Treatment with Acalabrutinib in patients with chronic lymphocytic leukemia
- Conditions
- Chronic lymphocytic leukemiaMedDRA version: 21.0Level: LLTClassification code 10008976Term: Chronic lymphocytic leukemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2019-001573-89-DK
- Lead Sponsor
- AstraZeneca AB
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 600
1. Men and women =18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place);
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 as per at least 1 of the following IWCLL 2018 criteria:
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.
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. Contraception measures and restrictions on sperm donation are not required for male subjects.
7. Fluorescence in situ hybridization (FISH) results 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. Participants must also have molecular analysis to detect IGHV mutation status at any time point since diagnosis.
8. 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 prote
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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To evaluate the safety and tolerability of acalabrutinib monotherapy in subjects with treatment-naive or relapsed/refractory chronic lymphocytic leukemia;Secondary Objective: To evaluate the investigator-assessed overall response rate, duration of response, and progression-free survival in subjects receiving acalabrutinib monotherapy;;Primary end point(s): Frequency and relatedness of all AEs, which will also include:<br>- Grade =3 AEs<br>- SAEs<br>- AESI defined as ventricular arrhythmias<br>- AEs that lead to discontinuation of treatment<br>- ECIs defined as cardiac rhythm disorders, opportunistic infections,interstitial lung disease, major hemorrhage, cytopenias and second primary malignancies;Timepoint(s) of evaluation of this end point: The final analyses at the study end
- Secondary Outcome Measures
Name Time Method Secondary end point(s): - ORR (objective response rate)<br>- DOR (duration of response)<br>- PFS (progression-free survival);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. <br>- 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. <br>- 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.