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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04008706




Registration number
NCT04008706
Ethics application status
Date submitted
19/06/2019
Date registered
5/07/2019
Date last updated
9/04/2024

Titles & IDs
Public title
Acalabrutinib Safety Study in Untreated and Relapsed or Refractory Chronic Lymphocytic Leukemia Patients
Scientific title
A Phase 3b, Multicenter, Open-Label, Single-Arm Study of Acalabrutinib (ACP-196) in Subjects With Chronic Lymphocytic Leukemia.
Secondary ID [1] 0 0
2019-001573-89
Secondary ID [2] 0 0
D8220C00008
Universal Trial Number (UTN)
Trial acronym
ASSURE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Lymphocytic Leukemia 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Acalabrutinib

Experimental: Acalabrutinib - Participants will be enrolled into 3 cohorts. In the treatment-naive cohort, a minimum of 300 participants with treatment-naïve chronic lymphocytic leukemia will be enrolled. In the relapsed/refractory cohort, approximately 200 participants with relapsed/refractory chronic lymphocytic leukemia will be enrolled. In the prior ibrutinib cohort, approximately 40 participants with Prior ibrutinib therapy will be enrolled.


Treatment: Drugs: Acalabrutinib
Acalabrutinib will be administered as one 100 mg capsule taken orally, twice daily with 8 ounces (approximately 240 mL) of water.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of participants with adverse events
Timepoint [1] 0 0
From screening to safety follow-up period (approximately 30 days from last dose)
Secondary outcome [1] 0 0
Overall response (OR)
Timepoint [1] 0 0
1 year after initial dose of study drug
Secondary outcome [2] 0 0
Duration of response (DOR)
Timepoint [2] 0 0
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)
Secondary outcome [3] 0 0
Progression-free survival (PFS)
Timepoint [3] 0 0
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

Eligibility
Key inclusion criteria
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 (Hallek et al. 2018):

1. 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

2. Prolymphocytes may comprise <55% of blood lymphocytes during screening

3. 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

1. 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).

2. Massive (i.e., =6 cm below the left costal margin), progressive, or symptomatic
splenomegaly.

3. Massive nodes (i.e., =10 cm in the longest diameter), progressive, or symptomatic
lymphadenopathy

4. 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 <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 (e.g.,
infections) should be excluded.

5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard
therapy

6. B-symptoms documented in the participant'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 o- Night sweats for =1 month before
screening without evidence of infection

4. Must meet one of the following criteria:

a. Have received no prior therapy for treatment of CLL and meets one 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 (i.e., defined as a participant who
discontinued a ibrutinib for any reason prior to disease progression) for CLL
(participants in the US will not be enrolled into the prior ibrutinib therapy cohort)

5. ECOG performance status of =2

6. Female participants 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 intervention.
Contraception measures and restrictions on sperm donation are not required for male
participants.

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), del(13q), del(11q), 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 (NGS is the preferred method) at screening if not done at any time point before
that since diagnosis.

8. Each participant (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.
Minimum age
18 Years
Maximum age
130 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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 (For prior ibrutinib therapy cohort
only, except in Finland and the Republic of South Korea, where this is applicable to
all 3 cohorts; also, the prior ibrutinib therapy cohort will not be enrolled in the
US).

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
(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 intervention.

1. 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.

2. Participants 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

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 intervention.

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 intervention. 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
intervention.

14. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Participants 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
intervention. Based on the known metabolic/transport pathways involved in the
disposition of acalabrutinib and the commonly known novel oral anticoagulants (eg,
apixaban, rivaroxaban, and edoxaban), no clinically relevant interaction is expected
following coadministration of these agents.

16. Absolute neutrophil count (ANC) <0.50 x 10^9/L or platelet count <30 x 10^9/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 >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 participant's 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

20. Received any chemotherapy, external beam radiation, investigational drug, or any other
anti-CLL therapy within 30 days before first dose of study intervention

21. Concurrent participation in another therapeutic clinical study

22. History of or ongoing interstitial lung disease

23. 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 intervention is prohibited.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
17/09/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/09/2025
Actual
Sample size
Target
Accrual to date
Final
552
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Research Site - Adelaide
Recruitment hospital [2] 0 0
Research Site - Bedford Park
Recruitment hospital [3] 0 0
Research Site - Clayton
Recruitment hospital [4] 0 0
Research Site - Fitzroy
Recruitment hospital [5] 0 0
Research Site - South Brisbane
Recruitment postcode(s) [1] 0 0
5000 - Adelaide
Recruitment postcode(s) [2] 0 0
5042 - Bedford Park
Recruitment postcode(s) [3] 0 0
3168 - Clayton
Recruitment postcode(s) [4] 0 0
3065 - Fitzroy
Recruitment postcode(s) [5] 0 0
4101 - South Brisbane
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
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United States of America
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California
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United States of America
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Florida
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United States of America
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Georgia
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United States of America
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Illinois
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United States of America
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Indiana
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United States of America
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Louisiana
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United States of America
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Minnesota
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Missouri
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Pennsylvania
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Tennessee
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Texas
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Brazil
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Belo Horizonte
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Brazil
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Curitiba
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Brazil
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Goiania
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Brazil
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Porto Alegre
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Brazil
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Sao Paulo
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Brazil
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São Paulo
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Alberta
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Canada
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British Columbia
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Canada
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Manitoba
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Canada
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Nova Scotia
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Canada
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Ontario
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Denmark
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Aalborg
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Aarhus
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Herlev
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København Ø
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Odense
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Denmark
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Roskilde
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Finland
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Hus
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Finland
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Kuopio
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Finland
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Tampere
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France
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Bordeaux
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France
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Brest
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France
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Limoges
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France
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Reims
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France
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Tours
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France
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Vandoeuvre-Les-Nancy
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Germany
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Bayern
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Germany
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Essen
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Germany
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Homburg
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Germany
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Porta Westfalica
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Germany
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Schwäbisch Hall
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Italy
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Catanzaro
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Italy
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Milano
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Italy
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Roma
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Italy
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Siena
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Korea, Republic of
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Busan
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Korea, Republic of
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Seoul
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Korea, Republic of
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Ulsan
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Netherlands
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Arnhem
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Dordrecht
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Netherlands
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Utrecht
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Norway
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Bergen
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Norway
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Oslo
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Norway
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Trondheim
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Russian Federation
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Moscow
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Russian Federation
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Nizhny Novgorod
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Russian Federation
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Petrozavodsk
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Russian Federation
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Saint Petersburg
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Russian Federation
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Saint-Petersburg
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Russian Federation
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Smolensk
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Russian Federation
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St. Petersburg
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Russian Federation
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Syktyvkar
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Spain
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Barcelona
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Spain
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Madrid
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Spain
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Marbella
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Spain
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Ourense
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Spain
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Oviedo
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Spain
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Vitoria
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Spain
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Zaragoza
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Sweden
State/province [72] 0 0
Luleå
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Sweden
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Lund
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Sweden
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Uppsala
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Taiwan
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Taichung
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Taiwan
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Tainan
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Taiwan
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Taipei
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United Kingdom
State/province [78] 0 0
Liverpool
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United Kingdom
State/province [79] 0 0
Newmarket

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
AstraZeneca
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Parexel
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This is a global, Phase IIIb, multicenter, open-label, single-arm study to evaluate the
safety and efficacy of acalabrutinib 100 mg twice daily (bid) in approximately 540
participants with chronic lymphocytic leukemia (CLL). Participants will be enrolled into 3
following cohorts: treatment-naive (TN), relapsed/refractory (R/R), and prior ibrutinib
therapy. For this study, participants in the UK will be enrolled ONLY into the R/R cohort or
the prior ibrutinib cohort. Participants in the US will be enrolled ONLY into the TN or R/R
cohort. Participants will remain on study intervention until completion of 48 cycles (28 days
per cycle), or until study intervention discontinuation due to, for example disease
progression, or toxicity, withdrawal of consent, loss to follow-up, death, or study
termination by the sponsor whichever occurs first. The duration of the study will be
approximately 72 months from the first participant enrolled. This duration includes an
estimated 24-month recruitment time and an assumed 48 cycles of study intervention (28 days
per cycle); additional study time will be accrued during the Disease Follow up period for
those participants remaining on study intervention after completion of 48 cycles prior to the
final data cutoff (DCO) (the amount of time will vary by participant).
Trial website
https://clinicaltrials.gov/ct2/show/NCT04008706
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Adel Habib, MD
Address 0 0
AstraZeneca
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04008706