Clinical trial NCT03968848
Conditions: Hepatic Impairment Hepatic Insufficiency Healthy Subjects
Keywords: Hepatic Acalabrutinib
Sponsor: Acerta Pharma BV
Start date: 2018-11-12; Completion date: 2019-03-29
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is investigate the influence of severe hepatic impairment on the pharmacokinetics of acalabrutinib and its metabolite.

Detailed description:

Arms: arm 1: Subjects with severe hepatic impairment (score of 10 to 15 on the Child-Pugh scale) will be administrated a 50-mg single oral dose of acalabrutinib. arm 2: Subjects with normal hepatic function will be administrated a 50-mg single oral dose of acalabrutinib.
Interventions: intervention 1: acalabrutinib
Intervention descriptions: intervention 1: A 50-mg single oral dose of acalabrutinib will be administered.

Protocol documents:
Prot_000.pdf: 




CONFIDENTIAL  
Acalabrutinib, Protocol CA24897(ACE-HI-102) Final 04Jun2018 
 
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2 
PRINCIPAL INVESTIGATOR – SIGNATORIES 
I have carefully read Protocol CA24897 (ACE-HI-102) entitled “A Phase 1, Open-Label, Single-Dose 
Study to Investigate the Influence of Severe Hepatic Impairment on the Pharmacokinetics of 
Acalabrutinib and its Metabolite (ACP-5862)”. 
I agree to conduct this study as outlined herein and in compliance with GCP, all applicable regulatory 
requirements, and with the ethical principles laid down in the Declaration of Helsinki. Furthermore, I 
understand that the Sponsor, Acerta Pharma, and the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) must approve any changes to the protocol in writing before implementation.  
I agree not to divulge to anyone, either during or after the termination of the study, any confidential 
information acquired regarding the investigational product and processes or methods of 
Acerta Pharma. All data pertaining to this study will be provided to Acerta Pharma. The policy of 
Acerta Pharma requires that any presentation or publication of study data by clinical investigators be 
reviewed by Acerta Pharma, before release, as specified in the protocol. 
 
 
 
 
Signature 
 
 
 
 
 
Print Name of Principal Investigator 
 
Date (DD Month YYYY) 
 
 




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TABLE OF CONTENTS 
1 
PROTOCOL REVISION HISTORY ............................................................................................. 2 
2 
PRINCIPAL INVESTIGATOR – SIGNATORIES.......................................................................... 3 
3 
ADDITIONAL KEY CONTACTS FOR THE STUDY .................................................................... 4 
4 
TABLE OF CONTENTS .............................................................................................................. 5 
5 
SYNOPSIS ................................................................................................................................. 8 
6 
STUDY EVENTS FLOW CHART .............................................................................................. 14 
6.1.1 
Subjects With Hepatic Impairment .................................................................... 14 
6.1.2 
Matched-Control Subjects ................................................................................ 16 
7 
ABBREVIATIONS .................................................................................................................... 18 
8 
INTRODUCTION ...................................................................................................................... 20 
8.1 
Background..................................................................................................................... 20 
8.1.1 
Lymphoid Cancers and the Role of Bruton Tyrosine Kinase.............................. 20 
8.1.2 
Acalabrutinib .................................................................................................... 20 
8.2 
Rationale ........................................................................................................................ 22 
8.2.1 
Rationale for this Study and Study Design ........................................................ 22 
8.2.2 
Child-Pugh Classification of Hepatic Impairment............................................... 22 
8.2.3 
Rationale for the Dose Selection ...................................................................... 23 
8.2.4 
Rationale for Endpoints .................................................................................... 24 
8.3 
Risks and/or Benefits to Subjects .................................................................................... 24 
9 
OBJECTIVES AND ENDPOINTS ............................................................................................. 25 
9.1 
Objectives ....................................................................................................................... 25 
9.2 
Endpoints ........................................................................................................................ 26 
10 STUDY DESIGN ....................................................................................................................... 26 
10.1 Overall Study Design and Plan ........................................................................................ 26 
10.1.1 
Confinement, Return Visits, and Follow-Up ...................................................... 27 
10.1.2 
End of Study Definition ..................................................................................... 27 
11 STUDY POPULATION.............................................................................................................. 27 
11.1 Inclusion Criteria ............................................................................................................. 27 
11.2 Exclusion Criteria ............................................................................................................ 28 
11.3 Early Termination of Subjects from the Study .................................................................. 30 
11.4 Study Restrictions ........................................................................................................... 30 
11.4.1 
Concomitant Therapy ....................................................................................... 30 
11.4.2 
Prohibitions ...................................................................................................... 32 
11.4.3 
Meals ............................................................................................................... 32 
11.4.4 
Activity ............................................................................................................. 32 
12 TREATMENTS ......................................................................................................................... 33 
12.1 Treatments Administered ................................................................................................ 33 
12.2 Dose Modification ........................................................................................................... 33 
12.3 Method of Treatment Assignment .................................................................................... 33 


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12.4 Blinding ........................................................................................................................... 33 
12.5 Treatment Compliance .................................................................................................... 33 
13 STUDY ASSESSMENTS AND PROCEDURES ........................................................................ 34 
13.1 Screening ....................................................................................................................... 34 
13.2 Safety Assessments ........................................................................................................ 34 
13.2.1 
Physical Examination ....................................................................................... 34 
13.2.2 
Vital Signs ........................................................................................................ 34 
13.2.3 
ECG Monitoring ............................................................................................... 35 
13.2.4 
Clinical Laboratory Tests .................................................................................. 35 
13.2.5 
Adverse Events ................................................................................................ 36 
13.2.5.1 
Adverse Event Definition................................................................. 36 
13.2.5.2 
Serious Adverse Event ................................................................... 37 
13.2.5.3 
Severity .......................................................................................... 38 
13.2.5.4 
Adverse Events of Special Interest ................................................. 38 
13.2.6 
Documenting and Reporting of Adverse and Serious Adverse Events .............. 38 
13.2.6.1 
Adverse Events Reporting Period ................................................... 38 
13.2.6.2 
Assessment of Adverse Events ...................................................... 39 
13.2.6.3 
Pregnancy ...................................................................................... 39 
13.2.6.4 
Expedited Reporting Requirements for Serious Adverse 
Events ............................................................................................ 39 
13.2.6.5 
Type and Duration of Follow-Up of Subjects after Adverse 
Events ............................................................................................ 40 
13.3 Pharmacokinetic Assessments ........................................................................................ 40 
13.3.1 
Blood Sampling and Processing ....................................................................... 40 
13.3.2 
Plasma Pharmacokinetic Parameters ............................................................... 40 
13.3.3 
Urine Sampling and Processing ....................................................................... 41 
13.3.4 
Urine Pharmacokinetic Parameters .................................................................. 42 
13.3.5 
Analytical Method ............................................................................................. 42 
13.4 Blood Volume Drawn for Study Assessments .................................................................. 43 
14 STATISTICAL CONSIDERATIONS .......................................................................................... 44 
14.1 Sample Size Determination ............................................................................................. 44 
14.2 Population for Analyses................................................................................................... 44 
14.3 Statistical Analyses ......................................................................................................... 44 
14.3.1 
Pharmacokinetic Analyses ............................................................................... 44 
14.3.1.1 
Descriptive Statistics....................................................................... 44 
14.3.1.2 
Analysis of Variance ....................................................................... 44 
14.3.2 
Other analysis .................................................................................................. 44 
14.3.3 
Safety Analyses ............................................................................................... 45 
15 STUDY ADMINISTRATION ...................................................................................................... 45 
15.1 Ethics .............................................................................................................................. 45 
15.1.1 
Institutional Review Board ................................................................................ 45 
15.1.2 
Ethical Conduct of the Study ............................................................................ 45 
15.1.3 
Subject Information and Consent ..................................................................... 45 
15.2 Termination of the Study ................................................................................................. 46 


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15.3 Data Quality Assurance................................................................................................... 46 
15.4 Direct Access to Source Data/Documents ....................................................................... 46 
15.5 Drug Supplies, Packaging and Labeling .......................................................................... 46 
15.6 Data Handling and Record Keeping ................................................................................ 46 
15.7 Report Format ................................................................................................................. 47 
15.8 Publication Policy ............................................................................................................ 47 
16 REFERENCES ......................................................................................................................... 47 
 
LIST OF TABLES 
Table 1: 
Child-Pugh Classification of the Severity of Liver Disease ..................................... 23 
Table 2: 
Blood Volume during the Study ............................................................................. 43 
 
LIST OF APPENDICES 
Appendix 1 – Known Strong and Moderate In Vivo Inhibitors or Inducers of CYP3A and 
P-gp ...................................................................................................................... 49 
Appendix 2 - Adverse Event Assessment Causality ................................................................... 51 
 
 




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Number of Subjects: 
A total of 16 adult men and/or women will be enrolled. 
Subjects with Severe HI:  Eight subjects with severe HI (a score of 
10 to 15, on the Child-Pugh scale) to obtain at least 6 evaluable 
subjects. Not more than 25% of the hepatic-impaired subjects (eg, 2 of 
8 subjects with HI) will be allowed to have a transjugular intrahepatic 
portosystemic shunt (TIPS). 
Matched-Control Subjects:  Eight subjects with normal hepatic function 
to match all evaluable subjects with severe HI in a 1:1 ratio. Subjects 
will be matched for age [within age groups <45 years old or ≥45 years 
old], body weight [± 20 %], and sex [1:1] to the subjects with HI. 
Inclusion Criteria: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All Subjects: 
1. Continuous 
non-smokers 
or 
smokers 
(of 
fewer 
than 
20 cigarettes/day or the equivalent). Subjects must agree to 
consume no more than 5 cigarettes or equivalent/day from 
24 hours before dosing and throughout the period of sample 
collection. 
2. Women must be of non-childbearing status (ie, subject is 
surgically sterile due to a hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy; has medically documented ovarian failure 
with serum estradiol and follicle stimulating hormone [FSH] levels 
within the institutional postmenopausal range as per Principal 
Investigator [PI] judgment; or is menopausal [≥ 50 years of age 
with amenorrhea for ≥ 6 months]). 
3. Understands the study procedures in the informed consent form 
(ICF) and be willing and able to comply with the protocol. 
4. Willingness and ability to swallow study drug capsules. 
Hepatic-Impaired Subjects Only: 
5. Adult men or women, 18 to 75 years of age, inclusive, at 
screening. 
6. Body mass index (BMI) ≥ 19 and ≤ 40 kg/m2, at screening. 
7. Have medical history, physical examination, vital signs, 12-lead 
electrocardiograms (ECGs), and laboratory safety test results 
consistent with a diagnosis of HI, but is otherwise judged to be in 
good health as determined by the PI. 
8. Subject has a diagnosis of chronic (> 3 months), stable (no acute 
episodes of illness within the previous 2 months due to 
deterioration in hepatic function) HI with features of cirrhosis due 
to any etiology. 
9. Subject’s score on the Child-Pugh scale must range from 10 to 15 
at screening. Subjects who have compensated HI while on 
medical therapy should be classified by their pretreatment 
parameters. 
Matched-Control Subjects Only: 
5. Adult men and women will be matched in a 1:1 ratio to a specific 
subject in the HI group based upon age, weight, and sex. The 
following criteria should be fulfilled: 


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Inclusion Criteria 
(continued): 
 
a. 18 to 75 years of age, inclusive, at screening. Age must be 
within the same age group (ie, <45 years old or ≥45 years old) 
of the matched subject’s age in the HI group. 
b. BMI ≥ 19 and ≤ 40 kg/m2 at screening. Weight must be within 
± 20% of the matched subject’s weight in the HI group. 
6. Medically healthy with no clinically significant medical history, 
physical examination, laboratory profiles (including serum amylase 
and lipase, hematology, and thyroid function), vital signs, or ECGs, 
as deemed by the PI. Liver function tests (eg, serum alanine 
aminotransferase [ALT], aspartate aminotransferase [AST]), and 
serum bilirubin (total), must be ≤ the upper limit of normal (ULN) at 
screening for inclusion. 
Exclusion Criteria: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All Subjects: 
1. History or presence of clinically significant or unstable medical or 
psychiatric condition or disease in the opinion of the PI. 
2. Subject is mentally or legally incapacitated or has significant 
emotional problems at the time of the screening visit or expected 
during the conduct of the study. 
3. History of any illness that, in the opinion of the PI, might confound 
the results of the study or poses an additional risk to the subject by 
their participation in the study. 
4. Presence of any clinically significant, ongoing systemic bacterial, 
fungal, or viral infections (including upper respiratory tract 
infections, but excluding localized cutaneous fungal infections), in 
the opinion of the PI. 
5. History of any major surgical procedure within 30 days before 
dosing. 
6. History of stroke or intracranial hemorrhage within 6 months 
before the dosing. 
7. History of a bleeding diathesis (eg, hemophilia, von Willebrand 
disease). 
8. Any clinically significant condition that may affect acalabrutinib 
absorption in the opinion of the PI, including gastric restrictions 
and bariatric surgery (eg, gastric bypass). Subjects with 
cholecystectomy will be allowed. 
9. Women with positive serum pregnancy test results or lactating. 
10. Positive results for human immunodeficiency virus (HIV) at 
screening or using HIV protease inhibitors. 
11. Have been on a diet incompatible with the on-study diet, in the 
opinion of the PI, within the 28 days before dosing, and throughout 
the study. 
12. Donation of blood > 500 mL or significant blood loss within 
56 days before the dose of study drug. 
13. Plasma donation within 7 days before dosing. 
14. Is working at or has an immediate family member (spouse or 
children) who works at the investigational site or is a Sponsor staff 


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Exclusion Criteria 
(continued): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
directly involved with this trial. 
15. Dosed in another clinical trial within 28 days before dosing of study 
drug and throughout the current study. The 28-day window will be 
derived from the date of dosing in the previous study to Day 1 of 
the current study. 
Hepatic-Impaired Subjects Only: 
16. History or presence of drug abuse within 2 years before screening.  
17. Positive results for the urine or breathalyzer alcohol test and/or 
urine drug screen at screening or check-in, unless the positive 
drug screen is due to prescription drug use and is approved by the 
PI and Acerta Pharma’s medical monitor. 
18. History of hepatitis B virus (HBV) infection or subjects with active 
hepatitis C virus (HCV) that have persistent elevations of 
transaminase levels > 6 times ULN. 
19. Unable to refrain from or anticipates the use of: 
• 
Any medication (including prescription or over the counter, 
vitamins supplements, natural or herbal supplements) that 
cannot be discontinued ≥ 14 days before dosing and 
throughout the study. Note:  hepatic-impaired subjects who 
are taking medications to treat stable diseases or to treat 
manifestations of hepatic disease and are on a stable dose, 
drug, and regimen for ~2 weeks before dosing will be allowed 
to participate in the study at the discretion of the PI. 
Consultation with Acerta Pharma’s medical monitor may occur 
on a case-by-case basis, as described in Section 11.4.1. 
Ibuprofen (up to 1200 mg per 24-hour period) may be 
permitted during the study. See Section 11.4.1 for additional 
details on allowable and prohibited concomitant therapy. 
• 
Any drug known to be a strong or moderate inhibitor or 
inducer of cytochrome P450 enzymes (CYP) 3A and/or 
P-glycoprotein (P-gp), including St. John’s Wort, should be 
restricted for 14 and 28 days, respectively, before dosing and 
throughout the study unless it was deemed acceptable 
following consultation with Acerta Pharma’s medical monitor 
and the PI. Appropriate sources, such as those listed in 
Appendix 1, will be reviewed by the PI or designee to confirm 
lack of PK and / or pharmacodynamic (PD) interaction with 
study drug. 
Matched-Control Subjects Only 
16. History or presence of alcoholism and/or drug abuse within 
2 years before screening.  
17. Positive results for the urine or breathalyzer alcohol test and/or 
urine drug screen at screening or check-in. 
18. Positive results at screening for hepatitis B surface antigen 
(HBsAg) or HCV. 
19. Seated blood pressure is < 90/40 mmHg or > 150/95 mmHg at 
screening. 
20. Seated heart rate is < 40 bpm or > 99 bpm at screening. 


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Exclusion Criteria 
(continued): 
 
21. Hemoglobin level below the lower limit of normal at screening, and 
considered clinically significant by the PI. 
22. Unable to refrain from or anticipates the use of: 
• 
Any medication (including prescription or over the counter, 
vitamins supplements, natural or herbal supplements) that 
cannot be discontinued ≥ 14 days before dosing and 
throughout the study. Ibuprofen (up to 1200 mg per 24-hour 
period) may be permitted during the study. See Section 11.4.1 
for additional details on allowable and prohibited concomitant 
therapy. 
• 
Any drug known to be a strong or moderate inhibitor or 
inducer of CYP3A and/or P-gp, including St. John’s Wort, 
should be restricted for 14 and 28 days, respectively, before 
dosing and throughout the study unless it was deemed 
acceptable 
following 
consultation 
with 
Acerta Pharma’s 
medical monitor and the PI. Appropriate sources, such as 
those listed in Appendix 1, will be reviewed by the PI or 
designee to confirm lack of PK and / or PD interaction with 
study drug. 
Dosage, Dosage Form, 
Route, and Dose 
Regimen: 
Each subject will receive a single oral dose of 50-mg acalabrutinib 
(1 x 50-mg capsules). 
Study drug will be administered orally with approximately 240 mL of 
water. 
Key Assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics 
The following PK parameters will be calculated for acalabrutinib and its 
metabolite, ACP-5862, in plasma, as appropriate:  AUC0-last, AUC0-inf, 
AUC0-24, AUC%extrap, Cmax, Tmax, Tlast, λz, t½, CL/F (parent only), Vz/F 
(parent only), metabolite-to-parent ratio (MR)_Cmax, MR_AUC0-last, and 
MR_AUC0-inf. 
An analysis of variance (ANOVA) will be performed on the natural log 
(ln)-transformed acalabrutinib AUC0-last, AUC0-24, AUC0-inf, and Cmax. 
Similar analyses may be performed on ACP-5862 PK parameters. 
The relationship between plasma acalabrutinib and ACP-5862 
pharmacokinetics and HI may be examined in an exploratory manner 
via a scatter plot of plasma acalabrutinib and ACP-5862 PK 
parameters versus the Child-Pugh score, including the data from 
subjects with severe HI, and matched-control subjects as reference. 
Relationships between plasma acalabrutinib and ACP-5862 PK 
parameters and the baseline laboratory components of the Child-Pugh 
score (ie, bilirubin and albumin levels) may be assessed graphically. 
 of acalabrutinib and ACP-5862 in plasma will be 
determined at specified timepoints from blood samples collected for 
this purpose as outlined in the Study Events Flow Chart (Section 6). 
Remaining PK blood samples may also be used to determine 
 
of acalabrutinib and ACP-5862. 
Remaining PK blood samples following analyses and dedicated 
 samples may be used for potential future analysis of 
liver function biomarkers (eg, CP-I and CP-III [Lai 2016]).  


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Key Assessments 
(continued): 
Urine samples may be used for potential future analysis to estimate 
acalabrutinib and ACP-5862 
 and 
 
 (eg, CP-I and CP-III [Lai 2016]). 
Safety 
Safety will be monitored through 12-lead ECGs, vital sign 
measurements, 
clinical 
laboratory 
tests, 
AEs, 
and 
physical 
examinations, as applicable. AEs will be tabulated and summary 
statistics for the 12-lead ECGs, vital signs, and clinical laboratory tests 
may be computed and provided, as deemed clinically appropriate. 
 








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n: 
For details on Procedures, refer to Section 13. 
o: 
Within 28 days prior to study drug administration. 
p: 
The CRU will attempt to contact all subjects who received the study drug (including subjects who terminate the study early) using their standard procedures approximately 
14 days after dosing to determine whether any AE has occurred since the last study visit. 
q: 
Subjects will be admitted to the CRU on Day -1, at the time indicated by the CRU. 
r: 
Symptom-driven physical examination may be performed, at the PI’s or designee’s discretion. 
s: 
To be performed on Day 2 or before early termination from the study. 
t: 
To be performed within 24 hours prior to dosing. 
u: 
Samples for serum chemistry at screening will be obtained after a fast of ≥ 12 hours. Samples for fasting cholesterol, triglycerides, amylase, and lipase will be collected only at 
screening  
v: 
On-study samples for serum chemistry (including check-in) will be obtained after a fast of ≥ 8 hours; however, in case of dropouts or rechecks, subjects may not have fasted for 
8 hours before the serum chemistry sample is taken. 
w: 
Remaining PK blood samples following analyses may also be used for potential future analysis to assess acalabrutinib and ACP-5862 
 and 
 
 
x: 
To be performed before dosing. 
y: 
Urine samples may be used for potential future analysis to estimate acalabrutinib and ACP-5862 
 and analysis 
 
Urine collection will be collected at the following intervals: pre-dose, 0 to 4, 4 to 24 hours after dosing. 
z: 
Blood sample collected for 
 will be assayed and may be reported separately from CSR, as appropriate. Remaining blood samples following analyses may also be 
used for potential future analysis to assess 
 
 
 
Abbreviations: ♀ = Women, AE = Adverse events, BP = Blood pressure, C-I = Check-in, Chem = Chemistry, CRU = Clinical research unit, CSR = Clinical Study Report, 
ECG = Electrocardiogram, FSH = Follicle stimulating hormone, FU = Follow-up, Hem = Hematology, HIV = Human immunodeficiency virus, HR = Heart rate, INR = international 
normalized ratio, PI = Principal Investigator, PK = Pharmacokinetic, PMP = Postmenopausal, Preg = Pregnancy, PRT = Protein, PT = prothrombin time, RR = Respiratory rate, Screen 
= Screening, T = Temperature, TSH = Thyroid stimulating hormone, UA = Urinalysis. 


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7 
ABBREVIATIONS 
ACP-5862 
Acalabrutinib active metabolite (M27) 
AE 
Adverse event 
Ae 
Amount recovered 
Aet1-t2 
Amount of unchanged drug excreted in t1 to t2 urine collection interval 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC%extrap 
Percent of AUC0-inf extrapolated 
AUC0-inf 
Area under the concentration-time curve, from time 0 extrapolated to infinity 
AUC0-last 
The area under the concentration-time curve, from time 0 to the last observed non-
zero concentration 
AUC0-24 
The area under the concentration-time curve from time 0 to the 24-hour time point 
BMI 
Body mass index 
bpm 
Beats per minute 
BTK 
Bruton tyrosine kinase 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL/F 
Apparent total plasma clearance after oral (extravascular) administration 
CLL 
Chronic lymphocytic leukemia 
CLR 
Renal clearance 
Cmax 
Maximum observed concentration 
CP-I 
coproporphyrin-I 
CP-III 
coproporphyrin-III 
CRU 
Clinical research unit 
CSR 
Clinical study report  
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
Cys 
Cysteine 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
Gly-Cys 
Glycine-cysteine 


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GSH 
Glutathione 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HI 
Hepatic Impairment 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
λz 
Apparent terminal elimination rate constant 
MCL 
Mantle cell lymphoma 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
MR 
Metabolite-to-parent ratio 
P-gp 
P-glycoprotein 
PD 
Pharmacodynamics 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PML 
Progressive multifocal leukoencephalopathy 
PT 
Prothrombin time 
QA 
Quality assurance 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SSRI 
Selective serotonin reuptake inhibitors 
TEAE 
Treatment-emergent adverse event 
Tlast 
Time of the last measurable concentration 
Tmax 
Time to reach maximum observed concentration 
TSH 
Thyroid stimulating hormone 
t½ 
Apparent terminal elimination half-life 
ULN 
Upper limit of normal 
US 
United States 
Vz/F 
Apparent volume of distribution during the terminal elimination phase after oral 
(extravascular) administration 
WHO 
World Health Organization 


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8 
INTRODUCTION 
8.1 
Background 
8.1.1 
Lymphoid Cancers and the Role of Bruton Tyrosine Kinase 
B cell lymphoid malignancies comprise the most common hematological malignancies (SEER 2014). 
These cancers arise from the accumulation of monoclonal B lymphocytes in lymph nodes and in 
organs such as blood, bone marrow, lymph nodes, spleen, and liver. Among the variants of these 
cancers are diffuse large B cell lymphoma, indolent non-Hodgkin lymphoma, mantle cell lymphoma 
(MCL), chronic lymphocytic leukemia (CLL), and Hodgkin lymphoma. These disorders are 
characterized by lymphadenopathy that is frequently disturbing for patients and can sometimes 
induce life-threatening organ dysfunction; patients may also have constitutional symptoms (fevers, 
night-sweats, and/or weight loss) and fatigue (Diehl 2004, Salles 2007, Dighiero 2008). 
The goal of therapy for these diseases is to induce tumor regression and delay tumor progression to 
control disease-related complications and potentially extend life. Patients who require treatment are 
commonly given chemotherapeutic and/or immunotherapeutic agents (Eichhorst 2011, Gribben 2011, 
Hoppe 2012, Zelenetz 2014). However, most treated patients will eventually experience disease 
relapse, and some will experience recurrent disease even with initial induction therapy and later 
salvage therapy. Despite use of agents with differing mechanisms of action, progressive resistance to 
treatment develops. Patients with progressive disease have a poor prognosis; median survival for 
these groups of patients is generally ≤ 2 years. Therefore, novel mechanisms of action are needed to 
offer additional treatment options for patients with lymphoid malignancies who are experiencing 
progressive lymphadenopathy or symptoms due to disease progression. 
Bruton tyrosine kinase (BTK) is a non-receptor enzyme of the Tec kinase family that is expressed 
among cells of hematopoietic origin, including B cells, myeloid cells, mast cells, and platelets, where it 
regulates multiple cellular processes including proliferation, differentiation, apoptosis, and cell 
migration (Mohamed 2009, Bradshaw 2010). Functional null mutations of BTK in humans cause the 
inherited disease, X-linked agammaglobulinemia, which is characterized by a lack of mature 
peripheral B cells (Vihinen 2000). Conversely, BTK activation is implicated in the pathogenesis of 
several B cell malignancies (Buggy 2012). Taken together, these findings have suggested that 
inhibition of BTK may offer an attractive strategy for treating B cell neoplasms. 
8.1.2 
Acalabrutinib 
Acalabrutinib is an imidazopyrazine analogue with a molecular weight of 465.5 g/mol. The compound 
has 1 stereogenic center, and acalabrutinib is the S-enantiomer. Acalabrutinib is a potent, highly 
selective covalent inhibitor of BTK (Covey 2015). Acalabrutinib is orally bioavailable in humans and is 
formulated as a capsule. For clinical testing, acalabrutinib has been manufactured and formulated 
according to current Good Manufacturing Practices. Summaries of relevant nonclinical and ongoing 
clinical studies are provided below. For more detailed background information, refer to the 
Investigator Brochure and Calquence product label. 
Acalabrutinib is an investigational product. On 31 October 2017, acalabrutinib (Calquence) was 
approved by United States Food and Drug Administration (FDA) under Accelerated Approval for New 
Drug Application 210259 for the treatment of adult patients with MCL who have received at least 1 
prior therapy. 


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Nonclinical Studies 
In vitro and in vivo safety pharmacology and in vivo toxicology studies with acalabrutinib have 
demonstrated a favorable nonclinical safety profile. For more detailed information on nonclinical 
safety of acalabrutinib, refer to the IB and Calquence product label. 
Metabolism and Transport 
In vivo, glutathione (GSH), glycine-cysteine (Gly-Cys), cysteine (Cys) and oxidized GSH conjugates 
were the major biotransformation products observed in rats and dogs. In vitro studies using human 
liver microsomes and recombinant systems expressing individual P450 isoforms showed that 
CYP3A4/5 is mainly responsible for oxidative metabolism of acalabrutinib. Based on available 
nonclinical and clinical data, acalabrutinib is cleared by multiple P450 and non-P450 metabolic 
pathways and CYP3A-mediated oxidation appears to be a major route of metabolism in humans. In 
vitro studies showed that acalabrutinib is a substrate for P-gp. 
The major circulating acalabrutinib metabolite, ACP-5862, is formed by CYP3A-mediated oxidation. 
ACP-5862 is the only human metabolite in plasma that accounted for > 10% of total acalabrutinib-
related material. In vitro evaluation of acalabrutinib and ACP-5862 demonstrated that ACP-5862 is 
also a covalent inhibitor of BTK. 
Please refer to the IB and Calquence product label for more details on the metabolism of 
acalabrutinib.  
Clinical Experience 
Summary of Acalabrutinib Clinical Pharmacology in Healthy Subjects 
The clinical pharmacology of acalabrutinib has been characterized in 10 studies conducted in healthy 
subjects, one of which also included subjects with mild and moderate HI, and in 7 Phase 1 and 2 
hematologic oncology studies. A list of clinical pharmacology studies which have been conducted with 
acalabrutinib is presented in Section 8 of the Investigator Brochure (Annex 4).  Acalabrutinib has a 
short PK half-life with a long-lasting PD effect due to covalent binding to BTK. PK properties of 
acalabrutinib in healthy adult subjects were evaluated after oral administration of 2 daily divided 
doses of 2.5 to 50 mg and a single dose of 100 mg. Acalabrutinib plasma Tmax values were between 
0.5 and 1.0 hour for all dose cohorts, and were independent of dose level. Mean half-life values 
ranged from 0.97 hours to 2.1 hours. 
Acalabrutinib has an absolute oral bioavailability of 25% and can be taken with or without food. 
Acalabrutinib does not accumulate in plasma upon repeat-dose administration. Based on population 
PK analysis, acalabrutinib PK was linear over the 75-mg to 250-mg dose range. At a dose of 100 mg 
twice daily, exposure and an elimination half-life of approximately 1 hour were relatively comparable 
across most individuals in healthy subject and patient studies. Based on a population PK analysis, 
acalabrutinib dose adjustment is not required based on a patient’s age, sex, body weight, ethnicity, 
race (white versus black), mild or moderate renal impairment status, mild HI status and/or Eastern 
Cooperative Oncology Group performance status (0 versus 1). Variability in exposure to acalabrutinib 
is mainly due to a combination of pH-dependent dissolution and absorption and predominantly 
CYP3A-mediated metabolism. Acalabrutinib is predominantly metabolized by CYP3A enzymes, and 
to a minor extent, by glutathione conjugation and amide hydrolysis, based on in vitro studies. 
Co-administration with a strong CYP3A inhibitor (200-mg itraconazole once daily for 5 days) 
increased the acalabrutinib Cmax by 3.9-fold and AUC by 5.1-fold in healthy subjects. 
Co-administration with a strong CYP3A inducer (600-mg rifampin once daily for 9 days) decreased 
acalabrutinib Cmax by 68% and AUC by 77% in healthy subjects. The most abundant circulating 
metabolite in human was ACP-5862 (denoted M27) which was formed by CYP3A and also circulated 
in nonclinical species. In a hepatic impairment study (HI-101), compared to subjects with normal liver 


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function (n=6), acalabrutinib exposure (AUC) was increased by less than 2-fold in subjects with mild 
(n=6) (Child-Pugh A) and moderate (n=6) (Child-Pugh B) HI, respectively. Therapeutic plasma 
acalabrutinib concentrations after a 100-mg dose or supra-therapeutic plasma acalabrutinib 
concentrations after a 400-mg dose in healthy subjects did not prolong the QTc interval in a thorough 
QT study. 
Refer to the IB and Calquence product label for detailed background information on acalabrutinib. 
8.2 
Rationale 
8.2.1 
Rationale for this Study and Study Design 
This study is designed to meet the objectives outlined in Section 9. 
The liver is involved in the clearance of many drugs through a variety of oxidative and conjugative 
metabolic pathways and/or through biliary excretion of the unchanged drug or metabolites. Alterations 
of these excretory and metabolic activities by HI can lead to higher drug exposure. Hepatic disease 
can alter the absorption and disposition of drugs as well as their efficacy and safety. 
Study ACE-HI-001 already evaluated the effect of mild to moderate HI on the single-dose 
pharmacokinetics of acalabrutinib. The geometric mean AUC of acalabrutinib increased by 
-fold 
and 
-fold in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) HI, 
respectively, compared with subjects with normal liver function. Based on a population PK analysis, 
no clinically relevant PK difference was observed in subjects with mild and moderate HI relative to 
subjects with normal liver function. 
The purpose of this study is to determine the effect of severe impaired hepatic function on the 
single-dose pharmacokinetics of acalabrutinib and its metabolite, ACP-5862. The data generated may 
provide guidance in developing dosage regimens for subjects with severe chronic hepatic 
dysfunction. 
A group of matched-control subjects will be enrolled in the study as controls for the hepatic-impaired 
subjects to detect clinically relevant PK differences. These subjects will be matched in a 1:1 ratio to a 
subject with HI for age, weight, and sex variables. 
8.2.2 
Child-Pugh Classification of Hepatic Impairment 
The Child-Pugh classification will be used to categorize HI due to its widespread use and acceptance 
by regulatory agencies (including the FDA). This study design is supported by FDA guidelines for 
drugs that undergo substantial hepatic metabolism and for which a dosage guideline is sought for 
subjects with HI.  
In the current study, subjects with chronic, stable HI with features of cirrhosis due to any etiology will 
be enrolled, and the Child-Pugh scale will be used to classify the severity of liver disease. The scale 
employs 5 clinical measures of liver disease listed in Table 1. Each measure is scored 1 to 3, with 3 
indicating most severe derangement. The bilirubin score in the table is dependent upon the type of 
cirrhosis (primary biliary cirrhosis versus all other causes). Subjects’ scores of 10 to 15 on this scale 
are classified as having severe hepatic failure. 
 


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Table 1: 
Child-Pugh Classification of the Severity of Liver Disease 
 
Points Score for Increasing Abnormality 
Assessment 
1 
2 
3 
Encephalopathya 
None 
Grade I or II  
(or suppressed 
by medication) 
Grade III or IV 
or subject 
receiving 
medication(s) to 
prevent 
encephalopathy / 
or subject 
receiving 
medication(s) to 
treat grade III or 
IV 
encephalopathy 
Ascites 
Absent 
Slight or on 1 
medication to 
control ascites  
Moderate or 
severe or on 2 
medications to 
control ascites 
Albumin (g/dL) 
>3.5 
2.8 to 3.5 
<2.8 
Prothrombin time (second prolonged) 
or 
International normalized ratio 
<4 
 
 
<1.7 
4 to 6 
 
 
1.7 to 2.2 
>6 
 
 
>2.2 
Bilirubin (mg/dL)—not PBCb 
Bilirubin (mg/dL)—only for PBCb 
<2 
<4 
2 to 3 
4 to 10 
>3 
>10 
a 
Portal-system encephalopathy is Staged 0 to 4. 
b 
Select only 1 dependent on type of cirrhosis. 
Abbreviation: PBC=Primary Biliary Cirrhosis. 
8.2.3 
Rationale for the Dose Selection  
A 50-mg single oral dose of acalabrutinib has been selected for this study since this dose has been 
used in previous patient and healthy subject studies, and was well tolerated with no safety concerns. 
To date, single doses of up to 400 mg in healthy subjects and repeat doses of 100 to 400 mg QD for 
≥ 28 days in subjects with relapsed/refractory CLL were tested and were well tolerated with no 
dose-limiting toxicity observed. In healthy subjects, the mean Cmax and AUC0-last values were 
1673 ng/mL and 3966 ng*h/mL, respectively, after a single 400-mg dose providing a clinical margin of 
safety for the 50-mg dose of approximately 7.5- and 16-fold for Cmax and AUC0-last, respectively. When 
a 50-mg dose was administered to subjects with moderate HI, the mean Cmax and AUC0-last values 
were 288 ng/mL and 535 ng*h/mL, respectively, well within the clinical margin of safety. Two potential 
mechanism pathways may be affected in subjects with HI; 1) CYP3A4/5-mediated metabolism of 
acalabrutinib; and 2) the direct conjugation of acalabrutinib with glutathione through glutathione 
S-transferase. In the CYP3A inhibitor study (ACE-HV-001), the mean plasma acalabrutinib Cmax and 
AUC0-last values increased 3.7-fold and 5.1-fold, respectively, in the presence of itraconazole, a strong 
inhibitor of CYP3A4/5, relative to no pretreatment. In this CYP3A interaction study in healthy subjects 
(n=17), no treatment-related AEs were reported. 


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8.2.4 
Rationale for Endpoints 
The primary objective of this study is to evaluate the plasma pharmacokinetics of acalabrutinib 
administered to subjects with severe HI. This study will be comparing the overall plasma PK profile 
(eg, AUC and Cmax) of acalabrutinib in subjects with severe HI with that in matched-control subjects 
(ie, by age, weight, and sex). 
8.3 
Risks and/or Benefits to Subjects 
The dose of acalabrutinib administered in this study is not anticipated to induce any potential risk or 
benefit to subjects participating in this study, because it is a single dose administered according to the 
recommendations listed in the IB. 
The safety monitoring practices employed by this protocol (ie, 12-lead ECG, vital signs, clinical 
laboratory tests, AE questioning, and physical examinations, as applicable) are adequate to protect 
the subjects’ safety and should detect all expected treatment-emergent AEs (TEAEs). 
There will be no direct health benefit for study participants from receipt of study drug. An indirect 
health benefit to the matched-control subjects enrolled in this study is the free medical tests received 
at screening and during the study. 
Risks Associated with Acalabrutinib Treatment 
The following summarizes the experience with acalabrutinib in hematological cancer studies. For 
more detailed information on TEAEs and details regarding the clinical safety of acalabrutinib, refer to 
the current acalabrutinib IB. 
Hemorrhage 
Bleeding events, some fatal, including central nervous system, respiratory, and gastrointestinal 
hemorrhage, have been reported in subjects treated with acalabrutinib. 
Subjects receiving antiplatelet or anticoagulant therapies may be at increased risk of hemorrhage and 
should be monitored for signs of bleeding. As a precaution, it is suggested per protocol that 
acalabrutinib be withheld for at least 3 days pre- and post-surgery.  
Subjects with hemorrhage should be managed per institutional guidelines or as clinically indicated. 
Infections 
Serious infections, including fatal events, have been reported in subjects treated with acalabrutinib. 
Subjects should be monitored for signs and symptoms of infection and treated as medically 
appropriate. 
Hepatitis B Reactivation 
Cases of HBV reactivation have been reported in subjects treated with acalabrutinib with 1 case 
resulting in liver failure and death.   
Progressive Multifocal Leukoencephalopathy (PML) 
Cases of PML have been reported in subjects treated with acalabrutinib. Signs and symptoms of PML 
may include cognitive and behavioral changes, language disturbances, visual disturbances, sensory 
deficits, weakness, and coordination and gait difficulties. If PML is suspected, hold further treatment 
with acalabrutinib until PML is excluded. A diagnostic evaluation may include (but is not limited to): 


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• 
Neurologic consultation 
• 
Brain magnetic resonance imaging 
• 
Polymerase chain reaction analysis for JC virus DNA in cerebrospinal fluid 
If PML is confirmed, permanently discontinue acalabrutinib. 
Cytopenias 
Grade 3 or 4 events of cytopenias, including neutropenia, anemia, and thrombocytopenia have 
occurred in subjects treated with acalabrutinib. Monitor blood counts as medically appropriate. 
Subjects with cytopenias should be managed according to institutional guidelines or as clinically 
indicated. 
Second Primary Malignancies 
Second primary malignancies, including non-skin carcinomas, have been reported in subjects treated 
with acalabrutinib. The most frequent second primary malignancy was skin cancer (squamous cell 
carcinoma of the skin). Subjects with a second primary malignancy should be managed according to 
institutional guidelines or as clinically indicated.  
Atrial Fibrillation 
Atrial fibrillation or flutter have been reported in subjects treated with acalabrutinib, Risk factors may 
include hypertension, diabetes mellitus, acute infections, or a previous history of atrial fibrillation. 
Subjects with atrial fibrillation should be managed per institutional guidelines or as clinically indicated. 
9 
OBJECTIVES AND ENDPOINTS 
9.1 
Objectives 
Primary: 
To compare the plasma pharmacokinetics of acalabrutinib and ACP-5862 in subjects with severe HI 
with that in matched-control subjects following a single-dose administration of 50-mg acalabrutinib. 
Secondary: 
To evaluate the safety and tolerability of acalabrutinib in subjects with severe HI after a single-dose 
administration of 50-mg acalabrutinib. 
Exploratory: 
The exploratory objectives listed below may be investigated at the discretion of the Sponsor: 
• 
To determine the 
 of acalabrutinib and ACP-5862 in subjects with severe HI and 
matched-control subjects following a single 50-mg dose of acalabrutinib. 
• 
To evaluate acalabrutinib and ACP-5862 
 in subjects with severe HI and 
matched-control subjects following a single 50-mg dose of acalabrutinib. 
• 
To assess the effect of acalabrutinib on plasma 
 in 
subjects with severe HI and matched-control subjects following a single 50-mg dose of 
acalabrutinib. 




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10.1.1 Confinement, Return Visits, and Follow-Up 
Subjects will be housed on Day -1, at the time indicated by the CRU, until after the 72-hour blood 
draw and/or study procedures for subjects with severe HI or until after the 24-hour blood draw and/or 
study procedures for matched-control subjects. At all times, a subject may be required to remain at 
the CRU for longer at the discretion of the PI or designee. 
The CRU will attempt to contact all subjects who received the study drug (including subjects who 
terminate the study early) using their standard procedures approximately 14 days after dosing to 
determine whether any AE has occurred since the last study visit. 
10.1.2 End of Study Definition 
The end of study is defined as the date of the last scheduled study procedure as outlined in the Study 
Events Flow Chart (Section 6). 
11 STUDY POPULATION 
11.1 Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the study: 
All Subjects: 
1. Continuous non-smokers or smokers (of fewer than 20 cigarettes/day or the equivalent). Subjects 
must agree to consume no more than 5 cigarettes or equivalent/day from 24 hours before dosing 
and throughout the period of sample collection. 
2. Women must be of non-childbearing status (ie, subject is surgically sterile due to a hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure with 
serum estradiol and FSH levels within the institutional postmenopausal range as per PI judgment; 
or is menopausal [≥ 50 years of age with amenorrhea for ≥ 6 months]). 
3. Understands the study procedures in the ICF and be willing and able to comply with the protocol. 
4. Willingness and ability to swallow study drug capsules. 
Hepatic-Impaired Subjects Only: 
5. Adult men or women, 18 to 75 years of age, inclusive, at screening. 
6. BMI ≥ 19 and ≤ 40 kg/m2, at screening. 
7. Have medical history, physical examination, vital signs, 12-lead ECGs, and laboratory safety test 
results consistent with a diagnosis of HI, but is otherwise judged to be in good health as 
determined by the PI. 
8. Subject has a diagnosis of chronic (> 3 months), stable (no acute episodes of illness within the 
previous 2 months due to deterioration in hepatic function) HI with features of cirrhosis due to any 
etiology. 
9. Subject’s score on the Child-Pugh scale must range from 10 to 15 at screening. Subjects who 
have compensated HI while on medical therapy should be classified by their pretreatment 
parameters. 
Matched-Control Subjects Only: 
5. Adult men and women will be matched in a 1:1 ratio to a specific subject in the HI group based 
upon age, weight, and sex. The following criteria should be fulfilled: 
a. 18 to 75 years of age, inclusive, at screening. Age must be within the same age group 
(ie, <45 years old or ≥45 years old) of the matched subject’s age in the HI group.  


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b. BMI ≥ 19 and ≤ 40 kg/m2 at screening. Weight must be within ± 20% of the matched subject’s 
weight in the HI group. 
6. Medically healthy with no clinically significant medical history, physical examination, laboratory 
profiles (including serum amylase and lipase, hematology, and thyroid function), vital signs, or 
ECGs, as deemed by the PI. Liver function tests (eg, serum ALT, AST), and serum bilirubin 
(total), must be ≤ the ULN at screening for inclusion. 
11.2 Exclusion Criteria 
Subjects must not be enrolled in the study if they meet any of the following criteria: 
All Subjects: 
1. History or presence of clinically significant or unstable medical or psychiatric condition or disease 
in the opinion of the PI. 
2. Subject is mentally or legally incapacitated or has significant emotional problems at the time of 
the screening visit or expected during the conduct of the study. 
3. History of any illness that, in the opinion of the PI, might confound the results of the study or 
poses an additional risk to the subject by their participation in the study. 
4. Presence of any clinically significant, ongoing systemic bacterial, fungal, or viral infections 
(including upper respiratory tract infections, but excluding localized cutaneous fungal infections), 
in the opinion of the PI. 
5. History of any major surgical procedure within 30 days before dosing. 
6. History of stroke or intracranial hemorrhage within 6 months before the dosing. 
7. History of a bleeding diathesis (eg, hemophilia, von Willebrand disease). 
8. Any clinically significant condition that may affect acalabrutinib absorption in the opinion of the PI, 
including gastric restrictions and bariatric surgery (eg, gastric bypass). Subjects with 
cholecystectomy will be allowed. 
9. Women with positive serum pregnancy test results or lactating. 
10. Positive results for HIV at screening or using HIV protease inhibitors. 
11. Have been on a diet incompatible with the on-study diet, in the opinion of the PI, within the 
28 days before dosing, and throughout the study. 
12. Donation of blood > 500 mL or significant blood loss within 56 days before the dose of study drug. 
13. Plasma donation within 7 days before dosing. 
14. Is working at or has an immediate family member (spouse or children) who works at the 
investigational site or is a Sponsor staff directly involved with this trial. 
15. Dosed in another clinical trial within 28 days before dosing of study drug and throughout the 
current study. The 28-day window will be derived from the date of dosing in the previous study to 
Day 1 of the current study. 


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Hepatic-Impaired Subjects Only: 
16. History or presence of drug abuse within 2 years before screening.  
17. Positive results for the urine or breathalyzer alcohol test and/or urine drug screen at screening or 
check-in, unless the positive drug screen is due to prescription drug use and is approved by the 
PI and Acerta Pharma’s medical monitor. 
18. History of HBV infection or subjects with active HCV that have persistent elevations of 
transaminase levels > 6 times ULN.  
19. Unable to refrain from or anticipates the use of: 
• 
Any medication (including prescription or over the counter, vitamins supplements, natural 
or herbal supplements) that cannot be discontinued ≥ 14 days before dosing and 
throughout the study. Note:  hepatic-impaired subjects who are taking medications to 
treat stable diseases or to treat manifestations of hepatic disease and are on a stable 
dose, drug, and regimen for ~2 weeks before dosing will be allowed to participate in the 
study at the discretion of the PI. Consultation with Acerta Pharma’s medical monitor may 
occur on a case-by-case basis, as described in Section 11.4.1. Ibuprofen (up to 1200 mg 
per 24-hour period) may be permitted during the study. See Section 11.4.1 for additional 
details on allowable and prohibited concomitant therapy. 
• 
Any drug known to be a strong or moderate inhibitor or inducer of CYP3A and/or P-gp, 
including St. John’s Wort, should be restricted for 14 and 28 days, respectively, before 
dosing and throughout the study unless it was deemed acceptable following consultation 
with Acerta Pharma’s medical monitor and the PI. Appropriate sources, such as those 
listed in Appendix 1, will be reviewed by the PI or designee to confirm lack of PK and / or 
PD interaction with study drug. 
Matched-Control Subjects Only 
16. History or presence of alcoholism and/or drug abuse within 2 years before screening. 
17. Positive results for the urine or breathalyzer alcohol test and/or urine drug screen at screening or 
check-in. 
18. Positive results at screening for HBsAg or HCV. 
19. Seated blood pressure is < 90/40 mmHg or > 150/95 mmHg at screening. 
20. Seated heart rate is < 40 bpm or > 99 bpm at screening. 
21. Hemoglobin level below the lower limit of normal at screening, and considered clinically 
significant by the PI. 
22. Unable to refrain from or anticipates the use of: 
• 
Any medication (including prescription or over the counter, vitamins supplements, natural 
or herbal supplements) that cannot be discontinued ≥ 14 days before dosing and 
throughout the study. Ibuprofen (up to 1200 mg per 24-hour period) may be permitted 
during the study. See Section 11.4.1 for additional details on allowable and prohibited 
concomitant therapy. 


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• 
Any drug known to be a strong or moderate inhibitor or inducer of CYP3A and/or P-gp, 
including St. John’s Wort, should be restricted for 14 and 28 days, respectively, before 
dosing and throughout the study unless it was deemed acceptable following consultation 
with Acerta Pharma’s medical monitor and the PI. Appropriate sources, such as those 
listed in Appendix 1, will be reviewed by the PI or designee to confirm lack of PK and / or 
PD interaction with study drug. 
11.3 Early Termination of Subjects from the Study 
Subjects are free to withdraw from the study at any time for any reason.  
In addition, subjects may be withdrawn from the study by the PI or designee for the following reasons: 
• 
AEs. 
• 
Difficulties in blood collection. 
• 
Positive pregnancy test result. 
A subject may be withdrawn by the PI (or designee) or the Sponsor if enrollment into the study is 
inappropriate, the study plan is violated, or for administrative and/or other safety reasons. 
The clinical report will include reasons for subject withdrawals as well as details relevant to the 
subject withdrawal. 
11.4 Study Restrictions 
11.4.1 Concomitant Therapy 
All prescription or non-prescription medications (including St. John’s Wort) that are strong or 
moderate inhibitors or inducers of CYP3A or P-gp transporters should be restricted. These inhibitors 
and inducers should not be allowed for 14 days and 28 days, respectively, before dosing and 
throughout the study. Appropriate sources, such as Appendix 1, will be consulted by the PI or 
designee to confirm lack of PK/PD interaction with study drug. 
Subjects with Severe HI: 
If a hepatic-impaired subject is taking a restricted medication, following discussion with Acerta 
Pharma’s medical monitor, the PI may switch the hepatic-impaired subject to an alternate 
non-restricted medication. The hepatic-impaired subject can be screened for the study after a 
sufficient time period has elapsed to allow stabilization on the new medication (~2 weeks). This switch 
will be done after the hepatic-impaired subject signs the consent form. 
Any medications (including prescription or over the counter, vitamins supplements, natural or herbal 
supplements) will be prohibited. They will not be allowed for ≥ 14 days before dosing and throughout 
the study, with the following exceptions:  
• 
Ethacrynic acid will be prohibited for ≥ 24 hours before dosing and throughout the study. 
• 
Proton pump inhibitors (eg, omeprazole) will be prohibited for ≥ 5 days before dosing and until 
12 hours after dosing. 
• 
Calcium carbonate containing drugs or supplements will be prohibited ≥ 2 hours before and after 
dosing. 


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• 
Lactulose and H2 receptor blockers (eg, ranitidine) will be prohibited ≥ 16 hours before and until 
6 hours after dosing. 
• 
Diuretics, neomycin, beta-blockers - prescription medications used to treat manifestations of 
hepatic disease in hepatic-impaired subjects:  restricted ≥ 4 hours before and after dosing on 
Day 1. Subjects must be on a stable dose, drug, and regimen for ~2 weeks before dosing. 
Note: Any diuretics or beta-blockers that are strong or moderate CYP3A inhibitors or inducers 
(eg, conivaptan) are not permitted. The PI should switch subjects to a weak CYP3A inhibitor or 
inducer and subjects should be on a stable dose and regimen as noted above (~2 weeks for 
subjects before dosing). 
• 
Other required prescribed concomitant medications needed to treat stable hepatic diseases:  
restricted ≥ 2 hours before and after dosing. 
• 
Selective serotonin reuptake inhibitors (SSRI): restricted ≥ 4 hours before and after dosing on 
Day 1. Subjects must be on a stable dose, drug, and regimen for ~2 weeks before dosing. Note: 
Any SSRI that are strong or moderate CYP3A inhibitors or inducers are not permitted. 
• 
Any prescribed concomitant medications needed to treat stable diabetes will be allowed on a 
case-by-case basis following discussion with Acerta Pharma’s medical monitor. Allowed 
diabetes concomitant medications will be restricted ≥ 4 hours before and after dosing on Day 1. 
Subjects must be on a stable dose, drug, and regimen for ~2 weeks before dosing. 
• 
Hormonal Replacement Therapy:  postmenopausal subjects will be allowed to continue to take 
hormonal replacement therapy if they have started 1 month before dosing. 
• 
Acetaminophen will be prohibited ≥ 2 hours before and after dosing. 
• 
Ibuprofen (up to 1200 mg per 24 hours):  may be administered at the discretion of the PI. 
Matched-Control Subjects: 
Any medications (including prescription or over the counter, vitamins supplements, natural or herbal 
supplements) will be prohibited. They will not be allowed for ≥ 14 days before dosing and throughout 
the study, with the following exceptions:  
• 
Ethacrynic acid will be prohibited for ≥ 24 hours before dosing and throughout the study. 
• 
Proton pump inhibitors (eg, omeprazole) will be prohibited for ≥ 5 days before dosing and until 
6 hours after dosing. 
• 
Calcium carbonate containing drugs or supplements will be prohibited ≥ 2 hours before and after 
dosing. 
• 
H2 receptor blockers (eg, ranitidine) will be prohibited ≥ 16 hours before and until 6 hours after 
dosing. 
• 
Hormonal Replacement Therapy:  postmenopausal subjects will be allowed to continue to take 
hormonal replacement therapy if they have started 1 month before dosing. 
• 
Acetaminophen will be prohibited ≥ 2 hours before and after dosing. 
• 
Ibuprofen (up to 1200 mg per 24 hours):  may be administered at the discretion of the PI. 


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The PI will review and approve all concurrent therapy with any medication during the course of the 
study including both prescription and non-prescription drugs in accordance with the restrictions listed 
above. However, if questions arise concerning the use of any medications, these must first be 
discussed between the PI and Acerta Pharma’s medical monitor before administration, unless 
appropriate medical care necessitates that therapy should begin before Acerta Pharma’s medical 
monitor can be consulted. 
Should there be a clinical indication for any additional medication during the course of the study, the 
name of the drug, dosage, date of administration, and reason for use must be recorded on the 
appropriate case report form. All medications taken by subjects during the course of the study will be 
recorded. The use of any non-study medication during this study may require discontinuation of the 
subject following discussion between the PI and the Sponsor. 
11.4.2 Prohibitions 
Consumption of foods and beverages containing the following substances will be prohibited as 
indicated: 
• 
Xanthines/Caffeine: 24 hours prior to dosing and throughout the period of PK sample collection 
(small amounts of caffeine derived from normal foodstuffs eg, 250 mL/8 oz./1 cup decaffeinated 
coffee or other decaffeinated beverage, per day, with the exception of espresso; 45 g/1.5 oz. 
chocolate bar, per day, would not be considered a deviation to this restriction); 
• 
Alcohol: 48 hours prior to dosing and throughout the period of PK sample collection; 
• 
Grapefruit/Seville orange: 14 days prior to dosing and throughout the period of PK sample 
collection. 
If deviations occur, the PI or designee in consultation with the Sponsor if needed will decide on a 
case-by-case basis whether the subject may continue participation in the study. 
11.4.3 Meals 
Water (except water provided with dosing) will be restricted 1 hour prior to and 1 hour after study drug 
administration, but will be allowed ad libitum at all other times. Other fluids may be given as part of 
meals and snacks but will be restricted at all other times throughout the confinement period. 
Subjects will fast overnight ≥ 10 hours before study drug administration and will continue the fast for 
≥ 2 hours after dosing. A low–fat snack (eg, 2 slices of toast with jelly) will be given 2 hours after 
dosing and should be consumed in its entirety. 
When confined, standard meals and snacks will be provided at appropriate times, except when they 
are required to fast. When confined in the CRU, subjects will be required to fast from all food and 
drink except water between meals and snacks. 
Each meal and/or snacks served at the CRU will be standardized and will be similar in caloric content 
and composition. 
11.4.4 Activity 
Subjects will remain ambulatory or seated upright for the first 4 hours after dosing, except when they 
are supine or semi-reclined for study procedures. However, should AEs occur at any time, subjects 
may be placed in an appropriate position or will be permitted to lie down on their right side. 


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Specific measures will be taken to prevent the subject from missing a urine collection by strictly 
controlling and providing access to designated restrooms only. Subjects will be asked to void prior to 
entering the shower. 
Subjects will be instructed to refrain from strenuous physical activity that could cause muscle aches 
or injury, including contact sports at any time from screening until completion of the study. 
Depending on the CRU rules and regulations, subjects may be prohibited from smoking during their 
confinement or during portions of their confinement. 
12 TREATMENTS 
12.1 Treatments Administered 
Acalabrutinib will be supplied as 50-mg hard gelatin capsules. 
Each subject will receive a single 50-mg acalabrutinib (1 x 50-mg capsules) to be administered orally 
with approximately 240 mL of water at Hour 0 on the morning of Day 1, after an overnight fast. 
Subjects will be instructed not to crush, split, or chew the study drug. 
The pharmacy at the CRU will provide each dose in individual unit dose containers for each subject. 
The exact clock time of dosing will be recorded. 
12.2 Dose Modification 
The dose and administration of the study drug to any subject may not be modified. If necessary a 
subject must be discontinued for the reasons described in Section 11.3. 
12.3 Method of Treatment Assignment 
Each subject will be assigned a unique identification number upon screening. Subjects who complete 
the study screening assessments and meet all the eligibility criteria will be assigned a unique 
identification number at the time of dosing, different from the screening number, and will receive 
acalabrutinib on 1 occasion. 
If replacement subjects are used, the replacement subject number will be 100 more than the original 
(eg, Subject No. 101 will replace Subject No. 1). 
12.4 Blinding 
This is an open-label study. 
12.5 Treatment Compliance  
A qualified designee will be responsible for monitoring the administration of the timed oral dose. A 
mouth check will be performed by the qualified designee to ensure that the subjects have swallowed 
the study drug. Once a subject has finished the dosing water, the qualified designee will use a 
flashlight and a tongue depressor to check the subject’s mouth. Subjects’ hands will also be verified 
to ensure that the study drug was ingested. 


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13 STUDY ASSESSMENTS AND PROCEDURES 
The Study Events Flow Chart (Section 6) summarizes the clinical procedures to be performed at each 
visit. Individual clinical procedures are described in detail below. Additional evaluations/testing may 
be deemed necessary by the PI or designee and/or the Sponsor for reasons related to subject safety. 
For this study, the blood collection for acalabrutinib and its metabolite ACP-5862 is the critical 
parameter and needs to be collected as close to the exact time point as possible. All other 
procedures should be completed as close to the prescribed/scheduled time as possible, but can be 
performed prior or after the prescribed/scheduled time. 
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures. 
13.1 Screening 
Within 28 days prior to dosing, medical history and demographic data, including name, sex, age, 
race, ethnicity, body weight (kg), height (cm), BMI (kg/m2) and tobacco use (including number of 
cigarettes smoked per day) will be reported. Each subject will have a physical examination, vital sign 
measurements (heart rate, blood pressure, temperature, and respiratory rate), 12-lead ECG, and the 
laboratory tests of hematological, coagulation, hepatic and renal function and additional tests as 
noted in Section 13.2.4.  
Re-evaluation of the following procedures may be performed for the purpose indicated below: 
1. For inclusion and Child-Pugh categorization laboratories that are deemed inconsistent with 
the usual stage of hepatic impairment of the subject may be repeated. 
2. For eligibility purposes, abnormal vital signs, laboratory, or ECG results may be repeated if 
an abnormal result is observed at the initial reading. 
3. In the event that the participation of a subject in the study is delayed and some screening 
procedures had been performed outside the prescribed screening window, outdated 
screening procedures can be repeated. 
4. Subjects who do not qualify based on a reversible medical condition or mild inter-current 
illness may be re-evaluated after further testing/examination or re-screened after the 
condition is resolved. 
13.2 Safety Assessments 
13.2.1 Physical Examination 
A full physical examination will be performed as outlined in the Study Events Flow Chart (Section 6). 
Symptom-driven physical examinations may be performed at other times, if deemed necessary by the 
PI or designee. 
13.2.2 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure and heart rate, will be 
measured as outlined in the Study Events Flow Chart (Section 6). Additional vital signs may be taken 
at any other times, if deemed necessary.  
Blood pressure and heart rate measurements will be performed with subjects in a seated position, 
except when they are supine or semi-reclined because of study procedures and/or AEs (eg, nausea, 
dizziness) or if deemed necessary by the PI or designee. 


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Vital signs will be measured within 24 hours prior to Day 1 dosing for the pre-dose time point. When 
scheduled after dosing, vital signs will be performed within approximately 15 minutes of the 
scheduled time point. 
13.2.3 ECG Monitoring 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart (Section 6). 
Additional ECGs may be taken at any other times, if deemed necessary by the PI or designee. 
ECGs will be performed with subjects in a supine position for ≥ 5 minutes. All ECG tracings will be 
reviewed by the PI or designee. 
ECGs will be measured within 24 hours prior to Day 1 dosing for the pre-dose time point. When 
scheduled after dosing, ECGs will be performed within approximately 20 minutes of the scheduled 
time point. 
13.2.4 Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Study Events Flow Chart (Section 6). In 
addition, laboratory safety tests may be performed at various unscheduled time points, if deemed 
necessary by the PI or designee. Laboratory results that are deemed inconsistent with the usual 
stage of HI of the subject may be repeated. 
Hematology 
 
Serum Chemistrya 
• 
Hemoglobin 
• 
Hematocrit  
• 
Total and differential leukocyte 
count 
• 
Red blood cell count 
• 
Platelet count 
 
Coagulation 
• 
prothrombin 
time 
(PT)/ 
international normalized ratio 
(INR) 
 
 
• 
Blood Urea Nitrogen 
• 
Bilirubin (total and direct) 
• 
Alkaline phosphatase 
• 
AST 
• 
ALT 
• 
Albumin 
• 
Protein (total) 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Calcium 
• 
Phosphorus 
• 
Glucose (fasting) 
• 
Gamma-glutamyl transferase 
• 
Lactate dehydrogenase 
• 
Uric acid 
• 
Cholesterol 
• 
Triglycerides 
• 
Amylase 
• 
Lipase 
• 
Creatinineb 
 


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Urinalysis 
 
Additional Tests 
• 
pH 
• 
Specific gravity 
• 
Proteinc 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Bloodc 
• 
Nitritec 
• 
Urobilinogen 
• 
Leukocyte esterasec 
 
• 
HIV test 
• 
HBsAg 
• 
HCV 
• 
Thyroid stimulating hormone (TSH) 
• 
Urine drug screen 
 Opiates 
 Amphetamines 
 Barbiturates  
 Benzodiazepines  
 Cocaine  
 Cannabinoids 
 Tricyclic antidepressants 
 Methadone 
• 
Urine/breathalyzer alcohol screen 
• 
Serum pregnancy test (for women only) 
• 
FSH (for postmenopausal women only) 
 
a 
Serum chemistry tests at screening will be performed after a fast of ≥ 12 hours. 
Samples for fasting cholesterol, triglycerides, amylase, and lipase will be collected 
only at screening. On-study samples (including check-in and before check-out) will 
be obtained after a fast of ≥ 8 hours; however, in case of dropouts or rechecks, 
subjects may not have fasted for 8 hours before the serum chemistry sample is 
taken. 
b 
At screening, creatinine clearance will be calculated using the Cockcroft-Gault 
formula. 
c 
If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a 
microscopic examination (for red blood cells, white blood cells, bacteria, casts, and 
epithelial cells) will be performed. 
13.2.5 Adverse Events 
13.2.5.1 Adverse Event Definition 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the 
use of an investigational (medicinal) product or other protocol-imposed intervention, regardless of 
attribution. 
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE reporting 
period (see Section 13.2.6.1) 
• 
Complications that occur as a result of protocol-mandated interventions (eg, invasive procedures 
such as biopsies) 
• 
Pre-existing medical conditions (other than the condition being studied) judged by the PI to have 
worsened in severity or frequency or changed in character during the protocol-specified AE 
reporting period. 
• 
Abnormal laboratory values considered clinically significant by the Investigator should be reported 
as AEs. 


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The following are NOT considered an AE: 
• 
Pre-existing condition: A pre-existing condition (documented on the medical history case report 
form) is not considered an AE unless the severity, frequency, or character of the event worsens 
during the study period.  
• 
Pre-planned hospitalization: A hospitalization planned before signing the ICF is not considered a 
serious adverse event (SAE), but rather a therapeutic intervention. However, if during the 
pre-planned hospitalization an event occurs, which prolongs the hospitalization or meets any 
other SAE criteria, the event will be considered an SAE. Surgeries or interventions that were 
under consideration, but not performed before signing the ICF, will not be considered serious if 
they are performed after signing the ICF for a condition that has not changed from its baseline 
level. Elective hospitalizations for social reasons, solely for the administration of chemotherapy, 
or due to long travel distances are also not SAEs.  
• 
Diagnostic testing and procedures: Testing and procedures should not be reported as AEs or 
SAEs, but rather the cause for the test or procedure should be reported. If a test or procedure is 
done to rule out a diagnosis, the sign or symptom leading to the test/procedure should be the 
event term, and the event term should only be updated to the diagnosis if/when the diagnosis is 
confirmed. Testing and procedures performed solely as screening measures (eg, routine 
screening mammography or colonoscopy) should not be reported as AEs or SAEs.  
Abnormal laboratory results that the Investigator considers to not be clinically significant: Abnormal 
laboratory results are not AEs unless they are clinically significant. For example, a clinically significant 
laboratory result is one that requires treatment (for example a blood transfusion for low hemoglobin) 
or requires a change in study drug (eg, lowering the dose or withholding study drug while the 
laboratory finding resolves or stabilizes). 
13.2.5.2 
Serious Adverse Event 
The terms “severe” and “serious” are not synonymous. Severity (or intensity) refers to the grade of an 
AE (see below). “Serious” is a regulatory definition and is based on subject or event outcome or 
action criteria usually associated with events that pose a threat to a subject’s life or functioning. 
Seriousness (not severity) serves as the guide for defining regulatory reporting obligations from the 
Sponsor to applicable regulatory authorities. 
An AE should be classified as an SAE if it meets any one of the following criteria: 
• 
It results in death (ie, the AE actually causes or leads to death). 
• 
It is life-threatening (ie, the AE, in the view of the PI, places the subject at immediate risk of 
death. It does not include an AE that, had it occurred in a more severe form, might have caused 
death). 
• 
It requires or prolongs in-patient hospitalization. 
• 
It results in persistent or significant disability/incapacity (ie, the AE results in substantial disruption 
of the subject’s ability to conduct normal life functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the 
investigational product. 
• 
It is considered a significant medical event by the PI based on medical judgment (eg, may 
jeopardize the subject or may require medical/surgical intervention to prevent one of the 
outcomes listed above). 


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13.2.5.3 
Severity 
Definitions found in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
(CTCAE 2017) will be used for grading the severity (intensity) of AEs. The CTCAE displays Grades 1 
through 5 with unique clinical descriptions of severity for each referenced AE. Should a subject 
experience any AE not listed in the CTCAE, the following grading system should be used to assess 
severity: 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special treatment, and 
not interfering with the subject’s daily activities 
• 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or concern to 
the subject, and which may interfere with daily activities, but are usually ameliorated by simple 
therapeutic measures 
• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly interrupt 
the subject’s usual daily activity, and require systemic drug therapy or other treatment 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be in 
imminent danger of death 
• 
Grade 5 (Death related to AE) – experiences which result in subject death 
13.2.5.4 
Adverse Events of Special Interest 
This protocol will record, on a specific electronic case report form (eCRF), any AEs related to risk of 
serious bleeding. The AEs of interest on this protocol are as follows: 
• 
Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, 
retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome 
• 
Bleeding causing a fall in hemoglobin level of ≥ 20 g/L or leading to transfusion of ≥ 2 units of 
whole blood or red cells 
• 
Bleeding resulting in a serious adverse drug experience (as defined in Section 13.2.5.2) 
13.2.6 
Documenting and Reporting of Adverse and Serious Adverse Events 
The PI is responsible for ensuring that all AEs and SAEs that are observed or reported during the 
study, as outlined in the previous sections, are recorded on the SAE report form.. All SAEs also must 
be reported on the SAE report form (see Section 13.2.6.4). 
13.2.6.1 
Adverse Events Reporting Period 
The AE reporting period for this study begins when the subject receives the dose of study drug and 
ends, irrespective of seriousness, 30 days after the last dose of study drug. An exception to this 
reporting period is any AE occurring due to a protocol-defined screening procedure. SAEs occurring 
30 days after the reporting period AND assessed by the PI as related to acalabrutinib must be 
reported. 
If an SAE is present at the last study visit, the SAE should be followed to resolution or until the PI 
assesses the subject as stable or the subject is lost to follow-up or withdraws consent. 
Resolution/stable means the subject has returned to baseline state of health or the PI does not 
expect any further improvement or worsening of the event. 


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13.2.6.2 
Assessment of Adverse Events 
The PI and/or designee will assess the occurrence of AEs and SAEs at all subjects’ evaluation time 
points during the study. All AEs and SAEs whether volunteered by the subject, discovered by study 
personnel during questioning, or detected through physical examination, or other means, will be 
recorded in the subject’s medical record and on the AE eCRF and, when applicable, on an SAE 
report form. 
Each recorded AE or SAE will be described by its duration (ie, start and end dates), severity, 
regulatory seriousness criteria, if applicable, suspected relationship to the study drug (see following 
guidance), and any actions taken. The relationship of AEs to the study drug will be assessed by 
means of the question:  ‘Is there a reasonable possibility that the event may have been caused by the 
study drug?’ Answer:  Yes or No. 
See Appendix 2 for more detail on assessing relationship. 
13.2.6.3 
Pregnancy 
The PI should report all pregnancies and pregnancies in the partners of subjects within 24 hours 
using the Pregnancy Report Form. This form should be faxed or emailed to Acerta Pharma Drug 
Safety (see personnel listed in Section 3). Any pregnancy-associated SAE must be reported using the 
SAE report form, according to the usual timelines and directions for SAE reporting (see 
Section 13.2.6.4). 
Any uncomplicated pregnancy that occurs with the subject or with the partner of a treated subject 
during this study will be reported. All pregnancies and partner pregnancies that are identified during 
or after this study, wherein the estimated date of conception is determined to have occurred from the 
time of consent to 30 days after dosing study medication will be reported, followed to conclusion, and 
the outcome reported. 
Monitoring of the pregnancy should continue until conclusion of the pregnancy at which point the 
Pregnancy Report Form must be completed and submitted to Acerta Pharma Drug Safety (see 
personnel listed in Section 3). If a viable baby is born, then 2 months postpartum the Pregnancy 
Report Form must be completed and submitted. 
Pregnancy itself is not regarded as an AE unless there is suspicion that the investigational product 
under study may have interfered with the effectiveness of a contraceptive medication. Likewise, 
elective abortions without complications are not considered AEs. Any SAEs associated with 
pregnancy (eg, congenital abnormalities/birth defects/spontaneous miscarriages or any other serious 
events) must additionally be reported as such using the SAE report form. 
Subjects should be instructed to immediately notify the PI of any pregnancies. Any women receiving 
acalabrutinib who become pregnant must immediately discontinue study drug. The PI should counsel 
the subject, discussing any risks of continuing the pregnancy and any possible effects on the fetus. 
13.2.6.4 
Expedited Reporting Requirements for Serious Adverse Events 
All SAEs must be reported within 24 hours of discovery. Initial SAE reports and follow-up information 
will be reported using the SAE report form. The paper SAE report form must be emailed or faxed to 
Acerta Pharma Drug Safety (see personnel listed in Section 3). Acerta Pharma Drug Safety may 
request follow-up and other additional information from the PI (eg, hospital admission/discharge notes 
and laboratory results). 
When possible, AEs/SAEs should be reported by diagnosis term not as a constellation of symptoms. 
All deaths should be reported with the primary cause of death as the AE term, as death is typically the 
outcome of the event, not the event itself. The primary cause of death on the autopsy report should 




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AUC0-inf: 
The area under the concentration-time curve from time 0 extrapolated to 
infinity. AUC0-inf is calculated as the sum of AUC0-last plus the ratio of the last 
measurable plasma concentration to the elimination rate constant. 
AUC%extrap: 
Percent of AUC0-inf extrapolated, represented as (1 - AUC0-last/AUC0-inf)*100. 
CL/F: 
Apparent total plasma clearance after oral (extravascular) administration, 
calculated as Dose/AUC0-inf (parent only). 
Cmax: 
Maximum observed concentration. 
Tmax: 
Time to reach Cmax. If the maximum value occurs at > 1 time point, Tmax is 
defined as the first time point with this value. 
Tlast: 
Time of the last measurable concentration. 
λz: 
Apparent terminal elimination rate constant; represents the fraction of drug 
eliminated per unit time. 
t½: 
Apparent first-order terminal elimination half-life will be calculated as 0.693/ 
λz. 
Vz/F: 
Apparent volume of distribution during the terminal elimination phase after 
oral (extravascular) administration, calculated as (Dose/AUC0-inf) x λz (parent 
only). 
fu 
Fraction of unbound drug in plasma (if evaluated). 
The following MR PK parameters will also be calculated after molar conversion: MR_Cmax, 
MR_AUC0-last, and MR_AUC0-inf. 
No value for λz, AUC0-inf, CL/F, Vz/F, or t½ will be reported for cases that do not exhibit a terminal 
log-linear phase in the concentration-time profile. 
No PK parameters will be calculated for subjects with 2 or fewer consecutive time points with 
detectable concentrations. 
Individual and mean plasma concentration-time curves (both linear and log-linear) will be included in 
the final report. 
PK parameters may also be expressed in terms of unbound concentrations (eg, Cmaxu, AUCu, and 
CLu/F) and may be reported separately from the clinical study report (CSR), as appropriate. 
13.3.3 Urine Sampling and Processing 
For all subjects, urine samples for the possible future analyses to estimate acalabrutinib and 
ACP-5862 
, as well as 
 will be collected at scheduled 
intervals as delineated in the Study Events Flow Chart (Section 6). 
Prior to the pre-dose sample, each subject will be instructed as to urine collection methods. All urine 
during an interval is to be collected.  
On Day 1, a spot collection will be obtained prior to dosing for the pre-dose sample. Subjects will be 
asked again to empty their bladder within approximately 15 minutes prior to dosing, and no urine will 
be collected at this time unless it is needed for the pre-dose sample. Only 1 pre-dose urine sample 
will be collected on Day 1. 
Subjects will be encouraged to void at the end of each collection interval. If they do void at any time 
during the collection interval, the time should be documented. Should this be the case, subjects need 


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to void again at the end of the collection period, as scheduled. However, should subjects be unable to 
void, this will be documented as well.  
Urine will be refrigerated during the collection intervals. At the end of each interval, urine will be 
pooled and thoroughly mixed. Total urine volume will be weighed and recorded.  
Instructions for urine sampling, collection, processing, and sample shipment will be provided 
separately document. 
13.3.4 Urine Pharmacokinetic Parameters 
PK parameters for urine acalabrutinib and ACP-5862 may be calculated if urine analysis is 
performed, as follows: 
Aet1-t2 
Amount of unchanged drug excreted in the urine collection interval from t1
 to t2. 
Ae: 
Total amount of drug excreted unchanged in the urine over the entire period of 
sample collection (0-X h), obtained by adding the amounts excreted over each 
collection interval.  
CLR: 
Renal clearance calculated as Ae(t’-t”)/AUC(t’-t”) where t’-t” is the longest interval of 
time during which Ae and AUC are both obtained.  
13.3.5 Analytical Method 
Samples will be analyzed for plasma acalabrutinib and ACP-5862 and 
 of acalabrutinib 
and ACP-5862 using validated bioanalytical methods. Possible future analyses of urine samples may 
be performed for acalabrutinib and ACP-5862 concentrations and 
 using 
validated bioanalytical methods. Samples from subjects to be assayed are specified in Section 14.2. 
Remaining plasma samples may be analyzed for 
 (ie. PK blood samples) and 
 
 (ie, PK and 
 blood samples), if deemed appropriate. 




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14 STATISTICAL CONSIDERATIONS 
Data will be handled and processed according to Celerion Standard Operating Procedures, which are 
written based on the principles of GCP. 
14.1 Sample Size Determination 
The sample size chosen for this study was selected without statistical considerations and was based 
on FDA guidance for Industry (FDA 2003). It has been determined adequate to meet the study 
objectives. 
14.2 Population for Analyses 
Safety Population: All subjects who received the study drug will be included in the safety evaluations. 
PK Population: All subjects who received the study drug and displayed evaluable PK profiles will be 
included in the PK evaluations and the statistical analyses. If subjects show unusual findings (e.g., 
vomiting at/or before 2 times median Tmax, incomplete dosing, non-compliance), these subjects may 
be excluded from PK evaluations and statistical analyses..  
14.3 Statistical Analyses 
Detailed methodology for summary and statistical analyses of the data collected in this study will be 
documented in a Statistical Analysis Plan (SAP). The SAP will be prepared by Celerion and agreed 
upon with the Sponsor. This document may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoints definition and/or its analysis will also be reflected in a 
protocol amendment. Additional statistical analyses other than those described in this section may be 
performed if deemed appropriate.  
14.3.1 Pharmacokinetic Analyses 
14.3.1.1 Descriptive Statistics 
Values will be calculated for the plasma concentrations and the PK parameters listed in 
Section 13.3.2 using appropriate summary statistics to be fully outlined in the SAP. If urine samples 
are analyzed, similar descriptive statistic for the urine concentrations and renal clearance may be 
calculated as appropriate. 
14.3.1.2 Analysis of Variance 
Individual AUC0-inf, AUC0-last, AUC0-24, and Cmax values of acalabrutinib after a single-dose 
administration of 50-mg acalabrutinib to subjects with severe HI and matched-control subjects 
(matched by age, weight, and sex to subjects with severe HI) will be ln-transformed and evaluated 
with an ANOVA. The ANOVA model will include population as fixed effects. The 90% confidence 
interval of the difference will be calculated. The estimates from the ANOVA will be back transformed 
to the original scale and presented. 
The unbound AUC and Cmax (ie, AUCu and Cmaxu) for 
 of acalabrutinib may be 
examined in an exploratory fashion and may be reported separately from CSR, as appropriate. 
Similar analyses may be performed for plasma ACP-5862 PK parameters. 
14.3.2 Other analysis 
The relationship between plasma acalabrutinib and ACP-5862 pharmacokinetics and HI may be 
examined in an exploratory manner via a scatter plot of plasma acalabrutinib and ACP-5862 PK 


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parameters versus the Child-Pugh score, including the data from subjects with HI, and 
matched-control subjects as reference.  
Relationships between plasma acalabrutinib and ACP-5862 PK parameters and the baseline 
laboratory components of the Child-Pugh score (ie, bilirubin and albumin levels) may be assessed 
graphically. 
14.3.3 Safety Analyses 
All safety data will be populated in the individual eCRFs. All safety data will be listed by subject. 
Dosing dates and times will be listed by subject. 
AEs will be coded using the most current version of Medical Dictionary for Regulatory Activities 
(MedDRA®) available at Celerion and summarized by population for the number of subjects reporting 
the TEAE and the number of TEAEs reported. A by-subject AE data listing including verbatim term, 
coded term, population, severity, and relationship to treatment will be provided.  
Safety data including ECGs, vital signs assessments, and clinical laboratory results will be 
summarized by population and time point of collection. 
Descriptive statistics using appropriate summary statistics will be calculated for quantitative safety 
data as well as for the difference to baseline, when appropriate. 
Concomitant medications will be listed by subject and coded using the most current version of WHO 
drug dictionary available at Celerion. Medical history will be listed by subject. 
15 STUDY ADMINISTRATION 
15.1 Ethics 
15.1.1 Institutional Review Board 
This protocol will be reviewed by an IRB and the study will not start until the IRB has approved the 
protocol or a modification thereof. The IRB is constituted and operates in accordance with the 
principles and requirements described in the US Code of Federal Regulations (21 CFR Part 56). The 
IRB is ICH compliant. 
15.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal Regulations, 
21 CFR Parts 50, 56, and 312, the ethical principles set forth in the Declaration of Helsinki, GCP, and 
the ICH harmonized tripartite guideline regarding GCP (E6 Consolidated Guidance, April 1996). 
15.1.3 Subject Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will be described 
to the subjects in non-technical terms. Subjects will be required to read, sign and date an ICF 
summarizing the discussion prior to screening, and will be assured that they may withdraw from the 
study at any time without jeopardizing their medical care. 
Subjects will be given a copy of their signed ICF. 


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15.2 Termination of the Study 
Celerion/clinical site reserves the right to terminate the study in the interest of subject welfare. 
Sponsor reserves the right to suspend or terminate the study at any time. 
15.3 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion/clinical site 
relevant to the quality of this study. Designated personnel of Celerion will be responsible for 
implementing and maintaining quality assurance (QA) and quality control systems to ensure that the 
study is conducted, and that data are generated, documented and reported in compliance with the 
study protocol, GCP and Good Laboratory Practice requirements as well as applicable regulatory 
requirements and local laws, rules and regulations relating to the conduct of the clinical study. 
The Clinical Study Report will be audited by the QA department and the QA audit certificate will be 
included in the study report. 
All clinical data will undergo a 100% quality control check prior to clinical database lock. Edit checks 
are then performed for appropriate databases as a validation routine using SAS® or comparable 
statistical program to check for missing data, data inconsistencies, data ranges, etc. Corrections are 
made prior to database lock. 
15.4 Direct Access to Source Data/Documents 
Celerion/clinical site will ensure that the Sponsor, IRB and inspection by domestic and foreign 
regulatory authorities will have direct access to all study-related sites, source data/documents, and 
reports for the purpose of monitoring and auditing (ICH[E6] 5.1.2 & 6.10). In the event that other 
study-related monitoring should be done by other parties, they will be required to sign a confidentiality 
agreement prior to any monitoring and auditing. 
15.5 Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of acalabrutinib capsules to allow completion of this 
study. The lot numbers and expiration dates (where available) of the study drug supplied will be 
recorded in the final report. 
Records will be made of the receipt and dispensing of the study drugs supplied. At the conclusion of 
the study, any unused study drugs will be retained by the site, returned to the Sponsor or designee, 
or destroyed, as per Sponsor instructions. If no supplies remain, this fact will be documented in the 
pharmacy product accountability records. 
15.6 Data Handling and Record Keeping 
Celerion standard eCRFs will be supplied. eCRFs are printed off directly from the database. Each 
eCRF is reviewed and signed by the PI. 
All raw data generated in connection with this study, together with the original copy of the final report, 
will be retained by Celerion until at least 5 years after the last approval of a marketing application in 
an ICH region and until there are no pending or contemplated marketing applications in an ICH region 
or at least 5 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period however if required 
by the applicable regulatory requirements or by an agreement with the Sponsor. It is the responsibility 
of the Sponsor to inform the PI/Institution as to when these documents no longer need to be retained. 


CONFIDENTIAL 
Acalabrutinib, Protocol CA24897(ACE-HI-102) Final 04Jun2018 
 
Page 47 
15.7 Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common Technical 
Document for the Registration of Pharmaceuticals for Human Use M4 and the ICH M2 Expert 
Working Group), the final report will be written according to the ICH E3 Guideline (Structure and 
Content of Clinical Study Reports). 
15.8 Publication Policy 
All unpublished information given to Celerion/clinical site by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor. 
The data generated by this study are considered confidential information and the property of the 
Sponsor. This confidential information may be published only in collaboration with participating 
personnel from the Sponsor or upon Sponsor’s written consent to publish the article. 
16 REFERENCES 
Bradshaw JM. The Src, Syk, and Tec family kinases: distinct types of molecular switches. Cell Signal 
2010;22:1175-1184. 
Buggy JJ, Elias L. Bruton tyrosine kinase (BTK) and its role in B cell malignancy. Int Rev Immunol 
2012;31:119-132. Erratum in:  Int Rev Immunol 2012;31:428. 
Calquence® (Acalabrutinib) capsule, full prescribing information (electronic monograph) published on 
the Drug@FDA website (document revised: 10/2017). 
Cancer Statistics. Surveillance, Epidemiology, and End Results Program (SEER). National Cancer 
Institute, available at:  http://seer.cancer.gov/statfacts/html/hodg.html, accessed on: 15Jul2014. 
Covey T, Barf T, Gulrajani M, et al. ACP-196: a novel covalent Bruton’s tyrosine kinase (BTK) 
inhibitor with improved selectivity and in vivo target coverage in chronic lymphocytic leukemia (CLL) 
patients. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer 
Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; 2015. Abstract #2596. 
Diehl V, Thomas RK, Re D. Part II: Hodgkin's lymphoma - diagnosis and treatment. Lancet Oncol 
2004;5:19-26. 
Dighiero G, Hamblin TJ. Chronic lymphocytic leukaemia. Lancet 2008;371:1017-1029. 
Eichhorst B, Dreyling M, Robak T, et al. Chronic lymphocytic leukemia: ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011;22 Suppl 6:vi50-54. 
Food and Drug Administration. Guidance for Industry:  Pharmacokinetics in Patients with Impaired 
Hepatic Function:  Study Design, Data Analysis, and Impact on Dosing and Labeling. (Draft Guidance 
May 2003). 
Gribben JG, O'Brien S. Update on therapy of chronic lymphocytic leukemia. J Clin Oncol 
2011;29:544-550 
Hoppe RT, Advani RH, Ai WZ, et al. Hodgkin lymphoma, version 2.2012 featured updates to the 
NCCN guidelines. J Natl Compr Canc Netw 2012;10:589-597. 
Investigator Brochure, Acerta Pharma, BV. Acalabrutinib (ACP-196), Edition 7.1, Dated:  15 February 
2018. 


CONFIDENTIAL 
Acalabrutinib, Protocol CA24897(ACE-HI-102) Final 04Jun2018 
 
Page 48 
Lai Y, Mandlekar S, Shen H, et al. Coproporphyrins in Plasma and Urine Can Be Appropriate Clinical 
Biomarkers to Recapitulate Drug-Drug Interactions Mediated by Organic Anion Transporting 
Polypeptide Inhibition. J Pharmacol Exp Ther 2016,358(3) 397-404 
Mohamed AJ, Yu L, Bäckesjö CM, et al. Bruton's tyrosine kinase (BTK): function, regulation, and 
transformation with special emphasis on the PH domain. Immunol Rev 2009;228:58-73. 
National Cancer Institute. Common Terminology Criteria for Adverse Events v5.0. NCI, NIH, DHHS. 
November 
17, 
2017. 
NIH 
publication 
# 
09-7473. 
Available 
online 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
The 
quick 
reference 
guide 
is 
available 
online 
at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Referen
ce_8.5x11.pdf 
Salles GA. Clinical features, prognosis and treatment of follicular lymphoma. Hematology Am Soc 
Hematol Educ Program 2007:216-225. 
Vihinen M, Mattsson PT, Smith CI. Bruton tyrosine kinase (BTK) in X-linked agammaglobulinemia 
(XLA). Front Biosci 2000;5:D917-928. 
Zelenetz AD, Gordon LI, Wierda WG, et al. Non-Hodgkin's Lymphomas, Version 2.2014. J Natl 
Compr Canc Netw 2014;12:916-946. 
 
 


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Acalabrutinib, Protocol CA24897(ACE-HI-102) Final 04Jun2018 
 
Page 49 
Appendix 1 – Known Strong and Moderate In Vivo Inhibitors or Inducers of CYP3A and P-gp 
Strong Inhibitors of CYP3Aa 
Strong Inducers of CYP3Ad 
boceprevir 
carbamazepine 
clarithromycin 
phenytoin 
cobicistat 
mitotane 
conivaptin 
rifampin 
indinavir 
St John's wort 
itraconazole 
enzalutamide 
ketoconazole 
 
lopinavir/ritonavir (combination drug) 
 
danoprevir/ritonavir (combination drug) 
 
elvitegravir/ritonavir (combination drug) 
 
Indinavir/ritonavir (combination drug) 
 
paritaprevir/ritonavir and (ombitasvir and/or 
dasabuvir) 
 
tipranavir/ritonavir (combination drug) 
 
Mibefradilb 
 
nefazodone 
 
nelfinavir 
 
posaconazole 
 
ritonavir 
 
saquinavir 
 
telaprevir 
 
telithromycin 
 
troleandomycin 
 
voriconazole 
 
 
 
Moderate Inhibitors of CYP3A 
Moderate Inducers of CYP3A 
aprepitant 
bosentan 
cimetidine 
efavirenz 
ciprofloxacin 
etravirine 
clotrimazole 
modafinil 
crizotinib 
 
cyclosporine 
 
dronedarone 
 
erythromycin  
 
fluconazole  
 
fluvoxamine 
 
imatinib 
 
tofisopam 
 
verapamil 
 
 
Inhibitors of P-gpc 
 
amiodarone 
 
carvedilol 
 
clarithromycin 
 
dronedarone 
 
itraconazole 
 
lapatinib 
 
lopinavir/ritonavir 
 
propafenone 
 
quinidine 
 
ranolazine 
 
ritonavir 
 


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Acalabrutinib, Protocol CA24897(ACE-HI-102) Final 04Jun2018 
 
Page 50 
saquinavir/ritonavir 
 
telaprevir 
 
tipranavir/ritonavir 
 
verapamil 
 
 
 
a. 
A strong inh bitor is defined as able to increases the AUC of a substrate by ≥ 5-fold. 
b. 
Withdrawn from the United States market because of safety reasons. 
c. 
Defined as able to increase the AUC of digoxin ≥ 2-fold with co-administration. 
d. 
A strong inducer is defined as an inducer that results in ≥ 80% decrease in the AUC of a substrate. 
 
 
Note: The list of drugs in these tables is not exhaustive. Any questions about drugs not on this list should be addressed to 
the medical monitor of the protocol. 
Based: 
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers . Web link 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ 
ucm093664.htm 
Abbreviation: CYP = cytochrome P450 enzymes 
 
 


CONFIDENTIAL 
Acalabrutinib, Protocol CA24897(ACE-HI-102) Final 04Jun2018 
 
Page 51 
Appendix 2 - Adverse Event Assessment Causality 
Is there a reasonable possibility that the event may have been caused by study drug? 
No___ Yes___ 
The descriptions provided below will help guide the principal investigator in making the decision to 
choose either “yes” or “no”: 
No = There is no reasonable possibility that the event may have been caused by study drug. 
The adverse event: 
• 
may be judged to be due to extraneous causes such as disease or environment or toxic 
factors 
• 
may be judged to be due to the subject’s clinical state or other therapy being administered 
• 
is not biologically plausible 
• 
does not reappear or worsen when study drug is re-administered 
• 
does not follow a temporal sequence from administration of study drug 
Yes = There is a reasonable possibility that the event may have been caused by study drug. 
The adverse event: 
• 
follows a temporal sequence from administration of study drug 
• 
is a known response to the study drug based on clinical or nonclinical data 
• 
could not be explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other therapy administered to the subject 
• 
disappears or decreases upon cessation or reduction of dose of study drug 
• 
reappears or worsens when study drug is re-administered 
 

SAP_001.pdf: 
Statistical Analysis Plan 
 
A Phase 1, Open-Label, Single-Dose Study to Investigate the Influence of Severe Hepatic 
Impairment on the Pharmacokinetics of Acalabrutinib and its Metabolite (ACP-5862) 
 
Protocol No: ACE-HI-102 
Final Protocol Date: 04 June 2018 
Compound Name: Acalabrutinib (ACP-196) 
 
 
 
Celerion Project CA24897 
Final Version 1.0 
Date: 25 April 2019 
 
Acerta Pharma, BV 
  
5349 AB, Oss,  
The Netherlands 
 
Celerion 
 
Lincoln, Nebraska 68502, US 
 Montreal, QC, H4M 2N8, Canada  
 
 




Acerta Pharma  
Acalabrutinib (ACP-196), Sponsor Project No. ACE-HI-102 
Celerion, Clinical Study Report No. CA24897 
 
Statistical Analysis Plan, 25 April 2019 
Page 3 of 92 
Table of Contents 
1. 
INTRODUCTION ..............................................................................................................5 
2. 
OBJECTIVES AND ENDPOINTS ....................................................................................5 
2.1 
Objectives ..................................................................................................................5 
2.2 
Endpoints ..................................................................................................................6 
3. 
STUDY DESIGN ...............................................................................................................6 
4. 
ANALYSIS POPULATIONS ............................................................................................7 
4.1 
Analysis Populations .................................................................................................7 
4.2 
Preliminary Data and Interim Analysis .....................................................................8 
5. 
TREATMENT DESCRIPTIONS .......................................................................................8 
6. 
PHARMACOKINETIC ANALYSIS .................................................................................8 
6.1 
Measurements and Collection Schedule ...................................................................8 
6.2 
Bioanalytical Method ................................................................................................9 
6.2.1 Acalabrutinib .................................................................................................9 
6.2.2 ACP-5862 ......................................................................................................9 
6.3 
Investigational Product and PK Analyte Information ...............................................9 
6.4 
Pharmacokinetic Concentrations .............................................................................10 
6.5 
Non-Compartmental Pharmacokinetic Analysis and Parameter Calculation .........10 
6.5.1 Plasma Pharmacokinetic Parameters ...........................................................10 
6.5.2 Urine Pharmacokinetic Parameters .............................................................12 
6.6 
Data Summarization and Presentation ....................................................................13 
6.7 
Statistical Analysis of PK Parameters .....................................................................14 
7. 
SAFETY ...........................................................................................................................15 
7.1 
Subject Discontinuation ..........................................................................................15 
7.2 
Demographics .........................................................................................................15 
7.3 
Adverse Events .......................................................................................................15 
7.4 
Clinical Laboratory Tests (Serum Chemistry, Hematology, Urinalysis) ................16 
7.5 
Vital Signs ...............................................................................................................17 
7.6 
Electrocardiogram ...................................................................................................17 
7.7 
Concomitant Medications .......................................................................................17 
7.8 
Physical Examination ..............................................................................................17 
8. 
SUMMARY OF CHANGES FROM PROTOCOL-PLANNED ANALYSIS ................18 
9. 
SUMMARY TABLES AND FIGURES ..........................................................................18 
9.1 
In-text Summary Tables and Figures ......................................................................18 
9.2 
Section 14 Summary Tables and Figures ................................................................20 
9.3 
Section 16 Data Listings .........................................................................................30 
10. TABLE AND FIGURE SHELLS .....................................................................................33 


Acerta Pharma  
Acalabrutinib (ACP-196), Sponsor Project No. ACE-HI-102 
Celerion, Clinical Study Report No. CA24897 
 
Statistical Analysis Plan, 25 April 2019 
Page 4 of 92 
10.1 In-text Summary Tables Shells ...............................................................................34 
10.2 Figures Shells ..........................................................................................................40 
10.3 Section 14 Summary Tables Shells .........................................................................45 
11. LISTING SHELLS ...........................................................................................................63 
 






Acerta Pharma  
Acalabrutinib (ACP-196), Sponsor Project No. ACE-HI-102 
Celerion, Clinical Study Report No. CA24897 
 
Statistical Analysis Plan, 25 April 2019 
Page 7 of 92 
On Day 1, a single oral dose of acalabrutinib will be administered followed by PK 
blood sampling for 24 hours in matched-control subjects and for 72 hours in subject 
with HI. Urine samples will also be collected over a 24-hour collection interval. 
Safety will be monitored throughout the study by repeated clinical and laboratory 
evaluations. 
Discontinued subjects may be replaced at the discretion of the sponsor. 
Subjects will be housed on Day -1, at the time indicated by the clinical research unit 
(CRU), until after the 72-hour blood draw and/or study procedures for subjects with 
severe HI or until after the 24-hour blood draw and/or study procedures for matched-
control subjects. At all times, a subject may be required to remain at the CRU for 
longer at the discretion of the PI or designee. 
The CRU will attempt to contact all subjects who received the study drug (including 
subjects who terminate the study early) using their standard procedures approximately 
14 days after dosing to determine whether any AE has occurred since the last study 
visit. 
4. ANALYSIS POPULATIONS 
4.1 
Analysis Populations 
Safety Population 
The Safety Population will include all subjects who received the study drug.  
Pharmacokinetic Population 
The PK Population will include data from all subjects who received the study drug 
and display an evaluable PK profile (eg, exposure to treatment, availability of 
measurements and absence of major protocol violations).  
All available data will be included in the concentration and PK parameter tables to the 
extent possible. Data for each subject will be included in the summary statistics and 
statistical comparisons of PK parameters with the exceptions described as follows: 
• Data from subjects who experience emesis at or before 2 times the median 
Tmax for a given analyte (acalabrutinib or ACP-5862) during the PK 
sampling period time course of the study may be excluded from the summary 
statistics for the given analyte and from the statistical comparison of 
PK parameters if emesis occurs. 
• Data from subjects who significantly violate a protocol inclusion or exclusion 
criteria, deviate significantly from the protocol, or have unavailable or 
incomplete data which may influence the PK analysis will be excluded from 
the PK analysis population.  


Acerta Pharma  
Acalabrutinib (ACP-196), Sponsor Project No. ACE-HI-102 
Celerion, Clinical Study Report No. CA24897 
 
Statistical Analysis Plan, 25 April 2019 
Page 8 of 92 
Any subject or data excluded from the analysis will be identified, along with their 
reason for exclusion, in the CSR. 
4.2 
Preliminary Data and Interim Analysis 
Celerion Biometrics will not perform interim analyses. 
5. TREATMENT DESCRIPTIONS 
Acalabrutinib will be supplied as 50-mg hard gelatin capsules. 
Each subject will receive a single 50-mg acalabrutinib (1 x 50-mg capsules) dose to 
be administered orally with approximately 240 mL of water at Hour 0 on the morning 
of Day 1, after an overnight fast. 
The treatment will be referred to in the text, tables and figures as a single oral dose of 
50 mg acalabrutinib. 
Subjects groups will be described based on the Child-Pugh classifications as follows 
in the treatment descriptions in the text, tables, figures, and listings: 
Subject Group 
(Column header) 
Short Description 
(Text) 
Long Description 
(footnotes, legends) 
Group C 
Severe HI 
Severe Hepatic Impairment (Child-
Pugh C) 
Group N 
Normal 
Normal Hepatic Function (Healthy 
Control) 
6. PHARMACOKINETIC ANALYSIS 
6.1 
Measurements and Collection Schedule 
For all subjects, blood samples for the determination of acalabrutinib and ACP-5862 
plasma concentrations will be collected at the following timepoints:  
- 
Pre-dose and, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, 48, 
60 and 72 hours post-dose in subjects with severe HI. 
- 
Pre-dose and, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 
hours post-dose in subjects with normal hepatic function. 


Acerta Pharma  
Acalabrutinib (ACP-196), Sponsor Project No. ACE-HI-102 
Celerion, Clinical Study Report No. CA24897 
 
Statistical Analysis Plan, 25 April 2019 
Page 9 of 92 
Remaining PK blood samples following analyses may be used for potential future 
analysis of acalabrutinib and ACP-5862 
 and 
 
. Remaining dedicated protein binding samples may also be used for 
potential future analysis of 
. 
Urine samples for determination of acalabrutinib and ACP-5862 will be collected at 
the following intervals: pre-dose, 0 to 4, 4 to 24 hours after dosing in subjects with 
severe HI and subjects with normal hepatic function. 
All concentration data will be included in the calculation of the individual PK 
parameters, the individual concentration-time plots (based on actual sample times), 
and in the mean concentration-time plots (based on nominal sample times). However, 
if there are any significant deviations from nominal sample times, some concentration 
data may be excluded from mean concentration-time plots and/or additional 
concentration-time plots of the mean data may be provided. All deviations and 
excluded data will be provided and discussed in the CSR. 
6.2 
Bioanalytical Method 
6.2.1 Acalabrutinib 
Plasma concentrations of acalabrutinib will be determined using validated 
bioanalytical methods at Covance Laboratories, (Indianapolis, Indiana).  The 
analytical range for acalabrutinib is expected to be 1.00 to 1000 ng/mL. 
Unbound plasma concentrations of acalabrutinib may be determined by an 
appropriate method at Sekisui Medical, Drug Development Solutions Center, (Naka-
gun, Ibaraki, Japan) for determination of protein binding.  
6.2.2 ACP-5862 
Plasma concentrations of ACP-5862 will be determined using validated bioanalytical 
methods at Covance Laboratories, (Indianapolis, Indiana).  The analytical range for 
ACP-5862 is expected to be 5 to 5000 ng/mL. 
Unbound plasma concentrations of ACP-5862 may be determined by an appropriate 
method at Sekisui Medical, Drug Development Solutions Center (Naka-gun, Ibaraki, 
Japan) for determination of protein binding. 
6.3 
Investigational Product and PK Analyte Information 
The molecular formula and molecular weight (MW) of acalabrutinib are provided 
below: 
- 
Molecular Formula:  C26H23N7O2 
- 
MW:  465.5 g/mol 


Acerta Pharma  
Acalabrutinib (ACP-196), Sponsor Project No. ACE-HI-102 
Celerion, Clinical Study Report No. CA24897 
 
Statistical Analysis Plan, 25 April 2019 
Page 10 of 92 
The molecular formula and MW of ACP-5862 are provided below: 
- 
Molecular Formula:  C26H23N7O3 
- 
MW:  481.5 g/mol 
6.4 
Pharmacokinetic Concentrations 
Plasma concentrations of acalabrutinib and ACP-5862 as determined at the collection 
times and per the bioanalytical method described in Section 6.1 and Section 6.2, 
respectively, will be used for the calculation of the plasma acalabrutinib and 
ACP-5862 PK parameters. 
6.5 
Non-Compartmental Pharmacokinetic Analysis and Parameter Calculation 
6.5.1 Plasma Pharmacokinetic Parameters 
The appropriate noncompartmental PK parameters will be calculated from the plasma 
acalabrutinib and ACP-5862 (total and unbound) concentration-time data using 
Phoenix® WinNonlin® Version 7.0 or higher. Actual sample times will be used in the 
calculations of the PK parameters. The calculation of the actual time will be in 
respect to the dose administration time of acalabrutinib. All PK parameters included 
in the protocol are listed in Table 6.1 below, and are defined as appropriate for study 
design. 
Table 6.1. Non-compartmental Plasma Pharmacokinetic Parameters to be 
Calculated 
Parameter 
Label to be 
Used in  
Post-Text 
Tables 
Definition 
Method of 
Determination 
AUC0-last 
AUC0-last 
Area under the concentration-time 
curve from time 0 to the time of the 
last observed/measured non-zero 
concentration. 
Calculated using the 
Linear Trapezoidal with 
Linear Interpolation 
Method.  
AUC0-24 
AUC0-24 
Area under the concentration-time 
curve from time 0 to the 24-hour 
timepoint. If the 24-hour plasma 
concentration is missing, below the 
limit of quantification or not 
reportable, then this parameter cannot 
be calculated. 
Calculated using the 
Linear Trapezoidal with 
Linear Interpolation 
Method.  
AUC0-inf 
AUC0-inf 
Area under the concentration-time 
curve from time 0 extrapolated to 
infinity. 
AUC0-inf = AUC0-last + 
(Clast/kel) 
where Clast is the last 
observed/measured 
concentration.  


Acerta Pharma  
Acalabrutinib (ACP-196), Sponsor Project No. ACE-HI-102 
Celerion, Clinical Study Report No. CA24897 
 
Statistical Analysis Plan, 25 April 2019 
Page 11 of 92 
Parameter 
Label to be 
Used in  
Post-Text 
Tables 
Definition 
Method of 
Determination 
AUC%extrap 
AUC%extrap 
Percent of AUC0-inf extrapolated. 
Calculated as: (1-
[AUC0-last/AUC0- inf]) 
x100. 
Cmax 
Cmax 
The maximum observed 
concentration. 
Taken directly from 
bioanalytical data. 
Tmax 
Tmax 
The time to reach Cmax. If the 
maximum value occurs at > 1 
timepoint, Tmax is defined as the first 
timepoint with this value. 
Taken from clinical 
database as the 
difference in the time of 
administration and the 
time of the blood draw 
which is associated with 
the Cmax. 
Tlast 
Tlast 
Time of the last measurable 
concentration. 
Taken from clinical 
database as the 
difference in the time of 
administration and the 
time of the blood draw 
which is associated with 
the last measurable 
concentration. 
Kel 
Kel 
Apparent first-order terminal 
elimination rate constant calculated 
from a semi-log plot of the plasma 
concentration versus time curve. 
Calculated by linear 
least-squares regression 
analysis using the 
maximum number of 
points in the terminal 
log-linear phase (eg, 3 or 
more non-zero plasma 
concentrations). 
t1/2 
t1/2 
Apparent first-order terminal 
elimination half-life. 
Calculated as 0.693/Kel. 
CL/F 
CL/F 
The apparent total plasma clearance 
after oral administration (calculated 
for acalabrutinib only). 
Calculated as 
Dose/(AUC0-inf).  
Vz/F 
Vz/F 
The apparent volume of distribution 
during the terminal elimination phase 
after oral administration (calculated 
for acalabrutinib only). 
Calculated as  
Dose/(AUC0-inf x Kel). 
MR_Cmax 
MR_Cmax 
Metabolite-to-parent 
molar ratio of Cmax. 
Calculated as: 
Cmaxmetabolite /Cmaxparent  x 
MWparent / MWmetabolite  
MR_AUC0-last 
MR_AUC0-last 
Metabolite-to-parent 
molar ratio of AUC0-last. 
Calculated as: 
AUCmetabolite /AUCparent  x 
MWparent / MWmetabolite  
MR_AUC0-inf 
MR_AUC0-inf 
Metabolite-to-parent 
molar ratio of AUC0-inf. 
Calculated as: 
AUCmetabolite /AUCparent  x 
MWparent / MWmetabolite  


Acerta Pharma  
Acalabrutinib (ACP-196), Sponsor Project No. ACE-HI-102 
Celerion, Clinical Study Report No. CA24897 
 
Statistical Analysis Plan, 25 April 2019 
Page 12 of 92 
Parameter 
Label to be 
Used in  
Post-Text 
Tables 
Definition 
Method of 
Determination 
fu 
fu 
Fraction of unbound drug in plasma 
(if evaluated). 
Taken from bioanalytical 
data. 
Pharmacokinetic parameters will not be calculated for subjects with ≤ 2 consecutive 
post-dose timepoints with quantifiable concentrations. Subjects for whom there are 
insufficient data to calculate the PK parameters will be included in the concentration 
tables only and excluded from the statistical analysis.  
For the calculation of the PK parameters, plasma concentrations below the limit of 
quantitation (BLQ) before the first quantifiable concentration will be set to 0 and 
plasma concentrations BLQ after the first quantifiable concentration will be treated as 
missing.  
The Kel will be determined using linear regressions composed of least 3 data points. 
The Kel will not be assigned if 1) the terminal elimination phase is not apparent, 2) if 
Tmax is one of the 3 last data points, or 3) if the R2 value is <0.75. In cases where the 
Kel interval is not assigned, the values of t½, AUC0-inf, CL/F, and Vz/F are considered 
not calculable and will not be reported. Wherever the resulting t½ is > half as long as 
the sampling interval, the Kel values and associated parameters (t½, AUC0-inf, CL/F, 
and Vz/F) will be presented as judged appropriate and in accordance with Celerion 
SOPs, but may be flagged.  
6.5.2 Urine Pharmacokinetic Parameters 
The following PK parameters will be calculated from urine acalabrutinib and 
ACP-5862 data using SAS®. 
Table 6.2. Noncompartmental Urine Pharmacokinetic Parameters to be 
Calculated 
Parameter 
Label to be 
Used in  
Post-Text 
Tables 
Definition 
Method of Determination
Conct1-t2 
Conct1-t2 
Drug concentration in the urine during the urine 
collection interval from t1 to t2 
Taken directly from 
bioanalytical data 
Volt1-t2 
Volt1-t2 
Sum of volume of urine collected over the entire 
urine collection interval from t1-t2  
Taken directly from CRF 
data 
Aet1-t2 
Aet1-t2 
Amount of drug excreted in the urine collection 
interval from t1 to t2 
Calculated as 
(Conct1-t2 x Volt1-t2) 


Acerta Pharma  
Acalabrutinib (ACP-196), Sponsor Project No. ACE-HI-102 
Celerion, Clinical Study Report No. CA24897 
 
Statistical Analysis Plan, 25 April 2019 
Page 13 of 92 
Parameter 
Label to be 
Used in  
Post-Text 
Tables 
Definition 
Method of Determination
CumAe 
CumAe 
Cumulative amount of drug excreted in the urine 
following a single dose administration 
Calculated as 
∑
−
=
+
=
1
1
i
1
i
i
i
)
 t− 
(t
 
Ae
 
 e
n
A
 
where t1 = 0 and tn = t and 
Aei is measured between ti
and ti+1, i=1,…,nth 
interval 
 
%Dose 
%Dose 
The percent of dose excreted into urine during the 
urine collection interval from t1 to t2 (calculated for 
acalabrutinib only). 
Calculated as  
[Aet1-t2]/Dose x 100 
Cum%Dose 
Cum%Dose 
The percent of dose excreted into urine over the 
entire sampling interval (calculated for acalabrutinib 
only). 
Calculated as  
[CumAe]/Dose x 100 
CLr 
CLr 
Renal clearance 
Calculated as Aet’-t” 
/AUCt’-t” where t- t” is 
the longest interval of time
during which Ae and AUC
are both obtained. 
For the calculation of descriptive statistics and urine PK parameters, urine 
concentrations that are BLQ will be set to zero. If a subject is unable to void, urine 
volume will be listed as 0 for the calculation of urine parameters (eg, amounts). 
Cumulative urine PK parameters (eg, CumAe) and derived parameters (eg, %Dose 
and Cum%Dose) for and after an unable to void interval will continue to be presented 
and included in summary statistics. Cumulative urine PK parameters and derived 
parameters after a missing sample (eg, lost part of void, volume not recorded, etc.) 
will continue to be presented, but will be excluded from the summary statistics. 
6.6 
Data Summarization and Presentation 
All plasma and urine PK concentrations and/or PK parameters descriptive statistics 
will be generated using SAS®. 
The plasma and urine concentrations of acalabrutinib and ACP-5862 will be tabulated 
by subject group (severe HI or Normal) and listed by nominal sample time for all 
subjects in the PK Population. All BLQ values will be presented as “BLQ” in the 
concentration table listings and footnoted accordingly. Plasma PK parameters of 
acalabrutinib and ACP-5862 will be tabulated by subject group and listed by 
parameter for all subjects in the PK Population.  
Summary statistics, including sample size (n), arithmetic mean (Mean), standard 
deviation (SD), coefficient of variation (CV%), standard error of the mean (SEM), 
minimum, median, and maximum will be calculated for all nominal concentration 


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timepoints and PK parameters. In addition, geometric mean (Geom Mean), geometric 
CV (Geom CV%) will be calculated for PK parameters. Excluded subjects will be 
included in the concentration listings but will be excluded from the summary statistics 
and noted as such in the tables. All BLQ values will be presented as “BLQ” in the 
concentration listings and footnoted accordingly.  
Plasma and urine concentrations of acalabrutinib and ACP-5862 will be presented 
with the same level of precision as received from the bioanalytical laboratory. Plasma 
and urine PK parameters will be reported to 3 significant figures for individual 
parameters, with the exception of Tmax, Tlast, and t½ (2 decimal places), Cmax, which 
will be presented in the same precision as the bioanalytical data, and urine volume 
which will be presented with the same precision as reported in the CRF. 
The level of precision for each statistic will be presented as follows:  
• minimum/maximum with the same precision as in individual data 
• Arithmetic mean, median and geometric mean with one more level of 
precision than minimum/maximum 
• SD with one more level of precision than mean/median 
• n will be presented as an integer  
• CV% will be presented to 1 decimal place. 
Mean and individual concentration-time profiles will be presented on linear and semi-
log scales. Linear mean plots will be presented with and without SD.  
The relationship between acalabrutinib and ACP-5862 PK and HI will be visually 
assessed via scatter plots of acalabrutinib and ACP-5862 PK parameters versus the 
Child-Pugh score, including the data from severe HI subjects and normal hepatic 
function subjects as reference.  
Relationships between acalabrutinib and ACP-5862 PK parameters and Child-Pugh 
scores, bilirubin and albumin levels, and prothrombin time will be assessed 
graphically. 
6.7 
Statistical Analysis of PK Parameters 
Individual AUC0-inf, AUC0-last, AUC0-24, and Cmax values of total and unbound 
acalabrutinib and ACP-5862 after a single dose administration of 50 mg acalabrutinib 
to subjects with severe HI and matched control subjects (matched by age, weight, and 
sex to subjects with severe HI) will be ln-transformed and evaluated with an analysis 
of variance (ANOVA) model using PROC MIXED of SAS®. The ANOVA model 
will include subject group as a fixed effect. The inferential results (least-squares 
means [LSM], difference between LSMs, and 90% CIs of the difference) will be 
exponentiated to the original scale. Geometric LSMs, geometric mean ratios (GMR) 
and 90% CIs will be presented. 


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The ANOVA analysis will be performed using the following SAS® code: 
PROC MIXED; 
CLASS GROUP SUBJECT; 
MODEL PK_PARAMETER=GROUP / ddfm=kr; 
REPEATED/GROUP = GROUP; 
LSMEANS GROUP/e diff cl alpha = 0.1 
ESTIMATE “Severe HI vs. Normal” GROUP 1 -1/ cl alpha=0.1 e; 
ODS output Estimates = LS_Diffs LSMeans = LS_Means CovParms = MSE ; 
 
where GROUP is C for Severe HI and N for Normal. 
7. SAFETY  
All case report form (CRF) data will be listed by subject and chronologically by 
assessment timepoints. This will include rechecks, unscheduled assessments, and 
early termination.  
Applicable continuous variables will be summarized using n, arithmetic mean, SD, 
minimum, median, and maximum.  
The level of precision will be presented as follows: minimum/maximum in the same 
precision as in the database, mean/median in one more precision level than 
minimum/maximum, SD in one more precision level than mean/median, and n will be 
presented as an integer. 
Where individual data points are missing because of dropouts or other reasons, the 
data will be summarized based on reduced denominators. 
7.1 
Subject Discontinuation 
Subjects will be summarized by number of subjects dosed, completed, and 
discontinued the study with discontinuation reasons by group (Severe HI and Normal) 
and overall. 
7.2 
Demographics 
Descriptive statistics will be calculated for continuous variables (age, weight, height, 
and body mass index) by group and overall.  
Frequency counts will be provided for categorical variables (race, ethnicity, and sex) 
for each group and overall.  
7.3 
Adverse Events 
All adverse events (AEs) occurring during this clinical study will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA®), Version 21.1.  


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All AEs captured in the database will be listed in by-subject data listings including 
verbatim term, coded term, treatment, severity, relationship to study medication, and 
action; however, only treatment-emergent AEs (TEAEs) will be summarized.  
A TEAE is defined as an AE that is starting or worsening at the time of or after study 
drug administration. Each TEAE will be attributed to treatment based on the onset 
date and time of the AE.  
If the onset time of an AE is missing and the onset date is the same as the treatment 
dosing date, then the AE will be considered treatment emergent. If onset time of an 
AE is missing and the onset date does not fall on a dosing date, then the AE will be 
considered treatment emergent. If the onset date of an AE is missing, then the AE will 
be considered treatment emergent unless the onset date is known to have occurred 
before treatment dosing. 
TEAEs will be tabulated by System Organ Class (SOC) and Preferred Term. 
Summary tables will include number of subjects reporting the AE and as percent of 
number of subjects dosed by group and overall. The number of AEs will be tabulated 
in a similar manner. Tables which tabulate the number of TEAEs by severity and 
relationship to study treatment will also be included.  
Serious adverse events (SAEs), if present, will also be listed. Applicable narratives 
will be included in the CSR.  
AE of special interest (AESI) are any AEs related to risk of serous bleeding as follow 
and will be discussed in the CSR: 
• Symptomatic bleeding in a critical area or organ, such as intracranial,  
intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or 
intramuscular with compartment syndrome 
• Bleeding causing a fall in hemoglobin level of ≥ 20 g/L or leading to transfusion 
of ≥ 2 units of whole blood or red cells 
• Bleeding resulting in a serious adverse drug experience (as defined in Section 
13.2.5.2 of the protocol) 
7.4 
Clinical Laboratory Tests (Serum Chemistry, Hematology, Urinalysis) 
Serum chemistry, hematology and urinalysis will be performed at Screening, Check-
in, 24 hours (Day 2) postdose and for severe HI subjects only 72 hours (Day 4) 
postdose.  
Out-of-range and clinically significant lab values will be listed.  
For all numeric laboratory values, descriptive statistics will be presented for each 
laboratory test by assessment timepoint and group. Change from baseline will be 
summarized in a similar manner. Baseline is defined as the result closest to and 
before the dose which may include unscheduled or recheck results. This will typically 


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be the result collected on Check-in (Day -1). Postdose unscheduled events or early 
termination results will not be included in summaries. 
For each laboratory test, a shift table will be developed to compare the frequency of 
the results at baseline (above normal, normal, or below normal) with the respective 
postdose results. For urinalysis tests, the categories are normal and outside normal.  
7.5 
Vital Signs 
Vital signs (heart rate, blood pressure, respiratory rate and temperature) will be 
assessed at Screening, predose and for normal subjects 24 hours (Day 2) and severe 
HI subjects 72 hours (Day 4) postdose.  
Descriptive statistics will be presented for each vital sign parameter by assessment 
timepoint and group. Change from baseline will be summarized in a similar manner. 
Baseline is defined as the result closest to and before the dose which may include 
unscheduled recheck results. This will typically be the result collected at predose on 
Day 1 (within 24 hours before dosing). Postdose unscheduled events or early 
termination results will not be included in summaries. 
7.6 
Electrocardiogram 
12-lead safety ECG (heart rate, blood pressure, respiratory rate and temperature) will 
be assessed at Screening, predose and for normal subjects 24 hours (Day 2) and 
severe HI subjects 72 hours (Day 4) postdose.  
Descriptive statistics will be presented for each vital sign parameter by assessment 
timepoint and group. Change from baseline will be summarized in a similar manner. 
Baseline is defined as the result closest to and before the dose which may include 
unscheduled recheck results. This will typically be the result collected at predose on 
Day 1 (within 24 hours before dosing). Postdose unscheduled events or early 
termination results will not be included in summaries. 
ECG results will be listed for each subject with QTcF >450 msec or QTcF increase 
from baseline >30 msec will be flagged. 
7.7 
Concomitant Medications 
All concomitant medications recorded during the study will be coded with the WHO 
Dictionary Version SEP2018 B3 and listed. 
7.8 
Physical Examination 
Physical examinations will be performed at Screening, Check-in and for normal 
subjects 24 hours (Day 2) and severe HI subjects 72 hours (Day 4) postdose. 
Abnormal findings will be reported as medical history or adverse events. All data 
found in the CRF will be listed.  


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8. SUMMARY OF CHANGES FROM PROTOCOL-PLANNED ANALYSIS 
The analyses described in this SAP are aligned with those analyses described in the 
protocol.  
9. SUMMARY TABLES AND FIGURES 
Summary tables and figures are numbered following the International Conference on 
Harmonization (ICH) structure but may be renumbered as appropriate during the 
compilation of the tables and figures for the CSR. Note that all PK and Safety 
summary tables and figures will be generated using SAS® Version 9.3 or higher. 
9.1 
In-text Summary Tables and Figures 
The following is a list of table and figure titles that will be included in the text of the 
CSR. Tables and figures will be numbered appropriately during compilation of the 
CSR. 
Section 10: 
Table 10-1  
Disposition Summary  
Section 11: 
Table 11-1  
Demographic Summary  
Table 11-2  
Summary of Total Plasma Acalabrutinib Pharmacokinetic Parameters  
Table 11-3  
Summary of Statistical Comparisons of Total Plasma Acalabrutinib 
Pharmacokinetic Parameters – Group C versus Group N 
Table 11-4  
Summary of Unbound Plasma Acalabrutinib Pharmacokinetic 
Parameters  
Table 11-5  
Summary of Statistical Comparisons of Unbound Plasma 
Acalabrutinib Pharmacokinetic Parameters – Group C versus Group N  
Table 11-6  
Summary of Total Plasma ACP-5862 Pharmacokinetic Parameters  
Table 11-7  
Summary of Total Statistical Comparisons of Plasma ACP-5862 
Pharmacokinetic Parameters – Group C versus Group N  
Table 11-8  
Summary of Unbound Plasma ACP-5862 Pharmacokinetic Parameters  
Table 11-9  
Summary of Statistical Comparisons of Unbound Plasma ACP-5862 
Pharmacokinetic Parameters – Group C versus Group N  


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Figure 11-1  
Arithmetic Mean Total Plasma Acalabrutinib Concentrations Versus 
Time in Subjects with Severe Hepatic Impairment and with Normal 
Hepatic Function (Linear Scale) 
Figure 11-2  
Arithmetic Mean Total Plasma Acalabrutinib Concentrations Versus 
Time in Subjects with Severe Hepatic Impairment and with Normal 
Hepatic Function (Semi-Log Scale) 
Figure 11-3  
Total Plasma Acalabrutinib Geometric Mean AUC0-24 and 
Corresponding 95% CIs and GMRs (%) with Corresponding 90% CIs 
Figure 11-4  
Total Plasma Acalabrutinib Geometric Mean AUC0-last and 
Corresponding 95% CIs and GMRs (%) with Corresponding 90% CIs 
Figure 11-5  
Total Plasma Acalabrutinib Geometric Mean AUC0-inf and 
Corresponding 95% CIs and GMRs (%) with Corresponding 90% CIs 
Figure 11-6  
Total Plasma Acalabrutinib Geometric Mean Cmax and Corresponding 
95% CIs and GMRs (%) with Corresponding 90% CIs 
Figure 11-7  
Arithmetic Mean Total Plasma ACP-5862 Concentrations Versus 
Time in Subjects with Severe Hepatic Impairment and with Normal 
Hepatic Function (Linear Scale) 
Figure 11-8  
Arithmetic Mean Total Plasma ACP-5862 Concentrations Versus 
Time in Subjects with Severe Hepatic Impairment and with Normal 
Hepatic Function (Semi-Log Scale) 
Figure 11-9  
Total Plasma ACP-5862 Geometric Mean AUC0-24 and Corresponding 
95% CIs and GMRs (%) with Corresponding 90% CIs 
Figure 11-10  Total Plasma ACP-5862 Geometric Mean AUC0-last and 
Corresponding 95% CIs and GMRs (%) with Corresponding 90% CIs 
Figure 11-11  Total Plasma ACP-5862 Geometric Mean AUC0-inf and Corresponding 
95% CIs and GMRs (%) with Corresponding 90% CIs 
Figure 11-12  Total Plasma ACP-5862 Geometric Mean Cmax and Corresponding 
95% CIs and GMRs (%) with Corresponding 90% CIs 
Section 12: 
Table 12-1 
Adverse Event Frequency by Group - Number of Subjects Reporting 
the Event (% of Subjects Dosed) 


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9.2 
Section 14 Summary Tables and Figures 
The following is a list of table and figure titles that will be included in Section 14 of 
the report. Table and figure titles may be renumbered as appropriate during the 
compilation of the report.  
14.1  Demographic Data Summary Tables  
Table 14.1.1 Summary of Disposition (Safety Population) 
Table 14.1.2 Summary of Demographics (Safety Population) 
14.2  Pharmacokinetic Data Summary Tables and Figures  
14.2.1  Acalabrutinib Tables and Figures 
14.2.1.1  Total Plasma Acalabrutinib Tables 
Table 14.2.1.1.1  Total Plasma Acalabrutinib Concentrations (ng/mL) 
Following a Single Oral Dose of 50 mg acalabrutinib in 
Subjects With Severe Hepatic Impairment (Child-Pugh C) 
(Pharmacokinetic Population) 
Table 14.2.1.1.2  Total Plasma Acalabrutinib Concentrations (ng/mL) 
Following a Single Oral Dose of 50 mg acalabrutinib in 
Subjects With Normal Hepatic Function (Healthy Control) 
(Pharmacokinetic Population) 
Table 14.2.1.1.3  Total Plasma Acalabrutinib Pharmacokinetic Parameters 
Following a Single Oral Dose of 50 mg acalabrutinib in 
Subjects With Severe Hepatic Impairment (Child-Pugh C) 
(Pharmacokinetic Population) 
Table 14.2.1.1.4  Total Plasma Acalabrutinib Pharmacokinetic Parameters 
Following a Single Oral Dose of 50 mg acalabrutinib in 
Subjects With Normal Hepatic Function (Healthy Control) 
(Pharmacokinetic Population) 
Table 14.2.1.1.5  Intervals (Hours) Used for Determination of Total Plasma 
Acalabrutinib Kel Values (Pharmacokinetic Population) 
Table 14.2.1.1.6  Statistical Comparisons of Total Plasma Acalabrutinib 
Pharmacokinetic Parameters: Severe Versus Healthy 
(Pharmacokinetic Population) 
14.2.1.2  Total Plasma Acalabrutinib Figures 
Figure 14.2.1.2.1  Mean (SD) Total Plasma Acalabrutinib Concentration 
Versus Time Profiles Following a Single Oral Dose of 50 
mg Acalabrutinib (Linear Scale) (Pharmacokinetic 
Population) 


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Figure 14.2.1.2.2  Mean Total Plasma Acalabrutinib Concentration Versus 
Time Profiles Following a Single Oral Dose of 50 mg 
Acalabrutinib (Linear Scale) (Pharmacokinetic Population) 
Figure 14.2.1.2.3  Mean Total Plasma Acalabrutinib Concentration Versus 
Time Profiles Following a Single Oral Dose of 50 mg 
Acalabrutinib (Semi-Log Scale) (Pharmacokinetic 
Population) 
Figure 14.2.1.2.4  Individual Total Plasma Acalabrutinib AUC0-24 Group 
Estimates, GMs and Corresponding 95% CI and GMR(%) 
with Corresponding 90% CI Following a Single Oral Dose 
of 50 mg Acalabrutinib (Linear Scale) (Pharmacokinetic 
Population) 
Figure 14.2.1.2.5  Individual Total Plasma Acalabrutinib AUC0-last Group 
Estimates, GMs and Corresponding 95% CI and GMR(%) 
with Corresponding 90% CI Following a Single Oral Dose 
of 50 mg Acalabrutinib (Linear Scale) (Pharmacokinetic 
Population) 
Figure 14.2.1.2.6  Individual Total Plasma Acalabrutinib AUC0-inf Group 
Estimates, GMs and Corresponding 95% CI and GMR(%) 
with Corresponding 90% CI Following a Single Oral Dose 
of 50 mg Acalabrutinib (Linear Scale) (Pharmacokinetic 
Population) 
Figure 14.2.1.2.7  Individual Total Plasma Acalabrutinib Cmax Group 
Estimates, GMs and Corresponding 95% CI and GMR(%) 
with Corresponding 90% CI Following a Single Oral Dose 
of 50 mg Acalabrutinib (Linear Scale) (Pharmacokinetic 
Population) 
Figure 14.2.1.2.8  Scatter Plot of Individual Total Plasma Acalabrutinib 
AUC0-last Following a Single Oral Dose of 50 mg 
Acalabrutinib Versus Child-Pugh Scores (Pharmacokinetic 
Population) 
Figure 14.2.1.2.9  Scatter Plot of Individual Total Plasma Acalabrutinib 
AUC0-inf Following a Single Oral Dose of 50 mg 
Acalabrutinib Versus Child-Pugh Scores (Pharmacokinetic 
Population) 
Figure 14.2.1.2.10  
Scatter Plot of Individual Total Plasma Acalabrutinib 
Cmax Following a Single Oral Dose of 50 mg 
Acalabrutinib Versus Child-Pugh Scores (Pharmacokinetic 
Population) 
Figure 14.2.1.2.11  
Scatter Plot of Individual Total Plasma Acalabrutinib 
AUC0-last Following a Single Oral Dose of 50 mg 
Acalabrutinib Versus Bilirubin Levels (Pharmacokinetic 
Population) 


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Figure 14.2.1.2.12  
Scatter Plot of Individual Total Plasma Acalabrutinib 
AUC0-inf Following a Single Oral Dose of 50 mg 
Acalabrutinib Versus Bilirubin Levels (Pharmacokinetic 
Population) 
Figure 14.2.1.2.13  
Scatter Plot of Individual Total Plasma Acalabrutinib 
Cmax Following a Single Oral Dose of 50 mg 
Acalabrutinib Versus Bilirubin Levels (Pharmacokinetic 
Population) 
Figure 14.2.1.2.14  
Scatter Plot of Individual Total Plasma Acalabrutinib 
AUC0-last Following a Single Oral Dose of 50 mg 
Acalabrutinib Versus Albumin Levels (Pharmacokinetic 
Population) 
Figure 14.2.1.2.15  
Scatter Plot of Individual Total Plasma Acalabrutinib 
AUC0-inf Following a Single Oral Dose of 50 mg 
Acalabrutinib Versus Albumin Levels (Pharmacokinetic 
Population) 
Figure 14.2.1.2.16  
Scatter Plot of Individual Total Plasma Acalabrutinib 
Cmax Following a Single Oral Dose of 50 mg 
Acalabrutinib Versus Albumin Levels (Pharmacokinetic 
Population) 
Figure 14.2.1.2.17  
Scatter Plot of Individual Total Plasma Acalabrutinib 
AUC0-last Following a Single Oral Dose of 50 mg 
Acalabrutinib Versus Prothrombin Time (Pharmacokinetic 
Population) 
Figure 14.2.1.2.18  
Scatter Plot of Individual Total Plasma Acalabrutinib 
AUC0-inf Following a Single Oral Dose of 50 mg 
Acalabrutinib Versus Prothrombin Time (Pharmacokinetic 
Population) 
Figure 14.2.1.2.19  
Scatter Plot of Individual Total Plasma Acalabrutinib 
Cmax Following a Single Oral Dose of 50 mg 
Acalabrutinib Versus Prothrombin Time (Pharmacokinetic 
Population) 
14.2.1.3  Unbound Plasma Acalabrutinib Tables 
Table 14.2.1.3.1  Unbound Plasma Acalabrutinib Concentrations (ng/mL) 
Following a Single Oral Dose of 50 mg acalabrutinib in 
Subjects With Severe Hepatic Impairment (Child-Pugh C) 
(Pharmacokinetic Population) 
Table 14.2.1.3.2  Unbound Plasma Acalabrutinib Concentrations (ng/mL) 
Following a Single Oral Dose of 50 mg acalabrutinib in 
Subjects With Normal Hepatic Function (Healthy Control) 
(Pharmacokinetic Population) 


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Table 14.2.1.3.3  Unbound Plasma Acalabrutinib Pharmacokinetic 
Parameters Following a Single Oral Dose of 50 mg 
acalabrutinib in Subjects With Severe Hepatic Impairment 
(Child-Pugh C) (Pharmacokinetic Population) 
Table 14.2.1.3.4  Unbound Plasma Acalabrutinib Pharmacokinetic 
Parameters Following a Single Oral Dose of 50 mg 
acalabrutinib in Subjects With Normal Hepatic Function 
(Healthy Control) (Pharmacokinetic Population) 
Table 14.2.1.3.5  Intervals (Hours) Used for Determination of Unbound 
Plasma Acalabrutinib Kel Values (Pharmacokinetic 
Population) 
Table 14.2.1.3.6  Statistical Comparisons of Unbound Plasma Acalabrutinib 
Pharmacokinetic Parameters: Severe Versus Healthy 
(Pharmacokinetic Population) 
14.2.1.4  Unbound Plasma Acalabrutinib Figures 
Figure 14.2.1.4.1  Mean (SD) Unbound Plasma Acalabrutinib Concentration 
Versus Time Profiles Following a Single Oral Dose of 50 
mg Acalabrutinib (Linear Scale) (Pharmacokinetic 
Population) 
Figure 14.2.1.4.2  Mean Unbound Plasma Acalabrutinib Concentration 
Versus Time Profiles Following a Single Oral Dose of 50 
mg Acalabrutinib (Linear Scale) (Pharmacokinetic 
Population) 
Figure 14.2.1.4.3  Mean Unbound Plasma Acalabrutinib Concentration 
Versus Time Profiles Following a Single Oral Dose of 50 
mg Acalabrutinib (Semi-Log Scale) (Pharmacokinetic 
Population) 
Figure 14.2.1.4.4  Individual Unbound Plasma Acalabrutinib AUC0-24 Group 
Estimates, GMs and Corresponding 95% CI and GMR(%) 
with Corresponding 90% CI Following a Single Oral Dose 
of 50 mg Acalabrutinib (Linear Scale) (Pharmacokinetic 
Population) 
Figure 14.2.1.4.5  Individual Unbound Plasma Acalabrutinib AUC0-last 
Group Estimates, GMs and Corresponding 95% CI and 
GMR(%) with Corresponding 90% CI Following a Single 
Oral Dose of 50 mg Acalabrutinib (Linear Scale) 
(Pharmacokinetic Population) 
Figure 14.2.1.4.6  Individual Unbound Plasma Acalabrutinib AUC0-inf 
Group Estimates, GMs and Corresponding 95% CI and 
GMR(%) with Corresponding 90% CI Following a Single 
Oral Dose of 50 mg Acalabrutinib (Linear Scale) 
(Pharmacokinetic Population) 


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Figure 14.2.1.4.7  Individual Unbound Plasma Acalabrutinib Cmax Group 
Estimates, GMs and Corresponding 95% CI and GMR(%) 
with Corresponding 90% CI Following a Single Oral Dose 
of 50 mg Acalabrutinib (Linear Scale) (Pharmacokinetic 
Population) 
 
14.2.1.5  Urine Acalabrutinib Tables 
Table 14.2.1.5.1  Urinary Excretion of Acalabrutinib Following a Single Oral 
Dose of 50 mg acalabrutinib in Subjects With Severe Hepatic 
Impairment (Child-Pugh C) (Pharmacokinetic Population) 
Table 14.2.1.5.2  Urinary Excretion of Acalabrutinib Following a Single Oral 
Dose of 50 mg acalabrutinib in Subjects With Normal 
Hepatic Function (Healthy Control) (Pharmacokinetic 
Population) 
14.2.1.6  Urine Acalabrutinib Figures 
Figure 14.2.1.6.1  Mean (SD) Cumulative Amount of Acalabrutinib Excreted 
in Urine Versus Time Profiles Following a Single Oral 
Dose of 50 mg Acalabrutinib (Linear Scale) 
(Pharmacokinetic Population) 
Figure 14.2.1.6.2  Mean Cumulative Amount of Acalabrutinib Excreted in 
Urine Versus Time Profiles Following a Single Oral Dose 
of 50 mg Acalabrutinib (Linear Scale) (Pharmacokinetic 
Population) 
Figure 14.2.1.6.3  Mean (SD) Cumulative Percent of Acalabrutinib Dose 
Excreted in Urine Versus Time Profiles Following a Single 
Oral Dose of 50 mg Acalabrutinib (Linear Scale) 
(Pharmacokinetic Population) 
Figure 14.2.1.6.4  Mean Cumulative Percent of Acalabrutinib Dose Excreted 
in Urine Versus Time Profiles Following a Single Oral 
Dose of 50 mg Acalabrutinib (Linear Scale) 
(Pharmacokinetic Population) 
 
14.2.2  ACP-5862 Tables and Figures 
14.2.2.1  Total Plasma ACP-5862 Tables 
Table 14.2.2.1.1  Total Plasma ACP-5862 Concentrations (ng/mL) 
Following a Single Oral Dose of 50 mg acalabrutinib in 
Subjects With Severe Hepatic Impairment (Child-Pugh C) 
(Pharmacokinetic Population) 


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Table 14.2.2.1.2  Total Plasma ACP-5862 Concentrations (ng/mL) 
Following a Single Oral Dose of 50 mg acalabrutinib in 
Subjects With Normal Hepatic Function (Healthy Control) 
(Pharmacokinetic Population) 
Table 14.2.2.1.3 Total Plasma ACP-5862 Pharmacokinetic Parameters 
Following a Single Oral Dose of 50 mg acalabrutinib in 
Subjects With Severe Hepatic Impairment (Child-Pugh C) 
(Pharmacokinetic Population) 
Table 14.2.2.1.4 Total Plasma ACP-5862 Pharmacokinetic Parameters 
Following a Single Oral Dose of 50 mg acalabrutinib in 
Subjects With Normal Hepatic Function (Healthy Control) 
(Pharmacokinetic Population) 
Table 14.2.2.1.5 Intervals (Hours) Used for Determination of Total Plasma 
ACP-5862 Kel Values (Pharmacokinetic Population) 
Table 14.2.2.1.6 Statistical Comparisons of Total Plasma ACP-5862 
Pharmacokinetic Parameters: Severe Versus Healthy 
(Pharmacokinetic Population) 
14.2.2.2 
Total Plasma ACP-5862 Figures 
Figure 14.2.2.2.1 Mean (SD) Total Plasma ACP-5862 Concentration Versus 
Time Profiles Following a Single Oral Dose of 50 mg 
Acalabrutinib (Linear Scale) (Pharmacokinetic Population) 
Figure 14.2.2.2.2 Mean Total Plasma ACP-5862 Concentration Versus Time 
Profiles Following a Single Oral Dose of 50 mg 
Acalabrutinib (Linear Scale) (Pharmacokinetic Population) 
Figure 14.2.2.2.3 Mean Total Plasma ACP-5862 Concentration Versus Time 
Profiles Following a Single Oral Dose of 50 mg 
Acalabrutinib (Semi-Log Scale) (Pharmacokinetic 
Population) 
Figure 14.2.2.2.4 Individual Total Plasma ACP-5862 AUC0-24 Group 
Estimates, GMs and Corresponding 95% CI and GMR(%) 
with Corresponding 90% CI Following a Single Oral Dose 
of 50 mg Acalabrutinib (Semi-Log Scale) (Pharmacokinetic 
Population) 
Figure 14.2.2.2.5 Individual Total Plasma ACP-5862 AUC0-last Group 
Estimates, GMs and Corresponding 95% CI and GMR(%) 
with Corresponding 90% CI Following a Single Oral Dose 
of 50 mg Acalabrutinib (Semi-Log Scale) (Pharmacokinetic 
Population) 
Figure 14.2.2.2.6 Individual Total Plasma ACP-5862 AUC0-inf Group 
Estimates, GMs and Corresponding 95% CI and GMR(%) 
with Corresponding 90% CI Following a Single Oral Dose 


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of 50 mg Acalabrutinib (Semi-Log Scale) (Pharmacokinetic 
Population) 
Figure 14.2.2.2.7 Individual Total Plasma ACP-5862 Cmax Group Estimates, 
GMs and Corresponding 95% CI and GMR(%) with 
Corresponding 90% CI Following a Single Oral Dose of 
50 mg Acalabrutinib (Semi-Log Scale) (Pharmacokinetic 
Population) 
Figure 14.2.2.2.8 Scatter Plot of Individual Total Plasma ACP-5862 AUC0-
last Following a Single Oral Dose of 50 mg Acalabrutinib 
Versus Child-Pugh Scores (Pharmacokinetic Population) 
Figure 14.2.2.2.9 Scatter Plot of Individual Total Plasma ACP-5862 AUC0-
inf Following a Single Oral Dose of 50 mg Acalabrutinib 
Versus Child-Pugh Scores (Pharmacokinetic Population) 
Figure 14.2.2.2.10 Scatter Plot of Individual Total Plasma ACP-5862 Cmax 
Following a Single Oral Dose of 50 mg Acalabrutinib 
Versus Child-Pugh Scores (Pharmacokinetic Population) 
Figure 14.2.2.2.11 Scatter Plot of Individual Total Plasma ACP-5862 AUC0-
last Following a Single Oral Dose of 50 mg Acalabrutinib 
Versus Bilirubin Levels (Pharmacokinetic Population) 
Figure 14.2.2.2.12 Scatter Plot of Individual Total Plasma ACP-5862 AUC0-
inf Following a Single Oral Dose of 50 mg Acalabrutinib 
Versus Bilirubin Levels (Pharmacokinetic Population) 
Figure 14.2.2.2.13 Scatter Plot of Individual Total Plasma ACP-5862 Cmax 
Following a Single Oral Dose of 50 mg Acalabrutinib 
Versus Bilirubin Levels (Pharmacokinetic Population) 
Figure 14.2.2.2.14 Scatter Plot of Individual Total Plasma ACP-5862 AUC0-
last Following a Single Oral Dose of 50 mg Acalabrutinib 
Versus Albumin Levels (Pharmacokinetic Population) 
Figure 14.2.2.2.15 Scatter Plot of Individual Total Plasma ACP-5862 AUC0-
inf Following a Single Oral Dose of 50 mg Acalabrutinib 
Versus Albumin Levels (Pharmacokinetic Population) 
Figure 14.2.2.2.16 Scatter Plot of Individual Total Plasma ACP-5862 Cmax 
Following a Single Oral Dose of 50 mg Acalabrutinib 
Versus Albumin Levels (Pharmacokinetic Population) 
Figure 14.2.2.2.17 Scatter Plot of Individual Total Plasma ACP-5862 AUC0-
inf Following a Single Oral Dose of 50 mg Acalabrutinib 
Versus Prothrombin Time (Pharmacokinetic Population) 
Figure 14.2.2.2.18 Scatter Plot of Individual Total Plasma ACP-5862 AUC0-
inf Following a Single Oral Dose of 50 mg Acalabrutinib 
Versus Prothrombin Time (Pharmacokinetic Population) 


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Figure 14.2.2.2.19 Scatter Plot of Individual Total Plasma ACP-5862 Cmax 
Following a Single Oral Dose of 50 mg Acalabrutinib 
Versus Prothrombin Time (Pharmacokinetic Population) 
14.2.2.3  Unbound Plasma ACP-5862 Tables 
Table 14.2.2.3.1  Unbound Plasma ACP-5862 Concentrations (ng/mL) 
Following a Single Oral Dose of 50 mg acalabrutinib in 
Subjects With Severe Hepatic Impairment (Child-Pugh C) 
(Pharmacokinetic Population) 
Table 14.2.2.3.2  Unbound Plasma ACP-5862 Concentrations (ng/mL) 
Following a Single Oral Dose of 50 mg acalabrutinib in 
Subjects With Normal Hepatic Function (Healthy Control) 
(Pharmacokinetic Population) 
Table 14.2.2.3.3 Unbound Plasma ACP-5862 Pharmacokinetic Parameters 
Following a Single Oral Dose of 50 mg acalabrutinib in 
Subjects With Severe Hepatic Impairment (Child-Pugh C) 
(Pharmacokinetic Population) 
Table 14.2.2.3.4 Unbound Plasma ACP-5862 Pharmacokinetic Parameters 
Following a Single Oral Dose of 50 mg acalabrutinib in 
Subjects With Normal Hepatic Function (Healthy Control) 
(Pharmacokinetic Population) 
Table 14.2.2.3.5 Intervals (Hours) Used for Determination of Unbound 
Plasma ACP-5862 Kel Values (Pharmacokinetic 
Population) 
Table 14.2.2.3.6 Statistical Comparisons of Unbound Plasma ACP-5862 
Pharmacokinetic Parameters: Severe Versus Healthy 
(Pharmacokinetic Population) 
14.2.2.4 
Unbound Plasma ACP-5862 Figures 
Figure 14.2.2.4.1 Mean (SD) Unbound Plasma ACP-5862 Concentration 
Versus Time Profiles Following a Single Oral Dose of 50 
mg Acalabrutinib (Linear Scale) (Pharmacokinetic 
Population) 
Figure 14.2.2.4.2 Mean Unbound Plasma ACP-5862 Concentration Versus 
Time Profiles Following a Single Oral Dose of 50 mg 
Acalabrutinib (Linear Scale) (Pharmacokinetic Population) 
Figure 14.2.2.4.3 Mean Unbound Plasma ACP-5862 Concentration Versus 
Time Profiles Following a Single Oral Dose of 50 mg 
Acalabrutinib (Semi-Log Scale) (Pharmacokinetic 
Population) 
Figure 14.2.2.4.4 Individual Unbound Plasma ACP-5862 AUC0-24 Group 
Estimates, GMs and Corresponding 95% CI and GMR(%) 
with Corresponding 90% CI Following a Single Oral Dose 


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of 50 mg Acalabrutinib (Semi-Log Scale) (Pharmacokinetic 
Population) 
Figure 14.2.2.4.5 Individual Unbound Plasma ACP-5862 AUC0-last Group 
Estimates, GMs and Corresponding 95% CI and GMR(%) 
with Corresponding 90% CI Following a Single Oral Dose 
of 50 mg Acalabrutinib (Semi-Log Scale) (Pharmacokinetic 
Population) 
Figure 14.2.2.4.6 Individual Unbound Plasma ACP-5862 AUC0-inf Group 
Estimates, GMs and Corresponding 95% CI and GMR(%) 
with Corresponding 90% CI Following a Single Oral Dose 
of 50 mg Acalabrutinib (Semi-Log Scale) (Pharmacokinetic 
Population) 
Figure 14.2.2.4.7 Individual Unbound Plasma ACP-5862 Cmax Group 
Estimates, GMs and Corresponding 95% CI and GMR(%) 
with Corresponding 90% CI Following a Single Oral Dose 
of 50 mg Acalabrutinib (Semi-Log Scale) (Pharmacokinetic 
Population) 
 
14.2.2.5 
Urine ACP-5862 Tables 
Table 14.2.2.5.1 Urinary Excretion of ACP-5862 Following a Single Oral 
Dose of 50 mg acalabrutinib in Subjects With Severe Hepatic 
Impairment (Child-Pugh C) (Pharmacokinetic Population) 
Table 14.2.2.5.2 Urinary Excretion of ACP-5862 Following a Single Oral 
Dose of 50 mg acalabrutinib in Subjects With Normal 
Hepatic Function (Healthy Control) (Pharmacokinetic 
Population) 
14.2.2.6 
Urine ACP-5862 Figures 
Figure 14.2.2.6.1 Mean (SD) Cumulative Amount of ACP-5862 Excreted in 
Urine Versus Time Profiles Following a Single Oral Dose 
of 50 mg Acalabrutinib (Linear Scale) (Pharmacokinetic 
Population) 
Figure 14.2.2.6.2 Mean Cumulative Amount of ACP-5862 Excreted in Urine 
Versus Time Profiles Following a Single Oral Dose of 50 
mg Acalabrutinib (Linear Scale) (Pharmacokinetic 
Population) 
 


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14.3 
Safety Data Summary Tables  
14.3.1 
Displays of Adverse Events 
Table 14.3.1.1 Treatment-emergent Adverse Event Frequency by Group – 
Number of Subjects Reporting the Event (% of Subject 
Dosed) (Safety Population) 
Table 14.3.1.2 Treatment-emergent Adverse Event Frequency by Group – 
Number of Adverse Events (% of Total Adverse Events) 
(Safety Population) 
Table 14.3.1.3 Treatment-emergent Adverse Event Frequency by Group, 
Severity, and Relationship to Drug – Number of Adverse 
Events (Safety Population) 
14.3.2 
Listings of Deaths, other Serious and Significant Adverse Events 
Table 14.3.2.1 Serious Adverse Events (Safety Population) 
 <if no serious adverse event occurred, a statement ‘No serious adverse event is reported’> 
14.3.3 
Narratives of Deaths, other Serious and Certain other 
Significant Adverse Events 
14.3.4 
Abnormal Laboratory Value Listing (each patient) 
Table 14.3.4.1 Out-of-Range Values and Recheck Results – Serum 
Chemistry (Safety Population) 
Table 14.3.4.2 Out-of-Range Values and Recheck Results – Hematology 
(Safety Population) 
Table 14.3.4.3 Out-of-Range Values and Recheck Results – Urinalysis 
(Safety Population) 
14.3.5 
Displays of Other Laboratory, Vital Signs, Electrocardiogram, 
Physical Examination, and Other Safety Data 
Table 14.3.5.1 Clinical Laboratory Summary and Change from Baseline – 
Serum Chemistry (Safety Population) 
Table 14.3.5.2 Clinical Laboratory Shift from Baseline – Serum Chemistry 
(Safety Population) 
Table 14.3.5.3 Clinical Laboratory Summary and Change from Baseline – 
Hematology (Safety Population) 
Table 14.3.5.4 Clinical Laboratory Shift from Baseline – Hematology 
(Safety Population) 
Table 14.3.5.5 Clinical Laboratory Summary and Change from Baseline – 
Urinalysis (Safety Population) 


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Table 14.3.5.6 Clinical Laboratory Shift from Baseline – Urinalysis (Safety 
Population) 
Table 14.3.5.7 Vital Sign Summary and Change from Baseline (Safety 
Population)  
Table 14.3.5.8 12-Lead Electrocardiogram Summary and Change from 
Baseline (Safety Population) 
9.3 
Section 16 Data Listings 
Data listings are numbered following the ICH structure but may be renumbered as 
appropriate during the compilation of the TFLs for the CSR. The following is a list of 
appendix numbers and titles that will be included as data listings: 
16.1 
Study Information 
Appendix 16.1.9 
Statistical Methods 
Appendix 16.1.10.1 
Clinical Laboratory Reference Ranges 
16.2 
Subject Data Listings 
16.2.1 
Subject Discontinuation 
Appendix 16.2.1 
Disposition (Safety Population) 
16.2.2 
Protocol Deviations 
Appendix 16.2.2 
Protocol Deviations 
16.2.3 
Subjects Excluded from Pharmacokinetic Analysis 
Appendix 16.2.3 
Subjects Excluded from Pharmacokinetic Analysis 
Note: Appendices 16.2.2 and 16.2.3 are generated in MS Word for inclusion 
in the study report. 
16.2.4 
Demographic Data 
Appendix 16.2.4.1 
Demographics (Safety Population) 
Appendix 16.2.4.2 
Child-Pugh Classification (Safety Population) 
Appendix 16.2.4.3 
Creatinine Clearance (Safety Population) 
Appendix 16.2.4.4.1 Physical Examination -Traditional Approach (Safety 
Population)  
Appendix 16.2.4.4.2 Physical Examination -Symptom Driven (Safety 
Population)  


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Appendix 16.2.4.5 
Medical and Surgical History (Safety Population) 
Appendix 16.2.4.6 
Alcohol Screen (Safety Population) 
Appendix 16.2.4.7 
Tobacco Use (Safety Population) 
16.2.5 
Compliance and/or Drug Concentration Data 
Appendix 16.2.5.1 
Subject Eligibility (Safety Population) 
Appendix 16.2.5.2 
Acalabrutinib Administration (Safety Population) 
Appendix 16.2.5.3 
Blood Collection - Acalabrutinib and ACP-5862 PK 
(Safety Population) 
Appendix 16.2.5.4 
Blood Collection – Protein Binding (Safety Population) 
Appendix 16.2.5.5 
Urine Collection – Acalabrutinib and ACP-5862 PK 
(Safety Population) 
Appendix 16.2.5.6 
Prior and Concomitant Medications (Safety Population) 
16.2.6 
Individual Pharmacokinetic Response Data 
Appendix 16.2.6.1 
Plasma Acalabrutinib (Unbound and Total) 
Concentrations Versus Time (Linear and Semi-Log 
Scale) for Subject # 
Appendix 16.2.6.2 
Plasma ACP-5862 (Unbound and Total) Concentrations 
Versus Time (Linear and Semi-Log Scale) for Subject #  
Appendix 16.2.6.3 
Protein Binding Parameters 
Programmer’s note: graphs for each subject will have 2 profiles: 1 for 
unbound concentrations and 1 for total concentrations. 
16.2.7 
Adverse Events Listings 
Appendix 16.2.7.1.1 Adverse Events (I of II) (Safety Population) 
Appendix 16.2.7.1.2 Adverse Events (II of II) (Safety Population) 
Appendix 16.2.7.2 
Adverse Event Preferred Term Classification (Safety 
Population) 
16.2.8 
Listings of Individual Laboratory Measurements and Other 
Safety Observations 
Appendix 16.2.8.1.1 Clinical Laboratory Report - Serum Chemistry (Safety 
Population)  
Appendix 16.2.8.1.2 Clinical Laboratory Report - Hematology (Safety 
Population) 
Appendix 16.2.8.1.3 Clinical Laboratory Report - Urinalysis (Safety 
Population) 
Appendix 16.2.8.1.4 Clinical Laboratory Report - Urine Drug Screening 
(Safety Population) 


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Appendix 16.2.8.1.5 Serum FSH (Safety Population) 
Appendix 16.2.8.1.6 Serum Pregnancy Test (Safety Population) 
Appendix 16.2.8.1.7 Hepatitis and HIV Serology (Safety Population) 
Appendix 16.2.8.1.8 Serum TSH (Safety Population) 
Appendix 16.2.8.1.9 Clinical Laboratory Report - Comments (Safety 
Population) 
Appendix 16.2.8.2 
Vital Signs (Safety Population) 
Appendix 16.2.8.3 
12-Lead Electrocardiogram (Safety Population) 
 
 


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10. TABLE AND FIGURE SHELLS  
The following table shells provide a framework for the display of data from this 
study. The shells may change due to unforeseen circumstances. These shells may not 
be reflective of every aspect of this study, but are intended to show the general layout 
of the tables that will be presented and included in the final report. Unless otherwise 
noted, all tables will be presented in Times New Roman font size 8. These tables will 
be generated off of the Celerion ADaM Version 2.1data structure.   
 


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11. LISTING SHELLS 
The following listing shells provide a framework for the display of data from this study. 
The shells may change due to unforeseen circumstances. These shells may not be 
reflective of every aspect of this study, but are intended to show the general layout of the 
listings that will be presented and included in the final report. These listings will be 
generated off of the Celerion SDTM Tabulation Model 1.4 mapped in accordance with 
SDTM Implementation Guide 3.2. All listings will be presented in Courier New size 
font 9.