CoChat
Sign Up
Cited by 114Lymphoma Diagnosis and TreatmentChronic Lymphocytic Leukemia ResearchNeutropenia and Cancer Infections

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

Davies, Andrew, Merli, Francesco, Mihaljevic, Biljana, Siritanaratkul, Noppadol, Solal-Céligny, Phillippe, Barrett, Martin, Berge, Claude, Bittner, Beate +3 more·2014·The Lancet Oncology
DOI 10.1016/s1470-2045(14)70005-1
Open this paper in CoChat — free account

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.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.

Integrity signals

Registry

Crossref · 10.1016/s1470-2045(14)70005-1

Cites

27 of 27 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Population pharmacokinetic modeling using data from clinical trials of various biotherapeutics has confirmed that fixed dosing of monoclonal antibodies could be feasible for the majority of molecules assessed, without impairing the safety and efficacy of the treatment.

    “Furthermore, population pharmacokinetic (PopPK) modeling using data from clinical trials of various biotherapeutics has confirmed that fixed dosing of mAbs could be feasible for the majority of molecules assessed, without impairing the safety and efficacy of the treatment [20–23].”

    From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [21]

  • When developing the subcutaneous formulation for trastuzumab and rituximab, the change from intravenous to subcutaneous administration included a switch from weight- and body surface area-adjusted dosing to a fixed dose.

    “When developing the subcutaneous formulation for trastuzumab and rituximab, the change from intravenous to subcutaneous administration included a switch from weight- and body surface area-adjusted dosing to a fixed dose [21, 39, 74].”

    From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [21]

  • The fixed-dose regimens for trastuzumab and rituximab were further supported by exposure-response analyses of response and grade ≥3 adverse events, which did not identify a statistically meaningful impact of bodyweight or body surface area, nor of exposure or route of administration of the respective mAbs.

    “The fixed-dose regimens for trastuzumab and rituximab were further supported by exposure–response analyses of response and grade ≥ 3 adverse events, which did not identify a statistically meaningful impact of bodyweight or body surface area, respectively, nor of exposure or route of administration of the respective mAbs [21, 74].”

    From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [21]

  • In both the HannaH and Sabrina studies, subcutaneous administration of trastuzumab and rituximab resulted in noninferior Ctrough and efficacy to intravenous dosing and a similar safety profile.

    “In both the HannaH and the Sabrina studies, subcutaneous administration of trastuzumab and rituximab resulted in noninferior Ctrough and efficacy to intravenous dosing and a similar safety profile [21, 39, 74].”

    From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [21]

  • In Sabrina, overall response at the end of induction was 84.9% (95% CI 79.2-89.5) in the intravenous group and 84.4% (78.7-89.1) in the subcutaneous group.

    “Overall response at the end of induction was 84.9% (95% CI 79.2–89.5) in the intravenous group and 84.4% (78.7–89.1) in the subcutaneous group.”

    From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [21]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Davies, A., Merli, F., Mihaljevic, B., Siritanaratkul, N., Solal-Céligny, P., Barrett, M., Berge, C., Bittner, B., Boehnke, A., McIntyre, C., & MacDonald, D.
Affiliations
  • Cancer Research UK (GB)
  • Santa Maria Nuova Hospital (IT)
  • Siriraj Hospital (TH)
  • Institut de Cancérologie de l'Ouest (FR)
  • Roche (United Kingdom) (GB)
  • F. Hoffmann-La Roche AG (CH)
  • Queen Elizabeth II Health Sciences Centre (CA)
Corresponding author
Davies, Andrew
ORCID
Venue
The Lancet Oncology
Publisher
Elsevier BV
Published
2014-03
Volume
15
Issue
3
Pages
343-352
ISSN
1470-2045 (ISSN-L)
DOI
10.1016/s1470-2045(14)70005-1
OpenAlex
W2120711586
Cited by
114
References
27
Citations by year
2026: 3 · 2025: 5 · 2024: 6 · 2023: 7 · 2022: 11 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 13 · 2017: 13 · 2016: 16 · 2015: 12 · 2014: 6
FWCI
11.65
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • The Lancet Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • ePrints Soton (University of Southampton) (submittedVersion)
Funders
F. Hoffmann-La Roche
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Oncology › Neutropenia and Cancer Infections
Keywords
follicular lymphoma, pharmacokinetics, non-inferiority, CD20-positive lymphoma, maintenance therapy, induction chemotherapy, fixed-dose dosing, adverse events, drug safety, previously untreated lymphoma, R-CHOP
MeSH terms
Rituximab, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Female, Humans, Injections, Subcutaneous, Lymphoma, Follicular, Male, Middle Aged, Neoplasm Staging, Antibodies, Monoclonal, Murine-Derived

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review