase inhibitor, has marked activity against HGGs. Patients and Methods: We conducted a phase 0/I single-center clinical trial (NCT03122197) to assess the tumoral availability, pharmacokinetics (PK), safety, and tolerability of LTZ in recurrent patients with HGG. Planned dose cohorts included 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and postsurgery or biopsy. Tumor samples were assayed for LTZ content and relevant biomarkers. The recommended phase 2 dose (R2PD) was determined as the dose that resulted in predicted steady-state tumoral extracellular fluid (ECF; Css,ecf) >2 μmol/L and did not result in ≥33% dose-limiting adverse events (AE) assessed using CTCAE v5.0. Results: Twenty-one patients were enrolled. Common LTZ-related AEs included fatigue, nausea, musculoskeletal, anxiety, and dysphoric mood. No DLTs were observed. The 15 mg dose achieved a Css,ecf of 3.6 ± 0.59 μmol/L. LTZ caused dose-dependent inhibition of estradiol synthesis and modulated DNA damage pathways in tumor tissues as evident using RNA-sequencing analysis. Conclusions: On the basis of safety, brain tumoral PK, and mechanistic data, 15 mg daily is identified as the RP2D for future trials. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu