Multi-Arm GlioblastoMa Australasia (MAGMA): protocol for a multiarm randomised clinical trial for people affected by glioblastoma

Abstract

IntroductionGlioblastoma (GBM) is the most common malignant primary central nervous system cancer in adults. The objective of the Multi-Arm GlioblastoMa Australasia (MAGMA) trial is to test hypotheses in real world setting to improve survival of people with GBM. Initial experimental arms are evaluating the effectiveness of interventions in newly diagnosed GBM (ndGBM). This study will compare maximal surgical resection followed by chemoradiotherapy plus adjuvant chemotherapy for 6 months with the addition of (1) ‘neoadjuvant’ chemotherapy beginning as soon as possible after surgery and/or (2) adjuvant chemotherapy continued until progression within the same study platform.Methods and analysisMAGMA will establish a platform for open-label, multiarm, multicentre randomised controlled testing of treatments for GBM. The study began recruiting in September 2020 and recruitment to the initial two interventions in MAGMA is expected to continue until September 2023.Adults aged ≥18 years with ndGBM will be given the option of undergoing randomisation to each study intervention separately, thereby giving rise to a partial factorial design, with two separate randomisation time points, one for neoadjuvant therapy and one for extended therapy. Patients will have the option of being randomised at each time point or continuing on with standard treatment.The primary outcome for the study is overall survival from the date of initial surgery until death from any cause. Secondary outcomes include progression-free survival, time to first non-temozolomide treatment, overall survival from each treatment randomisation, clinically significant toxicity as measured by grade 3 or 4 adverse events and health-related quality-of-life measures. Tertiary outcomes are predictive/prognostic biomarkers and health utilities and incremental cost-effectiveness ratio.The primary analysis of overall survival will be performed separately for each study intervention according to the intention to treat principle on all patients randomised to each study intervention.Ethics and disseminationThe study (Protocol version 2.0 dated 23 November 2020) was approved by a lead Human Research Ethics Committee (Sydney Local Health District: 2019/ETH13297). The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice.Trial registration numberACTRN12620000048987.

Inaugural Results of the Individualized Screening Trial of Innovative Glioblastoma Therapy: A Phase II Platform Trial for Newly Diagnosed Glioblastoma Using Bayesian Adaptive Randomization

“…34 In contrast to INSIGhT, GBM AGILE was developed as a seamless phase II/III with a built-in registrational component for both patients with newly diagnosed and recurrent glioblastoma. The INSIGhT trial, GBM AGILE, other master platform trials such as the N2M2, 35 and the upcoming MAGMA trial 36 are poised to serve as efficient clinical testing platforms that accelerate efficient drug development for glioblastoma.…”

Updated systematic review and meta-analysis of extended adjuvant temozolomide in patients with newly diagnosed glioblastoma

“…Further exploratory analysis based on MGMT gene promoter methylation status would be hypothesis-generating for testing the extended adjuvant TMZ paradigm in a biomarker-enriched (methylated) cohort. Two ongoing Australian trials EX-TEM (ACTRN12618001944224) 40 and MAGMA (ACTRN12620000048987) 41 are currently testing the safety and efficacy of extended adjuvant TMZ in patients with newly diagnosed GBM using MGMT status for stratification. Biomarker-based Optimization of Adjuvant Therapy (BOAT) study is the only prospective study (CTRI/2018/11/016349) that is randomly assigning GBM patients with methylated MGMT to standard 6-cycles of TMZ versus extended adjuvant TMZ.…”