Acalabrutinib in Combination With R-CHOP for Previously Untreated Diffuse Large B-cell Lymphoma (DLBCL)

Inclusion Criteria:

• Histologically confirmed DLBCL, expressing CD20. Sufficient diagnostic material mustbe available to forward to HMDS for gene expression profiling and central pathologyreview. The following diagnoses by 2016 WHO classification of lymphoid neoplasms maybe included:

• DLBCL, not otherwise specified (NOS)

• T-cell/histiocyte-rich large B-cell lymphoma

• Epstein-Barr virus positive DLBCL, NOS

• ALK-positive large B-cell lymphoma

• HHV8-positive DLBCL, NOS

• High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit lymphoma)

• High-grade B-cell lymphoma, NOS

• At least one bi-dimensionally measurable lesion, defined as >1.5 cm in its longestdimension as measured by CT.

• Not previously treated for lymphoma and fit enough to receive combinationchemoimmunotherapy with curative intent.

• 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.

• ECOG performance status 0-2 or 3 if this is directly attributable to lymphoma.

• Adequate bone marrow function with platelets > 100x109/L; neutrophils > 1.0x109/L atstudy entry, unless lower figures are attributable to lymphoma.

• Measured or calculated creatinine clearance > 30mls/min, (calculated using theformula of Cockcroft and Gault [(140-Age) x Mass (kg) x (1.04 (for women) or 1.23 (for men))/Serum Creatinine (μmolL)]).

• Serum bilirubin < 35μmol/L and transaminases < 1.5x upper limit of normal at time ofstudy entry.

• Cardiac function sufficient to tolerate 300mg/m2 of doxorubicin. A pre-treatmentechocardiogram or MUGA is required to establish baseline LVEF equal to or greaterthan institutional normal range.

• No concurrent uncontrolled medical condition.

• Life expectancy > 3 months.

• Aged 16 years or above.

• Willing and able to participate in all required evaluations and procedures in thisstudy protocol including swallowing capsules without difficulty.

• Ability to understand the purpose and risks of the study and provide signed anddated informed consent.

Exclusion Criteria:

• Previous history of treated or untreated indolent lymphoma. However newly diagnosedpatients with DLBCL who are found to also have small cell infiltration of the bonemarrow or other diagnostic material (discordant lymphoma) will be eligible.

• Patients who have received immunisation with a live vaccine within four weeks priorto enrolment will be ineligible.

• Diagnosis of primary mediastinal lymphoma.

• Diagnosis of primary Central Nervous System lymphoma or secondary CNS involvement.Those patients presenting with neurological symptoms should be investigated for CNSinvolvement. Routine CNS imaging or diagnostic lumbar puncture will not be requiredin the absence of symptoms.

• History of stroke or intracranial haemorrhage in preceding 6 months.

• History of bleeding diathesis (eg, haemophilia, von Willebrand disease).

• History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components).

• Requires or receiving anticoagulation with warfarin or equivalent antagonists (eg,phenprocoumon) within 7 days of first dose of acalabrutinib. However patients usingtherapeutic low molecule weight heparin or low dose aspirin will be eligible as willthose receiving direct oral anticoagulants.

• Prior exposure to an inhibitor in the BCR pathway (eg, Btk inhibitors,phosphoinositide-3 kinase (PI3K), or Syk inhibitors) or BCL-2 inhibitor (eg,ABT-199).

• Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer.

• Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole,lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Patients receivingproton pump inhibitors should switch to short-acting H2-receptor antagonists orantacids prior to the commencement of acalabrutinib, if randomised to receiveacalabrutinib.

• Active significant infection (e.g. progressive multifocal leukoencephalopathy (PML)).

• Uncontrolled autoimmune haemolytic anaemia (AIHA) or idiopathic thrombocytopenicpurpura (ITP).

• Major surgery in the preceding 4 weeks of first dose of acalabrutinib (ifapplicable). If a subject had major surgery, they must have recovered adequatelyfrom any toxicity and/or complications from the intervention before the first doseof acalabrutinib (if applicable).

• Corticosteroid use >30 mg/day of prednisone or equivalent, for purposes other thanfor lymphoma symptom control. Patients receiving corticosteroid treatment with <30mg/day of prednisone or equivalent must be documented to be on a stable dose of atleast 4 weeks' duration prior to the start of Cycle 1. If glucocorticoid treatmentis urgently required for lymphoma symptom control prior to the start of studytreatment, prednisone 100 mg or equivalent could be given for a maximum of 14 daysas a prephase. A dose of up to 30mg or prednisolone or equivalent may be used duringthe screening phase to control symptoms.

• Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,congestive heart failure, or myocardial infarction within 6 months of screening, orany Class 3 or 4 cardiac disease as defined by the New York Heart AssociationFunctional Classification.

• Serological positivity for Hepatitis B, C, or known HIV infection. As per standardof care, prior to initiation of immunochemotherapy, the results of hepatitisserology should be known prior to commencement of therapy.

1. Positive test results for chronic HBV infection (defined as positive HBsAgserology) 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.

2. Patients positive for HCV antibody are eligible only if polymerase chainreaction (PCR) is negative for HCV RNA.

• Women who can bear children must agree to use two highly effective forms ofcontraception or abstinence during the study and for 12 months after the lasttreatment dose.

• Breastfeeding or pregnant women.

• Men who can father children must agree to use two highly effective forms ofcontraception with additional barrier or abstinence during the study and for 12months after the last treatment dose.

• Men must agree to refrain from sperm donation during the study and for 12 monthsafter the last treatment dose.

• Serious medical or psychiatric illness likely to affect participation or that maycompromise the ability to give informed consent.

• Prior malignancy (other than DLBCL), except for adequately treated basal cell orsquamous cell skin cancer, in situ cervical cancer, or other cancer from which thesubject has been disease free for ≥ 2 years or which will not limit survival to < 2years.

• Has difficulty with or is unable to swallow oral medication, or has significantgastrointestinal disease, resection of the stomach or small bowel, partial orcomplete bowel obstruction or gastric restrictions and bariatric surgery, such asgastric bypass that would limit absorption of oral medication.

• Any immunotherapy within 4 weeks of 1st dose of the study.

• Concurrent participation in another therapeutic clinical trial.