An Open-label, Phase 2 Study of ACP-196 in Subjects With Waldenström Macroglobulinemia
Phase: PHASE2
Conditions: Waldenström Macroglobulinemia (WM)
Sponsor: Acerta Pharma BV

Product: ACP-196 (acalabrutinib) 
Version: 8.0 (Global) 
Protocol: ACE-WM-001 
 
 
Acerta Pharma 
Confidential 
 
Page 1  
PROTOCOL 
TITLE 
An Open-label, Phase 2 Study of ACP-196 in Subjects 
with Waldenström Macroglobulinemia1 
PROTOCOL NUMBER 
ACE-WM-001 
STUDY DRUG 
ACP-196 (acalabrutinib) 
IND NUMBER 
118717 
EUDRACT NUMBER 
2014-003212-36 
SPONSOR MEDICAL 
MONITOR 
 
 
SPONSOR 
Acerta Pharma BV 
 
Kloosterstraat 9 
5349 AB Oss 
The Netherlands 
PROTOCOL DATE 
Version 0.0 – 12 May 2014 
AMENDMENT 1 DATE 
Version 1.0 – 19 September 2014 (all sites) 
AMENDMENT 2 DATE 
Version 2.0 – 17 November 2014 (Netherlands only) 
Version 2.1 – 20 November 2014 (US only) 
Version 3.0 – 05 January 2015 (UK/US only) 
AMENDMENT 3 DATE 
Version 3.1 – 13 March 2015 (all sites) 
AMENDMENT 4 DATE 
Version 4.0 – 14 January 2016 (all sites) 
Version 4.1 – 01 April 2016 (Italy only) 
AMENDMENT 5 DATE 
Version 5.0 – 23 June 2016 (all sites) 
Version 5.1 – 04 October 2016 (Italy only) 
AMENDMENT 6 DATE 
Version 6.0 – 21 December 2016 (all sites) 
Version 6.1 – 30 January 2017 (Italy only) 
AMENDMENT 7 DATE 
Version 7.0 – 26 December 2017 (all sites) 
Version 7.1 – 26 December 2017 (Italy only) 
Version 7.2 – 06 March 2018 (France only) 
AMENDMENT 8 DATE 
Version 8.0 – 16 April 2019 (all sites) 
Version 8.1 – 16 April 2019 (Italy only) 
Version 8.2 – 16 April 2019 (France only) 
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/independent ethics committee.  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.  
                                               
1 In Italy only, the original protocol title “An Open-label, Phase 1b/2 Study of ACP-196 in Subjects with 
Waldenström Macroglobulinemia” remains in effect. 
 

Product: ACP-196 (acalabrutinib) 
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Protocol: ACE-WM-001 
 
 
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PROTOCOL APPROVAL 
I have carefully read Protocol ACE-WM-001 entitled “An Open-label, Phase 2 Study of 
ACP-196 in Subjects with Waldenström Macroglobulinemia2.”  I agree to conduct this 
study as outlined herein and in compliance with Good Clinical Practices, all applicable 
regulatory requirements, and with the ethical principles laid down in the Declaration of 
Helsinki.  Furthermore, I understand that the Sponsor, Acerta Pharma, and the 
Institutional Review Board/ Independent Ethics Committee 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 
 
                                               
2 In Italy only, the original protocol title “An Open-label, Phase 1b/2 Study of ACP-196 in Subjects with 
Waldenström Macroglobulinemia” remains in effect. 

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SUMMARY OF AMENDMENT 8.0 
This protocol is being amended to extend the study beyond 48 cycles allowing subjects 
continuing to receive clinical benefit to continue on treatment until a rollover protocol is 
available at which time the study will be closed.  In addition, the requirement of review of 
response (overall response rate, duration of overall response, and progression-free 
survival) by an independent review committee will no longer be conducted.   
Substantive changes (noted below) along with clarification edits and typographical 
corrections were made as part of this amendment.  
Change 
Rationale 
Protocol Title Page 
 
Updated name and contact information for medical 
monitor. 
Updated sponsor information. 
Listed amendment 8 and dates. 
Added new amendment number and date 
issued. 
Study Synopsis 
 
Updated to reflect changes made throughout the 
protocol.  
Updated to ensure consistency between the 
body of the protocol and the synopsis. 
Section 1.2.1 Chemistry 
 
Updated statement about Calquence® having 
been approved in the United States and other 
markets for the treatment of adult patients with 
mantle cell lymphoma who have received at least 
1 prior therapy. 
Updated to be consistent with current 
regulatory approvals of Calquence. 
Section 1.3.2 Clinical Experience 
 
Updated the number of subjects with who have 
received acalabrutinib in clinical studies. 
Updated data to be consistent with most 
current Investigator Brochure. 
Updated the subject population of Study 
ACE-CL-001 to be subjects with chronic 
lymphocytic leukemia (CLL), including subjects 
with relapsed/refractory CLL, treatment-naive 
subjects, ibrutinib-intolerant subjects, and subjects 
with Richter’s syndrome or prolymphocytic 
leukemia transformation.   
Updated for clarity. 
Updated the number of subjects in Study ACE-CL-
001 and the preliminary efficacy data for them.  
Updated data to be consistent with most 
current Investigator Brochure. 
Section 1.4 Secondary Objectives 
 
Deleted the description of Study ACE-CL-001. 
Deleted text because information is in the 
previous section. 
Deleted response data for Study ACE-CL-001. 
Changed to make text more general. 

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Change 
Rationale 
Section 2.2 Secondary Objectives 
 
Removed text from objectives referring to the 
review by an independent review committee. 
Updated because a review/confirmation by 
an independent review committee is no 
longer prescribed. 
Section 3.1 Description of Study 
 
Removed specific assessment times for safety 
parameters and added a link to Appendix 4 for the 
information. 
 
Added text that assessments for efficacy will be 
completed throughout the study as per Appendix 4.   
 
Deleted text stating that an independent review 
committee will be used to confirm overall response 
rate, duration of response, and progression-free 
survival.   
Updated because a review/confirmation by 
an independent review committee is no 
longer prescribed. 
Deleted the word "independent" describing the 
interim analysis. 
Updated for clarity. 
Updated text to define end of study as the last 
subject’s last visit and that the sponsor may 
terminate the study at any time. Added that the 
study duration is expected to be approximately 
6 years from enrollment of the last subject. 
Updated because study was extended 
2 years. 
Clarified that subjects who are deriving clinical 
benefit from acalabrutinib treatment may be eligible 
to enroll in a separate rollover study when it is 
available. 
Added to provide clarification that subjects 
could switch to a separate rollover study 
before the end of study. 
Section 3.2.2 Secondary Endpoints 
 
Removed text from objectives referring to the 
review by an independent review committee. 
Updated because a review/confirmation by 
an independent review committee is no 
longer prescribed. 
Section 3.7.7 Reproductive Toxicity 
 
Updated the definition of highly effective methods 
of contraception. 
Updated information to be consistent with 
most current Investigator Brochure and with 
other protocols across the program. 
Section 4.1.13 Serum Chemistry 
 
Added a reference to Appendix 5 for actions 
required in cases of increases in liver biochemistry 
and evaluation of Hy’s law. 
Added an appendix for Hy's law information 
to be consistent with protocols across the 
program. 
Section 4.1.21 Extramedullary Disease 
Assessment 
 
Changed frequency of radiologic assessments for 
extramedullary disease from every 3 cycles to 
every 6 cycles after Cycle 6.   
Changed from every 3 cycles to every 
6 cycles to reflect current standard of care.  
Removed text referring to the review by a central 
imaging vendor being used to provide independent 
radiologic assessments for the purposes of 
confirming overall response rate.  
Updated because a review/confirmation by 
an independent review committee is no 
longer prescribed. 

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Change 
Rationale 
Section 4.4 Follow-Up for Progression and 
Survival 
 
Changed text to indicate that during the 
discontinuation follow-up period, serum IgM and 
physical examinations will be collected every 
6 months. 
Changed from every month to every 
6 months was made to reflect current 
standard of care.  
Section 5.5.3 Analysis of Efficacy Parameters 
 
Removed text referring to the review by an 
independent review committee and improved 
clarity. 
Updated because a review/confirmation by 
an independent review committee is no 
longer prescribed. 
Section 5.7 Primary and Final Analysis 
 
Updated text to define end of study as the time 
when last subject completes his or her last visit. 
Updated because study was extended 
2 years. 
Section 6.1.3 Adverse Events of Special 
Interest 
 
Added new section. 
Added information to be consistent with 
protocols across the program. 
Section 6.1.5 Adverse Drug Reactions 
 
Added section with a reference to Section 6 of the 
Investigator Brochure for the reference safety 
information. 
Added section for additional clarification of 
reporting AEs and SAEs 
Section 6.2.4 Expedited Reporting 
Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
 
Included adverse events of special interest along 
with serious adverse events. 
Added for consistency with Section 6.1.3 
and to be consistent with protocols across 
the program. 
Appendix 4 Schedule of Assessments 
 
Updated column for Cycle 27+ to be Cycles 27 to 
48 
Updated because study was extended 
2 years. 
Added a column for Cycles 48+ and indicated the 
following assessments would be made for these 
cycles: physical examination/vital signs/weight, 
Eastern Cooperative Oncology Group status, urine 
or serum pregnancy test, hematology, serum 
chemistry, serum Ig and M protein, hepatitis B virus 
polymerase chain reaction, bone marrow (aspirate 
and biopsy), radiologic assessment for 
extramedullary sites, acalabrutinib dispensed, 
study drug compliance, response assessment, 
concomitant medications, and patient-reported 
outcomes. 
Updated because study was extended 
2 years. 
Updated footnotes to define end of study as the 
last subject’s last visit and that subjects who are 
deriving clinical benefit from acalabrutinib may 
continue on study until a rollover protocol is 
available.   
Updated because study was extended 
2 years. 

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Version: 8.0 (Global) 
Protocol: ACE-WM-001 
 
 
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Change 
Rationale 
Updated footnotes to indicate physical examination 
and weight assessments will be made every 3 
cycles through Cycle 48, then every 6 cycles 
thereafter. 
Updated because study was extended 
2 years. 
Updated footnotes to indicate vital signs 
assessments will be made every 3 cycles through 
Cycle 48, then every 6 cycles thereafter. 
Updated because study was extended 
2 years. 
Updated footnotes to indicate electrocardiogram 
assessments will be made every 3 cycles through 
Cycle 48, then every 6 cycles thereafter. 
Updated because study was extended 
2 years. 
Updated footnotes to indicate pregnancy testing, in 
general, will be made every 3 cycles through Cycle 
48, then every 6 cycles thereafter. 
Updated because study was extended 
2 years. 
Updated footnotes to indicate hematology 
assessments will be made every 3 cycles through 
Cycle 48, then every 6 cycles thereafter. 
Updated because study was extended 
2 years. 
Updated footnotes to indicate serum chemistry 
assessments will be made every 3 cycles through 
Cycle 48, then every 6 cycles thereafter. 
Updated because study was extended 
2 years. 
Updated footnotes to indicate T/B/natural killer cell 
count assessments during Cycle 6 through Cycle 
24, would only be done at end of Cycle 6, 12, 18, 
and 24, and that during Cycle 27 through Cycle 48, 
assessments would be done every 6 cycles 
starting at Cycle 27. It was also noted that 
assessments after Cycle 48 are not required. 
Updated because study was extended 
2 years. 
Updated footnotes to indicate serum 
immunoglobulin and serum M protein will be done 
every 3 cycles starting at Cycle 6 and going 
through Cycle 48, then every 6 cycles thereafter. 
Updated because study was extended 
2 years. 
Updated footnotes to indicate patient-reported 
outcome assessments after Cycle 6 will be done 
every 6 cycles until documentation of progressive 
disease or use of alternative anticancer therapy.  
Changed from every 3 cycles to every 6 
cycles was made to reflect current standard 
of care. 
Updated footnotes to indicate that subjects who are 
hepatitis B core antibody positive (or have a known 
history of hepatitis B virus infection) should be 
monitored monthly with a quantitative polymerase 
chain reaction test for hepatitis B virus DNA, and 
the assessments will be made monthly from Cycle 
6 to Cycle 48 or early discontinuation, and then 
every 3 months thereafter. Also, assessments were 
changed from monthly to every 3 months during 
the discontinuation follow-up period and the long-
term follow-up period.  
Changed from monthly to every 3 months 
because subjects negative for hepatitis B 
surface antigen, positive for hepatitis B core 
antibodies, and negative for polymerase 
chain reaction results are considered low 
risk for reactivation and can be monitored 
quarterly. 

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Version: 8.0 (Global) 
Protocol: ACE-WM-001 
 
 
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Change 
Rationale 
Appendix 5 Actions Required in Cases of 
Increases in Liver Biochemistry and Evaluation 
of Hy’s Law 
 
Added the appendix for actions required in cases 
of increases in liver biochemistry and evaluation of 
Hy’s law. 
Added an appendix for Hy's law information 
to be consistent with protocols across the 
program. 
 

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TABLE OF CONTENTS 
PROTOCOL APPROVAL .................................................................................... 2 
SUMMARY OF AMENDMENT 8.0 ....................................................................... 3 
TABLE OF CONTENTS ....................................................................................... 8 
IN–TEXT TABLES ............................................................................................. 11 
IN–TEXT FIGURES ............................................................................................ 12 
LIST OF APPENDICES ..................................................................................... 12 
ABBREVIATIONS .............................................................................................. 13 
STUDY SYNOPSIS ............................................................................................ 16 
STUDY SCHEMA ............................................................................................... 24 
1.0 
BACKGROUND INFORMATION ............................................................ 25 
1.1 
Role of BTK in Lymphoid Cancers ........................................................... 25 
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 ........................................................ 31 
1.3 
Clinical Studies ........................................................................................ 31 
1.3.1 
Pharmacokinetics and Pharmacodynamics of Acalabrutinib in 
Clinical Pharmacology Studies ................................................... 31 
1.3.2 
Clinical Experience ..................................................................... 32 
1.4 
Benefit/Risk .............................................................................................. 33 
1.5 
Summary and Conclusions ...................................................................... 33 
2.0 
STUDY OBJECTIVES ............................................................................. 33 
2.1 
Primary Objective .................................................................................... 33 
2.2 
Secondary Objectives .............................................................................. 33 
2.3 
Exploratory Objective ............................................................................... 33 
3.0 
STUDY DESIGN ...................................................................................... 34 
3.1 
Description of Study ................................................................................. 34 
3.2 
Study Endpoints and Parameters ............................................................ 35 
3.2.1 
Co-Primary Endpoints ................................................................ 35 
3.2.2 
Secondary Endpoints ................................................................. 35 

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3.2.3 
Exploratory Endpoints ................................................................ 36 
3.2.4 
Safety Parameters ...................................................................... 36 
3.2.5 
Pharmacokinetic and Pharmacodynamic Parameters ................ 36 
3.3 
Rationale for Study Design and Dosing Regimen .................................... 36 
3.4 
Selection of Study Population .................................................................. 37 
3.4.1 
Inclusion Criteria ......................................................................... 37 
3.4.2 
Exclusion Criteria ....................................................................... 37 
3.4.3 
Replacement of Subjects ........................................................... 38 
3.4.4 
Enrollment Procedures ............................................................... 39 
3.5 
Study Drug ............................................................................................... 39 
3.5.1 
Premedications ........................................................................... 39 
3.5.2 
Formulation, Packaging, and Storage ........................................ 39 
3.5.3 
Administration of Study Drug ...................................................... 40 
3.5.4 
Assuring Subject Compliance..................................................... 40 
3.5.5 
Dose Delays ............................................................................... 40 
3.5.6 
Dose Modification and Discontinuation ...................................... 41 
3.6 
Concomitant Therapy............................................................................... 42 
3.6.1 
Permitted Concomitant Therapy ................................................. 42 
3.6.2 
Guideline for Use of CYP Inhibiting/Inducing Drugs ................... 42 
3.6.3 
Guideline for Use of Drugs that Affect Gastric pH ...................... 42 
3.6.4 
Prohibited Concomitant Therapy ................................................ 43 
3.7 
Risks Associated with Acalabrutinib Treatment ....................................... 43 
3.7.1 
Hemorrhage ............................................................................... 43 
3.7.2 
Infections .................................................................................... 43 
3.7.3 
Cytopenia ................................................................................... 44 
3.7.4 
Second Primary Malignancies .................................................... 44 
3.7.5 
Atrial Fibrillation .......................................................................... 45 
3.7.6 
Dietary Restrictions .................................................................... 45 
3.7.7 
Reproductive Toxicity ................................................................. 45 
3.7.8 
Overdose Instructions ................................................................ 47 
3.8 
Withdrawal of Subjects from Study Treatment ......................................... 47 
3.9 
Reasons for Study Exit ............................................................................ 48 
3.10 
Data and Safety Monitoring ..................................................................... 48 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS ........................................... 48 
4.1 
Description of Procedures ........................................................................ 49 
4.1.1 
Informed Consent ....................................................................... 49 
4.1.2 
Medical History ........................................................................... 49 
4.1.3 
Adverse Events .......................................................................... 49 
4.1.4 
Concomitant Medications and Therapy ...................................... 49 

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4.1.5 
Confirmation of Eligibility ............................................................ 49 
4.1.6 
ECOG Performance Status ........................................................ 49 
4.1.7 
Physical Examination, Vital Signs, Height& Weight .................... 50 
4.1.8 
Patient-Reported Outcomes ....................................................... 50 
4.1.9 
Bone Marrow Aspirate and Biopsy ............................................. 50 
4.1.10 Electrocardiogram ...................................................................... 50 
4.1.11 Urine or Serum Pregnancy Test ................................................. 51 
4.1.12 Hematology ................................................................................ 51 
4.1.13 Serum Chemistry ........................................................................ 51 
4.1.14 Urinalysis .................................................................................... 51 
4.1.15 T/B/NK Cell Count ...................................................................... 51 
4.1.16 Serum Immunoglobulin and Serum M protein ............................ 51 
4.1.17 HBV PCR Testing ....................................................................... 51 
4.1.18 Pharmacodynamics .................................................................... 52 
4.1.19 Pharmacokinetics ....................................................................... 52 
4.1.20 Molecular Testing ....................................................................... 52 
4.1.21 Extramedullary Disease Assessment ......................................... 52 
4.1.22 Study Drug Accountability .......................................................... 53 
4.1.23 Routine Clinical Assessments .................................................... 54 
4.2 
Investigator’s Assessment of Response to Treatment ............................. 54 
4.3 
Treatment Termination and Safety Follow-Up Visits ................................ 56 
4.4 
Follow-Up for Progression and Survival ................................................... 57 
4.5 
Missed Evaluations .................................................................................. 57 
5.0 
STATISTICAL METHODS OF ANALYSIS .............................................. 57 
5.1 
General Considerations ........................................................................... 57 
5.2 
Sample Size Considerations .................................................................... 58 
5.3 
Definition of Analysis Populations ............................................................ 58 
5.4 
Missing Data Handling ............................................................................. 58 
5.5 
Endpoint Data Analysis ............................................................................ 58 
5.5.1 
Safety Analysis ........................................................................... 58 
5.5.2 
Demographics and Baseline Characteristics .............................. 59 
5.5.3 
Analysis of Efficacy Parameters ................................................. 59 
5.5.4 
Analysis of Pharmacokinetic/Pharmacodynamic Parameters .... 60 
5.5.5 
Explorative or Correlative Analyses ............................................ 61 
5.5.6 
Patient-Reported Outcome ......................................................... 61 
5.6 
Interim Analysis ....................................................................................... 61 
5.7 
Primary and Final Analysis ...................................................................... 62 
6.0 
ASSESSMENT OF SAFETY ................................................................... 62 
6.1 
Definitions ................................................................................................ 62 

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6.1.1 
Adverse Events .......................................................................... 62 
6.1.2 
Serious Adverse Event ............................................................... 64 
6.1.3 
Adverse Events of Special Interest ............................................. 64 
6.1.4 
Severity ...................................................................................... 65 
6.1.5 
Adverse Drug Reactions ............................................................ 65 
6.2 
Documenting and Reporting of Adverse and Serious Adverse Events .... 65 
6.2.1 
Adverse Event Reporting Period ................................................ 65 
6.2.2 
Assessment of Adverse Events .................................................. 66 
6.2.3 
Pregnancy .................................................................................. 66 
6.2.4 
Expedited Reporting Requirements for Serious Adverse Events 
and Adverse Events of Special Interest ...................................... 67 
6.2.5 
Type and Duration of Follow-up of Subjects After Adverse Events
 ................................................................................................... 68 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ...... 68 
7.1 
Regulatory and Ethical Compliance ......................................................... 69 
7.2 
Institutional Review Board and Independent Ethics Committee ............... 69 
7.3 
Informed Consent and Protected Subject Health Information Authorization
 ................................................................................................................. 69 
7.4 
Subject Screening Log ............................................................................. 70 
7.5 
Case Report Forms ................................................................................. 70 
7.6 
Study Monitoring Requirements ............................................................... 70 
7.7 
Investigational Study Drug Accountability ................................................ 71 
7.8 
Record Retention ..................................................................................... 72 
7.9 
Protocol Amendments.............................................................................. 72 
7.10 
Publication of Study Results .................................................................... 73 
7.11 
Clinical Study Insurance .......................................................................... 73 
7.12 
General Investigator Responsibilities ....................................................... 73 
8.0 
REFERENCES ........................................................................................ 74 
9.0 
APPENDICES ......................................................................................... 76 
 
IN–TEXT TABLES 
Table 1. Drug Discontinuation Actions for Acalabrutinib ................................................41 
Table 2. Pharmacokinetic Sample Schedule .................................................................52 
Table 3. Response Assessment Criteria for Waldenström Macroglobulinemia (Owen 
2013) .....................................................................................................................55 
Table 4. Progressive Disease Criteria for Waldenström Macroglobulinemia (Owen 
2013) .....................................................................................................................55 
Table 5. Response Assessment for Waldenström Macroglobulinemia (Modified 3rd 
IWWM Workshop Criteria; Kimby 2006) .................................................................56 
Table 6. Progressive Disease Criteria for Waldenström Macroglobulinemia (Modified 
3rd IWWM Workshop Criteria; Kimby 2006) ...........................................................56 

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IN–TEXT FIGURES 
Figure 1. NK Cell Natural Cytotoxicity ............................................................................28 
Figure 2. In Vivo Thrombus Formation...........................................................................29 
 
LIST OF APPENDICES 
Appendix 1. 
Performance Status Scores .................................................................76 
Appendix 2. 
Adverse Event Assessment of Causality .............................................77 
Appendix 3. 
Known Strong In Vivo Inhibitors and Inducers of CYP3A .....................78 
Appendix 4. 
Schedule of Assessments ...................................................................79 
Appendix 5. 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ...........................................................................................83 

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ABBREVIATIONS 
Abbreviation 
Definition 
λz 
terminal elimination rate constant 
ACP-196 
acalabrutinib 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-12 
area under the plasma concentration-time curve from 0 to 12 hours, 
calculated using linear trapezoidal summation 
AUC0-24calc 
area under the plasma concentration-time curve from 0 to 24 hours, 
calculated by doubling the value for AUC0-12 
AUC0-inf 
area under the plasma concentration-time curve from 0 to infinity, 
calculated using the formula:  AUC0-inf = AUC0-last + Ct / λz, where λz is the 
apparent terminal elimination rate constant 
AUC0-last 
area under the plasma concentration-time curve calculated using linear 
trapezoidal summation from time 0 to time last, where “last” is the time of 
the last measurable concentration 
BCL-2 
B-cell lymphoma 2 
BCR 
B-cell receptor 
BID 
twice a day 
BTK 
Bruton tyrosine kinase 
CL/F 
oral clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed plasma concentration 
CR 
complete response 
CRF 
case report form 
CSSF 
Clinical Supplies Shipping Receipt Form 
Ct 
concentration 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DOR 
duration of overall response 
ECG 
electrocardiogram 

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Abbreviation 
Definition 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
epidermal growth factor receptor 
EORTC 
European Organisation for Research and Treatment of Cancer 
FDA 
Food and Drug Administration 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
hERG 
human ether-à-go-go-related gene 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IFE 
immunofixation electrophoresis 
Ig 
immunoglobulin 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITK 
interleukin-2-inducible T-cell kinase 
IWWM 
International Workshops on Waldenström Macroglobulinemia 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
minor response 
MRI 
magnetic resonance imaging 
NK 
natural killer (cells) 
NOAEL 
no observable adverse effect level 
OATP 
organic-anion-transporting polypeptide 
ORR 
overall response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic 
PFS 
progression-free survival 
PI3K 
phosphoinositide-3 kinase 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial response 
PRO 
Patient-Reported Outcomes 
QD 
once a day 
QTc 
corrected QT interval 
SAE 
serious adverse event 

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Abbreviation 
Definition 
SFU 
safety follow-up 
SPEP 
serum protein electrophoresis 
SUSAR 
Suspected Unexpected Serious Adverse Reaction (report) 
SYK 
spleen tyrosine kinase 
t½ 
terminal elimination half-life 
Tmax 
time to maximum drug concentration 
TT 
treatment termination 
ULN 
upper limit of normal 
VGPR 
very good partial response  
VWF 
von Willebrand Factor 
Vz/F 
volume of distribution 
WM 
Waldenström macroglobulinemia 

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STUDY SYNOPSIS 
Protocol Number: 
ACE-WM-001 
Study Drug: 
ACP-196 (acalabrutinib) 
Protocol Title: 
An Open-label, Phase 2 Study of ACP-196 in Subjects with 
Waldenström Macroglobulinemia3 
Phase: 
Phase 2 
Comparator: 
None 
Background and 
Rationale for Study 
Clinical studies have shown that targeting the B-cell receptor 
(BCR) signaling pathway by inhibiting Bruton tyrosine kinase 
(BTK) produces significant clinical benefit in patients with non-
Hodgkin lymphoma, including Waldenström macroglobulinemia 
(WM).  Ibrutinib (IMBRUVICA®), an oral, small-molecule BTK 
inhibitor has been approved for the treatment for chronic 
lymphocytic leukemia (CLL), mantle cell lymphoma, and WM. 
Acerta Pharma BV (Acerta Pharma) has developed a novel BTK 
inhibitor, acalabrutinib, that achieves significant oral bioavailability 
and potency in preclinical models.  
The purpose of this study is to evaluate the safety, 
pharmacokinetics, pharmacodynamics, and activity of 
acalabrutinib in treating subjects with WM. 
Study Design: 
This study is a multicenter (approximately 30 global centers) 
open-label clinical study evaluating the safety and efficacy of 
acalabrutinib 100 mg twice a day (BID) in subjects with previously 
treated WM (N=76) using a Simon's optimal 2-stage design.  In 
addition, a small cohort (N=8–12) of subjects with treatment-naive 
WM will be enrolled as an exploratory cohort to determine the 
preliminary safety and efficacy of acalabrutinib in this patient 
population.  In The Netherlands and France, enrollment for the 
untreated WM cohort will begin after efficacy has been confirmed 
in Stage 1 of the Simon's optimal 2-stage design; in other 
locations, both previously treated and untreated cohorts will be 
enrolled simultaneously. 
Twenty-eight days of study drug administration is 1 cycle.  
Treatment with acalabrutinib may be continued until disease 
progression or an unacceptable drug-related toxicity occurs. Dose 
modification provisions are provided in the 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 3.8 for more information on 
assessing disease progression under these circumstances.  A 
                                               
3In Italy only, the original protocol title “An Open-label, Phase 1b/2 Study of ACP-196 in Subjects with 
Waldenström Macroglobulinemia” remains in effect. 

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treatment termination (TT) visit is required for safety assessments 
for any subjects who permanently discontinue study drug for any 
reason (except for death, loss to follow-up or withdrawal of 
consent), including disease progression, and should be scheduled 
within 7 days of his or her last dose of study drug, if possible.  In 
addition to the TT visit, all subjects who discontinue acalabrutinib 
will have a safety follow-up (SFU) visit 30 (+7) days after the last 
dose of study drug to monitor for resolution or progression of 
adverse events (AEs) and to document the occurrence of any 
new events, regardless of whether the subject receives a new 
anticancer therapy or demonstrates disease progression within 
this timeframe. Refer to Section 4.4 for information on follow-up 
for progression and survival.   
All subjects will have standard hematology, chemistry, and 
urinalysis safety panels done at screening.  Once dosing 
commences (Day 1), all subjects will be evaluated for safety, 
including serum chemistry and hematology according to 
Appendix 4.  Pharmacokinetic (PK) testing will be done in Cycle 1 
only, and pharmacodynamic (PD) testing will be done in Cycle 1 
and Cycle 2.  PK/PD will be done on all subjects in the treatment-
naive cohort and on up to 12 subjects in the previously treated 
cohort. 
Assessments for efficacy will be completed throughout the study 
as per Appendix 4.   
A single, interim analysis (see Section 5.6) of overall response 
rate (ORR) will be performed when subjects from Stage 1 
(28 subjects) are evaluable for response. 
Refer to Appendix 4 for a comprehensive list of study 
assessments and their timing. The end of study is defined as the 
last subject’s last visit.  The sponsor may terminate the study at 
any time. Subjects who are deriving clinical benefit from 
acalabrutinib may continue on study until a rollover protocol is 
available.  The study duration is expected to be approximately 
6 years from enrollment of the last subject.  A study schema is 
provided at the end of this synopsis.   
Study Objectives: 
Primary Objective: 
To determine the ORR of acalabrutinib in subjects with WM as 
assessed by the investigator. 
Secondary Objectives: 
• 
To determine the duration of overall response (DOR) of 
acalabrutinib assessed by the investigator  
• 
To determine the progression-free survival (PFS) of 
acalabrutinib assessed by the investigator  
• 
To determine the overall survival (OS) of acalabrutinib 

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• 
To characterize the PK profile of acalabrutinib  
• 
To characterize the safety of acalabrutinib 
• 
To evaluate the effect of acalabrutinib in health-related 
quality of life 
Exploratory Objective: 
• 
To evaluate the PD effects of acalabrutinib  
Study Endpoints: 
Co-Primary endpoints: 
• 
ORR, defined as a subject achieving a minor response 
(MR) or better according to the response assessment 
criteria for WM (Owen 2013), as assessed by the 
investigator 
• 
ORR, defined as a subject achieving a MR or better 
according to the response assessment criteria defined by 
modified 3rd International Workshops on Waldenström 
Macroglobulinemia (IWWM) workshop criteria (Kimby 
2006), as assessed by the investigator 
Secondary endpoints: 
Efficacy: 
• 
DOR assessed by the investigator using response 
assessment criteria for WM (Owen 2013) and modified 3rd 
IWWM workshop criteria (Kimby 2006) 
• 
PFS assessed by the investigator using response 
assessment criteria for WM (Owen 2013) and modified 3rd 
IWWM workshop criteria (Kimby 2006) 
• 
OS 
• 
Effect of acalabrutinib on peripheral T/B/natural killer (NK) 
cell counts 
• 
Effect of acalabrutinib on serum immunoglobulin levels 
Safety: 
• 
Frequency, severity, and relatedness of AEs 
• 
Frequency of AEs requiring discontinuation of study drug 
or dose reductions 
Pharmacokinetics: 
• 
Plasma pharmacokinetics of acalabrutinib 
Patient-Reported Outcomes (PRO): 
• 
Health-related quality of life 
Exploratory endpoints: 
Pharmacodynamics: 
• 
BTK occupancy and biologic markers of B-cell function 

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Pharmacokinetic 
Parameters: 
The plasma PK of acalabrutinib will be characterized using 
noncompartmental analysis.  The following PK parameters will be 
calculated, whenever possible, from plasma concentrations of 
acalabrutinib: 
• 
AUC0-last:  Area under the plasma concentration-time curve 
calculated using linear trapezoidal summation from time 0 
to time last, where “last” is the time of the last measurable 
concentration (Ct). 
• 
AUC0-12:  Area under the plasma concentration-time curve 
from 0 to 12 hours, calculated using linear trapezoidal 
summation. 
• 
AUC0-inf:  Area under the plasma concentration-time curve 
from 0 to infinity, calculated using the formula:  AUC0-inf = 
AUC0-last + Ct / λz, where λz is the apparent terminal 
elimination rate constant. 
• 
AUC0-24calc:  Area under the plasma concentration-time 
curve from 0 to 24 hours, calculated by doubling the value 
for AUC0-12 
• 
Cmax:  Maximum observed plasma concentration 
• 
Tmax:  Time of the maximum plasma concentration 
(obtained without interpolation) 
• 
t½:  Terminal elimination half-life (whenever possible) 
• 
λz: Terminal elimination rate constant (whenever possible) 
• 
CL/F:  Oral clearance 
• 
Vz/F:  Oral volume of distribution 
Pharmacodynamic 
Parameters: 
The occupancy of BTK by acalabrutinib will be measured in 
peripheral blood mononuclear cells and in bone marrow, when 
available, with the aid of a biotin-tagged acalabrutinib analogue 
probe.  The effect of acalabrutinib on biologic markers of B-cell 
function will also be evaluated. 
Sample Size: 
The Simon's optimal 2-stage portion of the study for evaluation of 
efficacy in subjects with previously treated WM will be 
approximately 76 subjects. 
The exploratory cohort in subjects with treatment-naive WM will 
enroll approximately 8 to 12 subjects. 
Inclusion Criteria: 
• 
Men and women ≥18 years of age. 
• 
Previously treated cohort only:  A confirmed diagnosis of 
WM, which has relapsed after, or been refractory to 
≥1 prior therapy for WM and which requires treatment. 

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• 
Treatment-naive cohort only:  A confirmed diagnosis of 
treatment-naive WM in subjects who require treatment and 
do not want to receive chemoimmunotherapy or have 
comorbidities that would preclude chemoimmunotherapy 
such as: 
o Symptomatic hyperviscosity with an 
immunoglobulin (Ig) M ≥5,000 mg/dL  
o Disease-related neuropathy 
• 
Serum concentration of IgM, as measured by serum 
protein electrophoresis (SPEP) and immunofixation 
electrophoresis (IFE), that exceeds the upper limits of 
normal or measurable nodal WM (defined as the presence 
of ≥1 lymph node that measures ≥2.0 cm in the longest 
diameter and ≥1.0 cm in the longest perpendicular 
diameter).  
• 
Eastern Cooperative Oncology Group (ECOG) 
performance status of ≤2. 
• 
Women who are sexually active and can bear children 
must agree to use highly effective forms of contraception 
during the study and for 2 days after the last dose of 
acalabrutinib.  Highly effective forms of contraception are 
defined in Section 3.7.7. 
• 
Willing and able to participate in all required evaluations 
and procedures in this study protocol including swallowing 
capsules without difficulty. 
• 
Ability to understand the purpose and risks of the study 
and provide signed and dated informed consent and 
authorization to use protected health information (in 
accordance with national and local patient privacy 
regulations). 
Exclusion Criteria: 
• 
Prior malignancy, except for adequately treated basal cell 
or squamous cell skin cancer, in situ cervical cancer, or 
other cancer from which the subject has been disease free 
for ≥2 years or which will not limit survival to <2 years. 
Note:  These cases must be discussed with the medical 
monitor. 
• 
A life-threatening illness, medical condition, or organ 
system dysfunction which, in the investigator’s opinion, 
could compromise the subject’s safety, interfere with the 
absorption or metabolism of acalabrutinib, or put the study 
outcomes at undue risk. 
• 
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 

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Heart Association Functional Classification, or corrected 
QT interval (QTc) >480 msec. 
• 
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. 
• 
Any immunotherapy within 4 weeks of first dose of study 
drug. 
• 
For subjects with recent chemotherapy or experimental 
therapy, the first dose of study drug must occur after 
5 times the half-life of the agent(s). 
• 
Prior exposure to a BCR inhibitor (e.g., BTK, 
phosphoinositide-3 kinase [PI3K], or spleen tyrosine 
kinase [SYK] inhibitors) or B-cell lymphoma 2 (BCL-2) 
inhibitor (e.g., ABT-199). 
• 
Ongoing immunosuppressive therapy, including systemic 
or enteric corticosteroids, for treatment of WM or other 
conditions.  Note:  Subjects may use topical or inhaled 
corticosteroids or low-dose steroids (≤10 mg of prednisone 
or equivalent per day) as therapy for comorbid conditions.  
During study participation, subjects may also receive 
systemic or enteric corticosteroids as needed for 
treatment-emergent comorbid conditions. 
• 
Grade ≥2 toxicity (other than alopecia) continuing from 
prior anticancer therapy including radiation. 
• 
Known history of HIV or active infection with hepatitis C 
virus (HCV) or hepatitis B virus (HBV) or any uncontrolled 
active systemic infection. 
• 
Major surgery within 4 weeks before first dose of study 
drug. 
• 
Uncontrolled autoimmune hemolytic anemia or idiopathic 
thrombocytopenia purpura. 
• 
History of a bleeding diathesis (e.g., hemophilia, von 
Willebrand disease). 
• 
History of stroke or intracranial hemorrhage within 
6 months before the first dose of acalabrutinib. 
• 
Requires or receiving anticoagulation with warfarin or 
equivalent vitamin K antagonist (e.g., phenprocoumon) 
within 28 days of first dose of study drug. 
• 
Requires treatment with proton-pump inhibitors (e.g., 
omeprazole, esomeprazole, lansoprazole, 
dexlansoprazole, rabeprazole, or pantoprazole). 
• 
Absolute neutrophil count (ANC) <0.75 x 109/L or platelet 
count <50 x 109/L.  For subjects with disease involvement 

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in the bone marrow, ANC <0.50 x 109/L or platelet count 
<30 x 109/L. 
• 
Creatinine >2.5 x institutional ULN; total bilirubin >2.5 x 
ULN; or aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) >3.0 x ULN. 
• 
Lactating or pregnant. 
• 
Concurrent participation in another therapeutic clinical 
study. 
Dosage Form and 
Strength: 
Acalabrutinib is provided as hard gelatin capsules prepared using 
standard pharmaceutical grade excipients.  
Dose Regimen/Route 
of Administration: 
Acalabrutinib is an orally administered product.  Acalabrutinib can 
be administered with or without food.  
Acalabrutinib 100 mg administered BID, 12 hours apart (BID 
dosing = total daily dose of 200 mg).  It is recommended that 
acalabrutinib be taken as close to the scheduled time as possible 
(preferably within 1 hour).  However, if a dose is missed, it can be 
taken up to 3 hours after the scheduled time with a return to the 
normal schedule with the following dose.   
Concomitant 
Medications: 
The effect of agents that reduce gastric acidity (antacids or 
proton-pump inhibitors) 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 for a period of at least 
2 hours before and at least 2 hours after taking acalabrutinib.  
Use of omeprazole, esomeprazole, lansoprazole or any other 
proton-pump inhibitors while taking acalabrutinib is not 
recommended due to a potential decrease in study drug 
exposure. However, the decision to treat with proton-pump 
inhibitors during the study is at the investigator’s discretion, with 
an understanding of the potential benefit to the subject’s 
gastrointestinal condition and a potential risk of decreased 
exposure to acalabrutinib. 
Although the effect of H2-receptor antagonists (such as 
famotidine or ranitidine) on acalabrutinib absorption has not been 
evaluated, if treatment with an H2-receptor antagonist is required, 
the H2-receptor antagonist should be taken approximately 
2 hours after an acalabrutinib dose. 
Concomitant use of strong inhibitors/inducers of cytochrome P450 
(CYP) 3A should be avoided when possible.  If a subject requires 
a strong or moderate CYP3A inhibitor while on study, monitor the 
subject closely for potential toxicities. 

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Statistical Methods: 
Simon's optimal 2-stage design for assessment of efficacy in 
previously treated subjects: 
 
 
 
 
 
 
 
 
 
 
  
Exploratory cohort for assessment of efficacy in treatment-naive 
subjects: 
No formal statistical tests of hypotheses will be performed.  Eight 
to 12 evaluable subjects will be enrolled in this cohort for 
evaluation of preliminary efficacy and safety in this patient 
population. 
Descriptive statistics (including means, standard deviations, and 
medians for continuous variables and proportions for discrete 
variables) will be used to summarize data, as appropriate. 

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1.0 
BACKGROUND INFORMATION 
1.1 
Role of BTK in Lymphoid Cancers 
BTK is a non-receptor enzyme of the Tec kinase family that is expressed among cells of 
hematopoietic origin, including B cells, myeloid cells, mast cells and platelets, where it 
regulates multiple cellular processes including proliferation, differentiation, apoptosis, 
and cell migration (Mohamed 2009, Bradshaw 2010). Functional null mutations of BTK in 
humans cause the inherited disease, X-linked agammaglobulinemia, which is 
characterized by a lack of mature peripheral B cells (Vihinen 2000).  Conversely, BTK 
activation is implicated in the pathogenesis of several B-cell malignancies (Buggy 2012).  
Taken together, these findings have suggested that inhibition of BTK may offer an 
attractive strategy for treating B-cell neoplasms. 
Ibrutinib (IMBRUVICA®), an oral, small-molecule BTK inhibitor has been approved for 
the treatment for CLL, mantle cell lymphoma (MCL), and WM.  
While highly potent in inhibiting BTK, ibrutinib has also shown in vitro activity against 
other kinases with a cysteine in the same position as Cys481 in BTK to which the drug 
covalently binds.  The inhibition of epidermal growth factor receptor (EGFR) is also 
observed in cellular assays and may be the cause of ibrutinib-related AEs of diarrhea 
and rash (IMBRUVICA® prescribing information).  In addition, ibrutinib is a substrate for 
CYP3A4; inhibition of CYP3A causes a 29-fold increase in Cmax and 24-fold increase in 
AUC for ibrutinib (IMBRUVICA® prescribing information).  This increases the possibility 
of drug-drug interactions in combination therapies with drugs currently used in 
management of subjects with cancer.  These liabilities support the development of 
alternative BTK inhibitors for use in the therapy of B-cell malignancies. 
Chemical optimization, pharmacologic characterization, and toxicologic evaluation have 
led to identification of acalabrutinib (also known as ACP-196), 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.  Key nonclinical differentiators of 
acalabrutinib versus ibrutinib are: 
• 
Acalabrutinib has been evaluated against ibrutinib in EGFR-expressing cell lines.  
Ibrutinib is a potent covalent inhibitor of EGFR (EC50=5.3 nM).  Acalabrutinib did 
not inhibit EGFR, even at the highest concentration tested (10 μM). 

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• 
Acalabrutinib and ibrutinib have been evaluated in NK cell functional assays.  
While ibrutinib inhibits NK cell functions including antibody-dependent cellular 
cytotoxicity (ADCC), lytic granule release and cytokine production (Kohrt 2014), 
the in vitro functional activity of acalabrutinib-treated NK cells was preserved. 
• 
Acalabrutinib has been evaluated against ibrutinib in an in vivo thrombus 
formation model.  Platelets from CLL patients treated with acalabrutinib had 
similar thrombus formation dynamics as platelets from healthy volunteers, while 
platelets from ibrutinib-treated CLL patients had impaired thrombus formation. 
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.   
1.2 
Preclinical Studies 
Summaries of preclinical studies are provided below.  For more detailed information, 
refer to the acalabrutinib Investigator Brochure.  
1.2.1 
Chemistry 
Acalabrutinib is an imidazopyrazine analogue with a molecular weight of 465.5 g/mol.  
The compound has 1 stereogenic center and acalabrutinib is the S-enantiomer.  
Acalabrutinib is orally bioavailable in humans and is suitable for formulating in capsules.  
For clinical testing, acalabrutinib has been manufactured and formulated according to 
current Good Manufacturing Practices. 
Calquence® has been approved in the United States on October 31, 2017 and other 
markets for the treatment of adult patients with MCL who have received at least 1 prior 
therapy. 
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 as seen with ibrutinib.  When profiled against 
395 human kinases, acalabrutinib is 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, 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 
was evaluated in a dose-escalation study in canine spontaneous B-cell lymphoma 
(Harrington 2016).  Twenty dogs were enrolled in the study and treated with 
acalabrutinib at dosages of 2.5 to 20 mg/kg every 12 or 24 hours. Acalabrutinib was 
generally well tolerated, with AEs consisting primarily of grade 1 or 2 anorexia, weight 
loss, vomiting, diarrhea and lethargy. Per Veterinary Cooperative Oncology Group 
criteria for assessment of response in peripheral nodal lymphoma (Vail 2010), the ORR 
was 25% (5/20) with a median PFS of 22.5 days. Clinical benefit was observed in 30% 
(6/20) of dogs.  These findings suggest that acalabrutinib is safe and exhibits activity in 
canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant 
model for human non-Hodgkin lymphoma.  These findings are similar to the responses 
(i.e., 1 dog with partial response (PR) out of 5 dogs treated with suspected or confirmed 
diffuse large B-cell lymphoma) observed with ibrutinib in dogs with spontaneous B-cell 
lymphoma (Honigberg 2010). 
1.2.4 
Acalabrutinib and Antibody-dependent Cell-mediated 
Cytotoxicity 
As acalabrutinib is not an inhibitor of interleukin-2-inducible T-cell kinase (ITK) kinase, it 
is expected to have less activity against non-malignant cells that require ITK for 
development and functional activation, such as T and NK cells. ITK kinase is required for 
Fc receptor-stimulated NK cell function including calcium mobilization, granule release, 
and overall ADCC.  Anti-CD20 antibodies are standard of care drugs, often as part of 
combination regimens, for the treatment of CD20+ B-cell malignancies; obinutuzumab 
has been specifically designed to increase Fc interactions and promote ADCC and 
phagocytosis of malignant CD20+ cells.  Ibrutinib has been evaluated for effects on NK 
activity, including ADCC, using in vitro assays of cytokine release, lytic granule release, 
and cellular cytotoxicity (Kohrt 2014). In contrast to more specific BTK inhibitors, ibrutinib 
inhibited all these NK cell functions, and impaired NK activity against rituximab-coated 
autologous CLL cells and in mouse tumor models requiring Fc-mediated effector 
functions (Kohrt 2014).  Acalabrutinib was tested in ADCC and natural cytotoxicity 
assays, using cells from healthy donors.  In these in vitro tests, NK cell function was 
preserved with acalabrutinib treatment, whereas ibrutinib inhibited functional activity, 
including natural cytotoxicity against K562 cells.  

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Figure 1. NK Cell Natural Cytotoxicity 
 
Peripheral blood mononuclear cells were cultured with 51Cr labelled K562 targets at an E:T ratio of 100:1 for 
4 hours.  Cytotoxicity was evaluated by scintillation counting of supernatants. Treatment, dose and 
interaction effect were significant in 2-way ANOVA (n=5 healthy donors; ibrutinib v. acalabrutinib p<0.0001; 
all ibrutinib doses p<0.0001 compared with control; p=0.0117 for control vs. acalabrutinib 1 µM, other 
acalabrutinib doses not statistically different from control condition).   
1.2.5 
Acalabrutinib and Thrombus Formation 
Ibrutinib is associated with an increased risk of bleeding (Kamel 2014).  Hence, the 
effects of acalabrutinib and ibrutinib were evaluated on human platelet-mediated 
thrombus formation by using the in vivo human thrombus formation in a von Willebrand 
Factor (VWFHA1) murine model, which has been previously described (Chen 2008). The 
in vivo function of platelets isolated from blood of healthy volunteers (n=5), CLL subjects 
treated with 420 mg once a day (QD) ibrutinib (n=5) or CLL subjects treated with 100 mg 
BID acalabrutinib (n=3) was evaluated in the VWFHA1 model.  Results from this study 
showed a reduction in platelet-vessel wall interactions of platelets from ibrutinib-treated 
CLL subjects, but not of those from CLL subjects treated with acalabrutinib (Byrd 2016).   
C o n tr o l 0 .2 5  u M
0 .5  u M
1  u M
0
5 0
1 0 0
K 5 6 2  C y to to x ic ity  (%  L y s is )
A c a la b ru tin ib
Ib ru tin ib

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Figure 2. In Vivo Thrombus Formation 
 
Platelets from patients treated with ibrutinib 420 mg once per day (n=5) or acalabrutinib 100 mg twice per 
day (n=3) were evaluated for their ability to support thrombus formation in laser injured arterioles of VWFHA1 
mice. Freshly isolated platelets from healthy volunteers (n=5) were used as non-drug treated controls. A 
minimum of 4 arterioles per mouse was used to assess thrombus formation for each patient/volunteer 
sample. Median fluorescence intensity as a function of time is provided in the figure (shading denotes 
standard error of the median). 
1.2.6 
Safety Pharmacology 
In vitro and in vivo safety pharmacology studies with acalabrutinib have demonstrated a 
favorable nonclinical safety profile.  
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 an IC50 of 
4.5 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 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 

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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 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 
Based on available preclinical and clinical data, acalabrutinib is cleared by multiple CYP 
and non-CYP metabolic pathways.  CYP3A-mediated oxidation appears to be a major 
route of metabolism in humans.  In excretion studies in preclinical species, metabolites 
were mainly related to direct conjugation of acalabrutinib with glutathione and 
conjugation with glutathione in vitro was mediated primarily by human glutathione 
transferases GSTM1 and GSTM2.  Metabolites also arose from oxidation (CYP3A) and 
amide hydrolysis, or combinations thereof.   
In a healthy volunteer study (ACE-HV-001), the effect of co-administration of a potent 
CYP3A and P-glycoprotein inhibitor, itraconazole, on the plasma levels of acalabrutinib 
was evaluated.  The mean plasma acalabrutinib Cmax and AUC0-inf values increased 
3.7-fold and 5.1-fold, respectively, in the presence of itraconazole relative to no 
pretreatment.  In a healthy volunteer study (ACE-HV-004) rifampin, a strong CYP3A 
inducer, dosed at 600 mg QD for 9 days decreased AUC to 23% of values obtained with 
acalabrutinib dosed alone.  Refer to Section 3.6.2 for detailed recommendations on 
concomitant administration of acalabrutinib with strong CYP3A inhibitors or inducers. 
Results from a healthy volunteer study (ACE-HV-004) also showed drugs that reduce 
gastric acidity can lower acalabrutinib exposure.  Refer to Section 3.6.3 for detailed 
recommendations regarding co-administration of acalabrutinib with agents that reduce 
gastric acidity.  
Acalabrutinib is unlikely to be a perpetrator of a drug-drug interaction at the level of 
inhibition or induction of CYP isoforms. 
Results from drug transporter studies suggest that acalabrutinib is not anticipated to alter 
the PK of other therapeutic agents that are substrates for multidrug resistance protein 1, 
organic-anion-transporting polypeptide (OATP)1B1, OATP1B3, OAT1, OAT3, and 
OCT2.  Acalabrutinib is a substrate and inhibitor of breast cancer resistance protein and 
may alter the PK of coadministered breast cancer resistance protein substrates. 

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Refer to the acalabrutinib Investigator Brochure for additional details on acalabrutinib 
PK; absorption, distribution, metabolism, and excretion; and drug interaction studies. 
1.2.8 
In Vivo General Toxicology 
The systemic toxicity of acalabrutinib has been fully evaluated in repeat-dose 
sub-chronic studies in mice, rats and dogs, reproductive toxicity studies in rats and 
rabbits, and ongoing chronic studies in rats and dogs.  The pivotal GLP studies were 
28- and 91-day repeat dose studies in rats and dogs, each with recovery periods to 
assess the reversibility of observed changes. 
In rats, 100 mg/kg/day was selected initially to represent the highest non-severely toxic 
dose; however, in subsequent studies the 100 mg/kg/day dose level was determined to 
be a no observable adverse effect level (NOAEL). In rats, the target organs of toxicity 
were the kidney, liver and heart.   
The NOAEL in the dog was 30 mg/kg/day; dose levels higher than 30 mg/kg/day were 
not tolerated. In dogs, the target organs of toxicity, observed only at doses exceeding 
the maximum tolerated dose, were the kidney and liver. Heart findings were also 
observed in 2 dogs with kidney toxicity, which were interpreted as possibly secondary to 
uremia, as has been reported for this species.   
In rats and dogs, no adverse ECG or histopathologic cardiovascular effects were noted 
at the planned conclusion of the sub-chronic studies or in the rat chronic toxicity study.  
However, in 5 of 6 rats from the 4-week study that died early, slight to moderate necrosis 
of the myocardium and/or white blood cell infiltration/inflammation of the myocardium 
were noted on microscopic examination of the hearts.   
1.3 
Clinical Studies 
A list of completed and ongoing clinical studies is provided in the acalabrutinib 
Investigator Brochure. 
1.3.1 
Pharmacokinetics and Pharmacodynamics of Acalabrutinib in 
Clinical Pharmacology Studies 
PK properties of acalabrutinib in healthy adult volunteers were evaluated after oral 
administration of 2 daily divided doses of 2.5 to 50 mg and a single dose of 100 mg 
(ACE-HV-001). Acalabrutinib Tmax values were between 0.5 and 1.0 hour for all dose 
cohorts, and were independent of dose level.  Mean t1/2 values ranged from 0.97 hour to 
2.1 hours.  Exposure increases were approximately linear from 25 mg up to and beyond 

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therapeutic doses of 100 or 200 mg. Rapid elimination was observed.  Acalabrutinib 
does not accumulate with daily administration. Similar PK results were observed in 
subjects with CLL treated with acalabrutinib.  In healthy subjects and subjects with CLL, 
dose-related increases in BTK occupancy were attained, and relatively high BTK 
occupancy (>90%) was observed with a single dose of 100 mg.  
Administration of acalabrutinib with a high-fat, high-calorie meal did not have a clinically 
significant effect on exposure so acalabrutinib can be taken without regard to meals.  In 
healthy volunteer studies, agents that lowered gastric acidity (e.g., calcium carbonate 
and omeprazole) lowered exposure of concomitantly administered acalabrutinib.  
Acalabrutinib is unlikely to be a perpetrator of a drug-drug interaction at the level of 
inhibition or induction of CYP isoforms.  However, the mean plasma acalabrutinib Cmax 
and AUC values increased 3.7- and 5.1-fold, respectively, in the presence of 
itraconazole, a strong CYP3A inhibitor, relative to no pretreatment.  Rifampin, a strong 
CYP3A inducer, dosed at 600 mg QD for 9 days decreased AUC to 23% of values 
obtained with acalabrutinib dosed alone. 
For more detailed information on acalabrutinib clinical pharmacology studies, refer to the 
acalabrutinib Investigator Brochure. 
1.3.2 
Clinical Experience 
As of 30 December 2018, acalabrutinib has been administered to over 2600 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 serious adverse events (SAEs) have been reported in 
the completed hepatic impairment study (Study ACE-HI-001) or in the healthy volunteer 
studies. For more detailed information on the clinical experience for acalabrutinib, refer 
to the Investigator Brochure.   
Study ACE-CL-001 (NCT02029443) is an ongoing, nonrandomized, sequential group, 
dose-escalation Phase 1/2 study in subjects with CLL, including subjects with 
relapsed/refractory CLL, treatment-naive subjects, ibrutinib-intolerant subjects, and 
subjects with Richter’s syndrome or prolymphocytic leukemia transformation.  As of 
01 December 2017, 134 subjects with relapsed/refractory CLL have been evaluated for 
tumor response based on International Working Group response criteria (Hallek 2008) 
as recently updated (Cheson 2012) to include PR with treatment-induced lymphocytosis.  
With a median time on study of 31.8 months, an ORR of 96.2% has been observed in 

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these subjects.  Preliminary data through 04 September 2018 are also available for 
99 enrolled subjects with treatment-naive CLL.  With a median time on study of 
41.6 months, the ORR was 99% in these subjects. 
1.4 
Benefit/Risk 
Acalabrutinib is a potent, orally administered small molecule inhibitor of BTK.  A PK/PD 
study has been completed with acalabrutinib in healthy volunteers (ACE-HV-001; 
Section 1.3.2).  The safety results showed no identified safety risks in healthy subjects 
receiving 1 or 2 days of acalabrutinib ≤100 mg.  In Study ACE-CL-001, no dose-limiting 
toxicities were reported at dosages of ≤400 mg QD or 100 and 200 mg BID.  Based on 
the results for subjects with CLL and other B-cell malignancies, the evaluation of 
acalabrutinib in subjects with WM is warranted.   
1.5 
Summary and Conclusions 
The design and conduct of this study are supported by an understanding of the natural 
history and current therapies for subjects with lymphoid cancers; knowledge of the 
efficacy and safety of the first-generation BTK inhibitor (ibrutinib) in subjects with 
hematologic cancers; and the available nonclinical and clinical information regarding 
acalabrutinib.  
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To determine the ORR of acalabrutinib in subjects with WM as assessed by the 
investigator. 
2.2 
Secondary Objectives 
• 
To determine the DOR of acalabrutinib assessed by the investigator  
• 
To determine the PFS of acalabrutinib assessed by the investigator  
• 
To determine the OS of acalabrutinib 
• 
To characterize the PK profile of acalabrutinib 
• 
To characterize the safety of acalabrutinib 
• 
To evaluate the effect of acalabrutinib in health-related quality of life 
2.3 
 
 
 

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3.0 
STUDY DESIGN 
3.1 
Description of Study 
This study is a multicenter (approximately 30 global centers), open-label clinical study 
evaluating the safety and efficacy of acalabrutinib 100 mg BID in subjects with previously 
treated WM (N=76) using a Simon's optimal 2-stage design (Simon 1989).  In addition, a 
small cohort (N=8–12) of subjects with treatment-naive WM will be enrolled as an 
exploratory cohort to determine the preliminary safety and efficacy of acalabrutinib in this 
patient population.  In The Netherlands and France, enrollment for the untreated WM 
cohort will begin after efficacy has been confirmed in Stage 1 of the Simon's optimal 
2-stage design; in other locations, both previously treated and untreated cohorts will be 
enrolled simultaneously. 
Twenty-eight days of study drug administration is 1 cycle.  Treatment with acalabrutinib 
may be continued until disease progression or an unacceptable drug-related toxicity 
occurs.  Dose modification provisions are provided in the protocol (Section 3.5.6).  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 3.8 for more 
information on assessing disease progression under these circumstances.  A TT visit is 
required for safety assessments for any subjects who permanently discontinue study 
drug for any reason (except for death, loss to follow-up, or withdrawal of consent), 
including disease progression, and should be scheduled within 7 days of his or her last 
dose of study drug, if possible.  In addition to the TT visit, all subjects who discontinue 
acalabrutinib will have a SFU visit 30 (+7) days after the last dose of study drug to 
monitor for resolution or progression of AEs and to document the occurrence of any new 
events, regardless of whether the subject receives a new anticancer therapy or 
demonstrates disease progression within this timeframe.  Refer to Section 4.4 for 
information on follow-up for progression and survival.   
All subjects will have standard hematology, chemistry, and urinalysis safety panels done 
at screening.  Once dosing commences (Day 1), all subjects will be evaluated for safety, 
including serum chemistry and hematology according to Appendix 4.  PK testing will be 
done in Cycle 1 only and PD testing will be done in Cycle 1 and Cycle 2.  PK/PD will be 
done on all subjects in the treatment-naive cohort and on up to 12 subjects in the 
previously treated cohort. 
Assessments for efficacy will be completed throughout the study as per Appendix 4.   

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A single interim analysis (see Section 5.6) of ORR will be performed when subjects from 
Stage 1 (28 subjects) are evaluable for response. 
Refer to Appendix 4 for a comprehensive list of study assessments and their timing.  The 
end of study is defined as the time the last subject’s last visit.  The sponsor may 
terminate the study at any time. Subjects who are deriving clinical benefit from 
acalabrutinib may continue on study until a rollover protocol is available.  The study 
duration is expected to be approximately 6 years from enrollment of the last subject.  
3.2 
Study Endpoints and Parameters 
3.2.1 
Co-Primary Endpoints 
• 
ORR, defined as a subject achieving a MR or better according to the response 
assessment criteria for WM (Owen 2013), as assessed by the investigator 
• 
ORR, defined as a subject achieving a MR or better according to the response 
assessment criteria defined by modified 3rd IWWM workshop criteria 
(Kimby 2006), as assessed by the investigator 
3.2.2 
Secondary Endpoints 
Efficacy: 
• 
DOR assessed by the investigator using response assessment criteria for WM 
(Owen 2013) and modified 3rd IWWM workshop criteria (Kimby 2006) 
• 
PFS assessed by the investigator using response assessment criteria for WM 
(Owen 2013) and modified 3rd IWWM workshop criteria (Kimby 2006) 
• 
OS 
• 
Effect of acalabrutinib on peripheral T/B/NK cell counts 
• 
Effect of acalabrutinib on serum immunoglobulin levels 
Safety: 
• 
Frequency, severity, and relatedness of AEs 
• 
Frequency of AEs requiring discontinuation of study drug or dose reductions 
Pharmacokinetics: 
• 
Plasma pharmacokinetics of acalabrutinib 
PRO: 
• 
Health-related quality of life 

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3.2.3 
 
 
 
 
3.2.4 
Safety Parameters 
The safety of acalabrutinib will be characterized by the type, frequency, severity, and 
relationship to study drug of any treatment-emergent AEs or abnormalities of laboratory 
tests; SAEs; or AEs leading to discontinuation or dose reduction of study treatment.  
For consistency of interpretation, AEs will be coded using the MedDRA, and the severity 
of AEs and laboratory abnormalities will be graded using the Common Terminology 
Criteria for Adverse Events (CTCAE), Version 4.03 or higher.  Standard definitions for 
seriousness will be applied (see Section 6.1). 
3.2.5 
Pharmacokinetic and Pharmacodynamic Parameters 
Standard PK parameters for acalabrutinib in plasma will be evaluated in this study.  A full 
description of the PK parameters is provided in Section 5.5.4. 
The occupancy of BTK by acalabrutinib will be measured in peripheral blood 
mononuclear cells and bone marrow, when available, with the aid of a biotin-tagged 
acalabrutinib analogue probe.  The effect of acalabrutinib on biologic markers of B-cell 
function will also be evaluated. 
3.3 
Rationale for Study Design and Dosing Regimen 
A total daily dose of 200 mg of acalabrutinib (100 mg BID) has been selected for this 
study.  Preliminary PK data from ACE-CL-001 as described in Section 1.3.2 suggest a 
plateauing of exposure after 250 mg QD.  PD results from this study also show similar 
BTK occupancy for 250 and 400 mg QD at 24 hours.  Therefore, based on PK/PD, 
safety, and efficacy results of the Phase 1/2 study, a 200-mg total daily dose (100-mg 
capsules administered BID) will be evaluated.  For the most recent information on 
acalabrutinib study results and dosing rationale, refer to the acalabrutinib Investigator 
Brochure.  

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3.4 
Selection of Study Population 
3.4.1 
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. Previously treated cohort only:  A confirmed diagnosis of WM, which has 
relapsed after, or been refractory to ≥1 prior therapy for WM and which requires 
treatment 
3. Previously untreated cohort only:  A confirmed diagnosis of previously untreated 
WM in subjects who require treatment and do not want to receive 
chemoimmunotherapy or have comorbidities that would preclude 
chemoimmunotherapy such as: 
 
Symptomatic hyperviscosity with an IgM ≥5,000 mg/dL  
 
Disease-related neuropathy 
4. Serum concentration of IgM, as measured by SPEP and IFE, that exceeds the 
upper limits of normal or measurable nodal WM (defined as the presence of 
≥1 lymph node that measures ≥2.0 cm in the longest diameter and ≥1.0 cm in the 
longest perpendicular diameter).  
5. ECOG performance status of ≤2. 
6. Women who are sexually active and can bear children must agree to use highly 
effective forms of contraception during the study and for 2 days after the last 
dose of acalabrutinib.  Highly effective forms of contraception are defined in 
Section 3.7.7. 
7. This criterion was removed as of Protocol Amendment 7. 
8. Willing and able to participate in all required evaluations and procedures in this 
study protocol including swallowing capsules without difficulty. 
9. Ability to understand the purpose and risks of the study and provide signed and 
dated informed consent and authorization to use protected health information (in 
accordance with national and local patient privacy regulations). 
3.4.2 
Exclusion Criteria 
Subjects will be ineligible for this study if they meet any of the following criteria: 
1. Prior malignancy, except for adequately treated basal cell or squamous cell skin 
cancer, in situ cervical cancer, or other cancer from which the subject has been 
disease free for ≥2 years or which will not limit survival to <2 years.  Note:  These 
cases must be discussed with the medical monitor. 
2. A life-threatening illness, medical condition, or organ system dysfunction which, 
in the investigator’s opinion, could compromise the subject’s safety, interfere with 
the absorption or metabolism of acalabrutinib, or put the study outcomes at 
undue risk. 
3. Significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of 

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screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart 
Association Functional Classification, or QTc >480 msec. 
4. 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. 
5. Any immunotherapy within 4 weeks of first dose of study drug. 
6. For subjects with recent chemotherapy or experimental therapy, the first dose of 
study drug must occur after 5 times the half-life of the agent(s). 
7. Prior exposure to a BCR inhibitor (e.g., BTK, PI3K, or SYK inhibitors) or BCL-2 
inhibitors (e.g., ABT-199). 
8. Ongoing immunosuppressive therapy, including systemic or enteric 
corticosteroids for treatment of WM or other conditions.  Note:  Subjects may use 
topical or inhaled corticosteroids or low-dose steroids (≤10 mg of prednisone or 
equivalent per day) as therapy for comorbid conditions.  During study 
participation, subjects may also receive systemic or enteric corticosteroids as 
needed for treatment-emergent comorbid conditions. 
9. Grade ≥2 toxicity (other than alopecia) continuing from prior anticancer therapy 
including radiation. 
10. Known history of HIV or active infection with HCV or hepatitis B virus (HBV) or 
any uncontrolled active systemic infection. 
11. Major surgery within 4 weeks before first dose of study drug. 
12. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia 
purpura. 
13. History of a bleeding diathesis (e.g., hemophilia, von Willebrand disease). 
14. History of stroke or intracranial hemorrhage within 6 months before the first dose 
of acalabrutinib. 
15. Requires or receiving anticoagulation with warfarin or equivalent vitamin K 
antagonists (e.g., phenprocoumon) within 28 days of first dose of study drug. 
16. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole) 
17. ANC <0.75 x 109/L or platelet count <50 x 109/L.  For subjects with disease 
involvement in the bone marrow, ANC <0.50 x 109/L or platelet count <30 x109/L.  
18. Creatinine >2.5 x institutional ULN; total bilirubin >2.5 x ULN; or AST or ALT >3.0 
x ULN. 
19. Lactating or pregnant. 
20. Concurrent participation in another therapeutic clinical trial. 
3.4.3 
Replacement of Subjects 
Any subject who does not complete Cycle 2 (at least 8 weeks) may be replaced at the 
discretion of the study investigator and sponsor. 

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3.4.4 
Enrollment Procedures 
Enrollment of a subject into the study will be performed according to the following 
procedures:  
• 
Notify the sponsor when a clinically eligible subject is identified and ready to 
screen, to ensure enrollment availability on the study. 
• 
After the subject has signed and dated the Informed Consent Form (ICF), all 
screening procedures have been completed, and eligibility has been confirmed, 
the subject can be officially enrolled in the study.  
• 
To enroll a subject, the study center will fax/email a completed Enrollment 
Confirmation Form to the sponsor.  The enrollment date will be the date that the 
sponsor confirms enrollment. 
• 
The sponsor will aim to fax/email a completed Enrollment Confirmation Form to 
the study center within 24 hours.  
Treatment must begin within the 21-day screening window (Section 4.1) and after the 
site has received approval from the sponsor.  Study treatment is not blinded on this 
study. 
3.5 
Study Drug 
3.5.1 
Premedications 
No specific premedications or supporting medications are required in conjunction with 
acalabrutinib administration.  
3.5.2 
Formulation, Packaging, and Storage 
Acalabrutinib is manufactured according to Good Manufacturing Practices regulations 
and will be provided to the investigational site by Acerta Pharma or designee.  
Acalabrutinib should be stored according to the instructions on the label that is affixed to 
the package containing the drug product.  Acalabrutinib capsules contain 100 mg of drug 
substance.  Acalabrutinib will be provided in white, high-density polyethylene bottles. 
If a drug shipment arrives damaged, or if there are any other drug complaints, a Product 
Complaint Form should be completed and emailed or faxed to the sponsor or the 
sponsor’s representative.  Refer to the acalabrutinib Investigator Brochure for additional 
information regarding the drug product to be used in this study. 

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3.5.3 
Administration of Study Drug 
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 100 mg (1 x 100-mg capsule) is to be administered BID, 12 hours apart 
(BID dosing = total daily dose of 200 mg). 
Acalabrutinib is intended to be administered orally BID with 8 ounces (approximately 
240 mL) of water (avoid grapefruit juice and Seville orange juice due to CYP3A 
inhibition).  Acalabrutinib may be administered with or without food. The capsules should 
be swallowed intact and subjects should not attempt to open capsules or dissolve them 
in water.   
It is recommended that acalabrutinib be taken as close to the scheduled time as possible 
(preferably within 1 hour).  However, 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 next scheduled time.  The missed dose will not be made up and must be returned 
to the site at the next scheduled visit. 
3.5.4 
Assuring Subject Compliance 
For treatments that are taken in the clinic, subjects should take the dose from the drug 
dispensed for them for that particular time period.  All other treatments will be taken at 
home.  Subjects will receive a diary to record the specific time each dose was taken and 
to record reasons for any missed doses.   
Subject compliance will be assessed at every visit.  The subject will be instructed to 
bring the diary and any remaining capsules to the clinic at their next visit.  The 
administrator will review the diary and ask the subject if all of the capsules were 
administered.  Any remaining or returned capsules will be counted and recorded as 
described in Section 7.7.  Returned capsules must not be redispensed to another 
subject.  The study staff will resupply the subject with the correct number of capsules 
needed for use until the next visit. 
3.5.5 
Dose Delays 
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 

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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 3.8 for more information on assessing disease progression under these 
circumstances. 
3.5.6 
Dose Modification and Discontinuation 
The actions in Table 1should be taken for the following toxicities: 
• 
Grade 4 ANC (<500/μL) for >7 days (Neutrophil growth factors are permitted per 
American Society of Clinical Oncology 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 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 100 mg 
once daily 
4th 
Discontinue acalabrutinib 
As appropriate, certain laboratory abnormalities may warrant more frequent monitoring 
(e.g., once per week) until abnormalities have recovered to Grade ≤1.  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. 
For full study treatment discontinuation criteria, refer to Section 3.8. 
3.6 
Concomitant Therapy 
3.6.1 
Permitted Concomitant Therapy 
Antiemetics are permitted if clinically indicated.  Standard supportive care medications 
are permitted as per institutional standards.   
For subjects considered at risk for tumor lysis syndrome:  Administer appropriate 
hydration, alkalinization of urine, and allopurinol or rasburicase per institutional 
standards before initiating treatment. 
3.6.2 
Guideline for Use of CYP Inhibiting/Inducing Drugs 
At the systemic exposure levels expected in this study, acalabrutinib inhibition of CYP 
metabolism is not anticipated.  However, as discussed in Section 1.2.7 concomitant 
administration of acalabrutinib with a strong or moderate CYP3A inhibitor increased 
exposure by approximately 5-fold.  Consequently, the concomitant use of strong 
inhibitors/inducers of CYP3A (Appendix 3) should be avoided when possible.  If a 
subject requires a strong or moderate CYP3A inhibitor while on study, monitor the 
subject closely for potential toxicities.  Conversely, concomitant administration of a 
strong inducer of CYP3A has the potential to decrease exposure of acalabrutinib and 
could reduce efficacy. 
3.6.3 
Guideline for Use of Drugs that Affect Gastric pH 
The effect of agents that reduce gastric acidity (antacids or proton-pump inhibitors) 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 for a period of at least 2 hours before and at least 
2 hours after taking acalabrutinib.   
Use of omeprazole, esomeprazole, lansoprazole or any other proton-pump inhibitors 
while taking acalabrutinib is not recommended due to a potential decrease in study drug 
exposure.  However, the decision to treat with proton-pump inhibitors during the study is 
at the investigator’s discretion, with an understanding of the potential benefit to the 

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subject’s gastrointestinal condition and a potential risk of decreased exposure to 
acalabrutinib. 
Although the effect of H2-receptor antagonists (such as famotidine or ranitidine) on 
acalabrutinib absorption has not been evaluated, if treatment with an H2-receptor 
antagonist is required, the H2-receptor antagonist should be taken approximately 
2 hours after an acalabrutinib dose. 
3.6.4 
Prohibited Concomitant Therapy 
Any chemotherapy, immunotherapy, kinase inhibitors, bone marrow transplantation, 
experimental therapy, and radiotherapy are prohibited.  High-dose corticosteroids used 
to treat underlying WM 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. 
Warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) are prohibited. 
3.7 
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 the 
acalabrutinib Investigator Brochure. 
3.7.1 
Hemorrhage 
Bleeding events, some fatal, including central nervous system, respiratory, and 
gastrointestinal hemorrhage, have been reported in patients treated with acalabrutinib.  
Subjects receiving antiplatelet or anticoagulant therapies may be at increased risk of 
hemorrhage and should be monitored for signs of bleeding. As a precaution, it is 
suggested per protocol that acalabrutinib be withheld for at least 3 days pre- and post-
surgery.  
Subjects with hemorrhage should be managed per institutional guidelines or as clinically 
indicated. 
3.7.2 
Infections 
Serious infections, including fatal events, have been reported in patients treated with 
acalabrutinib. Subjects should be monitored for signs and symptoms of infection and 
treated as medically appropriate. 

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3.7.2.1 
Progressive Multifocal Leukoencephalopathy 
Cases of progressive multifocal leukoencephalopathy (PML) have been reported in 
patients treated with acalabrutinib.  Signs and symptoms of PML may include cognitive 
and behavioral changes, language disturbances, visual disturbances, sensory deficits, 
weakness, and coordination and gait difficulties. 
If PML is suspected, hold further treatment with acalabrutinib treatment until PML is 
excluded.  A diagnostic evaluation may include (but is not limited to): 
• 
Neurologic consultation 
• 
Brain magnetic resonance imaging (MRI) 
• 
Polymerase chain reaction (PCR) analysis for John Cunningham virus DNA in 
cerebrospinal fluid 
If PML is confirmed, permanently discontinue acalabrutinib. 
3.7.2.2 
Hepatitis B Virus Reactivation 
Serious or life-threatening reactivation of viral hepatitis may occur in subjects treated 
with a BTK inhibitor (de Jésus Ngoma 2015).  Cases of HBV reactivation have been 
reported in patients treated with acalabrutinib with 1 case resulting in liver failure and 
death. Therefore, subjects with a history of HBV infection should be monitored monthly 
with a quantitative PCR test for HBV DNA from Cycle 6 to Cycle 48 or early 
discontinuation, and then every 3 months thereafter.  Monitoring should continue until 
12 months after last dose of acalabrutinib.  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.  
3.7.3 
Cytopenia 
Grade 3 or 4 events of cytopenia, 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.  Refer to Section 3.5.6 for 
study drug modification guidance. Subjects with cytopenia should be managed 
according to institutional guidelines or as clinically indicated. 
3.7.4 
Second Primary Malignancies 
Second primary malignancies, including non-skin carcinomas, have been reported in 
patients treated with acalabrutinib.  The most frequent second primary malignancy was 

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skin cancer (squamous cell carcinoma of the skin).  Subjects with a second primary 
malignancy should be managed according to institutional guidelines or as clinically 
indicated. 
3.7.5 
Atrial Fibrillation 
Atrial fibrillation or flutter has been reported in patients treated with acalabrutinib. Risk 
factors may include hypertension, diabetes mellitus, acute infections, or a previous 
history of atrial fibrillation.  Subjects with atrial fibrillation should be managed per 
institutional guidelines or as clinically indicated. 
3.7.6 
Dietary Restrictions 
Because acalabrutinib is metabolized by CYP3A (see Section 1.2.7), subjects should be 
strongly cautioned against excessive consumption of grapefruit, grapefruit juice, Seville 
oranges, or Seville orange juice (which contain potent CYP3A inhibitors) or using herbal 
remedies or dietary supplements (in particular, St. John’s wort, which is a potent 
CYP3A4 inducer).  Acalabrutinib can be taken with or without food.   
Otherwise, subjects should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea, or vomiting. 
3.7.7 
Reproductive Toxicity 
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 associated with reductions in fetal weights.  
For additional details, refer to the acalabrutinib Investigator Brochure. 
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 level in 
the postmenopausal range may be used to confirm a postmenopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 
12 months of amenorrhea, a single follicle stimulating hormone measurement is 
insufficient.);  
OR  

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2) Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks before screening;  
OR  
3) Have a congenital or acquired condition that prevents childbearing. 
Definition of 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 or intrauterine hormone-releasing system 
• 
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 only be used as the sole method of 
contraception if it is consistently employed during the entire period of risk associated 
with the study treatments as the subject’s preferred and usual lifestyle. Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, and postovulation methods) and 
withdrawal are not acceptable methods of contraception. 
If a contraceptive method is restricted by local regulations/guidelines, then it does not 
qualify as an acceptable highly effective method of contraception for subjects 
participating at sites in the relevant country/region. 
Female subjects with reproductive potential (see definition above) who are sexually 
active must use highly effective methods of contraception during the study and for 
2 days after the last dose of acalabrutinib.  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.   

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Subjects should promptly notify the investigator if they, or their partners, become 
pregnant during this study.  Female subjects must also notify the investigator if they 
become pregnant within 2 days after the last dose of acalabrutinib.  If a woman becomes 
pregnant during the treatment period, she must discontinue acalabrutinib immediately.  
Pregnancy in a female subject or a male subject’s partner must be reported as outlined 
in Section 6.2.3. 
3.7.8 
Overdose Instructions 
For any subject experiencing an acalabrutinib overdose (ingestion of more than the 
recommended dosage), observation for any symptomatic side effects should be 
instituted, and vital signs and 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 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 should be contacted if an acalabrutinib overdose occurs.  
3.8 
Withdrawal of Subjects from Study Treatment 
The investigator, in consultation with the medical monitor, may withdraw any subject 
from study treatment, if, in the investigator’s opinion, it is not in the subject’s best interest 
to continue.  
Any subject has the right to withdraw from the study at any time.  In addition, subjects 
may be withdrawn from study treatment for the following reasons: 
• 
Study treatment should be discontinued in the event of a toxicity requiring a dose 
hold lasting >28 days, unless reviewed and approved by the medical monitor.   
• 
Any subject who has confirmed objective evidence of cancer progression while 
receiving acalabrutinib should be withdrawn from the study treatment. If there is 
uncertainty regarding whether there is true cancer progression, the subject may 
continue study treatment and remain under close observation (e.g., evaluated at 
4-week intervals) pending confirmation of progression.  In particular, transient 
worsening of disease early in therapy or during temporary interruption of study 
therapy (e.g., for drug-related toxicity, surgery, or intercurrent illness) may not 
indicate cancer progression.  In such circumstances, and if medically 
appropriate, subjects may resume therapy and relevant clinical, laboratory, 

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and/or radiologic assessment can be attempted to document whether tumor 
control can be maintained or whether cancer progression has occurred. 
• 
Any subject whose medical condition substantially changes after entering the 
study should be carefully evaluated by the investigator in consultation with the 
medical monitor.  Such subjects should be withdrawn from study treatment if 
continuing would place them at risk.  
• 
Any subject who becomes pregnant should be removed from study treatment. 
• 
Any subject who becomes significantly noncompliant with study drug 
administration, study procedures, or study requirements should be withdrawn 
from study treatment in circumstances that increase risk or substantially 
compromise the interpretation of study results. 
3.9 
Reasons for Study Exit 
Reasons for study exit include: 
• 
Subject’s withdrawal of consent from study 
• 
Decision by sponsor to terminate the study 
• 
Subject lost to follow-up 
• 
Death 
3.10 Data and Safety Monitoring 
This study will be monitored in accordance with the sponsor’s pharmacovigilance 
procedures.  AEs and SAEs will be reviewed internally on an ongoing basis to identify 
safety concerns.  Conference calls with the investigators will be conducted as needed to 
discuss study progress, obtain investigator feedback and exchange, and discuss 
"significant safety events" (i.e., AEs that led to dose modifications, treatment-related 
SAEs, and deaths).   
4.0 
STUDY ACTIVITIES AND ASSESSMENTS 
The schedule of events is provided in Appendix 4.  Descriptions of the scheduled 
evaluations are outlined below and complete information on study drug and dosing is 
provided in Section 3.5. 
Before study entry, throughout the study, and at the follow-up evaluation, various clinical 
and diagnostic laboratory evaluations are required.  The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments.  

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Clinical evaluations and laboratory studies may be repeated more frequently if clinically 
indicated.  Such unscheduled assessments will be captured in the protocol-specific 
database as appropriate.  This study will primarily use central laboratory testing for 
laboratory evaluations.  Samples from sites' local laboratories may be used if central 
testing is unavailable.  
4.1 
Description of Procedures 
4.1.1 
Informed Consent 
The subject must read, understand, and sign the Institutional Review Board (IRB)/ 
Independent Ethics Committee (IEC)-approved 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. 
4.1.2 
Medical History 
Collect and record the subject’s complete history through review of medical records and 
by interview.  Concurrent medical signs and symptoms must be documented to establish 
baseline severities.  A disease history, including the date of initial diagnosis and list of all 
prior anticancer treatments, and responses and duration of responses to these 
treatments, also will be recorded. 
4.1.3 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 6.1.  The AE 
reporting period is described in Section 6.2.1.  Important additional requirements for 
reporting SAEs are explained in Section 6.1.5. 
4.1.4 
Concomitant Medications and Therapy 
Document all concomitant medications and procedures from within 21 days before the 
start of study drug administration through 30 days after the last dose of study drug. 
4.1.5 
Confirmation of Eligibility 
Subject eligibility for enrollment will be assessed per Section 3.4.  All screening 
procedures, unless otherwise indicated, should be completed within 21 days of the first 
dose of study drug. 
4.1.6 
ECOG Performance Status 
The ECOG performance index is provided in Appendix 1. 

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4.1.7 
Physical Examination, Vital Signs, Height& Weight 
The screening physical examination will include, at a minimum, the general appearance 
of the subject, height (screening only) and weight, and examination of the skin, eyes, 
ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous 
system, and lymphatic system. The nervous system examination will include attention to 
neurologic signs and symptoms of PML. 
Symptom-directed physical examinations, including extramedullary disease 
assessments by palpation, will be done during the treatment period and at the SFU 
visits. 
Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) will be 
assessed after the subject has rested in the sitting position.   
4.1.8 
Patient-Reported Outcomes 
A health-related quality of life questionnaire will be administered to each subject as 
outlined in the schedule of assessments.  Refer the PRO manual for this study for 
instructions on administering this questionnaire. 
4.1.9 
Bone Marrow Aspirate and Biopsy 
A bone marrow aspirate and biopsy will be done at screening or up to 60 days before the 
first dose of study drug.  This study requires a bone marrow aspirate and biopsy at the 
end of Cycle 2 and Cycle 12, which must be done within 4 weeks of the 
contemporaneous radiologic evaluation.  Per the current response criteria (Owen 2013), 
a bone marrow aspirate and biopsy will also be required at any time on study to confirm 
a complete response (CR).  Pathologic review of the bone marrow aspirate and biopsy 
will be performed by a central laboratory (or local laboratory, if central laboratory is 
unavailable) for confirmation of WM diagnosis.   
When available, any unused bone marrow tissue will be used for PD testing.  PD testing 
will be done by the sponsor. 
4.1.10 
Electrocardiogram 
Subjects should be in supine position and resting for ≥10 minutes before study-related 
ECGs.   

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4.1.11 
Urine or Serum Pregnancy Test 
Pregnancy tests will be required only for women of childbearing potential.  Testing will be 
done locally by use of central laboratory provided kits.  Pregnancy testing may be done 
by local laboratories and can be done more frequently than the protocol-defined 
schedule, if required by local regulatory authorities. 
4.1.12 
Hematology 
Hematology studies must include complete blood count with differential and platelet and 
reticulocyte counts.  Testing will be done by the central laboratory. 
4.1.13 
Serum Chemistry 
Serum chemistry must include albumin, alkaline phosphatase, ALT, AST, bicarbonate, 
blood urea nitrogen, bone-specific alkaline phosphatase, calcium, chloride, creatinine, c-
terminal telopeptide, glucose, lactate dehydrogenase, magnesium, phosphate, 
potassium, sodium, total bilirubin, total protein, and uric acid.  If an unscheduled ECG is 
done at any time, then an electrolyte panel (i.e., calcium, magnesium, and potassium) 
must be done to coincide with the ECG testing.  Testing will be done by the central 
laboratory. 
See Appendix 5 for actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s law. 
4.1.14 
Urinalysis 
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.  
Testing will be done by the central laboratory. 
4.1.15 
T/B/NK Cell Count 
Flow cytometry testing will include CD3+, CD4+, CD8+, CD19+, and CD16/56+ cells.  
Testing will be done by the central laboratory. 
4.1.16 
Serum Immunoglobulin and Serum M protein 
Testing for IgG, IgM, IgA, and serum M protein levels (by SPEP and IFE) will be done by 
the central laboratory. 
4.1.17 
HBV PCR Testing 
Refer to Section 3.7.2.2 and Appendix 4 for information on the required HBV PCR 
testing for subjects with a history of HBV infection. 

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4.1.18 
Pharmacodynamics 
PD assessments will be done on all subjects in the treatment-naive cohort and on up to 
12 subjects in the previously treated cohort.  Blood samples and bone marrow, when 
available, will be used for PD testing (e.g., BTK occupancy and B-cell activation).  Refer 
to the laboratory binder for instructions on collecting and processing these samples.  
Testing will be done by the sponsor. 
4.1.19 
Pharmacokinetics 
PK assessments will be done on all subjects in the treatment-naive cohort and on up to 
12 subjects in the previously treated cohort.  Refer to the laboratory binder for 
instructions on collecting and processing these samples.  Testing will be performed at 
the central clinical laboratory.  Leftover plasma samples may be used for exploratory 
acalabrutinib metabolite analyses.  The PK sampling timepoints are provided in Table 2. 
Table 2. Pharmacokinetic Sample Schedule 
Cycle 
Day 
Predose 
Hours Postdose 
0.5 
(±5 min) 
0.75 
(±5 min) 
1 
(±5 min) 
2 
(±10 min) 
4 
(±10 min) 
6 
(±10 min) 
1 
1 
X 
X 
X 
X 
X 
X 
X 
 
8 
X 
X 
X 
X 
X 
X 
X 
 
15, 22, 28 
X 
 
 
X 
 
 
 
All timepoints are relative to the morning dose. 
 
4.1.20 
Molecular Testing 
Molecular testing will include, but may not be limited to, immunoglobulin heavy-chain 
variable mutational status, CXCR4S338X, and MYD88 L265P.  Molecular testing may be 
performed using the blood samples collected for PD testing (when available), as a 
separate sample was not collected at screening.   
4.1.21 
Extramedullary Disease Assessment 
Pretreatment radiologic extramedullary disease assessment will be performed within 
30 days before the first dose. A computed tomography (CT) scan with contrast (unless 
contraindicated) of the chest, abdomen, and pelvis and any other disease sites (e.g., 
neck) are required for the pretreatment extramedullary disease assessment for all 
subjects. 

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On-study extramedullary disease assessments will also be done by physical 
examination and laboratory results. Bone marrow and radiologic (as applicable) 
assessments are required for confirmation of CR per clinical guidelines (see 
Section 4.2).  De-identified copies of all radiology results may be requested by the 
sponsor.   
For subjects with baseline (screening) extramedullary disease, follow-up radiologic 
assessments are required at the end of Cycle 2 (±7 days), Cycle 4 (±7 days), and 
Cycle 6 (±7 days), then every 3 cycles (12 weeks, ±7 days) until Cycle 27, and then 
every 6 cycles thereafter or more frequently at investigator discretion.  Subjects should 
have radiologic extramedullary disease 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.  MRI may be used to evaluate non-target lesions that 
cannot be adequately imaged using CT (in cases where MRI is desirable, the MRI must 
be obtained at baseline and at all subsequent response evaluations).  If MRI is required 
for any other reason, this must be discussed with the study medical monitor first. 
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. 
In the event disease progression is suspected in subjects with baseline extramedullary 
disease, a CT scan must be performed.  If the sole lesion lies within the field of prior 
radiotherapy, there must be evidence of disease progression in that lesion. 
4.1.22 
Study Drug Accountability 
See Section 7.7. 

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4.1.23 
Routine Clinical Assessments 
Routine clinical assessments include physical examinations, recording of symptoms, and 
hematologic evaluations to evaluate for both AEs and assessment of disease 
progression at times when the CT scan is not obtained.  If a subject shows signs of 
progression, the subject may continue treatment until progression is considered 
unequivocal progression by the investigator.  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 regardless of the administration of 
subsequent anticancer therapy.    
4.2 
Investigator’s Assessment of Response to Treatment 
The investigator must rate the subject’s response to treatment per the Owen criteria 
(Owen 2013) and modified 3rd IWWM workshop criteria (Kimby 2006); see Table 3 and 
Table 5.  Progression will be assessed by the Owen criteria (Owen 2013) and modified 
3rd IWWM workshop criteria (Kimby 2006); see Table 4 and Table 6. 
Overall response assessments will include evaluation of physical examinations, 
recording of symptoms, laboratory evaluations (Note:  Serum immunoglobulins and 
serum M protein must be done within 7 days and bone marrow aspirate and biopsy 
[when applicable] must be done within 4 weeks of the contemporaneous radiologic 
evaluation), and radiologic 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 examination and serum 
immunoglobulins and serum M protein to determine if disease progression is present.  
Additionally, any suspected case of disease progression should be assessed with a CT 
scan for subjects with baseline extramedullary disease, and should be reported to the 
medical monitor.  Subjects may continue study treatment until progression is confirmed 
by a serial examination (e.g., physical examination, serum immunoglobulins and serum 
M protein, or CT scan) at least 2 weeks later.   

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Table 3. Response Assessment Criteria for Waldenström Macroglobulinemia 
(Owen 2013) 
Response 
 Definition 
Complete 
response 
• 
Absence of serum monoclonal IgM protein by immunofixation 
• 
Normal serum IgM level 
• 
Complete resolution of extramedullary disease, i.e., lymphadenopathy 
and splenomegaly if present at baseline 
• 
Morphologically normal bone marrow aspirate and trephine biopsy 
Very good partial 
response  
• 
Monoclonal IgM protein is detectable 
• 
≥90% reduction in serum IgM level from baselinea 
• 
Complete resolution of extramedullary disease, i.e., 
lymphadenopathy/splenomegaly if present at baseline 
• 
No new signs or symptoms of active disease 
Partial response 
• 
Monoclonal IgM protein is detectable 
• 
≥50% but <90% reduction in serum monoclonal IgM level from 
baseline a 
• 
Reduction in extramedullary disease i.e., 
lymphadenopathy/splenomegaly if present at baseline 
• 
No new signs or symptoms of active disease 
Minor response 
• 
Monoclonal IgM protein is detectable 
• 
≥25% but <50% reduction in serum monoclonal IgM level from 
baseline a 
• 
No new signs or symptoms of active disease 
Stable Disease 
• 
Monoclonal IgM protein is detectable 
• 
<25% reduction and <25% increase in serum monoclonal IgM level 
from baseline a 
• 
No progression in extramedullary disease i.e., 
lymphadenopathy/splenomegaly 
• 
No new signs or symptoms of active disease 
IgM=immunoglobin M 
a Sequential changes in IgM levels may be determined either by M protein quantitation or total 
serum IgM quantitation by nephelometry. 
 
Table 4. Progressive Disease Criteria for Waldenström Macroglobulinemia (Owen 
2013) 
Definition 
• 
≥25% increase in serum IgM levela with an absolute increase of at least 500 mg/dL 
from lowest nadir (requires confirmation on ≥2 consecutive measurements at least 
4 weeks apart). 
AND/OR 
• 
Progression of clinical features attributable to the disease per Owen 2013. 
IgM=immunoglobin M 
a Sequential changes in IgM levels may be determined either by M protein quantitation or total 
serum IgM quantitation by nephelometry. 
 

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Table 5. Response Assessment for Waldenström Macroglobulinemia (Modified 3rd 
IWWM Workshop Criteria; Kimby 2006) 
Response 
 Definition 
Complete 
response 
• 
Resolution of all symptoms 
• 
Normalization of serum IgM 
• 
Complete disappearance of IgM paraprotein by immunofixation 
• 
Resolution of any adenopathy or splenomegaly 
Very good partial 
response 
• 
≥90% reduction in serum IgM level from baseline 
Partial response 
• 
≥50% but <90% reduction in serum monoclonal IgM level from 
baselinea 
Minor response 
≥25% but <50% reduction in serum monoclonal IgM level from 
baselinea 
Stable Disease 
• 
<25% reduction and <25% increase in serum monoclonal IgM level 
from baselinea  
• 
Absence of new or increasing adenopathy or splenomegaly and/or 
other progressive signs or symptoms of WM. 
IgM=immunoglobin M 
a Sequential changes in IgM levels may be determined either by M protein quantitation or total 
serum IgM quantitation by nephelometry. 
 
Table 6. Progressive Disease Criteria for Waldenström Macroglobulinemia 
(Modified 3rd IWWM Workshop Criteria; Kimby 2006) 
Definition 
• 
≥25% increase in serum IgM level with an absolute increase of at least 500 mg/dL 
from lowest attained response value.  Reconfirmation of the initial IgM increase is 
required when IgM is the sole criterion for progressive disease confirmation 
AND/OR 
• 
Progression of clinically significant disease-related symptom(s) 
AND/OR 
• 
Death from any cause or initiation of a new anti-neoplastic therapy will also be 
considered a progression event. 
IgM=immunoglobin M 
 
4.3 
Treatment Termination and Safety Follow-Up Visits 
A TT visit is required for safety assessments for any subjects who permanently 
discontinue study drug for any reason (except for death, loss to follow-up, or withdrawal 
of consent), including disease progression.  The TT visit should be scheduled within 7 
days of the last dose of study drug, if possible, and is not required for subjects who 
discontinue from study treatment within 10 days after a scheduled study visit.   
In addition to the TT visit, each subject should be followed for SFU visit 30 days after his 
or her last dose of study drug to monitor for resolution or progression of AEs and to 
document the occurrence of any new events, regardless of whether the subject receives 

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a new anticancer therapy or demonstrates disease progression within this timeframe.   
Subjects who withdraw consent for study treatment should still be encouraged to 
complete the SFU assessments before withdrawing consent, but these assessments 
cannot be mandated if subject consent for further study participation is withdrawn.  If the 
TT visit and the SFU visit coincide, then these can be combined into 1 visit.  The 
Schedule of Assessments (Appendix 4) describes the procedures required for the TT 
and SFU visits.  
4.4 
Follow-Up for Progression and Survival 
Follow-Up after Study Treatment Discontinuation 
Subjects who discontinue study treatment for reasons other than progressive disease 
(including subjects who discontinued due to AE and start use of alternative anticancer 
therapy) will be followed approximately every 3 months until disease progression. During 
this period, for subjects who require scans, the scans will be done every 3 months until 2 
years, and then every 6 months thereafter until progression.  Additionally, serum IgM 
and physical examinations will be collected every 6 months.  Refer to Appendix 4 for the 
full list of assessments required during this period.   
Long-Term Follow-Up 
Once subjects progress—for all subjects who have not withdrawn consent—they will be 
contacted approximately every 3 months by clinic visit or telephone, to assess survival 
and the use of alternative anticancer therapy until death or loss to follow-up. 
4.5 
Missed Evaluations 
Missed evaluations should be rescheduled and performed as close to the original 
scheduled date as possible.  An exception is made when rescheduling becomes, in the 
investigator’s opinion, medically unnecessary or unsafe because it is too close in time to 
the next scheduled evaluation.  In that case, the missed evaluation should be 
abandoned. 
5.0 
STATISTICAL METHODS OF ANALYSIS 
5.1 
General Considerations 
Descriptive statistics (including means, standard deviations, and medians for continuous 
variables and proportions for discrete variables) will be used to summarize data as 
appropriate. 

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5.2 
Sample Size Considerations 
Previously treated subjects:  Simon’s optimal 2-stage design  
Response includes CR, very good partial response (VGPR), PR, or MR as defined in 
Section 5.5.3.  This study will test the null hypothesis that the ORR is ≤35% against the 
alternative hypothesis that it is ≥55%.  Using Simon’s optimal 2-stage design, a total 
sample size of 76 subjects has 90% power to achieve a 1-sided significance level of 
0.025.  In Stage 1, 28 subjects will be evaluated for efficacy.  If ≥12 out of 28 subjects 
(43%) achieve a response, then the study will continue to full enrollment. In Stage 2, a 
further 48 subjects will be enrolled.  With Simon's optimal 2-stage design, an ORR of 
≥46% (i.e., ≥35 subjects responding out of 76 subjects evaluated) will achieve a 1-sided 
significance level of ≤0.025.   
Treatment-naive subjects:  Exploratory cohort 
No formal statistical tests of hypotheses will be performed.  Eight to 12 evaluable 
subjects will be enrolled in this cohort for evaluation of preliminary efficacy and safety in 
this patient population. 
5.3 
Definition of Analysis Populations 
The analysis population is defined as follows: 
All-Treated Population:  All enrolled subjects who receive ≥1 dose of study drug.  The 
safety analyses and primary efficacy analyses will be performed on the All-treated 
population. 
Efficacy-evaluable population: All subjects in the All-treated population who have 
≥ 1 evaluable response assessment after the first dose of study drug.  Sensitivity 
analyses for efficacy will be carried out on the efficacy-evaluable population. 
5.4 
Missing Data Handling 
No imputation of values for missing data will be performed except for missing or partial 
start and end dates for AEs and concomitant medications according to prespecified, 
conservative imputation rules. 
5.5 
Endpoint Data Analysis 
5.5.1 
Safety Analysis 
Safety summaries will be included in the form of tables and listings.  The frequency 
(number and percentage) of treatment-emergent AEs will be mapped using MedDRA 

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and reported in each treatment group by MedDRA System Organ Class and Preferred 
Term.  Summaries will also be presented by the severity of the AE (per CTCAE, v4.03 or 
higher) and by relationship to study drug.  SAEs and AEs leading to study drug 
discontinuation will be summarized. 
Laboratory shift tables containing counts and percentages will be presented by 
laboratory parameter and time.  Figures of changes in selected laboratory parameters 
over time will be generated. 
Results of vital sign assessments and physical examinations will be tabulated and 
summarized.   
Figures of change from baseline will be generated to assess effect of acalabrutinib on 
peripheral T/B/NK cell counts and on serum immunoglobulin levels.  
5.5.2 
Demographics and Baseline Characteristics 
Additional analyses will include summaries of subject demographics, baseline 
characteristics, and concurrent treatments.  Concomitant medications will be coded 
according to the World Health Organization Drug Dictionary and tabulated. 
5.5.3 
Analysis of Efficacy Parameters 
Efficacy parameters will be based on investigator assessment according to the response 
assessment criteria for WM (Owen 2013) and the modified 3rd IWWM workshop criteria 
(Kimby 2006).  Efficacy parameters will be analyzed by the investigator.  The co-primary 
endpoints are ORRs, defined as a subject achieving a MR or better according to the 
response assessment criteria for WM (Owen 2013) and by the modified 3rd IWWM 
workshop criteria (Kimby 2006), both as assessed by the investigator. 
Overall Response Rate 
ORR is defined as the proportion of subjects who achieve a CR, VGPR, PR, or MR.  
ORR will be calculated and the corresponding 95% 2-sided confidence interval will be 
derived. 
Duration of Response 
DOR is defined as the interval from the first documentation of CR, VGPR, PR, or MR to 
the earlier of the first documentation of definitive disease progression or death from any 
cause.  Kaplan-Meier methods will be used to estimate event-free curves and 
corresponding quartiles (including the median).  Data from surviving, non-progressing 

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subjects will be censored at the earliest of the time of initiation of anticancer treatment or 
the last time that lack of WM progression was documented.   
Progression-free Survival 
PFS is defined as the interval from the start of acalabrutinib therapy to the earlier of the 
first documentation of disease progression (per Table 4) or death from any cause.  
Kaplan-Meier methods will be used to estimate the event-free curves and corresponding 
quartiles (including the median). Data from surviving, non-progressing subjects will be 
censored at the earlier of the time of initiation of anticancer treatment or the last time that 
lack of disease progression was documented.   
Overall Survival 
The duration of OS will be measured from the start of acalabrutinib therapy until the date 
of death.  Subjects who are known to be alive as of their last known status will be 
censored at their date of last contact.  Kaplan-Meier methodology will be used to 
estimate overall survival curves and corresponding quartiles (including the median). 
5.5.4 
Analysis of Pharmacokinetic/Pharmacodynamic Parameters 
The plasma PK of acalabrutinib will be characterized using noncompartmental analysis.  
The following PK parameters will be calculated, whenever possible, from plasma 
concentrations of acalabrutinib: 
• 
AUC0-last 
Area under the plasma concentration-time curve calculated using 
linear trapezoidal summation from time 0 to time last, where “last” 
is the time of the last measurable Ct. 
• 
AUC0-12 
Area under the plasma concentration-time curve from 0 to 
12 hours, calculated using linear trapezoidal summation. 
• 
AUC0-inf 
Area under the plasma concentration-time curve from 0 to infinity, 
calculated using the formula:  AUC0-inf= AUC0-last+ Ct / λz, where λz 
is the apparent terminal elimination rate constant. 
• 
AUC0-24calc Area under the plasma concentration-time curve from 0 to 
24 hours, calculated by doubling the value for AUC0-12. 
• 
Cmax 
Maximum observed plasma concentration 
• 
Tmax 
Time of the maximum plasma concentration (obtained without 
interpolation) 

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• 
t½ 
Terminal elimination half-life (whenever possible)  
• 
λz 
Terminal elimination rate constant (whenever possible) 
• 
CL/F 
Oral clearance 
• 
Vz/F   
Oral volume of distribution 
Missing dates or times may be imputed for PK and PD samples if the missing values can 
be established with an acceptable level of accuracy based on other information obtained 
during the visit in question.  If PK and PD sampling for a given subject is not performed 
according to protocol instructions, the subject may be excluded from the PK and PD 
analyses. 
The PK parameters will be tabulated and summarized using descriptive statistics.  
For each PD variable, the change from baseline to each assessment will be 
summarized.  As appropriate, the on-treatment values will be compared with the 
pretreatment baseline values using paired t-tests.  Acalabrutinib concentration-effect 
relationships will be explored. 
5.5.5 
Explorative or Correlative Analyses 
Additional PK or PD analyses may be performed, as deemed appropriate. 
Correlations between subject characteristics and outcome measures and correlations 
among outcomes measures may be explored using regression models or other 
appropriate techniques. 
5.5.6 
Patient-Reported Outcome 
The European Organisation for Research and Treatment of Cancer (EORTC) Quality of 
Life Questionnaire (QLQ)-30 will be used to assess health-related quality of life.  The 
instrument will be scored, missing values handled, and standardized scores derived 
(ranging from 0–100) as recommended in the EORTC user manual.  At each 
assessment point, absolute scores and changes from baseline will be calculated for 
each subscale, including core and overall total score.  Tables and graphs will be 
generated to summarize the absolute scores and changes from baseline. 
5.6 
Interim Analysis 
One formal interim analysis for futility with respect to ORR will be performed and 
documented. The formal documentation of the interim analysis will occur when subjects 
in Stage 1 (28 subjects) have been enrolled and have 8 weeks of evaluable response 

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data for efficacy.  However, should at any time ≥12 responses (MR or better) be 
observed among the 28 subjects enrolled, Stage 2 enrollment will continue without hold. 
Further enrollment of subjects into Stage 2 will be halted if there are <12 responders 
(MR+PR+VGPR+CR) observed among these 28 subjects.  If there are at least 
12 responders at the time the twenty-eighth subject has enrolled, screening for and 
enrollment into Stage 2 will not be halted as the minimum criteria for continuing 
enrollment will have been met.   
In The Netherlands and France, enrollment in the exploratory cohort of subjects with 
treatment-naive WM will commence after efficacy has been confirmed in Stage 1 of the 
Simon’s optimal 2-stage design. 
5.7 
Primary and Final Analysis 
The primary analysis will occur when all subjects have completed Cycle 27 or have 
discontinued before Cycle 27.  A final analysis will be performed at end of study.  End of 
study is defined as the time when the last subject completes his or her last visit. 
6.0 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and recording AEs and SAEs; 
measurements of protocol-specified hematology, clinical chemistry, urinalysis, 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. 
6.1 
Definitions 
6.1.1 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational (medicinal) product, regardless of 
attribution. 
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the 
protocol-specified AE reporting period, including signs or symptoms associated 

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with WM that were not present before the AE reporting period (see 
Section 6.2.1). 
• 
Pre-existing medical conditions (other than the condition being studied) judged 
by the investigator to have worsened in severity or frequency or changed in 
character during the protocol-specified AE reporting period. 
• 
Abnormal laboratory values considered clinically significant by the investigator 
should be reported as an AE.   
The following are NOT considered an AE: 
• 
Pre-existing condition that has not worsened: 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 ICF is 
not considered an SAE, but rather a therapeutic intervention.  However, if during 
the preplanned hospitalization an event occurs, which prolongs the 
hospitalization or meets any other SAE criteria, the event will be considered an 
SAE.  Surgeries or interventions that were under consideration, but not 
performed before signing the ICF, will not be considered serious if they are 
performed after signing the ICF for a condition that has not changed from its 
baseline level.  Elective hospitalizations for social reasons, solely for the 
administration of chemotherapy, or due to long travel distances are also not 
SAEs.  
• 
Diagnostic testing and procedures: Testing and procedures should not be 
reported as AEs or SAEs, but rather the cause for the test or procedure should 
be reported. If a test or procedure is done to rule out a diagnosis, the sign or 
symptom leading to the test/procedure should be the event term, and the event 
term should only be updated to the diagnosis if/when the diagnosis is confirmed. 
Testing and procedures performed solely as screening measures (e.g., routine 
screening mammography or colonoscopy) should not be reported as AEs or 
SAEs. 
• 
Abnormal laboratory results that the investigator considers to not be 
clinically significant:  Abnormal laboratory results are not AEs unless they are 
clinically significant.  For example, a clinically significant laboratory result is one 
that requires treatment (for example a blood transfusion for low hemoglobin) or 

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requires a change in study drug (e.g., lowering the dose or withholding study 
drug while the laboratory finding resolves or stabilizes). 
6.1.2 
Serious Adverse Event 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to 
the grade of an AE (see below).  “Serious” is a regulatory definition and is based on 
subject or event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  Seriousness (not severity) serves as the guide 
for defining regulatory reporting obligations from the sponsor to applicable regulatory 
authorities. 
An AE should be classified as an SAE if it meets any 1 of the following criteria: 
• 
It results in death (i.e., the AE actually causes or leads to death). 
• 
It is life-threatening (i.e., the AE, in the view of the investigator, places the subject 
at immediate risk of death.  It does not include an AE that, had it occurred in a 
more severe form, might have caused death). 
• 
It requires or prolongs in-patient hospitalization. 
• 
It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the investigational product. 
• 
It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical 
intervention to prevent 1 of the outcomes listed above). 
6.1.3 
Adverse Events of Special Interest 
The following events are AEs of special interest (AESIs) for subjects who receive 
acalabrutinib and must be reported to the sponsor expeditiously (see Section 6.2.4 for 
reporting instructions), irrespective of regulatory seriousness criteria or causality:  
• 
Ventricular arrhythmias (e.g., ventricular extrasystoles, ventricular tachycardia, 
ventricular arrhythmia, ventricular fibrillation, etc.)  

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6.1.4 
Severity 
Definitions found in the CTCAE version 4.03 or higher will be used for grading the 
severity (intensity) of AEs.  The CTCAE displays Grades 1 through 5 with unique clinical 
descriptions of severity for each referenced AE.  Should a subject experience any AE 
not listed in the CTCAE, the following grading system should be used to assess severity: 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities 
• 
Grade 2 (Moderate AE) – experiences which introduce some level of 
inconvenience or concern to the subject, and which may interfere with daily 
activities, but are usually ameliorated by simple therapeutic measures 
• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, 
significantly interrupt the subject’s usual daily activities, 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 
6.1.5 
Adverse Drug Reactions 
For the purpose of reporting AEs and SAEs, see Section 6 of the Investigator Brochure, 
which contains the reference safety information. 
6.2 
Documenting and Reporting of Adverse and Serious Adverse Events 
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 on the SAE form (see Section 6.2.4). 
6.2.1 
Adverse Event Reporting Period 
After the signing of the ICF, all SAEs must be reported.  After the first dose of study 
drug, all AEs, irrespective of seriousness, must be reported.  
AE reporting, irrespective of seriousness, ends 30 days after the last dose of study drug.  
SAEs considered related to study drug(s) or study procedures occurring after the end of 
the AE reporting period (as defined above) must be reported.   

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If an SAE is present at the last study visit, the SAE should be followed to resolution or 
until the investigator assesses the subject as stable, or the subject is lost to follow-up or 
withdraws consent.  Resolution/stable means the subject has returned to baseline state 
of health or the investigator does not expect any further improvement or worsening of 
the event.  
6.2.2 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation 
timepoints during the study.  All AEs and SAEs whether volunteered by the subject, 
discovered by study personnel during questioning, detected through physical 
examination, clinically significant laboratory test (e.g., 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 form. 
Disease progression itself is not considered an AE; however, signs and symptoms of 
disease progression may be recorded as AEs or SAEs. 
Each recorded AE or SAE will be described by its duration (e.g., start and end dates), 
severity, regulatory seriousness criteria, if applicable, suspected relationship to the study 
drug (see following guidance), and any actions taken.  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?’  Answer Yes or No.  
See Appendix 2 for more detail on assessing causality. 
6.2.3 
Pregnancy 
The investigator should report all pregnancies in study subjects and in the partners of 
study subjects within 24 hours using the Pregnancy Report Form.  This form should be 
faxed or emailed to Acerta Pharma Drug Safety.  Any pregnancy-associated SAE must 
be reported using the SAE report form, according to the usual timelines and directions 
for SAE reporting (Section 6.2.4). 
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 

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last dose of study medication will be reported, 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 (e.g., congenital 
abnormalities/birth defects/spontaneous miscarriages or any other serious events) must 
additionally be reported as such using the SAE Form.  
Subjects should be instructed to immediately notify the investigator of any pregnancies.  
Any woman receiving acalabrutinib 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 
 
6.2.4 
Expedited Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest 
All SAEs and AESIs must be reported within 24 hours of discovery.  All initial SAE/AESI 
reports and follow-up information will be reported using the protocol-specific electronic 
data capture system.  If electronic SAE/AESI reporting is not available, paper SAE/AESI 
forms must be emailed or faxed to Acerta Pharma Drug Safety, or designee.  Acerta 
Pharma may request follow-up and other additional information from the investigator 
(e.g., hospital admission/discharge notes and laboratory results).  
Whenever possible, SAEs/AEs should be reported by diagnosis term not as a 
constellation of symptoms.  Death due to disease progression should be recorded on the 
appropriate form in the electronic data capture system.  If the primary cause of death is 
disease progression, the death due to disease progression should not be reported as an 
SAE.  If the primary cause of death is something other than disease progression, then 
the death should be reported as an SAE with the primary cause of death as the event 
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 Acerta Pharma Drug Safety, or designee, as 
outlined above. 

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If study drug is discontinued because of an SAE, this information must be included in the 
SAE report. 
An SAE may qualify for mandatory expedited reporting to regulatory authorities if the 
SAE is attributable to the investigational product (or if a causality assessment is not 
provided for the SAE, in which case a default of ‘related’ may be used for expedited 
reporting purposes) and the SAE is not listed in the current acalabrutinib Investigator 
Brochure (i.e., an unexpected event).  In this case, Acerta Pharma Drug 
Safety/Designee 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. 
Drug Safety Contact Information 
Fax 
 
 
Email 
 
6.2.5 
Type and Duration of Follow-up of Subjects After Adverse 
Events 
All AEs and SAEs that are encountered during the protocol-specified AE reporting period 
should be followed to resolution, or until the investigator assesses the event as stable, a 
new anticancer therapy is initiated, or the subject is lost to follow-up or withdraws 
consent. 
7.0 
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 include: 
• 
Unsatisfactory subject enrollment with regard to quality or quantity 
• 
Significant or numerous deviations from study protocol requirements, such as 
failure to perform required evaluations on subjects and maintain adequate study 
records 
• 
Inaccurate, incomplete, or late data recording on a recurrent basis 
• 
The incidence and/or severity of AEs in this or other studies indicating a potential 
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7.1 
Regulatory and Ethical Compliance 
This clinical study was designed and will be implemented in accordance with the 
protocol, the International Council on Harmonisation Harmonized Tripartite Guidelines 
for Good Clinical Practices, applicable local regulations (including US Code of Federal 
Regulations Title 21 and European Directive 2001/20/EC), and the ethical principles laid 
down in the Declaration of Helsinki. 
7.2 
Institutional Review Board and Independent Ethics Committee 
The investigator will submit this protocol, the ICF, Investigator Brochure, and any other 
relevant supporting information (e.g., 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 Good Clinical 
Practices and the applicable laws and regulations; must be forwarded to Acerta Pharma 
before screening subjects for the study.  Additionally, sites must forward a signed Food 
and Drug Administration (FDA) 1572 form (Statement of Investigator) to Acerta Pharma 
before screening subjects for study enrollment.  Amendments to the protocol must also 
be approved by the IRB/IEC and local regulatory agencies, as appropriate, before the 
implementation of changes in this study. 
7.3 
Informed Consent and Protected Subject Health Information 
Authorization 
A copy of the IRB/IEC-approved ICF must be forwarded to Acerta Pharma for regulatory 
purposes.  The investigator, or designee (designee must be listed on the Study 
Personnel Responsibility/Signature Log, see Section 7.12), 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 § 21 Code of Federal Regulations Part 
50 and other applicable national and local regulations governing informed consent.  
Each subject must provide a signed and dated ICF before enrollment into this study.  If 
allowed by the protocol, a legal representative may sign the ICF for a subject incapable 
of giving consent.  Signed consent forms must remain in each subject’s study file and be 
available for verification by study monitors at any time. 
In accordance with 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 

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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. 
7.4 
Subject Screening Log 
The investigator must keep a record that lists all subjects considered for enrollment 
(including those who did not undergo screening) in the study.  For those subjects 
subsequently excluded from enrollment, record the reason(s) for exclusion. 
7.5 
Case Report Forms 
Authorized study site personnel (see Section 7.12) will complete CRFs designed for this 
study according to the completion guidelines that will be provided.  The investigator will 
ensure that the CRFs are accurate, complete, legible, and completed promptly.  For 
record retention policies, refer to Section 7.8. 
7.6 
Study Monitoring 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 by the 
sponsor, regulatory authorities, or ethics committees. 
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 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, 

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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. 
7.7 
Investigational Study Drug Accountability 
Acalabrutinib capsules must be kept in a locked limited-access cabinet or space.  The 
study drug must not be used outside the context of this protocol.   
Study drug accountability records must be maintained and readily available for 
inspection by representatives of Acerta Pharma or regulatory authorities at any time.  
Each shipment of study drug will contain a Clinical Supplies Shipping Receipt Form 
(CSSF).  If it is used, the Drug Re-Order Form (provided in the pharmacy binder) must 
also be included in the site’s drug accountability records. 
Contents of each shipment must be visually inspected to verify the quantity and to 
document the condition of study drug capsules.  Following receipt of study drug, the 
designated recipient completes and signs the CSSF.  A copy of the signed and dated 
CSSF must be faxed or emailed to Acerta Pharma at the fax number/email address 
listed on the form; this completed form should be filed in the pharmacy binder. 
An Investigational Drug Accountability Log must be used for drug accountability.  For 
accurate accountability, the following information must be noted when drug supplies are 
used during the study: 
1. study identification number (ACE-WM-001) 
2. subject identification number 
3. lot number(s) of acalabrutinib dispensed for that subject 
4. date and quantity of drug dispensed 
5. any unused drug returned by the subject 
At study initiation, the monitor will evaluate and approve the site’s procedure for 
investigational product disposal/destruction to ensure that it complies with Acerta 
Pharma’s requirements.  If the site cannot meet Acerta Pharma’s requirements for 
disposal/destruction, arrangements will be made between the site and Acerta Pharma or 
its representative, for return of unused investigational product.  Before 
disposal/destruction, final drug accountability and reconciliation must be performed by 
the monitor. 

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All study supplies and associated documentation will be regularly reviewed and verified 
by the monitor. 
7.8 
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, and 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.  The investigator must notify Acerta Pharma and obtain 
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 returned 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. 
7.9 
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 

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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 study. 
7.10 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).   
7.11 Clinical Study Insurance 
Clinical study insurance has been obtained 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. 
7.12 General Investigator Responsibilities 
The principal investigator must ensure that: 
1. He or she will personally 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 Investigational New Drug Safety Reports and SUSAR Reports are submitted 
promptly to the IRB/IEC. 
12. All SAEs are reported to Acerta Pharma Drug Safety/Designee within 24 hours of 
knowledge and to the IRB/IEC per their requirements. 
 
 

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8.0 
REFERENCES 
Bradshaw JM. The Src, Syk, and Tec family kinases: distinct types of molecular 
switches. Cell Signal 2010;22:1175-84.  
Buggy JJ, Elias L. Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. Int Rev 
Immunol 2012;31:119-32. Erratum in: Int Rev Immunol 2012;31:428. 
Byrd JC, Harrington B, O'Brien S, et al.  Acalabrutinib (ACP-196) in Relapsed Chronic 
Lymphocytic Leukemia. NEJM 2016;374:323-332. 
Chen J, Tan K, Zhou H, Lo HF, Roux DT, Liddington RC, Diacovo TG. 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. J Clin Oncol 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-tumor activities of therapeutic CD20 antibodies: implications for combination 
therapy. Haematologica 24 October 2014 [epub ahead of print]. 
de Jésus Ngoma PD, Kabamba B, Dahlgvist G, et al.  Occult HBV reactivation induced 
by ibrutinib treatment: a case report. Acta Gastroenterol Belg. 2015;78:424-426. 
Furie B, Furie BC. Thrombus formation in vivo. J Clin Invest. 2005 Dec;115(12):3355-62 
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 
guidelines. Blood 2008;111:5446-5456. 
Harrington BK, Gardner HL, Izumi R, et al. Preclinical evaluation of the novel BTK 
inhibitor acalabrutinib in canine models of B-cell Non-Hodgkin Lymphoma. PLoS One 
2016 Jul 19;11(7):e0159607. doi: 10.1371/journal.pone.0159607. eCollection 2016. 
Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor 
PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease 
and B-cell malignancy. PNAS 2010;107:13075-13080. 
IMBRUVICA [prescribing information]. Horsham, PA: Janssen Biotech, Inc; 2014. 
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. 
Kamel S, Horton L, Ysebaert L, et al. Ibrutinib inhibits collagen-mediated but not 
ADP-mediated platelet aggregation. Leukemia 2014 Aug 20 [epub]. 
Kimby E, Treon SP, Anagnostopoulos A, et al. Update on recommendations for 
assessing response from the Third International Workshop on Waldenstrom’s 
Macroglobulinemia. Clin Lymphoma Myeloma. 2006:6 (5):380-3. 
Kohrt HE, Sagiv-Barfi I, Rafiq S, et al. Ibrutinib antagonizes rituximab-dependent NK 
cell-mediated cytotoxicity. Blood 2014 Mar 20;123(12):1957-1960. 

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Mohamed AJ, Yu L, Bäckesjö CM, et al. Bruton's tyrosine kinase (Btk): function, 
regulation, and transformation with special emphasis on the PH domain. Immunol Rev 
2009;228:58-73. 
Owen RG, Kyle RA, Stone MJ, et al. Response assessment in Waldenström 
macroglobulinaemia: update from the VIth International Workshop. BJH 2013;160:171-
176. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 
1989;10:1-10. 
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.  
J Clin Oncol 2015;33:3199-212. 
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. 
Vail DM, Michels GM, Khanna C, Selting KA, London CA; 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. 
Vihinen M, Mattsson PT, Smith CI. Bruton tyrosine kinase (BTK) in X-linked 
agammaglobulinemia (XLA). Front Biosci 2000;5:D917-D928. 
 

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9.0 
APPENDICES 
 
Appendix 1. Performance Status Scores 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light house 
work, 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 self-care, confined to bed or chair more 
than 50% of waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair 
5 
Dead 
As published in Am J Clin Oncol: 
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. 
Credit: Eastern Cooperative Oncology Group Chair: Robert Comis, MD 
Available at: http://www.ecog.org/general/perf_stat.html.  Accessed 23 August 2013. 
 
 
 
 

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Appendix 2. 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 3. Known Strong In Vivo Inhibitors and Inducers of CYP3A 
 
Strong Inhibitors of CYP3Aa 
Strong Inducers of CYP3Ae 
boceprevir 
carbamazepinef 
clarithromycinb 
phenytoinf 
conivaptinb 
rifampinf 
grapefruit juicec 
St John's wortf 
indinavir 
 
itraconazoleb 
 
ketoconazoleb 
 
lopinavir/ritonavirb (combination drug) 
 
mibefradild 
 
nefazodone 
 
nelfinavir 
 
posaconazole 
 
ritonavirb 
 
saquinavir 
 
telaprevir 
 
telithromycin 
 
voriconazole 
 
 
a. 
A strong inhibitor for CYP3A is defined as an inhibitor that increases the AUC of a substrate for CYP3A 
by ≥ 5-fold. 
b. 
In vivo inhibitor of P-glycoprotein. 
c. 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent.  Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when 
another preparation was used (e.g., low dose, single strength). 
d. 
Withdrawn from the United States market because of safety reasons. 
e. 
A strong inducer for CYP3A is defined as an inducer that results in ≥ 80% decrease in the AUC of a 
substrate for CYP3A. 
f. 
In vivo inducer of P-glycoprotein.   
 
Note:  The list of drugs in these tables is not exhaustive.  Any questions about drugs not on this list 
should be addressed to the medical monitor of the protocol. 
 
Source: 
FDA Drug Development and Drug Interactions:  Table of Substrates, Inhibitors and Inducers. Web link 
Accessed 21 January 2015: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabe
ling/ucm093664.htm#inVivo 
 
 

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Appendix 4. Schedule of Assessments 
 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 
3 
Cycles 
4 and 5 
Cycles 
6-12 
Cycles 
15, 18, 
21, 24 
Cycles 
27-48  
Cycles 
48+b 
TT 
Visitc 
SFU 
Visitc 
DFUd 
LTFUe 
Days (± 2) 
Days  
(± 2) 
Days  
(± 2) 
Days  
(± 2) 
Days  
(± 2) 
Days  
(± 2) 
Days  
(± 2) 
Days  
(± 2) 
1 
8 
15 
22 28 15 28 
28 
28 
28 
28 
28 
28 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PEf/Vital 
signsg/Weightf 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(Q6C) 
x 
x 
x 
 
ECOG statush 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(Q6C) 
x 
x 
 
 
ECGi 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
 
Laboratory 
assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine or serum 
pregnancy testj 
x 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
(Q6C) 
x 
x 
 
 
Hematologyk 
x 
xm 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(Q6C) 
x 
x 
 
 
Serum chemistryl 
x 
xm 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(Q6C) 
x 
x 
 
 
Urinalysisn 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T/B/NK cell counto 
 
xm 
x 
x 
 
x 
 
x 
 
 
C6 and 
C12 
only 
C18 & 
C24 
only 
Q6C 
starting 
at C27 
 
 
 
 
 
Serum Ig & M 
proteinp 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
(Q6C) 
x 
x 
x 
 
HBV PCRq 
 
 
 
 
 
 
x 
 
x 
x 
QM 
QM 
QM 
x 
(Q3M) 
 
 
Q3M 
Q3M 
Bone marrow 
(aspirate and 
biopsy)r 
x 
 
 
 
 
 
 
x 
 
 
C12 
only 
and to 
confirm 
CR 
Only to 
confirm 
CR 
Only to 
confirm 
CR 
Only to 
confirm 
CR 
 
 
 
 

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Screeninga 
Cycle 1 
Cycle 2 
Cycle 
3 
Cycles 
4 and 5 
Cycles 
6-12 
Cycles 
15, 18, 
21, 24 
Cycles 
27-48  
Cycles 
48+b 
TT 
Visitc 
SFU 
Visitc 
DFUd 
LTFUe 
Days (± 2) 
Days  
(± 2) 
Days  
(± 2) 
Days  
(± 2) 
Days  
(± 2) 
Days  
(± 2) 
Days  
(± 2) 
Days  
(± 2) 
1 
8 
15 
22 28 15 28 
28 
28 
28 
28 
28 
28 
Radiologic 
assessment (as 
applicable) for 
extramedullary sitesr 
x 
 
 
 
 
 
 
x 
 
C4 only 
Q3C 
and to 
confirm 
CR 
Q3C 
and to 
confirm 
CR 
Q6C 
and to 
confirm 
CR 
Q6C 
and to 
confirm 
CR 
 
 
x 
 
Pharmacodynamics/ 
Molecular Testing 
 
xs 
xs 
 
 
xt 
 
xt 
 
 
 
 
 
 
xt 
xt 
 
 
Pharmacokineticsu 
 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Acalabrutinib 
dispensed 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(Q6C) 
 
 
 
 
Study drug 
compliance 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(Q6C) 
 
 
 
 
Response 
assessmentr 
x 
 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
(Q6C) 
 
 
x 
 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(Q6C) 
x 
x 
 
 
Adverse eventsv 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PROw 
x 
 
 
 
 
 
 
x 
 
C4 only 
C6, C9 
& C12 
only 
x 
x 
x 
(Q6C) 
 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
AE=adverse event; C=cycle; CR=complete remission; DFU=discontinuation follow-up; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
ET=early termination; Ig=immunoglobulin; LTFU=long-term follow-up; PCR=polymerase chain reaction; PE=physical examination; PRO=patient-reported outcomes; 
Q3C=every 3 cycles; Q3M=every 3 months; Q6C=every 6 cycles; Q6M=every 6 months; QM=every month; SAE=serious adverse event; SFU=safety follow-up; 
TT=treatment termination. 
Footnotes for ACE-WM-001 Schedule of Assessments: 
a.  Screening tests should be performed within 21 days before the first administration of study drug, unless otherwise indicated. 
b. 
The end of study is defined as the last subject’s last visit.  Subjects who are deriving clinical benefit from acalabrutinib may continue on study until a rollover 
protocol is available.   
c. 
A TT visit is required for subjects who permanently discontinue study drug early for any reason, including disease progression.  A 30-day (+ 7 days) SFU visit after 
the last dose of study drug is required when subjects discontinue study drug.  The TT visit should be scheduled within 7 days of the last dose of study drug, if 
possible, and is not required for subjects who discontinue from study treatment within 10 days after a scheduled study visit.  Each subject should be followed until 
the SFU visit at 30 (+ 7) days after his or her last dose of study drug to monitor for resolution or progression of AEs and to document the occurrence of any new 
events, regardless of whether the subject receives a new anticancer therapy or demonstrates disease progression within this timeframe.   

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d. 
Subjects who discontinue for reasons other than progressive disease (including subjects who discontinued due to AE and start use of alternative anticancer 
therapy) will be followed approximately Q3M until progressive disease.  During this period, for subjects who require scans, scans will be done Q3M until 2 years, 
and then Q6M thereafter until progression.  Additionally, serum IgM and physical examination will be collected. 
e. 
Once subjects progress—for all subjects who have not withdrawn consent—they will be contacted approximately Q3M by clinic visit or telephone, to assess 
survival and the use of alternative anticancer therapy until death or loss to follow-up. 
f. 
The screening physical examination will include, at a minimum, the general appearance of the subject, height (screening only) and weight, and examination of the 
skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system.  Symptom-directed physical 
examinations, including extramedullary disease assessments by palpation, will be done thereafter.  Assessments will be made Q3C through Cycle 48, then Q6C 
thereafter. 
g. 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be assessed after the subject has rested in the sitting position.  Assessments will be 
made Q3C through Cycle 48, then Q6C thereafter. 
h. 
ECOG assessments will be made Q3C through Cycle 48, then Q6C thereafter. 
i. 
Subjects should be in supine position and resting for ≥ 10 minutes before study-related ECGs.   
j. 
Women of childbearing potential only.  Testing will be done locally by use of central laboratory provided kits.  Pregnancy testing may be done by local laboratories 
and can be done more frequently than the protocol-defined schedule, if required by local regulatory authorities. In general, assessments will be made Q3C through 
Cycle 48, then Q6C thereafter. 
k. 
Hematology will include complete blood count with differential and platelet and reticulocyte counts.  Cycle 1 Day 1 hematology does not need to be repeated if 
screening hematology was within 5 days. Assessments will be made Q3C through Cycle 48, then Q6C thereafter. 
l. 
Serum chemistry will include albumin, alkaline phosphatase, bone-specific alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bicarbonate, 
blood urea nitrogen, calcium, chloride, creatinine, c-terminal telopeptide, glucose, lactate dehydrogenase, magnesium, phosphate, potassium, sodium, total 
bilirubin, total protein, and uric acid.  Cycle 1 Day 1 serum chemistry does not need to be repeated if screening chemistry was within 5 days. Assessments will be 
made Q3C through Cycle 48, then Q6C thereafter. 
m. The indicated samples at this timepoint (Cycle 1 Day 1) must be drawn predose. 
n. 
Urinalysis will include pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.  
o. 
T/B/NK cell count (i.e., CD3+, CD4+, CD8+, CD19+, CD16/56+).  During Cycle 6 through Cycle 24, assessments will only be done at the end of Cycle 6, 12, 18, 
and 24.  During Cycle 27 through Cycle 48, assessments will be done Q6C starting at Cycle 27. Assessments after Cycle 48 are not required. 
p.  Serum immunoglobulin will include IgG, IgM, IgA and Serum M protein.  Starting at Cycle 6, IgG, IgM, IgA, and serum M protein will be done Q3C (12 weeks, 
± 7 days) through Cycle 48, then Q6C thereafter.  
q. 
Subjects who are hepatitis B core antibody positive (or have a known history of HBV infection) should be monitored monthly with a quantitative PCR test for HBV 
DNA.  Assessments will be made QM from Cycle 6 to Cycle 48 or early discontinuation, and then Q3M thereafter. 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. 
r 
Pretreatment extramedullary disease assessment including CT scan should be performed within 30 days before the first dose.  A CT scan with contrast (unless 
contraindicated) of the chest, abdomen, and pelvis and any other disease sites (e.g., neck) are required for the pretreatment assessment.  For subjects with 
baseline (screening) extramedullary disease, follow-up radiologic assessments are required at the end of Cycle 2 (±7 days), Cycle 4 (± 7 days), Cycle 6 (± 7 days), 
then every 3 cycles (12 weeks, ± 7 days) until Cycle 27, then every 6 cycles thereafter or more frequently at the investigator’s discretion.  At all other visits, 
extramedullary disease assessments will be done by physical examination and laboratory results.  A bone marrow aspirate and biopsy will be done at screening or 
up to 60 days before the first dose of study drug.  Bone marrow aspirate and biopsy are also required at end of Cycle 2 and Cycle 12, which must be done within 
4 weeks of the contemporaneous radiologic evaluation.  Furthermore, bone marrow and radiologic (as applicable) assessments are required for confirmation of 
complete remission. Pathologic review of the bone marrow aspirate and biopsy will be performed by a central laboratory (or local laboratory, if central laboratory is 
unavailable) for confirmation of WM diagnosis.  When possible, extra bone marrow tissue may be used for PD evaluation. 
s. 
PD samples will be drawn predose and 4 hours (± 10 minutes) postdose on the days indicated. This sampling will be limited to a subset of subjects as described in 
the protocol and timepoints are relative to the morning dose.  Molecular testing may be performed using the blood samples collected for PD testing (when 
available).  Molecular testing will include, but may not be limited to, immunoglobulin heavy-chain variable mutational status, CXCR4S338X, and MYD88 L265P. 
t. 
PD samples will be drawn predose on the days indicated.  This sampling will be limited to a subset of subjects as described in the protocol and timepoints are 
relative to the morning dose.  A PD sample will also be collected at disease progression (preferably at the TT visit). Molecular testing may be performed using the 

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blood samples collected for PD testing (when available).  Molecular testing will include, but may not be limited to, immunoglobulin heavy-chain variable mutational 
status, CXCR4S338X, and MYD88 L265P. 
u. 
PK samples will be drawn per Table 2.  This sampling will be limited to a subset of subjects as described in the protocol and timepoints are relative to the morning 
dose. 
v. 
After the end of the protocol-defined AE reporting period (see Section 6.2.1), only SAEs considered related to study drug(s) or study procedures are required to be 
collected. 
w. PRO assessment will be done at screening, at the end of Cycle 2, Cycle 4, and Cycle 6; and then Q6C thereafter until documentation of progressive disease or 
use of alternative anticancer therapy.  
 

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Appendix 5. 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). 

Product: ACP-196 (acalabrutinib) 
Version: 8.0 (Global) 
Protocol: ACE-WM-001 
 
 
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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.  
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. 

Product: ACP-196 (acalabrutinib) 
Version: 8.0 (Global) 
Protocol: ACE-WM-001 
 
 
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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. 
The investigator should determine the cause for the previous occurrence of PHL and answer the 
following question:  
Was the alternative cause for the previous occurrence of PHL determined to be the 
disease under study (e.g., chronic or progressing malignant disease, severe infection, or 
liver disease)?  
• 
If the answer is No:  
Follow the process described in “Potential Hy’s Law Criteria Met” in this appendix 
for reporting PHL as an SAE.  
• 
If the answer is Yes:   
Determine whether there has been a significant change in the subject’s condition 
compared with the previous occurrence of PHL.  Note:  A “significant” change in 
the subject’s condition refers to a clinically relevant change in any of the individual 

Product: ACP-196 (acalabrutinib) 
Version: 8.0 (Global) 
Protocol: ACE-WM-001 
 
 
Acerta Pharma 
Confidential 
 
Page 86  
liver biochemistry parameters (ALT, AST, or total bilirubin) in isolation or in 
combination or a clinically relevant change in associated symptoms.  The 
determination of whether there has been a significant change will be at the 
discretion of the investigator; this may be in consultation with the study medical 
monitor if there is any uncertainty.  
o 
If there is no significant change, no action is required.  
o 
If there is a significant change, follow the process described in “Potential 
Hy’s Law Criteria Met” in this appendix for reporting PHL as an SAE.  
LABORATORY TESTS 
The list below represents a comprehensive list of follow-up tests that may aid in assessing 
PHL/HL. 
Test results used to assess PHL/HL should be recorded on the appropriate eCRF.  
Additional standard chemistry and 
coagulation tests  
GGT  
LDH  
Prothrombin time  
INR  
Viral hepatitis  
IgM anti-HAV   
IgM and IgG anti-HBc  
HBsAg  
HBV DNA  
IgM and IgG anti-HCV  
HCV RNA  
IgM anti-HEV  
HEV RNA  
Other viral infections  
IgM & IgG anti-CMV  
IgM & IgG anti-HSV  
IgM & IgG anti-EBV  
Alcoholic hepatitis  
Carbohydrate deficient transferrin (CD-
transferrin)  
Autoimmune hepatitis  
Antinuclear antibody 
Anti-Liver/Kidney Microsomal Ab (Anti-
LKM)  
Anti-Smooth Muscle Ab (ASMA)  
Metabolic diseases  
alpha-1-antitrypsin  
Ceruloplasmin  
Iron  
Ferritin  
Transferrin  
Transferrin saturation  
Reference  
FDA Guidance for Industry (issued July 2009). Drug-induced liver injury: Premarketing clinical 
evaluation 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M174090.pdf