Repurposing Chlorpromazine in the Treatment of Glioblastoma

NCT ID: NCT04224441

Last Updated: 2020-01-13

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.

Recruitment Status

UNKNOWN

Clinical Phase

PHASE2

Total Enrollment

41 participants

Study Classification

INTERVENTIONAL

Study Start Date

2019-12-15

Study Completion Date

2022-12-15

Brief Summary

Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.

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

Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.

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.

Conditions

See the medical conditions and disease areas that this research is targeting or investigating.

Glioblastoma Multiforme MGMT-Unmethylated Glioblastoma

Study Design

Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.

Allocation Method

NA

Intervention Model

SINGLE_GROUP

Addition of chlorpromazine to the standard GBM treatment during the adjuvant phase of the therapeutic protocol in un-methylated GBM patients
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

Review each arm or cohort in the study, along with the interventions and objectives associated with them.

Standard protocol plus chlorpromazine (CPZ)

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)

Group Type EXPERIMENTAL

Chlorpromazine Pill

Intervention Type 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

Interventions

Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.

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

Intervention Type DRUG

Other Intervention Names

Discover alternative or legacy names that may be used to describe the listed interventions across different sources.

Temozolomide

Eligibility Criteria

Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.

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

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.
Minimum Eligible Age

18 Years

Maximum Eligible Age

70 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

Meet the organizations funding or collaborating on the study and learn about their roles.

Regina Elena Cancer Institute

OTHER

Sponsor Role collaborator

Carlo Besta Neurological Institute

OTHER

Sponsor Role collaborator

Istituto Oncologico Veneto IRCCS

OTHER

Sponsor Role collaborator

Marco G Paggi, MD, PhD

OTHER

Sponsor Role lead

Responsible Party

Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.

Marco G Paggi, MD, PhD

Medical Doctor, Clinical Pharmacologist

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

Learn about the lead researchers overseeing the trial and their institutional affiliations.

Marco G Paggi, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Regina Elena Cancer Institute

Locations

Explore where the study is taking place and check the recruitment status at each participating site.

Regina Elena Cancer Institute

Rome, Lazio, Italy

Site Status RECRUITING

Carlo Besta Neurological Institute

Milan, Lombardy, Italy

Site Status RECRUITING

Istituto Oncologico Veneto

Padua, Veneto, Italy

Site Status RECRUITING

Countries

Review the countries where the study has at least one active or historical site.

Italy

Central Contacts

Reach out to these primary contacts for questions about participation or study logistics.

Andrea Pace, MD

Role: CONTACT

+39 06 52666975

Diana Giannarelli, PhD

Role: CONTACT

+39 06 52665607

Facility Contacts

Find local site contact details for specific facilities participating in the trial.

Andrea Pace, MD

Role: primary

+39 06 52666975

Diana Giannarelli, PhD

Role: backup

+39 06 52665607

Antonio Silvani, MD

Role: primary

Giuseppe Lombardi, MD

Role: primary

References

Explore related publications, articles, or registry entries linked to this study.

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. doi: 10.1016/0024-3205(86)90111-6.

Reference Type BACKGROUND
PMID: 2879204 (View on PubMed)

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. doi: 10.1016/s0006-2952(99)00156-2.

Reference Type BACKGROUND
PMID: 10487524 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 29066348 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 18056463 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 23689352 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 28167075 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 31534222 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 31534219 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 31534217 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 30651332 (View on PubMed)

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.

Reference Type DERIVED
PMID: 38162492 (View on PubMed)

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.

Reference Type DERIVED
PMID: 33718225 (View on PubMed)

Other Identifiers

Review additional registry numbers or institutional identifiers associated with this trial.

2019-001988-75

Identifier Type: -

Identifier Source: org_study_id

More Related Trials

Additional clinical trials that may be relevant based on similarity analysis.