Elsevier

The Lancet Oncology

Volume 15, Issue 3, March 2014, Pages 343-352
The Lancet Oncology

Articles
Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study

https://doi.org/10.1016/S1470-2045(14)70005-1Get rights and content

Summary

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/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. Stage 2 follow-up is ongoing and is fully accrued. This study is registered with ClinicalTrials.gov, number NCT01200758.

Findings

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.

Interpretation

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.

Funding

F Hoffmann-La Roche.

Introduction

The chimeric anti-CD20 monoclonal antibody rituximab (F Hoffmann-La Roche, Basel, Switzerland) is a mainstay of therapy for B-cell malignancies, including follicular lymphoma. Rituximab increases time-to-treatment failure and overall survival in the first-line treatment of follicular lymphoma when used with chemotherapy.1, 2 Maintenance rituximab after first-line induction therapy has further improved progression-free survival in primary follicular lymphoma3, 4 and when treating subsequent remission.5

Standard rituximab administration involves intravenous infusions lasting 1·5–6 h, which is inconvenient to patients and a burden on health-care resources. Subcutaneous delivery could simplify administration and improve convenience, and has been assessed for rituximab, veltuzumab, trastuzumab, and alemtuzumab in various cancer settings.6, 7, 8, 9 Subcutaneous delivery could also reduce the incidence of severe administration-related reactions and costs.10, 11 Establishment of the subcutaneous route with the existing intravenous rituximab formulation was hindered by injection volumes exceeding those that are normally tolerated. Therefore, a subcutaneous rituximab formulation was developed for delivery at a fixed dose in 5–6 min.7, 12 Subcutaneous rituximab is concentrated at 120 mg/mL compared with the intravenous formulation of 10 mg/mL, and is coformulated with recombinant human hyaluronidase (rHuPH20). rHuPH20 transiently degrades interstitial hyaluronan at the injection site, increasing the volume that can be administered and facilitating drug entry into the circulation.13

To confirm efficacy and safety of subcutaneous rituximab, a pharmacokinetic-based clinical bridging approach was used to establish non-inferiority in pharmacokinetic (and similarity in clinical) endpoints for intravenous and subcutaneous administration of rituximab. Rituximab serum trough concentration (Ctrough) and area under the concentration time curves (AUC) correlate with clinical efficacy14, 15 whereas maximum concentration (Cmax) does not.15 Serum Ctrough levels after subcutaneous administration that are at least as high as those achieved after intravenous rituximab will provide at least the same degree of target-site saturation, which is expected to achieve the same degree of efficacy. By showing pharmacokinetic non-inferiority according to the established intravenous rituximab dose and dosing interval (pharmacokinetic bridging) and excluding reduction in rituximab's antilymphoma activity in one non-Hodgkin lymphoma indication (clinical bridging using follicular lymphoma as an example disease), the results can be applied to other non-Hodgkin lymphoma indications. A similar approach with subcutaneous trastuzumab led to European Commission approval in HER2-positive breast cancer.16, 17, 18, 19

Although cytotoxic drugs are generally dose-adjusted to body surface area or weight, for antibodies such as rituximab with wide therapeutic windows,20, 21 fixed dosing could offer advantages, including avoidance of dose errors and reduced costs from production and storage of one unit dose.22, 23 A simulation study of fixed-dose intravenous monoclonal antibodies, including rituximab, showed that interparticipant exposure variability was not increased significantly relative to dosing based on body size.24

The two-stage SparkThera (NCT00930514) study25 of fixed-dose subcutaneous rituximab (1400 mg) for untreated or relapsed follicular lymphoma suggested maintenance of serum Ctrough in the range of those achieved with standard intravenous maintenance dosing (375 mg/m2). The study then showed non-inferiority of this dose in terms of Ctrough by entering observed data into a population pharmacokinetic model to generate individually simulated serum concentration profiles, and calculated Ctrough and AUC following subcutaneous administration over a range of doses. Safety profiles of both formulations did not differ, apart from an increase in administration-related reactions (eg, injection-site erythema) with subcutaneous rituximab; however, most events were local, mild, reversible, and in line with the expected safety profile for subcutaneous administration.

The subcutaneous rituximab 1400 mg dose identified in SparkThera was selected for further development in SABRINA. This phase 3 study was designed to assess pharmacokinetic non-inferiority of fixed-dose subcutaneous rituximab (1400 mg) versus intravenous rituximab (375 mg/m2) given every 3 weeks and to investigate if the subcutaneous route of administration would impair rituximab's antilymphoma activity.12 SABRINA was done in the first-line induction immunochemotherapy and maintenance settings in follicular lymphoma. We report stage 1 of the study, which assessed pharmacokinetics, safety, and exploratory response rates. Stage 2 will provide additional data on safety and efficacy.

Section snippets

Study design and participants

In the two-stage, phase 3, randomised, controlled, open-label SABRINA study, we enrolled adults (aged ≥18 years) with previously untreated, histologically confirmed CD20-positive grade 1, 2, or 3a follicular lymphoma at 67 centres in 23 countries (appendix). Eligible patients had Eastern Cooperative Oncology Group performance statuses of 0–2, bidimensionally measured disease (by CT or MRI), life expectancy of at least 6 months, adequate haematological function for at least 28 days, and one or

Results

We enrolled 127 patients between Feb 4, 2010, and Oct 21, 2011, with data cutoff of June 12, 2012. In stage 1, 64 patients were randomly allocated to intravenous rituximab and 63 were randomly allocated subcutaneous rituximab (figure 1, table 1). One (2%) of 63 patients in the subcutaneous group discontinued treatment after the first intravenous infusion and was analysed as part of the intravenous group for safety analyses. In both groups, 63% of patients received CHOP and about 37% received

Discussion

Our phase 3 SABRINA study is designed to assess pharmacokinetics, safety, and efficacy in follicular lymphoma induction therapy followed by maintenance treatment (panel). In stage 1 of the study, we showed non-inferiority of a subcutaneous formulation of rituximab in terms of Ctrough compared with intravenous rituximab. Results from body surface area and sex subgroup analyses did not suggest any notably different results from the main analysis. However, these data should be interpreted

References (27)

  • O Shpilberg et al.

    Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin) using hyaluronidase

    Br J Cancer

    (2013)
  • DM Goldenberg et al.

    Veltuzumab (humanized anti-CD20 monoclonal antibody): characterization, current clinical results, and future prospects

    Leuk Lymphoma

    (2010)
  • E De Cock et al.

    Time savings with rituximab subcutaneous (SC) injection vs rituximab intravenous (IV) infusion: final analysis from a time-and-motion study in 8 countries

    Blood

    (2013)
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