Phase I Trial Of Concurrent Bortezomib, Paclitaxel, And External Beam Radiation In Patients With Unresectable Pancreatic Or Billiary Cancer

To determine the maximum tolerable dose of bortezomib (MTD) given intravenously once weekly with paclitaxel and radiation therapy in patients with locally advanced, non-metastatic pancreatic or biliary tract cancer. An open label, dose escalation, phase I clinical trial evaluated the safety of three dose levels of intravenously (IV) administered bortezomib (0.7 mg/m2, 1.0 mg/m2, and 1.3 mg/m2/dose) with paclitaxel 50 mg/m2 IV, both administered weekly for 5 weeks with conventionally fractionated radiation therapy (RT). RT was 45 Gy to primary tumor and regional lymphatics. Gross disease received an additional 5.4 Gy boost. All patients had histologically confirmed, unresectable, non-metastatic pancreatic, or biliary tract cancer. Dose limiting toxicity (DLT) was the primary endpoint. A DLT was defined as any grade ≥3 non-hematologic toxicity, grade 2 neuropathy with pain, neutropenia lasting > 7 days or any toxicity requiring treatment to be delayed for ≥ 2 weeks. A total of 12 patients were screened for inclusion. 2 patients were ineligible and did not receive trial therapy. Trial therapy was discontinued in a single patient experiencing a severe transfusion reaction to paclitaxel. All patients remaining on trial received >90% of planned therapy. No DLT was appreciated in cohort 1. A single DLT was appreciated in cohort 2 (grade 3 urinary tract infection; dehydration; hypotension.) Common adverse events not meeting criteria for DLT included lymphopenia (9), febrile neutropenia (1), pulmonary embolus (1), DVT (1), diarrhea (1), and rash (1). This trial was closed prior to initiation of cohort 3 due to poor accrual. Median survival was 14 months (range 3-39 months). Eight patients have died. All surviving patients experienced disease progression. Weekly bortezomib up to a maximum dose of 1 mg/m2 delivered concurrently with weekly paxclitaxel and external beam radiation was tolerable in a small cohort of patients with unresectable pancreatic/biliary tract cancer. Due to poor accrual, this trial failed to establish the MTD. Additional investigation is warranted to determine the MTD, safety profile, and efficacy associated with this treatment regimen.