P11.60.A RACTAC TRIAL: PHASE II MULTICENTRIC ITALIAN TRIAL ON REPOSITIONING OF THE ANTIPSYCHOTIC DRUG CHLORPROMAZINE AND ITS COMBINATION WITH TEMOZOLOMIDE IN MGMT UNMETHYLATED GLIOBLASTOMA PATIENTS

Abstract

Abstract BACKGROUND The poor prognosis of patients affected by glioblastoma (GBM) prompts the search for new and more effective therapies, particularly for GBMs with unmethylated MGMT. In this regard, drug repurposing, can represent a safe and inexpensive way to bring novel pharmacological approaches from bench to bedside. Chlorpromazine, a medication in use since six decades for the therapy of psychiatric disorders, shows in vitro features that make it eligible for repositioning in GBM therapy. In our experimentation on six GBM cell lines, chlorpromazine inhibited cell viability in an apoptosis-independent way, induced polyploidy, reduced cloning efficiency as well as neurosphere formation and downregulated the expression of stemness genes. Notably, we found that chlorpromazine synergized with temozolomide, in reducing cell viability and strongly cooperated in reducing cloning efficiency and inducing cell death in vitro for all the GBM cell lines assayed. MATERIAL AND METHODS With these assumptions, we started a multicentric Phase II clinical trial on newly diagnosed GBM patients with unmethylated MGMT by adding chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol. The experimental procedure involves the combination of CPZ with standard treatment with TMZ in the adjuvant phase of the Stupp protocol. CPZ was administered orally at a dose of 50 mg/day - GG 1-28 - of every cycle of the adjuvant treatment with TMZ. . Efficacy outcomes were evaluated using Kaplan-Meier methodology. OS was measured from diagnosis to death; PFS was determined from radiotherapy to the first sign of PD or death due to any cause. RESULTS The trial was closed on December 2022. 53 patients have been enrolled, 39 male, 14 female. 21 patients completed 6 cycles of treatment, without relevant toxicity.The results shows a median PFS of 7 months (St.Dev. 5,7) and a median OS of 15 months (St.Dev. 6,9). 23 patients are still alive (43%) CONCLUSION The addition of Chlorpromazine to the standard adjuvant chemotherapy with temozolomide was well tolerated in newly diagnosed Glioblastoma unmethylated patients, with promising impact on outcome measures. On the basis of the RACTAC trial RESULTS , a phase II multicentric trial evaluating Chlorpromazine added to standard treatment (RT+TMZ+adj TMZx 6 cycles plus CPZ) in newly diagnosed Glioblastoma patients is in preparation