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P14.124 EORTC 1709/CCTG CE.8: A phase III trial of marizomib in combination with standard temozolomide-based radiochemotherapy versus standard temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma

ABSTRACT: Abstract

BACKGROUND

The standard of care for patients with newly diagnosed glioblastoma includes maximal debulking surgery followed by radiotherapy (RT), and concomitant as well as maintenance therapy with the alkylating agent, temozolomide (TMZ). However, the prognosis remains poor and novel treatment strategies are urgently needed. Targeting the proteasome has been considered a promising anti-cancer approach for several years. Marizomib is a novel, irreversible and pan-proteasome inhibitor, which crosses the blood-brain barrier and has been assessed in phase I trials in patients with newly diagnosed or recurrent glioblastoma.

MATERIAL AND METHODS

EORTC 1709/CCTG CE.8 is a randomized, controlled, open label phase III superiority trial. Patients with histologically confirmed newly diagnosed glioblastoma and a performance status >70 are eligible. Patients are randomized in a 1:1 ratio to receive standard of care (TMZ/RT?TMZ) alone or TMZ/RT?TMZ plus marizomib. The study aims at enrolling 750 patients. Stratification factors include study site, age, performance status and extent of resection. The primary objective of this trial is to compare overall survival in patients receiving marizomib in addition to standard of care with those receiving standard treatment only. The testing strategy specifies the determination of this objective in the intent-to-treat population as well as the subgroup of patients with MGMT-unmethylated tumors. Secondary endpoints include progression-free survival, safety, neurocognitive function and quality of life. A translational research program has been set up. The study will be activated at approximately 50 EORTC sites across Europe, 25 sites in Canada and additional sites in the US. Patient recruitment started in June 2018 and as of April 29, 2019, a total of 164 patients have been randomized. An update on the enrolment status will be provided at the EANO meeting. ClinicalTrials.gov Identifier: NCT03345095

SUBMITTER: Roth P

PROVIDER: S-EPMC6795174 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Current standard of treatment for newly diagnosed patients with glioblastoma (GBM) is surgical resection with adjuvant normofractionated radiotherapy (NFRT) combined with temozolomide (TMZ) chemotherapy. Hyperfractionated accelerated radiotherapy (HFRT) which was known as an option from randomized controlled trials before the temozolomide era has not been compared to the standard therapy in a randomized setting combined with TMZ. METHODS:Data of 152 patients with newly diagnosed GBM treated from 10/2004 until 7/2018 at a single tertiary care institution were extracted from a clinical database and retrospectively analyzed. Thirty-eight patients treated with NFRT of 60?Gy in 30 fractions (34 with simultaneous and 2 with sequential TMZ) were compared to 114 patients treated with HFRT of 54.0?Gy in 30 fraction of 1.8?Gy twice daily (109 with simultaneous and 3 with sequential TMZ). The association between treatment protocol and other variables with overall survival (OS) was assessed using univariable and multivariable Cox regression analysis; the latter was performed using variables selected by the LASSO method. RESULTS:Median overall survival (OS) was 20.3?month for the entire cohort. For patients treated with NFRT median OS was 24.4?months compared to 18.5?months in patients treated with HFRT (p =?0.131). In univariable regression analysis the use of dexamethasone during radiotherapy had a significant negative impact on OS in both patient groups, HR 2.21 (95% CI 1.47-3.31, p =?0.0001). In multivariable analysis adjusted for O6-methylguanine-DNA methyl-transferase (MGMT) promotor methylation status, salvage treatment and secondary GBM, the use of dexamethasone was still a negative prognostic factor, HR 1.95 (95% CI 1.21-3.13, p =?0.006). Positive MGMT-methylation status and salvage treatment were highly significant positive prognostic factors. There was no strong association between treatment protocol and OS (p =?0.504). CONCLUSIONS:Our retrospective analysis supports the hypothesis of equivalence between HFRT and the standard protocol of treatment for GBM. For those patients who are willing to obtain the benefit of shortening the course of radiochemotherapy, HFRT may be an alternative with comparable efficacy although it was not yet tested in a large prospective randomized study against the current standard. The positive influence of salvage therapy and negative impact of concomitant use of corticosteroids should be addressed in future prospective trials. To confirm our results, we plan to perform a pooled analysis with other tertiary clinics in order to achieve better statistical reliability.

Dataset Information

P14.124 EORTC 1709/CCTG CE.8: A phase III trial of marizomib in combination with standard temozolomide-based radiochemotherapy versus standard temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma

BACKGROUND

MATERIAL AND METHODS

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