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

NCT04008706 | Completed Phase 3 FDA Drug

• 2 other identifiers: D8220C000082019-001573-89
• Study Type: interventional
• Target: 552
• Locations: 17 countries
• Sites: 108

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).

Conditions

Chronic Lymphocytic Leukemia

Keywords

Chronic lymphocytic leukemia; Acalabrutinib

Outcome Measures

Primary Outcomes (1)

• Number of participants with adverse events

  To evaluate the safety and tolerability of acalabrutinib monotherapy in participants with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia.

  From screening to safety follow-up period (approximately 30 days from last dose)

Secondary Outcomes (3)

• 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

Other Outcomes (3)

• Plasma concentrations of acalabrutinib and ACP 5862

  At Day 1 of Cycle 3 and Day 1 of Cycle 15

• European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)

  Up to 48 cycles (each cycle is 28 days)

• Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

  Up to 48 cycles (each cycle is 28 days)

Study Arms (1)

Acalabrutinib

EXPERIMENTAL

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.

Drug: Acalabrutinib

Interventions

Acalabrutinib DRUG

Acalabrutinib will be administered as one 100 mg capsule taken orally, twice daily with 8 ounces (approximately 240 mL) of water.

Also known as: ACP-196

Acalabrutinib

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy
• 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

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (108)

Research Site

Chandler, Arizona, 85224, United States

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Long Beach, California, 90806, United States

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Redlands, California, 92373, United States

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Whittier, California, 90603, United States

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Fort Myers, Florida, 33908, United States

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Jacksonville, Florida, 32256, United States

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St. Petersburg, Florida, 33705, United States

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Marietta, Georgia, 30060, United States

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Normal, Illinois, 61761, United States

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Peoria, Illinois, 61615, United States

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Fort Wayne, Indiana, 46845, United States

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Indianapolis, Indiana, 46260, United States

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Shreveport, Louisiana, 71105, United States

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Saint Cloud, Minnesota, 56303, United States

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Kansas City, Missouri, 64132, United States

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Bethlehem, Pennsylvania, 18015, United States

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Chattanooga, Tennessee, 37404, United States

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Nashville, Tennessee, 37203, United States

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Dallas, Texas, 75235, United States

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Adelaide, 5000, Australia

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Bedford Park, 5042, Australia

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Clayton, 3168, Australia

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Fitzroy, 3065, Australia

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Nedlands, 6009, Australia

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South Brisbane, 4101, Australia

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Belo Horizonte, 30130-100, Brazil

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Curitiba, 81520-060, Brazil

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Goiânia, 74605-020, Brazil

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Porto Alegre, 90035-003, Brazil

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Porto Alegre, 90110-270, Brazil

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Ribeirão Preto, 14048-900, Brazil

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São Paulo, 01236-030, Brazil

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São Paulo, 01323-900, Brazil

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Calgary, Alberta, T2N 4N2, Canada

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Edmonton, Alberta, T6G 1Z2, Canada

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Victoria, British Columbia, V8R 6V5, Canada

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Winnipeg, Manitoba, R3E 0V9, Canada

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Halifax, Nova Scotia, B3H 1V7, Canada

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Brampton, Ontario, L6R 3J7, Canada

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Newmarket, Ontario, L3Y 2P9, Canada

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Ottawa, Ontario, K1H 8L6, Canada

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Aalborg, 9100, Denmark

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Aarhus, 8200, Denmark

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Herlev, 2730, Denmark

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København Ø, 2100, Denmark

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Odense, 5000, Denmark

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Roskilde, 4000, Denmark

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Hus, 00029, Finland

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Kuopio, 70210, Finland

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Tampere, 33521, Finland

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Bordeaux, 33076, France

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Brest, 29609, France

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Limoges, 87042, France

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Reims, 51092, France

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Tours, 37000, France

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Vandœuvre-lès-Nancy, 54511, France

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Bayern, 63739, Germany

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Essen, 45147, Germany

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Homburg, 66421, Germany

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Porta Westfalica, 32457, Germany

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Schwäbisch Hall, 74523, Germany

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Catanzaro, 88100, Italy

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Milan, 20122, Italy

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Roma, 00161, Italy

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Roma, 00168, Italy

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Siena, 53100, Italy

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Arnhem, 6815 AD, Netherlands

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Dordrecht, 3318 AT, Netherlands

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Utrecht, 3584 CX, Netherlands

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Bergen, 5053, Norway

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Oslo, 1478, Norway

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Trondheim, 7006, Norway

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Moscow, 115478, Russia

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Moscow, 125167, Russia

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Moscow, 125284, Russia

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Nizhny Novgorod, 603126, Russia

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Petrozavodsk, 185019, Russia

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Saint Petersburg, 191024, Russia

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Saint Petersburg, 194291, Russia

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Saint Petersburg, 197022, Russia

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Saint Petersburg, 197110, Russia

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Saint Petersburg, 197341, Russia

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Smolensk, 214015, Russia

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Smolensk, 214031, Russia

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Syktyvkar, 167904, Russia

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Busan, 49241, South Korea

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Seoul, 03080, South Korea

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Seoul, 03722, South Korea

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Seoul, 06591, South Korea

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Seoul, 135-710, South Korea

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Ulsan, 44033, South Korea

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Barcelona, 08036, Spain

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Madrid, 28006, Spain

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Madrid, 28041, Spain

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Marbella, 29603, Spain

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Ourense, 32005, Spain

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Oviedo, 33011, Spain

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Vitoria-Gasteiz, 01009, Spain

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Zaragoza, 50009, Spain

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Luleå, 97180, Sweden

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Lund, 221 85, Sweden

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Uppsala, 75185, Sweden

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Taichung, 40705, Taiwan

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Tainan, 704, Taiwan

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Taipei, 10002, Taiwan

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Taipei, 11217, Taiwan

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Liverpool, L7 8XP, United Kingdom

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Newmarket, CB8 7XN, United Kingdom

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MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

acalabrutinib

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Adel Habib, MD

  AstraZeneca

  STUDY DIRECTOR

• Dr. Carsten Niemann, MD

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a single arm study in which participants will be enrolled into 3 cohorts. In the treatment-naive (TN) cohort, a minimum of 300 participants with treatment-naïve chronic lymphocytic leukemia will be enrolled. In the relapsed/refractory (R/R) cohort, approximately 200 participants with relapsed/refractory chronic lymphocytic leukemia will be enrolled. In the prior ibrutinib cohort, up to 40 participants with Prior ibrutinib therapy will be enrolled.

Study Record Dates

• First Submitted: June 19, 2019
• First Posted: July 5, 2019
• Study Start: September 17, 2019
• Primary Completion: November 4, 2025
• Study Completion: November 4, 2025
• Last Updated: December 1, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

SE (3); KR (6); GB (2); IT (5); NO (3); ES (8); US (19); NL (3); DK (6); FR (6); RU (13); BR (8); TW (4); DE (5); AU (6); CA (8); FI (3)