Preliminary Pharmacokinetic (PK) Analysis of Eastern Cooperative Oncology Group Protocol E4402: Rituximab Extended Schedule or Re-Treatment Trial (RESORT).

Background: E4402 is a randomized phase III study comparing two different rituximab dosing strategies for patients (pt) with low tumor burden, indolent histology non-Hodgkin’s lymphoma. Eligible pt receive rituximab weekly x 4 and responders are randomized to receive either re-treatment at progression or a scheduled dose every 3 months (mo). Each strategy is continued until the development of rituximab resistance with a primary endpoint of time to rituximab failure. Administration of a single rituximab dose every 3 mo was based on PK data derived from the Pivotal trial (ref) that suggested 25 mcg/mL may be an important threshold to maintain response, and a PK study (ref Gordon) that suggested this level could be maintained with a single dose administered every 3 mo.

Methods: Rituximab levels were measured within 30 minutes of completion of the 4^th infusion and at 12 weeks (time of response assessment). Pt randomized to re-treatment have trough levels measured at 6 mo, at 1^st relapse, and at the first restaging after re-treatment. Pt randomized to scheduled rituximab have trough levels measured at 6 and 12 mo and upon progression. Presented here is an analysis of serum rituximab levels in 159 and 161 follicular lymphoma pt with available data of week 4 and week 12, respectively.

Results: The median level after the 4^th infusion is 316 mcg/mL (range 56.4–754.0 mcg/mL). The median level at 12 weeks is 26.9 mcg/mL (range 0.0 -87.7). Fifty-three percent of the patients had levels ≥ 25 mcg/mL at 12 weeks. The median week 4 levels are somewhat lower than the Pivotal trial and a comparison of mean levels indicates a statistically significant difference, (312.9 mcg/mL vs. 450 mcg/mL, p-value < 0.0001). However the week 12 levels are similar (table). No correlation between week 4 and week 12 levels was observed in the 132 follicular lymphoma pt with paired data.

Conclusions: Despite the fact that the E4402 pt are untreated and have a low tumor burden, the week 4 serum drug levels are somewhat lower and the week 12 levels are very similar to the Pivotal trial. The week 4 level is not predictive of the week 12 level. These data suggest that serum levels in nearly half of patients receiving a single rituximab dose every 12 weeks will be below a 25 mcg/mL threshold. Future analysis will correlate week 4 and week 12 levels with initial response to rituximab. Later PK time points will be correlated to the time to rituximab resistance.