A phase II trial of the proteasome inhibitor bortezomib in patients with recurrent or metastatic adenocarcinoma of the bile duct or gallbladder (NCI #6135)

Abstract

e15605 Background: There is currently no standard therapy for recurrent or metastatic cancers of the bile duct or gallbladder and available chemotherapy is of uncertain benefit. As activation of NF-κB has been described in these tumors, we initiated a phase II trial of the proteasome inhibitor bortezomib in patients with recurrent or metastatic disease. Methods: Patients with measurable metastatic or unresectable adenocarcinoma of the bile duct or gallbladder who had received up to 2 prior chemotherapy regimens were eligible. Other eligibility criteria included ECOG PS 0–2, total bilirubin ≤1.5X ULN, and ALT/AST ≤2.5 X ULN. Patients with baseline neuropathy ≥grade 2 were excluded. Bortezomib was administered at a dose of 1.3 mg/m2 as an intravenous bolus on days 1, 4, 8, and 11 of 21 day cycles with CT evaluation every 6 weeks. The primary endpoint was response rate. Null hypothesis: PR/CR≤5%. Alternative hypothesis: PR/CR ≥20%. 35 patients were required for 90% power with an early stopping rule at 20. Results: 20 patients were enrolled: 11M/9F, PS 0/1 (7/13), 6 gallbladder /14 bile duct. There was one patient with an unconfirmed partial response, 9 patients with stable disease, and 10 patients with progressive disease. Accrual was halted after 20 patients were enrolled as the early stopping rule for futility was met. Median PFS was 48 days (95% CI [32,124]) and median OS was 284 days (95% CI [155, 513]). Grade 3/4 toxicities were observed in 13 patients (65%), most commonly fatigue (4 patients), thrombocytopenia (3 patients), hyperbilirubinemia (3 patients), and hypotension (2 patients). Other SAEs at least possibly related to bortezomib included grade 3 vasculitis (1 patient) and grade 2 meningitis (1 patient). Conclusions: Bortezomib is not an active agent in the treatment of metastatic gallbladder or biliary tract cancer. No significant financial relationships to disclose.