Glutamate Inhibitors in Glioblastoma

Studien-Informationen Einschlusskriterien Studien-Rationale Studien-Arme Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT05664464

Studienbeginn:
Januar 2023

Letztes Update:
24.03.2023

Wirkstoff:
Gabapentin, Sulfasalazine, Memantine, Temozolomide

Indikation (Clinical Trials):
Glioblastoma

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
-

Sponsor:
University of Zurich

Collaborator:
Swiss National Science Foundation

Studienleiter

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

Kontakt

Hans-Georg Wirsching, MD
Kontakt:
Phone: +41432532928
E-Mail: hans-georg.wirsching@usz.ch» Kontaktdaten anzeigen

Michael Weller, MD
Kontakt:
Phone: +41442555513
E-Mail: michael.weller@usz.ch» Kontaktdaten anzeigen

Studienlocations
(1 von 1)

University Hospital Zurich
8090 Zürich
SwitzerlandRekrutierend» Google-Maps
Ansprechpartner:
Hans-Georg Wirsching, MD
Phone: 044255500
E-Mail: hans-georg.wirsching@usz.ch» Ansprechpartner anzeigen

Studien-Informationen

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.

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

1. PFS-6 (Time Frame - 6 months):
progression-free survival at 6 months

Secondary outcome:

1. 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

2. 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

3. OS-12 (Time Frame - 12 months):
overall survival at 12 months

4. 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

5. SFS-6 (Time Frame - 6 months):
Seizure-free survival at 6 months

6. 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)

7. 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

8. 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

9. 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

Studien-Arme

Active Comparator: Standard of care
Radiotherapy 30 x 2 Gy with concomitant temozolomide followed by maintenance 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

Geprüfte Regime

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

Quelle: ClinicalTrials.gov

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