Clinical Trials List
Protocol NumberD8220C00008
NCT Number(ClinicalTrials.gov Identfier)NCT04008706
2019-11-15 - 2026-01-31
Phase III
Recruiting4
ICD-10C91.90
Lymphoid leukemia, unspecified not having achieved remission
A Phase 3b, Multicenter, Open-Label, Single-Arm Study of Acalabrutinib (ACP-196) in Subjects With Chronic Lymphocytic Leukemia.
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Trial Applicant
PAREXEL INTERNATIONAL CO., LTD.
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Sponsor
AstraZeneca AB
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- YU-HSUAN SHIH Division of Hematology & Oncology
- CHENG-HSIEN LIN Division of Hematology & Oncology
- 騰傑林 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Sin-Syue Li Division of Hematology & Oncology
- Ya-Ting Hsu Division of Hematology & Oncology
- Ya-Ping Chen Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Chia-Jen Liu Division of Hematology & Oncology
- Yao-Chung Liu Division of Hematology & Oncology
- Sheng-Hsuan Chien Division of Hematology & Oncology
- Hao-Yuan Wang Division of Hematology & Oncology
- Jyh-Pyng Gau Division of Hematology & Oncology
- Po-Shen Ko Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- MING YAO Division of Hematology & Oncology
- Chieh-Lung Cheng Division of Hematology & Oncology
- 田豐銘 Division of Hematology & Oncology
- - - Division of Hematology & Oncology
- Tai-Chung Huang Division of Hematology & Oncology
- Huai-Hsuan Huang Division of Hematology & Oncology
- 林建廷 Division of Hematology & Oncology
- HSIN-AN HOU Division of Hematology & Oncology
- Chien-Chin Lin Division of Hematology & Oncology
- - - Division of Hematology & Oncology
- Jih-Luh Tang Division of Hematology & Oncology
- Sheng-chieh Chou Division of Hematology & Oncology
- CHENG-HONG TSAI Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
Condition/Disease
Chronic Lymphocytic Leukemia
Objectives
Primary objective• To evaluate the safety and tolerability ofacalabrutinib monotherapy in subjects with TNor R/R CLLSecondary objective• To evaluate the investigator-assessed ORR,DOR, and PFS in subjects receivingacalabrutinib monotherapyExploratory objectives• To evaluate safety in subjects using concomitantvitamin K antagonist with acalabrutinibmonotherapy• To evaluate the investigator-assessed OS insubjects receiving acalabrutinib monotherapy• To evaluate the investigator-assessed EFS• To evaluate subject-reported symptoms andhealth-related quality of life following treatmentwith acalabrutinib monotherapy
Test Drug
Acalabrutinib (ACP-196)
Active Ingredient
Acalabrutinib
Dosage Form
Hard gelatin capsule
Dosage
100
Endpoints
Primary Outcome Measures :
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 TN or R/R CLL.
Secondary Outcome Measures :
Objective response rate (ORR) [ Time Frame: 1 year after initial dose of study drug ]
To evaluate the investigator-assessed ORR in participants receiving acalabrutinib monotherapy.
Duration of response (DOR) [ Time Frame: 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) ]
To evaluate the investigator-assessed DOR in participants receiving acalabrutinib monotherapy.
Progression-free survival (PFS) [ Time Frame: 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 ]
To evaluate the investigator-assessed PFS in participants receiving acalabrutinib monotherapy.
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 TN or R/R CLL.
Secondary Outcome Measures :
Objective response rate (ORR) [ Time Frame: 1 year after initial dose of study drug ]
To evaluate the investigator-assessed ORR in participants receiving acalabrutinib monotherapy.
Duration of response (DOR) [ Time Frame: 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) ]
To evaluate the investigator-assessed DOR in participants receiving acalabrutinib monotherapy.
Progression-free survival (PFS) [ Time Frame: 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 ]
To evaluate the investigator-assessed PFS in participants receiving acalabrutinib monotherapy.
Inclution 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 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
Prolymphocytes may comprise <55% of blood lymphocytes
Presence of ≥5 × 109 B lymphocytes/L (5000/μL) in the peripheral blood (at any point since the initial diagnosis)
Active disease as 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 subjects with initial blood lymphocyte counts of <30x109/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 subject'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 before screening without evidence of infection o- Night sweats for ≥1 month before screening without evidence of infection
Must meet 1 of the following criteria:
a. Have received no prior therapy for treatment of CLL and meets 1 of the following criteria: 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 BTKi therapy (i.e., defined as a subject who discontinued a BTKi for any reason except disease progression) for CLL d. Criterion deleted.
ECOG performance status of ≤2
Female subjects 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 treatment. Contraception measures and restrictions on sperm donation are not required for male subjects.
Fluorescence in situ hybridization (FISH) within 60 days before or during screening reflecting the presence or absence of del(17p), 13q del, 11q del, and trisomy of chromosome 12 along with the percentage of cells with the deletion, along with TP53 sequencing. Subjects must also have molecular analysis to detect IGHV mutation status at any time point since diagnosis.
Each subject (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.
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 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
Prolymphocytes may comprise <55% of blood lymphocytes
Presence of ≥5 × 109 B lymphocytes/L (5000/μL) in the peripheral blood (at any point since the initial diagnosis)
Active disease as 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 subjects with initial blood lymphocyte counts of <30x109/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 subject'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 before screening without evidence of infection o- Night sweats for ≥1 month before screening without evidence of infection
Must meet 1 of the following criteria:
a. Have received no prior therapy for treatment of CLL and meets 1 of the following criteria: 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 BTKi therapy (i.e., defined as a subject who discontinued a BTKi for any reason except disease progression) for CLL d. Criterion deleted.
ECOG performance status of ≤2
Female subjects 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 treatment. Contraception measures and restrictions on sperm donation are not required for male subjects.
Fluorescence in situ hybridization (FISH) within 60 days before or during screening reflecting the presence or absence of del(17p), 13q del, 11q del, and trisomy of chromosome 12 along with the percentage of cells with the deletion, along with TP53 sequencing. Subjects must also have molecular analysis to detect IGHV mutation status at any time point since diagnosis.
Each subject (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.
Exclusion Criteria
Exclusion Criteria:
Subjects 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 subject 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: Subjects with rate-controlled, asymptomatic atrial fibrillation are allowed to enroll in the study.
Malabsorption syndrome, disease significantly affecting gastrointestinal 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 subjects who are on ongoing anti-infective treatment and subjects who have received vaccination with a live attenuated vaccine within 4 weeks before the first dose of study treatment.
Subjects 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.
Subjects 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 treatment.
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 treatment. Note: Subjects who have had major surgery must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study treatment.
Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study.
All subjects requiring or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days before first dose of study treatment.
Absolute neutrophil count (ANC) <0.50 x 109/L or platelet count <30 x 109/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 subject's total bilirubin is elevated secondary to Gilbert's, the subject 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 treatment
Concurrent participation in another therapeutic clinical study
History of 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 drug is prohibited.
Subjects 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 subject 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: Subjects with rate-controlled, asymptomatic atrial fibrillation are allowed to enroll in the study.
Malabsorption syndrome, disease significantly affecting gastrointestinal 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 subjects who are on ongoing anti-infective treatment and subjects who have received vaccination with a live attenuated vaccine within 4 weeks before the first dose of study treatment.
Subjects 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.
Subjects 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 treatment.
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 treatment. Note: Subjects who have had major surgery must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study treatment.
Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study.
All subjects requiring or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days before first dose of study treatment.
Absolute neutrophil count (ANC) <0.50 x 109/L or platelet count <30 x 109/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 subject's total bilirubin is elevated secondary to Gilbert's, the subject 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 treatment
Concurrent participation in another therapeutic clinical study
History of 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 drug is prohibited.
The Estimated Number of Participants
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Taiwan
10 participants
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Global
540 participants
