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.

Abstract

2004 Background: Patients with newly diagnosed glioblastoma receive postoperative standard therapy with radiotherapy (RT), and concomitant and up to six cycles of maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). Marizomib is a novel, irreversible and brain-penetrant pan-proteasome inhibitor with encouraging findings in preclinical models and early-stage clinical trials for patients with newly diagnosed and recurrent glioblastoma. Therefore, a phase 3 trial was designed to explore the activity of marizomib in addition to TMZ/RT→TMZ. ClinicalTrials.gov Identifier: NCT03345095 Methods: EORTC 1709/CCTG CE.8 is a multicenter, randomized, controlled, open label phase 3 superiority trial. Eligibility criteria included histologically confirmed newly diagnosed glioblastoma and a Karnofsky performance status (KPS) > 70. Eligible patients were stratified for institution, age, KPS as well as extent of surgery, and centrally randomized in a 1:1 ratio. The primary objective of this study is to compare overall survival (OS) in patients receiving marizomib in addition to standard treatment with patients receiving standard treatment only. Secondary endpoints include progression-free survival (PFS), safety, neurocognitive function, and quality of life. Results: 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 June 2018 and was close to completion at the time of a planned interim analysis in September 2020. A total of 749 patients (of the planned 750) were randomized when the IDMC recommended to discontinue enrollment. Age, KPS and extent of resection were well balanced between the 2 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). Median PFS was 6.1 vs. 6.2 months (HR = 1.02). Patients in the marizomib group had more often grade 3/4 treatment-emergent adverse events (TEAE) compared to the standard therapy group (42.6% vs. 20.5%), including ataxia, hallucinations and headache. Conclusions: The addition of marizomib to standard radiochemotherapy did not improve OS or PFS in patients with newly diagnosed glioblastoma. Final survival analyses including determination of MGMT promoter methylation status and analyses of other secondary endpoints are ongoing. Clinical trial information: NCT03345095.

Safety and Efficacy of Crizotinib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib GEINO 1402 Trial

“…Crizotinib combined with standard TMZ and RT showed a median PFS of 10.7 months (95% CI: 7.7-13.8) and a median OS of 22.6 months (95% CI: 14.1-31.1), which are higher than the expected median PFS (6.9 months) and OS (14.6 months) from benchmark studies administering the Stupp scheme alone as a first-line treatment [1,2]. For example, the combination of RT and TMZ with iniparib, an intracellular converter of nitro radical ions, showed a median OS of 21.6 months [6], while the administration of RT and TMZ with anlotinib, a multitarget tyrosine kinase inhibitor, and vorinostat, a histone deacetylase (HDAC) inhibitor, reported a median OS of 17.4 and 16.1 months, respectively [7][8][9]. Preliminary analysis from a phase III randomized trial studying the combination of marizomib, a proteasome inhibitor, with the Stupp scheme failed to demonstrate a benefit in terms of survival, with a median OS of 15.7 months [8].…”

“…For example, the combination of RT and TMZ with iniparib, an intracellular converter of nitro radical ions, showed a median OS of 21.6 months [6], while the administration of RT and TMZ with anlotinib, a multitarget tyrosine kinase inhibitor, and vorinostat, a histone deacetylase (HDAC) inhibitor, reported a median OS of 17.4 and 16.1 months, respectively [7][8][9]. Preliminary analysis from a phase III randomized trial studying the combination of marizomib, a proteasome inhibitor, with the Stupp scheme failed to demonstrate a benefit in terms of survival, with a median OS of 15.7 months [8]. Considering our results in this context, the combination of chemoradiotherapy with crizotinib achieved a promising survival.…”

“…Molecular prognostic factors include: the O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status [3], and mutations in the isocitrate dehydrogenase 1 and 2 (IDH) genes [4,5]. Efforts are underway to identify molecular pathways involved in GBM resistance to standard chemoradiation [6][7][8][9][10].…”

ASCO 2021: Highlights in central nervous system tumors

“…In a previous extended phase I trial [15], the addition of the brain-penetrating, irreversible pan-proteasome inhibitor marizomib to standard radiochemotherapy was assessed in newly diagnosed GBM. Based on favorable efficacy and safety, the EORTC-1709/CCTG CE.8 phase III trial presented at ASCO 2021 was aimed to substantiate the clinical efficacy of marizomib added to TMZ-based ra-ASCO 2021: Highlights in central nervous system tumors K short review short review diochemotherapy [16]. A total of 749 patients was enrolled as the independent data monitoring committee recommended premature closure of the trial due to futility.…”

Enzymatic assembly of the salinosporamide γ-lactam-β-lactone anticancer warhead

“…1a ). 1 , 2 Despite the discovery of numerous natural analogs of 1 , 3 as well as extensive efforts to generate derivatives via chemical synthesis 4 and mutasynthesis, 5 , 6 it is the originally discovered natural product itself that entered clinical trials. Salinosporamide A’s compact yet densely functionalized -lactam- -lactone pharmacophore is distinct amongst proteasome inhibitors, including the FDA-approved bortezomib, carfilzomib, and ixazomib.…”