Repurposing Chlorpromazine in the Treatment of Glioblastoma

Study Overview
=================
Brief Summary
-----------------
This study evaluates the addition of chlorpromazine to the first-line therapeutic protocol, i.e. maximal well-tolerated surgical resection followed by radiotherapy plus concomitant and adjuvant chemotherapy with temozolomide, in newly diagnosed glioblastoma multiforme patients carrying a hypo-methylated O6-methylguanine-DNA-methyltransferase (MGMT) gene

Detailed Description
-----------------
Chlorpromazine (CPZ, Largactil, Thorazine) is a potent antagonist of the dopamine receptor D2 (DRD2) and has been effectively and safely employed for over half a century in the treatment of psychiatric disorders. CPZ displays a series of remarkable bio-molecular effects in cancer cells, as inhibition of cell growth, nuclear aberrations, inhibition of the phosphoinositide 3-kinase/mammilian target of rapamycin (PI3K/mTOR) axis, induction of cytotoxic autophagy, inhibition of glutamate and DRD2 receptors.

Official Title
-----------------
Repurposing the Antipsychotic Drug Chlorpromazine as a Therapeutic Agent in the Combined Treatment of Newly Diagnosed Glioblastoma Multiforme

Conditions
-----------------
Glioblastoma Multiforme, MGMT-Unmethylated Glioblastoma

Intervention / Treatment
-----------------
* Drug: Chlorpromazine Pill


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Newly diagnosed histologically-confirmed supra-tentorial GBM (World Health Organization grade IV) patients. Whenever feasible, patients will undergo maximal surgical resection or debulking, although patients with inoperable glioblastomas are also eligible. Progression-free patients after having undergone maximal safe debulking surgery when feasible or biopsy, and Patients undergone completed standard concomitant chemo-radiotherapy with temozolomide Patients with provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses. Patients (both males and females) should employ adequate contraceptive measures which should be maintained during the whole duration of the trial Additional eligibility criteria include: age between 18 and 70; Karnofsky Performance Status (KPS) score of 70 or higher; adequate kidney, liver, bone marrow, and cardiac function; total serum bilirubin level and liver- function values; isocitrate dehydrogenase 1/2 (IDH1/2) mutational status; MGMT methylation status assessment. Exclusion Criteria: Patients should not enter the study if any of the following exclusion criteria apply: Treatment with any of the following: Any other chemotherapy, immunotherapy or anticancer agents within 4 weeks before enrollment in the study. Any investigational agents or study drugs from a previous clinical study within 30 days before the first dose of study treatment. MGMT methylated As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including: uncontrolled hypertension; active bleeding diatheses; active hepatitis B virus (HBV), hepatitis C virus (HCV) or HIV infection. Screening for chronic conditions is not required; inadequate bone marrow reserve or organ function, as demonstrated by laboratory parameters. 4. Judgment by the investigator that the patient should not participate to the study if the patient is unlikely to comply with study procedures, restrictions and requirements. 5. Contraindications to MRI and or magnetic resonance spectroscopy (MRS). 6. Patients not able to sign informed consent.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Addition of chlorpromazine to the standard GBM treatment during the adjuvant phase of the therapeutic protocol in un-methylated GBM patients
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Standard protocol plus chlorpromazine (CPZ)<br>Combination of chlorpromazine to the standard treatment with temozolomide in the sole adjuvant phase of the standard protocol.Chlorpromazine will be administered at a dose of 50 mg/day concomitantly with the adjuvant treatment with temozolomide (TMZ) | Drug: Chlorpromazine Pill<br>* The experimental treatment involves the combination of chlorpromazine to the standard treatment with temozolomide solely in the adjuvant phase (after radio-chemotherapy, temozolomide for 5 days every 28, at a dose of 150-200 mg/mq for 6 cycles) of the Stupp protocol. Chlorpromazine will be administered at a dose of 50 mg/day concomitantly with the adjuvant treatment with temozolomide<br>* Other names: Temozolomide;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of toxicity | Toxicity evaluation of the combined treatment. Subjects will be evaluated for symptoms and adverse effects according to the NCI-CTCAE version 5.0 grading tool | 6 months | 
| Progression-free survival (PFS) | Effect of of adding CPZ to the standard GBM therapy, when compared with the standard therapy alone | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of tumor response | Effect of of adding CPZ to the standard glioblastoma multiforme (GBM) therapy, when compared with the standard therapy alone | 6 months | 
| Overall survival (OS) | Effect of of adding CPZ to the standard glioblastoma multiforme (GBM) therapy, when compared with the standard therapy alone | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
drug repurposing, antipsychotic drugs, glioblastoma