Repurposing Chlorpromazine in the Treatment of Glioblastoma

Phase 2

• Conditions: Glioblastoma Multiforme; MGMT-Unmethylated Glioblastoma
• Interventions: Drug: Chlorpromazine Pill

• Registration Number: NCT04224441
• Lead Sponsor: Marco G Paggi, MD, PhD

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.

Study Timeline

• Study Start: 2019-12-15
• Status Verified: 2020-01
• Study First Submitted: 2020-01-07
• Study First Submitted QC: 2020-01-09
• Last Update Submitted: 2020-01-09
• Study First Posted: 2020-01-13
• Last Update Posted: 2020-01-13
• Primary Completion: 2022-06-15
• Study Completion: 2022-12-15

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 41

Inclusion Criteria

1. 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.
2. Progression-free patients after having undergone maximal safe debulking surgery when feasible or biopsy, and
3. Patients undergone completed standard concomitant chemo-radiotherapy with temozolomide
4. Patients with provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.
5. Patients (both males and females) should employ adequate contraceptive measures which should be maintained during the whole duration of the trial
6. 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:

1. 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

2. 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.

3. 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.

4. Contraindications to MRI and or magnetic resonance spectroscopy (MRS). 6. Patients not able to sign informed consent.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Standard protocol plus chlorpromazine (CPZ)	Chlorpromazine Pill	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)

Primary Outcome Measures

Name	Time	Method
Evaluation of toxicity	6 months	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
Progression-free survival (PFS)	6 months	Effect of of adding CPZ to the standard GBM therapy, when compared with the standard therapy alone

Secondary Outcome Measures

Name	Time	Method
Evaluation of tumor response	6 months	Effect of of adding CPZ to the standard glioblastoma multiforme (GBM) therapy, when compared with the standard therapy alone
Overall survival (OS)	6 months	Effect of of adding CPZ to the standard glioblastoma multiforme (GBM) therapy, when compared with the standard therapy alone

Trial Locations

Locations (3)

Regina Elena Cancer Institute; 🇮🇹 Roma, Lazio, Italy

Carlo Besta Neurological Institute; 🇮🇹 Milano, Lombardia, Italy

Istituto Oncologico Veneto; 🇮🇹 Padova, Veneto, Italy