The ACCEPT study

ISRCTN	ISRCTN13626902
DOI	https://doi.org/10.1186/ISRCTN13626902
EudraCT/CTIS number	2015-003213-18
Secondary identifying numbers	CPMS 33203

Submission date: 13/02/2017
Registration date: 07/03/2017
Last edited: 22/10/2024

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English Summary

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-of-acalabrutinib-with-r-chop-for-people-with-diffuse-large-b-cell-lymphoma-accept

Contact information

Mr Joshua Caddy
Public

Southampton Clinical Trials Unit
MP131, Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom

Phone	+44 (0)23 8120 3509
Email	accept@soton.ac.uk

Ms Nicole Keyworth
Scientific

Southampton Clinical Trials Unit
MP131, Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom

Phone	+44 (0)23 8120 3785
Email	N.E.Keyworth@soton.ac.uk

Study information

Study design	Non-randomized; Interventional; Design type: Treatment, Screening, Diagnosis, Drug
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details to request a patient information sheet
Scientific 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)
Study acronym	ACCEPT
Study hypothesis	The aim of this study is to determine a suitable tolerated dose and efficacy of acalabrutinib in combination with standard R-CHOP immunochemotherapy to treat patients with diffuse large B-cell lymphoma (DLCBL).
Ethics approval(s)	South Central - Berkshire Research Ethics Committee, 26/01/2017, ref :16/SC/0657
Condition	Diffuse large B-cell lymphoma
Intervention	A multicentre open-label non-randomised phase Ib/II clinical trial conducted in two stages recruiting approximately 40 patients. Phase I Dose Escalation Cohort 1 The first 6 patients registered (cohort 1) will receive a first cycle of R-CHOP. Acalabrutinib, at a starting dose of 100 mg od, will be added from cycle 2 to 6. This will be followed by cycles 7 and 8 of acalabrutinib only 100mg od for 28 days for each cycle. Dose escalation to 200 mg daily (100 mg bd) of acalabrutinib will be decided by the Safety Review Committee based on safety data and patients’ compliance assessment Phase I Dose Escalation Cohort 2 The first 6 patients of cohort 2 will start acalabrutinib + R-CHOP at the daily dose of 200mg administered as 100mg bd from cycle 2 after the Safety Review Committee has approved dose escalation based on all the safety data from cohort 1. the Safety Review Committee will assess the safety of 200mg. If one or two instances of DLT is observed among the initial six patients of cohort 2, the cohort will be expanded to a further six patients. Depending on tolerability as set out, cohort 2 patients should receive cycle 1 of R-CHOP, cycles 2-6 R-CHOP plus acalabrutinib and then cycles 7 and 8 of acalabrutinib only at 200mg administered as 100mg bd. If a DLT attributable to acalabrutinib occurs, acalabrutinib will be withheld for that patient and reintroduced at 100 mg od when toxicity has resolved to < grade 1, all other patients will continue at acalabrutinib dosage of 200mg. If ≥ 3DLTs are attributable to acalabrutinib in the initial six patients acalabrutinib will be withheld from the patient(s) who have suffered the DLT and reintroduced at 100 mg od after toxicity has resolved to < grade 1 and all other patients dosage will be decreased to 100 mg od. When all patients have completed all 6 cycles of therapy, the Safety Review Committee will review patients’ compliance assessment, PK/PD measurements if available and safety data, including the identified MTD and MAD, to determine the recommended dose for Phase II (RP2D) which will be a dose where ≤ 33% of patients had a DLT. Phase II Fifteen patients will be recruited for stage 2 of the study. Following informed consent, they will receive 6 cycles of conventionally dosed R-CHOP with the addition of acalabrutinib at the RP2D on cycle 2 onwards.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase I/II
Drug / device / biological / vaccine name(s)	Acalabrutinib
Primary outcome measure	Phase I 1. Dose limiting toxicity of acalabrutinib combined to R-CHOP is measured using a physical examination, vital signs, laboratory tests FBC, renal and liver function, ECOG, at baseline and for all cycles and repeated for specific cycles day 8 and day 15 for cycle 2 and day 8 at cycle 4.* Phase II 1. Overall response rate of the combination acalabrutinib and R-CHOP is measured using PET/CT at baseline, cycle 7, month 12, month 24 End of treatment using the Lugano classification for NHL 2. Safety of the combination acalabrutinib and R-CHOP is measured using a physical examination, vital signs, laboratory tests FBC, renal and liver function, ECOG at baseline and for all cycles and repeated for specific cycles day 8 and day 15 for cycle 2 and day 8 at cycle 4.* *There will be 8 cycles if chemotheraphy administered. Cycle 1-6 will be 21 days and Cycle 7 and 8 will be 28 days Aclabrutinib will be administered from cycle 2 and will be taken from cycle 2 to cycle 7.
Secondary outcome measures	1. Pharmacokinetic of acalabrutinib, AUC, Cmax, Tmax, half-life T1/2 and other PK parameter is measured using serum concentration taken at cycle 2, Day 1, day 8 and day 15 half hour before the administration of acalabrutinib. Once acalabrutinib is administered serum concentration will be taken 45 mins, 1 hour, 2 hours and 8 hours and once again before acalabrutinib is administered at cycle 3 2. Overall response rate of the combination acalabrutinib and R-CHOP according to cell of origin is measured using of BCR DNA extracted from tumour material will be used to perform mutation detection on BCR pathway (eg Btk, PI3K, CD79b). Genetic abnormalities of BCR pathway will be correlated with clinical outcomes and the expression pathway target genes at baseline 3. Two years progression-free survival rate is measured using CT at 24 months 4. Two years overall survival rate is measured using CT at 24 months
Overall study start date	01/08/2015
Overall study end date	30/06/2022

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	16 Years
Sex	Both
Target number of participants	Planned Sample Size: 40; UK Sample Size: 40
Total final enrolment	38
Participant inclusion criteria	1. Histologically confirmed DLBCL, expressing CD20. Sufficient diagnostic material should be available to forward to a central laboratory for gene expression profiling and pathology review 2. Measurable disease of at least 15mm 3. Not previously treated for lymphoma and fit enough to receive combination chemoimmunotherapy with curative intent 4. Stage IAX (bulk defined as lymph node diameter >10cm) to stage IV disease and deemed to require a full course of chemotherapy. Patients with non-bulky IE disease are not eligible 5. ECOG performance status 0-2 or 3 if this is directly attributable to lymphoma 6. Adequate bone marrow function with platelets > 100x109/L; neutrophils > 1.0x109/L at study entry, unless lower figures are attributable to lymphoma 7. Measured or calculated creatinine clearance > 30mls/min, (calculated using the formula of Cockcroft and Gault [(140-Age) x Mass (kg)x(1.04 (for women)or 1.23 (for men))/Serum Creatinine (umolL)] 8. Serum bilirubin < 35μmol/L and transaminases < 2.5x upper limit of normal at time of study entry 9. Cardiac function sufficient to tolerate 300mg/m2 of doxorubicin. A pre-treatment echocardiogram or MUGA is required to establish baseline LVEF equal to or greater than 55% 10. No concurrent uncontrolled medical condition 11. Life expectancy > 3 months 12. Aged 16 years or above 13. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty 14. Ability to understand the purpose and risks of the study and provide signed and dated informed consent
Participant exclusion criteria	1. Previous history of treated or untreated indolent lymphoma. However newly diagnosed patients with DLBCL who are found to also have small cell infiltration of the bone marrow or other diagnostic material (discordant lymphoma) will be eligible 2. Diagnosis of primary mediastinal lymphoma 3. Diagnosis of primary Central Nervous System lymphoma. 4. History of stroke or intracranial haemorrhage in preceding 6 months 5. History of bleeding diathesis (eg. haemophilia, von Willebrand disease) 6. Requires or receiving anticoagulation with warfarin or equivalent antagonists (eg. phenprocoumon) within 7 days of first dose of acalabrutinib. However patients using therapeutic low molecule weight heparin or low dose aspirin will be eligible 7. Prior exposure to a BCR inhibitor(eg. BtK inhibitors, phosphoinositide-3 kinase (PI3K), or SyK inhibitors) or BCL-2 inhibitor (eg. ABT-199) 8. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer 9. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Patients receiving proton pump inhibitors who switch to short-acting H2-receptor antagonists or antacids are eligible for enrolment into this study. 10. Uncontrolled systemic infection 11. Major surgery in the preceding 4 weeks of first dose of study drug. If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug 12. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) > 480 msec at screening. 13. Serological positivity for Hepatitis B, C, or known HIV infection. As per standard of care, prior to initiation of immunochemotherapy, the results of hepatitis serology should be known prior to commencement of therapy. - Positive test results for chronic HBV infection (defined as positive HBsAg serology) will not be eligible. Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) will not be eligible. Patients who have protective titres of hepatitis B surface antibody (HBsAb) after vaccination will be eligible. - Positive test results for hepatitis C virus (HCV) antibody serology will not be eligible. 14. Women who are sexually active and can bear children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of acalabrutinib. Highly effective forms of contraception are defined in Section 4.7 14. Breastfeeding or pregnant 15. Men who are sexually active and can potentially father children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of acalabrutinib. Highly effective forms of contraception are defined in Section 4.7 16. Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of study drug. 17. Serious medical or psychiatric illness likely to affect participation or that may compromise the ability to give informed consent 18. Prior malignancy (other than DLBCL), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for ≥ 2 years or which will not limit survival to < 2 years. Note: these cases must be discussed with SCTU 19. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction or gastric restrictions and bariatric surgery, such as gastric bypass 20. Any immunotherapy within 4 weeks of 1st dose of the study 21. Concurrent participation in another therapeutic clinical trial
Recruitment start date	01/04/2017
Recruitment end date	02/01/2020

Locations

Countries of recruitment

England
United Kingdom

Study participating centres

Southampton General Hospital

Tremona Road
Southampton
SO16 6YD
United Kingdom

Queen's Medical Centre

Derby Road
Nottingham
NG7 2UH
United Kingdom

Churchill Hospital

Old Road
Oxford
OX3 7LE
United Kingdom

University College London Hospital

253 Euston Road
London
NW1 2PG
United Kingdom

Christie Hospital

550 Wilmslow Road
Withington
Manchester
MX20 4BX
United Kingdom

St. James's University Hospital

Beckett Street
Leeds
LS9 7TF
United Kingdom

Derriford Hospital

Derriford Road
Plymouth
PL6 8DH
United Kingdom

Sponsor information

University Hospital Southampton NHS Foundation Trust
Hospital/treatment centre

Mailpoint 18
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
England
United Kingdom

"ROR"	https://ror.org/0485axj58

Funders

Funder type

Industry

Acerta Pharma

No information available

Results and Publications

Intention to publish date	31/12/2024
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
Publication and dissemination plan	The result will be presented and published. Participating clinicians will be supplied with a lay summary of the results once the definitive analysis is presented publicly, in order to make this available to patients that they entered into the trial. The summary will also be submitted to the Lymphoma Association Newsletter and uploaded to the NCRN and cancer help website. No identifiable personal data will be captured on the study database. The study team will present results at national and international conferences and publish in a peer-reviewed journal. Results will be published on clinicaltrials.gov and we will send a lay summary of results to participants.
IPD sharing plan	The data sharing plans for the current study are unknown and will be made available at a later date.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol article	protocol	07/08/2020	26/10/2020	Yes	No
HRA research summary			28/06/2023	No	No

Editorial Notes

22/10/2024: The intention to publish date was changed from 31/03/2024 to 31/12/2024.
13/12/2023: The intention to publish date was changed from 31/12/2023 to 31/03/2024.
06/09/2023: Contact details updated.
29/06/2023: The intention to publish date was changed from 30/06/2023 to 31/12/2023.
03/04/2023: Total final enrolment added.
28/02/2023: The following changes were made to the trial record:
1. The overall trial end date was changed from 31/12/2021 to 30/06/2022.
2. The intention to publish date was changed from 01/02/2023 to 30/06/2023.
26/10/2020: Publication reference added.
07/05/2020: The intention to publish date was changed from 31/12/2019 to 01/02/2023. Contact details updated.
04/05/2020: The recruitment end date was changed from 01/04/2021 to 02/01/2020.
28/03/2019: The condition has been changed from "Specialty: Cancer, Primary sub-specialty: Haematological Oncology; UKCRC code/ Disease: Cancer/ Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissue" to "Diffuse large B-cell lymphoma" following a request from the NIHR.
26/07/2017: added intention to publish date.
20/07/2017: Added publication and dissemination plan. Added individual participant level data sharing statement.
06/06/2017: Cancer Help UK lay summary link added to plain English summary field