Acalabrutinib Safety Study in Untreated and Relapsed or Refractory Chronic Lymphocytic Leukemia Patients

This is a Global, Phase IIIb, multicenter, open-label, single-arm study to evaluate the safety and efficacy of acalabrutinib 100 mg bid in approximately 540 participants with CLL. Participants will be enrolled into one of the 3 following cohorts:

• Treatment-naive (TN): participants who have had no prior treatment for CLL and who have either a score > 6 on the cumulative illness rating scale and/or have a creatinine clearance of 30 to 69 mL/min using the Cockcroft-Gault equation (minimum of 300 participants). This cohort will not be enrolled in the UK.
• Relapsed/refractory (R/R): participants who have received prior treatment for CLL and who have either relapsed or refractory CLL (approximately 200 participants).
• Prior ibrutinib therapy cohort: participants who have received prior ibrutinib for CLL and who discontinued the medication for any reason prior to disease progression (up to 40 participants). This cohort will not be enrolled in the US.

Overall response and progression assessments will be conducted by the investigator in accordance with the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria. Overall response assessments will be based on physical examinations, recording of symptoms, radiologic evaluations, and hematologic evaluations.

Treatment period consists of 48 cycles [each cycle is 28 days). Study medication (acalabrutinib 100 mg bid) will be administered until disease progression, toxicity requiring discontinuation, completion of 48 cycles of study medication, withdrawal of consent, loss to follow-up, death, or study termination by the sponsor, whichever comes first.

48 Cycles: From Cycle 1 to Cycle 6, in-clinic visits will occur every cycle and during each visit, in-clinic assessments will be carried out. From Cycle 7 to Cycle 12, in-clinic visits will occur every 3 cycles and during each visit, in-clinic assessments will be carried out. From Cycle 13 to Cycle 48, in-clinic visits will occur every 3 cycles and in-clinic assessments will be carried out every 6 cycles.

Safety follow up visits will occur approximately 30 days from the last dose of study treatment.

If a participant continues to derive benefit from treatment at the end of 48 cycles prior to the final DCO, they will continue to be provided with study intervention and will be followed in the Disease Follow-up period every 24 weeks (q24w) until study intervention discontinuation due to, for example, disease progression or toxicity, withdrawal of consent, loss to follow-up, death, or study termination by the sponsor, whichever occurs first. Alternatively, at the end of 48 cycles, a participant can decide to switch to commercial off-study acalabrutinib, if available and permitted by local regulations. Post final DCO, 2 options will be considered: participants may be transitioned to another study or may shift to a commercial supply of acalabrutinib/off-study acalabrutinib as permitted by local regulations. Participants who switch to off-study acalabrutinib will be considered as having completed the study and therefore will not have any additional study assessments, including the safety follow-up visit and disease Follow-up period.

The duration of the study will be approximately 72 months from the first participant enrolled. This duration includes an estimated 24-month recruitment time and an assumed 48 cycles of study intervention (28 days per cycle); additional study time will be accrued during the Follow-up period for those participants remaining on study intervention after completion of 48 cycles prior to the final DCO (the amount of time will vary by participant).