Non-Inferior Pharmacokinetics with Comparable Safety and Response Rates for Subcutaneous (SC), Compared with Intravenous (IV), Rituximab in Combination with Fludarabine and Cyclophosphamide (FC) in Patients (Pts) with Untreated Chronic Lymphocytic Leukemia (CLL): Part 2 of the Phase Ib SAWYER Study (BO25341)

Background

Rituximab plus FC is standard treatment for pts with CLL (NCCN Clinical Practice Guidelines, v2.2014). Rituximab is currently administered by the IV route, which may take several hours. SC administration of rituximab is associated with significant administration time savings and is preferred by pts receiving rituximab for B-cell malignancies, compared with IV administration. Rituximab binds CD20 on the surface of systemic B-cells, and the SC formulation was developed to attain serum C_trough levels at least as high as with IV infusion, to achieve at least the same degree of target-site saturation and hence similar efficacy to IV administration.

Methods

SAWYER is a two-part, randomized, open-label Phase Ib study of rituximab SC or IV plus FC (oral or IV) for up to 6 cycles in previously untreated CLL pts. Part 1 of the study predicted that a rituximab SC fixed dose of 1600 mg would achieve C_trough levels non-inferior to those with rituximab IV 500 mg/m² (manuscript submitted: Assouline S, 2014). We report data from part 2 of the study, which aimed to confirm the non-inferiority of C_trough levels for fixed-dose rituximab SC 1600 mg compared with IV 500 mg/m² given 4-weekly. Pts were randomized 1:1 to receive rituximab IV (n=88) or SC (n=88) in combination with FC, stratified by Binet stage and route of FC administration (oral vs IV); all pts received rituximab IV 375 mg/m² in the first cycle. For cycles 2–6, pts received either rituximab IV 500 mg/m² or rituximab SC 1600 mg fixed dose. The primary endpoint of part 2 was non-inferiority in observed rituximab C_trough levels at cycle 5 (pre-dose cycle 6). The pre-specified margin for non-inferiority for the geometric mean C_trough,SC:C_trough,IV ratio was a lower limit of the 90% confidence interval [CI] of ≥0.8. Secondary endpoints included comparisons of area under the serum concentration–time curve (AUC), safety, end of treatment response, overall response rate (ORR) and complete response rate (CRR; including CR and CRi).

Results

Untreated pts with CD20+ B-CLL requiring treatment per iwCLL criteria received rituximab SC or IV. The median age was 60 years (range 25–78) and pt characteristics were well balanced, excepting more male pts in the SC arm (71%) than the IV arm (60%). Most pts had Binet stage B (62%), followed by stage C and A (24% and 14%, respectively). At enrollment, 69% of pts received IV FC. The primary endpoint was met: the geometric mean C_trough,SC:C_trough,IV ratio was 1.53 at cycle 5 (pre-dose cycle 6), with the lower limit of the 90% CI of 1.27, above the pre-specified non-inferiority margin. The geometric mean C_trough was 97.5 μg/mL in the rituximab SC arm and 61.5 μg/mL in the rituximab IV arm. The cycle 6 geometric mean ratio of AUC_SC:AUC_IV was 1.10 [90% CI: 0.98, 1.24]) indicating that AUC after SC was also at least as high as after IV administration. The investigator-assessed ORRs and CRRs at 3 months were 85% (95% CI: 76, 92) and 81% (95% CI: 71, 88); and 26% (95% CI: 17, 37) and 33% (95% CI: 23, 44) in the SC and IV arms, respectively. For both arms, these rates were within the expected range for a comparable CLL population treated with rituximab plus FC.

At a median follow-up of approximately 14 months (range 4–20), the overall safety profile for SC was similar to IV administration, with no unexpected adverse events (AEs). AEs were experienced by 96% (n=82) and 91% of pts (n=81) in the SC and IV arms, respectively. Severe (grade ≥3) AEs were observed in 69% of pts in the SC arm and 71% in the IV arm. Of individual grade ≥3 AEs, only neutropenia (56% SC, 52% IV) and leukopenia (14% SC, 12% IV) occurred in >10% of pts. Grade ≥3 infections (13% SC [n=11], 10% IV [n=9]) were similar between the two arms. The rate of administration-related reactions (ARRs; AEs occurring during/within 24 hours of drug administration considered treatment-related by the study investigator) was similar in the SC (44%) and IV (45%) arms; the majority being grade 1/2; 10 pts (n=6 SC, n=4 IV) experienced grade 3/4 ARRs. ARRs (all grades) occurring in ≥5% of pts in the SC vs IV arms were: chills (11% vs 7%), pyrexia (8% vs 9%), injection site erythema (12% vs 0%), nausea (2% vs 12%), vomiting (4% vs 7%), hypotension (1% vs 7%), and headache (2% vs 6%).

Conclusions

These data demonstrate non-inferiority of C_trough and AUC for rituximab SC 1600 mg compared with rituximab IV 500 mg/m² when given every 4 weeks in combination with FC in pts with CLL. Both administration routes were associated with comparable safety and response rates.