Phase III Randomized Study to Investigate the Use of Acalabrutinib in the Treatment of Patients With Early Stage CLL With High Risk of Early Disease Progression

INTERVENTION: Product Name: Acalabrutinib Product Code: ACP‐196 Pharmaceutical Form: Capsule, hard INN or Proposed INN: ACALABRUTINIB CAS Number: 1420477‐60‐6 Current Sponsor code: AstraZeneca Other descriptive name: ACP‐196 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ CONDITION: Early Stage CLL With High Risk of Early Disease Progression ; MedDRA version: 21.0 Level: LLT Classification code 10008976 Term: Chronic lymphocytic leukemia System Organ Class: 100000004864 Therapeutic area: Diseases [C] ‐ Blood and lymphatic diseases [C15] SECONDARY OUTCOME: ; Secondary end point(s): ‐ ORR is defined as the proportion of patients who achieve a CR, CRi, nPR, or PR over the course of the study. Patients who achieve a PR with lymphocytosis will be included in the ORR. The rate of MRD‐negative disease will also be calculated. The IWCLL guidelines (Hallek, 2018) will be used to measure response in CLL subjects. Isolated treatment related lymphocytosis will not be considered as disease progression as recommended by the IWCLL guidelines (Hallek, 2018). Response rates will be shown by the frequency and percentage distribution, and by using the 95%CI; ‐ PFS is defined as the time from the date of treatment initiation to confirmed disease progression (IWCLL 2018 criteria) or death from any cause, whichever occurs first. Patients who withdraw from the study or are considered lost to follow‐up without prior documentation of disease progression will be censored on the date of the last adequate disease assessment. Patients who start new anticancer therapy before documentation of disease progression will be censored on the date of the last adequate disease assessment that is on or before the start date of the new anticancer therapy.; ‐ OS is defined as the time from the date of treatment initiation to death due to any cause. Patients who are known to be alive or whose survival status is unknown will be censored at the last date the patient is known to be alive.; ‐ Time to next treatment (TTNT). [Time Frame: time from randomization until the date of initiation of subsequent treatment for CLL or death from any cause]; Distribution of PFS, OS, and TTNT will be summarized using the Kaplan‐Meier estimate of median and its corresponding 95% CIs.; Timepoint(s) of evaluation of this end point: Throughout the study PRIMARY OUTCOME: ; Main Objective: To compare the event‐free survival (EFS) rate between acalabrutinib and clinical observation (watch & wait).; EFS is defined as the time between the date of randomization and time point of symptomatic disease progression with treatment indication according to the iwCLL‐Guidelines, initiation of subsequent treatment for CLL or death by any cause, whichever occurs first. These will be counted as an event for EFS. [Time Frame: from randomization until progression, initiation of subsequent treatment for CLL or death by any cause, whichever occurs first].; ; Secondary Objective: • Response rates (Overall response rate (ORR); Complete Remission (CR); CR with incomplete marrow recovery (CRi); nodular partial remission (nPR); Partial Remission (PR).; • Progression‐free survival (PFS). [Time Frame: the time from randomization until symptomatic disease progression (as defined by the updated iwCLL‐guidelines) or death from any cause, whichever occurs first].; • Overall survival (OS). [Time Frame: time between the day of randomization to death from may cause]. Patients alive or lost to follow‐up will be censored.; • Time to next treatment (TTNT). [Time Frame: time from randomization until the date of initiation of subsequent treatment for CLL or death from any cause]; • Immunological recovery; • Safety of acalabrutinib: type, frequency, and severity of adverse events (AEs) and relationship of AEs to acalabrutinib; Primary end point(s): Event Free Survival is defined as the time between the date of randomization and time point of symptomatic disease progression with treatment indication according to the iwCLL‐Guidelines, initiation of subsequent treatment for CLL or death by any cause, whichever occurs first. These will be counted as event for EFS. Timepoint(s) of evaluation of this end point: Throughout the study INCLUSION CRITERIA: 1. Adult patients with previously untreated CLL according to IWCLL criteria (Hallek, 2018) 2. Must understand and voluntarily sign an informed consent form. 3. Age = 18 years at the time of signing the informed consent form and must be able to adhere to the study visit schedule and other protocol requirements. 4. Diagnosis of CLL < 6 months prior to inclusion in the study 5. Binet clinical stage A and Rai 0 or 1 6. Absence of criteria for the initiation of chemotherapy, defined by the IWCLL guidelines for diagnosis and treatment of CLL (Hallek, 2018): • Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. • Massive (i.e. =6 cm below the left costal margin) or progressive or symptomatic splenomegaly. • Massive nodes (i.e.