Prof. Kate DRUMMONDAustralia
Royal Melbourne Hospital/University of Melbourne
2017 to present | Director of Neurosurgery, The Royal Melbourne Hospital |
2017 to present | Professor, Department of Surgery, University of Melbourne |
Professor Kate Drummond, AM, MD, Grad Dip Theol, FRACS is Director of Neurosurgery at Royal Melbourne Hospital. Her research and clinical interests are in the biology and management of brain tumours. She is Co-Editor-in-Chief of the Journal of Clinical Neuroscience and on the Editorial Board of the Journal of Neurosurgery. She has served as Chief Examiner in Neurosurgery and Chair of the Women in Surgery Committee for the Royal Australasian College of Surgeons. She is Chair of Pangea Global Health Education. In 2019 she was awarded Member of the Order of Australia (AM) for services to medicine.
A perioperative study of Safusidenib in patients with IDH1 mutated glioma
1108 15:05-15:20
Neuro-oncology/305
James R. Whittle, Mark A. Rosenthal, Rob Tobler, Monique Topp, Sarah Cain Adam Valkovic, Montana Spiteri, Oluwaseun Fatunla, Jurgen Kriel, James Dimou, Samuel Roberts-Thomson, David McArdle, Elaine Lui, Brunda Nijagal, Sarah A. Best, Saskia Freytag, Katharine J. Drummond
Affiliations
1. Department of Medical Oncology, Peter MacCallum Cancer Centre, Australia, 3000
2. Personalised Oncology Division, WEHI, Australia, 3052
3. Department of Medical Biology, University of Melbourne, Australia, 3052
4. Department of Neurosurgery, Royal Melbourne Hospital, Australia, 3050
5. Department of Surgery, University of Melbourne, Australia, 3052
6. Department of Anatomical Pathology, Royal Melbourne Hospital, Australia, 3050
7. Department of Radiology, Royal Melbourne Hospital, Australia, 3050
8. Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia, 3010
Purpose: Phase 0 or perioperative trials provide a unique opportunity in glioma to study drug penetration, on-target effects and mechanisms of resistance. We report a perioperative trial of IDH inhibitor Safusidenib in IDH mutated glioma. Safusidenib (DS1001b/AB218), is an oral brain penetrant mutant IDH1 inhibitor with demonstrated activity in IDH1 mutated glioma.
Methodology: This single arm, open label perioperative trial assesses feasibility, pharmacokinetics and pharmacodynamics of treatment with Safusidenib (250 mg BID) for 4 weeks following surgical biopsy and prior to definitive resection of IDH1 mutated glioma not previously treated with radiation or chemotherapy. Following resection, Safusidenib continued until toxicity or progression. Extensive translational endpoints include paired whole genome transcriptome sequencing (WGTS), single nuclei RNA sequencing (snRNAseq), spatial transcriptomics and metabolomics and longitudinal sampling of blood and CSF for circulating tumor DNA.
Results: 10 patients have been enrolled (six astrocytoma, four oligodendroglioma). Mean tumor concentration of Safusidenib was 2457 ng/mL (range 957.0 – 4810) with tumour:plasma ratio 0.33. Consistent with mechanism of action tumour 2-HG reduced 86% from biopsy (mean 75.0M, range 7.8-203) to surgery (10.3M, range 2.3 – 30.8). Treatment was well tolerated. Paired tumour single cell analysis revealed transcriptional shift with increased immune infiltration post-treatment. There was reduction in heterogeneity and demethylation of target genes, consistent with a more differentiated tumour state. Patient acceptability of the study was determined using a validated Participant Experience Survey and was high.
Conclusions: We demonstrate feasibility of this novel perioperative approach for drug development in brain cancer to better understand genomic, transcriptomic and epigenetic treatment responses. Paired tumour biopsies demonstrated the metabolic and immunomodulatory mechanism of Safusidenib supporting future studies in combination.