E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic lymphocytic leukemia |
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E.1.1.1 | Medical condition in easily understood language |
Patients with chronic lymphocytic leukemia in need of treatment |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008976 |
E.1.2 | Term | Chronic lymphocytic leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety and tolerability of acalabrutinib monotherapy in subjects with treatment-naive or relapsed/refractory (R/R) chronic lymphocytic leukemia*
*For this study, subjects in the UK will be enrolled ONLY into the R/R cohort or the prior BTKi cohort.
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E.2.2 | Secondary objectives of the trial |
To evaluate the investigator-assessed overall response rate, duration of response, and progression-free survival in subjects receiving acalabrutinib monotherapy; |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Men and women ≥18 years of age; 2. Diagnosis of CLL that meets published diagnostic criteria: a. 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; b. Prolymphocytes may comprise <55% of blood lymphocytes; c. Presence of ≥5 × 10^9 B lymphocytes/L (5000/μL) in the peripheral blood (at any point since the initial diagnosis); 3. Active disease per IWCLL 2018 criteria that requires treatment: a. 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). b. Massive (i.e., ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly. c. Massive nodes (i.e., ≥10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy. d. 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 <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. e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy. f. B-symptoms documented in the participants chart with supportive objective measures, as appropriate, defined as ≥1 of the following disease-related symptoms or signs (please refer to protocol for related symptoms); 4. 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 participant who discontinued a BTKi for any reason except disease progression) for CLL. d. Have either TN or R/R CLL and are receiving concomitant vitamin K antagonists (e.g., coumadin). 5. ECOG performance status of ≤2; 6. 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. Non-sterilized male participants who are sexually active with a female partner of childbearing potential must use a male condom plus spermicide during the study. 7. Fluorescence in situ hybridization (FISH) results within 60 days before 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. Participants must also have molecular analysis to detect IGHV mutation status at any time point since diagnosis. 8. Participants 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.
*For this study, subjects in the UK will be enrolled ONLY into the R/R cohort or the prior BTKi cohort.
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E.4 | Principal exclusion criteria |
1. Participants who have had disease progression while on a BTKi for any malignant or nonmalignant condition. 2. 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. 3. History of confirmed progressive multifocal leukoencephalopathy. 4. 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. 5. 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. 6. 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. 7. Central nervous system (CNS) involvement by CLL. 8. 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 treatment. a. 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. b. 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. 9. 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). 10. History of stroke or intracranial hemorrhage within 6 months before the first dose of study treatment. 11. History of bleeding diathesis (e.g., hemophilia or von Willebrand disease). 12. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before Screening. 13. Major surgical procedure within 4 weeks before first dose of study treatment. 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 treatment. 14. 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. 15. All participants requiring or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days before first dose of study treatment except those participants who will be enrolled into the vitamin K antagonist cohort. 16. 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. 17. Total bilirubin >1.5 x upper limit of normal (ULN); or aspartate aminotransferase or alanine aminotransferase >3.0 x ULN. Exception will be for Gilbert syndrome; if an investigator feels that a participants 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. 18. 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). 19. Breastfeeding or pregnant. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Frequency and relatedness of all AEs, which will also include: - Grade ≥3 AEs - SAEs - AEs that lead to discontinuation of treatment - ECIs defined as cardiac rhythm disorders, opportunistic infections,interstitial lung disease, major hemorrhage, and cytopenias |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final analyses at the study end |
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E.5.2 | Secondary end point(s) |
- ORR (objective response rate) - DOR (duration of response) - PFS (progression-free survival) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- ORR will be defined as a subject achieving CR, CRi, or PR, according to the IWCLL 2018 criteria as assessed by the investigator. - Duration of response (DOR) will be defined as the time from the first objective response of CR, CRi, or PR to the time of documented disease progression or death due to any cause, whichever occurs first. - PFS will be defined as the interval from the start of study treatment with study treatment to completion of 48 cycles or the earlier of the first documentation of disease progression or death from any cause. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Brazil |
Canada |
China |
Denmark |
Finland |
France |
Germany |
Italy |
Korea, Republic of |
Netherlands |
Norway |
Russian Federation |
Spain |
Sweden |
Taiwan |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The duration of the study will be approximately 72 months from the first subject enrolled. This duration includes an estimated 24-month recruitment time and an assumed 48 cycles of study treatment (28 days per cycle); additional study time will be accrued during the follow-up period for those subjects remaining on study treatment after completion of 48 cycles (the amount of time will vary by subject). |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |