Title
A Phase Ib/II combination of acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for patient Diffuse Large B-cell Lymphoma (DLBCL)
Description
Retrospective molecular profiling of untreated DLBCL samples has recognised 3 distinct sub-classifications of this disease (ABC-DLBCL, GCB- DLBCL and unclassified DLBCL), each with unique biological features and clinical outcomes when treated with CHOP or R-CHOP chemotherapy. Dysregulation of B-cell receptors (BCR) signalling pathway is observed in ABC type and requires Bruton tyrosine kinase (Btk) activation.
Clinical studies have shown that targeting BCR signalling pathway by the inhibition of Btk with ibrutinib (a 1st generation Btk inhibitor) in combination with R-CHOP chemotherapy for previously untreated B-cell non Hodgkin lymphoma is safe. Acalabrutinib is a 2nd generation Btk inhibitor with increased target selectivity compared to ibrutinib. It is postulated that the addition of acalabrutinib to R-CHOP chemotherapy may improve tumour response compared to ibrutinib + R-CHOP.
ACCEPT is an open-label non-randomised phase Ib/II study conducted in two stages. Stage 1 will be dose escalation in a modified classical 6+6 design. Stage 2 will be an expansion cohort to gain additional information on safety and efficacy at the recommended phase II dose of acalabrutinib.
Objectives
Phase I:
- To propose a recommended dose for Phase II evaluation of acalabrutinib in combination with R-CHOP in patients with DLBCL
- To examine the safety and toxicity profile of acalabrutinib in combination with R-CHOP and defining the dose limiting toxicity or maximum administered dose
Phase II:
- To document anti-tumour activity of acalabrutinib in combination with R-CHOP in patients with previously untreated CD20 positive DLBCL
- To determine additional safety information of acalabrutinib in combination with R-CHOP
Trial Design
Open-label non-randomised phase Ib/II study conducted in two stages. Stage 1 will be dose escalation in a modified classical 6+6 design. Stage 2 will be an expansion cohort to gain additional information on safety and efficacy at the recommended phase II dose of acalabrutinib.
Trial Status
Closed
Population
Patients with previously untreated CD20 positive diffuse large B-cell lymphoma (DLBCL) requiring full course chemoimmunotherapy.
Contact Details
All trial enquiries should be sent to ctuadmin@soton.ac.uk
Publications
Davies A, et al; Acalabrutinib in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) As First Line Therapy for Patients with Diffuse Large B-Cell Lymphoma (DLBCL): The Accept Phase Ib/II Single Arm Study. Blood 2020; 136 (Supplement 1): 38–39. doi:Ìý
Davies A, et al; Acalabrutinib in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) As First Line Therapy for Patients with Diffuse Large B-Cell Lymphoma (DLBCL): The Accept Phase Ib/II Single Arm Study. Poster Presentation at the 62nd American Society of Haematology (ASH) Annual Meeting and Exposition, December 2020, San Diego CA, USA.
Davies A, et al. 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 trialÌý
Cummin, T., et al. (2019), 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). Hematol Oncol, 37: 71-72.Ìý
Cummin, T., et al. (2019), 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). Oral presentation at the 15th International Conference on Malignant Lymphoma, May 2019, Lugano Switzerland.
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). Poster presentation at the American Association for Cancer Research Annual Meeting 2018, April 2018, Chicago IL, USA
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This trial was endorsed by Cancer Research UK (award reference no. CRUKDE/16/006)