A randomized, open-label, multicenter phase II study of bortezomib with fludarabine in comparison to rituximab with fludarabine in follicular lymphoma subjects previously treated with rituximab.

TPS303 Background: Rituximab is routinely administered in several consecutive lines of therapy for follicular lymphoma. Although the frequency and significance of emerging rituximab resistance is not being prospectively quantified, a major question remains as to the therapeutic value of continuing rituximab beyond ≥2 lines of therapy. It is clear that the response rate decreases with subsequent treatment with rituximab. This study intends to compare the response rate of continued rituximab in combination with fludarabine (in patients heavily pretreated with rituximab), versus a new regimen of bortezomib (VELCADE) in combination with fludarabine. In vitro, the combination of bortezomib and fludarabine resulted in increased cytotoxicity associated with enhanced apoptosis. A phase I dose-escalation study combining fludarabine and bortezomib was previously reported by Snell et al (2006). The combination was found to be safe and tolerable, and several patients in this heavily pretreated cohort achieved CR/CRu and PRs. Methods: Eligible subjects must have received at least 12 prior doses of rituximab (and be fludarabine naïve), and have documented relapse or progression. One hundred ten subjects are expected to participate and will be randomized in a 1:1 ratio between the 2 treatment arms. It is expected that there will be 17 months of accrual. There are currently 7 countries and 34 sites participating, with the first patient now randomized. Subjects randomized to Arm A will receive bortezomib 1.6 mg/m2 i.v. on Days 1, 8, 15, 22 and fludarabine 40 mg/m2/day orally on Days 1 to 5. Subjects randomized to Arm B will receive fludarabine 40 mg/m2/day on Days 1 to 5 and rituximab 375 mg/m2 on Day 1 of every cycle. Treatment cycles will be repeated every 35 days for a maximum of 8 cycles. The primary efficacy endpoint is complete response rate. Disease response and progression will be evaluated according to modified IWRC criteria by radiographic imaging. The CT scans and other radiographic evaluations will be centrally assessed by an Independent Review Committee (IRC) to confirm disease response for the purpose of the efficacy analyses. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson Johnson & Johnson Johnson & Johnson Johnson & Johnson Johnson & Johnson