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72. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

06.06. - 09.06.2021

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Favourable tolerability in phase 1 study of CUSP9v3 (NCT02770378) in recurrent glioblastoma

Meeting Abstract

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  • Marc-Eric Halatsch - Ulm University Hospital, Department of Neurosurgery, Ulm, Deutschland
  • presenting/speaker Richard Kast - IIAIGC Study Center, Burlington, Burlington, MA, Vereinigte Staaten
  • Georg Karpel-Massler - Ulm University Hospital, Department of Neurosurgery, Ulm, Deutschland
  • Benjamin Mayer - Ulm University Hospital, Institute for Epidemiology and Medical Biometry, Ulm, Deutschland
  • Oliver Zolk - Ulm University Hospital, Department of Clinical Pharmacology, Ulm, Deutschland
  • Bernd Schmitz - Ulm University Hospital, Division of Neuroradiology, Department of Diagnostic and Interventional Radiology, Ulm, Deutschland
  • Angelika Scheuerle - Ulm University Hospital, Division of Neuropathology, Department of Pathology, Ulm, Deutschland
  • Ludwig Maier - Ulm University Hospital, Central Pharmacy, Ulm, Deutschland
  • Lars Bullinger - Ulm University Hospital, Division of Hematology and Oncology, Department of Internal Medicine, Ulm, Deutschland
  • Regine Mayer-Steinacker - Ulm University Hospital, Division of Hematology and Oncology, Department of Internal Medicine, Ulm, Deutschland
  • Carl Schmidt - Ulm University Hospital, Department of Neurosurgery, Ulm, Deutschland
  • Katharina Zeiler - Ulm University Hospital, Department of Neurosurgery, Ulm, Deutschland
  • Ziad Elshaer - Ulm University Hospital, Department of Neurosurgery, Ulm, Deutschland
  • Patricia Panther - Ulm University Hospital, Department of Neurosurgery, Ulm, Deutschland
  • Birgit Schmelzle - Ulm University Hospital, Institute of Experimental Cancer Research, Ulm, Deutschland
  • Anke Hallmen - Ulm University Hospital, Division of Hematology and Oncology, Department of Internal Medicine, Ulm, Deutschland
  • Annika Dwucet - Ulm University Hospital, Department of Neurosurgery, Ulm, Deutschland
  • Markus David Siegelin - Columbia University Irving Medical Center, Department of Pathology and Cell Biology, New York, NY, Vereinigte Staaten
  • Mike-Andrew Westhoff - Ulm University Hospital, Department of Pediatric and Adolescent Medicine, Basic Research Division, Ulm, Deutschland
  • Kristine Beckers - Anticancer Fund, Brüssel, Belgien
  • Gauthier Bouche - Anticancer Fund, Brüssel, Belgien
  • Tim Heiland - Ulm University Hospital, Department of Neurosurgery, Ulm, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 72. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgie. sine loco [digital], 06.-09.06.2021. Düsseldorf: German Medical Science GMS Publishing House; 2021. DocP035

doi: 10.3205/21dgnc323, urn:nbn:de:0183-21dgnc3232

Veröffentlicht: 4. Juni 2021

© 2021 Halatsch et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.

Gliederung

Text

Objective: In an attempt to address the variety and ever-shifting array of growth-promoting pathways glioblastomas (GB) use to thrive and circumvent our treatment efforts, we developed a nine repurposed drug regimen, CUSP9v3, designed to be given with temozolomide at 40 mg/m2/d. When conceptualizing this study, we judged that the advantages of continuous low-dose temozolomide - low side effect burden and rarity of severe adverse events - would outweigh any advantages of higher doses. The nine repurposed drugs all have robust preclinical databases of inhibiting experimental glioma growth. In vitro work by our laboratory, independently confirmed by others, showed that the combination of these nine repurposed non-oncological drugs was quite effective in inhibiting growth of GB cells.

Methods: Prospective clinical proof-of-concept trial NCT02770378, 10 patients, one arm. All patients with recurrent GB had previous first-line treatment with neurologically safe maximal tumour resection followed by irradiation and concomitant plus adjuvant temozolomide. Diagnoses were histologically proven on initial resection. Tumour recurrence was determined by contrast-enhanced magnetic resonance imaging.

Results: Three patients have currently achieved progression-free survival (PFS) of 38, 38, and 50 months, ongoing as of this writing, which clearly exceeds previous PFS on first-line treatment in these cases. Molecular status for 6-methylguanine-DNA methyltransferase promoter hypermethylation/isocitrate dehydrogenase was positive/mutant, positive/wild-type and negative/wild-type, respectively. Among the other patients, five died in the first few months after starting CUSP9v3, and two patients remained progression-free beyond 12 months of study treatment but died from delayed tumour progression thereafter. No deaths were deemed treatment-related. The most common side effects were nausea, fatigue and headache. Drug doses were reduced as required on individual bases. There was little evidence of bone marrow toxicity, and nausea was usually evanescent. In the three long-term survivors, the median neutrophil-to-lymphocyte ratio decreased from 2.5 to 1.5 during CUSP9v3 treatment while in the group of the three shortest-term survivors, that ratio increased from 4.7 to 14.3.

Conclusion: CUSP9v3 was well-tolerated and gave signal of potential benefit requiring confirmation in a phase 2 clinical trial which is currently being prepared.