Marc-Eric Halatsch, Richard Kast, Georg Karpel-Massler, Benjamin Mayer, Oliver Zolk, Bernd Schmitz, Angelika Scheuerle, Ludwig Maier, Lars Bullinger, Regine Mayer-Steinacker, Carl Schmidt, Katharina Zeiler, Ziad Elshaer, Patricia Panther, Birgit Schmelzle, Anke Hallmen, Annika Dwucet, Markus D Siegelin, Mike-Andrew Westhoff, Kristine Beckers, Gauthier Bouche, Tim Heiland from the Ulm University Hospital, Ulm, Germany; the Department of Neurosurgery, Cantonal Hospital of Winterthur, CH-8401 Winterthur, Switzerland, the IIAIGC Study Center, Burlington, Vermont, USA, the IIAIGC Study Center, Burlington, Vermont, USA and the AntiCancerFund, Brussels, Belgium have just published in Neuro-Oncoly Advances a phase I trial entitled : A phase Ib/IIa trial of 9 repurposed drugs combined with temozolomide for the treatment of recurrent glioblastoma: CUSP9v3

Background In 2013, a new concept to treat patients with recurrent GBM called Coordinated Undermining of Survival Paths (CUSP) was introduced. The CUSP concept attempts to block growth-driving signaling pathways active in GBM. It takes advantage of repurposing already-marketed non-oncological drugs and and relies on their ability to inhibit one or more of the identified GBM growth and cell survival pathways. Including pharmacology, drug interaction, and safety considerations. The dismal prognosis of glioblastoma (GBM) may be related to the ability of GBM cells to develop mechanisms of treatment resistance. designed a protocol called Coordinated Undermining of Survival Paths combining 9 repurposed non-oncological drugs with metronomic temozolomide—version 3—(CUSP9v3) was designed to address this issue. The aim of this phase Ib/IIa trial was to assess the safety of CUSP9v3.

Methods Ten adults with histologically confirmed GBM and recurrent or progressive disease were included. Treatment consisted of aprepitant, auranofin, celecoxib, captopril, disulfiram, itraconazole, minocycline, ritonavir, and sertraline added to metronomic low-dose temozolomide. Treatment was continued until toxicity or progression. Primary endpoint was dose-limiting toxicity defined as either any unmanageable grade 3–4 toxicity or inability to receive at least 7 of the 10 drugs at ≥ 50% of the per-protocol doses at the end of the second treatment cycle. Results One patient was not evaluable for the primary endpoint (safety). All 9 evaluable patients met the primary endpoint. Ritonavir, temozolomide, captopril, and itraconazole were the drugs most frequently requiring dose modification or pausing. The most common adverse events were nausea, headache, fatigue, diarrhea, and ataxia. Progression-free survival at 12 months was 50%.

Conclusions CUSP9v3 can be safely administered in patients with recurrent GBM under careful monitoring. A randomized phase II trial is in preparation to assess the efficacy of the CUSP9v3 regimen in GBM.

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