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

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

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.

Journal Article
1745-6215
Lim, Sean H.
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Linton, Kim M.
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Collins, Graham P.
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Dhondt, Joke
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Caddy, Joshua
c9f48059-2d70-45e4-a80a-978bf74fac34
Rossiter, Liz
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Vadher, Karan
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Fines, Keira
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Rogers, Laura E.
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Fernando, Diana
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Stanton, Louise
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Davies, Andrew J.
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Johnson, Peter W.M.
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Griffiths, Gareth
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Lim, Sean H.
43fdb60b-d81c-4b55-a647-d4302fa257da
Linton, Kim M.
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Collins, Graham P.
450338cb-2bb0-4cef-90a7-7bcd47a12e2f
Dhondt, Joke
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Caddy, Joshua
c9f48059-2d70-45e4-a80a-978bf74fac34
Rossiter, Liz
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Vadher, Karan
ccc053fe-6133-4a7e-854a-96c179db0323
Fines, Keira
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Rogers, Laura E.
9b178b49-c6bf-4a1e-b940-72858c13335d
Fernando, Diana
c4d90aca-c3d3-439e-b487-c23166ef3407
Stanton, Louise
8b827763-d839-4b4b-bbf2-358a84110294
Davies, Andrew J.
0fe6a40a-10d1-4ade-a7e6-d1dceb2470af
Johnson, Peter W.M.
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Griffiths, Gareth
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Lim, Sean H., Linton, Kim M., Collins, Graham P., Dhondt, Joke, Caddy, Joshua, Rossiter, Liz, Vadher, Karan, Fines, Keira, Rogers, Laura E., Fernando, Diana, Stanton, Louise, Davies, Andrew J., Johnson, Peter W.M. and Griffiths, Gareth (2018) RIVA - a phase IIa study of rituximab and varlilumab in relapsed or refractory B-cell malignancies: study protocol for a randomized controlled trial. Trials, 19 (1). (doi:10.1186/s13063-018-2996-6).

Record type: Article

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.

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More information

Accepted/In Press date: 16 October 2018
e-pub ahead of print date: 9 November 2018
Published date: 9 November 2018
Keywords: Journal Article

Identifiers

Local EPrints ID: 426570
URI: https://eprints.soton.ac.uk/id/eprint/426570
ISSN: 1745-6215
PURE UUID: 854c896e-9c74-4d93-8b0b-7ec418779118
ORCID for Peter W.M. Johnson: ORCID iD orcid.org/0000-0003-2306-4974
ORCID for Gareth Griffiths: ORCID iD orcid.org/0000-0002-9579-8021

Catalogue record

Date deposited: 30 Nov 2018 17:30
Last modified: 14 Mar 2019 01:49

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