BORTEM-17: A phase IB/II single arm, multicentre study investigating the efficacy of sequential bortezomib and temozolomide in recurrent GBM with unmethylated MGMT promoter-The results of an interim analysis

2019 Background: Glioblastoma (GBM) is the most frequent, lethal primary brain tumor in adults. Patients harboring tumors with functional O6 methylguanine DNA methyltransferase ( MGMT) DNA enzyme gain limited benefit from temozolomide therapy. As shown in preclinical studies, bortezomib depletes the MGMT enzyme, restoring the tumor ́s susceptibility to temozolomide, if administered in a precise schedule when the MGMT enzyme is depleted. We hypothesized that recurrent GBM patients with unmethylated MGMT promoter may obtain clinical benefit from sequential BTZ and TMZ treatment. Methods: BORTEM-17 is a multicenter, open label, single arm, non-randomized phase IB/II trial to investigate potential survival benefit for recurrent glioblastoma patients administered bortezomib 48hrs prior to temozolomide. Sample size is calculated to 63 patients, of whom 10 included in phase IB. The doses of bortezomib is 1.3mg/m2 intravenously days 1, 4, and 7 during 4-week cycle, and temozolomide 200mg/m2 days 5-7. The control group is a retrospective cohort of 467 patients treated at 2 referral hospitals in Norway from January 2015 to December 2017. For the survival analysis, the patients included in BORTEM-17 (n=44) were compared with MGMT unmethylated control, age matched patients (n=116). The pre-defined interim analysis was performed after inclusion of 15 patients and as more than 2 of 15 patients had clinical benefit, the study was continued. Results: Until January 2023, 44 patients with median age 55 years (range 25-69), 30 males and 14 females were treated. Median KPS was 90 (70-100) and median NANO score 1 (0-7). The interim analysis was performed after inclusion of 15 patients in the phase IB and II and clinical benefit was observed in 5 patients. Two of them had tumor volume reduction and three experienced stable disease. The study proceeded to the next step. No treatment related deaths were observed. The most common adverse effects included hematological toxicity, gastrointestinal symptoms, muscle weakness, lower back pain and fatigue. Patients that progressed during the BORTEM-17 trial and were fit for further therapy received treatment at their physician’s discretion. The preliminary data analysis after 44 of planned 63 patients were treated indicate prolonged median survival for BORTEM-17 patients 19.0 months vs 12.2 months of control MGMT unmethylated age matched patients. Median survival after recruitment is 5.5 months (1.0-23.8). Conclusions: The sequential BTZ+TMZ therapy is safe, feasible and effective as indicated by preliminary data when 70% of planned MGMT unmethylated patients have been included. Preliminary data indicate that the combination of BTZ and TMZ may offer an additional line of treatment with limited toxicity to the group of patients with particularly dismal prognosis. Clinical trial information: NCT03643549 .