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ACCEPT - combining acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for Diffuse Large B-cell Lymphoma (DLBCL): study protocol for a Phase Ib/II open-label non-randomised clinical trial

ACCEPT - combining acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for Diffuse Large B-cell Lymphoma (DLBCL): study protocol for a Phase Ib/II open-label non-randomised clinical trial
ACCEPT - combining acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for Diffuse Large B-cell Lymphoma (DLBCL): study protocol for a Phase Ib/II open-label non-randomised clinical trial
Background: over 13,000 new cases of non-Hodgkin’s lymphoma (NHL) are diagnosed in the UK, with approximately 4,900 attributable deaths each year. Diffuse Large B-cell Lymphoma (DLBCL) is the most common NHL comprising one third of adult NHL cases. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) is accepted as the international standard first-line regimen, but improvement in first line treatment is needed. Dysregulated B-cell receptor (BCR) signalling has been identified as a feature of DLBCL. Inhibition of Bruton’s tyrosine kinase (Btk), downstream of the BCR has proven efficacious in other B-cell malignancies and in combination with R-CHOP. The second generation Btk inhibitor, acalabrutinib, may have improved target potency and specificity, and therefore better efficacy and tolerability.

Methods: ACCEPT is an open-label non-randomised Phase Ib/II trial testing the addition of acalabrutinib to conventional R-CHOP therapy. ACCEPT incorporates an initial 6+6 modified Phase I design of up to 24 participants followed by 15 participant single arm Phase II expansion cohort in treatment naive patients with histologically confirmed DLBCL expressing CD20. Participants are recruited from UK secondary care sites. Phase I will establish the recommended Phase II dose (RP2D, primary endpoint) of acalabrutinib in combination with R-CHOP. Phase II will gain additional information on safety and efficacy on the RP2D. The primary endpoints of Phase II are overall response rate and toxicity profile. Secondary endpoints include duration of response (progression-free survival and overall survival OS) in relation to cell of origin. Analyses are not powered for formal statistical comparisons; descriptive statistics will describe rates of toxicity, efficacy and translational endpoints.

Discussion: ACCEPT will provide evidence for whether acalabrutinib in combination with R-CHOP is safe and biologically effective prior to future Phase II/III trials in patients with previously untreated CD20 positive DLBCL.

Trial registration: EudraCT Number: 2015-003213-18 (issued 16 July 2015); ISRCTN13626902 (registered 07 March 2017).
Btk inhibitor, Diffuse large B-cell lymphoma, R-CHOP, acalabrutinib, molecular profiling, phase I/II, Phase I/II, Molecular profiling, Acalabrutinib
1759-796X
Davies, Andrew
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Barrans, Sharon
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Burton, Cathy
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Mercer, Katy
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Caddy, Joshua
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Chinnery, Fay
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Day, Laura
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Fernando, Diana
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Ardeshna, Kirit
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Collins, Graham
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Radford, John
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Rule, Simon
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Mcmillan, Andrew
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Johnson, Peter
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Griffiths, Gareth
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Davies, Andrew
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Barrans, Sharon
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Burton, Cathy
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Mercer, Katy
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Caddy, Joshua
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Chinnery, Fay
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Day, Laura
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Fernando, Diana
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Ardeshna, Kirit
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Collins, Graham
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Radford, John
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Rule, Simon
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Mcmillan, Andrew
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Johnson, Peter
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Griffiths, Gareth
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Davies, Andrew, Barrans, Sharon, Burton, Cathy, Mercer, Katy, Caddy, Joshua, Chinnery, Fay, Day, Laura, Fernando, Diana, Ardeshna, Kirit, Collins, Graham, Radford, John, Rule, Simon, Mcmillan, Andrew, Johnson, Peter and Griffiths, Gareth (2022) ACCEPT - combining acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for Diffuse Large B-cell Lymphoma (DLBCL): study protocol for a Phase Ib/II open-label non-randomised clinical trial. F1000Research, 9, [941]. (doi:10.12688/f1000research.22318.1).

Record type: Article

Abstract

Background: over 13,000 new cases of non-Hodgkin’s lymphoma (NHL) are diagnosed in the UK, with approximately 4,900 attributable deaths each year. Diffuse Large B-cell Lymphoma (DLBCL) is the most common NHL comprising one third of adult NHL cases. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) is accepted as the international standard first-line regimen, but improvement in first line treatment is needed. Dysregulated B-cell receptor (BCR) signalling has been identified as a feature of DLBCL. Inhibition of Bruton’s tyrosine kinase (Btk), downstream of the BCR has proven efficacious in other B-cell malignancies and in combination with R-CHOP. The second generation Btk inhibitor, acalabrutinib, may have improved target potency and specificity, and therefore better efficacy and tolerability.

Methods: ACCEPT is an open-label non-randomised Phase Ib/II trial testing the addition of acalabrutinib to conventional R-CHOP therapy. ACCEPT incorporates an initial 6+6 modified Phase I design of up to 24 participants followed by 15 participant single arm Phase II expansion cohort in treatment naive patients with histologically confirmed DLBCL expressing CD20. Participants are recruited from UK secondary care sites. Phase I will establish the recommended Phase II dose (RP2D, primary endpoint) of acalabrutinib in combination with R-CHOP. Phase II will gain additional information on safety and efficacy on the RP2D. The primary endpoints of Phase II are overall response rate and toxicity profile. Secondary endpoints include duration of response (progression-free survival and overall survival OS) in relation to cell of origin. Analyses are not powered for formal statistical comparisons; descriptive statistics will describe rates of toxicity, efficacy and translational endpoints.

Discussion: ACCEPT will provide evidence for whether acalabrutinib in combination with R-CHOP is safe and biologically effective prior to future Phase II/III trials in patients with previously untreated CD20 positive DLBCL.

Trial registration: EudraCT Number: 2015-003213-18 (issued 16 July 2015); ISRCTN13626902 (registered 07 March 2017).

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More information

e-pub ahead of print date: 7 August 2020
Published date: 1 April 2022
Keywords: Btk inhibitor, Diffuse large B-cell lymphoma, R-CHOP, acalabrutinib, molecular profiling, phase I/II, Phase I/II, Molecular profiling, Acalabrutinib

Identifiers

Local EPrints ID: 443304
URI: http://eprints.soton.ac.uk/id/eprint/443304
ISSN: 1759-796X
PURE UUID: c2faec07-6b7a-4bf8-8f72-74f5c2e8a5cc
ORCID for Andrew Davies: ORCID iD orcid.org/0000-0002-7517-6938
ORCID for Fay Chinnery: ORCID iD orcid.org/0000-0002-8082-9016
ORCID for Gareth Griffiths: ORCID iD orcid.org/0000-0002-9579-8021

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Date deposited: 20 Aug 2020 16:31
Last modified: 23 Sep 2022 01:45

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Contributors

Author: Andrew Davies ORCID iD
Author: Sharon Barrans
Author: Cathy Burton
Author: Katy Mercer
Author: Joshua Caddy
Author: Fay Chinnery ORCID iD
Author: Laura Day
Author: Diana Fernando
Author: Kirit Ardeshna
Author: Graham Collins
Author: John Radford
Author: Simon Rule
Author: Andrew Mcmillan
Author: Peter Johnson

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