Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial

Assouline, Sarit; Buccheri, Valéria; Delmer, Alain; Gaïdano, Gianluca; Trněný, Marek; Berthillon, Natalia; Brewster, Michael; Catalani, Olivier; Li, Sai; McIntyre, Christine; Sayyed, Pakeeza; Badoux, Xavier C.

doi:10.1016/s2352-3026(16)00004-1

Cited by 39 publications

(47 citation statements)

References 24 publications

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“…Clinical efficacy and safety were confirmed by several large phase III trials, including the MabEASE, SABRINA and SAWYER studies, which demonstrated no difference in clinical outcomes between intravenous and subcutaneous routes of rituximab administration. [65][66][67] Safety findings appeared comparable as well, and no unexpected safety signals have been generated. However, the subcutaneous formulation has been associated with a slightly increased risk of administration reactions in some trials, as well as local injection site reactions, but these seem to be generally mild and easily managed.…”

Section: Rituximabmentioning

confidence: 62%

“…61,62 Thereafter, trials to demonstrate safety and pharmacokinetic equivalence were undertaken in patients with CLL, follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). [63][64][65] These studies consistently demonstrated the non-inferiority of the subcutaneous formulation for maintaining adequate trough levels of rituximab. Clinical efficacy and safety were confirmed by several large phase III trials, including the MabEASE, SABRINA and SAWYER studies, which demonstrated no difference in clinical outcomes between intravenous and subcutaneous routes of rituximab administration.…”

Section: Rituximabmentioning

confidence: 65%

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Anti-CD20 monoclonal antibodies: reviewing a revolution

Casan

Wong

Northcott

et al. 2018

Human Vaccines & Immunotherapeutics

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Since the inception of rituximab in the 1990s, anti-CD20 monoclonal antibodies have revolutionised the treatment of B cell hematological malignancies and have become a cornerstone of modern gold-standard practice. Additionally, the potent efficacy of these agents in depleting the B cell compartment has been used in the management of a broad array of autoimmune diseases. Multiple iterations of these agents have been investigated and are routinely used in clinical practice. In this review, we will discuss the physiology of CD20 and its attractiveness as a therapeutic target, as well as the pharmacology, pre-clinical and clinical data for the major anti-CD20 monoclonal antibodies: rituximab, obinutuzumab and ofatumumab.

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Section: Rituximabmentioning

confidence: 62%

Section: Rituximabmentioning

confidence: 65%

Anti-CD20 monoclonal antibodies: reviewing a revolution

Casan

Wong

Northcott

et al. 2018

Human Vaccines & Immunotherapeutics

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“…In part 2 of the SAWYER study, a separate group of previously untreated patients with CLL received induction treatment with FC, plus either a fixed 1600 mg dose of rituximab SC or 500 mg/m 2 rituximab IV every 4 weeks for up to six cycles [ 48 ]. In cycle 1, all patients received rituximab IV at 375 mg/m 2 .…”

Section: Clinical Studiesmentioning

confidence: 99%

“…OR rates 3 months after treatment completion were 85% and 81% for the rituximab SC and IV groups, respectively. CR rates were 26% and 33% [ 48 ].…”

Section: Clinical Studiesmentioning

confidence: 99%

Subcutaneous Rituximab for the Treatment of B-Cell Hematologic Malignancies: A Review of the Scientific Rationale and Clinical Development

et al. 2017

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Rituximab (MabThera®/Rituxan®), a chimeric murine/human monoclonal antibody that binds specifically to the transmembrane antigen CD20, was the first therapeutic antibody to enter clinical practice for the treatment of cancer. As monotherapy and in combination with chemotherapy, rituximab has been shown to prolong progression-free survival and, in some indications overall survival, in patients with various B-cell malignancies, while having a well-established and manageable safety profile and a wide therapeutic window. As a result, rituximab is considered to have revolutionized treatment practices for patients with B-cell malignancies. A subcutaneous (SC) formulation of rituximab has been developed, comprising the same monoclonal antibody as the originally marketed formulation [rituximab concentrate for solution for intravenous (IV) infusion], and has undergone a detailed, sequential clinical development program. This program demonstrated that, at fixed doses, rituximab SC achieves non-inferior serum trough concentrations in patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia, with comparable efficacy and safety relative to the IV formulation. The added benefit of rituximab SC was demonstrated in dedicated studies showing that rituximab SC allows for simplified and shortened drug preparation and administration times resulting in a reduced treatment burden for patients as well as improved resource utilization (efficiency) at the treatment facility. The improved efficiency of delivering rituximab’s benefit to patients may broaden patient access to rituximab therapy in areas with low levels of healthcare resources, including IV-chair capacity constraints. This article is a companion paper to G. Salles, et al., which is also published in this issue. FundingF. Hoffmann-La Roche Ltd.

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“…The PK bridging approach for the clinical development of MabThera SC included two Phase 1b clinical studies (SparkThera in FL and SAWYER in CLL) and one Phase 3 study (SABRINA in FL) aimed to confirm comparability of MabThera SC vs. IV in terms of PK. Clinical pharmacology data from these studies demonstrated a statistically noninferior exposure (C trough ) with fixed doses of 1400 mg and 1600 mg MabThera SC compared with the established MabThera IV body surface area-adjusted doses in NHL and CLL, respectively [30][31][32]. Based on extensive scientific knowledge on rituximab's mechanism of action and decades of clinical knowledge, achieving comparable rituximab exposure is expected to produce comparable target site saturation and B-cell depletion, resulting in analogous efficacy.…”

Section: What Are the Data Requirements For Approval Of Sc Formulationsmentioning

confidence: 99%

Development pathways for subcutaneous formulations of biologics versus biosimilar development

Zharkov

Barton

Heinzmann

et al. 2019

Expert Review of Precision Medicine and Drug Development

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Introduction: Biologics are highly complex drugs and many of their characteristics are defined by the manufacturing process. In recent years, several monoclonal antibody (mAb) biologics, which were hitherto only available for intravenous (IV) administration, have been reformulated for subcutaneous (SC) administration. Reformulation involves alterations to the established manufacturing process and it has been argued that a SC formulation should therefore be considered a biosimilar version of its previously approved IV formulation. Areas covered: Developing an SC version of an approved IV mAb product requires the adaptation of its formulation and route of administration. This process is illustrated via case examples of trastuzumab and rituximab and summarize what data requirements support the regulatory approval of these new formulations. Furthermore, we discuss similarities and differences between the development of an SC product vs. the development of a biosimilar. Expert opinion: The production process of a biosimilar is independently established from the very beginning, while the development of an SC formulation affects later stages of an already established production process and builds on extensive experience with the IV formulation. Considering these fundamentally different situations, a biologic product reformulated for SC administration should not be considered a 'biosimilar' version of itself. ARTICLE HISTORY

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Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial

Cited by 39 publications

References 24 publications

Anti-CD20 monoclonal antibodies: reviewing a revolution

Anti-CD20 monoclonal antibodies: reviewing a revolution

Subcutaneous Rituximab for the Treatment of B-Cell Hematologic Malignancies: A Review of the Scientific Rationale and Clinical Development

Development pathways for subcutaneous formulations of biologics versus biosimilar development

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