A Two-Stage Phase Ib Study to Investigate the Pharmacokinetics, Safety and Tolerability of Subcutaneous Rituximab In Patients with Follicular Lymphoma as Part of Maintenance Treatment

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 (AUC_0-57) 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 C_trough non-inferiority testing in stage 2 of the trial.