A trial evaluating the effectiveness of combining standard R-CHOP treatment with acalabrutinib in patients with newly diagnosed diffuse large B-cell lymphoma

ISRCTN	ISRCTN14251143
DOI	https://doi.org/10.1186/ISRCTN14251143
EudraCT/CTIS number	2020-000998-25
IRAS number	266600
ClinicalTrials.gov number	NCT04546620
Secondary identifying numbers	CPMS 46717, Grant Codes: ESR 19-20180, IRAS 266600

Submission date: 09/07/2021
Registration date: 16/08/2021
Last edited: 24/01/2025

Recruitment status: Recruiting
Overall study status: Ongoing
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-looking-at-acalabrutinib-for-diffuse-large-b-cell-lymphoma-remodl

Background and study aims
Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin’s lymphomas. Non-Hodgkin lymphoma is a type of cancer that develops in the lymphatic system, a network of vessels and glands spread throughout your body.
Whilst the majority of patients will respond well to conventional treatment (R-CHOP a type of immunochemotherapy), a significant number of patients with lymphoma will not respond to initial therapy or their disease will return after completion of therapy. In a number of B-cell diseases an enzyme called Bruton tyrosine kinase (BTK) prevents death of tumour cells, including in DLBCL. Acalabrutinib is an orally active BTK inhibitor and it is thought that stopping BTK from being activated may help in treating B-cell diseases. It is hypothesised that the addition of Acalabrutinib to standard R-CHOP immunochemotherapy may improve the outcomes of patients with DLBCL.

Who can participate?
Patients aged 16 years or older, with DLBCL

What does the study involve?
Patients will be allocated to either Arm A, receiving R-CHOP immunochemotherapy alone, or Arm B, where they will receive R-CHOP immunochemotherapy in combination with Acalabrutinib. Both arms will receive a maximum of 6 cycles of treatment. Cycles will last 21 days. Those with an International Prognostic Index (IPI) of 0-1 will be randomly assigned a treatment arm, and those with an IPI of 2-5 will be automatically assigned to the R-CHOP Acalabrutinib combination arm.
At the end of the treatment phase, 3-8 weeks after they have received the last dose of R-CHOP medication, patients will attend an end-of-treatment visit for some tests.

What are the possible benefits and risks of participating?
Possible benefits:
1. The trial treatment may help to control your lymphoma
2. You will be helping to further our knowledge of how to treat cancer and this will benefit society and others with the same condition in the future
Possible risks/disadvantages:
1. The trial treatment may not control your lymphoma
2. There may be some unpleasant side effects
3. There could be risks to your child if you, or your partner, become pregnant, or begin breastfeeding
4. You may need to attend more clinic visits and provide more blood samples than if you were not taking part in the trial.

Where is the study run from?
Southampton General Hospital (UK)

When is the study starting and how long is it expected to run for?
September 2018 to October 2027

Who is funding the study?
AstraZeneca (UK)

Who is the main contact?
remodla@soton.ac.uk

Study website

Contact information

Ms Abigail Morgan-Fox
Scientific

MP131
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom

Phone	+44 (0)23 8120 5154
Email	remodla@soton.ac.uk

Study information

Study design	Interventional randomized controlled trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
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 randomised phase II evaluation of molecular guided therapy for diffuse large B-cell lymphoma with acalabrutinib
Study acronym	REMoDL-A
Study hypothesis	Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin’s lymphomas. Whilst the majority of patients will respond well to conventional treatment (R-CHOP a type of immunochemotherapy), a significant number of patients lymphoma will not respond to initial therapy or their disease will return after completion of therapy. In a number of B-cell diseases an enzyme called, Bruton tyrosine kinase (BTK) prevents death of tumour cells, including in DLBCL. Acalabrutinib is an orally active BTK-inhibitor and it is thought that stopping BTK being activated may help in treating B-cell diseases. It is hypothesised that the addition of Acalabrutinib to standard R-CHOP immunochemotherapy may improve outcomes of patients with DLBCL. The main aims of this randomised phase II clinical study are: - To determine if combining Acalabrutinib with R-CHOP improves efficacy, compared to R-CHOP alone, for the treatment of previously untreated patients with DLBCL. - To compare progression-free survival, overall survival, event free survival, disease free survival, time to progression, response duration and overall response rate between both treatment and molecular groups. - To assess differences in toxicity between the assigned treatments - To assess differences in quality of life in different treatment arms - To explore correlation of molecular characteristics in tumour material to clinical outcomes. - To explore correlation of baseline PET features including metabolic tumour volume, tumour lesion glycolysis, extranodal sites and bone marrow involvement with clinical risk factor and molecular characteristics in tumour material. - To compare metabolic response rates between molecular groups.
Ethics approval(s)	Approved 14/05/2021, South Central - Berkshire REC (Level 3, Block B, Whitefriars, Lewins Mead, Bristol, BS1 2NT, UK; +44 (0)207 104 8222; berkshire.rec@hra.nhs.uk ), ref: 21/SC/0122
Condition	Diffuse large B-cell lymphoma
Intervention	Current interventions as of 30/01/2024: Approximately 375 will be recruited to the clinical trial with 302 patients randomised to the experimental arm. Patients with an International Prognostic Index (IPI) of 0-1 will be randomised to a treatment arm 2:1 in favour of the experimental arm. Patients with an IPI of 2-5 will be allocated to the experimental arm without randomisation. The study will be conducted in approximately 50 UK sites. Patients will have histologically confirmed DLBCL, expressing CD20. Sufficient tumour material should be available to forward to a central laboratory for gene expression profiling and pathology review. Patients should have measurable disease of at least 15mm, previously untreated for lymphoma and fit enough to receive combination chemoimmunotherapy with curative intent. Before Treatment: The patient will be given information about the trial by the site team. The trial will be explained to them in detail by their physician and they will be given the opportunity to ask questions. The patient will be given a minimum of 24 hours before giving written informed consent. After each patient has given informed consent, they will have a screening visit (this may be done over a period of days) where they will have a number of routine investigations to confirm their suitability for the trial. Intervention: Patients recruited to the study will be randomised or assigned to either Arm A, receiving R-CHOP immunochemotherapy alone, or Arm B, where they will receive R-CHOP immunochemotherapy in combination with Acalabrutinib. Both arms will receive a maximum of 6 cycles of treatment. Cycles will last 21 days: the R-CHO infusion will be given on day 1; oral prednisolone will be self-administered on days 1-5 and Acalabrutinib capsules will be taken daily during cycles 2-6. Patients will also attend hospital during cycle 2 for an interim PET-CT scan. Drug Dose Rituximab 375 mg/m² Cyclophosphamide 750 mg/m² Vincristine 1.4 mg/m² (max 2 mg) Doxorubicin 50 mg/m² Prednisolone 100 mg OD Acalabrutinib (Arm B only) 100 mg BD After treatment: At the end of the treatment, 3-8 weeks after they have received the last dose of R-CHOP medication, patients will attend an end-of-treatment visit (this may be done over a period of days). They will then go on to the follow-up phase of the trial. Patients will be followed up initially at 3 months, 6 months, 9 months, 12 months, 16 months, 20 months and 24 months. After 24 months, patients will be followed up yearly for progression, second-line therapy and survival data until 114 PFS events have been observed. Previous interventions: Up to 558 patients (453 randomised) will be recruited to the clinical trial with 302 patients randomised to the experimental arm and 151 to the control arm in a 2:1 randomisation. The study will be conducted in approximately 50 UK sites. Patients will have histologically confirmed DLBCL, expressing CD20. Sufficient tumour material should be available to forward to a central laboratory for gene expression profiling and pathology review. Patients should have measurable disease of at least 15mm, previously untreated for lymphoma and fit enough to receive combination chemoimmunotherapy with curative intent. Before Treatment: The patient will be given information about the trial by the site team. The trial will be explained to them in detail by their physician and they will be given the opportunity to ask questions. The patient will be given a minimum of 24 hours before giving written informed consent. After each patient has given informed consent, they will have a screening visit (this may be done over a period of days) where they will have a number of routine investigations to confirm their suitability for the trial. Intervention: Patients recruited to the study will be randomised to either Arm A, receiving R-CHOP immunochemotherapy alone, or Arm B, where they will receive R-CHOP immunochemotherapy in combination with Acalabrutinib. Both arms will receive a maximum of 6 cycles of treatment. Cycles will last 21 days: the R-CHO infusion will be given on day 1; oral prednisolone will be self-administered on days 1-5 and Acalabrutinib capsules will be taken daily during cycles 2-6. Patients will also attend hospital during cycle 2 for an interim PET-CT scan. Drug Dose Rituximab 375 mg/m² Cyclophosphamide 750 mg/m² Vincristine 1.4 mg/m² (max 2 mg) Doxorubicin 50 mg/m² Prednisolone 100 mg OD Acalabrutinib (Arm B only) 100 mg BD After treatment: At the end of the treatment, 3-8 weeks after they have received the last dose of R-CHOP medication, patients will attend an end-of-treatment visit (this may be done over a period of days). They will then go on to the follow-up phase of the trial. Patients will be followed up initially at 3 months, 6 months, 9 months, 12 months, 16 months, 20 months and 24 months. After 24 months, patients will be followed up yearly for progression, second-line therapy and survival data until 114 PFS events have been observed.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	Rituximab, cyclophosphamide, vincristine, doxorubicin, prednisolone, acalabrutinib
Primary outcome measure	Progression-free survival at 2 years measured using patient records
Secondary outcome measures	1. To compare PFS between molecular groups. [ Time Frame: Last patient's last follow-up, approximately 4.5 years. ] PFS interaction with cell of origin phenotype (ABC, GCB and unclassifiable). 2. To compare PFS between treatment groups. [ Time Frame: Last patient's last follow-up, approximately 4.5 years. ] PFS interaction with clinical variables, including for example IPI, bulk, components of IPI, age and others to be determined in the SAP. 3. To compare overall survival (OS) between both treatment and molecular groups. [ Time Frame: Last patient's last follow-up, approximately 4.5 years. Patients who do not experience an OS event will be censored at the date of last follow-up. ] Overall survival (OS), defined as time from registration to death from any cause. 4. To compare event free survival (EFS) between both treatment and molecular groups. [ Time Frame: Last patient's last follow-up, approximately 4.5 years. Patients who do not experience an EFS event will be censored at the date of last follow-up. ] Event-free survival (EFS), or time to treatment failure, defined as time from registration to any treatment failure including disease progression, or discontinuation of treatment for any reason. 5. To compare disease free survival (DFS) between both treatment and molecular groups. [ Time Frame: Last patient's last follow-up, approximately 4.5 years. Patients who do not experience a DFS event will be censored at the date of last follow-up. ] Disease-free survival (DFS), defined as time of documentation of disease-free state to disease recurrence or death as a result of lymphoma or acute toxicity of treatment. 6. To compare time to progression (TTP) between both treatment and molecular groups. [ Time Frame: Last patient's last follow-up, approximately 4.5 years. Patients who do not experience a TTP event will be censored at the date of last follow-up. ] Time to progression (TTP), defined as time from registration until documented lymphoma progression or death as a result of lymphoma. Deaths from other causes are censored at the time of death. 7. To compare duration of response (DoR) between both treatment and molecular groups. [ Time Frame: Last patient's last follow-up, approximately 4.5 years. Patients who do not experience a RD event will be censored at the date of last follow-up. ] Response duration (DoR), defined as the time from documentation of response until the documentation of relapse or progression. 8. To compare overall response rate (ORR) and complete response rate (CR) between both treatment groups. [ Time Frame: Complete and overall response rates, as recorded at the end of treatment (up to 21 weeks) . ] Assessment using the Lugano Response Criteria for Malignant Lymphoma. 9. To assess differences in toxicity between assigned treatments. [ Time Frame: At all visits up to 24 months follow-up. ] Evaluation of toxicity according to CTCAE version 5. 10. To assess differences in quality of life between treatment arms. [ Time Frame: At baseline, cycle 2 day 1, cycle 3 day 1, cycle 5 day 1, end of treatment and at 3, 6, 12, 20 and 24 month follow-ups. Each cycle is 21 days. ] Application of the EORTC QLQ-C30 and FACT-Lym questionnaires.
Overall study start date	30/09/2018
Overall study end date	31/10/2027

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	16 Years
Sex	Both
Target number of participants	Planned Sample Size: 375; UK Sample Size: 375
Participant inclusion criteria	Current inclusion criteria as of 30/01/2024: 1. Histologically confirmed DLBCL, expressing CD20. Sufficient diagnostic material should be available to forward to HMDS for gene expression profiling and central pathology review. The following diagnoses by 2016 WHO classification of lymphoid neoplasms may be included: 1.1. DLBCL, not otherwise specified (NOS) 1.2. T-cell/histiocyte-rich large B-cell lymphoma 1.3. Epstein-Barr virus positive DLBCL, NOS 1.4. ALK-positive large B-cell lymphoma 1.5 HHV8-positive DLBCL, NOS 1.6. High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit lymphoma) 1.7. High-grade B-cell lymphoma, NOS 2. At least one bi-dimensionally measurable lesion, defined as >1.5 cm in its longest dimension. 3. Not previously treated for lymphoma and fit enough to receive combination chemoimmunotherapy with curative intent 4. Stage IAX (bulk defined as lymph node mass [either single or conglomerate] diameter >7.5cm) to stage IV disease and deemed to require a full course of chemotherapy. Patients with non-bulky IE disease will not be 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 prior to cycle 1 treatment, 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 (µmolL)]). 8. Serum bilirubin ≤35μmol/L and transaminases (AST or ALT) <1.5x upper limit of normal prior to cycle 1 treatment. 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 institutional normal range. 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. Previous inclusion criteria: 1. Histologically confirmed DLBCL, expressing CD20. Sufficient diagnostic material should be available to forward to HMDS for gene expression profiling and central pathology review. The following diagnoses by 2016 WHO classification of lymphoid neoplasms may be included: 1.1. DLBCL, not otherwise specified (NOS) 1.2. T-cell/histiocyte-rich large B-cell lymphoma 1.3. Epstein-Barr virus positive DLBCL, NOS 1.4. ALK-positive large B-cell lymphoma 1.5 HHV8-positive DLBCL, NOS 1.6. High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit lymphoma) 1.7. High-grade B-cell lymphoma, NOS 2. At least one bi-dimensionally measurable lesion, defined as >1.5 cm in its longest dimension as measured by CT 3. Not previously treated for lymphoma and fit enough to receive combination chemoimmunotherapy with curative intent 4. Stage IAX (bulk defined as lymph node mass [either single or conglomerate] diameter >7.5cm) to stage IV disease and deemed to require a full course of chemotherapy. Patients with non-bulky IE disease will not be 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 (µmolL)]). 8. Serum bilirubin <35μmol/L and transaminases <1.5x 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 institutional normal range. 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	Current exclusion criteria as of 30/01/2024: 1. Previous history of treated or untreated indolent lymphoma. Newly diagnosed patients with DLBCL found to have small cell infiltration of the bone marrow or other diagnostic material (discordant lymphoma) will be eligible. 2. Patients who have received immunisation with a live vaccine within four weeks prior to enrolment will be ineligible. 3. Diagnosis of primary mediastinal lymphoma. 4. Diagnosis of primary Central Nervous System lymphoma or secondary CNS involvement. 5. History of stroke or intracranial haemorrhage in preceding 6 months. 6. History of bleeding diathesis (e.g.haemophilia, von Willebrand disease). 7. History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components). 8. Requires or receiving anticoagulation with warfarin or equivalent antagonists (e.g. phenprocoumon) within 7 days of first dose of acalabrutinib. Patients using therapeutic low molecule weight heparin or low dose aspirin will be eligible, as will those receiving direct oral anticoagulants. 9. Prior exposure to an inhibitor in the BCR pathway (e.g. Btk inhibitors, phosphoinositide-3 kinase (PI3K), or Syk inhibitors) or BCL-2 inhibitor (e.g. ABT-199). 10. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. 11. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Patients receiving proton pump inhibitors should switch to short-acting H2-receptor antagonists or antacids prior to the commencement of acalabrutinib, if randomised to receive acalabrutinib. 12. Active significant infection (e.g. progressive multifocal leukoencephalopathy (PML), tuberculosis, sepsis, and opportunistic infections). 13. Uncontrolled autoimmune haemolytic anaemia (AIHA) or idiopathic thrombocytopenic purpura (ITP). 14. Major surgery in the preceding 4 weeks of first dose of Acalabrutinib (if applicable). 15. Corticosteroid use >30 mg/day of prednisone or equivalent, for purposes other than for lymphoma symptom control. Patients receiving corticosteroid treatment with <30 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4 weeks’ duration prior to the start of Cycle 1. If glucocorticoid treatment is urgently required for lymphoma symptom control, this may be delivered in the 28 days prior to initiating therapy, with no maximum dose. 16. Any of the following in the previous 6 months: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, NYHA Class II or greater congestive heart failure, cerebrovascular accident or transient ischemic attack. 17. Serological positivity for Hepatitis B, C, or known HIV infection. a. 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. b. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. 18. Men who can father children must agree to use one highly effective form of contraception with additional barrier or abstinence during the study and for 12 months after the last treatment dose. 19. Breastfeeding or pregnant women. 20. Men who can father children must agree to use two highly effective forms of contraception with additional barrier or abstinence during the study and for 12 months after the last treatment dose. 21. Men must agree to refrain from sperm donation during the study and for 12 months after the last treatment dose. 22. Serious medical or psychiatric illness likely to affect participation or that may compromise the ability to give informed consent. 23. 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. 24. Has difficulty with or is unable to swallow oral medication, or has significant gastrointestinal disease, resection of the stomach or small bowel, partial or complete bowel obstruction or gastric restrictions and bariatric surgery, such as gastric bypass that would limit absorption of oral medication. 25. Any immunotherapy within 4 weeks of 1st dose. 26. Concurrent participation in another therapeutic clinical trial. 27. History of pneumonitis. Previous exclusion criteria from 11/05/2023 to 30/01/2024: 1. Previous history of treated or untreated indolent lymphoma. Newly diagnosed patients with DLBCL found to have small cell infiltration of the bone marrow or other diagnostic material (discordant lymphoma) will be eligible. 2. Patients who have received immunisation with a live vaccine within four weeks prior to enrolment will be ineligible. 3. Diagnosis of primary mediastinal lymphoma. 4. Diagnosis of primary Central Nervous System lymphoma or secondary CNS involvement. 5. History of stroke or intracranial haemorrhage in preceding 6 months. 6. History of bleeding diathesis (e.g.haemophilia, von Willebrand disease). 7. History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components). 8. Requires or receiving anticoagulation with warfarin or equivalent antagonists (e.g. phenprocoumon) within 7 days of first dose of acalabrutinib. Patients using therapeutic low molecule weight heparin or low dose aspirin will be eligible, as will those receiving direct oral anticoagulants. 9. Prior exposure to an inhibitor in the BCR pathway (e.g. Btk inhibitors, phosphoinositide-3 kinase (PI3K), or Syk inhibitors) or BCL-2 inhibitor (e.g. ABT-199). 10. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. 11. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Patients receiving proton pump inhibitors should switch to short-acting H2-receptor antagonists or antacids prior to the commencement of acalabrutinib, if randomised to receive acalabrutinib. 12. Active significant infection (e.g. progressive multifocal leukoencephalopathy (PML), tuberculosis, sepsis, and opportunistic infections). 13. Uncontrolled autoimmune haemolytic anaemia (AIHA) or idiopathic thrombocytopenic purpura (ITP). 14. Major surgery in the preceding 4 weeks of first dose of Acalabrutinib (if applicable). 15. Corticosteroid use >30 mg/day of prednisone or equivalent, for purposes other than for lymphoma symptom control. Patients receiving corticosteroid treatment with <30 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4 weeks’ duration prior to the start of Cycle 1. If glucocorticoid treatment is urgently required for lymphoma symptom control prior to the start of study treatment, prednisone 100 mg or equivalent could be given for a maximum of 14 days as a prephase. A dose of upto 30mg or prenisolone or equivalent may be used during the screening phase to control symptoms. 16. Any of the following in the previous 6 months: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, NYHA Class II or greater congestive heart failure, cerebrovascular accident or transient ischemic attack. 17. Serological positivity for Hepatitis B, C, or known HIV infection. a. 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. b. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. 18. Men who can father children must agree to use one highly effective form of contraception with additional barrier or abstinence during the study and for 12 months after the last treatment dose. 19. Breastfeeding or pregnant women. 20. Men who can father children must agree to use two highly effective forms of contraception with additional barrier or abstinence during the study and for 12 months after the last treatment dose. 21. Men must agree to refrain from sperm donation during the study and for 12 months after the last treatment dose. 22. Serious medical or psychiatric illness likely to affect participation or that may compromise the ability to give informed consent. 23. 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. 24. Has difficulty with or is unable to swallow oral medication, or has significant gastrointestinal disease, resection of the stomach or small bowel, partial or complete bowel obstruction or gastric restrictions and bariatric surgery, such as gastric bypass that would limit absorption of oral medication. 25. Any immunotherapy within 4 weeks of 1st dose. 26. Concurrent participation in another therapeutic clinical trial. 27. History of pneumonitis. Original exclusion criteria: 1. Previous history of treated or untreated indolent lymphoma. Newly diagnosed patients with DLBCL found to have small cell infiltration of the bone marrow or other diagnostic material (discordant lymphoma) will be eligible. 2. Patients who have received immunisation with a live vaccine within four weeks prior to enrolment will be ineligible. 3. Diagnosis of primary mediastinal lymphoma. 4. Diagnosis of primary Central Nervous System lymphoma or secondary CNS involvement. 5. History of stroke or intracranial haemorrhage in preceding 6 months. 6. History of bleeding diathesis (e.g.haemophilia, von Willebrand disease). 7. History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components). 8. Requires or receiving anticoagulation with warfarin or equivalent antagonists (e.g. phenprocoumon) within 7 days of first dose of acalabrutinib. Patients using therapeutic low molecule weight heparin or low dose aspirin will be eligible, as will those receiving direct oral anticoagulants. 9. Prior exposure to an inhibitor in the BCR pathway (e.g. Btk inhibitors, phosphoinositide-3 kinase (PI3K), or Syk inhibitors) or BCL-2 inhibitor (e.g. ABT-199). 10. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. 11. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). 12. Active significant infection (e.g. progressive multifocal leukoencephalopathy (PML), tuberculosis, sepsis, and opportunistic infections). 13. Uncontrolled autoimmune haemolytic anaemia (AIHA) or idiopathic thrombocytopenic purpura (ITP). 14. Major surgery in the preceding 4 weeks of first dose of study drug. 15. Corticosteroid use >30 mg/day of prednisone or equivalent, for purposes other than for lymphoma symptom control. Patients receiving corticosteroid treatment with <30 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4 weeks’ duration prior to the start of Cycle 1. If glucocorticoid treatment is urgently required for lymphoma symptom control prior to the start of study treatment, prednisone 100 mg or equivalent could be given for a maximum of 14 days as a prephase. A dose of upto 30mg or prenisolone or equivalent may be used during the screening phase to control symptoms. 16. Any of the following in the previous 6 months: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, NYHA Class II or greater congestive heart failure, cerebrovascular accident or transient ischemic attack. 17. Serological positivity for Hepatitis B, C, or known HIV infection. a. 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. b. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. 18. Men who can father children must agree to use one highly effective form of contraception with additional barrier or abstinence during the study and for 12 months after the last treatment dose. 19. Breastfeeding or pregnant women. 20. Men who can father children must agree to use two highly effective forms of contraception with additional barrier or abstinence during the study and for 12 months after the last treatment dose. 21. Men must agree to refrain from sperm donation during the study and for 12 months after the last treatment dose. 22. Serious medical or psychiatric illness likely to affect participation or that may compromise the ability to give informed consent. 23. 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. 24. Has difficulty with or is unable to swallow oral medication, or has significant gastrointestinal disease, resection of the stomach or small bowel, partial or complete bowel obstruction or gastric restrictions and bariatric surgery, such as gastric bypass that would limit absorption of oral medication. 25. Any immunotherapy within 4 weeks of 1st dose. 26. Concurrent participation in another therapeutic clinical trial. 27. History of pneumonitis.
Recruitment start date	19/10/2021
Recruitment end date	30/06/2025

Locations

Countries of recruitment

England
Scotland
United Arab Emirates
United Kingdom
Wales

Study participating centres

Southampton General Hospital

Tremona Road
Southampton
SO16 6YD
United Kingdom

Churchill Hospital

Churchill Hospital
Old Road
Headington
Oxford
OX3 7LE
United Kingdom

Beatson West of Scotland Cancer Centre

1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

Colchester General Hospital

Colchester District General Hosp.
Charter Way
Turner Road
Colchester
CO4 5JL
United Kingdom

Queen's Hospital

Rom Valley Way
Romford
RM7 0AG
United Kingdom

Freeman Hospital

Newcastle Upon Tyne Hospital Trust
Freeman Road
High Heaton
Newcastle
NE7 7DN
United Kingdom

Victoria Hospital

Whinney Heys Road
Blackpool
FY3 8NR
United Kingdom

Royal Cornwall Hospital (treliske)

Treliske
Truro
TR1 3LJ
United Kingdom

Nottingham City Hospital

Hucknall Road
Nottingham
NG5 1PB
United Kingdom

Chase Farm Hospital

127 the Ridgeway
Enfield
EN2 8JL
United Kingdom

East Kent Hospitals University NHS Foundation Trust

Kent & Canterbury Hospital
Ethelbert Road
Canterbury
CT1 3NG
United Kingdom

Ipswich Hospital

Heath Road
Ipswich
IP4 5PD
United Kingdom

Torbay Hospital

Newton Road
Torquay
TQ2 7AA
United Kingdom

St James' University Hospital

Beckett Street
Leeds
LS9 7TF
United Kingdom

Lewisham and Greenwich NHS Trust

University Hospital Lewisham
Lewisham High Street
London
SE13 6LH
United Kingdom

Milton Keynes University Hospital NHS Foundation Trust

Standing Way
Eaglestone
Milton Keynes
MK6 5LD
United Kingdom

NHS Lanarkshire

14 Beckford Street
Hamilton
ML3 0TA
United Kingdom

Norfolk and Norwich University Hospitals NHS Foundation Trust

Colney Lane
Colney
Norwich
NR4 7UY
United Kingdom

Derriford Hospital

University Hospitals Plymouth NHS Trust
Derriford Road
Derriford
Plymouth
PL6 8DH
United Kingdom

The Maidstone Hospital

Maidstone and Tunbridge Wells NHS Trust
Hermitage Lane
Maidstone
ME16 9QQ
United Kingdom

Royal Bournemouth Hospital

Castle Lane East
Bournemouth
BH7 7DW
United Kingdom

Royal Devon and Exeter Hospital

Royal Devon & Exeter Hospital
Barrack Road
Exeter
EX2 5DW
United Kingdom

University College London Hospitals NHS Foundation Trust

250 Euston Road
London
NW1 2PG
United Kingdom

University Hospitals Sussex NHS Foundation Trust

Worthing Hospital
Lyndhurst Road
Worthing
BN11 2DH
United Kingdom

Leicester Royal Infirmary

University Hospitals of Leicester NHS Trust
Infirmary Square
Leicester
LE1 5WW
United Kingdom

The Christie NHS Foundation Trust

550 Wilmslow Road
Withington
Manchester
M20 4BX
United Kingdom

Queen Alexandra Hospital

Portsmouth Hospitals NHS Trust
Southwick Hill Road
Cosham
Portsmouth
PO6 3LY
United Kingdom

Royal Stoke University Hospital

Newcastle Road
Stoke-on-trent
ST4 6QG
United Kingdom

Poole Hospital

University Hospitals Dorset NHS Foundation Trust
Longfleet Road
Poole
BH15 2JB
United Kingdom

Swansea Bay University Local Health Board

One Talbot Gateway
Seaway Drive
Seaway Parade
Industrial Estate
Baglan
Port Talbot
SA12 7BR
United Kingdom

Chelsea and Westminster Hospital NHS Foundation Trust

Chelsea & Westminster Hospital
369 Fulham Road
London
SW10 9NH
United Kingdom

Broomfield Hospital

Court Road
Broomfield
Chelmsford
CM1 7ET
United Kingdom

Southend Hospital

Prittlewell Chase
Westcliff-on-sea
SS0 0RY
United Kingdom

Darent Valley Hospital

Darenth Wood Road
Dartford
DA2 8DA
United Kingdom

James Cook University Hospital

Marton Road
Middlesbrough
TS4 3BW
United Kingdom

United Lincolnshire Hospitals NHS Trust

Lincoln County Hospital
Greetwell Road
Lincoln
LN2 5QY
United Kingdom

Bolton Royal Hospital

Minerva Road
Farnworth
Bolton
BL4 0JR
United Kingdom

Sandwell General Hospital

Lyndon
West Bromwich
B71 4HJ
United Kingdom

Harrogate District Hospital

Lancaster Park Road
Harrogate
HG2 7SX
United Kingdom

Addenbrookes

Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom

South Warwickshire University NHS Foundation Trust

Warwick Hospital
Lakin Road
Warwick
CV34 5BW
United Kingdom

The Royal Oldham Hospital

Rochdale Road
Oldham
OL1 2JH
United Kingdom

Stoke Mandeville Hospital

Mandeville Road
Aylesbury
HP21 8AL
United Kingdom

Wycombe Hospital

Queen Alexandra Road
High Wycombe
HP11 2TT
United Kingdom

Hampshire Hospitals NHS Foundation Trust

Basingstoke and North Hampshire Hos
Aldermaston Road
Basingstoke
RG24 9NA
United Kingdom

University Hospitals Coventry and Warwickshire NHS Trust

Walsgrave General Hospital
Clifford Bridge Road
Coventry
CV2 2DX
United Kingdom

Royal United Hospital

Combe Park
Bath
BA1 3NG
United Kingdom

West Suffolk Hospital

Hardwick Lane
Bury St. Edmunds
IP33 2QZ
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

Phone	+44 (0)2381205078
Email	Sharon.Davies-Dear@uhs.nhs.uk
Website	http://www.uhs.nhs.uk/home.aspx
"ROR"	https://ror.org/0485axj58

Funders

Funder type

Industry

AstraZeneca
Government organisation / For-profit companies (industry)

Alternative name(s): AstraZeneca PLC, Pearl Therapeutics
Location: United Kingdom

Results and Publications

Intention to publish date	01/01/2028
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	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 the patients that they entered into the trial. The study team will present results at national and international conferences and publish in a peer-reviewed journal. Results will also be published on clinicaltrials.gov.
IPD sharing plan	The current data sharing plans for this study are unknown and will be available at a later date.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No

Editorial Notes

24/01/2025: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/01/2025 to 30/06/2025.
2. The overall end date was changed from 31/07/2027 to 31/10/2027.
3. The contact name was changed.
30/01/2024: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/10/2024 to 31/01/2025.
2. The overall study end date was changed from 31/03/2027 to 31/07/2027.
3. The intention to publish date was changed from 01/07/2027 to 01/01/2028.
4. The interventions, inclusion and exclusion criteria and contact details were updated.
5. The target number of participants was changed from 453 to 375.
6. The study participant centres were updated to remove Burton Hospital, North Manchester General Hospital, East Kent Hospitals University NHS Foundation Trust, Torbay Hospital, Bradford Teaching Hospitals NHS Foundation Trust, Royal Berkshire Hospital, Royal Sussex County Hospital, Clatterbridge Cancer Centre, and Castle Hill Hospital; and add Harrogate District Hospital, Addenbrookes, South Warwickshire University NHS Foundation Trust, The Royal Oldham Hospital, Stoke Mandeville Hospital, Wycombe Hospital, Hampshire Hospitals NHS Foundation Trust, University Hospitals Coventry and Warwickshire NHS Trust, Royal United Hospital, and West Suffolk Hospital.
11/05/2023: The following changes were made to the trial record:
1. The exclusion criteria were changed.
2. The recruitment end date was changed from 29/02/2024 to 31/10/2024.
05/12/2022: The following changes have been made:
1. The recruitment end date has been changed from 01/09/2023 to 29/02/2024.
2. The overall trial end date has been changed from 30/06/2026 to 31/03/2027 and the plain English summary updated accordingly.
3. John Radcliffe Hospital, Royal Hallamshire Hospital, Royal Free Hospital, Croydon University Hospital, Royal Derby Hospital, Wexham Park Hospital, Worcestershire Royal Hospital, Manchester University NHS Foundation Trust, Cardiff & Vale University LHB, Harrogate District Hospital, Kent & Canterbury Hospital, Salisbury District Hospital, East Surrey Hospital, West Suffolk Hospital, Queen Elizabeth Hospital, Royal United Hospitals Bath NHS Foundation Trust, University Hospital Coventry has been removed and Churchill Hospital, Chase Farm Hospital, Burton Hospital, Royal Devon and Exeter Hospital, East Kent Hospitals University NHS Foundation Trust, Pennine Acute Hospitals NHS Trust, Chelsea and Westminster Hospital NHS Foundation Trust, Bradford Teaching Hospitals NHS Foundation Trust, Broomfield Hospital, Southend University Hospital, Royal Berkshire Hospital, Darent Valley Hospital, United Lincolnshire Hospitals NHS Trust, Bolton Royal Hospital, Castle Hill Hospital and Sandwell General Hospital added to the trial participating centres.
02/12/2021: The Cancer Research UK plain English summary has been added.
19/10/2021: The recruitment start date has been changed from 01/09/2021 to 19/10/2021.
17/08/2021: Internal review.
09/07/2021: Trial's existence confirmed by the National Institute for Health Research (NIHR) (UK).