Pharmacokinetics and safety of subcutaneous rituximab plus fludarabine and cyclophosphamide for patients with chronic lymphocytic leukaemia.

AIMS: The aim of the phase Ib, two part SAWYER study (BO25341; NCT01292603) was to investigate the pharmacokinetics and safety of subcutaneous (s.c.) rituximab compared with intravenous (i.v.) rituximab, both in combination with fludarabine and cyclophosphamide (FC), as first line treatment for patients with chronic lymphocytic leukaemia (CLL). METHODS: During part 1 (dose-finding), CLL patients received rituximab i.v. followed by a single dose of rituximab s.c. at one of three fixed doses (1400, 1600 or 1870 mg) in cycle 6. The primary objective was to identify a fixed s.c. dose that would achieve comparable rituximab serum trough concentrations (Ctrough ) to those achieved with the standard 4 weekly 500 mg m(-2) rituximab i.v. dose. RESULTS: Fifty-five patients received a fixed dose of rituximab s.c., 16 received 1400 mg, 17 received 1600 mg and 22 received 1870 mg. The 1600 mg dose was predicted to achieve non-inferior Ctrough to standard rituximab i.v. TREATMENT: The rituximab s.c. safety profile was comparable with rituximab i.v., except that local administration-related reactions, mainly mild/moderate injection site reactions, occurred more frequently with rituximab s.c., which was not unexpected. Subcutaneous administration was preferred to i.v. administration by >90% of patients and nurses (n = 112). CONCLUSIONS: SAWYER part 1 data predict that rituximab s.c. 1600 mg will achieve non-inferior Ctrough concentrations to rituximab i.v. 500 mg m(-2) , administered 4 weekly. This fixed s.c. dose is currently undergoing formal non-inferiority assessment in SAWYER part 2. In future, CLL treatment regimens comprising rituximab s.c. and oral FC could substantially reduce i.v. chair time.

Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial.

BACKGROUND: Part one of the two-part SAWYER study predicted that subcutaneous rituximab 1600 mg would achieve trough serum concentrations that were non-inferior to those achieved with intravenous rituximab 500 mg/m(2) in patients with chronic lymphocytic leukaemia. In part two of the study, we aimed to confirm the pharmacokinetic non-inferiority of subcutaneous rituximab, and investigate its safety and efficacy. METHODS: We did this phase 1b, open-label, randomised controlled non-inferiority study at 68 centres in 19 countries in Europe, North America, South America, and Australasia. Patients aged 18 years or older with untreated chronic lymphocytic leukaemia were randomly assigned, via an interactive voice-response system with a permuted block randomisation scheme (block size of ten), to receive subcutaneous rituximab 1600 mg or intravenous rituximab 500 mg/m(2) plus fludarabine and cyclophosphamide every 4 weeks for up to six cycles. In cycle one, all patients received intravenous rituximab 375 mg/m(2). Randomisation was stratified by Binet stage and fludarabine and cyclophosphamide administration route (oral vs intravenous). Study investigators and patients were not masked to group allocation, but allocation was concealed from the statistician, clinical scientist, and clinical pharmacologist. The primary endpoint was trough serum concentration at cycle five, with a non-inferiority margin of 0·8 for the adjusted geometric mean ratio of the subcutaneous to the intravenous dose. We did the primary analysis in patients in the intention-to-treat population with complete pharmacokinetic data (pharmacokinetic population). This trial is registered with ClinicalTrials.gov, number NCT01292603, and is ongoing, although the treatment stage is now complete. FINDINGS: Between Aug 20, 2012, and June 17, 2013, we randomly assigned 176 patients to receive subcutaneous rituximab (n=88) or intravenous rituximab (n=88); 134 (76%) patients comprised the pharmacokinetic population. As of May 7, 2014, median follow-up was 13·9 months (IQR 11·9-16·0) for patients in the subcutaneous group and 14·1 months (11·6-16·5) for patients in the intravenous group. At cycle five, the geometric mean trough serum concentration in patients given subcutaneous rituximab was non-inferior to that in patients given intravenous rituximab (97·5 µg/mL vs 61·5 µg/mL), with an adjusted geometric mean ratio of 1·53 (90% CI 1·27-1·85). In the safety analysis, the proportion of patients reporting adverse events was similar between the subcutaneous and intravenous groups (all grades: 82 [96%] of 85 patients and 81 [91%] of 89 patients; serious adverse events: 25 [29%] and 29 [33%] patients; grade ≥3: 59 [69%] and 63 [71%] patients, respectively). The most common adverse event of grade 3 or higher was neutropenia (48 [56%] patients in the subcutaneous group and 46 [52%] patients in the intravenous group); the most common serious adverse event was febrile neutropenia (n=9 [11%] and n=4 [4%], respectively). We recorded administration-related reactions in 37 (44%) patients given subcutaneous rituximab and 40 (45%) patients given the intravenous dose, with differences between administration routes for injection-site erythema (n=10 [12%] and n=0, respectively) and nausea (n=2 [2%] and n=11 [12%], respectively). More patients reported local cutaneous reactions after subcutaneous rituximab (n=36 [42%]) than after intravenous rituximab (n=2 [2%]); most of these reactions were grade 1 or 2. INTERPRETATION: When combined with fludarabine and cyclophosphamide, subcutaneous rituximab 1600 mg achieved trough serum concentrations that were pharmacokinetically non-inferior to those achieved with intravenous rituximab 500 mg/m(2), with a similar safety and efficacy profile between the two groups. Treatment with subcutaneous rituximab should allow patients with chronic lymphocytic leukaemia to receive clinical benefit from the drug via a more convenient delivery method than the intravenous route, and might also be used in combination regimens with approved and emerging oral regimens. FUNDING: F Hoffmann-La Roche.

Sustained polymeric delivery of gene silencing antisense ODNs, siRNA, DNAzymes and ribozymes: in vitro and in vivo studies.

Small interfering RNA (siRNA), antisense oligonucleotides (ODNs), ribozymes and DNAzymes have emerged as sequence-specific inhibitors of gene expression that may have therapeutic potential in the treatment of a wide range of diseases. Due to their rapid degradation in vivo, the efficacy of naked gene silencing nucleic acids is relatively short lived. The entrapment of these nucleic acids within biodegradable sustained-release delivery systems may improve their stability and reduce the doses required for efficacy. In this study, we have evaluated the potential in vitro and in vivo use of biodegradable poly (D,L-lactide-co-glycolide) copolymer (PLGA) microspheres as sustained delivery devices for ODNs, ribozyme, siRNA and DNA enzymes. In addition, we investigated the release of ODN conjugates bearing 5'-end lipophilic groups. The in vitro sustained release profiles of microsphere-entrapped nucleic acids were dependent on variables such as the type of nucleic acid used, the nature of the lipophilic group, and whether the nucleic acid used was single or double stranded. For in vivo studies, whole body autoradiography was used to monitor the bio-distribution of either free tritium-labelled ODN or that entrapped within PLGA microspheres following subcutaneous administration in Balb-c mice. The majority of the radioactivity associated with free ODN was eliminated within 24 h whereas polymer-released ODN persisted in organs and at the site of administration even after seven days post-administration. Polymer microsphere released ODN exhibited a similar tissue and cellular tropism to the free ODN. Micro-autoradiography analyses of the liver and kidneys showed similar bio-distribution for polymer-released and free ODNs with the majority of radioactivity being concentrated in the proximal convoluted tubules of the kidney and in the Kupffer cells of the liver. These findings suggest that biodegradable PLGA microspheres offer a method for improving the in vivo sustained delivery of gene silencing nucleic acids, and hence are worthy of further investigation as delivery systems for these macromolecules.

Comparison of subcutaneous versus intravenous administration of rituximab as maintenance treatment for follicular lymphoma: results from a two-stage, phase IB study.

PURPOSE: This two-stage phase IB study investigated the pharmacokinetics and safety of subcutaneous (SC) versus intravenous (IV) administration of rituximab as maintenance therapy in follicular lymphoma. PATIENTS AND METHODS: In stage 1 (dose finding), 124 patients who responded to rituximab induction were randomly assigned to SC rituximab (375 mg/m2, 625 mg/m2, or an additional group at 800 mg/m2) or IV rituximab (375 mg/m2). The objective was to determine an SC dose that would yield a rituximab serum trough concentration (Ctrough) in the same range as that of IV rituximab. In stage 2, 154 additional patients were randomly assigned (1:1) to SC rituximab (1,400 mg) or IV rituximab (375 mg/m2) given at 2- or 3-month intervals. The objective was to demonstrate noninferior rituximab Ctrough of SC rituximab relative to IV rituximab 375 mg/m2. RESULTS: Stage 1 data predicted that a fixed dose of 1,400 mg SC rituximab would result in a serum Ctrough in the range of that of IV rituximab. Noninferiority (ie, meeting the prespecified 90% CI lower limit of 0.8) was then confirmed in stage 2, with geometric mean Ctrough SC:Ctrough IV ratios for the 2- and 3-month regimens of 1.24 (90% CI, 1.02 to 1.51) and 1.12 (90% CI, 0.86 to 1.45), respectively. Overall safety profiles were similar between formulations (in stage 2, 79% of patients experienced one or more adverse events in each group). Local administration-related reactions (mainly mild to moderate) occurred more frequently after SC administration. CONCLUSION: The fixed dose of 1,400 mg SC rituximab predicted by using stage 1 results was confirmed to have noninferior Ctrough levels relative to IV rituximab 375 mg/m2 dosing during maintenance, with a comparable safety profile. Additional investigation will be required to determine whether the SC route of administration for rituximab provides equivalent efficacy compared with that of IV administration.