Glutamate Inhibitors in Glioblastoma

NCT05664464 | Recruiting Phase 1 DMC

• 1 other identifier: 2022-01877
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this 1:1 randomized, multi-center, open-label phase Ib/II clinical trial is to explore the efficacy of the add-on of the anti-glutamatergic drugs gabapentin, sulfasalazine and memantine to standard chemoradiotherapy with temozolomide compared to chemoradiotherapy alone in patients with newly diagnosed glioblastoma.

Conditions

Glioblastoma

Keywords

IDH wild-type; newly diagnosed; glutamate; epilepsy

Outcome Measures

Primary Outcomes (1)

• PFS-6

  progression-free survival at 6 months

  6 months

Secondary Outcomes (9)

• PFS

  From date of randomization until the date of first documented tumor progression or date of death from any cause, whichever came first, assessed for a minimum of 6 months and up to 42 months

• OS

  From date of randomization until the date of death from any cause, assessed for at least 6 months and up to 42 months

• OS-12

  12 months

• SFS

  From date of randomization until the date of first documented seizure or date of death from any cause, whichever came first, assessed for a minimum of 6 months and up to 42 months

• SFS-6

  6 months

Other Outcomes (6)

• Overall response rate

  From date of randomization until the date of first documented tumor progression or date of death from any cause, whichever came first, assessed for a minimum of 6 months and up to 42 months

• Tumor glutamate levels

  From date of randomization until the date of first documented tumor progression or date of death from any cause, whichever came first, assessed for a minimum of 6 months and up to 42 months

• General condition

  From date of randomization until the date of first documented tumor progression or date of death from any cause, whichever came first, assessed for a minimum of 6 months and up to 42 months

Study Arms (2)

Standard of care

ACTIVE COMPARATOR

Radiotherapy 30 x 2 Gy with concomitant temozolomide followed by maintenance temozolomide

Drug: Temozolomide; Radiation: Radiotherapy

Standard of care plus glutamate signaling inhibitors

EXPERIMENTAL

Radiotherapy 30 x 2 Gy with concomitant temozolomide followed by maintenance temozolomide plus combined daily gabapentin, sulfasalazine and memantine

Drug: Gabapentin; Drug: Sulfasalazine; Drug: Memantine; Drug: Temozolomide; Radiation: Radiotherapy

Interventions

Gabapentin DRUG

Weekly dose escalations over 4 weeks of daily 3 x 300 mg up to 3 x 1200 mg

Standard of care plus glutamate signaling inhibitors

Sulfasalazine DRUG

Weekly dose escalations over 3 weeks of daily 3 x 500 mg up to 3 x 1500 mg

Standard of care plus glutamate signaling inhibitors

Memantine DRUG

Weekly dose escalations over 4 weeks of daily 1 x 5-20 mg

Standard of care plus glutamate signaling inhibitors

Temozolomide DRUG

Concomitant with radiotherapy at 75 mg/m2 daily followed by maintenance 150-200 mg/m2 on 5/28 days

Standard of care; Standard of care plus glutamate signaling inhibitors

Radiotherapy RADIATION

30 x 2 Gy involved field radiotherapy with concomitant temozolomide

Standard of care; Standard of care plus glutamate signaling inhibitors

Eligibility Criteria

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

You may qualify if:

• Diagnosis: Newly diagnosed supratentorial glioblastoma according to the 2021 World Health Organization (WHO) Classification of Central Nervous System Tumors
• Signed informed consent
• Age \>18 years
• Eligible for standard chemoradiotherapy with temozolomide (TMZ/RT-\>TMZ, hypofractionated RT regimen not allowed)
• KPS 70 or more
• Ability to judge per local investigator estimate (at least oriented to time, place and situation)
• Paraffin-embedded tissue for central pathology review
• Adequate heamatological, liver and renal function

You may not qualify if:

• Scheduled for hypofractionated radiotherapy
• Women who are pregnant or breast feeding,
• Intention to become pregnant during the course of the study or intention to father a child,
• Lack of safe contraception, defined as: Female participants of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases. Female participants who are surgically sterilised / hysterectomised or post-menopausal for longer than 2 years are not considered as being of child bearing potential.
• Other clinically significant concomitant disease states (e.g., renal failure, hepatic dysfunction, cardiovascular disease),
• Known or suspected non-compliance, drug or alcohol abuse,
• Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant,
• Participation in another study with investigational drug within the 30 days preceding and during the present study,
• Previous enrolment into the current study,
• Being an investigator, his/her family members, employees and other dependent persons,
• Any prior radiotherapy of the brain or radiotherapy with potential overlap of the irradiation fields,
• Active malignancy that may interfere with the study treatment,
• Abnormal ECG with QTc \>450 ms,
• Contraindication for Gadolinium-enhanced MRI,
• Previous intolerance reactions to one of the study drugs,

Sponsors & Collaborators

• University of Zurich: lead
• Swiss National Science Foundation: collaborator

Study Sites (1)

University Hospital Zurich

Zurich, Canton of Zurich, 8090, Switzerland

RECRUITING

Related Publications (1)

• Mastall M, Roth P, Bink A, Fischer Maranta A, Laubli H, Hottinger AF, Hundsberger T, Migliorini D, Ochsenbein A, Seystahl K, Imbach L, Hortobagyi T, Held L, Weller M, Wirsching HG. A phase Ib/II randomized, open-label drug repurposing trial of glutamate signaling inhibitors in combination with chemoradiotherapy in patients with newly diagnosed glioblastoma: the GLUGLIO trial protocol. BMC Cancer. 2024 Jan 15;24(1):82. doi: 10.1186/s12885-023-11797-z.

  PMID: 38225589 BACKGROUND

Related Links

• Related Info

MeSH Terms

Conditions

Glioblastoma; Epilepsy

Interventions

Gabapentin; Sulfasalazine; Memantine; Temozolomide; Radiotherapy

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; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Amines; Organic Chemicals; gamma-Aminobutyric Acid; Aminobutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Cyclohexanecarboxylic Acids; Acids, Carbocyclic; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Amino Acids; Amino Acids, Peptides, and Proteins; Sulfonamides; Amides; Sulfones; Sulfur Compounds; Amantadine; Adamantane; Bridged-Ring Compounds; Dacarbazine; Triazenes; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics

Study Officials

• Hans-Georg Wirsching, MD

  University Hospital and University of Zurich

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Hans-Georg Wirsching, MD

CONTACT

+41432532928; hans-georg.wirsching@usz.ch

Michael Weller, MD

CONTACT

+41442555513; michael.weller@usz.ch

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 7, 2022
• First Posted: December 23, 2022
• Study Start: January 1, 2023
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: May 10, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1)