In a phase III trial of marizomib in combination with temozolomide-based radiochemotherapy vs. temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma, marizomib failed to improve the overall and progression-free survival compared to standard treatment alone. In addition, marizomib was associated with neurotoxicity and psychiatric adverse events in a proportion of patients.
To date, standard of care for patients with newly diagnosed glioblastoma consists of maximal safe surgery, involved-field radiotherapy and concomitant temozolomide followed by up to six cycles of maintenance temozolomide. Marizomib is an irreversible proteasome inhibitor with broad activity against proteasomal activities and crosses the blood-brain barrier. Based on encouraging phase I/II study data with marizomib in patients with newly diagnosed or recurrent glioblastoma, a phase III trial was launched.
MIRAGE study design
EORTC 1709/CCTG CE.8 (MIRAGE) is a multicentre, randomised, controlled, open-label phase III superiority trial. Eligibility criteria included histologically confirmed newly diagnosed glioblastoma and a Karnofsky performance status (KPS) >70, eligible for standard treatment. Patients should have stable or decreasing dose of steroids for at least one week prior to inclusion, a life expectancy of at least three months and no prior treatment for glioblastoma other than surgery. Patients were randomised (1:1) to standard treatment or standard treatment plus marizomib. All patients received radiotherapy five times a week, with a total dose of 60Gy in 30 fractions. Furthermore, patients received temozolomide 75mg/m2 orally for six weeks (during radiotherapy), followed – after a four-week interval – by up to six cycles of maintenance temozolomide chemotherapy 150-200 mg/m2 orally on days 1-5 of each 28-day cycle. Finally, patients in the marizomib arm received 0.8 mg/m2 intravenous marizomib on days 1, 8, 15, 29 and 36 during radiotherapy, followed – after a four-week interval – by adjuvant treatment at days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, withdrawal of consent or up to 18 cycles. The primary objective of this study was to compare overall survival (OS) of the treatment and control arm in the total population, and specifically in patients with MGMT promotor-unmethylated tumours. Secondary endpoints included progression-free survival (PFS) in the total population and specified by MGMT status, safety, neurocognitive function, and quality of life.
No clinical benefit
The study was opened at 49 EORTC sites in Europe, 23 CCTG sites in Canada, and 8 sites in the US. Patient enrolment started in August 2018 and was close to completion (99.9%) at the time of a planned interim analysis in September 2020. A total of 749 patients (of the planned 750) were randomised when the independent data monitoring committee (IDMC) recommended discontinuing enrolment. Age, KPS and extent of resection were well balanced between the two study arms.
No difference in median OS was observed between the standard arm (15.9 months) and the marizomib arm (15.7 months; HR= 0.99). Kaplan-Meier estimates for OS at the 12-month landmark were 71.7% and 68.8%, respectively. Furthermore, with median PFS of 6.1 vs. 6.2 months, there was no benefit of marizomib in terms of PFS (HR = 1.02). Grade 3/4 treatment-emergent adverse events (TEAEs) were more frequent in the marizomib group as compared to the standard therapy group (42.6% vs. 20.5%), including central nervous system-related TEAEs (19% vs. 5.7%) and psychiatric TEAEs (9.8% vs. 0.7%). Patients were mainly complaining about grade 3/4 hallucinations (4.6%), ataxia (3.9%), headache (3.3%), confusional state (2.3%), balance disorders (1%), dizziness (1%), insomnia (0.7%) and dysarthria (0.7%).
Marizomib in combination with temozolomide-based radiochemotherapy did not improve OS or PFS compared to standard treatment alone. In addition, marizomib was associated with neurotoxicity and psychiatric adverse events in a proportion of patients. Enrolment was stopped following a pre-planned interim analysis and according to the suggestion of the study IDMC. Further analyses, including survival data stratified based on the MGMT promoter methylation status will be added and exploratory analyses and translational research program is ongoing.
Roth P, et al. EORTC 1709/CCTG CE.8: A phase III trial of marizomib in combination with temozolomide-based radiochemotherapy versus temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma. Presented at ASCO 2021; Abstract 2004.