ALBERT

Description: Journal of Medicinal Chemistry DOI: 10.1021/jm400459m

Description: 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 Ctrough 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 Ctrough 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 Ctrough 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 Ctrough levels at cycle 5 (pre-dose cycle 6). The pre-specified margin for non-inferiority for the geometric mean Ctrough,SC:Ctrough,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 Ctrough,SC:Ctrough,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 Ctrough 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 AUCSC:AUCIV 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 Ctrough 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. Disclosures Assouline: Roche: Honoraria, Research Funding. Off Label Use: This abstract reports on the use of subcutaneous rituximab in combination with oral or IV chemotherapy (fludarabine plus cyclophosphamide) in patients with untreated CLL. Subcutaneous administration of rituximab for NHL indications (but not CLL), is currently licensed in Europe but not in the US.. Buccheri:Janssen-Cilag Farmaceutica Ltd: Membership on an entity's Board of Directors or advisory committees. Delmer:Roche: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria. Gaidano:Roche: Consultancy; GSK: Consultancy; Onyx: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Brewster:Roche Products Ltd.: Employment. Catalani:Roche: Employment. Li:F. Hoffmann–La Roche Ltd.: Employment. McIntyre:Roche Products Ltd.: Employment. Sayyed:F. Hoffmann–La Roche Ltd.: Employment. Badoux:Roche: Honoraria.

Description: Abstract 2858 Rituximab-containing regimens have become the standard of care for patients suffering from various CD20-positive B-cell malignancies. Currently, rituximab is administered as an intravenous (IV) infusion over several hours. These long infusion times and the side effects related to the infusion were cited by some patients as uncomfortable consequences of the current therapeutic treatment. Furthermore, the required procedure to establish intravenous access is considered invasive and can be painful, particularly in patients with malignant diseases who are treated repeatedly. Subcutaneous (SC) administration could significantly simplify treatment, shortening administration to less than 10 minutes and improving patient experience. Recombinant human hyaluronidase (rHuPH20) has been developed and approved to improve dispersion and absorption of co-administered drugs. It has been combined with rituximab to allow injection volumes larger than 10 mL to be safely and comfortably administered SC. The aims of this Phase Ib study were to select the dose of a new SC rituximab formulation with rHuPH20 giving comparable exposure to IV rituximab and to assess its safety and tolerability in male and female follicular lymphoma (FL) patients during maintenance treatment. This presentation shows the stage 1 data of a two-stage randomized, open-label, multi-centre adaptive Phase Ib study. 124 patients have been randomized to one of four rituximab maintenance treatment groups: 16 patients IV control, 34 patients SC dose 1 [375 mg/m2], 34 patients SC dose 2 [625 mg/m2] and 40 patients SC dose 3 [800 mg/m2]. Prior to randomization, eligible patients were treated with at least one IV rituximab dose at 375 mg/m2 in the maintenance setting. For patients randomized to one of the SC cohorts, a single IV dose was replaced by an SC dose. Patients received rituximab either on a q2m or q3m regimen, as per local practice. Safety data are available from a total of 119 patients. Rituximab SC was generally well tolerated. No clinically significant observations or treatment-related serious adverse events have been reported. A total of 95 adverse events (AEs) were reported in 46 patients (39%). The most commonly documented AE was “administration-associated reaction” (AAR, including rash, erythema and mild discomfort). These AARs were reversible, predominantly mild in intensity and only 1 event necessitated any treatment (metoclopramide for nausea). Overall, the AE profile is not significantly different to that expected in patients treated with rituximab IV (after AAR, the most frequent events were gastrointestinal disorders and mild infections). Four serious adverse events (SAEs) were reported in 4 separate patients, all reported as unrelated to study medication. There were no AEs leading to death, withdrawal or treatment discontinuation. The total volume administered SC in each patient ranged between 4.4 – 15.0 mL. The average injection duration was 2 mL/min. Rituximab maximum serum concentrations in the SC cohorts occurred between Day 2 and Day 8 (48 h and 168 h). Pharmacokinetic parameters were linear with respect to dose over the range of SC doses administered (375, 625 and 800 mg/m2). Rituximab concentrations on Day 28 (C28) and the extent of serum exposure (AUC0-57) in patients administered 625 mg/m2 rituximab SC were comparable to those in patients administered the standard rituximab IV dose of 375 mg/m2 SC. In conclusion, subcutaneous rituximab can be delivered quickly, comfortably and safely while achieving serum exposure comparable to the approved intravenous formulation in FL patients during maintenance treatment. The patient experience was favourable. These results support further testing of subcutaneous rituximab and a fixed dose of 1400 mg rituximab SC has been selected for formal Ctrough non-inferiority testing in stage 2 of the trial. Disclosures: McIntyre: Hoffmann-La Roche Ltd.: Employment. Sayyed: Hoffmann-La Roche Ltd.: Employment. Bittner: Hoffmann-La Roche Ltd.: Employment.

Description: Abstract 1629 Rituximab and chemotherapy induction followed by maintenance rituximab is the backbone of therapy for FL. IV rituximab administration can take several hours; therefore, a SC formulation has been developed which may shorten administration times and increase convenience for pts. Achieving clinically effective rituximab serum concentrations is essential for optimal activity (Yin et al, ASCO 2010, abstract e13108). Therefore, achieving non-inferior Ctrough levels with SC compared with IV dosing is expected to provide comparable efficacy. BO22334 (NCT01200758) is a two-stage, phase III, international, randomized, controlled, open-label study of SC vs IV rituximab combined with up to 8 cycles of CHOP or 8 cycles of CVP chemotherapy followed by maintenance in pts with previously untreated FL. Pts were scheduled to receive 8 cycles of rituximab, regardless of the number of chemotherapy cycles. In the SC arm, rituximab was administered IV (375 mg/m2) for the first cycle, with following cycles administered SC (1400 mg). Stage 1 aimed to confirm that the SC rituximab dose of 1400 mg (dose based on phase I study BP22333; Salar et al, EHA 2012, abstract 0794), resulted in non-inferior Ctrough rituximab levels compared with the 375 mg/m2 IV dose when given as 3-weekly induction therapy combined with chemotherapy. The stage 1 primary endpoint was non-inferiority of the Ctrough,SC:Ctrough,IV ratio (limit for non-inferiority was Ctrough ratio 〉 0.8) at Cycle 7 of induction. Secondary endpoints included comparisons of SC vs IV: area under the serum concentration–time curve (AUC); end of induction ORR; CR (CR/CRu); and safety. Previously untreated pts with histologically confirmed CD20-positive grade 1, 2, or 3a FL requiring treatment (N = 127) were randomized 1:1 to SC (n = 63) or IV (n = 64) rituximab, stratified by Follicular Lymphoma International Prognostic Index score, chemotherapy, and region. Allocation to R-CHOP or R-CVP was at the investigator's discretion; 40 pts in each arm (63%) received CHOP chemotherapy and the remaining pts (37%) received CVP chemotherapy. The primary PK endpoint was met with a geometric mean of 134.6 μg/mL for the rituximab SC arm (n = 48) and 83.1 μg/mL for the rituximab IV arm (n = 54) resulting in an SC:IV ratio of 1.62 (90% confidence interval [CI]: 1.36, 1.94). The Ctrough achieved with SC rituximab was therefore concluded to be non-inferior to IV administration. The geometric mean ratio of AUCSC:AUCIV (1.378 [90% CI: 1.241, 1.530]) was also non-inferior. After a median follow-up of approximately 9 months, the overall safety profile was as would be expected for IV administration, with no new or unexpected adverse events (AEs). In the SC and IV arms AEs were experienced by 92% (n = 57) and 88% of pts (n = 57), respectively. Grade 3/4 AE were observed in 47% of pts in the SC arm and 46% in the IV arm. The only grade 3/4 AE occurring in 〉 10% of pts was neutropenia (26% in the SC arm, 22% in the IV arm) which was not associated with increased infection rate (grade 3/4 infections and infestations: 5% SC vs 9% IV). Total administration-related reactions (ARRs; any events occurring during/within 24 hours of drug administration that were considered treatment-related by the study investigator) were higher in the SC vs IV arm (50% vs 32%) with the majority being grade 1/2; there were no grade 4 ARRs. Individual ARRs (all grades) occurring in ≥5% of pts in the SC vs IV arms were: erythema (8% vs 3%), pruritus (6% vs 3%), chills (3% vs 6%), injection site erythema (10% vs 0%), and vomiting (3% vs 6%). Investigator-assessed ORR was 90.5% (95% CI: 80.4, 96.4) in the SC arm and 84.4% (95% CI: 73.1, 92.2) in the IV arm. Complete response (CR/CRu) rates were 46.0% (29/63 pts, 95% CI: 33.4, 59.1) for the SC arm and 29.7% (19/64 pts, 95% CI: 18.9, 42.4) for the IV arm. Stable and progressive disease rates were similar in each arm. An independent review of response assessments is planned. Data demonstrate PK non-inferiority and comparable efficacy for SC (1400 mg) compared with IV (375 mg/m2) rituximab administration, with similar ORR and CR rates in the rituximab SC and IV arms. Overall, SC and IV rituximab AE profiles were similar; ARRs were mostly of mild/moderate intensity. Stage 1 pts are continuing to receive maintenance treatment with SC or IV rituximab. Stage 2 of the study has opened recruitment of an additional 280 pts who will be randomized to receive SC (1400 mg) or IV rituximab. Disclosures: Davies: Roche: Consultancy, Honoraria, Research Funding. Off Label Use: Pharmacokinetics (PK), safety and overall response rate (ORR) achieved with subcutaneous (SC) administration of rituximab in combination with chemotherapy were comparable to those achieved with intravenous (IV) administration in patients (pts) with follicular lymphoma (FL) in the first-line setting. Siritanaratkul:Roche: Research Funding. Solal-Céligny:Roche, France: Consultancy, Honoraria, Research Funding. Boehnke:F. Hoffmann-La Roche: Employment. Berge:Roche: Employment. McIntyre:Roche: Employment. Barrett:Roche: Employment. Macdonald:Roche, Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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.