A Phase 1/2 interventional study of Gabapentin and Sulfasalazine in Glioblastoma, sponsored by University of Zurich. Recruiting at 1 site in Switzerland. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-05-10.
Sponsored by University of Zurich · Phase 1/2, Interventional, and Treatment
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.
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.
1,921 studies on the registry are indexed under Glioblastoma; 451 are open to participants now.
This study's planned enrollment of 120 is above the median of 36 across 1,618 interventional studies indexed under Glioblastoma.
Browse Glioblastoma studies →University of Zurich is the lead sponsor of 1,030 studies on the registry; 130 are open to participants now.
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Exclusion criteria
Radiotherapy 30 x 2 Gy with concomitant temozolomide followed by maintenance temozolomide
Drug: Temozolomide · Radiation: Radiotherapy
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
Weekly dose escalations over 4 weeks of daily 3 x 300 mg up to 3 x 1200 mg
Weekly dose escalations over 3 weeks of daily 3 x 500 mg up to 3 x 1500 mg
Weekly dose escalations over 4 weeks of daily 1 x 5-20 mg
Concomitant with radiotherapy at 75 mg/m2 daily followed by maintenance 150-200 mg/m2 on 5/28 days
30 x 2 Gy involved field radiotherapy with concomitant temozolomide
PFS-6
progression-free survival at 6 months
Time frame: 6 months
PFS
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
OS
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
OS-12
overall survival at 12 months
Time frame: 12 months
SFS
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
SFS-6
Seizure-free survival at 6 months
Time frame: 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)
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
Symptom burden
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
Quality of life of an informal caregiver
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
Cognitive Functioning
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
Overall response rate
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
Tumor glutamate levels
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
General condition
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
Anticonvulsant drug use and steroid use
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
Subgroup survival analyses
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
Subgroup survival analyses
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
Plan to share: No
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