Trial Title

A randomised Phase II Evaluation of Molecular Guided Therapy for Diffuse Large B-Cell Lymphoma with Acalabrutinib (REMoDL-A).

Trial Description

Retrospective molecular profiling of untreated DLBCL samples has recognised 4 distinct sub-classifications of this disease (ABC-DLBCL, GCB- DLBCL, unclassified DLBCL and MHG 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.

REMoDL-A is an open label randomised phase II trial examining efficacy of combined R-CHOP and acalabrutinib chemoimmunotherapy in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) compared to R-CHOP alone.

Trial Objectives

Primary Objective:

To establish if combining acalabrutinib with R-CHOP improves efficacy, compared to R-CHOP alone, for the treatment of previously untreated patients with DLBCL to a degree that justifies further development of this approach.

Secondary Objectives:

·         To compare progression free survival between both treatment and molecular groups.

·         To compare overall survival between both treatment and molecular groups.

·         To compare event free survival between both treatment and molecular groups.

·         To compare time to treatment failure between both treatment and molecular groups.

·         To compare disease free survival between both treatment and molecular groups.

·         To compare time to progression between both treatment and molecular groups.

·         To compare response duration between both treatment and molecular groups.

·         To compare overall response rate and complete response rate between both treatment groups.

·         To assess differences in toxicity between assigned treatments.

·         To assess differences in quality of life in different treatment arms.

Tertiary Objectives

·         To explore correlation of baseline PET features including metabolic tumour volume (MTV), tumour lesion glycolysis (TLG), extranodal sites and bone marrow involvement with clinical risk factor and molecular characteristics in tumour material.

·         To compare metabolic response rates between molecular groups.

·         To explore correlation of molecular characteristics in tumour material to clinical outcomes.

Trial Design

This is a multicentre, stratified, open-label, randomised phase II trial.

We aim to recruit approximately 375 patients. This study will have two treatment arms.

Following informed consent, all patients will receive one cycle of R-CHOP. At the same time, the diagnostic pathology block will be sent for molecular profiling and assignment of subtype to GCB, ABC, Unclassifiable, MHG or failed RNA extraction.

Patients with an International Prognostic Index (IPI) of 0-1 will be randomised between Arm A (R-CHOP only for a further 5 cycles) and Arm B (R-CHOP + acalabrutinib for a further 5 cycles), with treatment cycles lasting 21 days. Two thirds of patients who are randomised will be assigned to Arm B, and one third will be randomised to Arm A.

Patients with an IPI of 2-5 will be allocated to Arm B without randomisation and receive R-CHOP + acalabrutinib for the remaining 5 cycles.

Recruitment is expected over 44 months with a follow-up duration of at least 2 years.

Trial Status

Open to recruitment

Population

Patients aged ≥ 16 years with previously untreated CD20 positive diffuse large B-cell lymphoma (DLBCL) requiring full course chemoimmunotherapy.

Funder

This trial is funded by an unrestricted educational grant from AstraZeneca and is endorsed by Cancer Research UK (award reference no. C30423/A29680) with support from the NIHR.

Watch a video on the REMoDL-A trial