Dataset Information

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.

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); ISRCTN 13626902 (registered 07 March 2017).

SUBMITTER: Davies A

PROVIDER: S-EPMC7551525 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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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.

Davies Andrew A Barrans Sharon S Burton Cathy C Mercer Katy K Caddy Joshua J Chinnery Fay F Day Laura L Fernando Diana D Ardeshna Kirit K Collins Graham G Radford John J Rule Simon S McMillan Andrew A Johnson Peter P Griffiths Gareth G

F1000Research 20200807

<b>Background:</b> 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 ...[more]

PMID: 33093947

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Project description:PurposeIbrutinib has shown activity in non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-germinal center B-cell DLBCL.Patients and methodsPatients were randomly assigned at a one-to-one ratio to ibrutinib (560 mg per day orally) plus R-CHOP or placebo plus R-CHOP. The primary end point was event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.ResultsA total of 838 patients were randomly assigned to ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). Median age was 62.0 years; 75.9% of evaluable patients had ABC subtype disease, and baseline characteristics were balanced. Ibrutinib plus R-CHOP did not improve EFS in the ITT (hazard ratio [HR], 0.934) or ABC (HR, 0.949) population. A preplanned analysis showed a significant interaction between treatment and age. In patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS (HR, 0.579), PFS (HR, 0.556), and OS (HR, 0.330) and slightly increased serious adverse events (35.7% v 28.6%), but the proportion of patients receiving at least six cycles of R-CHOP was similar between treatment arms (92.9% v 93.0%). In patients age 60 years or older, ibrutinib plus R-CHOP worsened EFS, PFS, and OS, increased serious adverse events (63.4% v 38.2%), and decreased the proportion of patients receiving at least six cycles of R-CHOP (73.7% v 88.8%).ConclusionThe study did not meet its primary end point in the ITT or ABC population. However, in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety. In patients age 60 years or older, ibrutinib plus R-CHOP was associated with increased toxicity, leading to compromised R-CHOP administration and worse outcomes. Further investigation is warranted.

Dataset Information

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.

Publications

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.

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