A Phase 3b, Multicenter, Open-Label, Single-Arm Study of Acalabrutinib (ACP-196) in Subjects With Chronic Lymphocytic Leukemia.
Overview
- Phase
- Phase 3
- Intervention
- Acalabrutinib
- Conditions
- Chronic Lymphocytic Leukemia
- Sponsor
- AstraZeneca
- Enrollment
- 552
- Locations
- 1
- Primary Endpoint
- Number of participants with adverse events
- Status
- Completed
- Last Updated
- 5 months ago
Overview
Brief Summary
This is a global, Phase IIIb, multicenter, open-label, single-arm study to evaluate the safety and efficacy of acalabrutinib 100 mg twice daily (bid) in approximately 540 participants with chronic lymphocytic leukemia (CLL). Participants will be enrolled into 3 following cohorts: treatment-naive (TN), relapsed/refractory (R/R), and prior ibrutinib therapy. For this study, participants in the UK will be enrolled ONLY into the R/R cohort or the prior ibrutinib cohort. Participants in the US will be enrolled ONLY into the TN or R/R cohort. Participants will remain on study intervention until completion of 48 cycles (28 days per cycle), or 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. 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 Disease Follow up period for those participants remaining on study intervention after completion of 48 cycles prior to the final data cutoff (DCO) (the amount of time will vary by participant).
Detailed Description
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).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Men and women ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place)
- •Diagnosis of CLL that meets all published diagnostic criteria (Hallek et al. 2018):
- •Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥1 B-cell marker (CD19, CD20, and CD23) and CD5 during screening
- •Prolymphocytes may comprise \<55% of blood lymphocytes during screening
- •Presence of ≥5 × 10\^9 B lymphocytes/L (5000/μL) in the peripheral blood (at any point since the initial diagnosis)
- •Active disease per at least 1 of the following iwCLL 2018 criteria
- •Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin \<10 g/dL) and/or thrombocytopenia (platelets \<100,000/μL).
- •Massive (i.e., ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
- •Massive nodes (i.e., ≥10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy
- •Progressive lymphocytosis with an increase of \>50% over a 2-month period or a lymphocyte doubling time (LDT) of \<6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte count obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In participants with initial blood lymphocyte counts of \<30x10\^9/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded.
Exclusion Criteria
- •Participants who have had disease progression while on a BTKi for any malignant or nonmalignant condition
- •Prior malignancy (other than CLL), except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, early stage prostate cancer, or other cancer from which the participant has been disease-free for ≥2 years
- •History of confirmed progressive multifocal leukoencephalopathy
- •Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months before screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval using Fridericia's formula (QTcF) \>480 msec at screening. Note: Participants with rate-controlled, asymptomatic atrial fibrillation are allowed to enroll in the study (For prior ibrutinib therapy cohort only, except in Finland and the Republic of South Korea, where this is applicable to all 3 cohorts; also, the prior ibrutinib therapy cohort will not be enrolled in the US).
- •Malabsorption syndrome, disease significantly affecting gastrointestinal (GI) function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
- •Evidence of active Richter's transformation. If Richter's transformation is suspected (i.e., lactate dehydrogenase \[LDH\] increased, asymmetric fast lymph node growth or clinical suspicion), it should be ruled out with positron emission tomographycomputed tomography (PET-CT) and/or biopsy according to guidelines.
- •Central nervous system (CNS) involvement by CLL.
- •Known history of human immunodeficiency virus, serologic status reflecting active hepatitis B virus or hepatitis C virus infection, any uncontrolled active systemic infection along with participants who are on ongoing anti-infective treatment and participants who have received vaccination with a live attenuated vaccine within 4 weeks before the first dose of study intervention.
- •Participants who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antibody (anti-HBs) negative will need to have a negative hepatitis B virus PCR result before enrollment. Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B virus PCR positive will be excluded.
- •Participants who are hepatitis C virus antibody positive will need to have a negative hepatitis C virus PCR result before enroll.lment. Those who are hepatitis C virus PCR positive will be excluded
Arms & Interventions
Acalabrutinib
Participants will be enrolled into 3 cohorts. In the treatment-naive cohort, a minimum of 300 participants with treatment-naïve chronic lymphocytic leukemia will be enrolled. In the relapsed/refractory cohort, approximately 200 participants with relapsed/refractory chronic lymphocytic leukemia will be enrolled. In the prior ibrutinib cohort, approximately 40 participants with Prior ibrutinib therapy will be enrolled.
Intervention: Acalabrutinib
Outcomes
Primary Outcomes
Number of participants with adverse events
Time Frame: From screening to safety follow-up period (approximately 30 days from last dose)
To evaluate the safety and tolerability of acalabrutinib monotherapy in participants with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia.
Secondary Outcomes
- Overall response (OR)(1 year after initial dose of study drug)
- Duration of response (DOR)(The time from the first objective response to the time of documented disease progression or death due to any cause, whichever occurs first within the time period to complete up to 48 cycles of treatment (each cycle is 28 days))
- Progression-free survival (PFS)(The interval from the start of study treatment to completion of 48 cycles (each cycle is 28 days) or the earlier of the first documentation of disease progression or death from any cause)