CTNI-38. 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 The poor prognosis of patients affected by glioblastoma (GBM) prompts the search for more effective therapies, particularly for GBMs with unmethylated MGMT. Drug repurposing, can represent a safe and inexpensive way to bring novel pharmacological approaches from bench to bedside. Chlorpromazine, a medication in use for 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, induced polyploidy, reduced cloning efficiency as well as neurosphere formation. Moreover, chlorpromazine synergized with temozolomide, in reducing cell viability and cooperated in reducing cloning efficiency and inducing cell death. 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 PD or death due to any cause. Between April 2020 and June 2022, 45 patients who met the eligibility requirements were screened. Forty-one patients received at least one cycle of treatment and were included in the analysis. 43 patients have been enrolled, 29 male, 12 female. 20 patients completed 6 cycles of treatment, without relevant toxicity. The results show a median PFS of 8 months (St.Dev. 5,7) and a median OS of 15 months (St.Dev. 6,9). The addition of Chlorpromazine to temozolomide was well tolerated in newly diagnosed Glioblastoma unmethylated patients, with promising impact on outcome measures.