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Abstract
Background
Glioblastoma (GBM) is the most common adult malignant brain tumour, with an incidence of 5 per 100,000 per year in England. Patients with tumours showing O -methylguanine-DNA methyltransferase (MGMT) promoter methylation represent around 40% of newly diagnosed GBM. Relapse/tumour recurrence is inevitable. There is no agreed standard treatment for patients with GBM, therefore, it is aimed at delaying further tumour progression and maintaining health-related quality of life (HRQoL). Limited clinical trial data exist using cannabinoids in combination with temozolomide (TMZ) in this setting, but early phase data demonstrate prolonged overall survival compared to TMZ alone, with few additional side effects. Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray containing a blend of cannabis plant extracts, that we aim to assess for preliminary efficacy in patients with recurrent GBM.
Methods
ARISTOCRAT is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to assess cannabinoids in patients with recurrent MGMT methylated GBM who are suitable for treatment with TMZ. Patients who have relapsed ≥ 3 months after completion of initial first-line treatment will be randomised 2:1 to receive either nabiximols or placebo in combination with TMZ. The primary outcome is overall survival time defined as the time in whole days from the date of randomisation to the date of death from any cause. Secondary outcomes include overall survival at 12 months, progression-free survival time, HRQoL (using patient reported outcomes from QLQ-C30, QLQ-BN20 and EQ-5D-5L questionnaires), and adverse events.
Discussion
Patients with recurrent MGMT promoter methylated GBM represent a relatively good prognosis sub-group of patients with GBM. However, their median survival remains poor and, therefore, more effective treatments are needed. The phase II design of this trial was chosen, rather than phase III, due to the lack of data currently available on cannabinoid efficacy in this setting. A randomised, double-blind, placebo-controlled trial will ensure an unbiased robust evaluation of the treatment and will allow potential expansion of recruitment into a phase III trial should the emerging phase II results warrant this development.
Trial registration
ISRCTN: 11460478. ClinicalTrials.Gov: NCT05629702
Glioblastoma (GBM) is the most common adult malignant brain tumour, with an incidence of 5 per 100,000 per year in England. Patients with tumours showing O -methylguanine-DNA methyltransferase (MGMT) promoter methylation represent around 40% of newly diagnosed GBM. Relapse/tumour recurrence is inevitable. There is no agreed standard treatment for patients with GBM, therefore, it is aimed at delaying further tumour progression and maintaining health-related quality of life (HRQoL). Limited clinical trial data exist using cannabinoids in combination with temozolomide (TMZ) in this setting, but early phase data demonstrate prolonged overall survival compared to TMZ alone, with few additional side effects. Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray containing a blend of cannabis plant extracts, that we aim to assess for preliminary efficacy in patients with recurrent GBM.
Methods
ARISTOCRAT is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to assess cannabinoids in patients with recurrent MGMT methylated GBM who are suitable for treatment with TMZ. Patients who have relapsed ≥ 3 months after completion of initial first-line treatment will be randomised 2:1 to receive either nabiximols or placebo in combination with TMZ. The primary outcome is overall survival time defined as the time in whole days from the date of randomisation to the date of death from any cause. Secondary outcomes include overall survival at 12 months, progression-free survival time, HRQoL (using patient reported outcomes from QLQ-C30, QLQ-BN20 and EQ-5D-5L questionnaires), and adverse events.
Discussion
Patients with recurrent MGMT promoter methylated GBM represent a relatively good prognosis sub-group of patients with GBM. However, their median survival remains poor and, therefore, more effective treatments are needed. The phase II design of this trial was chosen, rather than phase III, due to the lack of data currently available on cannabinoid efficacy in this setting. A randomised, double-blind, placebo-controlled trial will ensure an unbiased robust evaluation of the treatment and will allow potential expansion of recruitment into a phase III trial should the emerging phase II results warrant this development.
Trial registration
ISRCTN: 11460478. ClinicalTrials.Gov: NCT05629702
| Original language | English |
|---|---|
| Article number | 83 |
| Number of pages | 12 |
| Journal | BMC Cancer |
| Volume | 24 |
| DOIs | |
| Publication status | Published - 15 Jan 2024 |
Bibliographical note
AcknowledgementsWe would like to thank staff from the CRCTU, University of Birmingham including Professor Colin Watts, Andy Pope, and Dr Ian Nutt for their work in developing this trial and helping integrate it within TJBM study, as well as Komal Chahal (trial coordinator), Rosie Hail (data manager), and Laura Smallbone (PPI representative).
We especially want to acknowledge the dedication and enthusiasm of Dr Louisa Jeffery throughout the setup of ARISTOCRAT. Louisa was excited to open ARISTOCRAT in her role as the trial coordinator, but very sadly passed away on 4th January 2023 before the trial opened to recruitment. We dedicate this publication to Louisa. Staff at the CRCTU are also supported by core funding grants from Cancer Research UK (C22436/A25354 & CTUQQR-Dec22/100006). This study was supported by TJBM study funded by The Brain Tumour Charity (GN-000580), Experimental Cancer Medicine Centres (ECMC) funding (Ref. 25127 & 100007) and the ECMC Network.
Funding
This is an investigator-initiated and investigator-led trial funded by The Brain Tumour Charity (GN-000705). The ARISTOCRAT trial protocol underwent full external scientific peer review by The Brain Tumour Charity as part of the grant application. Nabiximols and matched placebo will be provided free of charge by Jazz Pharmaceuticals. This trial has been adopted into the National Institute for Health Research Clinical Research Network Portfolio.
Keywords
- aristocrat
- Glioblastoma
- cannabinoids
- cannabidiol
- cannabis
- brain
- brain tumour
- Temozolomide
- Cancer
ASJC Scopus subject areas
- Oncology
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Dive into the research topics of 'A randomised phase II trial of temozolomide with or without cannabinoids in patients with recurrent glioblastoma (ARISTOCRAT): Protocol for a multi-centre, double-blind, placebo-controlled trial'. Together they form a unique fingerprint.Projects
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A randomised phase II study of temozolomide with or without cannabinoids in patients with recurrent glioblastoma: ARISTOCRAT
Patel, A., Billingham, L. & Savage, J.
1/02/23 → 28/02/25
Project: Research