ACCEPT
Research type
Research Study
Full title
A Phase Ib/II combination trial of acalabrutinib with rituximab, cyclophosphamide, doxorubicin,vincristine and prednisolone (R-CHOP) for patients with diffuse large B-cell lymphoma (DLBCL)
IRAS ID
182046
Contact name
Sharon Davies-Dear
Contact email
Eudract number
2015-003213-18
Duration of Study in the UK
4 years, 0 months, 3 days
Research summary
Research Summary:
Diffuse large B-cell lymphoma (DLCBL) is the commonest of the non-Hodgkin's lymphomas. Whilst the majority of patients will respond well to conventional immunochemotherapy (R-CHOP), a significant number of patients will either fail to respond to initial therapy or relapse after completion of therapy. Bruton's tyrosine kinase (BTK) is an enzyme dysregulated in numerous B-cell malignancies, including DLCBL. Acalabrutinib is an orally active BTK-inhibitor. It is hypothesised that the addition of acalabrutinib to standard R-CHOP immunochemotherapy may improve outcomes of patients with DLCBL.
The proposed study is a phase Ib/II clinical trial to determine a suitable tolerated dose and efficacy of acalabrutinib in combination with standard R-CHOP immunochemotherapy to treat patients with DLBCL.
The main aims of this clinical study are to find out:
-The maximum dose of acalabrutinib that can safely be given to patients
-More about the potential side effects of acalabrutinib and how they can be managed
-The effect the combination of R-CHOP and acalabrutinib has on DLBCLApproximately 6-24 patients with DLBCL will be entered into the dose-escalation phase, and a further 15 patients will be recruited to a dose expansion cohort. The final number will depend on the number of dose escalations required.
Summary of Results:
This trial was sponsored by the University Hospital Southampton NHS Foundation Trust and was managed on their behalf by Southampton Clinical Trials Unit. The study was funded by AstraZeneca and endorsed by Cancer Research UK.
PURPOSE
This trial looked at combining one of the standard treatments for Diffuse Large B-cell Lymphoma (DLBLC) called R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with a new drug called acalabrutinib. Acalabrutinib is known as a Bruton Tyrosine Kinase (BTK) inhibitor. It works by blocking a protein in the lymphoma cells which plays a role in promoting the cells to grow and stopping them from dying. It was thought that adding acalabrutinib to R-CHOP may improve the way R-CHOP works.
The trial had two parts. The first part (phase I) of the ACCEPT trial aimed to find out how safe acalabrutinib is when given with R-CHOP, how it may impact on the way it is processed in the body and the safest amount (dose) that can be given when used together. The second part (phase II) of the trial aimed to see how the combination of acalabrutinib with R-CHOP works as a treatment for DLBCL and to learn more about the side effects of acalabrutinib with R-CHOP.
PARTICIPANTS
The trial involved people who had been newly diagnosed with DLBCL who had not received any treatment yet for their lymphoma. Between May 2017 and January 2020, a total of 38 patients (14 in phase I and 24 in phase II) with DLBCL entered in to the ACCEPT trial across 7 hospitals in the UK.
TREATMENT
In phase I, two different doses of acalabrutinib were tested so the best dose of acalabrutinib could be found. The first few participants entered on to ACCEPT were given a lower dose of acalabrutinib (one 100mg capsule of acalabrutinib once a day). This dose was safe so the next few participants were given a higher dose (one 100mg capsule of acalabrutinib twice a day). This dose was also shown to be safe.
In phase II, all participants were given the same dose of acalabrutinib (one 100mg capsule of acalabrutinib twice a day).Drug Day
1 2 3 4 5
Rituximab
Cyclophosphamide
Vincristine
Doxorubicin
Prednisolone
Acalabrutinib
Taken on days 1 -21 during cycles 2-6. Then taken on days 1-28 for cycles 7 and 8.After 6 cycles of treatment, all patients had an imaging scan (PET-CT scan) to assess their disease.
Each participant was then given acalabrutinib alone for another two cycles, each lasting 28 days (56 days in total). After finishing the last two cycles of acalabrutinib, participants were then followed up regularly.
RESULTS
Of the 38 participants that were entered into the study, it was possible to assess safety in all 38 participants. It was also possible to assess how well acalabrutinib and R-CHOP worked as a treatment for DLBCL in 30 of these participants. This is because during the trial some people were found not to meet all criteria needed to take part in the trial so they could not be included in all evaluations.The study data showed that R-CHOP and acalabrutinib may be a useful treatment for DLBCL as it was found that the lymphoma:
• went away in 23 people (77%)
• 5 people had a partial response (17%)
• 1 person had stable disease (3%)
• got worse in 1 person (3%)For those patients whose lymphoma responded to treatment, the benefit appears to be lasting.
All patients experienced side effects. The most common side effects were nausea, a drop in white blood cells (also called neutropenia), constipation, diarrhoea, fatigue, and headache. These are side effects that we would expect to see with R-CHOP alone. There was nothing to suggest that they were more frequent or severe when acalabrutinib was added.
Overall, the combination of R-CHOP and acalabrutinib was found to be safe and may be a useful treatment for DLBCL. The combination is now being studied in larger clinical trials comparing R-CHOP with acalabrutinib to R-CHOP alone.
REC name
South Central - Berkshire Research Ethics Committee
REC reference
16/SC/0657
Date of REC Opinion
5 Jan 2017
REC opinion
Favourable Opinion