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Trials. 2018 Nov 9;19(1):619. doi: 10.1186/s13063-018-2996-6.

RIVA - a phase IIa study of rituximab and varlilumab in relapsed or refractory B-cell malignancies: study protocol for a randomized controlled trial.

Author information

1
Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton, Southampton, UK.
2
Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, Southampton, UK.
3
Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
4
Southampton Clinical Trials Unit, Centre for Cancer Immunology, University of Southampton, Southampton, UK. J.Dhondt@soton.ac.uk.
5
Southampton Clinical Trials Unit, Centre for Cancer Immunology, University of Southampton, Southampton, UK.
6
ECMC Southampton, University of Southampton, Southampton, UK.
7
CRUK Centre Southampton, University of Southampton, Southampton, UK.

Abstract

BACKGROUND:

Over 12,000 new cases of B-cell malignancies are diagnosed in the UK each year, with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) being the most common subtypes. Standard frontline therapy consists of immunochemotherapy with a CD20 monoclonal antibody (mAb), such as rituximab, delivered in combination with multi-agent chemotherapy. Despite being considered a treatable and potentially curable cancer, approximately 30% of DLBCL cases will relapse after frontline therapy. Advanced stage FL is incurable and typically has a relapsing and remitting course with a frequent need for re-treatment. Based on supportive preclinical data, we hypothesised that the addition of varlilumab (an anti-CD27 mAb) to rituximab (an anti-CD20 mAb) can improve the rate, depth and duration of the response of rituximab monotherapy in patients with relapsed or refractory B-cell malignancies.

METHODS/DESIGN:

Combination treatment of varlilumab plus rituximab, in two different dosing regimens, is being tested in the RIVA trial. RIVA is a two-stage open-label randomised phase IIa design in up to 40 patients with low- or high-grade relapsed or refractory CD20+ B-cell lymphoma. The study is open to recruitment in the UK. Enrolled patients are randomised 1:1 to two different experimental varlilumab to rituximab combinations. The primary objective is to determine the safety and tolerability of the combination and the anti-tumour activity (response) in relapsed or refractory B-cell malignancies. Secondary objectives will include an evaluation of the duration of the response and overall survival. Tertiary translational objectives include assessment of B-cell depletion, changes in immune effector cell populations, expression of CD27 as a biomarker of response and pharmacokinetic properties. Analyses will not be powered for formal statistical comparisons between treatment arms.

DISCUSSION:

RIVA will determine whether the combination of rituximab and varlilumab in relapsed or refractory B-cell malignancies is active and safe prior to future phase II/III trials.

TRIAL REGISTRATION:

EudraCT, 2017-000302-37. Registered on 16 January 2017. ISRCTN, ISRCTN15025004 . Registered on 16 August 2017.

KEYWORDS:

B-cell malignancy; CD20; CD27; immunotherapy; lymphoma; monoclonal antibody; phase IIa; randomised trial; rituximab; varlilumab

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