Repurposing Chlorpromazine in the Treatment of Glioblastoma

Glioblastoma Multiforme Clinical Trial

— RACTAC  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04224441
• Other study ID #: 2019-001988-75
• Status: Recruiting
• Phase: Phase 2
• Start date: December 15, 2019
• Est. completion date: December 15, 2022

Study information

• Verified date: January 2020
• Source: Regina Elena Cancer Institute
• Contact: Andrea Pace, MD
• Phone: +39 06 52666975
• Email: andrea.pace[@]ifo.gov.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 41
• Est. completion date: December 15, 2022
• Est. primary completion date: June 15, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

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.

Related Conditions & MeSH terms

• Glioblastoma
• Glioblastoma Multiforme
• MGMT-Unmethylated Glioblastoma

Intervention

Drug:
• Chlorpromazine Pill
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

Locations

Country	Name	City	State
Italy	Carlo Besta Neurological Institute	Milano	Lombardia
Italy	Istituto Oncologico Veneto	Padova	Veneto
Italy	Regina Elena Cancer Institute	Roma	Lazio

Sponsors (4)

Lead Sponsor	Collaborator
Marco G Paggi, MD, PhD	Carlo Besta Neurological Institute, Istituto Oncologico Veneto IRCCS, Regina Elena Cancer Institute

Country where clinical trial is conducted

Italy, 

References & Publications (10)

Barygin OI, Nagaeva EI, Tikhonov DB, Belinskaya DA, Vanchakova NP, Shestakova NN. Inhibition of the NMDA and AMPA receptor channels by antidepressants and antipsychotics. Brain Res. 2017 Apr 1;1660:58-66. doi: 10.1016/j.brainres.2017.01.028. Epub 2017 Feb 3. — View Citation

Caragher SP, Shireman JM, Huang M, Miska J, Atashi F, Baisiwala S, Hong Park C, Saathoff MR, Warnke L, Xiao T, Lesniak MS, James CD, Meltzer H, Tryba AK, Ahmed AU. Activation of Dopamine Receptor 2 Prompts Transcriptomic and Metabolic Plasticity in Glioblastoma. J Neurosci. 2019 Mar 13;39(11):1982-1993. doi: 10.1523/JNEUROSCI.1589-18.2018. Epub 2019 Jan 16. — View Citation

Cohen BM, Lipinski JF. In vivo potencies of antipsychotic drugs in blocking alpha 1 noradrenergic and dopamine D2 receptors: implications for drug mechanisms of action. Life Sci. 1986 Dec 29;39(26):2571-80. — View Citation

Lee MS, Johansen L, Zhang Y, Wilson A, Keegan M, Avery W, Elliott P, Borisy AA, Keith CT. The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action. Cancer Res. 2007 Dec 1;67(23):11359-67. — View Citation

Nordenberg J, Fenig E, Landau M, Weizman R, Weizman A. Effects of psychotropic drugs on cell proliferation and differentiation. Biochem Pharmacol. 1999 Oct 15;58(8):1229-36. — View Citation

Pinheiro T, Otrocka M, Seashore-Ludlow B, Rraklli V, Holmberg J, Forsberg-Nilsson K, Simon A, Kirkham M. A chemical screen identifies trifluoperazine as an inhibitor of glioblastoma growth. Biochem Biophys Res Commun. 2017 Dec 16;494(3-4):477-483. doi: 10.1016/j.bbrc.2017.10.106. Epub 2017 Oct 21. — View Citation

Shin SY, Lee KS, Choi YK, Lim HJ, Lee HG, Lim Y, Lee YH. The antipsychotic agent chlorpromazine induces autophagic cell death by inhibiting the Akt/mTOR pathway in human U-87MG glioma cells. Carcinogenesis. 2013 Sep;34(9):2080-9. doi: 10.1093/carcin/bgt169. Epub 2013 May 20. — View Citation

Venkataramani V, Tanev DI, Strahle C, Studier-Fischer A, Fankhauser L, Kessler T, Körber C, Kardorff M, Ratliff M, Xie R, Horstmann H, Messer M, Paik SP, Knabbe J, Sahm F, Kurz FT, Acikgöz AA, Herrmannsdörfer F, Agarwal A, Bergles DE, Chalmers A, Miletic H, Turcan S, Mawrin C, Hänggi D, Liu HK, Wick W, Winkler F, Kuner T. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature. 2019 Sep;573(7775):532-538. doi: 10.1038/s41586-019-1564-x. Epub 2019 Sep 18. — View Citation

Venkatesh HS, Morishita W, Geraghty AC, Silverbush D, Gillespie SM, Arzt M, Tam LT, Espenel C, Ponnuswami A, Ni L, Woo PJ, Taylor KR, Agarwal A, Regev A, Brang D, Vogel H, Hervey-Jumper S, Bergles DE, Suvà ML, Malenka RC, Monje M. Electrical and synaptic integration of glioma into neural circuits. Nature. 2019 Sep;573(7775):539-545. doi: 10.1038/s41586-019-1563-y. Epub 2019 Sep 18. — View Citation

Zeng Q, Michael IP, Zhang P, Saghafinia S, Knott G, Jiao W, McCabe BD, Galván JA, Robinson HPC, Zlobec I, Ciriello G, Hanahan D. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature. 2019 Sep;573(7775):526-531. doi: 10.1038/s41586-019-1576-6. Epub 2019 Sep 18. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Progression-free survival (PFS)	Effect of of adding CPZ to the standard GBM therapy, when compared with the standard therapy alone	6 months
Secondary	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
Secondary	Overall survival (OS)	Effect of of adding CPZ to the standard glioblastoma multiforme (GBM) therapy, when compared with the standard therapy alone	6 months