Subcutaneous Rituximab in Combination with Fludarabine and Cyclophosphamide for Patients with CLL: Initial Results of a Phase Ib Study (SAWYER [BO25341]) Show Non-Inferior Pharmacokinetics and Comparable Safety to That of Intravenous Rituximab

Abstract 1637

Rituximab in combination with fludarabine and cyclophosphamide (FC) is recommended as the standard treatment for patients (pts) with chronic lymphocytic leukemia (CLL) where the goal of therapy is to achieve complete remission (ESMO Clinical Practice Guidelines, Ann Oncol 2011). Rituximab is currently administered intravenously (IV) where infusions may take several hours. A subcutaneous (SC) formulation of rituximab has been developed which could significantly shorten administration times, increasing patient convenience and potentially improving tolerability. Here we report part 1 data of a two part, randomized, open-label Phase Ib study of rituximab SC + FC vs rituximab IV + FC in previously untreated pts with CLL (SAWYER [BO25341]). The part 1 objectives were to ensure that the SC dose predicted from the BP22333 study (Salar et al. EHA 2012; ASH 2010) would result in comparable trough serum rituximab concentration (C_trough) to IV in the CLL setting, and to assess safety and tolerability.

Pts (≥18 years old) were enrolled in the study at any point during their initial standard treatment with rituximab IV + FC × 6, prior to commencement of Cycle 5. In Cycle 5, pts received rituximab at 500mg/m² IV + FC and in Cycle 6 rituximab IV was replaced with rituximab SC at 1400 mg, 1600 mg or 1870 mg. Rituximab PK was evaluated on an ongoing basis throughout Cycles 5 and 6 and integrated into a population PK model using nonlinear mixed effects modeling. Model-based simulations were performed to predict serum C_trough and AUC for various rituximab SC fixed doses (1400–1650 mg).

A total of 64 pts were enrolled in part 1 of the study, 55 of these received rituximab SC + FC at doses of either 1400 mg (n = 16), 1600 mg (n=17) or 1870 mg (n=22). Eight pts discontinued treatment prior to Cycle 6 and one pt enrolled to receive 1870 mg rituximab SC at Cycle 6 received a lower dose in error. The median age of pts was 60 years and pts were classified as Binet stage A (27%), B (55%), or C (19%).

At Cycle 6, predicted mean C_trough values for a fixed dose of 1600 mg rituximab SC were 75.2 μg/ml (90% CI: 60.1–90.1 μg/ml) compared with 62.5 μg/ml (90% CI: 49.4–73.6 μg/ml) for a 500 mg/m² dose of rituximab IV. Furthermore, AUC values for 1600 mg rituximab SC were 3760 μg/ml (90% CI: 3250–4240 μg/ml) compared with 3470 μg/ml (90% CI: 3100–3820 μg/ml) for 500 mg/m² rituximab IV, suggesting that a rituximab SC dose of 1600 mg would result in a C_trough and AUC non-inferior to that of the approved IV regimen, independent of pt body surface area.

The majority of adverse events (AEs) reported over the course of Cycles 5 plus 6 were grade 1 or 2 in intensity with 10/16 (63%) pts in the 1400 mg group, 11/17 (65%) pts in the 1600 mg group and 20/22 (91%) pts in the 1870 mg group reporting at least one AE. More pts experienced at least one grade ≥3 AE during Cycle 5 (19 pts following rituximab IV) than Cycle 6 (11 pts following rituximab SC) with the most common grade ≥3 AE reported being neutropenia. Two serious AEs occurred in Cycle 5 and two in Cycle 6. There were no deaths and no withdrawals from treatment due to AEs during Cycles 5 and 6. AEs that occurred during or within 24 h of the administration and were assessed by the investigator as related to rituximab IV/SC were defined as administration-related reactions (ARRs). Two pts reported ARRs at Cycle 5 compared with 12 pts at Cycle 6, with the majority of the Cycle 6 ARRs being related to local injection site reactions. After Cycle, 6 pts and nurses were asked if they preferred SC or IV administration. Of the 56 questionnaires completed, over 90% of pts and their treating nurses preferred the SC route of administration.

In conclusion, results of the population PK analysis propose the selection of a 1600 mg rituximab SC fixed dose for pts with CLL to be administered in part 2 of the study. Safety profiles for rituximab SC were comparable with rituximab IV. A greater number of ARRs were observed after treatment with rituximab SC, these were mainly transient injection site pain and erythema. Questionnaire results after one cycle of rituximab SC indicated clearly that the preferred route of administration, for both nurses and pts was SC. In this study FC could be administered IV or orally; the opportunity to administer FC orally permits the possibility of a chemoimmunotherapy free from IV infusions. The study is ongoing to establish non-inferiority in observed C_trough levels between the confirmed rituximab SC dose and the reference rituximab IV dose.