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RBTT-08. 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 maximum safe surgery, involved-field radiotherapy (RT), and concomitant and up to six cycles of maintenance temozolomide (TMZ) chemotherapy (TMZ/RT?TMZ). However, the prognosis remains poor and there is a high unmet need to provide new drugs to patients with glioblastoma. Marizomib is a novel, brain-penetrant irreversible pan-proteasome inhibitor that has been successfully assessed in phase I studies in patients with newly diagnosed as well as recurrent glioblastoma. METHODS EORTC 1709/CCTG CE.8 is a multicenter, randomized, controlled, open label phase III superiority trial. To be eligible, patients need to have histologically confirmed newly diagnosed glioblastoma. A total of 750 patients will be enrolled and randomized 1:1. Stratification factors include institution, age, Karnofsky performance status and extent of surgery. The primary objective of this study is to compare overall survival in patients receiving marizomib in addition to standard treatment (TMZ/RT?TMZ) with patients receiving standard treatment only. The testing strategy is defined to assess this objective in both the intent-to-treat population and the subgroup of patients with tumors harboring an unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter. Secondary endpoints include progression-free survival, safety, neurocognitive function and quality of life. An accompanying translational research program has been set up. The study will be opened at 50 EORTC sites in Europe and done as an intergroup collaboration with the Canadian Cancer Trials Group (CCTG) with 25 sites in Canada and additional sites in the US. Patient enrolment is planned to start in June 2018 and an update on the enrolment status will be provided at the SNO conference. ClinicalTrials.gov Identifier: NCT03345095

SUBMITTER: Roth P

PROVIDER: S-EPMC6217655 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Project description:Abstract BACKGROUND EORTC study 26091 showed that addition of bevacizumab (BEV) to temozolomide (TMZ) does not improve overall survival (OS) or progression-free survival (PFS) in recurrent grade II and III 1p/19q intact gliomas; regardless of isocitrate dehydrogenase (IDH) mutational status. This abstract reports the neurocognitive functioning (NCF) outcomes. METHODS NCF was evaluated before randomization and at every 12 weeks during treatment using Hopkins Verbal Learning Test (Free Recall, Delayed Recall, and Delayed Recognition), Trail Making Test (TMT A/B); and Controlled Oral Word Association Test (COWA). RESULTS 148/155 patients had at least one NCF assessment. Compliance was 91.5% at baseline and dropped to 61.9% at week 60. Primary analysis (at 5% significance level) compared NCF at the last disease assessment before or at week 60 in patients who had at least one NCF assessment after baseline. Patients in the temozolomide+bevacizumab arm did not differ from patients in the temozolomide only arm. Except for Delayed Recognition, all NCF outcomes were positively associated with WHO performance status. TMT A (p=0.03), TMT B (p=0.006) and COWA (p<0.0001) were significantly worse in patients receiving steroids at study entry. Furthermore, delayed recognition was worse in patients with larger tumors (>26.5 vs <=26.5 mm; p=0.04). Memory performance was poorer in patients with tumors in the left hemisphere (Free Recall; p=0.0002), Delayed Recall; p<0.0001, Delayed Recognition; p=0.004). Except for Free Recall and Delayed Recognition, all other baseline raw scores were associated with OS in univariate analyses. In a multivariate Cox regression model, TMT B and tumor size were identified as independent OS prognostic factors while baseline WHO performance status and steroids use were not included. CONCLUSION At the group level patients in the temozolomide+bevacizumab arm do not differ from patients with temozolomide only, individual patients’ verbal memory capacity might negatively be affected by tumor volume and tumor location.

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.

Project description:BACKGROUND: The EORTC (26981-22981)/NCIC CTG (CE.3) RCT in newly diagnosed GBM showed increased survival with concomitant and adjuvant temozolomide (TMZ) added to radiotherapy (RT). Study pts were 18-71 (median 56) years; however a sub-group analysis noted a trend of decreasing benefit from the addition of TMZ with increasing age, such that for age 65-71, the hazard ratio of 0.8 did not reach statistical significance (p = 0.340). This may reflect a lack of efficacy in elderly patients, or simply be due to a lack of statistical power in this subgroup. Recent RCTs in elderly GBM found improved survival with RT compared to supportive care alone and detected non-inferiority of 40 Gy/15 vs. a 60 Gy/30 RT regimen and superior survival was noted for MGMT-methylated patients treated with TMZ alone vs RT alone. Based upon these results short-course hypofractionated RT is often recommended for elderly pts. However, whether the addition of TMZ to RT confers a survival advantage in elderly pts, particularly for those with methylated MGMT, remains unanswered. METHODS: We conducted a global randomized phase III clinical trial for patients ≥65 yrs of age with histologically confirmed newly diagnosed glioblastoma, ECOG 0-2, randomized 1:1 to receive 40Gy/15 RT vs. 40Gy/15 RT with 3 weeks of concomitant temozolomide plus monthly adjuvant TMZ until progression or 12 cycles. Stratification is by centre, age (65-70, 71-75, or 76+), ECOG 0,1 vs 2, and biopsy vs resection. RESULTS: Accrual of n = 562 patients was completed Sept 19, 2013. Accrual by participating group was NCIC CTG 199, EORTC 249, TROG 97, and Japan 17 patients. Median age of randomized patients was 73 (65-90) years with 70% of patients over the age of 71. The study was powered to detect a HR of 0.75 in median OS, requiring 520 events for analysis. At the time of writing the required number of deaths had not been reached. A comprehensive analysis, including MGMT promoter methylation and QOL, is planned. CONCLUSIONS: A global cooperative group trial was completed randomizing 562 elderly patients with glioblastoma. The final results will add to our knowledge on the optimal treatment of these patients. SECONDARY CATEGORY: n/a.

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RBTT-08. 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

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