Abstract CT114: BORTEM-17 - phase IB/II single arm, non-randomized controlled multicenter study investigating whether sequential bortezomib and temozolomide is safe and effective in recurrent GBM with unmethylated MGMT promoter
Authors: Goplen Dorota , Rahman Mohummad Aminur , Brekke Jorunn , Arnesen Victoria , Simonsen Anne , Waha Andreas , Marienhagen Kirstin , Oltedal Leif , Haasz Judit , Miletic Hrvoje , Solheim Tora Skeidsvoll , Brandal Petter , Lie Stein Atle , Chekenya Martha 
Published: June 2022

Abstract
Background: Glioblastoma (GBM) is an aggressive brain tumor where median survival is approx. 12 months in unselected patients, largely due to activity of O6-methylguanine DNA methyltransferase (MGMT) that renders GBM resistant to temozolomide (TMZ) chemotherapy. There is no standard treatment for recurrent GBM patients who progress under TMZ treatment. We previously demonstrated that bortezomib (BTZ) depletes MGMT protein and sensitizes MGMT unmethylated GBM cells to TMZ in vitro and in PDX models when administered in precise dose and sequential schedule. TMZ dose escalation in phase IB part of the trial was tolerated, safe and associated with immunological responses in selected patients. We hypothesized that recurrent GBM patients with unmethylated MGMT promoter may obtain clinical benefit from sequential combination of BTZ and TMZ treatment.
Methods: The sample size was calculated to 63 patients for this phase IB/II study, 10 were included in the phase IB and the rest are ongoing in phase II. A cohort of 467 patients treated at Oslo and Haukeland University Hospitals were used as controls. We report interim results of n=32 MGMT unmethylated recurrent GBM patients progressing at least 12 weeks after completion of postoperative radiotherapy, with adequate organ function, Karnofsky performance status (KPS) ≥70 and radiologically measurable lesions treated on BORTEM-17 protocol. The patients received intravenous BTZ 1.3mg/m2 on days 1,4,7, during each 4-week chemotherapy cycle starting on day 3 with per oral TMZ at 200mg/m2 5 days/week. Mantel-Cox regression analyses was used to calculate survival.
Results: Until January 2022, 32 patients with median age 54 yrs (range 25-66 yrs), 23 male and 9 female were treated at 3 different referral university hospitals in Norway. 81% (26/32) were IDH wt. Median KPS was 90 (70-100) and median NANO score was 1 (0-7). 9/32 patients are still alive. Preliminary data indicates 20% of patients showed clinical and radiological responses, where 4/6 (67%) obtained partial response and 2/6 (33%) had stable disease. BORTEM-17 patients’ median survival was significantly better than all controls (23.7 months vs 12.1 months) HR0.61, 95% CI [0.44-0.85], P=0.003. The Median survival for BORTEM-17 patients was 23.7 months vs 11.4 months for control MGMT unmethylated patients HR0.46, 95% CI [0.33-0.63], P&lt;0.0001. When adjusted for age, BORTEM-17 patients’ median survival was 23.7 months vs 12.9 months of control MGMT unmethylated patients HR0.51, 95% CI [0.34-0.75], P=0.0007. Patients’ self-reported quality of life was good. Majority of the side effects were mild or moderate. Patients with disease progression from the study received another line of treatment according to the institutional practice.
Conclusion: Combination of BTZ and TMZ administered sequentially is safe. Interim analysis indicates objective radiological response and increased median survival of MGMT unmethylated patients. ClinicalTrials.gov identifier: NCT03643549
Citation Format: Dorota Goplen, Mohummad Aminur Rahman, Jorunn Brekke, Victoria Arnesen, Anne Simonsen, Andreas Waha, Kirstin Marienhagen, Leif Oltedal, Judit Haasz, Hrvoje Miletic, Tora Skeidsvoll Solheim, Petter Brandal, Stein Atle Lie, Martha Chekenya. BORTEM-17 - phase IB/II single arm, non-randomized controlled multicenter study investigating whether sequential bortezomib and temozolomide is safe and effective in recurrent GBM with unmethylated MGMT promoter [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT114.