Repurposing chlorpromazine as add-on in the adjuvant phase of first-line glioblastoma therapeutic protocol in patients carrying hypo-/un-methylatedMGMTgene promoter: RACTAC, a Phase II multicenter single-arm clinical trial

Abstract

AbstractBackgroundGlioblastoma (GBM) is a devastating brain tumor with poor prognosis, characterized by rapid growth and invasion into surrounding brain tissue. It is a hard-to-treat cancer and represents an unmet medical need. In recent years, there has been a growing interest in developing novel approaches to improve the outcomes of GBM patients; among these, drug repurposing. Our preclinical studies identified the antipsychotic chlorpromazine (CPZ) as an important modulator of signal transduction and energy metabolism in GBM cells, so we embarked on a Phase II clinical trial in which CPZ has been added to the standard disease treatment.MethodsWith these assumptions, we started a multicenter phase II clinical trial on newly diagnosed GBM patients carrying hypo-/un-methylatedMGMTgene promoter by adding CPZ to temozolomide (TMZ) in the adjuvant phase of the standard first-line therapeutic protocol RACTAC schedule). Primary endpoints: Progression-Free Survival (PFS) and Combination treatment toxicity. Secondary endpoints: Overall Survival (OS) and Quality of Life (QoL)ResultsThe RACTAC schedule showed an overall clinical benefit in GBM patients carrying hypo-/un-methylatedMGMTgene promoter. When compared with historical cohorts, these patients displayed longer PFS, with toxicity described as a dose-dependent sedation and liver toxicity, both expected. One case of severe liver toxicity has been reported. OS and QoL are still under evaluation.ConclusionsThis clinical trial confirms the anticancer properties of CPZ, as described in several preclinical studies. In addition, the RACTAC study can be considered at least as a proof-of-concept in demonstrating the effectiveness of interfering with the well-described oncogenic monoamine signaling between neurons and GBM.