A Randomized, Multicenter, Open-Label, Non-Inferiority, Phase III Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Subjects With High Risk Chronic Lymphocytic Leukemia
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia
Sponsor: Acerta Pharma BV

Product: ACP-196 (acalabrutinib) 
Protocol ACE-CL-006 
PROTOCOL 
TITLE: 
A Randomized, Multicenter, Open-Label, Non-Inferiority, Phase 3 
Study of ACP-196 Versus Ibrutinib in Previously Treated Subjects 
with High Risk Chronic Lymphocytic Leukemia 
PROTOCOL NUMBER: 
ACE-CL-006 
STUDY DRUG: 
ACP-196 (acalabrutinib) 
IND NUMBER: 
118717 
EUDRACT NUMBER: 
2014-005530-64 
SPONSOR MEDICAL 
MONITOR: 
Acerta Pharma, BV 
Phone
Email: 
SPONSOR: 
Acerta Pharma BV 
 
5349 AB Oss 
The Netherlands  
Original Protocol Date: 
Version 0.0 – 02 March 2015 
Amendment 1 Date: 
Version 1.0 – 25 March 2015 
Amendment 2 Date: 
Version 2.0 – 01 April 2015 
Amendment 3 Date: 
Version 3.0 – 01 March 2016 
Amendment 4 Date: 
Version 4.0 – 14 December 2017 
Amendment 5 Date: 
Version 5.0 – 21 October 2020 
Confidentiality Statement 
This document contains proprietary and confidential information of Acerta Pharma BV that 
must not be disclosed to anyone other than the recipient study staff and members of the 
institutional review board (IRB)//independent ethics committee (IEC). This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Acerta Pharma BV. 
PPD
PPD
PPD

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PROTOCOL APPROVAL:  AMENDMENT 5 
I have carefully read Protocol ACE-CL-006 entitled “A Randomized, Multicenter, Open-Label, 
Non-Inferiority, Phase 3 Study of ACP-196 Versus Ibrutinib in Previously Treated Subjects with 
High Risk Chronic Lymphocytic Leukemia”.  I agree to conduct this study as outlined herein and 
in compliance with Good Clinical Practices (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 IRB/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 BV requires that any presentation or publication of study data by 
clinical investigators be reviewed by Acerta Pharma, before release, as specified in the protocol. 
 
 
 
Principal Investigator’s Signature 
Date 
 
 
Print Name 
 
 
 

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SUMMARY OF AMENDMENT 5 
Clarifying edits and typographical changes have been made throughout the protocol.   
The following substantive changes were made as part of this amendment: 
Change 
Rationale 
Global Update: 
Section numbers added as applicable. 
Added additional section numbers to 
enable ease of locating information in 
the protocol amendment. 
Title Page 
Updated Medical Monitor. 
Updated Medical Monitor and contact 
information. 
Protocol Approval Page 
Deleted company signatory 
Align with other acalabrutinib protocols. 
Synopsis 
Updated to reflect changes in the protocol. 
Updated to align with changes in the 
protocol. 
Section 1.2.1 Chemistry 
Updated approval language to include chronic lymphocytic 
leukemia (CLL) and small lymphocytic lymphoma (SLL). 
Updated to reflect current 
CALQUENCE® approval language. 
Section 1.3.2 Clinical Experience of Acalabrutinib in 
CLL 
Deleted number of participants in clinical studies.  
Updated to remove date and number of 
participants and only reference 
acalabrutinib Investigator Brochure for 
latest information. 
Section 3.2.3 Exploratory Objectives 
  
Section 4 Study Design 
Added rollover language. 
Added clarification. 
Section 6.1.2 IMBRUVICA (Ibrutinib) 
Added tablet form of ibrutinib 140-mg. 
Updated to reflect availability of 
capsules and tablets. 
Section 6.2.1 Acalabrutinib  
Removed statement to avoid grapefruit juice and Seville 
orange juice. 
Updated to align with current 
acalabrutinib Investigator Brochure 
(version 9.0). 
Section 6.2.5.1 Reference Safety Information 
Added Reference Safety Information section with reference 
to the Investigator Brochure. 
Updated to align with current 
acalabrutinib Investigator Brochure 
(version 9.0). 
Section 6.2.5.2 Hemorrhage 
Updated information regarding hemorrhage. 
Updated to align with the current 
acalabrutinib Investigator Brochure 
(version 9.0). 
Section 6.2.5.3 Infections 
Updated information regarding infections. 
Updated to align with current 
acalabrutinib Investigator Brochure 
(version 9.0). 
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Change 
Rationale 
Section 6.2.5.3.1 Hepatitis B Virus Reactivation 
Updated information regarding Hepatitis B virus 
reactivation and monitoring requirements. 
Updated to align with current 
acalabrutinib Investigator Brochure 
(version 9.0) and to give more detailed 
guidance on required timing of testing 
based on the NCCN guidelines. 
Section 6.2.5.3.2 Progressive Multifocal 
Leukoencephalopathy 
Updated language regarding progressive multifocal 
leukoencephalopathy. 
Updated to align with current 
acalabrutinib Investigator Brochure 
(version 9.0). 
Section 6.2.5.5 Second Primary Malignancies 
Updated information regarding second primary 
malignancies. 
Updated to align with current 
acalabrutinib Investigator Brochure 
(version 9.0). 
Section 6.2.5.6 Atrial Fibrillation 
Updated information regarding atrial fibrillation. 
Updated to align with the current 
acalabrutinib Investigator Brochure 
(version 9.0). 
Section 6.2.7 Dosage Regimen and Administration for 
Ibrutinib 
Added ibrutinib 140-mg tablet. 
Updated to reflect availability of ibrutinib 
capsules and tablets. 
Section 6.2.10.2.1 Hepatitis B Virus Reactivation 
Added hepatitis B virus reactivation language. 
Add to reflect current ibrutinib package 
insert.  
Section 6.2.10.8 Cerebrovascular Accidents 
Added information regarding cerebrovascular accidents 
and ibrutinib. 
Added risk section for cerebrovascular 
accidents to reflect current ibrutinib 
package insert. 
Section 6.2.10.9 Interstitial Lung Disease 
Added information regarding interstitial lung disease and 
ibrutinib. 
Added risk section on interstitial lung 
disease to reflect current ibrutinib 
package insert. 
Section 6.2.10.10 Leukostasis 
Added information on leukostasis and ibrutinib. 
Added risk section on leukostasis to 
reflect current ibrutinib package insert. 
Section 6.2.11 Reproductive Toxicity 
Updated contraception language. 
Updated contraceptive language to 
reflect acalabrutinib Investigator 
Brochure (version 9.0).  The male 
contraceptive and sperm donation 
change was not made in the inclusion 
criteria because the study is no longer 
enrolling. 
Section 6.3.1 Allowed Concomitant Medications 
Added information regarding tumor lysis syndrome. 
Updated to address health authority 
feedback. 
Section 6.3.2 Guideline for Use of CYP 
Inhibiting/Inducing Drugs 
Updated guidance for acalabrutinib. 
Updated to reflect current acalabrutinib 
Investigator Brochure (version 9.0) and 
the USPI. 
Section 6.3.4 Prohibited Concomitant Medications 
Updated guidance for acalabrutinib. 
Updated to align with acalabrutinib 
Investigator Brochure (version 9.0) and 
the USPI. 

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Change 
Rationale 
Section 6.5 Dietary Restrictions 
Removed information regarding grapefruit, grapefruit juice 
and Seville orange juice. 
Updated to align with current 
acalabrutinib Investigator Brochure 
(version 9.0) and the USPI. 
Section 7 Efficacy and Safety Procedures 
Added reference to Appendix K for management of study 
procedures during the pandemic. 
Added reference to new appendix. 
Section 7.1 Description of Procedures 
Added reference to Schedule of Assessments 
(Appendix A) to clarify frequency of CT scans. 
Added reference to Appendix A, 
Schedule of Assessments, for 
frequency of CT scans. 
Section 7.1 Description of Procedures 
Updated information regarding reporting of adverse events. 
Updated per Safety recommendation to 
align with other acalabrutinib protocols. 
Section 7.2.2.1 Adverse Event Reporting Period 
Updated language for AE reporting period. 
Updated per Safety recommendation to 
reflect current language in other 
acalabrutinib protocols. 
Section 7.2.2.3 Adverse Events of Special Interest 
Added section for adverse events of special interest to 
include ventricular arrhythmias. 
Added section to align with current 
acalabrutinib Investigator Brochure 
(version 9.0). 
Section 7.2.2.4 Second Primary Malignancies 
Added section for second primary malignancies. 
Added section on second primary 
malignancies to align with current 
acalabrutinib Investigator Brochure 
(version 9.0). 
Section 7.2.2.5 Pregnancy 
Updated contact information to reflect AstraZeneca 
Representative. 
Updated contact information to remove 
Acerta as process transitions to 
AstraZeneca. 
Section 7.2.2.6 Overdose Instructions 
Updated language regarding overdose. 
Updated to align with acalabrutinib 
Investigator Brochure (version 9.0) and 
to include ibrutinib. 
Section 7.2.2.7 Expedited Reporting Requirements for 
Serious Adverse Events/Adverse Events of Special 
Interest 
Clarified language to include adverse events of special 
interest (AESIs). 
Updated information to reflect AstraZeneca 
Representative. 
Updated per Safety to add AESI 
reporting language. 
Updated contact information to remove 
Acerta as process transitions to 
AstraZeneca. 
Events of Special Interest 
Deleted section on Events of Special Interest (7.2.2) 
Removed to align protocol. 
Section 7.2.2.9 Hy’s Law 
Added information regarding Hy’s law. 
Added section on Hy’s law to align with 
other acalabrutinib protocols and 
AstraZeneca procedure. 
Section 8.2 Reasons for Study Exit 
Updated language regarding study withdrawal. 
Updated to provide clarification. 
Section 9.6.1 Primary Endpoint and Methods 
Clarified events and added reference to SAP. 
To clarify the primary endpoint PFS is 
based on IRC assessment. Add 

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Change 
Rationale 
language to allow for ad hoc sensitivity 
and subgroup analysis. 
Section 9.6.2 Secondary Endpoints and Methods 
Updated SAP statement for clarification. 
Updated to provide clarification 
(editorial change). 
Section 9.6.3 Exploratory Endpoints 
 
 
 
 
 
 
 
   
 
 
   
Section 9.7 Safety Analysis 
Deleted AEs of special interest and other AEs of interest 
sections for ibrutinib. 
Updated lymphocytosis section. 
Updated ECOG performance status and vital signs and 
weight. 
Updated for clarification. 
Section 10.9 INVESTIGATOR RESPONSIBILITIES 
Updated information to reflect AstraZeneca 
Representative. 
Updated contact information to remove 
Acerta as process transitions to 
AstraZeneca. 
Appendix A:  Schedule of Assessments 
Updated to reflect changes in the protocol. 
Aligned with changes made in the 
protocol. 
Appendix C:  Examples of Coadministered Drugs That 
Need Additional Consideration 
Updated current table and added additional tables 
regarding coadministration. 
Updated with current information from 
the FDA. 
Appendix E:  Ibrutinib Full Prescribing and Reference 
Safety Information 
Removed this appendix from the protocol amendment. 
Removed ibrutinib United States label 
from the appendix and referenced 
current label in the protocol. 
Appendix J:  Actions Required in Cases of Increases in 
Liver Biochemistry and Evaluation of Hy’s law 
Added appendix on Hy’s law. 
Added appendix on Hy’s law to provide 
additional information to new section 
added to protocol. 
Appendix K:  Management of Study Procedures During 
Pandemic 
Added appendix to discuss management of study 
procedures during COVID pandemic. 
Added appendix on management of 
study procedures during the COVID 
pandemic. 
 
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SYNOPSIS 
Study Title: 
A Randomized, Multicenter, Open-Label, Non-Inferiority, Phase 3 
Study of ACP-196 Versus Ibrutinib in Previously Treated 
Subjects with High Risk Chronic Lymphocytic Leukemia 
Protocol Number: 
ACE-CL-006 
Study Phase: 
3 
Study Duration: 
Approximately 6 years including enrollment time 
Investigational Product 
and Reference Therapy: 
The investigational product, ACP-196 (acalabrutinib), will be 
supplied as hard gelatin capsules for oral administration. 
Commercially available ibrutinib (IMBRUVICA®) will be used as 
the reference therapy. 
Objectives: 
Primary Objective: 
To assess whether acalabrutinib is non-inferior to ibrutinib with 
respect to progression-free survival (PFS) based on independent 
review committee (IRC) assessment in subjects with relapsed or 
refractory chronic lymphocytic leukemia (CLL) with high-risk 
prognostic markers.  The IRC will use the International Workshop 
on Chronic Lymphocytic Leukemia Criteria (IWCLL; Hallek 2008) 
with incorporation of the clarification for treatment-related 
lymphocytosis (Cheson 2012)—hereafter referred to as IWCLL 
2008 criteria.  
Secondary Objectives: 
To evaluate the benefit/risk of acalabrutinib versus ibrutinib in 
terms of: 
• 
Grade ≥ 3 infections  
• 
Richter’s transformation 
• 
Atrial fibrillation  
• 
Overall survival (OS) 
Safety Objective: 
• 
Safety and tolerability including adverse events (AEs) of 
interest and laboratory assessments 
Exploratory Objectives: 
 
 
 
 
 
 
 
 
 
 
 
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Study Design: 
This randomized, multicenter, open-label, non-inferiority (NI) 
Phase 3 study is designed to evaluate the efficacy and safety of 
acalabrutinib (100 mg twice daily) versus ibrutinib (420 mg once 
daily) in subjects with relapsed or refractory CLL who have high-
risk prognostic factors per National Comprehensive Cancer 
Network guidelines (NCCN Version 1.2016).  These high-risk 
prognostic factors are as follows: 
• 
Presence of 17p deletion mutation (17p del) 
• 
Presence of 11q deletion mutation (11q del) 
Approximately 500 eligible subjects will be randomized in a 
1:1 ratio into 2 arms to receive either acalabrutinib (Arm A; 
N=250) or ibrutinib (Arm B; N=250). 
This study will use an Interactive Web Response System (IWRS) 
for randomization.  Randomization will be used to minimize bias 
in the assignment of subjects to treatment groups, to increase the 
likelihood that known and unknown subject attributes (eg, 
demographic and baseline characteristics) are evenly balanced, 
and to enhance the validity of statistical comparisons across 
treatment groups.   
Randomization will be performed stratified by the following 
factors: 
• 
Presence of 17p del 
• 
Eastern Cooperative Oncology Group (ECOG) 
performance status (ECOG = 2 versus ECOG ≤1) 
• 
Number of prior therapies (1-3 versus ≥ 4) 
Subject participation will include a Screening Phase, a Treatment 
Phase, Post-treatment Phase and a Post-disease Progression 
Phase.  The Screening Phase will last up to 28 days before first 
dose of study drug, during which the subject’s eligibility and 
baseline characteristics will be determined.  Treatment with study 
drug may be continued until an unacceptable drug-related toxicity 
occurs or until disease progression (ie, Treatment Phase).  Dose 
modification provisions are provided in the study protocol.  Note: 
temporary withholding of study drug for as little as 7 days can 
cause a transient worsening of disease and/or of constitutional 
symptoms.  Refer to Section 8.1 for more information on 
assessing disease progression under these circumstances.  
Assessment for tumor response and progression will be 
conducted in accordance with the IWCLL 2008 criteria until 
disease progression.  Disease assessments are required every 
12 weeks from Week 1 Day 1 through Week 100, and then every 
24 weeks until 5 years on study and then yearly thereafter for all 
subjects (including subjects who discontinue from the study due 
to an AE) until confirmation of disease progression or death, 
consent withdrawal, or lost to follow-up. 
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All subjects who discontinue study drug will have a safety 
follow-up visit 30 (+ 7) days after the last dose of study treatment 
regardless of whether the subject receives another anticancer 
therapy or demonstrates disease progression within that 
timeframe.  As described above, all subjects who discontinue 
study drug due to an intolerable AE will be followed on study for 
disease progression or death (ie, Post-treatment Phase).   
The Post-disease Progression Phase will begin once a subject 
has progressive disease confirmed by the IRC.  During this 
phase, subsequent anticancer therapy with start date of therapy, 
IWCLL indication for treatment initiation, additional malignancy 
occurrence, and subject survival status will be recorded.  The 
Post-disease Progression Phase will continue until death, lost to 
follow up, consent withdrawal, or study closure, whichever occurs 
first. 
Population: 
Subjects with previously treated CLL with high-risk prognostic 
factors as defined in the inclusion criteria. 
Centers: 
Approximately 200 centers in North America, Europe, Australia, 
and New Zealand. 
Key Inclusion Criteria: 
1. Men and women ≥ 18 years of age. 
2. ECOG performance status of 0 to 2. 
3. Diagnosis of CLL that meets published diagnostic criteria 
(Hallek 2008): 
a. Monoclonal B-cells (either kappa or lambda light 
chain restricted) that are clonally co-expressing 
≥ 1 B-cell marker (CD19, CD20, or CD23) and 
CD5. 
b. Prolymphocytes may comprise ≤ 55% of blood 
lymphocytes. 
c. Presence of ≥ 5 x 109 B lymphocytes/L (5000 µL) 
in the peripheral blood (at any point since 
diagnosis) 
4. Must have ≥ 1 of the following high-risk prognostic factors:  
a. Presence of 17p del by central laboratory 
b. Presence of 11q del by central laboratory 
5. Active disease meeting ≥ 1 of the following IWCLL 2008 
criteria for requiring treatment: 
a. Evidence of progressive marrow failure as 
manifested by the development of, or worsening 
of, anemia (hemoglobin < 10 g/dL) and/or 
thrombocytopenia (platelets < 100,000/μL). 
b. Massive (ie, ≥ 6 cm below the left costal margin), 
progressive, or symptomatic splenomegaly 
c. Massive nodes (ie, ≥ 10 cm in the longest 
diameter), progressive, or symptomatic 
lymphadenopathy. 
d. Progressive lymphocytosis with an increase of 
> 50% over a 2-month period or a lymphocyte 
doubling time (LDT) of < 6 months. LDT may be 
obtained by linear regression extrapolation of 

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absolute lymphocyte counts (ALC) obtained at 
intervals of 2 weeks over an observation period of 
2 to 3 months. In subjects with initial blood 
lymphocyte counts of < 30 X 109/L (30,000/μL), 
LDT should not be used as a single parameter to 
define indication for treatment. In addition, factors 
contributing to lymphocytosis or lymphadenopathy 
other than CLL (eg, infections) should be 
excluded. 
e. Autoimmune anemia and/or thrombocytopenia that 
is poorly responsive to standard therapy. 
f. Constitutional symptoms documented in the 
subject’s chart with supportive objective 
measures, as appropriate, defined as ≥ 1 of the 
following disease-related symptoms or signs: 
i. Unintentional weight loss ≥ 10% within the 
previous 6 months before Screening. 
ii. Significant fatigue (ie, ECOG performance 
status 2 or worse; inability to work or 
perform usual activities). 
iii. Fevers higher than 100.5°F or 38.0°C for 
2 or more weeks before Screening without 
evidence of infection. 
iv. Night sweats for > 1 month before 
Screening without evidence of infection. 
6. Must have received ≥ 1 prior therapies for CLL. 
8. Meet the following laboratory parameters: 
a. Absolute neutrophil count (ANC) ≥ 750 cells/μL 
(0.75 x 109/L) or ≥ 500 cells/μL (0.50 x 109/L) in 
subjects with documented bone marrow 
involvement and independent of growth factor 
support 7 days before assessment. 
b. Platelet count ≥ 30,000 cells/μL (30 x 109/L) 
without transfusion support 7 days before 
assessment. Subjects with transfusion-dependent 
thrombocytopenia are excluded. 
c. Serum aspartate transaminase (AST/SGOT) and 
alanine transaminase (ALT/SGPT) ≤ 3.0 x upper 
limit of normal (ULN). 
d. Total bilirubin ≤ 1.5 x ULN. 
e. Estimated creatinine clearance (ie, estimated 
glomerular filtration rate [eGFR] using 
Cockcroft-Gault) ≥ 30 mL/min. 
9. Able to receive all outpatient treatment, all laboratory 
monitoring, and all radiologic evaluations at the institution 
that administers study drug for the entire study. 
10. Women who are sexually active and can bear children 
must agree to use highly effective forms of contraception 
while on the study and for 2 days after the last dose of 
acalabrutinib or 90 days after the last dose of ibrutinib, 

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whichever is longer.  Highly effective forms of 
contraception are defined in Section 6.2.11.   
11. Men who are sexually active and can beget children must 
agree to use highly effective forms of contraception during 
the study and for 2 days after the last dose of 
acalabrutinib or 90 days after the last dose of ibrutinib, 
whichever is longer.  Highly effective forms of 
contraception are defined in Section 6.2.11. 
12. Men must agree to refrain from sperm donation during the 
study and for 2 days after the last dose of acalabrutinib or 
90 days after the last dose of ibrutinib, whichever is 
longer. 
13. Are willing and able to adhere to the study visit schedule, 
understand and comply with other protocol requirements, 
and provide written informed consent and authorization to 
use protected health information.  Note vulnerable 
subjects are not allowed on this protocol (eg, prisoners or 
institutionalized subjects). 
Key Exclusion Criteria: 
1. Known central nervous system (CNS) lymphoma or 
leukemia. 
2. Known prolymphocytic leukemia or history of, or currently 
suspected, Richter’s syndrome. 
3. Uncontrolled autoimmune hemolytic anemia (AIHA) or 
idiopathic thrombocytopenic purpura (ITP) defined as 
declining hemoglobin or platelet count secondary to 
autoimmune destruction within the screening period or 
requirement for high doses of steroids (> 20 mg daily of 
prednisone daily or equivalent). 
4. Prior exposure to ibrutinib or to a B-cell receptor (BCR) 
inhibitor (eg, Bruton tyrosine kinase [Btk] inhibitors or 
phosphoinositide-3 [PI3] kinase inhibitors or Syk 
inhibitors) or a BCL-2 inhibitor (eg, ABT-199). 
5. Received any chemotherapy, external beam radiation 
therapy, anticancer antibodies, or investigational drug 
within 30 days before first dose of study drug. 
6. Corticosteroid use > 20 mg within 1 week before first dose 
of study drug, except as indicated for other medical 
conditions such as inhaled steroid for asthma, topical 
steroid use, or as premedication for administration of 
study drug or contrast. For example, subjects requiring 
steroids at daily doses > 20 mg prednisone equivalent 
systemic exposure daily, or those who are administered 
steroids for leukemia control or white blood cell count 
lowering are excluded. 
7. Prior radio- or toxin-conjugated antibody therapy. 
8. Prior allogeneic stem cell transplant or autologous 
transplant. 

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9. Major surgery within 4 weeks before first dose of study 
drug. 
10. History of prior malignancy except for the following: 
a. Malignancy treated with curative intent and with no 
evidence of active disease present for more than 
3 years before Screening and felt to be at low risk 
for recurrence by treating physician.   
b. Adequately treated lentigo maligna melanoma 
without current evidence of disease or adequately 
controlled non-melanomatous skin cancer 
c. Adequately treated cervical carcinoma in situ 
without current evidence of disease 
11. Significant cardiovascular disease such as uncontrolled or 
symptomatic arrhythmias, congestive heart failure, or 
myocardial infarction within 6 months of screening, or any 
Class 3 or 4 cardiac disease as defined by the New York 
Heart Association Functional Classification, or corrected 
QT interval (QTc) > 480 msec at screening. 
12. Unable to swallow capsules or malabsorption syndrome, 
disease significantly affecting gastrointestinal function, or 
resection of the stomach or small bowel or gastric bypass, 
symptomatic inflammatory bowel disease, or partial or 
complete bowel obstruction. 
13. Uncontrolled active systemic fungal, bacterial, viral, or 
other infection (defined as exhibiting ongoing 
signs/symptoms related to the infection and without 
improvement, despite appropriate antibiotics or other 
treatment) or ongoing intravenous anti-infective treatment. 
14. Known history of infection with human immunodeficiency 
virus (HIV). 
15. Serologic status reflecting active hepatitis B or C infection. 
Subjects with hepatitis B core antibody positive who are 
surface antigen negative or who are hepatitis C antibody 
positive will need to have a negative polymerase chain 
reaction (PCR) result before randomization. Those who 
are hepatitis B surface antigen positive or hepatitis B PCR 
positive and those who are hepatitis C PCR positive will 
be excluded. 
16. History of stroke or intracranial hemorrhage within 
6 months before randomization. 
17. History of bleeding diathesis (eg, hemophilia, von 
Willebrand disease). 
18. Requires or receiving anticoagulation with warfarin or 
equivalent vitamin K antagonists (eg, phenprocoumon) 
within 7 days of first dose of study drug. 
19. Requires treatment with a strong cytochrome P450 3A 
(CYP3A) inhibitor/inducer. 

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20. Requires treatment with proton-pump inhibitors (eg, 
omeprazole, esomeprazole, lansoprazole, 
dexlansoprazole, rabeprazole, or pantoprazole) 
21. Breastfeeding or pregnant. 
22. Concurrent participation in another therapeutic clinical 
trial. 
23. Presence of a gastrointestinal ulcer diagnosed by 
endoscopy within 3 months before screening 
Primary Endpoint for 
Final Analysis: 
The primary endpoint of the study is PFS.  The primary 
hypothesis is acalabrutinib is non-inferior to ibrutinib with respect 
to PFS as assessed by IRC review per IWCLL 2008 criteria. 
Secondary Endpoints: 
To compare between acalabrutinib and ibrutinib in terms of: 
• 
Incidence of Grade ≥ 3 infections 
• 
Incidence of Richter’s transformation 
• 
Incidence of atrial fibrillation  
• 
OS  
Safety Endpoints: 
• 
Frequency, severity, and relatedness of AEs 
• 
Frequency of AEs requiring discontinuation of study drug or 
dose reductions 
• 
Change in laboratory assessments 
Exploratory Endpoints: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Treatment: 
Acalabrutinib 100 mg Twice per Day (Treatment Arm A): 
Acalabrutinib is provided as 100-mg hard gelatin capsules.  
Acalabrutinib 100 mg will be orally administered twice per day 
(BID).  Doses will be administered 12 hours apart with a window 
of ± 1 hour.  Acalabrutinib will be administered daily until disease 
progression or unacceptable toxicity.   
Ibrutinib 420 mg Once per Day (Treatment Arm B): 
Commercially available ibrutinib supplied as hard gelatin 
capsules or tablets (140-mg strength) for oral administration will 
be administered per the IMBRUVICA approved label.  Ibrutinib 
420 mg (3 capsules or tablets) will be orally administered once 
per day (QD).  Ibrutinib will be administered until disease 
progression or unacceptable toxicity   
Concomitant Therapy 
and Clinical Practice: 
Permitted Concomitant Therapy: 
Standard supportive care medications are permitted.  Use of 
hematopoietic growth factors is permitted per the American 
Society of Clinical Oncology (ASCO) guidelines. 
Prohibited Concomitant Therapy: 
Any chemotherapy, anticancer immunotherapy, corticosteroids 
(at dosages equivalent to prednisone > 20 mg/day), warfarin or 
equivalent vitamin K antagonists, experimental therapy, and 
radiotherapy are prohibited.   
Acalabrutinib and Concomitant Therapy: 
The effect of agents that reduce gastric acidity (eg, proton-pump 
inhibitors, H2-receptor antagonists or antacids) on acalabrutinib 
absorption was evaluated in a healthy volunteer study 
(ACE-HV-004). Results from this study indicate that subjects 
should avoid the use of calcium carbonate containing drugs or 
supplements (eg, antacids and calcium supplements) for a period 
of at least 2 hours before and after taking acalabrutinib. 
Subjects should also avoid the use of H2-receptor antagonists for 
a period at least 2 hours before and after taking acalabrutinib.  
Use of omeprazole or esomeprazole or lansoprazole (or any 
other proton-pump inhibitors) while taking acalabrutinib is not 
recommended as it may lower acalabrutinib exposure.  
Concomitant administration of strong CYP3A inhibitors/inducers 
and acalabrutinib should be avoided, when possible. 
Safety Plan: 
An independent Data Monitoring Committee (DMC), chaired by a 
physician with expertise in CLL, will monitor the safety of the 
subjects in this study. 
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An early safety analysis will be performed after approximately 
50 subjects have been treated for approximately 8 weeks.  This 
analysis will focus on deaths, treatment discontinuations, serious 
adverse events (SAEs), and Grade 3/4 AEs as well as special 
events of interest.  The Medical Monitor will review, in a blinded 
fashion, this information on an ongoing basis until this early 
safety analysis is conducted.  Detailed information on the role of 
the DMC and frequency of meetings will be provided in the DMC 
charter separate from this protocol. 
Statistical Methods and 
Data Analysis: 
All efficacy analyses will be performed using the intent-to-treat 
(ITT) population. 
Primary Efficacy Analysis: 
The primary efficacy endpoint is PFS, which is defined as the 
time from the date of randomization until disease progression 
(assessed by the IRC per IWCLL 2008 criteria) or death from any 
cause, whichever occurs first.  The primary analysis is event-
based and will be conducted after enrollment is completed and 
approximately 250 IRC-assessed events have occurred.   
The primary analysis for this study will be conducted to assess 
whether acalabrutinib is non-inferior (NI) to ibrutinib with respect 
to PFS. The two-sided 95% confidence interval (CI) for the 
hazard ratio (HR) of acalabrutinib versus ibrutinib will be 
estimated using a stratified Cox regression model.  
The upper bound of the 95% CI for HR will be compared with NI 
bound of calculated. 
Secondary Endpoints and Analysis:  
If acalabrutinib is shown non-inferior to ibrutinib, the secondary 
endpoints will be tested in a manner that maintains the Type I 
error rate at ≤ 5%. 
The incidences of treatment-emergent Grade ≥ 3 infections, 
Richter’s transformation and atrial fibrillation will be summarized 
and compared between the 2 treatment arms using 2-sided 
Cochran-Mantel-Haenszel tests adjusted for the randomization 
strata.  
Differences between the treatment arms in OS will be assessed 
using Kaplan-Meier methods and a stratified log-rank test.  The 
OS HR and its 95% CI will be presented using a stratified Cox 
regression model. 
The Statistical Analysis Plan (SAP) will describe the methodology 
to be used for multiplicity adjustment. 
Safety Analysis: 
Detailed tabulations of safety data (AEs and clinical laboratory 
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drug.  The number and percent of subjects with 
treatment-emergent AEs (TEAEs) will be summarized.  Summary 
of other safety parameters by treatment group will be provided 
where appropriate. 
Sample Size: 
A recently completed trial that studied PFS in CLL (Byrd 2014) 
showed that ibrutinib (the reference/comparator drug in Protocol 
ACE-CL-006) was superior to ofatumumab, a drug approved for 
the treatment of CLL in patients with previously treated CLL. 
Superiority in that study was shown in the overall study 
population (HR=0.21) as well as in patients with 17p del 
(HR=0.25) or 11q del (HR=0.14).  
Protocol ACE-CL-006 is designed to have 80% power to show 
that the upper bound of a 2-sided 95% CI for PFS is < 1.429 (the 
NI bound).    
With randomization in a 1:1 ratio, the trial will require 
approximately 250 events if acalabrutinib and ibrutinib are truly 
equally effective. Assuming an enrollment period of about 
 and a follow-up period of approximately 
 
after the last subject enters the study, the estimated sample size 
is 500 subjects (250 per arm).   
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TABLE OF CONTENTS 
SYNOPSIS ................................................................................................................................ 7 
TABLE OF CONTENTS ............................................................................................................17 
LIST OF TABLES ......................................................................................................................19 
LIST OF FIGURES ...................................................................................................................19 
LIST OF APPENDICES ............................................................................................................19 
LIST OF ABBREVIATIONS AND DEFINITIONS .......................................................................20 
1 
BACKGROUND INFORMATION .......................................................................................24 
1.1 
Btk Inhibition for the Treatment of CLL ..................................................................24 
1.2 
Preclinical Studies ................................................................................................26 
1.2.1 
Chemistry ..............................................................................................26 
1.2.2 
Mechanism of Action of Acalabrutinib ...................................................26 
1.2.3 
Dog Lymphoma Study ...........................................................................26 
1.2.4 
Acalabrutinib and Antibody-dependent Cell-mediated Cytotoxicity ........27 
1.2.5 
Acalabrutinib and Thrombus Formation ................................................28 
1.2.6 
Safety Pharmacology ............................................................................29 
1.2.7 
Drug-drug Interaction Potential .............................................................30 
1.2.8 
In Vivo General Toxicology ...................................................................30 
1.3 
Clinical Studies .....................................................................................................31 
1.3.1 
Pharmacokinetics and Pharmacodynamics of Acalabrutinib..................31 
1.3.2 
Clinical Experience of Acalabrutinib in CLL ...........................................32 
1.4 
Summary and Conclusions ...................................................................................32 
2 
STUDY RATIONALE .........................................................................................................33 
2.1 
Dose Selection Rationale for acalabrutinib ...........................................................33 
2.2 
Non-Inferiority Design and Ibrutinib as Comparator ..............................................33 
2.3 
Selection of the Patient population ........................................................................34 
2.4 
Benefit/Risk ..........................................................................................................35 
3 
STUDY OBJECTIVES .......................................................................................................35 
3.1 
Primary Objective .................................................................................................35 
3.2 
Secondary Objectives ...........................................................................................36 
3.2.1 
Efficacy Objectives ................................................................................36 
3.2.2 
Safety Objective ....................................................................................36 
3.2.3 
Exploratory Objectives ..........................................................................36 
4 
STUDY DESIGN ...............................................................................................................36 
5 
SELECTION OF SUBJECTS .............................................................................................39 
5.1 
Inclusion Criteria ...................................................................................................39 
5.2 
Exclusion Criteria ..................................................................................................40 
6 
DOSAGE AND ADMINISTRATION ...................................................................................42 
6.1 
Identification of Investigational Product .................................................................42 
6.1.1 
Acalabrutinib .........................................................................................42 
6.1.2 
IMBRUVICA (Ibrutinib) ..........................................................................42 
6.2 
Drug Preparation and Administration ....................................................................42 
6.2.1 
Acalabrutinib .........................................................................................42 
6.2.2 
Assessment of Toxicity .........................................................................43 

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6.2.3 
Dose Delays for Acalabrutinib ...............................................................43 
6.2.4 
Dose Modification and Discontinuation for Acalabrutinib .......................43 
6.2.5 
Risks Associated with Acalabrutinib Treatment .....................................45 
6.2.6 
IMBRUVICA (Ibrutinib) ..........................................................................47 
6.2.7 
Dosage Regimen and Administration for Ibrutinib .................................47 
6.2.8 
Dose Delays for Ibrutinib .......................................................................47 
6.2.9 
Dose Modification and Discontinuation for Ibrutinib ...............................48 
6.2.10 
Risks Associated with Ibrutinib Treatment .............................................48 
6.2.11 
Reproductive Toxicity ............................................................................50 
6.3 
Concomitant Medications ......................................................................................52 
6.3.1 
Allowed Concomitant Medications.........................................................52 
6.3.2 
Guideline for Use of CYP Inhibiting/Inducing Drugs ..............................53 
6.3.3 
Guideline for Use of Drugs that Affect Gastric pH .................................53 
6.3.4 
Prohibited Concomitant Medications .....................................................54 
6.4 
Treatment Compliance .........................................................................................54 
6.5 
Dietary Restrictions ...............................................................................................54 
7 
EFFICACY AND SAFETY PROCEDURES .......................................................................55 
7.1 
Description of Procedures .....................................................................................55 
7.2 
Assessment of Safety ...........................................................................................64 
7.2.1 
Definitions .............................................................................................64 
7.2.2 
Documenting and Reporting of Adverse and Serious Adverse Events 
by Investigators .....................................................................................69 
7.2.3 
Reporting of Serious Adverse Events by Sponsor .................................73 
8 
WITHDRAWAL OF SUBJECT FROM TREATMENT OR ASSESSMENT ..........................73 
8.1 
Withdrawal of Subjects from Study Treatment ......................................................73 
8.2 
Reasons for Study Exit .........................................................................................73 
9 
STATISTICAL METHODS .................................................................................................74 
9.1 
General Considerations ........................................................................................74 
9.2 
Randomization ......................................................................................................75 
9.3 
Determination of Sample Size ..............................................................................75 
9.4 
Analysis Populations .............................................................................................75 
9.5 
Handling of Missing Values/Censoring/Discontinuations .......................................76 
9.6 
Efficacy Analyses..................................................................................................76 
9.6.1 
Primary Endpoint and Methods .............................................................76 
9.6.2 
Secondary Endpoints and Methods .......................................................76 
9.6.3 
Exploratory Endpoints ...........................................................................77 
9.7 
Safety Analyses ....................................................................................................78 
10 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ..................................79 
10.1 
Regulatory and Ethical Compliance ......................................................................80 
10.2 
Institutional Review Board (IRB) and Independent Ethics Committee (IEC) 
Approval ...............................................................................................................80 
10.3 
Informed Consent and Protected Subject Health Information Authorization ..........80 
10.4 
Quality Control and Quality Assurance .................................................................81 
10.5 
Study Files and Record Retention ........................................................................81 

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10.6 
Case Report Forms and Record Maintenance ......................................................82 
10.7 
Investigational Study Drug Accountability .............................................................82 
10.8 
Study Monitoring/Audit Requirements ...................................................................82 
10.9 
Investigator ResponsiBilities .................................................................................83 
10.10 Clinical Trial Insurance .........................................................................................84 
10.11 Protocol Amendments ..........................................................................................84 
10.12 Publication of Study Results .................................................................................84 
11 
REFERENCE LIST ............................................................................................................85 
12 
APPENDICES ...................................................................................................................88 
LIST OF TABLES 
Table 1-1.  Assessment of Acalabrutinib Active-site Occupancy in Fine Needle Aspirates of 
Canine Lymph Node Tumors (N=4) ................................................................... 27 
Table 6-1.  Drug Discontinuation Actions for Acalabrutinib .................................................. 44 
Table 6-2.  Dose Discontinuation Actions for Ibrutinib ......................................................... 48 
 
LIST OF FIGURES 
Figure 1-1.  Effect of Acalabrutinib (1 μM) and Ibrutinib (1 μM) on Thrombus Formation ..... 29 
Figure 4-1.  Study Schema.................................................................................................. 37 
 
LIST OF APPENDICES 
Appendix A: 
Schedule of Assessments ...................................................................... 89 
Appendix B: 
Performance Status Scores ................................................................... 92 
Appendix C: 
Examples of Coadministered Drugs That Need Additional Consideration93 
Appendix D: 
Response Assessment Criteria (Hallek 2008) ........................................ 95 
Appendix E: 
Hematologic Adverse Event Grading Scheme (Hallek 2008) .................. 96 
Appendix F: 
Adverse Event Assessment of Causality ................................................ 97 
Appendix G: 
................................................................................. 98 
Appendix H: 
............................................................................... 100 
Appendix I: 
............................................................................... 103 
Appendix J: 
Actions Required in Cases of Increases In Liver Biochemistry and 
Evaluation of Hy’s Law .................................................................................... 104 
Appendix K: 
Management of Study Procedures During Pandemic ........................... 107 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
11q del 
chromosome deletion 11q22.3 
17p del 
chromosome deletion 17p13.1 
ACP-196 
acalabrutinib 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE(s) 
adverse event(s) 
AESI 
adverse events of special interest  
AIHA 
autoimmune hemolytic anemia  
ALC 
absolute lymphocyte count 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
hepatitis B core antibody 
ASCO 
American Society of Clinical Oncology  
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-12 
area under the plasma concentration-time curve from time 0 to the 
12-hour time point 
AUC0-24 
area under the plasma concentration-time curve from time 0 to the 
24-hour time point 
AUC0-inf 
area under the plasma concentration-time curve from time 0 to infinity 
BCR 
B-cell receptor 
BID 
twice per day 
Btk 
Bruton tyrosine kinase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
CI 
confidence interval 
CL/F 
oral clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed drug concentration 
CNS 
central nervous system 
 
CRF 
case report form 
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CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVA 
cerebrovascular accident 
CYP 
cytochrome P450 
DLBCL 
diffuse large B cell lymphoma 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DMSO 
dimethyl sulfoxide 
DOL 
duration of lymphocytosis  
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eGFR 
estimated glomerular filtration rate 
EGFR 
epidermal growth factor receptor 
EMEA 
European Medicines Agency 
 
ET 
early termination 
 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
IC50 
half maximal inhibitory concentration  
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
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IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IgVH 
immunoglobulin heavy-chain variable 
ILD 
interstitial lung disease  
ITP 
idiopathic thrombocytopenia purpura 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITT 
Intent-to-treat 
IV 
intravenous 
IVIG 
intravenous immunoglobulins 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IWRS 
Interactive Web Response System 
LDH 
lactate dehydrogenase 
LDT 
lymphocyte doubling time 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NDA 
New Drug Application 
NHL 
non-Hodgkin lymphoma 
NI 
non-inferiority 
NK 
natural killer (cells) 
 
 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PFS 
progression free survival 
PI3 
phosphoinositide-3 (kinase) 
PK 
pharmacokinetics 
PML 
progressive multifocal leukoencephalopathy 
 
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QD 
once per day 
QM 
every month 
QTc 
corrected QT interval 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SD 
stable disease or standard deviation 
SEM 
standard error of mean  
SFU 
safety follow-up 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
half life 
TEAE(s) 
treatment-emergent adverse events 
Tmax 
time to maximum drug concentration 
ULN 
upper limit of normal 
Vz/F 
volume of distribution 
WBC 
white blood cell (count) 
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1 
BACKGROUND INFORMATION 
1.1 BTK INHIBITION FOR THE TREATMENT OF CLL 
Chronic lymphocytic leukemia (CLL) is a malignancy of B cells that predominantly affects the 
older population.  Chemoimmunotherapy, in particular the combination of purine analogs 
(eg, fludarabine) with cyclophosphamide and rituximab, has become a standard for the 
treatment of young and/or fit individuals with CLL who require treatment.  However, elderly 
subjects and those with comorbidities are often unable to tolerate combination 
chemoimmunotherapy regimens, or experience inferior clinical outcomes when treated with 
these regimens.  In addition, those subjects who have high risk cytogenetics have inferior 
outcomes and may prove to be refractory to therapy and/or experience short remission 
durations and rapid progression of disease when treated with standard and currently available 
treatment regimens (Hallek 2010, Hillmen 2007).   
In February 2014, ibrutinib (IMBRUVICA®) monotherapy, the first Btk inhibitor developed for 
clinical use, was awarded marketing approval in the United States for the treatment of patients 
with CLL who have had ≥ 1 prior therapy or 17p del.  Approval in Europe was in October 2014 
with an indication for the treatment of patients with CLL who have received ≥ 1 prior therapy or 
as first-line therapy in the presence of 17p deletion or TP53 mutation in patients unsuitable for 
chemoimmunotherapy.  These approvals for ibrutinib were based on data from single-arm 
Phase 2 studies (PCYC 1102/1103) and the randomized Phase 3 study (RESONATE) 
(IMBRUVICA package insert).  In the RESONATE study, which had a median follow up of 
9.4 months, ibrutinib demonstrated improvement in PFS (HR=0.21 all patients; HR=0.25 for 17p 
del; HR=0.14 for 11q del), OS (HR=0.43) and ORR (42.6% vs 4.1%) compared with an active 
comparator, ofatumumab as adjudicated by the IRC.  The progression and survival benefits 
seen with ibrutinib treatment were demonstrated in all subgroup analyses including patients with 
high-risk cytogenetic factors (Byrd 2014).  Longer follow up on the PCYC 1102/1103 study 
shows the median PFS has not been reached with 30 months of ibrutinib treatment as assessed 
by investigators (Brown 2014).  However, subgroup analyses suggest patients with 17p deletion 
(17p del) had the shortest duration of response on ibrutinib treatment with a median duration of 
response of 27 months by investigator assessment (O’Brien 2014a). 
The considerable efficacy observed with ibrutinib is tempered by important safety risks and 
adverse reactions of interest.  The following adverse reactions have been reported for ibrutinib 
(IMBRUVICA package insert): 

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• 
Fatal and non-fatal infections:  25% of patients with mantle cell lymphoma (MCL) and 
26% of patients with CLL had infections Grade ≥ 3.  
• 
Atrial fibrillation and atrial flutter in 6% to 9% of all patients.   
• 
Second primary malignancies in 3% to 16% of all patients.   
• 
Major hemorrhages, which include Grade ≥ 3 bleeding (eg, subdural hematomas, 
gastrointestinal bleeding, hematuria and post-procedural bleeding), in 6% of all patients. 
• 
Diarrhea:  51% of patients with MCL and 63% of patients with CLL had diarrhea, 
including 4% to 5% Grade 3 or 4 diarrhea. 
As mentioned previously, patients with 17p del have the poorest outcome on ibrutinib treatment.  
Of particular note is newly emerging clinical data suggesting a high rate of Richter’s 
transformation with ibrutinib treatment.  O’Brien and colleagues (O’Brien 2014b) report 7.6% 
(11/144) of patients with 17p del developed Richter’s transformation with a median of 13 months 
of follow-up, with 7 of these cases occurring within the first 24 weeks of ibrutinib treatment. 
Chemical optimization, pharmacologic characterization, and toxicologic evaluation have led to 
identification of ACP-196 (also known as acalabrutinib), an orally bioavailable, new chemical 
entity that covalently inhibits Btk and shows encouraging activity and acceptable safety in 
nonclinical studies.  Within the class of Btk inhibitors, acalabrutinib is a more selective inhibitor 
of Btk than ibrutinib.  An improved kinase selectivity profile for acalabrutinib may translate to 
pharmacologic benefits as outlined below: 
• 
Ibrutinib is a potent covalent inhibitor of the epidermal growth factor receptor (EGFR); 
acalabrutinib is not (Section 1.2.2).   
• 
Ibrutinib is a potent covalent inhibitor of Itk kinase.  As such, ibrutinib interferes with 
natural killer (NK) cell-mediated function and anti-tumor activities of therapeutic CD20 
antibodies (Da Roit 2015).  Acalabrutinib does not inhibit Itk.  Consequently, in vitro 
studies show no effect of acalabrutinib on NK cell function (Section 1.2.4) or antitumor 
activities of therapeutic CD20 antibodies (Rajasekaran 2014). 
• 
Ibrutinib is also a potent covalent inhibitor of Txk kinase.  Itk and Txk kinases regulate 
the development of cytotoxic CD8+ T cells (Atherly 2006) and modulate interferon 
gamma release (Takeba 2002).  Acalabrutinib is not a potent inhibitor of Txk.  In vivo 
tumor models show robust expansion of CD8+ T cells with acalabrutinib treatment 
compared with ibrutinib and in vitro T-cell studies show reduced CD8+ T cell viability with 
ibrutinib treatment compared with acalabrutinib (Acerta data on file).  The differential 
potency of acalabrutinib vs ibrutinib on key modulators of T-cell function may lead to 
better clinical outcomes in patients, such as a reduced incidence of infections with 
acalabrutinib treatment. 

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• 
Ibrutinib is associated with bleeding events in patients.  The mechanism for the bleeding 
events is not well understood.  However, ibrutinib impairs thrombus formation in an in 
vivo model at physiologically relevant concentrations; acalabrutinib does not 
(Section 1.2.5).  
The nonclinical and toxicology results of acalabrutinib suggest it may have an improved 
therapeutic window relative to ibrutinib; it may be more readily combined with other agents for 
the treatment of cancer.   
This Phase 3 study will investigate whether acalabrutinib is non-inferior to ibrutinib, based on 
centrally determined, independently reviewed PFS, in subjects with previously treated CLL and 
high-risk prognostic factors (eg, 17p del and 11q del).  In addition, the study aims to evaluate 
safety, tolerability and efficacy, by standard response criteria (Cheson 2012, Hallek 2008), of 
acalabrutinib compared with ibrutinib. 
1.2 PRECLINICAL STUDIES 
Summaries of preclinical studies are provided below.  For more detailed information, please 
refer to the acalabrutinib Investigator Brochure.  
1.2.1 
 
 
 
 
 
 
 
 
 
 
 
1.2.2 Mechanism of Action of Acalabrutinib 
Acalabrutinib was specifically designed to be a more potent and selective inhibitor of Btk to 
avoid off-target side effects seen with other Btk inhibitors.  When profiled against 395 human 
kinases, acalabrutinib was more selective than ibrutinib (Covey 2015).  For additional details, 
refer to the acalabrutinib Investigator Brochure.   
1.2.3 Dog Lymphoma Study 
Spontaneous canine B-cell lymphoma shares many characteristics with human non-Hodgkin 
lymphoma (NHL), including diagnostic classifications and response to Btk inhibition 
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(Honigberg 2010). The life expectancy in untreated animals with aggressive disease is 
~6 weeks, thus enabling rapid assessment of drug efficacy (Vail 2004). Acalabrutinib is currently 
being evaluated in an ongoing study in canine spontaneous B-cell lymphoma.  Fourteen dogs, 
all of which had diffuse large B-cell lymphoma (DLBCL) confirmed by histology, have been 
treated with acalabrutinib for at least 2 weeks.  The dosages have ranged from 2.5 to 20 mg/kg 
QD or BID.  To date, per Veterinary Cooperative Oncology Group criteria for assessment of 
response in peripheral nodal lymphoma (Vail 2010), PRs been observed in 4 of 14 dogs (29%) 
and stable disease (SD) have been observed in 8 of 14 dogs (57%).  No acalabrutinib-related 
AEs have been reported to date in this study.  These findings are preliminary and similar to the 
clinical responses observed with ibrutinib in dogs with spontaneous B-cell lymphoma 
(Honigberg 2010). 
Preliminary results assessing Btk occupancy using a biotin-tagged analogue of acalabrutinib 
show near complete Btk occupancy over 24 hours with BID dosing in canine tumor tissue (Table 
1-1). 
Table 1-1.  Assessment of Acalabrutinib Active-site Occupancy in Fine Needle Aspirates 
of Canine Lymph Node Tumors (N=4) 
Timing 
Dog Identification and Acalabrutinib Dosing Regimen 
DL-10 
DL-12 
DL-14 
DL-16 
5 mg/kg QD 
10 mg/kg BID 
20 mg QD 
20 mg/kg QD 
Btk Occupancy (% versus predose) 
Day 1 (3 hours 
after morning 
dose) 
98% 
99% 
98% 
99% 
Day 7 (before 
morning dose) 
80% 
98% 
77% 
93% 
BID = twice per day; Btk = Bruton tyrosine kinase; QD = once per day 
1.2.4 Acalabrutinib and Antibody-dependent Cell-mediated Cytotoxicity 
Acalabrutinib is not a potent inhibitor of Itk kinase in contrast to ibrutinib.  Itk kinase is required 
for FcR-stimulated NK cell function including calcium mobilization, granule release 
(Khurana 2007), and overall antibody-dependent cell-mediated cytotoxicity (ADCC).  As 
anti-CD20 antibodies like rituximab are standard of care drugs, often as part of combination 
regimens, for the treatment of CD20+ B-cell malignancies, the potential of ibrutinib or 
acalabrutinib to antagonize ADCC was evaluated in vitro.  We hypothesized that Btk inhibitor, 
acalabrutinib, which does not have activity against Itk, may preserve NK cell function and 
therefore synergize rather than antagonize rituximab-mediated ADCC.  Briefly, rituximab-
dependent NK-cell mediated cytotoxicity was assessed using lymphoma cell lines as well as 

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autologous CLL tumor cells.  In vitro NK cell cytokine secretion, degranulation and cytotoxicity 
were assessed by IFN-γ release, CD107a mobilization, and chromium release.   
Ibrutinib—in a dose-dependent manner (0.1 and 1 μM)—inhibited rituximab-induced NK cell 
cytokine secretion (48% p=0.018; 72% p=0.002, respectively).  At 1 μM, acalabrutinib did not 
significantly inhibit cytokine secretion (3.5%).  Similarly, acalabrutinib had no inhibitory effect on 
rituximab-stimulated NK cell degranulation (< 2%) while ibrutinib reduced degranulation by 
~50% (p=0.24).  At a constant NK:target cell ratio (25:1), 1 μM of ibrutinib, but not acalabrutinib, 
reduced lysis of chromium-labeled Raji and autologous CLL tumor cells by ~4-fold.  Therefore, 
acalabrutinib resulted in greater in vitro cytotoxicity of rituximab-coated, chromium-labeled 
lymphoma cells compared with ibrutinib at high NK:target cell ratios.  These results suggest 
acalabrutinib may provide an alternative to ibrutinib for use in combination with antibodies that 
have ADCC as a mechanism of action. 
1.2.5 Acalabrutinib and Thrombus Formation 
Ibrutinib is associated with an increased risk of bleeding (Kamel 2015).  Hence, the effects of 
acalabrutinib and ibrutinib were evaluated on human platelet-mediated thrombosis by using the 
in vivo human thrombus formation in VWFHA1 murine model, which has been previously 
described (Chen 2008).  Purified human platelets were preincubated with various 
concentrations of ibrutinib and acalabrutinib (0.1 µM, 0.5 µM, or 1 µM for each) or dimethyl 
sulfoxide (DMSO) and then administered to VWFHA1 mice followed by laser-induced thrombus 
formation.  Ibrutinib- and acalabrutinib-treated human platelets were fluorescently labeled and 
infused continuously through a catheter inserted into the femoral artery.  Thrombus formation in 
response to laser-induced vascular injury was monitored in real time using 2-channel confocal 
intravital microscopy (as described in Furie 2005) (Figure 1-1).  Upon induction of arteriole injury 
untreated platelets rapidly formed thrombi with a mean (± standard error of mean [SEM]) 
thrombus size of 6,450 ± 292 mm2.  Similarly, acalabrutinib (1 μM) treated platelets formed a 
slightly smaller, but not significantly different thrombi, with a mean thrombus size of 5733 ± 
393 mm2.  In contrast, a significant reduction in thrombus size occurred in platelets pretreated 
with ibrutinib (1 μM), mean size of 2600 ± 246 mm2, representing in a reduction in maximal 
thrombus size by approximately 61% compared with control (P=0.001).  Similar results were 
obtained with platelets pretreated with 500 nM of acalabrutinib or ibrutinib: mean thrombus size 
of 5946 ± 283 mm2 and 2710 ± 325 mm2, respectively.  These preliminary results showing 
reduced thrombus formation for ibrutinib at physiologically relevant concentrations (0.5 to 1 μM) 
may provide some mechanistic background for the Grade ≥ 3 bleeding events (eg, subdural 

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hematoma, gastrointestinal bleeding, hematuria and postprocedural hemorrhage) that have 
been reported ≤ 6% of patients treated with ibrutinib (IMBRUVICA package insert). 
Figure 1-1.  Effect of Acalabrutinib (1 μM) and Ibrutinib (1 μM) on Thrombus Formation 
 
 
1.2.6 Safety Pharmacology  
In vitro and in vivo safety pharmacology studies with acalabrutinib have demonstrated a 
favorable nonclinical safety profile.  

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When screened at 10 μM in binding assays evaluating interactions with 80 known 
pharmacologic targets such as G-protein-coupled receptors, nuclear receptors, proteases, and 
ion channels, acalabrutinib shows significant activity only against the A3 adenosine receptor; 
follow-up dose-response experiments indicated a half-maximal inhibitory concentration (IC50) of 
2.7 µM, suggesting a low clinical risk of off-target effects.   
The in vitro effect of acalabrutinib on human ether-à-go-go-related gene (hERG) channel activity 
was investigated in vitro in human embryonic kidney cells stably transfected with hERG. 
Acalabrutinib inhibited hERG channel activity by 25% at 10 μM, suggesting a low clinical risk 
that acalabrutinib would induce clinical QT prolongation as predicted by this assay. 
Acalabrutinib was well tolerated in standard in vivo Good Laboratory Practices (GLP) studies of 
pharmacologic safety.  A functional observation battery in rats at doses through 300 mg/kg (the 
highest dose level) revealed no adverse effects on neurobehavioral effects or body temperature 
at any dose level.  A study of respiratory function in rats also indicated no treatment-related 
adverse effects at doses through 300 mg/kg (the highest dose level).  In a cardiovascular 
function study in awake telemeterized male beagle dogs, single doses of acalabrutinib at dose 
levels through 30 mg/kg (the highest dose level) induced no meaningful changes in body 
temperature, cardiovascular, or electrocardiographic (ECG) (including QT interval) parameters. 
The results suggest that acalabrutinib is unlikely to cause serious off-target effects or adverse 
effects on critical organ systems. 
1.2.7 Drug-drug Interaction Potential 
For more detailed information on drug-drug interaction potential for acalabrutinib, refer to the 
Investigator Brochure. 
Please refer to Section 6.3 for guidance on drugs that may cause drug-drug interactions. 
1.2.8 In Vivo General Toxicology 
The systemic toxicity of acalabrutinib has been investigated in 6 repeat-dose general toxicology 
studies, 3 with recovery periods, in the rat and the dog.  The pivotal GLP studies were two 
28-day repeat dose studies in Sprague Dawley rats with 32- and 28-day recovery periods, and a 
28-day study in Beagle dogs with a 28-day recovery period.  For details on the results of these 
studies refer to the Investigator Brochure. 

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1.3 CLINICAL STUDIES 
1.3.1 Pharmacokinetics and Pharmacodynamics of Acalabrutinib 
ACE-HV-001 was a PK/pharmacodynamic (PD), dose-ranging, food-effect, and drug-drug 
interaction study evaluating BID and QD dosing for 1 or 2 days in healthy volunteers.  This study 
evaluated the PK/PD of acalabrutinib at various dose levels and regimens.  The starting dose 
for acalabrutinib was 2.5 mg BID.  This study has been completed and no adverse laboratory, 
vital signs, or ECG findings were observed (2.5 to 50 mg BID; 50 to 100 mg QD).  Three AEs 
related to study drug were reported.  Each AE was Grade 1 and resolved without treatment.  
The AEs were constipation (2.5 mg BID), feeling cold (75 mg QD), and somnolence (75 mg 
QD). 
In Part 1, PK properties of acalabrutinib were evaluated after oral administration of 2 daily 
divided doses of 2.5 to 50 mg and a single dose of 100 mg.  Of the 30 subjects evaluated, all 
observed systemic concentrations of acalabrutinib.  Acalabrutinib plasma time to maximum 
concentration (Tmax) values were between 0.5 and 1.0 hour for all dose cohorts and were 
independent of dose level.  The increase in mean maximum observed drug concentration (Cmax) 
values was greater than dose proportional based on the increases of Cmax from the first dose 
administered.  When evaluating AUC0-12, AUC0-24 or AUC0-inf, the mean values increased in a 
dose proportional manner based on the increases of the total dose administered.  Mean half-life 
(t1/2) values ranged from 0.97 to 2.1 hours, and appeared to decrease as the dose increased.  
The mean calculated oral clearance (CL/F: 165 to 219 L/h) and volume of distribution values 
(Vz/F: 233 to 612 L) appeared to be independent of the dose administered. 
Acalabrutinib was not detected in the urine of subjects receiving the 2.5- or 5.0-mg BID doses of 
acalabrutinib.  Acalabrutinib was detected in urine of other subjects (0.4% to 0.6% of dose) and 
amounts increased in a dose-dependent manner. 
In Part 2, the effect of food on the PK of acalabrutinib (75 mg) after a single oral administration 
was evaluated in 6 men and 6 women.  Median acalabrutinib plasma Tmax values were 
increased in the fed state (2.5 hours) relative to the fasted state (0.5 hour).  The mean plasma 
acalabrutinib Cmax fed values decreased to 27.3% of the Cmax values observed in the fasted 
state.  In contrast, the relative AUC exposure of acalabrutinib remained mostly unchanged in 
both states.  This decrease in exposure in not clinically significant.  Therefore, acalabrutinib can 
be taken without regard to meals. 

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In Part 3, the effect of itraconazole on the PK of acalabrutinib (50 mg) after a single oral 
administration was evaluated in 17 subjects.  No difference in acalabrutinib Tmax values was 
observed in the presence or absence of itraconazole. 
Mean acalabrutinib exposures (as assessed by Cmax, AUC0-last, AUC0-24, and AUC0-inf) increased 
in the presence of itraconazole.  The mean plasma acalabrutinib Cmax values increased 3.7-fold 
in the presence of itraconazole.  The mean plasma AUC0-last, AUC0-24, and AUC0-inf values also 
increased between 4.9- to 5.1-fold in the presence of itraconazole. Mean CL/F and Vz/F values 
decreased in the presence of itraconazole (CL/F: 217 vs 44 L/h; Vz/F: 1190 vs 184 L).  No 
differences in half-life values were observed (3.3 vs 2.5 hours). 
The PD of acalabrutinib was evaluated using a Btk occupancy assay and correlated with a 
functional assay that determines the level of Btk inhibition by measuring expression of CD69 
and CD86 on B cells.  A dose-dependent increase in Btk occupancy and corresponding 
decrease in CD69/86 expression was observed in this study.  Full Btk occupancy (≥ 90%) and 
complete CD86 and CD69 inhibition (≥ 90%) occurred at the 75- and 100-mg single dosed 
cohorts 1 to 3 hours after administration.  However, only the 100-mg cohort maintained high Btk 
occupancy (91.5%) and high BCR functional inhibition (CD86: 86 ± 3% and CD69: 78 ± 8%) at 
24 hours.  For subjects receiving a second dose of acalabrutinib 12 hours after the first 
administration, full Btk target occupancy was observed 3 hours after the second dose for the 
50-mg dosed cohort (Btk occupancy 97 ± 4%). 
1.3.2 Clinical Experience of Acalabrutinib in CLL 
Acalabrutinib has been administered to participants in clinical studies, including subjects with 
hematologic malignancies, solid tumors, or rheumatoid arthritis, and participants who are 
healthy volunteers or with mild to moderate hepatic impairment.  No SAEs have been reported 
in the hepatic impairment study or in the healthy volunteer studies.  No expected serious 
adverse reactions have been identified for acalabrutinib to date.  For more detailed information 
on the clinical experience for acalabrutinib, please refer to the Investigator Brochure.   
1.4 SUMMARY AND CONCLUSIONS 
This study will evaluate the safety and activity of a potent, second-generation Btk inhibitor, 
acalabrutinib, versus ibrutinib in subjects with previously treated CLL with high-risk cytogenetics. 
The design and conduct of this study is supported by an understanding of the natural history 
and current therapies for subjects with CLL; knowledge of the activity and safety of the 
first-generation BCR inhibitor (ie, ibrutinib) in subjects with B-cell malignancies; and the 
available nonclinical and clinical information regarding acalabrutinib.  Clinical studies have 

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shown that acalabrutinib is an orally bioavailable Btk inhibitor with fast absorption and rapid 
clearance that maintains optimal target coverage over 24 hours with a dosage of 100 mg BID.  
Acalabrutinib has been well tolerated in healthy volunteers and subjects with CLL or Richter’s 
syndrome.  Despite poor prognostic characteristics in the CLL study population, acalabrutinib 
has induced sustained decreases in lymphadenopathy and provides more rapid reduction 
and/or resolution of lymphocytosis than ibrutinib.  No specific drug-related toxicity has been 
identified to date for acalabrutinib. 
2 
STUDY RATIONALE   
This randomized controlled Phase 3 study is designed to assess whether acalabrutinib is 
non-inferior to ibrutinib with respect to PFS in subjects with previously treated CLL who have 
high-risk prognostic factors per NCCN guidelines (NCCN Version 1.2016). 
2.1 DOSE SELECTION RATIONALE FOR ACALABRUTINIB 
Preliminary PK data from ACE-CL-001 suggests a plateauing of exposure after 250 mg QD.  PD 
results from this study also suggest Btk resynthesis occurs in malignant B cells within 24 hours.  
While all dosages evaluated show full Btk occupancy 4 hours after dosing, the 100-mg BID 
cohort shows full target coverage over 24 hours (≥ 97% Btk occupancy at 4 and 24 hours).  
Therefore, based on PK/PD and efficacy results of the Phase 1/2 study, acalabrutinib 100 mg 
BID will be evaluated in this Phase 3 study.  This regimen is expected to provide optimal target 
coverage with lower exposure levels (Cmax) of acalabrutinib to avoid any potential off-target 
effects from acalabrutinib. 
2.2 NON-INFERIORITY DESIGN AND IBRUTINIB AS COMPARATOR 
Assessment of the non-inferiority of acalabrutinib relative to ibrutinib, the reference Btk inhibitor, 
as therapy for patients with previously treated CLL is the most appropriate approach to 
describing the therapeutic characteristics of acalabrutinib in this treatment setting.  Consistent 
with increasing scientific discussion regarding comparative effectiveness studies in oncology 
(Hahn 2012), such a study provides efficacy and safety information that is most relevant to 
patients, clinicians, regulatory authorities, and health economists in addressing the question of 
whether the clinical benefit of acalabrutinib can reasonably substitute for that of ibrutinib.  The 
design of such a study offers many strengths that conform to the FDA draft guidance regarding 
non-inferiority studies (FDA March 2010): 
• 
The benefit:risk of ibrutinib has been established in a large (N=391), well-conducted, 
randomized, controlled registration study evaluating its therapeutic efficacy relative to 

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ofatumumab (Byrd 2014, Brown 2014).  This pivotal trial of ibrutinib offers a strong 
foundation upon which to evaluate the non-inferiority (NI) of acalabrutinib. 
o The ibrutinib study showed a large treatment difference in PFS and OS between 
ibrutinib and an active comparator, thus providing a basis for a non-inferiority 
margin in the planned trial of acalabrutinib. 
o In the registration study, ibrutinib therapy was associated with a very high ORR 
(43% to 68% by independent and investigator assessment, respectively), thus 
providing compelling supportive evidence of drug effectiveness that supplements 
the ibrutinib treatment effect on PFS. 
o Accrual to the ibrutinib trial occurred between June 2012 and April 2013, 
ensuring the relevance of the findings to the current practice of oncology and 
increasing the prospect of a valid constancy assumption between the former 
ibrutinib trial and the proposed acalabrutinib study.  
o The ibrutinib study data have been subjected to thorough FDA and European 
Medicines Agency (EMEA) review for product labeling, ensuring the veracity of 
the results as the basis for considering a new comparative trial with acalabrutinib. 
• 
Ibrutinib and acalabrutinib are covalent inhibitors of Btk and thus offer similar pharmacology 
as the basis for comparative efficacy and safety. 
• 
The proposed trial addresses the single-agent effects of each drug, thereby avoiding 
confounding factors that might arise from co-administration of other drugs for the therapy of 
CLL. 
• 
Due to greater selectivity for Btk inhibition, acalabrutinib may offer a safety profile distinct 
from ibrutinib that can be directly evaluated in the context of the proposed trial.   
The planned NI margin is designed to evaluate the unique benefit:risk profile of an alternative 
Btk inhibitor, while ensuring preservation of substantial benefit of the reference drug, ibrutinib. 
2.3 SELECTION OF THE PATIENT POPULATION 
The presence of 17p del or 11q del is associated with the worst clinical outcomes in patients 
with CLL (Gonzalez 2011, NCCN Version 1.2016) with a median survival of < 2 years in the 
relapsed/refractory setting.  Treatment with chemoimmunotherapy for patients with CLL and 17p 
del is suboptimal (eg, a median PFS of 11.3 months has been reported for front-line fludarabine, 
cyclophosphamide and rituximab [Hallek 2010]).  The recent development of agents targeting 
BCR signaling has provided substantial improvement in clinical outcome for this aggressive 

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form of the disease.  However, as noted in Section 1.1, patients with 17p del have the poorest 
outcome on ibrutinib therapy and seem to have a high rate of Richter’s transformation.   
Study ACE-CL-006 will use eligibility criteria that are substantially similar to those used in the 
RESONATE study in addition to limiting enrollment to patients with high-risk prognostic factors.  
This will allow testing of the hypothesis that a more selective Btk inhibitor may lead to greater 
clinical benefit in high-risk patients including a reduction in the incidence of Richter’s 
transformation.   
2.4 BENEFIT/RISK 
Acalabrutinib is a potent, orally available small-molecule inhibitor of Btk.  In the Phase 1/2 study 
of acalabrutinib in subjects with CLL or Richter’s syndrome (ACE-CL-001), no dose-limiting 
toxicities (DLTs) have been identified at dosages of ≤ 400 mg QD or 100 to 200 mg BID.  To 
date, no specific drug-related toxicity for acalabrutinib has been identified.  The ORR in the 
evaluable subjects in ACE-CL-001 is currently 94% with some subjects obtaining PRs after only 
2 cycles of therapy.  In summary, the preliminary data suggest that acalabrutinib is well 
tolerated and has robust activity as a single agent in the treatment of subjects with relapsed or 
refractory CLL including those with 17p del or 11q del.  In addition, PK/PD results show the 
100-mg BID regimen produces optimal target coverage over 24 hours (ie, more complete 
coverage of de novo synthesis of Btk), which may provide greater clinical benefit than the QD 
regimen of ibrutinib.   
As described previously, ibrutinib is approved for the treatment of patients with previously 
treated CLL and patients with CLL with 17p del.  The most common adverse reactions (≥ 20%) 
in patients with CLL treated with ibrutinib are thrombocytopenia, neutropenia, diarrhea, anemia, 
fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia 
(IMBRUVICA package insert).  Note: For detailed information on the management of these 
adverse reactions refer to the IMBRUVICA package insert. 
3 
STUDY OBJECTIVES 
3.1 PRIMARY OBJECTIVE  
To assess whether acalabrutinib is non-inferior to ibrutinib with respect to PFS, based on IRC 
assessment, in subjects with relapsed or refractory CLL with high-risk prognostic markers.   

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3.2 SECONDARY OBJECTIVES 
3.2.1 Efficacy Objectives 
To evaluate the benefit:risk of acalabrutinib versus ibrutinib in terms of: 
• 
Grade ≥ 3 infections  
• 
Richter’s transformation 
• 
Atrial fibrillation  
• 
OS 
3.2.2 Safety Objective 
The safety and tolerability including adverse events (AEs) of interest and laboratory 
assessments 
3.2.3 Exploratory Objectives 
 
 
 
 
 
 
 
 
 
 
4 
STUDY DESIGN 
This randomized, multicenter (ie, approximately 200 global centers), open-label, non-inferiority 
Phase 3 study is designed to evaluate the efficacy and safety of acalabrutinib versus ibrutinib in 
subjects with relapsed or refractory CLL who have high-risk prognostic markers (eg, 17p del 
and/or 11q del) per NCCN guidelines (NCCN Version 1.2016). 
CCI

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Figure 4-1.  Study Schema 
 
 
Approximately 500 eligible subjects will be randomized in a 1:1 ratio into 2 arms to receive 
either acalabrutinib 100 mg BID (Arm A; N=250) or ibrutinib 420 mg QD (Arm B; N=250). 
This study will use an IWRS for randomization.  Randomization will be used to minimize bias in 
the assignment of subjects to treatment groups, to increase the likelihood that known and 
unknown subject attributes (eg, demographic and baseline characteristics) are evenly balanced, 
and to enhance the validity of statistical comparisons across treatment groups.   
Randomization will be performed stratified by the following factors: 
• 
Presence of 17p del 
• 
ECOG performance status (ECOG = 2 versus ECOG ≤1) 
• 
Number of prior therapies (1-3 versus ≥ 4) 
 
Subject participation will include a Screening Phase, a Treatment Phase, a Post-treatment 
Phase, and a Post-disease Progression Phase.  The Screening Phase will last up to 28 days 
before first dose of study drug, during which the subject’s eligibility and baseline characteristics 
will be determined.  The Treatment Phase will last from randomization until study drug 
discontinuation.  Subjects will receive study drug daily until disease progression or unacceptable 
toxicity.  The Post-treatment Phase will follow subjects for disease progression or death, if they 

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discontinued study drug treatment due to unacceptable toxicity or any reason.  Subjects who 
withdraw consent or are lost to follow will not be followed for disease progression or survival. 
The Post-disease Progression Phase will begin once the IRC has confirmed that a subject has 
progressive disease. In this phase, subsequent anticancer therapy with start date of therapy, 
IWCLL indication for treatment initiation, additional malignancy occurrence, and subject survival 
status will be recorded.  The Post-disease Progression Phase will continue until death, lost to 
follow up, consent withdrawal, or study closure, whichever occurs first.  Survival status must be 
assessed, and the date of death must be documented for each subject randomized to 
treatment, regardless of whether or not the subject received treatment.    
Assessment of response and progression will be conducted in accordance with the IWCLL 2008 
criteria with the modification that treatment-related lymphocytosis in the absence of other signs 
or symptoms of disease progression will not be considered progressive disease.  The 
Investigator will evaluate sites of disease by radiologic imaging (primary), physical examination 
or other procedures as necessary, review of hematology and serum chemistry results, and 
disease-related symptoms.  The same methods of assessment used to assess disease at 
baseline should be used throughout the study.  A central laboratory will perform all hematology 
testing for the primary endpoint analysis.  The primary efficacy analysis will be based on 
assessment from an IRC.  As part of the IRC review, radiographic evaluations assessed by 
independent central radiologists and hematology results from a central laboratory will be 
provided.  Detailed procedures will be described in a separate charter.  An independent DMC 
will be formed and constituted according to regulatory agency guidelines.  Detailed information 
regarding the composition of the DMC and detailed DMC procedures will be provided in a 
separate charter.  The DMC will review the safety data periodically and provide 
recommendations according to the charter. 
The end of trial is defined as the point when the last subject on study has completed 
 
of follow up or has been lost of follow up, whichever occurs first.  In the event that a rollover or 
safety extension study is available, subjects who remain in this study (Study ACE-CL-006) may 
be transitioned to such a study.  Once all eligible subjects are moved to a rollover or safety 
extension study, Study ACE-CL-006 would be considered closed.  Any subject who would be 
proposed to move to a rollover or safety extension study would be asked to sign an ICF for the 
rollover or safety extension study.  The rollover or safety extension study would ensure 
treatment continuation with visit assessments per its protocol.   
CCI

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5 
SELECTION OF SUBJECTS 
5.1 INCLUSION CRITERIA 
Eligible subjects will be considered for inclusion in this study if they meet all of the following 
criteria: 
1. Men and women ≥ 18 years of age. 
2. ECOG performance status of 0 to 2. 
3. Diagnosis of CLL that meets published diagnostic criteria (Hallek 2008): 
a. Monoclonal B-cells (either kappa or lambda light chain restricted) that are 
clonally co-expressing ≥ 1 B-cell marker (CD19, CD20, or CD23) and CD5. 
b. Prolymphocytes may comprise ≤ 55% of blood lymphocytes. 
c. Presence of ≥ 5 x 109 B lymphocytes/L (5000 µL) in the peripheral blood (at any 
point since diagnosis); this applies to CLL only. 
4. Must have ≥ 1 of the following high-risk prognostic factors:   
a. Presence of 17p del by central laboratory. 
b. Presence of 11q del by central laboratory. 
5. Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment: 
a. Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelets 
< 100,000/μL). 
b. Massive (ie, ≥ 6 cm below the left costal margin), progressive, or symptomatic 
splenomegaly 
c. Massive nodes (ie, ≥ 10 cm in the longest diameter), progressive, or symptomatic 
lymphadenopathy. 
d. Progressive lymphocytosis with an increase of > 50% over a 2-month period or a 
LDT of < 6 months.  LDT may be obtained by linear regression extrapolation of 
ALC obtained at intervals of 2 weeks over an observation period of 2 to 
3 months. In subjects with initial blood lymphocyte counts of < 30 X 109/L 
(30,000/μL), LDT should not be used as a single parameter to define indication 
for treatment.  In addition, factors contributing to lymphocytosis or 
lymphadenopathy other than CLL (eg, infections) should be excluded. 
e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to 
standard therapy. 
f. Constitutional symptoms documented in the subject’s chart with supportive 
objective measures, as appropriate, defined as ≥ 1 of the following 
disease-related symptoms or signs: 
i. Unintentional weight loss ≥ 10% within the previous 6 months before 
Screening. 
ii. Significant fatigue (ie, ECOG performance status 2 or worse; inability to 
work or perform usual activities). 

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iii. Fevers > 100.5°F or 38.0°C for ≥ 2 weeks before Screening without 
evidence of infection. 
iv. Night sweats for > 1 month before Screening without evidence of 
infection. 
6. Must have received ≥ 1 prior therapies for CLL. 
8. Meet the following laboratory parameters: 
a. ANC ≥ 750 cells/μL (0.75 x 109/L) or ≥ 500 cells/μL (0.50 x 109/L) in subjects with 
documented bone marrow involvement, and independent of growth factor 
support 7 days before assessment. 
b. Platelet count ≥ 30,000 cells/μL (30 x 109/L) without transfusion support 7 days 
before assessment. Subjects with transfusion-dependent thrombocytopenia are 
excluded. 
c. Serum AST/SGOT and ALT/SGPT ≤ 3.0 x ULN. 
d. Total bilirubin ≤ 1.5 x ULN. 
e. Estimated creatinine clearance (ie, eGFR using Cockcroft-Gault) ≥ 30 mL/min. 
9. Able to receive all outpatient treatment, all laboratory monitoring, and all radiologic 
evaluations at the institution that administers study drug for the entire study. 
10. Women who are sexually active and can bear children must agree to use highly effective 
forms of contraception while on the study and for 2 days after the last dose of 
acalabrutinib or 90 days after the last dose of ibrutinib, whichever is longer.  Highly 
effective forms of contraception are defined in Section 6.2.11.  
11. Men who are sexually active and can beget children must agree to use highly effective 
forms of contraception during the study and for 2 days after the last dose of acalabrutinib 
or 90 days after the last dose of ibrutinib, whichever is longer.  Highly effective forms of 
contraception are defined in Section 6.2.11. 
12. Men must agree to refrain from sperm donation during the study and for 2 days after the 
last dose of acalabrutinib or 90 days after the last dose of ibrutinib, whichever is longer. 
13. Must be willing and able to adhere to the study visit schedule, understand and comply 
with other protocol requirements, and provide written informed consent and authorization 
to use protected health information (in accordance with national and local patient privacy 
regulations).  Note vulnerable subjects, as defined in the International Conference on 
Harmonisation (ICH) GCP, are not allowed on this protocol (eg, prisoners or 
institutionalized subjects). 
5.2 EXCLUSION CRITERIA 
Subjects will be ineligible for this study if they meet any of the following criteria: 
1. Known CNS lymphoma or leukemia. 
2. Known prolymphocytic leukemia or history of, or currently suspected, Richter’s 
syndrome. 
3. Uncontrolled AIHA or ITP defined as declining hemoglobin or platelet count secondary to 
autoimmune destruction within the screening period or requirement for high doses of 
steroids (> 20 mg daily of prednisone daily or equivalent). 

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4. Prior exposure to ibrutinib or to a BCR inhibitor (eg Btk or PI3 kinase or Syk inhibitors) or 
a BCL-2 inhibitor (eg, ABT-199). 
5. Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or 
investigational drug within 30 days before first dose of study drug. 
6. Corticosteroid use > 20 mg within 1 week before first dose of study drug, except as 
indicated for other medical conditions such as inhaled steroid for asthma, topical steroid 
use, or as premedication for administration of study drug or contrast.  For example, 
subjects requiring steroids at daily doses > 20 mg prednisone equivalent systemic 
exposure daily, or those who are administered steroids for leukemia control or white 
blood cell count lowering are excluded. 
7. Prior radio- or toxin-conjugated antibody therapy. 
8. Prior allogeneic stem cell or autologous transplant. 
9. Major surgery within 4 weeks before first dose of study drug. 
10. History of prior malignancy except for the following: 
a. Malignancy treated with curative intent and with no evidence of active disease 
present for more than 3 years before Screening and felt to be at low risk for 
recurrence by treating physician.  
b. Adequately treated lentigo maligna melanoma without current evidence of 
disease or adequately controlled non-melanomatous skin cancer 
c. Adequately treated cervical carcinoma in situ without current evidence of disease 
11. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
congestive heart failure, or myocardial infarction within 6 months of screening, or any 
Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional 
Classification, or QTc > 480 msec at screening. 
12. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or small bowel or gastric bypass, 
symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. 
13. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as 
exhibiting ongoing signs/symptoms related to the infection and without improvement, 
despite appropriate antibiotics or other treatment) or ongoing intravenous anti-infective 
treatment. 
14. Known history of infection with HIV. 
15. Serologic status reflecting active hepatitis B or C infection.  Subjects with hepatitis B 
core antibody positive who are surface antigen negative or who are hepatitis C antibody 
positive will need to have a negative polymerase chain reaction (PCR) result before 
randomization.  Those who are hepatitis B surface antigen positive or hepatitis B PCR 
positive and those who are hepatitis C PCR positive will be excluded. 
16. History of stroke or intracranial hemorrhage within 6 months before randomization. 
17. History of bleeding diathesis (eg, hemophilia, von Willebrand disease). 
18. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists 
(eg, phenprocoumon) within 7 days of first dose of study drug. 
19. Requires treatment with a strong CYP3A inhibitor/inducer. 

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20. Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). 
21. Breastfeeding or pregnant. 
22. Concurrent participation in another therapeutic clinical trial. 
23. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before 
screening 
 
6 
DOSAGE AND ADMINISTRATION 
6.1 IDENTIFICATION OF INVESTIGATIONAL PRODUCT 
6.1.1 Acalabrutinib 
Acalabrutinib is provided as hard gelatin capsules for oral administration.  The capsules are 
packaged in opaque high-density polyethylene (HDPE) plastic bottles with labels bearing the 
appropriate label text as required by governing regulatory agencies.  The drug product is 
manufactured for Acerta Pharma by a contract manufacturer.  All formulation excipients are 
compendial and are commonly used in oral formulations. 
Refer to the Investigator Brochure for additional information regarding the drug product to be 
used in this study. 
6.1.2 IMBRUVICA (Ibrutinib) 
This study will use commercially available ibrutinib.  The Sponsor will either directly supply sites 
with ibrutinib or the sites will be reimbursed to prescribe ibrutinib; this will be detailed separately 
in each site’s clinical trial agreement.   
Ibrutinib is provided as 140-mg capsules or tablets. Refer to IMBRUVICA approved label for 
details. 
6.2 DRUG PREPARATION AND ADMINISTRATION 
6.2.1 Acalabrutinib 
Investigators are prohibited from supplying acalabrutinib to any subjects not properly enrolled in 
this study.  The investigator must ensure that subjects receive acalabrutinib only from personnel 
who fully understand the procedures for administering the drug. 
Acalabrutinib is intended to be administered orally BID (with the second daily dose 11 to 
13 hours after first dose) with 8 ounces (approximately 240 mL) of water.  The capsules should 
be swallowed intact and subjects should not attempt to open capsules or dissolve them in liquid.   

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If a dose is missed, it can be taken up to 3 hours after the scheduled time with a return to the 
normal schedule for the next dose.  If it has been > 3 hours, the dose should not be taken and 
the subject should take the next dose at the scheduled time.  The missed dose will not be made 
up and must be returned to the site at the next scheduled visit. 
6.2.2 Assessment of Toxicity 
The evaluation of potential treatment-induced toxicity in subjects with advanced CLL may be 
quite difficult requiring careful consideration of the manifestations of the underlying disease, as 
well as adverse reactions to the therapy under study.  Some of the conventional criteria for 
toxicity are not applicable especially under circumstances of progressive bone marrow failure 
from the CLL itself.  Dose modifications for hematologic toxicity in subjects with CLL must 
consider the increased frequency of hematologic compromise at the initiation of therapy.  
Therefore the standard criteria used for solid tumors are difficult to be applied directly; many 
subjects would be considered to have Grade 2 to 4 hematologic toxicity at presentation. 
As a consequence, dose modification decisions for subjects with cytopenia (below the lower 
limit of the normal range) at baseline will be based on the IWCLL 2008 grading scale for 
hematologic toxicity in CLL studies (see Appendix E).   
For dose modifications or discontinuation guidance of acalabrutinib in Arm A, see Section 6.2.4.  
For dose modifications or discontinuation guidance of ibrutinib in Arm B, see Section 6.2.9. 
6.2.3 Dose Delays for Acalabrutinib  
Treatment with acalabrutinib should be held for any unmanageable, potentially study drug-
related toxicity that is Grade ≥ 3 in severity.  Any other clinically important events where dose 
delays may be considered appropriate by the investigator must be discussed with the Medical 
Monitor.  Study drug may be held for a maximum of 28 consecutive days from expected dose 
due to toxicity.  Study treatment should be discontinued in the event of a toxicity lasting 
> 28 days, unless reviewed and approved by the Medical Monitor. 
Note: temporary withholding of study drug for as little as 7 days can cause a transient 
worsening of disease and/or of constitutional symptoms.  Refer to Section 8.1 for more 
information on assessing disease progression under these circumstances. 
6.2.4 Dose Modification and Discontinuation for Acalabrutinib 
Treatment-related Lymphocytosis 
Treatment-related lymphocytosis is defined as ALC > 5000/μL and an increase above baseline, 
and is associated with agents known to inhibit BCR (Hallek 2008, NCCN Version 1.2016, 

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Cheson 2012).  Given the known mechanism of action of BCR-inhibiting agents including 
ibrutinib, treatment-related lymphocytosis is an expected and frequent phenomenon observed 
with initiation (or re-initiation) of Btk inhibitors.  Specifically, the IMBRUVICA approved label 
states an increase in lymphocyte counts (≥ 50% increase from baseline and above absolute 
lymphocyte count of 5,000/μL) occurred in 77% of subjects (N=195) in the pivotal Phase 3 CLL 
study.  The onset of lymphocytosis occurred during the first month of ibrutinib therapy and 
resolved by a median of 23 weeks (range: 1 to 104+ weeks).  Asymptomatic treatment-related 
lymphocytosis should not be considered an AE and subjects should remain on study treatment.  
A high number of circulating malignant cells (≥ 400,000/μL) may confer increased risk; these 
subjects should be closely monitored.  Administer supportive care such as hydration and/or 
leukophoresis as indicated.  Acalabrutinib may be temporarily held and the Medical Monitor 
should be contacted. 
The actions in Table 6-1 should be taken for the following toxicities: 
• 
Grade 4 ANC (< 500/μL) for > 7 days (Neutrophil growth factors are permitted per ASCO 
guidelines [Smith 2015] and use must be recorded on the case report form [CRF]). 
• 
Grade 3 platelet decreases in presence of significant bleeding. 
• 
Grade 4 platelet decreases. 
• 
Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal antiemetic 
and/or anti-diarrheal therapy.  
• 
Any other Grade 4 toxicity or unmanageable Grade 3 toxicity. 
Table 6-1.  Drug Discontinuation Actions for Acalabrutinib 
Occurrence 
Action 
1st - 2nd 
Hold acalabrutinib until recovery to Grade ≤ 1 or baseline; may restart at 
original dose level 
3rd 
Hold acalabrutinib until recovery to Grade ≤ 1 or baseline; restart at one dose 
level lower (100 mg once daily) 
4th 
Discontinue acalabrutinib 
 
Any changes to the dosing regimen must be recorded in the Dosage Administration CRF. 
If acalabrutinib is reduced for apparent treatment-related toxicity, the dose need not be 
re-escalated, even if there is minimal or no toxicity with the reduced dose.  However, if the 
subject tolerates a reduced dose of acalabrutinib for ≥ 4 weeks then the dose may be increased 
to the next higher dose level, at the discretion of the investigator.  Such re-escalation may be 

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particularly warranted if further evaluation reveals that the AE that led to the dose reduction was 
not treatment-related.  However, the maximum dose of acalabrutinib is 100 mg BID for this 
protocol. 
Any changes to the dosing regimen must be recorded in the Dosage Administration CRF. 
6.2.5 Risks Associated with Acalabrutinib Treatment 
The following summarizes the experience with acalabrutinib in hematological cancer studies.  
Full details regarding the clinical safety of acalabrutinib are presented in Sections 5 and 6 of the 
acalabrutinib Investigator Brochure. 
 Reference Safety Information 
For the purpose of reporting AEs and serious adverse events (SAEs): 
The Investigator Brochure contains the Reference Safety Information (RSI) for 
acalabrutinib. 
 Hemorrhage  
Serious hemorrhagic events, including fatal events, have occurred in clinical trials with 
acalabrutinib.  
Patients receiving antithrombotic agents may be at increased risk of hemorrhage.  Use caution 
with antithrombotic agents and consider additional monitoring for signs of bleeding when 
concomitant use is medically necessary.  As a precaution, it is suggested that acalabrutinib be 
withheld for at least 3 days pre- and post-surgery.  
Patients with hemorrhage should be managed per institutional guidelines with supportive care 
and diagnostic evaluations or as clinically indicated. 
 Infections 
Serious infections (bacterial, viral, and fungal), including fatal events, have occurred in clinical 
studies with acalabrutinib.  The most frequent reported Grade ≥3 infection was pneumonia 
(preferred term).  
Consider prophylaxis in subjects who are at increased risk for opportunistic infections.  Subjects 
should be monitored for signs and symptoms of infection and treated as medically appropriate.  
Refer to Section 6.2.5.3.1 and Section 7.1 for additional information and monitoring guidance for 
viral hepatitis and Section 6.2.5.3.2 for additional information and management guidance for 
signs and symptoms of PML. 

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 HEPATITIS B VIRUS REACTIVATION  
Cases of hepatitis B virus (HBV) reactivation have occurred in clinical studies with acalabrutinib.  
Therefore, subjects who are hepatitis B core antibody (anti-HBc) positive, or have a known 
history of HBV infection, should be monitored every 3 months with a quantitative PCR test for 
HBV DNA.  Monitoring should continue until 12 months after last dose of study drug(s).  Any 
subject with a rising viral load (above lower limit of detection) should discontinue study drug and 
have antiviral therapy instituted and a consultation with a physician with expertise in managing 
hepatitis B.  Insufficient data exist regarding the safety of resuming acalabrutinib in subjects who 
develop HBV reactivation.   
 PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY 
Cases of progressive multifocal leukoencephalopathy (PML) have occurred in clinical studies 
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): 
• 
Neurologic consultation 
• 
Brain magnetic resonance imaging (MRI) 
• 
Polymerase chain reaction analysis for John Cunningham 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 patients treated with acalabrutinib.  Monitor blood counts as specified in the 
schedule of assessments and as medically appropriate.  Please refer to Sections 6.2.3 and 
6.2.4 for study drug modification guidance.  Patients with cytopenias should be managed 
according to institutional guidelines or as clinically indicated. 
 Second Primary Malignancies   
Second primary malignancies, including solid tumors and skin cancers, have been reported in 
subjects treated with acalabrutinib.  The most frequent second primary malignancy was skin 
cancer (basal cell carcinoma).  Subjects should be monitored for signs and symptoms of 
malignancy.  Subjects who develop a second primary malignancy should be managed 

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according to institutional guidelines with diagnostic evaluations as clinically indicated, and it may 
be necessary for subjects to permanently discontinue study treatment.  Continuation of 
acalabrutinib treatment should be discussed with the medical monitor.  Refer to Section 7.2.2.4 
for second primary malignancy reporting guidance. 
 Atrial Fibrillation 
Atrial fibrillation or flutter has occurred in clinical studies with acalabrutinib, particularly in 
subjects with cardiac risk factors of hypertension, diabetes mellitus, acute infections, or a 
previous history of atrial fibrillation.  
Monitor for symptoms of atrial fibrillation and atrial flutter (e.g., palpitations, dizziness, syncope, 
chest pain, dyspnea) and obtain an ECG as clinically indicated.  Patients with atrial fibrillation 
should be managed per institutional guidelines with supportive care and diagnostic evaluations 
as clinically indicated. 
6.2.6 IMBRUVICA (Ibrutinib) 
Refer to the United States IMBRUVICA approved label as a reference; refer to country-specific 
labels for detailed product information, dosage and administration, dose interruptions and 
modifications, and precautions and adverse reactions. 
6.2.7 Dosage Regimen and Administration for Ibrutinib 
Ibrutinib 420 mg is taken QD (three 140-mg capsules or tablets once daily).  Capsules or tablets 
should be taken orally with 8 ounces (approximately 240 mL) of water (avoid grapefruit juice and 
Seville orange juice due to CYP3A inhibition).  The capsules or tablets should be swallowed 
intact and subjects should not attempt to open capsules or dissolve them in water.   
6.2.8 Dose Delays for Ibrutinib 
Treatment with ibrutinib should be held for any unmanageable, potentially study drug-related 
toxicity that is Grade ≥ 3 in severity. Any other clinically important events where dose delays 
may be considered appropriate by the investigator must be discussed with the Medical Monitor. 
Study drug may be held for a maximum of 28 days from expected dose due to toxicity.  Study 
treatment should be discontinued in the event of a toxicity lasting > 28 days, unless reviewed 
and approved by the Medical Monitor. 
Note: temporary withholding of study drug for as little as 7 days can cause a transient 
worsening of disease and/or of constitutional symptoms.  Refer to Section 8.1 for more 
information on assessing disease progression under these circumstances. 

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6.2.9 Dose Modification and Discontinuation for Ibrutinib 
The actions in Table 6-2 should be taken for the following toxicities: 
• 
Grade 4 ANC (< 500/μL) for > 7 days (Neutrophil growth factors are permitted per ASCO 
guidelines [Smith 2015] and use must be recorded on the CRF). 
• 
Grade 3 platelet decreases in presence of significant bleeding. 
• 
Grade 4 platelet decreases. 
• 
Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal antiemetic 
and/or anti-diarrheal therapy 
• 
Any other Grade 4 toxicity or unmanageable Grade 3 toxicity. 
 
Table 6-2.  Dose Discontinuation Actions for Ibrutinib 
Occurrence 
Action 
1st  
Hold ibrutinib until recovery to Grade ≤ 1 or baseline; may restart at original 
dose level (420 mg daily) 
2nd 
Hold ibrutinib until recovery to Grade ≤ 1 or baseline; may restart at 280 mg 
daily 
3rd 
Hold ibrutinib until recovery to Grade ≤ 1 or baseline; may restart at 140 mg 
daily 
4th 
Discontinue ibrutinib 
 
Any changes to the dosing regimen must be recorded in the Dosage Administration CRF. 
Note:  If local regulations require following local prescribing information for dose 
modifications/discontinuation, and they differ from the aforementioned, then the local regulations 
should be followed. 
6.2.10 Risks Associated with Ibrutinib Treatment 
Refer to the IMBRUVICA approved label for precautions including information on withholding 
ibrutinib 3 to 7 days before and after surgery and treatment-related lymphocytosis.  In addition, 
the following warnings and precautions apply to ibrutinib treatment: 
 
Hemorrhage 
Grade ≥ 3 bleeding events (intracranial hemorrhage, subdural hematoma, gastrointestinal 
bleeding, hematuria and postprocedural hemorrhage) have occurred in ≤ 6% of patients.  
Bleeding events of any grade, including bruising and petechiae, occurred in approximately half 
the patients treated with ibrutinib. 

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Infections 
Fatal and non-fatal infections have occurred with ibrutinib therapy.  Twenty-five percent of 
patients with MCL and 26% of patients with CLL had infections Grade ≥ 3. 
 HEPATITIS B VIRUS REACTIVATION 
Cases of hepatitis B virus (HBV) reactivation have been observed in post-approval use of 
ibrutinib.  Therefore, subjects who are anti-HBc positive, or have a known history of HBV 
infection, should be monitored every 3 months with a quantitative PCR test for HBV DNA. 
Monitoring should continue until 12 months after last dose of study drug(s). Any subject with a 
rising viral load (above lower limit of detection) should discontinue study drug and have antiviral 
therapy instituted and a consultation with a physician with expertise in managing hepatitis B.  
Insufficient data exist regarding the safety of resuming ibrutinib in subjects who develop HBV 
reactivation. 
 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias, including neutropenia (range, 23% to 29%), 
thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%), occurred in patients 
treated with ibrutinib. 
 
Atrial Fibrillation 
Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with 
ibrutinib, particularly in patients with cardiac risk factors, acute infections, and a previous history 
of atrial fibrillation.  
 
Hypertension 
Hypertension has occurred in 6% to 17% of patients treated with ibrutinib with a median time to 
onset of 4.6 months (range: 0.03 to 22 months). 
 
Second Primary Malignancies 
Other malignancies (range: 3% to 16%) including non-skin carcinomas (range: 1% to 4%) have 
occurred in patients treated with ibrutinib. The most frequent second primary malignancy was 
nonmelanoma skin cancer (range: 2% to 13%). 

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Tumor Lysis Syndrome 
Tumor lysis syndrome has been reported with ibrutinib therapy.  Monitor patients closely and 
take appropriate precautions in patients at risk for tumor lysis syndrome (eg, high tumor 
burden). 
 
Cerebrovascular Accidents  
Cases of cerebrovascular accident (CVA), transient ischemic attack, and ischemic stroke 
including fatalities have been reported with the use of ibrutinib, with and without concomitant 
atrial fibrillation and/or hypertension.  Monitor patients closely for signs and symptoms 
compatible with CVA events.  
 
Interstitial Lung Disease  
Cases of interstitial lung disease (ILD) have been reported in patients treated with IMBRUVICA.  
Monitor patients for pulmonary symptoms indicative of ILD.  
 
Leukostasis  
Cases of leukostasis have been reported in patients treated with IMBRUVICA.  A high number 
of circulating lymphocytes (>400,000/mcL) may confer increased risk.  
 
Embryo-fetal Toxicity   
Based on findings in animals, ibrutinib can cause fetal harm when administered to a pregnant 
woman. 
6.2.11 Reproductive Toxicity 
Definition of Women of Non-reproductive Potential:  
Women will be considered of non-reproductive potential if they are either:  
(1) Postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle-stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a post-menopausal state in women not 
using hormonal contraception or hormonal replacement therapy.  In the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening;  

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OR  
(3) Have a congenital or acquired condition that prevents childbearing. 
 
Highly Effective Methods of Contraception‡  
Highly effective methods of contraception (to be used during heterosexual activity) are defined 
as methods that can achieve a failure rate of <1% per year when used consistently and 
correctly.  Such methods include:  
• 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation, which may be oral, intravaginal, or transdermal  
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation, which may 
be oral, injectable, or implantable  
• 
Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)  
• 
Bilateral tubal occlusion  
• 
Vasectomy of a female subject’s male partner (with medical assessment and confirmation of 
vasectomy surgical success)  
• 
Sexual abstinence† (only if refraining from heterosexual intercourse during the entire period 
of risk associated with the study treatments)  
 
Hormonal contraception may be susceptible to interaction with study or other drugs, which may 
reduce the efficacy of the contraception method. 
 †Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and IECs/IRBs.  Periodic abstinence (eg, calendar, 
ovulation, sympto-thermal, and post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does 
not qualify as an acceptable method of contraception for subjects participating at sites in this 
country/region. 
Developmental and reproductive toxicology studies in rats have not identified acalabrutinib-
related toxicities for fertility, reproductive success, embryofetal development or embryofetal 
survival.  In rabbits, at dose levels which resulted in maternal toxicities, skeletal variations were 

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associated with reductions in fetal weights.  Effects on parturition and post-natal development 
are pending.  For additional details, refer to the Acalabrutinib Investigator Brochure. 
Women who are sexually active and can bear children (see definition above) must agree to use 
highly effective forms of contraception during the study and for 2 days after the last dose of 
acalabrutinib or 90 days after the last dose of ibrutinib, whichever is longer.  Men who are 
sexually active and can beget children must agree to use highly effective forms of contraception 
during the study and for 90 days after the last dose of ibrutinib.  Men must also refrain from 
donating sperm during the study and for 90 days after the last dose of ibrutinib.  
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  To participate in the study 
subjects of childbearing potential must adhere to the contraception requirement (described 
above) from the day of study medication initiation (or 14 days prior to the initiation of study 
medication for oral contraception) throughout the study period and for 2 days after the last dose 
of acalabrutinib or 90 days after the last dose of ibrutinib, whichever is longer.  If there is any 
question that a subject of childbearing potential will not reliably comply with the requirements for 
contraception, that subject should not be entered into the study. 
Subjects should promptly notify the investigator if they, or their partners, become pregnant 
during this period.  Female subjects must also notify the investigator if they become pregnant 
within 2 days after the last dose of acalabrutinib.  If a female subject becomes pregnant during 
the treatment period, she must discontinue study drug immediately.  Pregnancy in a female 
subject or a male subject’s partner must be reported as outlined in Section 7.2.2.  
6.3 CONCOMITANT MEDICATIONS 
6.3.1 Allowed Concomitant Medications 
Antiemetics are permitted if clinically indicated.  Standard supportive care medications are 
permitted.  Use of hematopoietic growth factors is permitted per the ASCO guidelines 
(Smith 2015). 
Tumor Lysis Syndrome 
For subjects considered at risk for tumor lysis syndrome (TLS):  Administer appropriate 
hydration and allopurinol or rasburicase per institutional standards prior to initiating treatment. 

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6.3.2 Guideline for Use of CYP Inhibiting/Inducing Drugs 
Acalabrutinib 
At the systemic exposure levels expected in this study, acalabrutinib inhibition of CYP-mediated 
metabolism of other drugs is not anticipated.  However, acalabrutinib is metabolized in part by 
CYP3A.  In a clinical drug-drug interaction study, co-administration of the potent CYP3A 
inhibitor, itraconazole, increased the mean plasma exposures of acalabrutinib by about 5-fold 
(Section 1.3.1).  In addition, concomitant administration of a strong inducer of CYP3A, 
rifampicin, reduced the exposure of acalabrutinib to 23%, relative to acalabrutinib dosed alone.  
Concomitant administration of strong CYP3A inhibitors/inducers and acalabrutinib should be 
avoided when possible (see Appendix C for a list of these agents).  Subjects requiring long-term 
(>1 week) treatment with a strong CYP3A inhibitor/inducer are excluded from the study.  In 
addition, the use of strong CYP3A inhibitors or inducers within 7 days of the first dose of study 
drug is prohibited.  If a subject requires short-term treatment (≤7 days) with a strong CYP3A 
inhibitor, acalabrutinib treatment should be interrupted.  If the subject requires treatment with 
a moderate CYP3A inhibitor, the acalabrutinib dose should be reduced to 100 mg QD.  
Co-administration of strong CYP3A inducers should be avoided.  If a subject requires treatment 
with a strong CYP3A inducer, the acalabrutinib dose should be increased to 200 mg BID.   
Ibrutinib 
Refer to the section titled “Dose Modifications for Use with CYP3A Inhibitors” in the IMBRUVICA 
approved label. 
6.3.3 Guideline for Use of Drugs that Affect Gastric pH 
Acalabrutinib 
The effect of agents that reduce gastric acidity (eg, proton-pump inhibitors, H2-receptor 
antagonists or antacids) on acalabrutinib absorption was evaluated in a healthy volunteer study 
(ACE-HV-004). Results from this study indicate that subjects should avoid the use of calcium 
carbonate containing drugs or supplements (eg, antacids and calcium supplements) for a period 
of at least 2 hours before and after taking acalabrutinib. 
Subjects should also avoid the use of H2-receptor antagonists for a period at least 2 hours 
before and after taking acalabrutinib.  Use of omeprazole or esomeprazole or lansoprazole (or 
any other proton-pump inhibitors) while taking acalabrutinib is not recommended as it may lower 
acalabrutinib exposure.  

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Ibrutinib 
No specific instructions are provided in the approved label for ibrutinib regarding agents that 
reduce gastric acidity (refer to approved label for ibrutinib). 
6.3.4 Prohibited Concomitant Medications 
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy for 
treating CLL are prohibited if being used to treat the disease initially under study.  Short course 
use of steroids (≤ 2 weeks) > 20 mg/day is permitted for premedication use, or to manage 
infusion related reactions or to manage other inflammatory reactions, such as asthma 
exacerbations.  High-dose corticosteroids used to treat the underlying CLL are not allowed on 
study.  Localized, short courses of radiotherapy are allowed for the treatment of lesions 
unrelated to the disease under study, if approved by the medical monitor.  Should a subject 
develop a second primary malignancy while on trial, continuation on trial medication after 
curative treatment of the second primary malignancy may be considered after discussion with 
the medical monitor.   
Warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) are prohibited. 
The concomitant use of strong inhibitors/inducers of CYP3A (see Appendix C) should be 
avoided when possible (see Section 6.3.2).  Concomitant administration of a strong inducer of 
CYP3A has the potential to decrease exposure of acalabrutinib and could reduce efficacy.  For 
additional information on drugs with potential drug-drug interactions, refer to Section 6.3. 
6.4 TREATMENT COMPLIANCE 
Subject compliance with acalabrutinib/ibrutinib will be assessed at each study visit.  Compliance 
will be assessed by the investigator and/or study personnel at each visit using direct 
questioning, examination of subject drug administration diaries, or pill counts.   
6.5 DIETARY RESTRICTIONS 
Acalabrutinib should be taken with water and may be taken with or without food.  Because 
acalabrutinib is metabolized by CYP3A, subjects should be strongly cautioned against using 
herbal remedies or dietary supplements (in particular, St. John’s wort, which is a potent CYP3A 
inducer).  Otherwise, subjects should maintain a normal diet unless modifications are required 
to manage an AE such as diarrhea, nausea, or vomiting. 

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7 
EFFICACY AND SAFETY PROCEDURES 
The Schedule of Assessments is provided in Appendix A.  Descriptions of the scheduled 
evaluations are outlined below.  See Appendix K for management of study procedures during 
pandemic.  
Before study entry, throughout the study, and at the follow-up evaluation, various clinical and 
diagnostic laboratory evaluations are outlined.  The purpose of obtaining these detailed 
measurements is to ensure adequate safety and efficacy assessments.  Clinical evaluations and 
laboratory studies may be repeated more frequently if clinically indicated.  Such assessments 
will be captured in the protocol-specific electronic database as appropriate.  This study will 
primarily use central laboratory testing for laboratory evaluations.  Samples from sites' local 
laboratories will be used if central testing is unavailable. 
Some study centers may choose to provide subjects with clinical trial cards, which provide 
information about the study and emergency contact details.   
7.1 DESCRIPTION OF PROCEDURES 
Informed Consent 
The subject must read, understand and sign the IRB/IEC-approved informed consent form (ICF) 
confirming his or her willingness to participate in this study before initiating any screening 
activity that is not considered standard of care by institutional standards.  Subjects must also 
grant permission to use protected health information if required by local regulations.  In addition, 
subjects must sign all approved ICF amendments per the site IRB/IEC’s guidelines during the 
course of the study.  
Confirmation of Eligibility 
Perform all necessary procedures and evaluations to document that the subject meets each 
eligibility criterion (Section 5).  Blood samples for hematology and serum chemistry collected at 
Screening will be evaluated by a central laboratory to confirm eligibility. With the exception of 
fluorescence in situ hybridization (FISH), if central laboratory results submitted during the 
screening period are unavailable, the Medical Monitor may review local laboratory results and 
approve the subject for randomization based on these laboratory values on a case-by-case 
basis provided another sample is redrawn and submitted before treatment.  The following 
de-identified documentation will be reviewed before enrollment: 
• 
Copies of a pathology report confirming diagnosis of CLL 

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• 
Radiology reports from screening CT/MRI documenting measurable nodal disease. 
• 
Copies of bone marrow aspirate and biopsy report. 
• 
Copies of FISH denoting if the subject has 17p del and/or 11q del. 
Treatment with study drug should begin within 7 days of randomization. 
Medical History 
Collect and record the subject’s complete history including concurrent medical signs and 
symptoms, alcohol use and, if a smoker, cigarette use.  Disease history, including the date of 
initial diagnosis, Rai and Binet staging within 28 days of first dose with study drug, 
documentation of refractory disease, prior anticancer treatments with best responses and 
progression-free interval to these treatments, and history of autoimmune CLL complications and 
their treatment will also be recorded based upon available documents and subject history. 
Physical Examination 
The physical examination includes height (Screening only) and weight, and examination of the 
skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, and lymphatic system.  The 
lymphatic system examination will include bidimensional measurements of palpable lymph 
nodes and measurement of spleen and liver sizes by centimeters below the costal margin on 
the respective side.  Only physicians, physician assistant, or oncology nurse practitioners 
should perform the lymphatic system examination.  As much as possible, the same person 
should perform all the lymphatic exams for a given subject.   
Disease-related Symptoms 
Disease-related symptoms will be assessed and recorded in the subject records and are 
defined per Hallek 2008 as: 
a. Unintentional weight loss of 10% of more within the previous 6 months; 
b. Significant fatigue (ie ECOG performance status 2 or worse; inability to work or perform 
usual activities); 
c. Fevers higher than 100.5°F or 38°C for 2 or more weeks without other evidence of 
infection; or 
d. Night sweats for more than 1 month without evidence of infection 
Vital signs 
Vital signs will include blood pressure, heart rate, respiratory rate, and body temperature. 

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Electrocardiogram 
Subjects should be in supine position and resting for at least 10 minutes before any 
protocol-specified ECGs.     
ECOG Performance Status 
The ECOG performance index is provided in Appendix B. 
Hepatitis Serologies 
Hepatitis serology testing must include hepatitis B surface antigen (HBsAg), hepatitis B surface 
antibody (HBsAb), anti-HBc, and hepatitis C (HCV) antibody.  Since intravenous 
immunoglobulins (IVIG) may cause false positive hepatitis serology, subjects who are receiving 
prophylactic IVIG and have positive HBsAg or anti-HBc must have negative hepatitis B DNA to 
be eligible.  In addition, any subjects testing positive for any hepatitis serology, must have PCR 
testing (see Appendix A and exclusion criterion #15).  Testing will be done by local or central 
laboratory.   
Refer to Section 6.2.5 and Appendix A regarding monitoring of subjects who are anti-HBc 
positive. 
Cytogenetics and FISH Panel 
Screening peripheral blood (required) will be sent to a central vendor to be tested for 17p del, 
13q-, +12, 11q- by FISH and stimulated karyotyping. 
Genetic and Molecular Prognostic Markers  
A blood sample will be collected and analyzed centrally to study the pretreatment prognostic 
factors. These prognostic factors have previously been associated with disease outcome in CLL 
subjects. 
Immunoglobulin Heavy-chain Variable (IgVH) and p53 Mutational Status 
One sample will be collected for IgVH and p53 mutational status. 
CD38 and ZAP-70 Leukemia Cell Expression 
One sample will be collected to study the leukemia cell expression of CD38 and ZAP-70. 

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Pregnancy Test 
Serum pregnancy testing per the Schedule of Assessments (Appendix A) will be required only 
for women with childbearing potential.  This test may be performed more frequently if required 
by local regulatory authorities.  
Hematology 
Hematology will be evaluated by a central laboratory and will include a complete blood count 
(CBC) with white blood cell (WBC) differential.  Any missing central laboratory blood samples 
should be redrawn as soon as possible.  In the event that the missing central laboratory sample 
is unrecoverable, local laboratory results will be collected, if available, and entered in the clinical 
database for response or progression confirmation. 
Determination of T/B/NK Cell Count 
Whole blood samples will be analyzed for absolute T/B/NK counts (CD3, CD19, CD4, CD8, 
CD16/56) using a standard cell marker panel.  This assay will be performed at the central 
laboratory on the same blood sample collected for standard hematology.  
Serum Chemistry 
Serum chemistry will be evaluated by a central laboratory and will include albumin, alkaline 
phosphatase, ALT, AST, blood urea nitrogen (BUN), calcium, creatinine, glucose, lactate 
dehydrogenase (LDH), phosphate/phosphorus, potassium, sodium, total bilirubin, and uric acid. 
Any missing central laboratory blood samples should be redrawn as soon as possible 
Serum Immunoglobulins and β2-microglobulin 
Sample(s) will be sent to a central laboratory for quantitative immunoglobulin (Ig) (ie, IgG, IgM, 
and IgA) levels and serum β2-microglobulin. 
 
 
 
  
 
 
 
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Bone Marrow Aspirate and Biopsy 
For Eligibility 
A unilateral bone marrow aspirate and biopsy will be done at screening or ≤ 3 months before 
randomization.  The Screening sample must be sent to the central laboratory for analysis. 
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Subjects who have a bone marrow biopsy done within 3 months of randomization may use 
these results in lieu of the Screening sample required for this study.  If slides (both bone marrow 
and aspirate) are available, these should be sent to the central laboratory for analysis. 
For Response Evaluation (more details provided in Appendix D) 
 
 
 
 
  In cases where cytopenic progression is suspected, a bone 
marrow aspirate or biopsy should be performed to distinguish autoimmune and drug-related 
cytopenias.  In cases where Richter’s transformation is suspected (eg, rapidly progressive 
B symptoms; bulky lymphadenopathy; organomegaly; anemia; a low platelet count; and 
elevated serum LDH, calcium, and β2 microglobulin levels), obtain whole body PET-CT to 
pinpoint the area for diagnostic biopsy (SUV > 5) (Jain 2012).  Confirm diagnosis by biopsy of 
lymph nodes, bone marrow, or involved organs.  Pathology analyses can be done at local 
laboratories in addition to central laboratory testing for confirmation of Richter’s transformation.  
Bone marrow aspirate and biopsy samples must be sent to the central laboratory for analysis. 
CT Scans 
Radiologic imaging by computed tomography (CT) with contrast is required and must include 
the pelvis, abdomen, chest, and neck.  Subjects who are intolerant to intravenous (IV) CT 
contrast agents will have CT scans performed with oral contrast.  When possible, all subjects 
should have radiographic tumor measurements done at the participating study center or an 
acceptable alternate imaging facility using an identical imaging protocol and similar equipment. 
The same imaging equipment should be used for all scans whenever possible.  The same 
radiologist should be assigned to read all the scans for a given subject throughout the study as 
much as possible.  MRI may be used for imaging assessments if a contrast CT scan is 
contraindicated or unobtainable (in cases where MRI is desirable, the MRI must be obtained at 
baseline and at all subsequent response evaluations). 
Computed tomography scans will be performed until disease progression is confirmed by the 
IRC regardless of whether or not the subject remains on treatment.  In the event disease 
progression is suspected due to physical examination or laboratory test, a CT scan must be 
performed to confirm disease progression.  If the sole measurable lesion lies within the field of 
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prior radiotherapy, there must be evidence of disease progression in that lesion that has not 
been previously irradiated.  Refer to the Schedule of Assessments (Appendix A) to determine 
the frequency that CT scans need to be obtained.  
Up to 6 measurable lymph nodes (only target lesions > 1.5 cm in the longest diameter may be 
assessed), clearly measurable in 2 perpendicular dimensions, will be followed as target lesions 
for each subject.  Measurable sites of disease should be chosen such that they are 
representative of the subject’s disease.  In addition, selection of target lesions should be from as 
disparate regions of the body as possible when these areas are significantly involved.  If 
additional lesions are present but are not included in the target lesion assessment, they can be 
added as non-target lesions followed throughout the study.  The cranial-caudal measurement of 
the spleen and longest diameter of the liver will be assessed at Screening and all subsequent 
response evaluations. 
A central imaging service will be used to provide independent radiologic assessments for the 
purposes of the primary endpoint. These measurements will not be reported back to the site. 
 
 
 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 7.2.1.  Important additional 
requirements for reporting SAEs are explained in Section 7.2.2.  See Section 7.2.2.1 for details 
regarding adverse event reporting. 
Prior and Concomitant Medications  
Document all concomitant medications and procedures from 14 days before the start of study 
drug administration through 30 days after the last dose of all study drugs, or at documented 
disease progression, whichever is longer. 
After a subject discontinues study treatment, receipt of all subsequent anticancer therapies will 
be collected. 
Routine Clinical Assessments 
Routine clinical assessments include physical exams, recording of symptoms, and hematologic 
evaluations to evaluate for both AEs and for disease progression at times when the CT scan is 
not obtained.  If a subject shows signs of progression, the subject may continue treatment until 
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progression is confirmed by the IRC.  The Investigator should report any suspected disease 
progression to the Sponsor or designee.  Subjects should continue to be followed and adhere to 
study-related procedures until progression has been confirmed by the IRC regardless of the 
administration of subsequent anticancer therapy.  New anticancer therapy should be withheld if 
clinically appropriate in the absence of IRC-confirmed progressive disease.  In addition, 
laboratory assessments for disease progression will need to be confirmed by the central 
laboratory. 
Overall Response Evaluations 
Overall response assessments will include evaluation of physical exams, recording of 
symptoms, hematologic evaluations (Note: CBC with differential must be done within 7 days and 
bone marrow aspirate/biopsy [when applicable] must be done within 4 weeks of the 
contemporaneous radiographic evaluation), and radiographic evaluations per the schedule of 
assessments.  Subjects who have signs and symptoms of progression outside of the scheduled 
assessment, should be evaluated by the investigator with a physical exam and a CBC with 
differential to determine if disease progression is present.  Any suspected case of disease 
progression should be confirmed with a CT scan if one was not obtained and should be reported 
to the Sponsor or designee.  Subjects may continue study treatment until progression is 
confirmed by a serial exam at least 2 weeks later.  In addition, when clinically appropriate, 
based on investigator perceived risk:benefit assessment, a subject may continue treatment until 
progression is confirmed by the IRC, unless considered medically contraindicated.  New 
anticancer therapy should be withheld if clinically appropriate in the absence of confirmed 
progressive disease by the IRC.  The blood samples for response or disease progression 
determination are to be confirmed by a central laboratory (samples from local laboratories can 
be used if central testing is unavailable). 
Early Termination (ET) Visit/Safety Follow-up (SFU) Visit 
An ET visit is required for safety assessments for any subjects who permanently discontinue 
treatment for any reason, including disease progression.  The ET visit should be performed 
within 7 days of the last dose of all study drugs, if possible, and is not required for subjects who 
discontinue from the study within 10 days of a scheduled study visit or if the ET visit would be 
performed within 14 days of the SFU visit.   
A SFU visit should be conducted at 30 (+ 7) days after his or her last dose of all study drugs to 
monitor for resolution or progression of AEs and to document the occurrence of any new events, 

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regardless of whether the subject receives a new anticancer therapy or demonstrates disease 
progression within this time frame.  Refer to Appendix A for the assessments required for the ET 
and SFU visits.   
Survival 
After progression, subjects will be contacted to assess survival status approximately every 
12 weeks until death, withdrawal by subject, lost to follow-up, or study terminated by Sponsor, 
whichever comes first.  At study closure, a survival sweep will be conducted.  All subjects who 
are on study and not known to have died before the survival sweep will be contacted at that 
time. 
Subsequent Anticancer Therapies 
After study drug treatment is complete, the following information on subsequent anticancer 
therapies will be collected approximately every 12 weeks until death, withdrawal by subject, lost 
to follow-up, or study terminated by Sponsor, whichever comes first: 
• 
Receipt of all subsequent anticancer therapies 
• 
IWCLL indication for initiation of subsequent anticancer therapy 
• 
Response to all subsequent anticancer therapies 
7.2 ASSESSMENT OF SAFETY  
The safety of this study will be assessed by an independent DMC.  All randomized subjects will 
be evaluated clinically and using standard laboratory testing during their participation in this 
study.  Safety assessments will consist of monitoring and recording AEs and SAEs; 
measurements of protocol-specified hematology, clinical chemistry, and other laboratory 
variables; measurement of protocol-specified vital signs; and other protocol-specified tests that 
are deemed critical to the safety evaluation of the study drug(s). 
7.2.1 Definitions 
Adverse Events 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational study drug, whether or not considered related to the study drug (FDA Guidance 
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For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions. 
Disease progression is not an AE; rather it may be the cause of an AE.  The clinical diagnosis 
that is associated with disease progression must be reported as all other AEs. “Disease 
progression” should never be used as an AE term. 
AEs may include, but are not limited to: 
• 
Subjective or objective symptoms spontaneously offered by the subject and/or observed 
by the Investigator or study staff including laboratory abnormalities of clinical significance 
(Note: “clinical significance” is defined as requiring change in study drug dose or 
discontinuation of study drug or any other medical intervention). 
• 
Any AEs experienced by the subject through the completion of final study procedures. 
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with CLL that were not present 
before the AE reporting period. 
The following are NOT considered an AE: 
• 
Pre-existing condition: A pre-existing condition (documented on the medical history 
CRF) is not considered an AE unless the severity, frequency, or character of the event 
worsens during the study period. 
• 
Preplanned hospitalization: A hospitalization planned before signing the informed 
consent form is not considered an 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 
enrollment in the study, will not be considered serious if they are performed after 
enrollment in the study 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. 
• 
Abnormal laboratory results:  Abnormal laboratory results are not AEs unless they are 
clinically significant.  For example, a clinically significant laboratory result is one that 

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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).  
Serious Adverse Event 
Note: 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. 
A serious adverse event (experience) (SAE) or reaction is any untoward medical occurrence 
that at any dose: 
• 
Results in death (ie, the AE actually causes or leads to death) 
• 
Is life-threatening (with regards to determining if an AE is serious, “life-threatening” is 
defined as an AE in which the subject was at risk of death at the time of the event.  It 
does not refer to an event which hypothetically might have caused death if it were more 
severe.  If either the Investigator or the Sponsor believes that an AE meets the definition 
of life-threatening, it will be considered life-threatening.) 
• 
Requires in-subject hospitalization > 24 hours or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity (ie, the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions) 
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event that may not result in death, be immediately life-
threatening or require hospitalization, but may be considered a serious adverse 
experience when, based upon appropriate medical judgment, the event may jeopardize 
the subject or subject and may require intervention to prevent one of the other outcomes 
listed in this definition.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsion 
that do not result in hospitalization; or development of drug dependency or drug abuse 
Given that the Investigator’s perspective may be informed by having actually observed the 
event, and the Sponsor is likely to have broader knowledge of the drug and its effects to inform 
its evaluation of the significance of the event, if either the Sponsor or the Investigator believes 
that the event is serious, the event will be considered serious. 

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Suspected Adverse Reaction 
The FDA has published a guidance on the reporting of SAEs.  This document directs Sponsors 
to consider more carefully the AEs that are reported in an expedited (urgent) fashion to the 
FDA.  Key elements of this guidance are outlined below: 
The guidance defines any AE for which there is a “reasonable possibility” that the drug caused 
the AE as a Suspected Adverse Reaction.  
“Reasonable Possibility”, for the purposes of safety reporting, means there is evidence to 
suggest a causal relationship between the drug and the AE.  Examples of evidence that would 
suggest a causal relationship between the drug and the AE are: 
• 
A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (eg, angioedema, blood dyscrasias, rhabdomyolysis, hepatic injury, 
anaphylaxis, and Stevens - Johnson syndrome).  
• 
One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (eg, include 
tendon rupture or heart valve lesions in young adults, or intussusception in healthy 
infants).  If the event occurs in association with other factors strongly suggesting 
causation (eg, strong temporal association, event recurs on rechallenge), a single case 
may be sufficiently persuasive; but often, more than one occurrence (from one or 
multiple studies) would be needed before the Sponsor could make a determination of 
whether the drug caused the event.  
• 
An aggregate analysis of specific events that can be anticipated to occur in the study 
population independent of drug exposure.  Such events include known consequences of 
the underlying disease or condition under investigation (eg, symptoms or disease 
progression), or events unlikely to be related to the underlying disease or condition 
under investigation, but commonly occur in the study population independent of drug 
therapy (eg, cardiovascular events in an elderly population).  An aggregate analysis 
(across studies) will identify those events that occur more frequently in the drug 
treatment group than in a concurrent or historical control group. 
This definition of “suspected adverse reaction” and the application of the “reasonable possibility” 
causality standard is considered to be consistent with the concepts and discussion about 
causality in the ICH E2A guidance (FDA Guidance for Industry 1995). 

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Severity 
Definitions found in the Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03 or higher will be used for grading the severity (intensity) of nonhematologic AEs.  The 
CTCAE v4.03 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 v4.03 or higher, 
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 
The grading scale for hematologic toxicity in subjects with CLL is provided in Appendix E. 
Causality 
The causality 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?’ per FDA 
guidance on safety reporting requirements (FDA Guidance 2012).  
See Appendix F for more detail on assessing causality. 
Unexpected Adverse Events 
An “unexpected” AE is an AE that is not listed in the Investigator Brochure for acalabrutinib, the 
approved label for ibrutinib, or is not listed at the specificity or severity that has been observed.  
For example, hepatic necrosis would be “unexpected” (by virtue of greater severity) if the 
Investigator Brochure referred only to elevated hepatic enzymes or hepatitis.  Similarly, cerebral 
thromboembolism and cerebral vasculitis would be “unexpected” (by virtue of greater specificity) 
if the Investigator Brochure/package insert listed only cerebral vascular accidents.  

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"Unexpected" also refers to AEs that are mentioned in the Investigator Brochure as occurring 
with a class of drugs or as anticipated from the pharmacologic properties of the drug, but are not 
specifically mentioned as occurring with the study drug under investigation. 
7.2.2 Documenting and Reporting of Adverse and Serious Adverse Events by 
Investigators 
The Investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, as outlined in the prior sections, are recorded on the CRF.  All SAEs also must 
be reported using the SAE report form (see “Expedited Reporting Requirements for Serious 
Adverse Events” later in this section).  
 Adverse Event Reporting Period 
After the signing of the ICF and prior to the first dose of study drug, all SAEs must be reported. 
After the first dose of study drug, all AEs/SAEs, irrespective of attribution of causality, must be 
reported.  
All adverse events will be reported until 30 days after the last dose of study drug or the start of 
new anticancer therapy (whichever comes first).  After this period, investigators should report 
serious adverse events or other adverse events of concern that are believed to be related to 
prior treatment with study drug. 
All SAEs that occur during the reporting period should be followed to resolution or until the 
Investigator assesses the subject as stable or until the subject is lost to follow up or withdraws 
consent.  Resolution/stable means the subject has returned to baseline state of health or the 
Investigator does not expect any further improvement or worsening of the event. 
 Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject 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, clinically significant 
laboratory test (ie, requiring change in study drug dose or discontinuation of study drug or any 
other medical intervention), or other means will be recorded in the subject’s medical record and 
on the AE CRF and, when applicable, on an SAE/Product Complaint form. 
Each recorded AE or SAE will be described by its diagnostic term, duration (ie, start and end 
dates), severity, regulatory seriousness criteria (if applicable), suspected relationship to study 
drug, and any actions taken. 

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 Adverse Events of Special Interest 
The following events are adverse events of special interest (AESIs) and must be reported to the 
sponsor expeditiously (see Section 7.2.2.7 for reporting instructions), irrespective of regulatory 
seriousness criteria or causality: 
• 
Ventricular arrhythmias (e.g., ventricular extrasystoles, ventricular tachycardia, 
ventricular arrhythmia, ventricular fibrillation) 
 
 Second Primary Malignancies 
Adverse events (AEs) for malignant tumors reported during a study should generally be 
assessed as serious AEs (SAEs).  If no other seriousness criteria apply, the “Important Medical 
Event” criterion should be used.  In certain situations, however, medical judgment on an 
individual event basis should be applied to clarify that the malignant tumor event should be 
assessed and reported as a nonserious AE.  For example, if the tumor is included as medical 
history and progression occurs during the study but the progression does not change treatment 
and/or prognosis of the malignant tumor, the AE may not fulfill the attributes for being assessed 
as serious, although reporting of the progression of the malignant tumor as an AE is valid and 
should occur.  Also, some types of malignant tumors, which do not spread remotely after a 
routine treatment that does not require hospitalization, may be assessed as nonserious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
removed via cone biopsy. 
The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (i.e., it is not the tumor for which entry into the study is a criterion and that is 
being treated by the IP under study and is not the development of new or progression of existing 
metastasis to the tumor under study).  Malignant tumors that—as part of normal, if rare, 
progression—undergo transformation (e.g., Richter's transformation of B cell chronic 
lymphocytic leukemia into diffuse large B cell lymphoma) should not be considered a new 
malignant tumor.   
 Pregnancy 
The investigator should report all pregnancies and pregnancies of the partners of subjects within 
24 hours of notification using the Pregnancy Report Form.  This form should be faxed or 
emailed to the AstraZeneca Representative.  Any pregnancy-associated SAE must be reported 

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using the SAE report form, according to the usual timeline and direction for SAE reporting as 
described below. 
Any uncomplicated pregnancy that occurs in a study subject or a partner of a treated subject 
during this study will be reported for tracking purposes only, if agreed to by the subject or the 
partner of the subject in this study.  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 2 days after the last dose of acalabrutinib or 90 days after 
the last dose of ibrutinib (whichever is longer), will be followed to conclusion, and the outcome 
reported, as long as the subject or partner has consented to participate in follow-up. 
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 miscarriage 
or any other serious events) must additionally be reported as such using the SAE report form. 
Subject should be instructed to immediately notify the investigator of any pregnancies.  Any 
female subjects who become pregnant must immediately discontinue study drug.  The 
investigator should counsel the subject, discussing any risks of continuing the pregnancy and 
any possible effects on the fetus. 
Upon completion of the pregnancy, additional information on the mother, pregnancy, and baby 
will be collected and sent to the AstraZeneca Representative. 
 Overdose Instructions 
In the event of ingestion of more than the recommended dosage per protocol, additional clinical 
monitoring is recommended by the sponsor.  For any subject experiencing an acalabrutinib or 
ibrutinib overdose (ingestion of more than the recommended dosage), observation for any 
symptomatic side effects should be instituted, and vital signs, biochemical and hematologic 
parameters should be followed closely (consistent with the protocol or more frequently, as 
needed).  Appropriate supportive management to mitigate adverse effects should be initiated.  If 
the overdose ingestion of acalabrutinib or ibrutinib is recent and substantial, and if there are no 
medical contraindications, use of gastric lavage or induction of emesis may be considered. 
The medical monitor must be contacted if a study drug overdose occurs. 

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 Expedited Reporting Requirements for Serious Adverse Events/Adverse 
Events of Special Interest 
All SAEs/AESIs must be reported within 24 hours of discovery.  All initial SAE/AESIs reports 
and follow-up information will be reported using the protocol-specific electronic data capture 
system.  If electronic SAE/AESIs reporting is not available, paper SAE/AESIs report forms must 
be sent to the AstraZeneca Representative, or designee.  The AstraZeneca Representative may 
request follow-up and other additional information from the investigator (eg, hospital 
admission/discharge notes and laboratory results). 
Whenever possible, SAEs/AESIs 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 be the term reported.  Autopsy and postmortem reports must be 
forwarded to the AstraZeneca Representative, or designee, as outlined above. 
If study drug is discontinued because of an SAE/AESIs, this information must be included in the 
SAE/AESIs report. 
An SAE/AESIs may qualify for mandatory expedited reporting to regulatory authorities if the 
SAE/AESIs is attributable to the study drug and is not listed in the current Investigator Brochure 
(ie, an unexpected event). In this case, Acerta Pharma will forward a formal notification 
describing the suspected unexpected serious adverse reaction (SUSAR) to all investigators.  
Each investigator must then notify his or her IRB/IEC of the SUSAR. 
 
 Other Safety Issues Requiring Expedited Reporting 
For studies being conducted in Europe, expedited reporting is required for safety issues that 
might materially alter the current benefit-risk assessment of an investigational medicinal product 
or that would be sufficient to consider changes in the investigational medicinal products 
administration or in the overall conduct of the trial.  For a detailed description of safety issues 
that may qualify for expedited reporting please refer to the European Commission guidance 
titled, “Detailed guidance on the collection, verification and presentation of adverse reaction 
reports arising from clinical trials on medicinal products for human use – April 2006” available at 
http://ec.europa.eu/health/files/eudralex/vol-10/21_susar_rev2_2006_04_11_en.pdf. 

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 Hy’s Law 
Cases where a subject shows elevations in liver biochemistry may require further evaluation, 
and occurrences of AST or ALT ≥3×ULN together with total bilirubin ≥2×ULN may need to be 
reported as SAEs.  Refer to Appendix J for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s law. 
7.2.3 Reporting of Serious Adverse Events by Sponsor 
Regulatory Authorities, IRBs/IECs, and Investigators will be notified of SAEs in accordance with 
applicable requirements (eg, GCP, ICH guidelines, national regulations, and local 
requirements).  For the purpose of this protocol, Acerta Pharma considers acalabrutinib and 
ibrutinib as investigational agents and will follow applicable guidelines for reporting SAEs for 
both drugs. 
8 
WITHDRAWAL OF SUBJECT FROM TREATMENT OR ASSESSMENT 
8.1 WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT 
Subjects may be withdrawn from study treatment for the following reasons: 
• 
Any subject who has objective evidence of disease progression while receiving 
protocol-required study drug should be withdrawn from the study treatment.  If there is 
uncertainty regarding whether there is disease progression, the subject may continue 
study treatment and remain under close observation (eg, evaluated at 2- to 4-week 
intervals) pending IRC confirmation of disease progression.  In particular, transient 
worsening of disease during temporary interruption of study therapy (eg, for drug-related 
toxicity, surgery, or intercurrent illness) may not indicate disease progression.  In such 
circumstances, and if medically appropriate, subjects may resume therapy and relevant 
clinical, laboratory, and/or radiologic assessments should be done to document whether 
tumor control can be maintained or whether actual disease progression has occurred. 
• 
Toxicity as defined in dose discontinuation sections of the protocol 
• 
Withdrawal from treatment by subject including withdrawal of informed consent 
• 
Drug hold > 28 days 
• 
Second primary malignancy necessitating systemic treatment 
• 
Pregnancy in a subject 
• 
Investigator decision 
• 
Requires prohibited treatment 
• 
Study terminated by sponsor 
 
8.2 REASONS FOR STUDY EXIT 
Reasons for study exit include: 

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• 
Subject’s withdrawal of consent from study 
• 
Decision by sponsor to terminate the study 
• 
Subject lost to follow-up 
• 
Death 
 
In case a subject is lost to follow-up, every reasonable effort must be made by the study site 
personnel to contact the subject and determine the reason for discontinuation.  The measures 
taken to follow up must be documented. 
When a subject withdraws before completing the study, the reason for withdrawal and scope of 
withdrawal (e.g., complete or only from treatment and/or protocol assessments) must be 
documented in the CRF and in the source documents.  Subjects who withdraw consent should 
still be encouraged to complete the safety follow-up assessments before withdrawing consent, 
but these assessments cannot be mandated once consent is withdrawn.  In cases of partial 
withdrawal of consent, subjects should be encouraged to allow future contact for survival 
follow-up. 
Subjects who are withdrawn or removed from study treatment will not be replaced. 
9 
STATISTICAL METHODS 
9.1 GENERAL CONSIDERATIONS 
The statistical and analytical plans presented below summarize the more complete plans to be 
detailed in the statistical analysis plan (SAP).  A change to the data analysis methods described 
in the protocol will require a protocol amendment only if it alters a principal feature of the 
protocol.  The SAP will be finalized before database lock.  Any changes to the methods 
described in the final SAP will be described and justified in the clinical study report. 
Independent Review Committee 
The IRC will be chaired by a physician with expertise in CLL and will conduct response 
evaluations in accordance with the IRC charter. 
Data Monitoring Committee 
A DMC, chaired by a physician with expertise in CLL, will monitor the safety of the subjects in 
this study.  An early safety analysis will be performed after approximately 50 subjects have been 
treated for approximately 8 weeks.  This analysis will focus on deaths, treatment 
discontinuations, SAEs, and Grade 3/4 AEs as well as special events of interest.  The Medical 

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Monitor will review, in a blinded fashion, this information on an ongoing basis until this early 
safety analysis is conducted.  Detailed information on the role of the DMC and frequency of 
meetings, which occur at least every 6 months, will be provided in the DMC charter separate 
from this protocol. 
9.2 RANDOMIZATION 
This study will use an IWRS for randomization.  Subjects will be randomized in a 1:1 ratio to 
receive either acalabrutinib or ibrutinib with the following stratification factors:  
• 
Presence of 17p del 
• 
ECOG performance status (ECOG = 2 versus ECOG ≤ 1) 
• 
Number of prior therapies (1-3 versus ≥ 4) 
The treatment assignment for any individual study subject will not be known to study and site 
personnel or the subject before subject randomization into the study. 
9.3 DETERMINATION OF SAMPLE SIZE 
A recently completed trial that studied PFS in CLL (Byrd 2014) showed that ibrutinib (the 
reference/comparator drug in Protocol ACE-CL-006) was superior to ofatumumab, a drug 
approved for the treatment of CLL in patients with previously treated CLL. Superiority in that 
study was shown in the overall study population (HR=0.21) as well as in patients with 17p del 
(HR=0.25) or 11q del (HR=0.14).  
Protocol ACE-CL-006 is designed to have 80% power to show that the upper bound of a 2-sided 
95% CI for PFS is < 1.429 (the NI bound).  
With randomization in a 1:1 ratio, the trial will require approximately 250 events if acalabrutinib 
and ibrutinib are truly equally effective.  Assuming an enrollment period of about 
 and 
a follow-up period of approximately 
 after the last subject enters the study, the 
estimated sample size is 500 subjects (250 per arm).   
9.4 ANALYSIS POPULATIONS 
Intent-to-Treat (ITT) Population 
The ITT population will be defined as all subjects randomized.   
All efficacy analysis will be performed in the ITT population and will be analyzed as randomized.  
In addition, the ITT population will be used to summarize demographics, and baseline and 
disease characteristics. 
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Safety Population 
The safety population includes all subjects who received at least one dose of study drug.  The 
safety population will be the analysis population for the safety analyses.  Subjects will be 
analyzed as treated.  
 
 
 
 
 
 
9.5 HANDLING OF MISSING VALUES/CENSORING/DISCONTINUATIONS 
Missing or partial start and end dates for AEs and concomitant medications will be imputed 
according to prespecified, conservative imputation rules.  The SAP will describe the details for 
handling missing data. 
9.6 EFFICACY ANALYSES 
9.6.1 Primary Endpoint and Methods 
The primary efficacy endpoint is PFS, which is defined as the time from the date of 
randomization until disease progression (assessed by the IRC per IWCLL 2008 criteria) or 
death from any cause, whichever occurs first.  The primary analysis is event-based and will be 
conducted after enrollment is completed and approximately 250 IRC-assessed events have 
occurred.  
The primary analysis for this study will be conducted to assess whether acalabrutinib is non-
inferior to ibrutinib with respect to PFS based on comparison of the upper bound of the 95% CI 
of HR to the prespecified NI margin of 1.429.  The two-sided 95% CI for the HR of acalabrutinib 
versus ibrutinib will be estimated using a stratified Cox proportional hazard model.   
Additional sensitivity and subgroup analyses may be conducted and will be described in SAP. 
9.6.2 Secondary Endpoints and Methods 
If acalabrutinib is shown non-inferior to ibrutinib, the secondary endpoints will be tested in 
manner that maintains the Type I error rate at ≤ 5%.  The SAP will describe the methodology to 
be used for multiplicity adjustment. 
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Grade ≥ 3 Infections, Richter’s Transformation, and Atrial Fibrillation 
The incidences of treatment-emergent Grade ≥ 3 infections, Richter’s transformation, and atrial 
fibrillation will be summarized and compared between the 2 treatment arms using 2-sided 
Cochran-Mantel-Haenszel tests adjusted for the randomization strata.   
Richter’s transformation will be assessed by central pathology.  Incidence of Grade ≥ 3 
infections and atrial fibrillation will be collected as described for all AEs (Section 7.2.2). 
Overall Survival 
Differences between the treatment arms in OS will be assessed using Kaplan-Meier methods 
and a stratified log-rank test. Medians, ranges, hazard ratios and corresponding 95% CIs will be 
presented.  The OS HR and its 95% CI will be presented using a stratified Cox regression 
model. 
9.6.3 Exploratory Endpoints 
 
 
   
 
 
 
 
   
 
  
   
Other Exploratory Endpoints 
 
 
 
 
 
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9.7 SAFETY ANALYSES 
Safety data will be summarized for the safety population.  The baseline value for safety analysis 
is defined as the value collected at the time closest to and before the start of study drug 
administration.  
Adverse Events 
AEs will be graded by the investigator according the National Cancer Institute (NCI) CTCAE 
v4.03 or higher for non-hematologic AEs.  Hematologic toxicity will be assessed by the grading 
scale for hematologic toxicity in CLL studies in the IWCLL 2008 guidelines.  Each AE verbatim 
term will be coded to a system organ class and a preferred term using the Medical Dictionary for 
Regulatory Activities (MedDRA). 
Treatment-emergent Adverse Events  
All TEAEs will be summarized by treatment arm as treated. In addition, AE incidence rates will 
also be summarized by severity and relationship to study drug.  
Grade 3 or Grade 4 TEAEs; TEAEs leading to permanent study drug treatment discontinuation; 
TEAEs leading to dose reduction; serious TEAEs; TEAEs of special interest and TEAEs 
resulting in death will be summarized by treatment arm as treated. 
Clinical Laboratory Tests 
Data Summary Methods: 
For gradable parameters, a summary of worst post baseline toxicity grade will be provided in the 
treatment-emergent period and worst toxicity grade (any grade and Grade 3/4).  The difference 
between groups in percentages will be displayed.  
Liver function abnormality by Hy's law and frequencies of abnormal treatment emergent uric 
acid will be summarized. 
Analysis of Lymphocytosis: 
For all subjects with baseline and any post-baseline ALC measurements, ALC at peak summary 
will be provided by treatment arm.  Median percentage change in ALC from baseline with its 
95% CI will also be displayed graphically over time. 
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ECOG Performance Status 
ECOG performance status will be collected as scheduled in Appendix A.  ECOG performance 
status grade ranges from 0 to 5.  Descriptive statistics will be provided for each visit over time.  
Vital Signs and Weight 
Body temperature, heart rate (beats/min), systolic blood pressure (mmHg), diastolic blood 
pressure (mmHg), respiratory rate (breaths/min), and weight will be collected as scheduled in 
Appendix A.  For each parameter, descriptive statistics will be provided over time.  
10 STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
Acerta Pharma retains the right to terminate the study and remove all study materials from a 
study site at any time.  Specific circumstances that may precipitate such termination are: 
• 
Unsatisfactory subject enrollment with regard to quality or quantity 
• 
Significant or numerous deviations from study protocol requirements, such as failures to 
perform required evaluations on subjects and maintain adequate study records 
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• 
Inaccurate, incomplete and/or late data recording on a recurrent basis 
• 
The incidence and/or severity of AEs in this or other studies indicating a potential health 
hazard caused by the study treatment 
10.1 REGULATORY AND ETHICAL COMPLIANCE  
This clinical study was designed and will be implemented in accordance with the protocol, the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local 
regulations (including US Code of Federal Regulations [CFR] Title 21 and European Directive 
2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki.  
10.2 INSTITUTIONAL REVIEW BOARD (IRB) AND INDEPENDENT ETHICS 
COMMITTEE (IEC) APPROVAL 
The investigator will submit this protocol, the informed consent, Investigator Brochure, and any 
other relevant supporting information (eg, all advertising materials) to the appropriate IRB/IEC 
for review and approval before study initiation.  A signed protocol approval page; a letter 
confirming IRB/IEC approval of the protocol and informed consent; and a statement that the 
IRB/IEC is organized and operates according to GCP and the applicable laws and regulations; 
must be forwarded to Acerta Pharma before screening subjects for the study.  Additionally, 
sites must forward a signed FDA 1572 form (Investigator Obligation Form) or local equivalent to 
Acerta Pharma before screening subjects for study enrollment.  Amendments to the protocol 
must also be approved by the IRB/IEC and local regulatory agency, as appropriate, before the 
implementation of changes in this study. 
10.3 INFORMED CONSENT AND PROTECTED SUBJECT HEALTH INFORMATION 
AUTHORIZATION 
A copy of the IRB/IEC-approved informed consent must be forwarded to Acerta Pharma for 
regulatory purposes.  The investigator, or designee (designee must be listed on the Study 
Personnel Responsibility/Signature Log), must explain to each subject the purpose and nature 
of the study, the study procedures, the possible adverse effects, and all other elements of 
consent as defined in the Code of Federal Regulations § 21CFR Part 50, and other applicable 
national and local regulations governing informed consent.  Each subject must provide a signed 
and dated informed consent before enrollment into this study.  In the case of a subject who is 
incapable of providing informed consent, the investigator (or designee) must obtain a signed 
and dated informed consent form from the subject’s legal guardian.  Signed consent forms must 
remain in each subject’s study file and be available for verification by study monitors at any 
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In accordance to individual local and national patient privacy regulations, the investigator or 
designee must explain to each subject that for the evaluation of study results, the subject’s 
protected health information obtained during the study may be shared with Acerta Pharma and 
its designees, regulatory agencies, and IRBs/IECs.  As the study Sponsor, Acerta Pharma will 
not use the subject’s protected health information or disclose it to a third party without applicable 
subject authorization.  It is the investigator’s or designee’s responsibility to obtain written 
permission to use protected health information from each subject, or if appropriate, the subject’s 
legal guardian.  If a subject or subject’s legal guardian withdraws permission to use protected 
health information, it is the investigator’s responsibility to obtain the withdrawal request in writing 
from the subject or subject’s legal guardian and to ensure that no further data will be collected 
from the subject.  Any data collected on the subject before withdrawal will be used in the 
analysis of study results. 
10.4 QUALITY CONTROL AND QUALITY ASSURANCE 
Sponsor shall implement and maintain quality control and quality assurance procedures to 
ensure that the study is conducted and data are generated, documented and reported in 
compliance with the protocol, GCP, and applicable regulatory requirements.  This study shall be 
conducted in accordance with the provisions of the Declaration of Helsinki (October 2008) and 
all revisions thereof, and in accordance with FDA regulations (21 CFR Parts 11, 50, 54, 56, and 
312, Subpart D – Responsibilities of Sponsors and Investigators) and with the ICH guidelines on 
GCP (ICH E6).   
10.5 STUDY FILES AND RECORD RETENTION 
The investigator and other appropriate study staff are responsible for maintaining all 
documentation relevant to the study.  Mandatory documentation includes copies of study 
protocols and amendments, each FDA Form 1572, IRB/IEC approval letters, signed ICFs, drug 
accountability records, SAE forms transmitted to Acerta Pharma, subject files (source 
documentation) that substantiate entries in CRFs, all relevant correspondence and other 
documents pertaining to the conduct of the study. 
An investigator shall retain records for a period of at least 2 years after the date the last 
marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and regulatory authorities have 
been notified.  Local regulations may require a longer period for record retention; said local 
regulations will supersede this protocol.  The investigator must notify Acerta Pharma and obtain 

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written approval from Acerta Pharma before destroying any clinical study records at any time. 
Acerta Pharma will inform the investigator of the date that study records may be destroyed or 
return to Acerta Pharma. 
Acerta Pharma must be notified in advance of, and Acerta Pharma must provide express written 
approval of, any change in the maintenance of the foregoing documents if the investigator 
wishes to move study records to another location or assign responsibility for record retention to 
another party.  If the investigator cannot guarantee the archiving requirements set forth herein at 
his or her study site for all such documents, special arrangements must be made between the 
investigator and Acerta Pharma to store such documents in sealed containers away from the 
study site so that they can be returned sealed to the investigator for audit purposes. 
10.6 CASE REPORT FORMS AND RECORD MAINTENANCE 
Authorized study site personnel (see Section 10.9) will complete CRFs designed for this study 
according to the completion guidelines that will be provided as part of the clinical database.  The 
investigator will ensure that the CRFs are accurate, complete, legible, and completed promptly.  
Refer to Section 10.5 for record retention requirements. 
10.7 INVESTIGATIONAL STUDY DRUG ACCOUNTABILITY 
Acalabrutinib capsules must be kept in a locked limited cabinet or space.  The study drug must 
not be used outside the context of the protocol.  
Study drug accountability records must be maintained and readily available for inspection by 
representatives of Acerta Pharma and are open to inspections by regulatory authorities at any 
time.  
All study supplies and associated documentation will be regularly reviewed and verified by the 
monitor. 
10.8 STUDY MONITORING/AUDIT REQUIREMENTS 
Representatives of Acerta Pharma or its designee will monitor this study until completion.  
Monitoring will be conducted through personal visits with the investigator and site staff as well 
as any appropriate communications by mail, fax, email, or telephone.  The purpose of 
monitoring is to ensure compliance with the protocol and the quality and integrity of the data.  
This study is also subject to reviews or audits. 
Every effort will be made to maintain the anonymity and confidentiality of all subjects during this 
clinical study.  However, because of the experimental nature of this treatment, the investigator 
agrees to allow the IRB/IEC, representatives of Acerta Pharma, its designated agents, and 

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authorized employees of the appropriate regulatory agencies to inspect the facilities used in this 
study and, for purposes of verification, allow direct access to the hospital or clinic records of all 
subjects enrolled into this study.  This includes providing by fax, email, or regular mail de-
identified copies of radiology, pathology, and/or laboratory results when requested by the 
Sponsor.  A statement to this effect will be included in the informed consent and permission 
form authorizing the use of protected health information. 
10.9 INVESTIGATOR RESPONSIBILITIES 
A complete list of Investigator responsibilities are outlined in the clinical trial research agreement 
and the Statement of Investigator FDA Form 1572, both of which are signed by the Investigator 
before commencement of the study.  The principal investigator must ensure that: 
1. 
He or she will conduct or supervise the study. 
2. 
His or her staff and all persons who assist in the conduct of the study clearly understand 
their responsibilities and have their names included in the Study Personnel 
Responsibility/Signature Log. 
3. 
The study is conducted according to the protocol and all applicable regulations. 
4. 
The protection of each subject’s rights and welfare is maintained. 
5. 
Signed and dated informed consent and, when applicable, permission to use protected 
health information are obtained from each subject before conducting nonstandard of 
care study procedures.  If a subject or subject’s legal guardian withdraws permission to 
use protected health information, the investigator will obtain a written request from the 
subject or subject’s legal guardian and will ensure that no further data be collected from 
the subject. 
6. 
The consent process is conducted in compliance with all applicable regulations and 
privacy acts. 
7. 
The IRB/IEC complies with applicable regulations and conducts initial and ongoing 
reviews and approvals of the study. 
8. 
Any amendment to the protocol is submitted promptly to the IRB/IEC. 
9. 
Any significant protocol deviations are reported to Acerta Pharma and the IRB/IEC 
according to the guidelines at each study site. 
10. 
CRF pages are completed promptly. 
11. 
All IND Safety Reports/ SUSAR Reports are submitted promptly to the IRB/IEC. 
12. 
All SAEs are reported to the AstraZeneca Representative within 24 hours of knowledge 
and to the IRB//IEC per their requirements. 
 

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10.10 CLINICAL TRIAL INSURANCE 
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted.  An insurance certificate will be made available to the participating sites 
at the time of study initiation. 
10.11 PROTOCOL AMENDMENTS 
Acerta Pharma will initiate any change to the protocol in a protocol amendment document. The 
amendment will be submitted to the IRB/IEC together with, if applicable, a revised model ICF.  If 
the change in any way increases the risk to the subject or changes the scope of the study, then 
written documentation of IRB/IEC approval must be received by Acerta Pharma before the 
amendment may take effect.  Additionally under this circumstance, information on the increased 
risk and/or change in scope must be provided to subjects already actively participating in the 
study, and they must read, understand, and sign any revised ICF confirming willingness to 
remain in the trial. 
10.12 PUBLICATION OF STUDY RESULTS 
Authorship, in general, will follow the recommendations of the International Committee of 
Medical Journal Editors (International Committee of Medical Journal Editors 2014).   

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11 REFERENCE LIST  
Atherly LO, Lucas JA, Felices M, et al.  The Tec family tyrosine kinases Itk and Rlk regulate the 
development of conventional CD8+ T cells.  Immunity 2006;25:79-91. 
Brown JR, Hillmen P, O’Brien S, et al. Updated efficacy including genetic and clinical subgroup 
analysis and overall safety in the phase 3 Resonate™ trial of ibrutinib versus ofatumumab in 
previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma. Blood 2014 Nov 
15; 24 (21): Abstract 3331. 
Byrd JC, Brown JR, O'Brien S, et al.; RESONATE Investigators. Ibrutinib versus ofatumumab in 
previously treated chronic lymphoid leukemia. NEJM 2014 Jul 17;371(3):213-23. 
 
 
Chen J, Tan K, Zhou H, et al. Modifying murine von Willebrand factor A1 domain for in vivo 
assessment of human platelet therapies. Nat Biotechnol. 2008 Jan; 26(1):114-9 
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end 
points in chronic lymphocytic leukemia. JCO 2012 30:2820-2822. 
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. 
Da Roit F, Engelberts PJ, Taylor RP, et al.  Ibrutinib interferes with the cell-mediated anti-
tumour activities of therapeutic CD20 antibodies: implications for combination therapy.  
Haematologica 2015 Jan;100(1):77-86. 
 
 
 
FDA Guidance for Industry.  ICH E2A Clinical Safety Data Management:  Definitions and 
Standards for Expedited Reporting.  1995 Mar.  Available at: 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ 
ucm065004.htm 
FDA March 2010. Guidance for industry (draft): Non-inferiority clinical trials. 2010 Mar. Available 
at: http://www.fda.gov/downloads/Drugs/Guidances/UCM202140.pdf. 
FDA Guidance 2012. Guidance for Industry and Investigators:  Safety Reporting Requirements 
for INDs and BA/BE Studies (December 2012). Available 
at: http://www.fda.gov/downloads/Drugs/.../Guidances/UCM227351.pdf, accessed 
on:  28January2016. 
Furie B, Furie BC. Thrombus formation in vivo. J Clin Invest 2005 Dec;115(12):3355-62 
Gonzalez D, Martinez P, Wade R, et al. Mutational status of the TP53 gene as a predictor of 
response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 
trial. JCO 2011;29:2223-2229. 
Hahn OM, Schilsky RL. Randomized controlled trials and comparative effectiveness research.  
JCO 2012;30:4194-4201. 
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Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and 
cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, 
phase 3 trial. Lancet 2010;376:1164-74. 
Hallek M, Cheson BD, Catovsky D, et al.  Guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic 
Leukemia updating the National Cancer Institute-Working Group 1996 guideline Blood 
2008;111:5446-5456 
Hillmen P, Skotnicki AB, Robak T, et al.  Alemtuzumab compared with chlorambucil as first-line 
therapy for chronic lymphocytic leukemia.  JCO 2007;25:5616-5623. 
Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor ACP-196 
blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell 
malignancy. Proc. Natl Acad. Sci.  2010;107:13075-13080. 
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals. 2014 Dec.  Available 
from: http://www.ICMJE.org.  Accessed February 04, 2015. 
Jain P, O’Brien S.  Richter’s transformation in chronic lymphocytic leukemia.  Oncology 
2012;26:1146-1152. 
Kamel S, Horton L, Ysebaert L, et al.  Ibrutinib inhibits collagen-mediated but not ADP-mediated 
platelet aggregation.  Leukemia 2015 Apr;29(4):783-7. 
Khurana D, Arneson LN, Schoon RA, et al.  Differential regulation of human NK cell-mediated 
cytotoxicity by the tyrosine kinase Itk. J Immunol 2007;178:3575-3582. 
NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphomas. Version 1.2016.  
Available at NCCN.org. 
O’Brien SM, Furman RR, Coutre SE, et al.  Independent evaluation of ibrutinib efficacy 3 years 
post-initiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic 
leukemia including deletion 17p disease.  JCO 2014a;32:5s(suppl; abstr 7014). 
O’Brien SM, Jones JA, Coutre S, et al.  Efficacy and Safety of Ibrutinib in Patients with 
Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia with 
17p Deletion: Results from the Phase II RESONATE™-17 Trial.  2014b Annual ASH Meeting 
Abstract #327. 
Oken MM, Creech RH, Tormey DC, et al. (1982) Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655. 
Rajasekaran N, Sadaram M, Hebb J, et al.  Three BTK-specific inhibitors, in contrast to ibrutinib, 
do not antagonize rituximab-dependent NK-cell mediated cytotoxicity.  Blood 2014 ASH Annual 
Meeting Abstract #3118 
Smith TJ, Bohlke K, Lyman GH, et al.  Recommendations for the Use of WBC Growth Factors: 
American Society of Clinical Oncology Clinical Practice Guideline Update.  JCO 2015;33:3199-
212. 
Takeba Y, Nagafuchi H, Takeno M, et al.  Txk, a member of nonreceptor tyrosine kinase of Tec 
family, acts as a Th1 cell-specific transcription factor and regulates IFN-gamma gene 
transcription.  J Immunol 2002;168:2365-2370. 
 
 
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Vail DM, Michels GM, Khanna C, et al. Veterinary Cooperative Oncology Group. Response 
evaluation criteria for peripheral nodal lymphoma in dogs (v1.0)—a Veterinary Cooperative 
Oncology Group (VCOG) consensus document. Vet Comp Oncol 2010;8:28-37. 
Vail DM, Thamm DH. Spontaneously occurring tumors in companion animals as models for 
drug development. In: Teicher BA, Anders PA, eds. Anticancer Drug Development Guide: 
Preclinical Screening, Clinical Trials, and Approval. 2nd Ed. Totowa, NJ: Human Press; 
2004:259-284.  

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12 APPENDICES 

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Appendix A: Schedule of Assessments 
 
Treatment Phasea 
 
 
 
Study Weeks 
Screenin
g Phase 
1 
2 
3 
4 
5 
6 
7 
8 
Q4W starting 
Wk12 
≥25 
Q12W 
Post Treatment 
Phasei/ 
Response 
Evaluationb 
Q12W/ Q24W 
ET/SFU visitc 
Post-disease 
Progression 
Phasej Q12W 
 
Study Windows 
-28 days 
± 3 days 
± 7 days 
+7 days 
± 7 days 
IP Dispensation 
 
x 
 
 
x 
 
 
 
x 
x 
x 
 
 
 
Study Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ARM A 
Acalabrutinib 
100 mg BID PO 
 
Continuous Daily Dosing 
 
 
Arm 
B 
Ibrutinib 
420 mg QD PO 
 
Continuous Daily Dosing 
 
 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility & 
randomize 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG status 
x 
 
 
 
 
 
 
 
x 
x 
x 
 
 
 
Physical Exam  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
Pregnancy test 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Hepatitis serologiesf 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV PCRg 
 
 
 
 
 
x 
 
 
 
x 
x 
 
 
x 
Cytogenetics, FISH panel & molecular 
markers 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ANC, ALC, PLT, Hgb 
(within 7 days of  CT) 
x 
 
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Serum chemistry 
x 
x 
 
 
x 
 
 
 
x 
x 
x 
 
x 
 
Serum immunoglobulins, β2-
microglobulin, T/B/NK counts 
x 
 
 
 
 
 
 
 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scans 
xh 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Overall response assessment 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Bone marrow biopsy and aspirate 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Survival status and new anticancer 
therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Abbreviations:  ALC = absolute lymphocyte count; ANC = absolute neutrophil count; anti-HBc = hepatitis B core antibody; 
 CT 
= computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ET = early termination; FISH = fluorescence in situ 
hybridization;  HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; Hgb = hemoglobin 
level; IV = intravenous; IVIG = intravenous immunoglobulins; 
 PLT = platelet count; PO = oral; 
 Q12W = 
every 12 weeks; Q24W = every 24 weeks; QM = every month; SFU = safety follow-up. 
a. 
Treatment Period begins with randomization and ends with last dose of study drug.  Subjects will take study drug until disease progression or unacceptable 
toxicity.  Subjects will have weekly visits during the first 8 weeks then will have visits every 4 weeks (ie, after Week 8 the next scheduled visit would be at 
Week 12) through 24 weeks.  Thereafter, visits will be every 12 weeks (ie, after Week 24 the next scheduled visit would be at Week 36).   
b. 
Response evaluations will be done every 12 weeks from Week 1 Day 1 through Week 100, and then every 24 weeks until 5 years on study and then yearly 
thereafter until disease progression regardless of whether or not a subject has discontinued study drug.  Hematology results must be done within 7 days of CT 
scans.  
 
c. 
An early termination visit will be done for subjects who permanently discontinue study drug early for any reason. The safety follow up visit is conducted 30 
(+ 7) days after the last dose of study treatment regardless of whether the  subject receives a new anticancer therapy or demonstrates disease progression 
within this timeframe.  The ET visit should be performed within 7 days of the last dose of all study drugs, if possible, and is not required for subjects who 
discontinue from the study within 10 days of a scheduled study visit or if the ET visit would be performed within 14 days of the SFU visit. 
d. 
 
 
e. 
 
 
 
f. 
Hepatitis serology must include hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (anti-HBc), and hepatitis 
C (HCV) antibody.  Subjects who are receiving prophylactic intravenous immunoglobulins (IVIG) and have positive HBsAg or anti-HBc must have negative 
hepatitis B DNA to be eligible.  In addition, any subjects testing positive for any hepatitis serology, must have polymerase chain reaction (PCR) testing (see 
exclusion criterion #15). 
g. 
Subjects who are anti-HBc positive should be monitored every 3 months with a quantitative PCR test for HBV DNA. Monitoring should continue until 
12 months after last dose of study drug(s).  Any subject with a rising viral load (above lower limit of detection) should discontinue study drug and have antiviral 
therapy instituted and a consultation with a physician with expertise in managing hepatitis B.  
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h. 
Subjects who have standard of care CT/MRI results may use these results in lieu of the Screening CT/MRI required for this study, provided the CT/MRI was 
done within 28 days of first dose and was acquired in accordance with the guidelines outlined in Section 7.1 CT Scans. 
i. 
Subjects who discontinue study drug for reasons other than disease progression will enter the Post Treatment Phase and will have Response Evaluation 
assessed every 12 weeks (+7 days) through Week 100, and then every 24 weeks until 5 years on study and then yearly thereafter until disease progression.  
j. 
Post-disease Progression Phase will begin once a subject has progressive disease. 
 

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Appendix B: Performance Status Scores 
Status 
Eastern Cooperative Oncology Group (ECOG) Performance Status* 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light housework, office work. 
2 
Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair. 
5 
Dead. 
*  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin 
Oncol 5:649-655, 1982. 
Available at: http://www.ecog.org/general/perf_stat.html.  Accessed March 2015. 

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Appendix C: Examples of Coadministered Drugs That Need Additional 
Consideration 
The lists of drugs in these tables are not exhaustive.  Any questions about drugs not on this list 
should be addressed to the medical monitor of this study. 
Strong Inhibitors of CYP3A 
Moderate Inhibitors of 
CYP3A 
boceprevir 
aprepitant 
clarithromycina 
cimetidine 
cobicistata 
ciprofloxacin 
conivaptana 
clotrimazole 
danoprevir and ritonavirb 
crizotinib 
diltiazema 
cyclosporine 
elvitegravir and ritonavirb 
dronedaronea 
grapefruit juice 
erythromycin 
idelalisib 
fluconazole 
indinavir and ritonavirb 
fluvoxamine 
itraconazolea 
imatinib 
ketoconazole 
tofisopam 
lopinavir and ritonavira,b 
verapamila 
nefazodone 
 
nelfinavira 
 
paritaprevir and ritonavir and (ombitasvir 
and/or dasabuvir)b 
 
posaconazole 
 
ritonavira, b 
 
saquinavir and ritonavira, b 
 
telaprevira 
 
tipranavir and ritonavira, b 
 
troleandomycin 
 
voriconazole 
 
a. 
Inhibitor of P-glycoprotein. 
b.  
Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs 
in clinical practice. Caution should be used when extrapolating the observed 
effect of ritonavir alone to the effect of combination regimens on CYP3A 
activities. 
 
Strong Inducers of CYP3A 
Moderate Inducers of CYP3A 
carbamazepine 
bosentan 
enzalutamide 
efavirenz 
mitotane 
etravirine 
phenytoin 
modafinil 
rifampin 
 
St. John’s worta 
 
a. 
The effect of St. John’s wort varies widely and is preparation-dependent. 
 

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P-gp Inhibitors 
BCRP Inhibitors 
Narrow Therapeutic 
Index P-gp Substrates 
amiodarone 
curcumin 
digoxin 
carvedilol 
cyclosporine A 
everolimus 
clarithromycin 
eltrombopag 
sirolimus 
dronedarone 
 
 
itraconazole 
 
 
lapatinib 
 
 
lopinavir and ritonavir 
 
 
propafenone 
 
 
quinidine 
 
 
ranolazine 
 
 
ritonavir 
 
 
saquinavir and ritonavir 
 
 
telaprevir 
 
 
tipranavir and ritonavir 
 
 
verapamil 
 
 
Source:  FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers. Web link Accessed 18 July 2018: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
onsLabeling/ucm093664.htm#inVivo 
 
 

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Appendix D: 
 
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Appendix E: 
Hematologic Adverse Event Grading Scheme (Hallek 2008) 
An evaluation of the hematologic toxicity in subjects with advanced CLL must consider the high 
frequency of marrow involvement and previous exposure to chemotherapy with consequent 
medullary compromise at the initiation of therapy. The standard hematologic grading system for 
solid tumors cannot, therefore, be directly applied. A substantial proportion of subjects would be 
considered to have Grade 2 to 4 hematologic toxicity before any therapy is given. Therefore, the 
following modified schema will be used to quantitate hematologic deterioration in subjects with 
CLL. 
Hematologic Grading Scheme 
Grade1 
Decrease in platelets2 or 
Hb3 (nadir) from 
pretreatment value 
Absolute neutrophil 
count/μL4 (nadir) 
0 
No change to 10% 
≥ 2000 
1 
11%-24% 
≥ 1500 and < 2000 
2 
25%-49% 
≥ 1000 and < 1500 
3 
50%-74% 
≥ 500 and < 1000 
4 
≥ 75% 
< 500 
1. Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal.  Death occurring as a result of 
toxicity at any level of decrease from pretreatment will be reported as Grade 5. 
2. Platelet counts must be below normal levels for Grades 1 to 4.  If, at any level of decrease, the 
platelet count is < 20 x 109/L (20,000/μL), this will be considered Grade 4 toxicity, unless a severe or 
life-threatening decrease in the initial platelet count (eg, < 20 x 109/L [20,000/μL]) was present 
pretreatment, in which case the patient is not evaluable for toxicity referable to platelet counts. 
3. Hemoglobin (Hb) levels must be below normal levels for Grades 1 to 4. Baseline and subsequent Hb 
determinations must be performed before any given transfusions. The use of erythropoietin is 
irrelevant for the grading of toxicity, but should be documented. 
4. If the ANC reaches < 1 x 109/L (1000/μL), it should be judged to be Grade 3 toxicity. Other decreases 
in the white blood cell count, or in circulating neutrophils, are not to be considered because a 
decrease in the white blood cell count is a desired therapeutic endpoint. A gradual decrease in 
granulocytes is not a reliable index in CLL for stepwise grading of toxicity. If the ANC was < 1 x 109/L 
(1000/μL) before therapy, the patient is not evaluable for toxicity referable to the ANC. The use of 
growth factors such as granulocyte colony-stimulating factor (G-CSF) is not relevant to the grading of 
toxicity, but should be documented. 
 
 
 
 

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Appendix F: 
Adverse Event Assessment of 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 preclinical 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 
 
 

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Appendix G: 
 
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Appendix H: 
 
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Appendix I: 
 
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Appendix J: 
Actions Required in Cases of Increases In Liver 
Biochemistry and Evaluation of Hy’s Law 
INTRODUCTION 
This Appendix describes the process to be followed to identify and appropriately report potential 
Hy’s law (PHL) cases and Hy’s law (HL) cases.  It is not intended to be a comprehensive guide 
to the management of elevated liver biochemistries.  
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a subject meets PHL 
criteria at any point during the study.  All sources of laboratory data are appropriate for the 
determination of PHL and HL events; this includes samples taken at scheduled study visits and 
other visits, including central and all local laboratory evaluations, even if collected outside of the 
study visits (e.g., PHL criteria could be met by an elevated ALT from a central laboratory and/or 
elevated total bilirubin from a local laboratory).  The investigator will also review adverse event 
(AE) data (e.g., for AEs that may indicate elevations in liver biochemistry) for possible PHL 
events. 
The investigator participates with the sponsor in the review and assessment of cases meeting 
PHL criteria to agree whether HL criteria are met.  HL criteria are met if there is no alternative 
explanation for the elevations in liver biochemistry other than drug-induced liver injury (DILI) 
caused by the investigational medicinal product (IMP).  The investigator is responsible for 
recording data pertaining to PHL/HL cases and for reporting AEs and serious adverse events 
(SAEs) according to the outcome of the review and assessment in line with standard safety-
reporting processes.  
DEFINITIONS 
Potential Hy’s Law  
AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN at any point during the study after 
the start of study drug, irrespective of an increase in alkaline phosphatase.  
Hy’s Law 
AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN, where no reason other than the IMP 
can be found to explain the combination of increases (e.g., elevated alkaline phosphatase 
indicating cholestasis, viral hepatitis, or another drug).   
For PHL and HL, the elevation in transaminases must precede or be coincident with (i.e., on the 
same day) the elevation in total bilirubin, but there is no specified timeframe within which the 
elevations in transaminases and total bilirubin must occur. 

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IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
Laboratory data must be comprehensively reviewed by the investigator for each subject to 
identify laboratory values meeting the following criteria: 
• 
ALT ≥3 x ULN 
• 
AST ≥3 x ULN 
• 
Total bilirubin ≥2 x ULN 
When the identification criteria are met from central or local laboratory results, the investigator 
will perform the following: 
• 
Notify the sponsor representative/Medical Monitor by telephone and report the case as an 
SAE of Potential Hy’s law; seriousness criteria “Important medical event” and causality 
assessment “yes/related” or in accordance with the clinical study protocol as appropriate. 
• 
Request a repeat of the test (new blood draw) without delay 
• 
Complete the appropriate unscheduled laboratory electronic Case Report Form (eCRF) 
module(s)  
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the clinical study protocol, as applicable 
 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
The instructions in this section should be followed by the investigator for all cases where PHL 
criteria are met. 
As soon as possible after the biochemistry abnormality is initially detected, the study medical 
monitor and the investigator will review available data, to agree whether there is an alternative 
explanation for meeting PHL criteria other than DILI caused by the IMP and to ensure that 
timely analysis and reporting to health authorities within 15 calendar days from the date PHL 
criteria were met.   
Where there is an agreed alternative explanation for the ALT or AST and total bilirubin 
elevations, a determination of whether the alternative explanation is an AE will be made and, 
subsequently, whether the AE meets the criteria for an SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF. 

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• 
If the alternative explanation is an AE/SAE, update the previously submitted PHL SAE 
accordingly with the new information (reassessing event term, causality, and seriousness 
criteria) following the sponsor’s standard processes. 
If it is agreed that there is no explanation that would explain the ALT or AST and total bilirubin 
elevations other than the IMP, then: 
• 
Send updated SAE (report term “Hy’s law”) according to the sponsor’s standard processes:  
o The “Medically Important” serious criterion should be used if no other serious criteria 
apply. 
o Because there is no alternative explanation for the HL case, a causality assessment of 
“related” should be assigned. 
If there is an unavoidable delay of over 15 calendar days in obtaining the information necessary 
to assess whether the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until an informed decision can be made: 
• 
Provide any further update to the previously submitted SAE of PHL (report term now “Hy’s 
law case”), ensuring causality assessment is related to IMP and seriousness criteria are 
medically important, according to clinical study protocol process. 
• 
Continue follow-up and review according to the agreed plan.  After the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met.  Update the previously submitted PHL SAE report following 
the clinical study protocol process, according to the outcome of the review. 
ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S LAW 
This section is applicable when a subject meets PHL criteria while receiving study treatment and 
has already met PHL criteria at a previous on-study treatment visit.  The requirement to conduct 
follow-up, review, and assessment of a repeat occurrence(s) of PHL is based on the nature of 
the alternative cause identified for the previous occurrence.   

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Appendix K: Management of Study Procedures During Pandemic 
This appendix consolidates guidance for subject safety and ongoing access to medical care and 
investigational product during the global COVID-19 pandemic.  The measures detailed below 
will be implemented across Acerta Pharma studies on a temporary basis until the pandemic is 
considered resolved by governmental and public health organizations, as applicable.  
Regardless of the guidance below, please consider public health advice in your local market 
and individual risk/benefit in treatment decisions for patients at your study site during the 
pandemic.  Please also consider logistical requirements such as the ability of patients to travel 
to the study site, accessibility of public transport, etc. 
If the subject is unable or unwilling to visit the study site due to COVID-19 related reasons, 
investigators may ask enrolled subjects to use healthcare facilities local to the subject to ensure 
safety and efficacy measures are done per protocol. If a study assessment is not done at either 
the site or a facility local to the subject, then its absence should be documented as a  protocol 
deviation in the standard manner.  Any protocol deviations resulting from the COVID-19 
situation should be recorded and prefixed with COVID-19. 
CONDUCT OF TELEPHONE VISITS 
Due to the current pandemic, it is conceivable that not all subject visit commitments may be able 
to be fulfilled.  If a subject is unable or unwilling to attend a study visit, adaptation of the onsite 
visit to a telephone visit is recommended to ensure continuity of study care (as an interim 
measure; e.g., telephone contacts instead of visits, shipping study medication to the subject).  
Priority should be given to maintaining ongoing safety follow-up (even if this is conducted by 
telephone contacts).  Study sites should speak with their site monitor before performing a 
telephone visit so he or she may provide guidance regarding logistics that may need 
consideration.  Also, study sites should speak with the site monitor if the subject cannot attend 
more than one onsite visit in succession, because multiple incomplete visits may have the 
potential to impact evaluation of study endpoints. 
ACALABRUTINIB DOSE MODIFICATION RECOMMENDATION FOR COVID-19 
The sponsor recognizes that coronavirus 2019-nCoV (COVID-19) presents an increased risk for 
all patients.  Due to the potential impact of COVID-19 on multiple organ systems, the sponsor 
recommends the following dose modification and management plan for patients with confirmed 
or suspected COVID-19 while receiving treatment with acalabrutinib.  
First and foremost, the following safety reporting guidelines are required:  

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All confirmed or suspected COVID-19-related adverse events (AEs) must be recorded in the 
eCRF. All dose modifications should be based on the worst Common Terminology Criteria for 
Adverse Events (CTCAE) grade.  All interruptions or modifications must be recorded on the AE 
and drug administration eCRFs.  The CTCAE general grading criteria should be used to 
evaluate COVID-19.  
If an event is suspected to be COVID -19 infection, the sponsor recommends interrupting 
acalabrutinib and testing for COVID-19 per local guidance.  
• 
If COVID-19 is ruled out, standard clinical practice and the study protocol procedures 
should be followed regarding any dose modifications required for management of 
severe infections.  
• 
If COVID-19 is confirmed or diagnosis is suspected after evaluation, COVID-19 infection 
should be managed per local guidance until the subject achieves full recovery, defined 
as no signs or symptoms.  
 
In case of COVID-19 positivity, the investigator must determine the risk and benefit of 
interruption versus continuation of acalabrutinib and whether to resume it at full or modified 
doses or discontinue treatment.  
Please contact the study medical monitor for further discussion.  
COMPARATOR DRUGS OR DRUGS USED IN COMBINATION WITH ACALABRUTINIB: 
• 
Please refer to guidance from the manufacturer.  
 
Drug-drug interactions (DDI) may occur with some of the drugs being used as best supportive 
care (e.g., drugs that are strong inducers or inhibitors of cytochrome P450 [CYP]3A). Guidance 
is provided below:  
Drug-Drug Interaction Guidance for Investigators with Subjects Enrolled in an 
Acalabrutinib Clinical Study who are COVID-19 Positive:  
• 
The potential combination with chloroquine or 8-8-OH-chloroquine (8-OH-CHQ) and 
azithromycin are not predicted to have a pharmacokinetic DDI with acalabrutinib.  
However, both agents are known to cause cardiovascular risk of QT-prolongation.  
Therefore, the risk/benefit of initiating 8-OH-CHQ + azithromycin should be discussed 
with the medical monitor.  
• 
Many antivirals and antibiotics are considered strong CYP3A4 inhibitors or inducers and 
are therefore likely to cause complex DDIs with acalabrutinib.  The risk-benefit balance 
of acalabrutinib use in the setting of COVID-19 treatment should be discussed between 
the investigator and the medical monitor.  
• 
Remdesivir is rapidly metabolized to a pharmacologically active metabolite, GS-443902.  
Based on published and publicly available data, remdesivir does not appear to inhibit 

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CYP isoforms and will likely not interact in a meaningful way with drug transport 
systems.  Remdesivir does not prolong QTc interval.  
• 
Systemic steroids and acalabrutinib may impair the ability of the body to fight infection; it 
is best to avoid high-dose systemic steroids while taking acalabrutinib.  
• 
The study protocol and investigator brochure should be referenced for other DDI 
information.  
 
COVID-19 Specific Data Entry Instructions for Investigational Sites 
Adverse Event Recording: 
Currently no changes to normal data capture procedures are required for COVID-19 data in the 
eCRF.  For subjects who have confirmed or who are suspected of having coronavirus infection, 
the infection should be documented as an AE or serious adverse event (SAE), in line with 
instructions for safety reporting documented in the clinical study protocol.  Either “COVID-19 
Confirmed” or “COVID-19 Suspected” should be used when reporting the event as follows: 
• 
If test is positive, “COVID-19 confirmed” should be recorded in the AE field. 
• 
If test is negative, AE/SAE signs and symptoms and/or other diagnosis should be 
recorded in the AE field(s). 
• 
If test is not available and signs and symptoms, as judged by the investigator, are highly 
suspicious of COVID-19 infection, record “COVID-19 suspected” in the AE field. 
 
Details of any testing or procedure to determine the status of COVID-19 infection should be 
documented on the Concomitant Procedure Form if available or on the appropriate eCRF page 
in the study. 
For fatal SAEs, the Death Information Form, End of Study Treatment Form, and Study Exit 
Form should be completed.  
Study Treatment Recording: 
If an AE or SAE is associated with COVID-19, the investigator should determine whether the 
subject’s treatment with investigational product should continue, be interrupted, or be 
discontinued in accordance with the clinical study protocol. 
For dosing interruptions, where applicable, the following guidelines should be used: 
• 
Related to AE:  
On the Dose Administration Forms(s), dose change/missed should be indicated with 
AE as the reason.  The dosing stop date must correlate to the AE/SAE start/stop dates. 
• 
Related to Logistics:  

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For subjects who have missed a study treatment due to an inability to travel to the 
clinic or for some other logistical reason, on the Dose Administration Form(s) dose 
change/missed should be indicated with Other as the reason, and “Logistic” as Other, 
Specify. 
 
If these options are not available in the eCRF, then either dose discontinuation should be 
recorded (if permanently stopped) or a protocol deviation should be recorded, prefixed 
COVID19. 
For dosing discontinuations, where applicable, the dosing discontinuation guidelines should 
be followed, and the End of Treatment Form(s) completed. 
Capturing telephone contacts with subjects: 
If a telephone visit is substituted for an onsite study visit, the following are guidelines for data 
capture: 
1. 
If the visit is specified as a phone visit as per protocol, no additional action is required.  
2. 
If the visit is listed as on-site but the subject will be contacted by phone, data should be 
completed as per a normal visit (i.e., using the relevant eCRF pages to capture a phone 
Visit Date, and any possible assessment that can be obtained remotely should be captured, 
such as AEs, study drug administration and/or concomitant medications, and any additional 
safety information).  All assessments that cannot be performed should be marked as not 
done or eCRF inactivated/marked Blank.  A protocol deviation should be recorded in the 
clinic notes prefixed COVID19 detailing the use of a phone visit in place of an onsite visit.   
3. 
If the visit requires procedures that cannot be performed via telephone contact (e.g., MRI or 
CT Scan), this should be discussed with the site monitor because this procedure may 
impact primary efficacy or safety analyses. 
 
Acalabrutinib Site-to-Subject Drug Shipment Instructions During Pandemic Containment 
or in Case of Force Majeure 
If a subject is definitively unable to physically go to the study site or unable to be represented by 
a third person because of pandemic containment or other force majeure, the study site's 
pharmacy may ship the study drug to the home of the subject following approval by the sponsor.  
For such a shipment, the following conditions must be met: 
• 
The sponsor is responsible for delivery of the study drug to the study site.  Any 
shipments made from the site to the subject will be the responsibility of the study site. 
• 
The subject is informed about the shipment method, confirms the address for receipt of 
the drug, and agrees that his or her personal information (i.e., name and address) may 
be given to a professional carrier. 

Product: ACP-196 (acalabrutinib) 
Protocol ACE-CL-006 
 
 
Acerta Pharma 
Confidential 
Page 111 
• 
The pharmacy securely packages the drug for shipment.  
• 
A professional carrier is used by the pharmacy to ship the drug securely and maintain 
chain of custody, with evidence provided.  Acalabrutinib must be stored and shipped at 
room temperature (15°C to 30°C).  The professional carrier must ensure that 
temperature monitoring is conducted for all shipments. 
• 
To respect patient confidentiality, the carrier should only be given the name and address 
of the subject.  The sponsor should not receive any personal information about the 
patient. 
• 
A procedure is defined with the carrier to confirm the receipt of the drug by the subject 
and that it is received in good condition. 
• 
The site contacts the subject to confirm the receipt and integrity of the drug and gives 
instructions about the drug administration. 
• 
The pharmacy completes its accountability with each shipment made directly to a 
subject.