A phase II trial evaluating tumor penetration of bortezomib in patients with recurrent malignant gliomas treated prior to surgery and then treated with bortezomib and temozolomide postoperatively.

Abstract

2035 Background: NF-Kappa B is one of the mechanisms of resistance for malignant gliomas. A few trials have assessed bortezomib in the treatment of malignant gliomas with limited activity. This may in part be due to limitations in dose escalation from peripheral neuropathy. We performed a phase II trial with the goal of measuring bortezomib in tumor tissue and also its effects on NF-Kappa B. Methods: Patients felt to be surgical candidates were enrolled after signing an IRB approved consent. They were treated with bortezomib 1.7 mg/m2 IV on day 1, 4 and 8 and then had surgery on day 8 or 9. Approximately, 14 days post operatively, patients were started on temozolomide 75 mg/m2 PO on days 1-7 and 14-21; on day 7 and day 21 they received bortezomib 1.7 mg/m2 (1 cycle was 1 month). Treatment continued until progression. If <1 patient had a PFS at 6 months the trial would be stopped. Results: 10 patients were enrolled (8 M and 2 F). Median age and KPS were 50 (42-64) and 90% (70-90). All but 1 patient went to surgery, one had an intracranial hemorrhage. The median number of cycles post operatively was 2 (1-4), with two patients discontinuing for wound infection (post 3 cycles, not restarted due to prolonged delays) and meningitis (post 2 cycles then withdrew from trial). Six patients are deceased. Trial was stopped as no patient had a PFS-6. PK analysis revealed measurable drug levels in tumor tissue. Conclusions: Post operative treatment with temozolomide and Bortezomib did not have any activity. Bortezomib can achieve measurable drug levels in tumor but may not be sufficient for anti-tumor activity. Tissue will be assessed for bortezomib effects on NF-Kappa B.