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Combination of 9 repurposed drugs with low-dose chemotherapy in brain cancer

A proof-of-concept clinical trial assessing the safety of the coordinated undermining of survival paths by 9 repurposed drugs combined with metronomic temozolomide for recurrent glioblastoma (CUSP9v3).

Cancer types
Brain cancer
Trial phase


ACF donation
Estimated trial cost

Why this trial

Glioblastoma multiforme (GBM) is the most common and most aggressive type of brain tumours in humans. It is a rare cancer type, affecting 2-3 people annually per 100,000 in Europe and North America.

Currently available treatment consists of surgery, radiation, and chemotherapy using temozolomide. In general, only 15-20% of patients are still alive 5 years after first treatment. For decades, new experimental therapies have repeatedly failed to improve the outcome of patients relapsing after initial treatment of glioblastoma.

There is a clear unmet need for more and better options for these patients.

Why this intervention

In 2013, investigators Marc-Eric Halatsch and Richard Kast suggested that the repeated failures of new experimental therapies could be due to the capability of glioblastoma to escape the action of a single therapy. Glioblastoma studies have identified many mechanisms that cause the growth of tumours. Many drugs currently marketed for other indications than cancer have shown to suppress one or more of these systems, and could therefore possibly be used to suppress mechanisms involved in tumour growth. A group of researchers led by Marc-Eric Halatsch and Richard Kast performed an extensive literature search to identify drugs that could qualify.

After a thorough examination of existing scientific data, taking into account low side effect profile, good quality of life (QOL) maintenance, and adequate clinical experience with the drug in question as additional selection criteria, the researchers identified and selected 9 drugs.

The 9 drugs are, with their main mechanism of action in parentheses: Aprepitant (NK-1 Receptor inhibitor), Minocycline (tetracycline antibiotic), Auranofin (gold complex), Disulfiram (ALDH inhibitor), Ritonavir (protease inhibitor), Itraconazole (triazole antifungal agent), Captopril (ACE inhibitor), Sertraline (SSRI) and Celecoxib (COX inhibitor).

Trial design

In this monocentre ‘proof of concept’ clinical trial 10 patients were treated with the 9 drugs, administered simultaneously and together with low-dose, uninterrupted daily temozolomide.

The optimal dose of each of the 9 drugs was determined for each patient by adding the drugs one by one at a low dose, and gradually increasing the doses while carefully monitoring the side effects (induction and up-dosing cycle) while administering temozolomide daily. Thereafter, each patient was treated with the nine drugs at doses established in the induction and up-dosing cycle, in addition to temozolomide.

The objectives of this trial were to assess the safety and preliminary indication of the efficacy of the treatment plan.



After analysis of the data, it was concluded that the CUSP9v3 regimen can be safely administered in patients with recurrent GBM under careful monitoring.

  • Preliminary results confirming safety of the experimental treatment were presented at the Society for Neuro-Oncology meeting in 2018.
  • The results of the trial were published in Neuro-Oncology Advances.



  • Prof. Marc-Eric Halatsch,Ulm University Hospital, Ulm, Germany (Principal Investigator)
  • Prof. Dr. Lars Bullinger, Ulm University Hospital, Ulm, Germany (Sub Investigator)


  • Ulm University Hospital, Ulm, Germany

ACF co-funding partner:

  • Fondation Dutmala

Our role

Financial support
Protocol writing and documentation

Why we support this trial

Intervention has little or no commercial value

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Expected survival benefit

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Use in a population with high unmet needs

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ACF donation
Estimated trial cost

Questions about participation?

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Questions about this trial?

The Anticancer Fund
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More info on NCT02770378

Kast, R.E., et al. (2013). A conceptually new treatment approach for relapsed glioblastoma: coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care. Oncotarget 4(4),502–30. doi:10.18632/oncotarget.969

Kast, R.E., et al. (2014). CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide. Oncotarget, 5(18), 8052-82. doi:10.18632/oncotarget.2408

Omuro, A., et al. (2013). Glioblastoma and other malignant gliomas: a clinical review. JAMA, 310(17), 1842–50. doi:10.1001/jama.2013.280319

Stupp, R., et al. (2005). Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med, 352(10), 987– 96. doi:10.1056/NEJMoa043330

Author: Kristine Beckers (Trial Manager)

Last updated: September 2021.