Treatment with Acalabrutinib in patients with chronic lymphocytic leukemia
- Conditions
- Chronic lymphocytic leukemiaTherapeutic area: Diseases [C] - Cancer [C04]MedDRA version: 21.0Level: LLTClassification code 10008976Term: Chronic lymphocytic leukemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
- Registration Number
- EUCTR2019-001573-89-FI
- Lead Sponsor
- AstraZeneca AB
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 540
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 all published diagnostic criteria as stated
below:
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 during screening
b. Prolymphocytes may comprise <55% of blood lymphocytes during
screening
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 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 (ie, =6 cm below the left costal margin), progressive, or
symptomatic splenomegaly
c. Massive nodes (ie, =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 subjects 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 (eg, infections) should be excluded
e. Autoimmune anemia and/or thrombocytopenia that is poorly
responsive to standard therapy
f. 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 (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 (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 (ie, defined as a subject who
discontinued ibrutinib for any reason prior to disease progression) for
CLL (please refer to protocol for definition of ibrutinib intolerance)
5. ECOG performance status of =2.
6. Female subjects of childbearing potential (ie, not surgically sterile or
post-menopausal) 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) for which the next-
generation sequencing (NGS) method is preferred) within 60 days during
screening up to before the first dose 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 (NGS is the preferred method) at screening if not done any tim
1. Subjects who have had disease progression while on a BTKi for any
malignant or non-malignant 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 subject 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: Subjects with rate-controlled, asymptomatic atrial fibrillation are allowed to enroll in the study (For prior ibrutinib therapy cohort only), except in Finland, where this is applicable to all 3 cohorts.
5. 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.
6. Evidence of active Richter's transformation. If Richter's
transformation is suspected (ie, lactate dehydrogenase [LDH] increased,
asymmetric fast lymph node growth or clinical suspicion), it should be
ruled out with positron emission tomography-computed tomography
(PET-CT) and/or biopsy according to guidelines.
7. Central nervous system 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 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.
a. 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.
b. Subjects 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 (eg, hemophilia or von Willebrand
disease).
12. Presence of a GI ulcer diagnosed by endoscopy within 3 months
before screening.
13. 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.
14. Requires treatment with proton-pump inhibitors (eg, omeprazole,
esomeprazole, lansoprazole, dexlansoprazole, rabeprazo
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, duration of response, and progression-free survival in subjects receiving acalabrutinib monotherapy;;Primary end point(s): Frequency, severity 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 events, hepatotoxicity, hypertension,<br>infections, interstitial lung disease/pneumonitis, hemorrhage (major<br>hemorrhage), cytopenias (anemia, leukopenia, thrombocytopenia),<br>second primary malignancies, and tumor lysis syndrome as defined in<br>the protocol.<br>;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): - OR (overall response)<br>- DOR (duration of response)<br>- PFS (progression-free survival);Timepoint(s) of evaluation of this end point: - Overall Response (OR) will be defined as a subject's best OR to the<br>treatment. A subject will be considered a responder if s(he) achieves CR,<br>CRi, or PR, according to the iwCLL 2018 criteria as assessed by the<br>investigator.<br>- Duration of response (DOR) will be defined as the time from the first<br>objective response of CR, CRi, or PR to the time of documented disease<br>progression or death due to any cause, whichever occurs first.<br>- Progression-Free Survival (PFS) will be defined as the interval from the<br>start of study treatment to<br>the earlier of the first documentation of disease progression or death<br>from any cause.