ALBERT

Description: Abstract 1641 Rituximab has proven efficacy and tolerability for treating B-cell malignancies. IV rituximab administration can take several hours, consuming considerable healthcare resources. A SC rituximab formulation has been developed which may shorten administration time, increase patient (pt) convenience, and potentially reduce IV administration-associated costs. Rituximab efficacy depends on CD20 binding, and Ctrough rituximab levels reflect rituximab exposure throughout the therapy cycle; therefore, achieving a non-inferior Ctrough level with SC dosing is expected to provide comparable efficacy to IV dosing. BP22333 (NCT00930514) is a two-stage phase Ib study assessing PK and tolerability of SC vs IV maintenance rituximab in pts with first-line or relapsed FL. Stage 1 dose-finding results (Salar et al, ASH 2010, abstract 2858; Salar et al, EHA 2012, abstract 0794) identified a fixed dose of 1400 mg for formal Ctrough non-inferiority testing in Stage 2. We report Stage 2 data. The Stage 2 objective was to demonstrate non-inferiority of simulated Ctrough of rituximab SC and IV, using a non-inferiority test with a lower boundary of 0.8 for the 90% confidence interval (CI). Secondary endpoints include SC vs IV rituximab safety and area under the serum concentration-time curve. Eligible pts (N = 157) were aged ≥18 years with an ECOG performance status of ≤ 2, and histologically confirmed CD20-positive grade 1, 2, or 3a FL requiring treatment. Eligible pts must have achieved a complete or partial response following IV rituximab-based induction therapy for FL and have received ≥1 cycle of IV rituximab maintenance within 16 weeks of completing induction. Pts (N = 154) were randomized 1:1 to receive SC rituximab (1400 mg) or IV rituximab (375 mg/m2) for their remaining maintenance cycles, stratified by 2-monthly (q2m) vs 3-monthly (q3m) regimen. Study arms were balanced for age, sex, body surface area, FL grade at diagnosis, induction therapy and number of maintenance doses prior to study entry. As of May 11, 2012, 13 SC pts had withdrawn (7 for progressive disease [PD], 4 for AEs, 1 at investigator's decision, 1 for ineligibility) and 17 IV pts had withdrawn (10 for PD, 4 for AEs, 3 for ineligibility). Median treatment duration on-study was 14.8 months (range, 0–19) in the SC arm and 13.8 months (range, 0–19) in the IV arm. The primary endpoint of the study was met. Geometric mean Ctrough,SC:Ctrough,IV ratios were 1.24 and 1.12, respectively, for q2m and q3m, and lower limits of the two-sided 90% CI (1.02 and 0.86, respectively) exceeded the protocol-specified non-inferiority limit (Ctrough,SC:Ctrough,IV ratio of 0.8). Therefore, 1400 mg SC rituximab was concluded to be non-inferior to 375 mg/m2 IV rituximab administration. AE incidence and intensity were generally balanced; 79% of pts in each arm experienced AEs. Serious AEs were observed in 12% and 14% of pts in the SC and IV arms, respectively; none occurred in 〉 1 pt in either arm. Grade 3/4 AEs occurred in 18% and 17% of pts in the SC and IV arms, respectively; the only grade 3/4 AEs occurring in 〉 1 pt in either arm were neutropenia (2 pts in each arm) and arthralgia (2 pts in the IV arm). Administration-related reactions (ARRs) were the most frequent AE and had a higher incidence in the SC arm (reported in 31% of SC vs 4% of IV pts). ARRs were mostly local reactions; the most common in the SC arm were: erythema (13%), injection site erythema (5%), and myalgia (5%). Further safety data will be presented. PK data for SC and IV rituximab administration demonstrate non-inferiority of 1400 mg rituximab SC administration to that of the approved IV rituximab maintenance regimen for both q2m and q3m schedules. The overall AE profiles were similar for SC and IV rituximab administration, with the exception of local ARRs, which had a higher incidence in the SC arm compared with the IV arm, reflecting the expected change in the ARR profile with SC administration. Induction and maintenance therapy using the 1400 mg SC rituximab dose is being assessed in the phase III BO22334 study. Disclosures: Salar: Roche: Consultancy. Off Label Use: Subcutaneous (SC) administration of rituximab as maintenance therapy in patients with follicular lymphoma (FL). Larouche:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Brewster:Roche: Employment, Equity Ownership. Catalani:Roche: Employment, Equity Ownership. McIntyre:Roche: Employment. Sayyed:Roche: Employment. Haynes:Roche: Consultancy, Honoraria.

Description: 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 (Ctrough) 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 Ctrough 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 Ctrough 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 Ctrough 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 Ctrough levels between the confirmed rituximab SC dose and the reference rituximab IV dose. Disclosures: Assouline: Roche: Honoraria. Off Label Use: Subcutaneous rituximab in combination with fludarabine and cyclophosphamide for patients with CLL. Delmer:French Society of Hematology: Consultancy, Honoraria, Research Funding, participation in French advisory board Other. Gaidano:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Participated in Advisory Boards Other; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Participated in Advisory Boards, Participated in Advisory Boards Other; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Participated in Advisory Boards, Participated in Advisory Boards Other; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Participated in Advisory Boards, Participated in Advisory Boards Other. McIntyre:Roche: Employment. Brewster:Roche: Employment, Equity Ownership. Hourcade-Potelleret:Roche: Employment. Sayyed:Roche: Employment.