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LOGGIC/FIREFLY-2: a phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating RAF alteration
CM. van Tilburg, LB. Kilburn, S. Perreault, R. Schmidt, AA. Azizi, O. Cruz-Martínez, M. Zápotocký, K. Scheinemann, AYNS. Meeteren, A. Sehested, E. Opocher, PH. Driever, S. Avula, DS. Ziegler, D. Capper, A. Koch, F. Sahm, J. Qiu, LP. Tsao, SC....
Language English Country England, Great Britain
Document type Randomized Controlled Trial, Multicenter Study, Clinical Trial, Phase III, Journal Article
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- MeSH
- Child MeSH
- Glioma * drug therapy genetics metabolism MeSH
- Humans MeSH
- Mitogen-Activated Protein Kinases MeSH
- Young Adult MeSH
- Mutation MeSH
- Oximes MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Proto-Oncogene Proteins B-raf MeSH
- Pyridones MeSH
- Pyrimidinones therapeutic use MeSH
- Fireflies * metabolism MeSH
- Treatment Outcome MeSH
- Animals MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Young Adult MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
BACKGROUND: Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use. METHODS: LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m2 (not to exceed 600 mg), or investigator's choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate. DISCUSSION: The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022.
Children's National Hospital Washington DC USA
CHU Sainte Justine Université de Montréal Montréal QC Canada
Clinical Cooperation Unit Pediatric Oncology German Cancer Research Center Heidelberg Germany
Day One Biopharmaceuticals Brisbane CA USA
Department of Neuro oncology Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands
Department of Neuropathology Charité Universitätsmedizin Berlin Berlin Germany
Department of Neuropathology German Cancer Research Center Heidelberg Germany
Department of Pediatrics and Adolescent Medicine Rigshospitalet Copenhagen Denmark
Department of Pediatrics McMaster Children's Hospital and McMaster University Hamilton Canada
Department of Radiology Alder Hey Children's Hospital NHS Foundation Trust Liverpool UK
Division of Oncology Hematology Children's Hospital of Eastern Switzerland St Gallen Switzerland
Division of Pediatric Glioma Research German Cancer Research Center Heidelberg Germany
DKTK Partner Site Berlin Germany
Faculty of Health Sciences and Medicine University of Lucerne Lucerne Switzerland
German Cancer Consortium Heidelberg Germany
Hopp Children's Cancer Center Heidelberg Heidelberg Germany
Institute of Biostatistics and Clinical Research Münster Germany
Kids Cancer Centre Sydney Children's Hospital Randwick NSW Australia
National Center for Tumor Diseases Heidelberg Germany
Neuro oncology Unit Pediatric Cancer Center Hospital Sant Joan de Déu Barcelona Spain
School of Clinical Medicine University of New South Wales Sydney NSW Australia
References provided by Crossref.org
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