Acalabrutinib in Combination With R-miniCHOP in Older Adults With Untreated Diffuse Large B-Cell Lymphoma

Inclusion Criteria: Informed consent

1. Ability to understand the purpose and risks of the study and capable of giving signedinformed consent which includes:
2. Compliance with the requirements and restrictions listed in the informed consentform (ICF).
3. Authorization to use protected health information/data [in accordance with theGeneral Data Protection Regulation (GDPR)].
4. Provision of signed and dated, written ICF prior to any mandatory study specificprocedures, sampling, and analyses
5. Willing and able to participate in all required evaluations and procedures in thisstudy protocol, including swallowing capsules and tablets without difficulty. Age/Sex
6. Men and women >80 years of age or >60 up to 80 years of age and ineligible for fulldose R-CHOP according to investigator assessment*. We recommend classifying patients aged 61-80 as full-dose R-CHOP ineligible if theyfulfill one of the following criteria: ADL <5, IADL <6, CIRS-G ≥1 score = 3, or > 8score = 2.
7. Male patients who are sexually active with women of childbearing potential (definitions see section 17.8) must agree to use highly effective forms ofcontraception with the addition of a barrier method (condom) during the study (seesection 17.8.1) as well as to the restrictions mentioned in section 9.13.
8. Female patients of childbearing potential (definitions see 17.8) who are sexuallyactive must agree to use highly effective forms of contraception while on the study aswell as to the restrictions mentioned in section 9.13. Disease characteristics
9. Histologically proven, previously untreated CD20+ diffuse large B-cell lymphoma (DLBCL) according to the 2017 WHO classification including:
10. diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS)
11. primary cutaneous DLBCL leg type
12. intravascular large B-cell lymphoma
13. EBV+ DLBCL, NOS
14. HHV8+DLBCL, NOS
15. primary mediastinal (thymic) large B-cell lymphoma
16. B-cell lymphoma, with intermediate features between DLBCL and classical Hodgkinlymphoma
17. follicular lymphoma grade 3B
18. high-grade B-cell lymphoma, NOS
19. high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
20. T-cell/histiocyte-rich large B-cell lymphoma
21. DLBCL associated with chronic inflammation
22. ALK+ large B-cell lymphoma
23. large B-cell lymphoma with IRF4 rearrangement Please note: patients in whomindolent lymphoma is diagnosed concurrently with the one of the above listeddiagnoses can also be included.
24. Disease Stage I with bulk ≥7.5cm, II, III or IV according to Ann Arbor ClassificationType of patient and clinical characteristics
25. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. An ECOGScore of 3 is acceptable only if this is directly attributable to lymphoma.
26. Meet the following laboratory parameters:
27. Absolute neutrophil count (ANC) ≥ 1500 cells/µl or platelet count ≥ 100.000/µlunless directly attributable to lymphoma.
28. Serum AST and ALT ≤3 x upper limit of normal (ULN) unless directly attributableto lymphoma.
29. Total bilirubin ≤1.5 x ULN, unless directly attributable to Gilbert's syndrome orlymphoma.
30. Estimated creatinine clearance of ≥30 mL/min, calculated by Cockcroft-Gault (using actual body weight) (if male, [140-Age] x Mass [kg] / [72 x creatininemg/dL]; multiply by 0.85 if female), or serum creatinine ≤2.5 x ULN.

Exclusion Criteria: Medical conditions

1. Evidence of disease (such as severe or uncontrolled systemic diseases, includinguncontrolled hypertension and renal transplant) that, in the investigator's opinion,make it undesirable for the patient to participate in the study or that wouldjeopardize compliance with the protocol [e.g. a single score of 4 on one singlecategory on the CIRS-G-Score (but not a cumulative score of 4)].
2. Significant cardiovascular disease such as symptomatic arrhythmias, congestive heartfailure, or myocardial infarction within 6 months of randomization or any Class 3 or 4cardiac disease as defined by the New York Heart Association FunctionalClassification, or LVEF < 40%. Patients with controlled, asymptomatic atrialfibrillation are allowed to enroll on study.
3. Severe pulmonary dysfunction (CTCAE grade 3 or 4) unless associated with lymphoma.
4. Severe psychiatric or neurologic disease that, in the investigator's opinion, make itundesirable for the patient to participate in the study or that would jeopardizecompliance with the protocol.
5. Persistent neuropathy CTCAE grade 3 or 4.
6. Refractory nausea and vomiting, inability to swallow acalabrutinib, or malabsorptionsyndrome; chronic severe gastrointestinal disease, gastric restrictions, or bariatricsurgery such as gastric bypass; partial or complete bowel obstruction, or previoussignificant bowel resection that would preclude adequate absorption, distribution,metabolism, or excretion of study treatment.
7. History of prior malignancy that could affect compliance with the protocol orinterpretation of results, except for the following:
8. Curatively treated localised basal cell carcinoma or localised squamous cellcarcinoma of the skin or carcinoma in situ of the cervix or carcinoma in situ /low risk carcinoma of the prostate requiring only observation, as well asuntreated low grade lymphoma except chronic lymphocytic leukemia.
9. Other cancers not specified above that have been curatively treated by surgeryand/or radiation therapy from which patient is disease-free for ≥2 years (≥5years for those treated with chemotherapy) without further treatment or which arenot expected to limit survival to < 2 years.
10. Received a live virus vaccination within 28 days of randomization.
11. Known history of infection with HIV.
12. Any active significant infection (e.g., bacterial, viral or fungal) as assessed by theinvestigator.
13. History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).
14. Serologic status reflecting active hepatitis B or C infection.
15. Patients who are hepatitis B core antibody (anti-HBc) positive and who arehepatitis B surface antigen (HBsAg) negative will need to have a negative PCRresult before randomization and must be willing to undergo DNA PCR testing duringthe study. Those who are HBsAg-positive or hepatitis B PCR positive will beexcluded.
16. Patients who are hepatitis C antibody positive will need to have a negative PCRresult before randomization. Those who are hepatitis C PCR positive will beexcluded.
17. History of stroke or intracranial hemorrhage within 6 months before randomization.
18. History of clinically relevant bleeding diathesis (e.g., hemophilia, von Willebranddisease).
19. Major surgical procedure within 30 days before randomization. Note: If a patient hadmajor surgery, they must have recovered adequately from any toxicity and/orcomplications from the intervention before the first dose of study drug.
20. Breastfeeding or pregnant women.
21. Current life-threatening illness, medical condition, organ system dysfunction, social,geographical or economic condition which, in the Investigator's opinion, couldcompromise the patient's safety or put the study at risk.
22. Diagnosis of primary central nervous system lymphoma or secondary central nervoussystem or meningeal involvement by lymphoma
23. Diagnosis of Richter's Transformation/transformed CLL Prior/Concomitant therapy
24. Requires or receiving anticoagulation with warfarin or equivalent vitamin Kantagonists. Patients using therapeutic low molecule weight heparin, direct oralanticoagulants or low dose aspirin will be eligible. Switching from vitamin Kantagonists to one of the allowed anticoagulants above prior to trial entry ispermitted.
25. Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor or inducer. Theuse of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeksof the first dose of study drug is prohibited. See details in section 9.12.1.
26. Prior exposure to a BTK inhibitor.
27. Prior anthracycline use ≥300 mg/m2.
28. Already initiated lymphoma therapy except for steroid (max. total dose of 1000mg),vincristine (max. 1 mg once) or rituximab (max. 375mg/m2) prephase.
29. Concurrent participation in another therapeutic clinical trial.
30. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole,lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Patients receivingproton pump inhibitors who switch to H2-receptor antagonists or antacids are eligiblefor enrolment into this study.
31. Received any investigational drug within 30 days or 5 half-lives (whichever isshorter) before first dose of study drug.