A randomised Phase II Evaluation of Molecular Guided Therapy for Diffuse Large B-Cell Lymphoma with Acalabrutinib (REMoDL-A).
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.
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.
This is a multicentre, stratified, open-label, randomised phase II trial.
We aim to recruit 453 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 whose biopsies are molecularly typed GCB, ABC or Unclassifiable will be randomised.
Two thirds of patients (Arm B) will be randomised to receive a further 5 cycles (every 21 days) of R-CHOP with Acalabrutinib and one third of patients (Arm A) will be randomised to receive with 5 cycles of R-CHOP.
Recruitment is expected over 24 months with a follow-up duration of at least 2 years.
Open to recruitment
Patients aged ≥ 16 years with previously untreated CD20 positive diffuse large B-cell lymphoma (DLBCL) requiring full course chemoimmunotherapy.
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.
Senior Trial Manager
Joshua Caddy
Trial Manager
Nicole Keyworth
Trial Coordinator
Tiffany Joyce
Data Manager
Nicola Scott
Clinical Data Coordinator
Robert Waugh
Email - remodla@soton.ac.uk
SCTU fax - 0844 7740 621
Email: ctu@soton.ac.uk
Phone: 0844 7740 621
REMoDL-A - Protocol v3 12-May-2021
REMoDL-A - Patient Information Sheet v4 18-May-2021
REMoDL-A - Patient Information Sheet Tissue Block Screening v2 05-May-2021
REMoDL-A - Pregnant Partner Patient Information Sheet v2 05-May-2021
REMoDL-A - Informed Consent Form v4 18-May-2021
REMoDL-A - Informed Consent Form Tissue Block Screening v2 05-May-2021
REMoDL-A - Pregnant Partner Informed Consent Formt v2 05-May-2021
REMoDL-A - GP Letter v2 15-Jan-2021
REMoDL-A - Patient Diary v2 22-Jan-2021
REMoDL-A - Patient Information Card v2 07-Dec 2020
REMoDL-A - Eligibility Checklist v2 08-Jun-2021
REMoDL-A - FACT-Lym ENG Final v4 16-Nov-2007
REMoDL-A - Investigator Site File Index v2 28-May-2021
REMoDL-A - Study Contacts and Information Page v1 28-May-2021
REMoDL-A - Site Delegation Log v2 25-Nov-2021
REMoDL-A - Patient Screening Log v3 28-May-2021
REMoDL-A - Master Patient List v2 07-Dec 2020
REMoDL-A - Site Training Log v2 07-Dec-2020
REMoDL-A - Site Visit Log v2 07-Dec-2020
REMoDL-A - PI Protocol Acknowledgement Form v1 28-May-2021
REMoDL-A - Pharmacy Manual v3 12-May-2021
REMoDL-A - Drug Order Form v2 07-Dec-2020
REMoDL-A - Acalabrutinib Accountability Log v3 02-Feb-2021
REMoDL-A - Acalabrutinib Subject Dispensing Log v3 02-Feb-2021
REMoDL-A - R-CHOP Drug Dispensing Log v2 29-Jan-2021
REMoDL-A - Pharmacy Site File Index v1 27-Jan-2021
REMoDL-A - Imaging Manual v2 18-Jan-2022
REMoDL-A - PET Acquisition Form v2 18-Jan-2022
REMoDL-A - Lab Manual v3 14-Jan-2021
REMoDL-A - HMDS Tissue Samples Dispatch Log v3 14-Jan-2021
REMoDL-A - HMDS Sample Shipment Form v3 14-Jan-2021
REMoDL-A - Blank SAE SUSAR form v1 23-Jul-2021 (adjusted formatting)
REMoDL-A - Instructions for adverse and serious adverse event reporting v1 27-Jan-2021
REMoDL-A - Acalabrutinib IB v10
REMoDL-A -Vincristine 1mgml Injection - SMPC - Feb-2020
REMoDL-A - Cyclophosphamide Injection500mg - SmPC - 07-Jun-2016
REMoDL-A - Doxorubicin Hydrochloride2mgml Solutionfor Infusion - SmPC - 09-Oct-2020
REMoDL-A - MabThera 100mg Concentrate for Solution - SmPC - Oct 2021
REMoDL-A - Predisolone 25mg Tablets - SmPC - May 2021
Link to RAVE database (patient registration and eCRF completion): https://login.imedidata.com/login
REMoDL-A - eCRF completion guidelines v1 06-OCT-2021
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