Glutamate Inhibitors in Glioblastoma (GLUGLIO)

May 8, 2024 updated by: University of Zurich

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 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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

120

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Standard of care
Radiotherapy 30 x 2 Gy with concomitant temozolomide followed by maintenance temozolomide
Drug: Temozolomide
Concomitant with radiotherapy at 75 mg/m2 daily followed by maintenance 150-200 mg/m2 on 5/28 days
Radiation: Radiotherapy
30 x 2 Gy involved field radiotherapy with concomitant temozolomide
Experimental: Standard of care plus glutamate signaling inhibitors
Radiotherapy 30 x 2 Gy with concomitant temozolomide followed by maintenance temozolomide plus combined daily gabapentin, sulfasalazine and memantine
Drug: Temozolomide
Concomitant with radiotherapy at 75 mg/m2 daily followed by maintenance 150-200 mg/m2 on 5/28 days
Radiation: Radiotherapy
30 x 2 Gy involved field radiotherapy with concomitant temozolomide
Drug: Gabapentin
Weekly dose escalations over 4 weeks of daily 3 x 300 mg up to 3 x 1200 mg
Drug: Sulfasalazine
Weekly dose escalations over 3 weeks of daily 3 x 500 mg up to 3 x 1500 mg
Drug: Memantine
Weekly dose escalations over 4 weeks of daily 1 x 5-20 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
PFS-6
Time Frame: 6 months
progression-free survival at 6 months
6 months

Secondary Outcome Measures

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

Outcome Measure
Measure Description
Time Frame
Overall response rate
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
as defined by RANO
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
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
determined by MRI spectroscopy
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
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
Karnofsky Performance Status (KPS)
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
Anticonvulsant drug use and steroid use
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
Documentation of drug name, dose, frequency and duration of intake
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
Subgroup survival analyses
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
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
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
Subgroup survival analyses
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
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
From date of randomization until the date of death from any cause, assessed for at least 6 months and up to 42 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Zurich

Collaborators

Swiss National Science Foundation

Investigators

  • Principal Investigator: Hans-Georg Wirsching, MD, University Hospital and University of Zurich

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2023

Primary Completion (Estimated)

June 1, 2026

Study Completion (Estimated)

December 1, 2026

Study Registration Dates

First Submitted

December 7, 2022

First Submitted That Met QC Criteria

December 15, 2022

First Posted (Actual)

December 23, 2022

Study Record Updates

Last Update Posted (Actual)

May 10, 2024

Last Update Submitted That Met QC Criteria

May 8, 2024

Last Verified

May 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2022-01877

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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