Repurposing Chlorpromazine in the Treatment of Glioblastoma

NCT04224441 | Unknown Phase 2

• 1 other identifier: 2019-001988-75
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 3

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

Conditions

Glioblastoma Multiforme; MGMT-Unmethylated Glioblastoma

Keywords

drug repurposing; antipsychotic drugs; glioblastoma

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (2)

• Evaluation of tumor response

  6 months

• Overall survival (OS)

  6 months

Study Arms (1)

Standard protocol plus chlorpromazine (CPZ)

EXPERIMENTAL

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

Interventions

Chlorpromazine Pill DRUG

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

Also known as: Temozolomide

Standard protocol plus chlorpromazine (CPZ)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

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

Sponsors & Collaborators

• Marco G Paggi, MD, PhD: lead
• Regina Elena Cancer Institute: collaborator
• Carlo Besta Neurological Institute: collaborator
• Istituto Oncologico Veneto IRCCS: collaborator

Study Sites (3)

Regina Elena Cancer Institute

Rome, Lazio, 00144, Italy

RECRUITING

Carlo Besta Neurological Institute

Milan, Lombardy, 20133, Italy

RECRUITING

Istituto Oncologico Veneto

Padua, Veneto, 35128, Italy

RECRUITING

Related Publications (12)

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• 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. doi: 10.1158/0008-5472.CAN-07-2235.

  PMID: 18056463 BACKGROUND

• 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.

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• 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.

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• 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, Suva 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.

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• Venkataramani V, Tanev DI, Strahle C, Studier-Fischer A, Fankhauser L, Kessler T, Korber C, Kardorff M, Ratliff M, Xie R, Horstmann H, Messer M, Paik SP, Knabbe J, Sahm F, Kurz FT, Acikgoz AA, Herrmannsdorfer F, Agarwal A, Bergles DE, Chalmers A, Miletic H, Turcan S, Mawrin C, Hanggi 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.

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• Zeng Q, Michael IP, Zhang P, Saghafinia S, Knott G, Jiao W, McCabe BD, Galvan 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.

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• 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.

  PMID: 30651332 BACKGROUND

• Pace A, Lombardi G, Villani V, Benincasa D, Abbruzzese C, Cestonaro I, Corra M, Padovan M, Cerretti G, Caccese M, Silvani A, Gaviani P, Giannarelli D, Ciliberto G, Paggi MG. Efficacy and safety of chlorpromazine as an adjuvant therapy for glioblastoma in patients with unmethylated MGMT gene promoter: RACTAC, a phase II multicenter trial. Front Oncol. 2023 Dec 14;13:1320710. doi: 10.3389/fonc.2023.1320710. eCollection 2023.

  PMID: 38162492 DERIVED

• Matteoni S, Matarrese P, Ascione B, Buccarelli M, Ricci-Vitiani L, Pallini R, Villani V, Pace A, Paggi MG, Abbruzzese C. Anticancer Properties of the Antipsychotic Drug Chlorpromazine and Its Synergism With Temozolomide in Restraining Human Glioblastoma Proliferation In Vitro. Front Oncol. 2021 Feb 26;11:635472. doi: 10.3389/fonc.2021.635472. eCollection 2021.

  PMID: 33718225 DERIVED

MeSH Terms

Conditions

Glioblastoma

Interventions

Chlorpromazine; Temozolomide

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Phenothiazines; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Dacarbazine; Triazenes; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring

Study Officials

• Marco G Paggi, MD, PhD

  Regina Elena Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Andrea Pace, MD

CONTACT

+39 06 52666975; andrea.pace@ifo.gov.it

Diana Giannarelli, PhD

CONTACT

+39 06 52665607; diana.giannarelli@ifo.gov.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Medical Doctor, Clinical Pharmacologist

Model Details: Addition of chlorpromazine to the standard GBM treatment during the adjuvant phase of the therapeutic protocol in un-methylated GBM patients

Study Record Dates

• First Submitted: January 7, 2020
• First Posted: January 13, 2020
• Study Start: December 15, 2019
• Primary Completion: June 15, 2022
• Study Completion: December 15, 2022
• Last Updated: January 13, 2020

Record last verified: 2020-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, CSR
• Time Frame: Data will be available after 6 months after study completion
• Access Criteria: Upon request. A valid Uniform Resource Locator (URL) will be reported

Locations

IT (3)