| Eligibility |
Inclusion Criteria:
Informed consent
1. Ability to understand the purpose and risks of the study and capable of giving signed
informed consent which includes:
1. Compliance with the requirements and restrictions listed in the informed consent
form (ICF).
2. Authorization to use protected health information/data [in accordance with the
General Data Protection Regulation (GDPR)].
2. Provision of signed and dated, written ICF prior to any mandatory study specific
procedures, sampling, and analyses
3. Willing and able to participate in all required evaluations and procedures in this
study protocol, including swallowing capsules and tablets without difficulty.
Age/Sex
4. Men and women >80 years of age or >60 up to 80 years of age and ineligible for full
dose R-CHOP according to investigator assessment*.
We recommend classifying patients aged 61-80 as full-dose R-CHOP ineligible if they
fulfill one of the following criteria: ADL <5, IADL <6, CIRS-G =1 score = 3, or > 8
score = 2.
5. Male patients who are sexually active with women of childbearing potential
(definitions see section 17.8) must agree to use highly effective forms of
contraception with the addition of a barrier method (condom) during the study (see
section 17.8.1) as well as to the restrictions mentioned in section 9.13.
6. Female patients of childbearing potential (definitions see 17.8) who are sexually
active must agree to use highly effective forms of contraception while on the study as
well as to the restrictions mentioned in section 9.13.
Disease characteristics
7. Histologically proven, previously untreated CD20+ diffuse large B-cell lymphoma
(DLBCL) according to the 2017 WHO classification including:
1. diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS)
2. primary cutaneous DLBCL leg type
3. intravascular large B-cell lymphoma
4. EBV+ DLBCL, NOS
5. HHV8+DLBCL, NOS
6. primary mediastinal (thymic) large B-cell lymphoma
7. B-cell lymphoma, with intermediate features between DLBCL and classical Hodgkin
lymphoma
8. follicular lymphoma grade 3B
9. high-grade B-cell lymphoma, NOS
10. high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
11. T-cell/histiocyte-rich large B-cell lymphoma
12. DLBCL associated with chronic inflammation
13. ALK+ large B-cell lymphoma
14. large B-cell lymphoma with IRF4 rearrangement Please note: patients in whom
indolent lymphoma is diagnosed concurrently with the one of the above listed
diagnoses can also be included.
8. Disease Stage I with bulk =7.5cm, II, III or IV according to Ann Arbor Classification
Type of patient and clinical characteristics
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. An ECOG
Score of 3 is acceptable only if this is directly attributable to lymphoma.
10. Meet the following laboratory parameters:
1. Absolute neutrophil count (ANC) = 1500 cells/µl or platelet count = 100.000/µl
unless directly attributable to lymphoma.
2. Serum AST and ALT =3 x upper limit of normal (ULN) unless directly attributable
to lymphoma.
3. Total bilirubin =1.5 x ULN, unless directly attributable to Gilbert's syndrome or
lymphoma.
4. Estimated creatinine clearance of =30 mL/min, calculated by Cockcroft-Gault
(using actual body weight) (if male, [140-Age] x Mass [kg] / [72 x creatinine
mg/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, including
uncontrolled hypertension and renal transplant) that, in the investigator's opinion,
make it undesirable for the patient to participate in the study or that would
jeopardize compliance with the protocol [e.g. a single score of 4 on one single
category on the CIRS-G-Score (but not a cumulative score of 4)].
2. Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart
failure, or myocardial infarction within 6 months of randomization or any Class 3 or 4
cardiac disease as defined by the New York Heart Association Functional
Classification, or LVEF < 40%. Patients with controlled, asymptomatic atrial
fibrillation 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 it
undesirable for the patient to participate in the study or that would jeopardize
compliance with the protocol.
5. Persistent neuropathy CTCAE grade 3 or 4.
6. Refractory nausea and vomiting, inability to swallow acalabrutinib, or malabsorption
syndrome; chronic severe gastrointestinal disease, gastric restrictions, or bariatric
surgery such as gastric bypass; partial or complete bowel obstruction, or previous
significant 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 or
interpretation of results, except for the following:
1. Curatively treated localised basal cell carcinoma or localised squamous cell
carcinoma 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 as
untreated low grade lymphoma except chronic lymphocytic leukemia.
2. Other cancers not specified above that have been curatively treated by surgery
and/or radiation therapy from which patient is disease-free for =2 years (=5
years for those treated with chemotherapy) without further treatment or which are
not expected to limit survival to < 2 years.
8. Received a live virus vaccination within 28 days of randomization.
9. Known history of infection with HIV.
10. Any active significant infection (e.g., bacterial, viral or fungal) as assessed by the
investigator.
11. History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).
12. Serologic status reflecting active hepatitis B or C infection.
1. Patients who are hepatitis B core antibody (anti-HBc) positive and who are
hepatitis B surface antigen (HBsAg) negative will need to have a negative PCR
result before randomization and must be willing to undergo DNA PCR testing during
the study. Those who are HBsAg-positive or hepatitis B PCR positive will be
excluded.
2. Patients who are hepatitis C antibody positive will need to have a negative PCR
result before randomization. Those who are hepatitis C PCR positive will be
excluded.
13. History of stroke or intracranial hemorrhage within 6 months before randomization.
14. History of clinically relevant bleeding diathesis (e.g., hemophilia, von Willebrand
disease).
15. Major surgical procedure within 30 days before randomization. Note: If a patient had
major surgery, they must have recovered adequately from any toxicity and/or
complications from the intervention before the first dose of study drug.
16. Breastfeeding or pregnant women.
17. Current life-threatening illness, medical condition, organ system dysfunction, social,
geographical or economic condition which, in the Investigator's opinion, could
compromise the patient's safety or put the study at risk.
18. Diagnosis of primary central nervous system lymphoma or secondary central nervous
system or meningeal involvement by lymphoma
19. Diagnosis of Richter's Transformation/transformed CLL Prior/Concomitant therapy
20. Requires or receiving anticoagulation with warfarin or equivalent vitamin K
antagonists. Patients using therapeutic low molecule weight heparin, direct oral
anticoagulants or low dose aspirin will be eligible. Switching from vitamin K
antagonists to one of the allowed anticoagulants above prior to trial entry is
permitted.
21. Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor or inducer. The
use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks
of the first dose of study drug is prohibited. See details in section 9.12.1.
22. Prior exposure to a BTK inhibitor.
23. Prior anthracycline use =300 mg/m2.
24. Already initiated lymphoma therapy except for steroid (max. total dose of 1000mg),
vincristine (max. 1 mg once) or rituximab (max. 375mg/m2) prephase.
25. Concurrent participation in another therapeutic clinical trial.
26. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Patients receiving
proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible
for enrolment into this study.
27. Received any investigational drug within 30 days or 5 half-lives (whichever is
shorter) before first dose of study drug.
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