NCT03643549

Bortezomib and Temozolomide in Recurrent Grade-4 Glioma Unmethylated MGMT Promoter (BORTEM-17)

Bortezomib Sensitization of Recurrent Grade-4 Glioma With Unmethylated MGMT Promoter to Temozolomide Phase 1B/II Study

• Status: Unknown
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 63 (estimated)
• Sponsor: Haukeland University Hospital · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This phase IB/II trial is designed to investigate the safety and survival benefits for patients with recurrent grade-4 with unmethylated MGMT promoter treated with Bortezomib and Temozolomide in a specific schedule.

Detailed description

Patients harbouring tumours with functional O6 methylguanine DNA methyltransferase (MGMT) DNA repair enzyme efficiently repair the DNA damage inflicted by Temozolomide and gain limited benefit from this chemotherapy. 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 inhibits the growth of tumour cells by blocking autophagy flux. Temozolomide causes genotoxic stress in cancer cells that in turn respond by inducing protective processes such as autophagy. If both autophagy and MGMT DNA repair enzyme are blocked a priori, the efficacy of Temozolomide will be enhanced. Thus, pre-treating the tumour with Bortezomib prior to administration of Temozolomide leads to DNA repair enzyme depletion and blockade of autophagy-induced survival signals. The combined effect will sensitize the tumour to therapy, improve chemotherapy efficacy and prolong patient survival outcomes. Hypothesis: Pretreatment with Bortezomib administered prior to Temozolomide will sensitize recurrent GBM with unmethylated MGMT promoter to standard TMZ in palliative setting. Objective: * Assessment of safety and tolerability of Bortezomib administered with Temozolomide. * Determining the optimal dose of TMZ, when administered as combination therapy * Estimate the progression free survival (PFS) and overall survival (OS) of patients with recurrent or progressed glioblastoma after pre-treatment with Bortezomib prior to combination with Temozolomide. Key secondary objectives * Tumour response to the therapy assessed by RANO and NANO criteria * Determine physiological, molecular and biochemical changes in blood and tumour tissue that correlate with treatment responses.

Conditions

• Glioblastoma

Interventions

Type	Name	Description
DRUG	Bortezomib and Temozolomide Phase IB	In the Phase IB of the study the following dose escalation of TMZ will be performed: The first cohort of 3 patients will receive 150 mg/m2 of IMP (TMZ) for 5 days q4w. If one patient in this cohort develops a dose limiting toxicity, another cohort of 3 patients will be treated at the same dose level until 2 or more patients in the group of 3-6 develop DLT.
DRUG	Bortezomib and Temozolomide Phase II	The patientes will be treated with the maximum recommended starting dose of Temozolomide and Bortezomib established in the IB phase of the study

Timeline

• Start date: 2018-08-30
• Primary completion: 2025-06-30
• Completion: 2025-12-31
• First posted: 2018-08-22
• Last updated: 2024-02-29

Locations

2 sites across 1 country: Norway