title: Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study.
abstract: BACKGROUND
  Intravenous rituximab is a mainstay of treatment for follicular lymphoma. A subcutaneous formulation that achieves equivalent rituximab serum concentrations might improve convenience and save health-care resources without sacrificing clinical activity. We aimed to assess pharmacokinetic non-inferiority of 3 week cycles of fixed-dose subcutaneous rituximab versus standard intravenous rituximab.
  
  
  METHODS
  In our two-stage, randomised, open-label, phase 3 trial, we enrolled patients with previously untreated grade 1-3a, CD20-positive follicular lymphoma at 67 centres in 23 countries. In stage 1, we randomly allocated patients 1:1 with the Pocock and Simon algorithm to intravenous rituximab (375 mg/m(2)) or fixed-dose subcutaneous rituximab (1400 mg), stratified by induction chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, prednisone or cyclophosphamide, vincristine, prednisone), Follicular Lymphoma International Prognostic Index score, and region. After randomisation, patients received one induction dose of intravenous rituximab in cycle 1 and then allocated treatment for cycles 2-8. Patients with a complete or partial response following induction therapy continued intravenous or subcutaneous rituximab as maintenance every 8 weeks. The primary endpoint was the ratio of observed rituximab serum trough concentrations (Ctrough) between groups at cycle 7 (before cycle 8 dosing) of induction treatment in a per-protocol population. Patients were analysed as treated for safety endpoints. Stage 2 follow-up is ongoing and is fully accrued. This study is registered with ClinicalTrials.gov, number NCT01200758.
  
  
  RESULTS
  Between Feb 4, 2010, and Oct 21, 2011, we enrolled 127 patients. Pharmacokinetic data were available for 48 (75%) of 64 patients randomly allocated intravenous rituximab and 54 (86%) of 63 patients randomly allocated subcutaneous rituximab. Geometric mean Ctrough was 83·13 μg/mL in the intravenous group and 134·58 μg/mL in the subcutaneous group (ratio 1·62, 90% CI 1·36-1·94), showing non-inferiority of subcutaneous rituximab. 57 (88%) of 65 patients in the intravenous rituximab safety population had adverse events (30 [46%] grade ≥3), as did 57 (92%) of 62 patients in the subcutaneous rituximab safety population (29 [47%] grade ≥3). The most common grade 3 or worse adverse event in both groups was neutropenia (14 [22%] patients in the intravenous group and 16 [26%] patients in the subcutaneous group). Adverse events related to administration were mostly grade 1-2 and occurred in 21 (32%) patients in the intravenous group and 31 (50%) patients in the subcutaneous group.
  
  
  CONCLUSIONS
  Stage 1 data show that the pharmacokinetic profile of subcutaneous rituximab was non-inferior to intravenous rituximab and was not associated with new safety concerns. Stage 2 will provide data for efficacy and safety of the subcutaneous administration.
  
  
  BACKGROUND
  F Hoffmann-La Roche.
authors: Cancer Research UK Centre, University of Southampton Faculty of Medicine, Southampton, UK. Electronic address: A.Davies@southampton.ac.uk.
authors: Andrew
authors: A
authors: Davies
authors: Hematology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.
authors: Francesco
authors: F
authors: Merli
authors: Clinic of Hematology, CCS, and Faculty of Medicine, University of Belgrade, Serbia.
authors: Biljana
authors: B
authors: Mihaljevic
authors: Division of Hematology, Department of Medicine, Siriraj Hospital, Bangkok, Thailand.
authors: Noppadol
authors: N
authors: Siritanaratkul
authors: Institut de Cancérologie de l'Ouest, Nantes, France.
authors: Phillippe
authors: P
authors: Solal-Céligny
authors: Clinical Development, Roche Products, Welwyn Garden City, UK.
authors: Martin
authors: M
authors: Barrett
authors: Clinical Development, F Hoffmann-La Roche, Basel, Switzerland.
authors: Claude
authors: C
authors: Berge
authors: Clinical Development, F Hoffmann-La Roche, Basel, Switzerland.
authors: Beate
authors: B
authors: Bittner
authors: Clinical Development, F Hoffmann-La Roche, Basel, Switzerland.
authors: Axel
authors: A
authors: Boehnke
authors: Clinical Pharmacology, Roche Products, Welwyn Garden City, UK.
authors: Christine
authors: C
authors: McIntyre
authors: Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.
authors: David
authors: D
authors: Macdonald
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000069283:Rituximab
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab