The DAY101-EAP is a multicenter, open-label, expanded access treatment protocol designed to provide access to tovorafenib (DAY101) for eligible patients.

开始日期-

申办/合作机构

Day One Biopharmaceuticals, Inc.

NCT04775485 / Recruiting临床2期

FIREFLY-1: A Phase 2, Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of the Oral Pan-RAF Inhibitor DAY101 in Pediatric Patients With RAF-Altered, Recurrent or Progressive Low-Grade Glioma and Advanced Solid Tumors

FIREFLY-1 is an ongoing, Phase 2, multi center, open-label study to evaluate the safety and efficacy of oral pan-RAF inhibitor DAY101 in pediatric, adolescent, and young adult patients with recurrent or progressive low-grade glioma or an advanced solid tumor harboring a known RAF alteration.

开始日期2021-04-22

申办/合作机构

Day One Biopharmaceuticals, Inc.

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100 项与 BRAF V600 突变的低级别胶质瘤相关的临床结果

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100 项与 BRAF V600 突变的低级别胶质瘤相关的转化医学

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0 项与 BRAF V600 突变的低级别胶质瘤相关的专利（医药）

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项与 BRAF V600 突变的低级别胶质瘤相关的文献（医药）

2024-10-01·Child's Nervous System

Molecular-targeted therapy for childhood low-grade glial and glioneuronal tumors

Review

作者: Kilburn, Lindsay B ; Siegel, Benjamin I ; Packer, Roger J ; Duke, Elizabeth S

Since the discovery of the association between BRAF mutations and fusions in the development of childhood low-grade gliomas and the subsequent recognition that most childhood low-grade glial and glioneuronal tumors have aberrant signaling through the RAS/RAF/MAP kinase pathway, there has been a dramatic change in how these tumors are conceptualized. Many of the fusions and mutations present in these tumors are associated with molecular targets, which have agents in development or already in clinical use. Various agents, including MEK inhibitors, BRAF inhibitors, MTOR inhibitors and, in small subsets of patients NTRK inhibitors, have been used successfully to treat children with recurrent disease, after failure of conventional approaches such as surgery or chemotherapy. The relative benefits of chemotherapy as compared to molecular-targeted therapy for children with newly diagnosed gliomas and neuroglial tumors are under study. Already the combination of an MEK inhibitor and a BRAF inhibitor has been shown superior to conventional chemotherapy (carboplatin and vincristine) in newly diagnosed children with BRAF-V600E mutated low-grade gliomas and neuroglial tumors. However, the long-term effects of such molecular-targeted treatment are unknown. The potential use of molecular-targeted therapy in early treatment has made it mandatory that the molecular make-up of the majority of low-grade glial and glioneuronal tumors is known before initiation of therapy. The primary exception to this rule is in children with neurofibromatosis type 1 who, by definition, have NF1 loss; however, even in this population, gliomas arising in late childhood and adolescence or those not responding to conventional treatment may be candidates for biopsy, especially before entry on molecular-targeted therapy trials.

2024-05-02·Pharmacogenomics

A critical review of RAF inhibitors in BRAF-mutated glioma treatment

Review

作者: Attieh, Fouad ; Kesrouani, Carole ; Boutros, Marc ; Wehbe, Sophie ; Khoury, John-Victor El ; Kourie, Hampig Raphaël

BRAF gliomas have garnered significant attention in research due to the lack of effective treatments and their notable incidence, constituting 3% of all gliomas. This underlines the importance of investigating this area and the impact that targeted therapies could hold. This review discusses the development of targeted therapies for these tumors, examining the effectiveness of first-generation BRAF inhibitors such as Vemurafenib, Dabrafenib and Encorafenib, while addressing the challenges posed by paradoxical ERK activation. The advent of pan-RAF inhibitors, notably Tovorafenib, offers a promising advance, demonstrating enhanced efficacy and better penetration of the blood-brain barrier, without the issue of paradoxical activation. Nevertheless, continued research is essential to refine therapeutic strategies for BRAF-mutated gliomas, given the evolving nature of targeted therapy development.

2023-04-01·Gynecologic Oncology

The potential of RAS/RAF/MEK/ERK (MAPK) signaling pathway inhibitors in ovarian cancer: A systematic review and meta-analysis

Review

作者: van der Ploeg, P ; Theelen, P M M ; Piek, J M J ; Hendrikse, C S E ; Boere, I A ; Westgeest, H M ; Lambrechts, S ; van de Stolpe, A ; Ottevanger, P B ; Thijs, A M J ; Bekkers, R L M

BACKGROUNDThe RAS/RAF/MEK/ERK (MAPK) pathway plays a role in ovarian carcinogenesis. Low-grade serous ovarian carcinoma (LGSOC) frequently harbors activating MAPK mutations. MAPK inhibitors have been used in small subsets of ovarian carcinoma (OC) patients to control tumor growth. Therefore, we performed a meta-analysis to evaluate the effectiveness of MAPK inhibitors in OC patients. We aimed to determine the clinical benefit rate (CBR), the subgroup of MAPK inhibitors with the best CBR and overall response rate (ORR), and the most common adverse events.METHODSWe conducted a search in PubMed, Embase via Ovid, the Cochrane library and clinicaltrials.gov on studies evaluating the efficacy of single MAPK pathway inhibition with MAPK pathway inhibitors in OC patients. Our primary outcome included the CBR, defined by the proportion of patients with stable disease (SD), complete (CR) and partial response (PR). Secondary outcomes included the ORR (including PR and CR) and grade 3 and 4 adverse events. Meta-analysis was performed using a random-effects model.RESULTSWe included nine studies with a total of 319 OC patients, for which we determined a pooled CBR of 63% (95%-CI 39-84%, I² = 92%). Combined treatment with Raf- and MEK inhibitors in in BRAF^v600 mutated LGSOC (n = 6) had the greatest efficacy with a CBR of 100% and ORR of 83%. MEK inhibitors had the best efficacy as a single agent. Subgroup analysis by tumor histology demonstrated a significantly higher CBR and ORR in patients with LGSOC, with a pooled CBR and ORR of 87% (95%-CI 81-92%, I² = 0%) and 27% (95%-CI 10-48%, I² = 77%) respectively. Adverse events of grade 3 or higher were reported frequently: 123 in 167 patients.CONCLUSIONSMEK inhibitors are the most promising single agents in (LGS)OC. However, dual MAPK pathway inhibition should be considered in patients with a BRAF^v600 mutation, or non-mutated OC with depleted treatment options due indications of higher efficacy and tolerable toxicity profiles.