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Clinical Trials List

Protocol NumberD8221C00001
NCT Number(ClinicalTrials.gov Identfier)NCT03836261

2019-05-01 - 2025-06-30

Phase III

Recruiting2

Terminated4

ICD-10C91.10

Chronic lymphocytic leukemia of B-cell type not having achieved remission

A Randomized, Multicenter, Open-Label, Phase 3 Study to Compare the Efficacy and Safety of Acalabrutinib (ACP-196) in Combination With Venetoclax With and Without Obinutuzumab Compared to Investigator's Choice of Chemoimmunotherapy in Subjects With Previously Untreated Chronic Lymphocytic Leukemia Without Del(17p) or TP53 Mutation

  • Trial Applicant

  • Sponsor

    Acerta Pharma BV/AstraZeneca

  • Trial scale

    Multi-Regional Multi-Center

  • Update

    2025/08/20

Investigators and Locations

Principal Investigator Su-Peng Yeh Division of Hematology & Oncology
China Medical University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Liang-Tsai Hsiao Division of Hematology & Oncology
Taipei Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Principal Investigator 王銘崇 Division of General Internal Medicine
Kaoshiung Chang Gung Memorial Hospital of the C.G.M.F.

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Principal Investigator Tsai-Yun Chen 無
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Shang-Ju Wu Division of General Internal Medicine
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Principal Investigator Po-Nan Wang Division of Hematology & Oncology
Linkou Chang Gung Medical Foundation

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Condition/Disease

Chronic Lymphocytic Leukemia

Objectives

Primary Efficacy Objective• To evaluate the efficacy of AV (Arm A) compared with chemoimmunotherapy(FCR/BR; Arm C) on the basis of the following endpoint:o PFS, defined as the time from randomization to the first occurrence ofdisease progression or death from any cause (whichever occurs first), asdetermined by the Independent Review Committee (IRC) according to theIWCLL 2018 criteriaSecondary Efficacy Objectives• To evaluate the efficacy of AVG (Arm B) versus FCR/BR (Arm C) based on thefollowing endpoint:o PFS, defined as the time from randomization to the first occurrence ofdisease progression or death from any cause (whichever occurs first), asdetermined by the IRC assessment according to the IWCLL 2018 criteria• To evaluate the efficacy of AV (Arm A) versus FCR/BR (Arm C) and AVG (Arm B)versus FCR/BR (Arm C) on the basis of the following endpoints:o ORR, defined as the proportion of subjects with a CR, CRi, or PR per theinvestigator and IRC assessment as per IWCLL 2018 criteriao DOR, defined as the time from the first occurrence of a documented objectiveresponse to disease progression or death from any cause per the investigatorand IRC assessment as per IWCLL 2018 criteriao Time to next Therapy (TTNT), defined as the time from randomization toinstitution of non-protocol specified treatment for CLLo MRD negativity rate (determined as the proportion of subjects with MRDnegativity) measured in the peripheral blood by flow cytometry (10-4) at thestart of Cycle 9 (in Arm A), the start of Cycle 10 (in Arm B), and 12 weeksafter the start of Cycle 6 (in Arm C)o OS, defined as the time from randomization to death from any causeExploratory Efficacy Objective• To evaluate patient-reported outcomes (PROs) for subjects on AV (Arm A) comparedwith FCR/BR (Arm C), and for subjects on AVG (Arm B) compared with FCR/BR(Arm C), on the basis of the following endpoints:o Disease-related symptoms and health-related quality of life (HRQoL) asmeasured with the European Organisation for Research and Treatment ofCancer (EORTC) Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)and symptoms from the EORTC item libraryo Fatigue as measured by the Functional Assessment of Chronic IllnessTherapy-Fatigue (FACIT-Fatigue)o Subjects’ overall impression of the change in their health status since the startof study treatment using single-item patient global impression of change(PGIC)o Subjects’ overall impression of the severity of their cancer symptoms usingpatient global impression of severity of cancer symptoms (PGIS)SAFETY OBJECTIVE• To evaluate the safety and tolerability of AV, with and without obinutuzumab, insubjects with previously untreated CLL without del(17p) or TP53 mutation, comparedwith FCR/BR (Arm C), on the basis of the following endpoint:o Incidence and severity of adverse events (AEs), with severity determinedaccording to National Cancer Institute (NCI) Common Terminology Criteria forAdverse Events (CTCAE) v5.0

Test Drug

Acalabrutinib (ACP-196)

Active Ingredient

Acalabrutinib

Dosage Form

capsule

Dosage

100

Endpoints

Primary Outcome Measures :
To evaluate the efficacy of acalabrutinib with venetoclax (Arm A) compared to chemoimmunotherapy fludarabine/cyclophosphamide/rituximab [FCR] or bendamustine/rituximab [BR] (Arm C): PFS [ Time Frame: 6 years ]
Progression-free survival (PFS) after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the Independent Review Committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria


Secondary Outcome Measures :
To evaluate the efficacy of acalabrutinib with venetoclax in combination with obinutuzumab (Arm B) compared with FCR or BR (Arm C): PFS [ Time Frame: 6 years ]
PFS after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the IRC assessment and investigator assessment

To evaluate the efficacy of acalabrutinib with venetoclax (Arm A) compared with FCR or BR (Arm C): PFS defined the same as above per investigator assessment. [ Time Frame: 6 years ]
PFS after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the IRC assessment and investigator assessment

Inclution Criteria

1. Men and women ≥18 years of age.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0–2.
3. Diagnosis of CLL that meets published diagnostic criteria (Hallek et al. 2018):
a. Monoclonal B-cells (either kappa or lambda light chain restricted) that are
clonally co-expressing B-cell marker (CD19, CD20, and CD23) and CD5.
b. Prolymphocytes may comprise <55% of blood lymphocytes.
c. Presence of ≥5x109 B lymphocytes/L (5000/µL) in the peripheral blood (at any
point since the initial diagnosis).
4. Active disease per IWCLL 2018 criteria that requires treatment (see Section 4.5.6).
5. Meet the following laboratory parameters:
a. Adequate bone marrow function independent of growth factor or transfusion
support within 1 week of Screening, as follows:
i. ANC ≥750 cells/μL (0.75x109
/L); ANC ≥500 cells/μL (0.50x109
/L) in
subjects with documented bone marrow involvement of CLL.
ii. Platelet count ≥50,000 cells/μL (50x109
/L); platelet count ≥30,000
cells/μL (30x109
/L) in subjects with documented bone marrow
involvement of CLL.
b. Serum aspartate aminotransferase (AST) and alanine aminotransferase
(ALT) ≤2.5xULN.
c. Total bilirubin ≤2xULN, unless directly attributable to Gilbert’s syndrome
d. Estimated creatinine clearance of ≥50 mL/min, calculated using the Cockcroft
and Gault equation (if male, [140Age] x Mass [kg] / [72 x creatinine mg/dL];
multiply by 0.85 if female); estimated creatinine clearance of ≥70 mL/min for
subjects selected by investigator to receive FCR in Arm C.
6. Women who are sexually active and can bear children must agree to use highly
effective forms of contraception while on the study and for 2 days after the last dose of
acalabrutinib, 30 days after the last dose of venetoclax, 6 months after the last dose of
fludarabine or bendamustine, 12 months after the last dose of rituximab or
cyclophosphamide, or 18 months after the last dose of obinutuzumab, whichever is
longer. Highly effective forms of contraception are defined in Section 5.1.2.8.2.
7. Men who are sexually active must agree to use highly effective forms of contraception
with the addition of a barrier method (condom) during the study and for 90 days after
the last dose of venetoclax, obinutuzumab, or rituximab, or 6 months after the last dose
of fludarabine, cyclophosphamide, or bendamustine, whichever is longer. Highly
effective forms of contraception are defined in Section 5.1.2.8.2.
8. Men must agree to refrain from sperm donation during the study and for 90 days after
the last dose of venetoclax, obinutuzumab, or rituximab, or 6 months after the last dose
of fludarabine, cyclophosphamide, or bendamustine, whichever is longer.
9. Willing and able to participate in all required evaluations and procedures in this study
protocol, including swallowing capsules and tablets without difficulty.
10. Ability to understand the purpose and risks of the study and provide signed and dated
informed consent and authorization to use protected health information (in accordance
with national and local patient privacy regulations).

Exclusion Criteria

1. Any prior CLL-specific therapies (except corticosteroid treatment administered due to
necessary immediate intervention; within the last 10 days before start of study
treatment, only dose equivalents up to 20 mg prednisone daily are permitted).
2. Detected del(17p) or TP53 mutation.
3. Transformation of CLL to aggressive non-Hodgkin lymphoma (NHL) (e.g., Richter’s
transformation, PLL, or diffuse large B cell lymphoma [DLBCL]), or central nervous
system (CNS) involvement by leukemia.
4. Any comorbidity or organ system impairment rated with a single CIRS score of 4
(excluding the eyes/ears/nose/throat/larynx organ system), or a total CIRS score of >6.
5. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura.
6. History of confirmed progressive multifocal leukoencephalopathy (PML).
7. Received any investigational drug within 30 days before first dose of study drug.
8. Major surgical procedure within 30 days before the first dose of study drug. Note: If a
subject had major surgery, they must have recovered adequately from any toxicity
and/or complications from the intervention before the first dose of study drug.
9. History of prior malignancy that could affect compliance with the protocol, or
interpretation of results, except for the following:
a. Curatively treated basal cell carcinoma or squamous cell carcinoma of the
skin or carcinoma in situ of the cervix or carcinoma in situ of the prostate at
any time prior to study.
b. Other cancers not specified above which have been curatively treated by
surgery and/or radiation therapy from which subject is disease-free for
≥3 years without further treatment.
10. Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart
failure, or myocardial infarction within 6 months of Screening, or any Class 3 or 4
cardiac disease as defined by the New York Heart Association Functional
Classification at Screening. Note: Subjects with controlled, asymptomatic atrial
fibrillation are allowed to enroll on study.
11. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach, or extensive small bowel resection that is likely to affect
absorption, symptomatic inflammatory bowel disease, or partial or complete bowel
obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
12. Received a live virus vaccination within 28 days of first dose of study drug.
13. Known history of infection with human immunodeficiency virus (HIV).
14. Any active significant infection (e.g., bacterial, viral or fungal, including subjects with
positive cytomegalovirus [CMV] DNA-PCR).
15. Serologic status reflecting active hepatitis B or C infection.
a. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are
hepatitis B surface antigen (HBsAg) negative will need to have a negative
PCR result before randomization and must be willing to undergo DNA PCR
testing during the study. Those who are HbsAg-positive or hepatitis B PCR
positive will be excluded.
b. Subjects who are hepatitis C antibody positive will need to have a negative
PCR result before randomization. Those who are hepatitis C PCR positive
will be excluded.
16. History of known hypersensitivity or anaphylactic reactions to study drugs or excipients,
xanthine oxidase inhibitors, or rasburicase.
17. History of stroke or intracranial hemorrhage within 6 months before first dose of study
drug.
18. History of bleeding diathesis (e.g., hemophilia, von Willebrand disease).
19. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists.
20. Requires treatment with a strong CYP3A inhibitor. The use of strong or moderate
CYP3A inhibitors or inducers within 7 days of the first dose of study drug is prohibited.
21. Breastfeeding or pregnant.
22. Concurrent participation in another therapeutic clinical trial.

The Estimated Number of Participants

  • Taiwan

    19 participants

  • Global

    1115 participants

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