Study Results
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Basic Information
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RECRUITING
PHASE1/PHASE2
120 participants
INTERVENTIONAL
2023-01-01
2026-12-31
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Standard of care
Radiotherapy 30 x 2 Gy with concomitant temozolomide followed by maintenance temozolomide
Temozolomide
Concomitant with radiotherapy at 75 mg/m2 daily followed by maintenance 150-200 mg/m2 on 5/28 days
Radiotherapy
30 x 2 Gy involved field radiotherapy with concomitant temozolomide
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
Gabapentin
Weekly dose escalations over 4 weeks of daily 3 x 300 mg up to 3 x 1200 mg
Sulfasalazine
Weekly dose escalations over 3 weeks of daily 3 x 500 mg up to 3 x 1500 mg
Memantine
Weekly dose escalations over 4 weeks of daily 1 x 5-20 mg
Temozolomide
Concomitant with radiotherapy at 75 mg/m2 daily followed by maintenance 150-200 mg/m2 on 5/28 days
Radiotherapy
30 x 2 Gy involved field radiotherapy with concomitant temozolomide
Interventions
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Gabapentin
Weekly dose escalations over 4 weeks of daily 3 x 300 mg up to 3 x 1200 mg
Sulfasalazine
Weekly dose escalations over 3 weeks of daily 3 x 500 mg up to 3 x 1500 mg
Memantine
Weekly dose escalations over 4 weeks of daily 1 x 5-20 mg
Temozolomide
Concomitant with radiotherapy at 75 mg/m2 daily followed by maintenance 150-200 mg/m2 on 5/28 days
Radiotherapy
30 x 2 Gy involved field radiotherapy with concomitant temozolomide
Eligibility Criteria
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Inclusion Criteria
* 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
* 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.
18 Years
ALL
No
Sponsors
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Swiss National Science Foundation
OTHER
University of Zurich
OTHER
Responsible Party
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Principal Investigators
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Hans-Georg Wirsching, MD
Role: PRINCIPAL_INVESTIGATOR
University Hospital and University of Zurich
Locations
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University Hospital Zurich
Zurich, Canton of Zurich, Switzerland
Countries
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Central Contacts
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Facility Contacts
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References
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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.
Related Links
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Other Identifiers
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2022-01877
Identifier Type: -
Identifier Source: org_study_id
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