Evaluation of Acalabrutinib Monotherapy in Treatment-Naive or Relapsed/Refractory Chronic Lymphocytic Leukemia: A Phase 3b, Multicenter, Open-Label Study

Trial ID: 2023-507669-24-00
Protocol: D8220C00008
Sponsor: AstraZeneca AB

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Diseases & Conditions

Chronic lymphocytic leukaemia

Objectives

The primary objective of this study is to evaluate the **safety** and tolerability of acalabrutinib monotherapy in participants with treatment-naive or relapsed/refractory **chronic lymphocytic leukemia**. This is clinically relevant as it aims to determine the potential adverse effects and overall patient tolerance to acalabrutinib, which is crucial for assessing its viability as a treatment option for this patient population.

Secondary objectives include evaluating the investigator-assessed overall response, duration of response, and progression-free survival in participants receiving acalabrutinib monotherapy. These measures are important for understanding the efficacy of the treatment in terms of its ability to induce and sustain a therapeutic response, as well as delaying disease progression.

Participants

The clinical trial involves a total of **459 participants** diagnosed with **chronic lymphocytic leukemia** (CLL). The study population includes both male and female subjects aged 18 years and older, encompassing those who are treatment-naive or have relapsed/refractory CLL. Participants were selected based on specific diagnostic criteria, including the presence of monoclonal B-cells and active disease as per iwCLL 2018 criteria. The trial includes individuals with varying degrees of prior treatment, including those who have received no prior therapy, those with refractory or relapsed CLL, and those who have previously undergone ibrutinib therapy. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Lifestyle considerations such as diet and physical activity are not specified, but female participants of childbearing potential must adhere to strict contraceptive measures. The trial population is considered vulnerable, and all participants must provide written informed consent and comply with the study protocol.

Plans and Procedures

The clinical trial is a **Phase 3b**, multicenter, open-label, single-arm study designed to evaluate the safety and tolerability of **acalabrutinib** monotherapy in participants with treatment-naive or relapsed/refractory **chronic lymphocytic leukemia** (CLL). The trial is expected to run from December 13, 2019, to September 1, 2025. Participants will be administered **Calquence 100 mg hard capsules** orally, with a maximum daily dose of 200 mg and a total treatment period of up to 257 days. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess overall outcomes.

Participants will be involved in the study for the duration of the treatment period, with the possibility of early termination if they experience severe adverse events (AEs) or if they do not adhere to the study protocol. The primary endpoints include the frequency, severity, and relatedness of all AEs, with a focus on grade ≥3 AEs, serious adverse events (SAEs), and adverse events of special interest (AESI) such as ventricular arrhythmias. Secondary endpoints will assess overall response, duration of response, and progression-free survival.

Inclusion criteria require participants to be adults aged 18 years or older with a confirmed diagnosis of CLL, meeting specific diagnostic criteria. Participants must have active disease as defined by the iwCLL 2018 criteria and must meet additional health and treatment history requirements. Exclusion criteria are not specified in the provided data. The study aims to provide comprehensive data on the safety profile of acalabrutinib in a real-world setting, contributing to the understanding of its therapeutic potential in CLL management.

Treatment

The clinical trial involves the administration of **acalabrutinib**, marketed under the name Calquence, in the form of 100 mg hard capsules. Acalabrutinib is a chemical substance, also known by its synonyms ACP-196 and (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)-imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)-benzamide. The pharmaceutical form of the medication is a hard capsule, and it is intended for **oral use**. The maximum daily dose of acalabrutinib is 200 mg, with a total maximum dose of 360.4 grams over the course of the treatment. The maximum treatment period is 257 days. The medication is provided in a different primary package with clinical labeling specific to the trial requirements.

In this study, acalabrutinib is administered as a monotherapy to participants diagnosed with **chronic lymphocytic leukemia**. The trial is designed as a Phase 3b, multicenter, open-label, single-arm study, focusing on evaluating the safety and tolerability of acalabrutinib in subjects who are either treatment-naive or have relapsed/refractory chronic lymphocytic leukemia. There are no non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, included in this study. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

Efficacy

Efficacy in this clinical trial will be assessed using several key endpoints. The primary endpoints include the frequency, severity, and relatedness of all adverse events (AEs), with a focus on Grade ≥3 AEs, serious adverse events (SAEs), adverse events of special interest (AESI) such as ventricular arrhythmias, and adverse events leading to discontinuation of treatment. Additionally, events of clinical interest (ECIs) will be monitored, including cardiac events, hepatotoxicity, hypertension, infections, interstitial lung disease/pneumonitis, hemorrhage (major hemorrhage), cytopenias (anemia, leukopenia, thrombocytopenia), second primary malignancies, and tumor lysis syndrome.

Secondary endpoints will evaluate overall response, duration of response, and progression-free survival. These parameters will be measured and collected at specified intervals throughout the study to ensure comprehensive data analysis. The trial is designed to assess the efficacy of **acalabrutinib** monotherapy in subjects with chronic lymphocytic leukemia, focusing on both treatment-naive and relapsed/refractory cases. The data collected will be analyzed to determine the therapeutic impact of the intervention, with the aim of providing robust evidence on the efficacy of the treatment regimen.

Inclusion and Exclusion Criteria

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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): 1. 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 2. Prolymphocytes may comprise <55% of blood lymphocytes during screening 3. 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 1. 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). 2. Massive (i.e., ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly. 3. Massive nodes (i.e., ≥10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy 4. 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. 5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy 6. B-symptoms documented in the participant's chart with supportive objective measures, as appropriate, defined as ≥1 of the following disease-related symptoms or signs: o- Unintentional weight loss ≥10% within the previous 6 months before screening o- Significant fatigue (Eastern Cooperative Oncology Group [ECOG] performance status ≥2; inability to work or perform usual activities) o- Fevers higher than 100.5°F or 38.0°C for ≥2 weeks o- Night sweats for ≥1 month before screening without evidence of infection
Must meet one of the following criteria: a. Have received no prior therapy for treatment of CLL and meets one of the following criteria (for this study, participants in the UK will be enrolled ONLY in the R/R or the prior ibrutinib cohort): i. A score of >6 on the Cumulative Illness Rating Scale (CIRS) ii. Creatinine clearance of 30 to 69 mL/min using the Cockcroft-Gault equation b. Have previously received therapy for CLL and have either refractory or relapsed CLL c. Have received prior ibrutinib therapy (i.e., defined as a participant who discontinued a ibrutinib for any reason prior to disease progression) for CLL (participants in the US will not be enrolled into the prior ibrutinib therapy cohort)
ECOG performance status of ≤2
Female participants of childbearing potential (i.e., not surgically sterile or postmenopausal) who are sexually active with a non-sterilized male partner must use ≥1 highly effective method of contraception from the time of screening and must agree to continue using such precautions for 2 days after the last dose of study intervention. Contraception measures and restrictions on sperm donation are not required for male participants.
Fluorescence in situ hybridization (FISH) for which the next-generation sequencing (NGS) method is preferred) within 60 days during screening up to before the first dose reflecting the presence or absence of del(17p), del(13q), del(11q), and trisomy of chromosome 12 along with the percentage of cells with the deletion, along with TP53 sequencing. Participants must also have molecular analysis to detect IGHV mutation status (NGS is the preferred method) at screening if not done at any time point before that since diagnosis.
Each participant (or legally authorized representative if allowed per local regulations) must be willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information.

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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. 1. 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. 2. Participants who are hepatitis C virus antibody positive will need to have a negative hepatitis C virus PCR result before enrollment. Those who are hepatitis C virus PCR positive will be excluded.
Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (>20 mg daily of prednisone or equivalent for longer than 2 weeks).
History of stroke or intracranial hemorrhage within 6 months before the first dose of study intervention.
History of bleeding diathesis (e.g., hemophilia or von Willebrand disease).
Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
Major surgical procedure within 4 weeks before first dose of study intervention. Note: Participants who have had major surgery must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study intervention.
Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Participants receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study.
All participants requiring or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days before first dose of study intervention. Based on the known metabolic/transport pathways involved in the disposition of acalabrutinib and the commonly known novel oral anticoagulants (eg, apixaban, rivaroxaban, and edoxaban), no clinically relevant interaction is expected following coadministration of these agents.
Absolute neutrophil count (ANC) <0.50 x 10^9/L or platelet count <30 x 10^9/L, unless proven due to CLL and raised above the limits by granulocyte colony-stimulating factor (G-CSF) therapy and/or pooled platelet transfusion.
Total bilirubin >3.0x upper limit of normal (ULN); or aspartate aminotransferase or alanine aminotransferase >3.0x ULN. Exception will be for Gilbert syndrome; if an investigator feels that a participant's total bilirubin is elevated secondary to Gilbert's, the participant must have a documented unconjugated bilirubin being >80% of the total bilirubin number. The investigator must also document that hemolysis has been ruled out along with (near)-normal lactate dehydrogenase and haptoglobin.
Estimated creatinine clearance of <30 mL/min, calculated using the formula of Cockcroft and Gault or by direct assessment (i.e., creatinine clearance or ethylene diamine tetra-acetic acid (EDTA) clearance measurement).
Breastfeeding or pregnant.
Received any chemotherapy, external beam radiation, investigational drug, or any other anti-CLL therapy within 30 days before first dose of study intervention.
Concurrent participation in another therapeutic clinical study
History of or ongoing interstitial lung disease
Requiring long-term (> 1 week) treatment with a strong cytochrome CYP3A inhibitor/inducer. In addition, the use of strong or moderate CYP3A inhibitors or inducers within 7 days of the first dose of study intervention is prohibited.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Denmark	Not Recruiting	13 Dec 2019	43
Finland	Not Recruiting	13 Dec 2019	6
France	Not Recruiting	13 Dec 2019	18
Germany	Not Recruiting	13 Dec 2019	17
Italy	Not Recruiting	13 Dec 2019	19
The Netherlands	Not Recruiting	13 Dec 2019	—
Norway	Not Recruiting	13 Dec 2019	23
Spain	Not Recruiting	13 Dec 2019	37
Sweden	Not Recruiting	13 Dec 2019	11
Netherlands	—	—	4