CLL-Frail - A prospective, multicenter phase II trial of acalabrutinib in very old (≥80y) or frail CLL-Patients

Prior treatment

• >1 prior CLL-specific therapy (corticosteroid treatment is not counted as prior treatment; within the last 10 days before start of study treatment, only corticosteroid dose equivalents up to 20 mg prednisolone are permitted).
• Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
• Use of investigational agents which might interfere with the study drug within 28 days prior to registration for study screening.
• Requirement of therapy with strong CYP3A4 inhibitors/inducers or anticoagulant with phenprocoumon (marcumar) or other vitamin K-antagonists. Please note: Switch to alternative anticoagulants for vitamin K antagonists is permitted.
• Prior exposure to acalabrutinib.
• Progression during previous treatment with another BTK inhibitor, and/or presence of known mutations associated with resistance to therapy, e.g. Bruton´s Tyrosine Kinase (BTK) and Phospholipase C Gamma 2 (PLCg2).
• Uncontrolled concomitant malignancy, i.e. any concomitant malignancy that may compromise the assessment of CLL stage and the response assessment of the study treatment.

Other illness

• Patients with known infection with human immunodeficiency virus (HIV).
• Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 3 months of screening, or any class 4 cardiac disease as defined by the New York Heart Association Functional Classification at Screening. Please note: Subjects with controlled, asymptomatic atrial fibrillation are allowed to enroll in the study.
• Significantly increased risk of bleeding according to the investigator´s evaluation, e.g. due known bleeding diathesis (e.g. von-Willebrandt´s disease or hemophilia), major surgical procedure ≤ 4 weeks or stroke/intracranial hemorrhage ≤ 6 months.
• Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML).
• Patients with uncontrolled autoimmune haemolytic anaemia or immune thrombocytopenia.
• Uncontrolled or active infection (including positive SARS-Cov-2 PCR result).

Other

• Inability to swallow tablets.
• Legal incapacity.
• Prisoners or subjects who are institutionalized by regulatory or court order.
• Persons who are in dependence to the sponsor or an investigator.
• Transformation of CLL to aggressive NHL (Richter’s transformation or pro-lymphocytic leukaemia).
• Eastern Cooperative Oncology Group Performance Status (ECOG) performance status >3.

• Age ≥80 years AND/OR considered too frail for intensive/standard treatment defined by a frailty score of >2 on the FRAIL scale via the patient´s assessment.
• In case of a recent previous treatment, patients must have recovered from acute toxicities and treatment regimen must be stopped within the following time periods before start of the study treat-ment in the CLL-Frail trial: i. chemotherapy ≥ 28 days, ii. antibody treatment ≥ 14 days, iii. kinase inhibitors (see also exclusion criterion 6), BCL2-antagonists or immuno-modulatory agents ≥ 3 days, iv. corticosteroids may be applied until the start of the study therapy, these have to be reduced to an equivalent of ≤ 20mg prednisolone per day during treatment.
• Signed informed consent and, in the investigator’s judgment, able to comply with the study protocol.
• Have documented CLL requiring treatment according to iwCLL 2018 criteria.
• Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
• GFR >30ml/min directly measured with 24hr urine collection or calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 – age) x bodyweight)/ (72 x creatinine), for women x 0, 85) or an equally accurate method. Please note: Patients currently on hemodialysis are excluded from participating in the trial.
• Adequate liver function as indicated by a total bilirubin ≤ 3 x, AST/ ALT ≤ 3 x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome.
• Adequate marrow function independent of growth factor or transfusion support as follows, unless cytopenia is due to marrow involvement of CLL: i. Absolute neutrophil count ≥ 1.0 × 10^9/L. ii. Platelet counts ≥ 30 × 10^9/L; in cases of thrombocytopenia clearly due to marrow involvement of CLL (per the discretion of the investigator); platelet count should be ≥ 10 × 10^9/L if there is bone marrow involvement. iii. Total haemoglobin ≥ 9 g/dL (without transfusion support, unless anaemia is due to marrow involvement of CLL).
• Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month/every three months if persistently negative until 12 months after last month of treatment), negative testing for hepatitis C RNA within 6 weeks prior to registration.
• Life expectancy ≥ 3 months.
• Maximum of 1 previous treatment for CLL.