P14.09 BORTEM-17: A Phase IB/II Single-Arm, Control Non-Randomized, Multicentre, Open Label Clinical Trial for Recurrent Glioblastoma with unmethylated MGMT promoter (NCT03643549)
Authors: Goplen D , Rahman M A , Arnesen V S , Brekke J , Simonsen A , Andreas W , Marienhagen K , Oltedal L , Haasz J , Miletic H , Solheim T S , Brandal P , Lie S A , Chekenya M 
Published: September 2021

Abstract

BACKGROUND
Glioblastoma (GBM) is the most malignant primary brain tumor in adults where median survival in unselected patients is approximately 10 months. There is no standard treatment for patients who progress on temozolomide and patients are best treated within investigational clinical protocols. Patients harbouring tumours with functional O6 methylguanine DNA methyltransferase (MGMT) DNA repair enzyme have particularly poor prognosis with median overall survival of 12.7 months, compared to 21.7 months for patients with hypermethylated MGMT promoter. The pre-clinical studies have shown that Bortezomib depletes the MGMT enzyme, restoring the tumour ́s susceptibility to Temozolomide, if the chemotherapy is administered in the precise schedule when the MGMT enzyme is depleted. Additionally, Bortezomib shows an antitumour effect by blocking autophagy flux. Based on the promising pre-clinical results, a non-randomized, open label phase IB/II clinical trial was designed. The primary endpoints include assessment of safety of Bortezomib administered with Temozolomide for phase IB and median progression free survival, overall survival as well as progression free rate at 6 months.

MATERIAL AND METHODS
Recurrent glioblastoma patients with unmethylated MGMT promotor, progressing at least 12 weeks after completion of postoperative radiotherapy, with adequate organ function, performance status Karnofsky 70 or better and radiologically measurable lesions are screened for study inclusion. The experimental treatment consists of Bortezomib 1.3mg/m2 administered IV on days 1, 4, 7, during each 4-week chemotherapy cycle with per oral Temozolomide at 200mg/m2 5 days/week every 4 weeks starting on day 3. Study group will be compared to historical controls on conventional management. The sample size was calculated to 63 patients, ten of them were included in the phase IB.

RESULTS
The phase IB of the trial was completed in 2019 and the combination of Temozolomide and Bortezomib was shown to be safe and well tolerated. Until April 2021 a total number of 23 patients were included into the trial. The patients are treated at 4 different referral university hospitals in Norway. A clinical treatment benefit with both radiological tumor volume response and stable disease were observed. The patient inclusion in the trial is delayed due COVID-19. The majority of observed side effects are mild or moderate. The grade 3 or 4 adverse effects included thrombocytopenia, ataxia, muscle weakness, delirium and hyperglycemia. Patients that progressed under the treatment received another line of therapy according to the institutional practice.

CONCLUSION
A combination of Bortezomib and Temozolomide administered in a defined time sequence to achieve sensitization of glioblastoma to alkylating agent is safe and feasible and may represent a novel treatment option for patients with this devastating disease.