Artikel
Interim results from a proof-of-concept clinical trial assessing the safety of the coordinated undermining of survival paths by 9 repurposed drugs (version 3) combined with metronomic temozolomide (CUSP9v3) protocol for recurrent glioblastoma
Interim-Ergebnisse einer proof-of-concept Studie (NCT02770378) zur Verträglichkeitsuntersuchung der koordinierten Unterbindung von Tumorstoffwechselwegen durch 9 umgenutzte Medikamente (Version 3) kombiniert mit metronomischen Temozolomid (CUSP9v3) zur Behandlung des Glioblastomrezidivs
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Autoren
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Marc-Eric Halatsch
- Uniklinik Ulm, Neurochirurgie, Ulm, Deutschland
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Richard Eric Kast
- IIAIGC Study Center, Burlington, VT, United States
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Georg Karpel-Massler
- Uniklinik Ulm, Neurochirurgie, Ulm, Deutschland
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Bernd Schmitz
- Uniklinik Ulm, Abteilung für Diagnostische und Interventionelle Radiologie, Ulm, Deutschland
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Oliver Zolk
- Universität Ulm, Klinische Pharmakologie, Ulm, Deutschland
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Lars Bullinger
- Charité Berlin, Internistische Onkologie, Berlin, Deutschland
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Regine Mayer-Steinacker
- Uniklinik Ulm, Innere Medizin III, Ulm, Deutschland
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Ludwig Maier
- Uniklinik Ulm, Zentralapotheke, Ulm, Deutschland
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Angelika Scheuerle
- Uniklinik Ulm, Neuropathologie, Ulm, Deutschland
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Benedikt Mayer
- Universität Ulm, Epidemiologie, Ulm, Deutschland
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Christopher Schmidt
- Uniklinik Ulm, Neurochirurgie, Ulm, Deutschland
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Katharina Zeiler
- Uniklinik Ulm, Neurochirurgie, Ulm, Deutschland
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Ziad Elshaer
- Uniklinik Ulm, Neurochirurgie, Ulm, Deutschland
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Fadi Awad
- Uniklinik Ulm, Neurochirurgie, Ulm, Deutschland
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Patricia Panther
- Uniklinik Ulm, Neurochirurgie, Ulm, Deutschland
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Birgit Schmelzle
- Uniklinik Ulm, Neurochirurgie, Ulm, Deutschland
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Kristine Beckers
- Anticancer Fund, Brüssel, Belgium
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Markus David Siegelin
- Columbia University, Pathology, New York, NY, United States
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Mike-Andrew Westhoff
- Uniklinik Ulm, Pädiatrie, Ulm, Deutschland
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Christian Rainer Wirtz
- Uniklinik Ulm, Neurochirurgie, Ulm, Deutschland
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Gauthier Bouche
- Anticancer Fund, Brüssel, Belgium
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Tim Heiland
- Uniklinik Ulm, Neurochirurgie, Ulm, Deutschland
| Veröffentlicht: | 8. Mai 2019 |
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Gliederung
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Objective: Despite refinements of neurosurgical techniques and emerging adjuvant therapies, patients with recurrent glioblastoma continue to face a dismal prognosis. We report interim results of a prospective clinical trial (NCT02770378) evaluating a protocol of 9 repurposed drugs (aprepitant, minocyclin, disulfiram, celecoxib, sertraline, captopril, itraconazole, ritonavir, auranofin) and low-dose metronomic temozolomide in patients with recurrent or progressive glioblastoma.
Methods: Between November 2016 and October 2018, 10 patients (age ≥ 18, KPS ≥ 70%) with glioblastoma recurrence or progression during or after standard therapy were included in the CUSP9v3 single-arm proof-of-concept clinical trial. The primary endpoint was dose-limiting toxicity during the first 12 weeks of treatment. Secondary endpoints were overall survival and best tumor response during the 12-month medication period according to RANO criteria.
Results: Fifty-five cycles of CUSP9v3 were administered. Median follow-up was 9.2 months (1.9–24 months) on October 31st, 2018. No drug-related serious adverse events were observed. In two patients, a permanent dose reduction (-50% of the daily dose) was instituted for one drug (ritonavir). For eight patients, a temporary dose reduction for one to three drugs (including aprepitant, auranofin, captopril, ritonavir and/or temozolomide) was necessary so far. Five patients showed partial response or stable disease. Progression was observed in five patients, two of which died during the first 6 weeks after study entry. Three additional patients died from tumor progression after completing three, five and seven treatment cycles, respectively.
Conclusion: With close ambulatory monitoring and drug schedule adaptations according to individual side effects, CUSP9v3 appears to be a safe protocol with adverse effects comparable to those of more established second- and third-line treatments. Assessment of efficiency is preliminary but suggests notable antitumor activity. The six-month progression-free survival in this ongoing study of recurrent glioblastoma is 50%.
