ACCEPT

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

In follow-up

Population

Patients with previously untreated CD20 positive diffuse large B-cell lymphoma (DLBCL) requiring full course chemoimmunotherapy.

This trial is endorsed by Cancer Research UK (award reference no. CRUKDE/16/006)