Background

DLBCL is the most common non-Hodgkin lymphoma (NHL) comprising one third of all adult NHL cases, accounting for an annual incidence in the UK of approximately 5,000 patients. R-CHOP has been accepted as the international standard first-line regimen, with cure rates of around 60-70%. There is a need to further improve efficacy of first line treatment.

Chronic and tonic B-cell receptor (BCR) signaling has been identified as a feature of DLBCL. Preclinical models of this lymphoma have demonstrated cytotoxicity through interruption of BCR-signaling. Inhibition of Bruton's tyrosine kinase (BTK), downstream of the BCR has proven active clinical trials in DLBCL, particularly in the activated B-cell subtype. The second generation BTK inhibitor, acalabrutinib, has demonstrated improved target specificity and bioavailability, with potential for better efficacy and tolerability compared to earlier agents. It is appealing to combine this targeted agent with R-CHOP in untreated de novo DLBCL to understand its safety profile and efficacy.

Method

Patients must be 16 years or older, treatment naive with histologically confirmed DLBCL. All will receive 6 cycles of R-CHOP chemotherapy on a standard 21-day schedule, with the addition of acalabrutinib in cycles 2-6, to allow determination of the subtype by whole transcriptome gene expression profiling during cycle 1. This will be followed by a continuation phase of acalabrutinib only, for 2 cycles of 28 days. The primary objective of the phase I is to establish a recommended phase II dose of acalabrutinib in combination with R-CHOP. The primary objective of the phase II is to assess activity of the combination (by overall response rate) and determine additional safety information. Secondary endpoints include duration of response, PFS and OS and their relation to the cell of origin subtype, and BTK receptor occupancy in peripheral blood mononuclear cells and tumor measured by a drug analogue enzyme-linked immunosorbent assay. The effect of acalabrutinib on antibody-directed cellular cytotoxicity mediated by rituximab will be measured in vitro during treatment.

The trial is coordinated by the Cancer Research UK Southampton Clinical Trials Unit. It will recruit up to 24 patients during phase I in a modified classical 6+6 design, and 15 patients during phase II.

This is an investigator initiated study that has been granted free access to investigational medicinal product, trial Management and translational study support through a grant from Acerta Pharma B.V. (IST-LY-801) and has endorsement from Cancer Research UK (CRUKDE/16/006). Trial registration: ISRCTN11965217

Progress

Phase I of the study opened in April 2017 and has recruited 6 eligible patients to the first cohort at a dose of 100mg acalabrutinib once daily, with a further 4 patients recruited to the second cohort at a dose of 100mg twice daily.

Citation Format: Peter W M Johnson, Joshua Caddy, Tom Cumin, Bridgen Merton, Tom Maishman, Angelic Galanopoulou, Gareth Griffiths, Andrew Davies. ACCEPT: A phase Ib/II combination of acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for patients with diffuse large B-cell lymphoma (DLBCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT162.