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

Background Glioblastoma (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. Methods With these assumptions, we started a multicenter phase II clinical trial on newly diagnosed GBM patients carrying hypo-/un-methylated MGMT gene 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) Results The RACTAC schedule showed an overall clinical benefit in GBM patients carrying hypo-/un-methylated MGMT gene 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. Conclusions This 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. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial EudraCT # 2019-001988-75; ClinicalTrials.gov Identifier: [NCT04224441][1] ### Clinical Protocols ### Funding Statement Work partially financed by Funds Ricerca Corrente 2018-2019, 2020-2021, 2022-2023 from Italian Ministry of Health (MGP) and by the European Union, Next Generation EU, PNRR M4C2, Investment 1.3 via MUR (MGP). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study has been approved by the Institutional Ethics Committee (Comitato Etico Centrale IRCCS - Sezione IFO-Fondazione Bietti, Rome, Italy) on September 6, 2019 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04224441&atom=%2Fmedrxiv%2Fearly%2F2023%2F02%2F24%2F2023.02.21.23286088.atom