Intravenous Rituximab ( MabThera, Rituxan ) 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.
A study has assessed pharmacokinetic non-inferiority of 3 week cycles of fixed-dose subcutaneous Rituximab versus standard intravenous Rituximab.
In the two-stage, randomised, open-label, phase 3 trial, researchers have enrolled patients with previously untreated grade 1-3a, CD20-positive follicular lymphoma at 67 centres in 23 countries.
In stage 1, researchers have randomly allocated patients 1:1 with the Pocock and Simon algorithm to intravenous Rituximab ( 375 mg/m2 ) 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.
During the period 2010-2011, researchers have 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 mcg/mL in the intravenous group and 134.58 mcg/mL in the subcutaneous group ( ratio 1.62 ), showing non-inferiority of subcutaneous Rituximab. 5
7 ( 88% ) of 65 patients in the intravenous Rituximab safety population had adverse events ( 30 [ 46% ] grade greater than or equal to 3 ), as did 57 ( 92% ) of 62 patients in the subcutaneous Rituximab safety population ( 29 [ 47% ] grade greater than or equal to 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.
In conclusion, stage 1 data have shown that the pharmacokinetic profile of subcutaneous Rituximab was non-inferior to intravenous Rituximab and was not associated with new safety concerns. ( Xagena )
Davies A et al, The Lancet Oncology 2014; 15: 343-352