search
Back to results

Glutamate Inhibitors in Glioblastoma (GLUGLIO)

Primary Purpose

Glioblastoma

Status
Recruiting
Phase
Phase 1
Locations
Switzerland
Study Type
Interventional
Intervention
Gabapentin
Sulfasalazine
Memantine
Temozolomide
Radiotherapy
Sponsored by
University of Zurich
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma focused on measuring IDH wild-type, newly diagnosed, glutamate, epilepsy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria 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 Exclusion criteria 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, Intolerance reactions to sulfonamides or salicylates, Acute intermittend porphyria, Known glucose-6-phosphate dehydrogenase deficiency, Concomitant therapy with digoxin, cyclosporin, methotrexate, History of exfoliative dermatitis, Stevens-Johnson-Syndrome, toxic epidermal necrolysis, DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome or renal tubular acidosis.

Sites / Locations

  • University Hospital ZurichRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Standard of care

Standard of care plus glutamate signaling inhibitors

Arm Description

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

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

Outcomes

Primary Outcome Measures

PFS-6
progression-free survival at 6 months

Secondary Outcome Measures

PFS
progression-free survival
OS
overall survival
OS-12
overall survival at 12 months
SFS
Seizure-free survival
SFS-6
Seizure-free survival at 6 months
QoL
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Brain Tumor Module BN20 (EORTC QLQ-C30/BN20)
Symptom burden
MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) questionnaire, Neurologic assessment in neuro-oncology (NANO) scale
Quality of life of an informal caregiver
CareGiver Oncology Quality of Life (CarGO-QOL) questionnaire
Cognitive Functioning
Montreal Cognitive Assessment (MoCA) test

Full Information

First Posted
December 7, 2022
Last Updated
March 21, 2023
Sponsor
University of Zurich
Collaborators
Swiss National Science Foundation
search

1. Study Identification

Unique Protocol Identification Number
NCT05664464
Brief Title
Glutamate Inhibitors in Glioblastoma
Acronym
GLUGLIO
Official Title
A Phase Ib/II Randomized, Open Label Drug Repurposing Trial of Glutamate Signaling Inhibitors in Combination With Chemoradiotherapy in Patients With Newly Diagnosed Glioblastoma
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 1, 2023 (Actual)
Primary Completion Date
June 2026 (Anticipated)
Study Completion Date
December 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Zurich
Collaborators
Swiss National Science Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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.
Detailed Description
Background: Glioblastoma is the most common and the most aggressive primary malignant brain tumor in adults. The clinical course of glioblastoma is invariably fatal despite multimodal therapy comprising surgical resection followed by chemoradiotherapy. Population-based median overall survival is in the range of only 12 months. Glioblastomas synthesize and secrete large quantities of the excitatory neurotransmitter glutamate, driving epilepsy, neuronal death, tumor growth and invasion. Rationale: Several brain-penetrating drugs that have obtained clinical approval in other contexts can inhibit glutamate synthesis, secretion and signalling, including (i) the anti-epileptic drug gabapentin, which is a potent inhibitor of the critical glutamate synthesis enzyme branched chain amino acid transaminase 1 (BCAT-1), (ii) the anti-inflammatory drug sulfasalazine, which is a potent inhibitor of glutamate secretion by blocking the cystine-glutamate exchanger system Xc, and (iii) the cognitive enhancer memantine, which can prevent glutamate-driven, calcium-induced neuronal death and tumor cell invasion by blocking N-methyl-D-aspartate (NMDA) type glutamate receptors. The omnipresence and pleiotropic functions of glutamate in glioblastoma lends rationale for a combined anti-glutamatergic therapeutic approach. The well-documented tolerability of these drugs support the feasibility of a repurposing approach in combination with standard chemoradiotherapy. There is limited commercial interest in exploring the activity of these drugs as anti-cancer agents. Aim: The aim of the herein proposed clinical trial is to explore the tolerability and efficacy of combined anti-glutamatergic treatment as an add-on to standard chemoradiotherapy in newly diagnosed glioblastoma. The trial is designed to explore the efficacy of a triple anti-glutamatergic treatment regimen to justify and statistically plan a subsequent phase III expansion trial. Methodology: This randomized phase Ib/II, parallel-group, open-label, multicenter trial will be conducted in 120 adult patients with newly diagnosed glioblastoma. Any study treatments will be administered orally in combination with standard chemoradiotherapy and will be continued until tumor progression. The trial design comprises a per-patient dose-escalation approach in the experimental arm, i.e. doses of the study drugs will be increased weekly to pre-specified maximum dose levels and will be reduced if toxicities attributed to either study drug occur. The primary endpoint is progression-free survival at 6 months (PFS-6) and will be analysed by intent-to-treat. After the first 20 events in the experimental study arm, an interim toxicity analysis will be performed to evaluate study discontinuation and maximum target dose level adaptions. Secondary endpoints include estimates of median PFS and overall survival (OS), OS at 12 months, seizure-free survival (SFS) and SFS-6. Secondary objectives include the central review of neuropathological diagnoses, central response assessment on magnetic resonance imaging scans (MRI) utilizing the Response Assessment in Neuro-Oncology (RANO) working group criteria, determination of quality of life of patients and their care givers, symptom burden, cognitive functioning, anti-epileptic drug use, steroid use and exploratory analyses of outcome among molecular glioblastoma subtypes determined by methylome and gene panel sequencing.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma
Keywords
IDH wild-type, newly diagnosed, glutamate, epilepsy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Standard of care
Arm Type
Active Comparator
Arm Description
Radiotherapy 30 x 2 Gy with concomitant temozolomide followed by maintenance temozolomide
Arm Title
Standard of care plus glutamate signaling inhibitors
Arm Type
Experimental
Arm Description
Radiotherapy 30 x 2 Gy with concomitant temozolomide followed by maintenance temozolomide plus combined daily gabapentin, sulfasalazine and memantine
Intervention Type
Drug
Intervention Name(s)
Gabapentin
Intervention Description
Weekly dose escalations over 4 weeks of daily 3 x 300 mg up to 3 x 1200 mg
Intervention Type
Drug
Intervention Name(s)
Sulfasalazine
Intervention Description
Weekly dose escalations over 3 weeks of daily 3 x 500 mg up to 3 x 1500 mg
Intervention Type
Drug
Intervention Name(s)
Memantine
Intervention Description
Weekly dose escalations over 4 weeks of daily 1 x 5-20 mg
Intervention Type
Drug
Intervention Name(s)
Temozolomide
Intervention Description
Concomitant with radiotherapy at 75 mg/m2 daily followed by maintenance 150-200 mg/m2 on 5/28 days
Intervention Type
Radiation
Intervention Name(s)
Radiotherapy
Intervention Description
30 x 2 Gy involved field radiotherapy with concomitant temozolomide
Primary Outcome Measure Information:
Title
PFS-6
Description
progression-free survival at 6 months
Time Frame
6 months
Secondary Outcome Measure Information:
Title
PFS
Description
progression-free survival
Time Frame
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
Title
OS
Description
overall survival
Time Frame
From date of randomization until the date of death from any cause, assessed for at least 6 months and up to 42 months
Title
OS-12
Description
overall survival at 12 months
Time Frame
12 months
Title
SFS
Description
Seizure-free survival
Time Frame
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
Title
SFS-6
Description
Seizure-free survival at 6 months
Time Frame
6 months
Title
QoL
Description
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Brain Tumor Module BN20 (EORTC QLQ-C30/BN20)
Time Frame
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
Title
Symptom burden
Description
MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) questionnaire, Neurologic assessment in neuro-oncology (NANO) scale
Time Frame
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
Title
Quality of life of an informal caregiver
Description
CareGiver Oncology Quality of Life (CarGO-QOL) questionnaire
Time Frame
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
Title
Cognitive Functioning
Description
Montreal Cognitive Assessment (MoCA) test
Time Frame
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
Other Pre-specified Outcome Measures:
Title
Overall response rate
Description
as defined by RANO
Time Frame
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
Title
Tumor glutamate levels
Description
determined by MRI spectroscopy
Time Frame
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
Title
General condition
Description
Karnofsky Performance Status (KPS)
Time Frame
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
Title
Anticonvulsant drug use and steroid use
Description
Documentation of drug name, dose, frequency and duration of intake
Time Frame
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
Title
Subgroup survival analyses
Description
PFS compared between subgroups segregated by baseline parameters including age, extent of resection, KPS, MGMT promotor methylation status, steroid intake, presence or absence of seizures, tumor volumes, glutamate levels determined by MR spectroscopy, and molecular subtypes
Time Frame
From date of randomization until the date of first documented tumor progression, or death from any cause, whatever occurs first, assessed for at least 6 months and up to 42 months
Title
Subgroup survival analyses
Description
OS compared between subgroups segregated by baseline parameters including age, extent of resection, KPS, MGMT promotor methylation status, steroid intake, presence or absence of seizures, tumor volumes, glutamate levels determined by MR spectroscopy, and molecular subtypes
Time Frame
From date of randomization until the date of death from any cause, assessed for at least 6 months and up to 42 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria 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 Exclusion criteria 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, Intolerance reactions to sulfonamides or salicylates, Acute intermittend porphyria, Known glucose-6-phosphate dehydrogenase deficiency, Concomitant therapy with digoxin, cyclosporin, methotrexate, History of exfoliative dermatitis, Stevens-Johnson-Syndrome, toxic epidermal necrolysis, DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome or renal tubular acidosis.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Hans-Georg Wirsching, MD
Phone
+41432532928
Email
hans-georg.wirsching@usz.ch
First Name & Middle Initial & Last Name or Official Title & Degree
Michael Weller, MD
Phone
+41442555513
Email
michael.weller@usz.ch
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hans-Georg Wirsching, MD
Organizational Affiliation
University Hospital and University of Zurich
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Zurich
City
Zürich
State/Province
Zurich
ZIP/Postal Code
8090
Country
Switzerland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hans-Georg Wirsching, MD
Phone
044255500
Email
hans-georg.wirsching@usz.ch

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Glutamate Inhibitors in Glioblastoma

We'll reach out to this number within 24 hrs