An Open-label, Phase 2 Study of ACP-196 in Subjects With Mantle Cell Lymphoma
Phase: PHASE2
Conditions: Mantle Cell Lymphoma (MCL)
Sponsor: Acerta Pharma BV

Product: Acalabrutinib (ACP-196) 
Protocol: ACE-LY-004 
 
 
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PROTOCOL 
TITLE: 
An Open-label, Phase 2 Study of ACP-196 in Subjects 
with Mantle Cell Lymphoma 
PROTOCOL NUMBER: 
ACE-LY-004 
STUDY DRUG: 
Acalabrutinib (ACP-196) 
IND NUMBER: 
118717 
EUDRACT NUMBER: 
2014-002117-28 
SPONSOR MEDICAL 
MONITOR: 
Phone: 
 
Email: 
 
SPONSOR: 
Acerta Pharma BV 
 
5349 AB Oss 
The Netherlands 
PROTOCOL DATE: 
Version 0.0 - 02 July 2014 
AMENDMENT 1 DATE:  
Version 1.0 – 22 November 2014 
AMENDMENT 2 DATE:  
Version 2.0 – 16 March 2015  
AMENDMENT 3 DATE:  
Version 3.0 – 17 July 2015 
AMENDMENT 4 DATE: 
Version 4.0 – 14 November 2015 
AMENDMENT 5 DATE: 
Version 5.0 – 05 January 2016  
AMENDMENT 6 DATE: 
Version 6.0 – 19 July 2016 
AMENDMENT 7 DATE: 
Version 7.0 – 18 April 2017 
AMENDMENT 8 DATE: 
Version 8.0 – 22 November 2017  
Version 8.1 – 06 March 2018 (France Only) 
AMENDMENT 9 DATE: 
Version 9.0 – 28 February 2020  
Version 9.1 – 28 February 2020 (France Only) 
AMENDMENT 10 DATE: 
Version 10.0 – 11 June 2020 
Version 10.1 – 11 June 2020 (France Only) 
 
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Confidentiality Statement 
This document contains proprietary and confidential information of Acerta Pharma BV 
that must not be disclosed to anyone other than the recipient study staff and members of 
the Institutional Review Board (IRB)/Independent Ethics Committee (IEC).  This 
information cannot be used for any purpose other than the evaluation or conduct of the 
clinical investigation without the prior written consent of Acerta Pharma BV.  

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PROTOCOL APPROVAL PAGE 
VERSION 10.1 
I have carefully read Protocol ACE-LY-004 entitled “An Open-label, Phase 2 Study of 
ACP-196 in Subjects with Mantle Cell Lymphoma.”  I agree to conduct this study as 
outlined herein and in compliance with Good Clinical Practices (GCP), all applicable 
regulatory requirements and with the ethical principles laid down in the Declaration of 
Helsinki.  Furthermore, I understand that the sponsor, Acerta Pharma, and the IRB/IEC 
must approve any changes to the protocol in writing before implementation. 
I agree not to divulge to anyone, either during or after the termination of the study, any 
confidential information acquired regarding the investigational product and processes or 
methods of Acerta Pharma BV.  All data pertaining to this study will be provided to 
Acerta Pharma BV.  The policy of Acerta Pharma BV requires that any presentation or 
publication of study data by clinical investigators be reviewed by Acerta Pharma BV, 
before release, as specified in the protocol. 
 
Principal Investigator’s Signature 
Date 
 
 
Print Name 
 
 

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SUMMARY OF AMENDMENT 10 
This protocol is being amended to clarify the definition of the end of the study and the 
time points for the follow-up analyses.  A sentence regarding the continuation of 
treatment of acalabrutinib for subjects with disease progression was incorrectly added to 
the previous protocol amendment (Amendment 9).  This text is not applicable to this 
protocol, and pertinent information regarding continuation of acalabrutinib for subjects 
beyond this study can be located in Section 3.1, as added in Protocol Amendment 9. 
Updates were made to the designee for receipt of serious adverse events and 
pregnancy reporting from Acerta Pharma Drug Safety to AstraZeneca Representative.  
An appendix was added to consolidate guidance for subject safety and ongoing access 
to medical care and investigational product during the global COVID-19 pandemic. 
The following changes were made as part of this amendment; newly added text is 
indicated in bold, and deleted text is indicated by strikethrough: 
Change  
Rationale 
Study Synopsis 
Updated to reflect changes 
in the body of the protocol 
Section 3.1 Description of Study 
This study will enroll approximately 117 subjects.   
Refer to Appendix 4 for a comprehensive list of study assessments 
and their timing.  The end of trial is defined as the point when the 
last subject on the study exits the study for any reasonstudy is 
defined as the last subject last visit date.   
The primary efficacy analyses will be based on investigator 
assessment.  An Independent Review Committee (IRC) will assess 
the efficacy endpoints in accordance with the IRC charter provided 
separately from this document. 
Subjects who are still on treatment at the end of the studytime of 
close-out analysis and are deriving clinical benefit from 
acalabrutinib treatment may continue treatment.  At the time of the 
final data cutoff (DCO) and database closure, subjects who remain 
in this study may be transitioned to a separate rollover study or 
remain within this study protocol for continued access to study 
drug.  Once all active subjects are eligible to continue to receive 
acalabrutinib and after database closure, this study would be 
considered closed.  Tthere will be no further data collection other 
than reporting of SAEs per Section 6.2.  Access to study 
treatment within this study protocol will enable continued 
treatment with visit assessments per standard of care, whereas the 
separate rollover study will enable treatment continuation with visit 
assessments and data collection per the rollover study protocol. 
Text was revised to clarify 
the timing of the end of the 
study. 

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Change  
Rationale 
Section 3.8 Withdrawal of Subjects from Study Treatment 
The date the subject is withdrawn from study treatment or from the 
study (including long-term follow-up) and the reason for 
discontinuation will be recorded on the appropriate CRF. 
Subjects who meet criteria of disease progression and are 
continuing to gain clinical benefit from therapy may be able to 
temporarily remain on acalabrutinib after discussion with the 
medical monitor. 
Deleted text that was 
incorrectly added in the 
previous amendment.  This 
text was not applicable to 
this protocol. 
Section 4.0 Study Activities and Assessments 
The schedule of events is provided in Appendix 4.  See 
Appendix 6 for management of study procedures during 
pandemic.  Descriptions of the scheduled evaluations are outlined 
below and complete information on study drug and dosing is 
provided in Section 3.5. 
Reference to new appendix 
(Appendix 6) was added. 
Section 5.6 Final and Follow-up Analyses 
The final analysis of primary and secondary efficacy endpoints will 
occur approximately 14 months after the last subject has been 
enrolled.  A follow-up analysis will be performed when all subjects 
have completed their study participation24 months after the last 
subject has been enrolled, and close-out analysis will be 
performed approximately 54 months after enrollment of the 
last subject.  
Text was revised to clarify 
time points for follow-up 
analyses. 
Section 6.2.5 Pregnancy 
The investigator should report all pregnancies in study subjects and 
the partners of study subjects within 24 hours of notification using 
the Pregnancy Report Form.  This form should be faxed or 
emailedsent to Acerta Pharma Drug Safetythe AstraZeneca 
Representative.   
… 
Upon completion of the pregnancy, additional information on the 
mother, pregnancy, and baby will be collected and sent to 
the AstraZeneca Representative. 
Revised designee of 
reports of pregnancy to 
allow for the transition of 
reporting from Acerta to 
AstraZeneca 
Representative 
Section 6.2.6 Expedited Reporting Requirements for Serious 
Adverse Events 
If electronic SAE reporting is not available, paper SAE forms must 
be emailed or faxedsent to Acerta Pharma Drug Safety, or 
designeethe AstraZeneca Representative.  Acerta Pharma Drug 
SafetyThe AstraZeneca Representative may request follow-up 
and other additional information from the investigator (eg, hospital 
admission/discharge notes and laboratory results). 
… 
Autopsy and postmortem reports must be forwarded to Acerta 
Pharma Drug Safety, or designeethe AstraZeneca 
Representative, as outlined above. 
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 
and is not listed in the current Acalabrutinib IB (ie, an unexpected 
event).  In this case, Acerta Pharma Drug Safety/Designee will 
forward a formal notification describing the suspected unexpected 
Revised designee of 
reports of serious adverse 
events to allow for the 
transition of reporting from 
Acerta to AstraZeneca 
Representative 
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Change  
Rationale 
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: 
United States)  
or
for outside 
United States) 
Email: 
 
 
 
Section 7.12 General Investigator Responsibilities 
The principal investigator must ensure that: 
… 
11. All IND Safety Reports and SUSAR Reports are submitted 
promptly to the IRB/IEC. 
12. All SAEs are reported to Acerta Pharma Drug 
Safety/Designeethe AstraZeneca Representative within 
24 hours of knowledge and to the IRB/IEC per their 
requirements. 
Revised designee of 
reports of serious adverse 
events to allow for the 
transition of reporting from 
Acerta to AstraZeneca 
Representative 
Appendix 6  Management of Study Procedures During 
Pandemic 
Appendix added to 
consolidate guidance for 
subject safety and ongoing 
access to medical care and 
investigational product 
during the global COVID-19 
pandemic. 
 
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TABLE OF CONTENTS 
 
PROTOCOL APPROVAL PAGE VERSION 10 ................................................... 3 
SUMMARY OF AMENDMENT 10 ........................................................................ 4 
TABLE OF CONTENTS ....................................................................................... 7 
IN–TEXT TABLES ............................................................................................. 10 
IN–TEXT FIGURES ............................................................................................ 10 
LIST OF APPENDICES ..................................................................................... 10 
ABBREVIATIONS .............................................................................................. 12 
STUDY SYNOPSIS ............................................................................................ 15 
1.0 
BACKGROUND INFORMATION ............................................................ 21 
1.1 
Role of BTK in Lymphoid Cancers ........................................................... 21 
1.2 
Mantle Cell Lymphoma ............................................................................ 22 
1.3 
Therapeutic Options for Previously-treated Mantle Cell Lymphoma ........ 23 
1.4 
Preclinical Studies ................................................................................... 23 
1.4.1 
Chemistry ................................................................................... 23 
1.4.2 
Mechanism of Action of Acalabrutinib ........................................ 24 
1.4.3 
Dog Lymphoma Study ................................................................ 24 
1.4.4 
Acalabrutinib and Antibody-dependent Cell-mediated Cytotoxicity
 ................................................................................................... 24 
1.4.5 
Acalabrutinib and Thrombus Formation ..................................... 25 
1.4.6 
Safety Pharmacology and Toxicology ........................................ 26 
1.4.7 
Drug-drug Interaction Potential................................................... 26 
1.5 
Clinical Studies ........................................................................................ 27 
1.5.1 
Pharmacokinetics and Pharmacodynamics of Acalabrutinib in 
Healthy Volunteers ..................................................................... 27 
1.5.2 
Clinical Experience ..................................................................... 27 
1.6 
Benefits/Risks .......................................................................................... 28 
1.7 
Summary and Conclusions ...................................................................... 28 
2.0 
STUDY OBJECTIVES ............................................................................. 28 
2.1 
Primary Objective .................................................................................... 28 
2.2 
Secondary Objectives: ............................................................................. 28 
3.0 
STUDY DESIGN ...................................................................................... 28 
3.1 
Description of Study ................................................................................. 28 
3.2 
Study Endpoints and Parameters ............................................................ 30 
3.2.1 
Efficacy Endpoints ...................................................................... 30 
3.3 
Rationale for Study Design and Dosing Regimen .................................... 30 

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3.4 
Selection of Study Population .................................................................. 31 
3.4.1 
Inclusion Criteria ......................................................................... 31 
3.4.2 
Exclusion Criteria ....................................................................... 32 
3.4.3 
Numbers of Subjects .................................................................. 33 
3.4.4 
Enrollment Procedures ............................................................... 33 
3.5 
Study Drug ............................................................................................... 34 
3.5.1 
Premedications ........................................................................... 34 
3.5.2 
Formulation, Packaging, and Storage ........................................ 34 
3.5.3 
Administration of Study Drug ...................................................... 34 
3.5.4 
Assuring Subject Compliance..................................................... 35 
3.5.5 
Dose Delays ............................................................................... 35 
3.5.6 
Dose Modification and Discontinuation ...................................... 35 
3.6 
Concomitant Therapy............................................................................... 36 
3.6.1 
Permitted Concomitant Therapy ................................................. 36 
3.6.2 
Guideline for Use of CYP Inhibiting/Inducing Drugs ................... 36 
3.6.3 
Guideline for Use of Drugs that Affect Gastric pH ...................... 37 
3.6.4 
Prohibited Concomitant Therapy ................................................ 37 
3.7 
Precautions .............................................................................................. 38 
3.7.1 
Risks Associated with Acalabrutinib Treatment .......................... 38 
3.7.2 
Dietary Restrictions .................................................................... 40 
3.7.3 
Reproductive Toxicity ................................................................. 40 
3.7.4 
Overdose Instructions ................................................................ 42 
3.8 
Withdrawal of Subjects From Study Treatment ........................................ 42 
3.9 
Reasons for Study Exit ............................................................................ 43 
3.10 
Data and Safety Monitoring ..................................................................... 44 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS ........................................... 44 
4.1 
Description of Procedures ........................................................................ 44 
4.1.1 
Informed Consent ....................................................................... 44 
4.1.2 
Medical History ........................................................................... 44 
4.1.3 
Adverse Events .......................................................................... 45 
4.1.4 
Concomitant Medications and Therapy ...................................... 45 
4.1.5 
Confirmation of Eligibility ............................................................ 45 
4.1.6 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status ......................................................................................... 45 
4.1.7 
Physical Examination, Vital Signs, Height & Weight ................... 45 
4.1.8 
 45 
4.1.9 
Bone Marrow Aspirate and Biopsy ............................................. 46 
4.1.10 Electrocardiogram ...................................................................... 46 
4.1.11 Urine Pregnancy Test ................................................................. 46 
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4.1.12 Hematology ................................................................................ 46 
4.1.13 Serum Chemistry ........................................................................ 46 
4.1.14 Urinalysis .................................................................................... 47 
4.1.15 T/B/NK Cell Count ...................................................................... 47 
4.1.16 Serum Immunoglobulin .............................................................. 47 
4.1.17 HBV PCR Testing ....................................................................... 47 
4.1.18 Pharmacodynamics .................................................................... 47 
4.1.19 Pharmacokinetics ....................................................................... 47 
4.1.20 Tumor Assessment .................................................................... 48 
4.1.21 Study Drug Accountability .......................................................... 50 
4.1.22 Routine Clinical Assessments .................................................... 50 
4.2 
Investigator’s Assessment of Response to Treatment ............................. 50 
4.3 
Early Termination/Safety Follow-up Visit ................................................. 53 
4.4 
Follow-up for Progression and Survival ................................................... 54 
4.5 
Missed Evaluations .................................................................................. 54 
5.0 
STATISTICAL METHODS OF ANALYSIS .............................................. 55 
5.1 
General Considerations ........................................................................... 55 
5.2 
Sample Size Considerations .................................................................... 55 
5.3 
Definition of Analysis Population .............................................................. 55 
5.4 
Missing Data Handling ............................................................................. 55 
5.5 
Endpoint Data Analysis ............................................................................ 56 
5.5.1 
Demographics and Baseline Characteristics .............................. 56 
5.5.2 
Study Treatment Administration ................................................. 56 
5.5.3 
Analysis of Efficacy Parameters ................................................. 56 
5.5.4 
Analysis of Safety Endpoints ...................................................... 57 
5.5.5 
Analysis of Pharmacokinetic/Pharmacodynamic Endpoints ....... 58 
5.5.6 
Explorative or Correlative Analyses ............................................ 58 
5.5.7 
 59 
5.5.8 
 
 59 
5.5.9 
 
 59 
5.6 
Final and Follow-up Analyses .................................................................. 59 
6.0 
ASSESSMENT OF SAFETY ................................................................... 59 
6.1 
Definitions ................................................................................................ 60 
6.1.1 
Adverse Events .......................................................................... 60 
6.1.2 
Serious Adverse Event ............................................................... 60 
6.1.3 
Adverse Events of Special Interest ............................................. 61 
6.1.4 
Severity ...................................................................................... 61 
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6.2 
Documenting and Reporting of Adverse and Serious Adverse Events .... 62 
6.2.1 
Adverse Event Reporting Period ................................................ 62 
6.2.2 
Assessment of Adverse Events .................................................. 62 
6.2.3 
Second Primary Malignancies .................................................... 63 
6.2.4 
Hy’s Law ..................................................................................... 63 
6.2.5 
Pregnancy .................................................................................. 64 
6.2.6 
Expedited Reporting Requirements for Serious Adverse Events 64 
6.2.7 
Type and Duration of Follow-up of Subjects After Adverse Events
 ................................................................................................... 65 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ...... 65 
7.1 
Regulatory and Ethical Compliance ......................................................... 66 
7.2 
Institutional Review Board and Independent Ethics Committee ............... 66 
7.3 
Informed Consent and Protected Subject Health Information Authorization
 ................................................................................................................. 66 
7.4 
Subject Screening Log ............................................................................. 67 
7.5 
Case Report Forms ................................................................................. 67 
7.6 
Study Monitoring Requirements ............................................................... 67 
7.7 
Investigational Study Drug Accountability ................................................ 68 
7.8 
Record Retention ..................................................................................... 69 
7.9 
Protocol Amendments.............................................................................. 70 
7.10 
Publication of Study Results .................................................................... 70 
7.11 
Clinical Trial Insurance............................................................................. 70 
7.12 
General Investigator Responsibilities ....................................................... 70 
8.0 
REFERENCES ........................................................................................ 72 
9.0 
APPENDICES ......................................................................................... 74 
IN–TEXT TABLES 
Table 3-1.  Drug Discontinuation Actions for Acalabrutinib ..................................... 36 
Table 4-1.  Pharmacokinetic Sample Schedule ...................................................... 48 
Table 4-2.  Response Assessment Criteria for MCL (Cheson 2014) ...................... 51 
 
IN–TEXT FIGURES 
Figure 1-1.  NK Cell Natural Cytotoxicity ................................................................ 25 
Figure 1-2.  In Vivo Thrombus Formation ............................................................... 26 
 
LIST OF APPENDICES 
Appendix 1. Performance Status Scores ................................................................ 75 
Appendix 2. Adverse Event Assessment of Causality ............................................ 76 
Appendix 3. Known Strong in Vivo Inhibitors and Inducers of CYP3A ................... 77 

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Appendix 4. Schedule of Assessments .................................................................. 78 
Appendix 5. Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ....................................................................... 81 
Appendix 6. Management of Study Procedures During Pandemic ......................... 86 

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ABBREVIATIONS 
Abbreviation 
Definition 
λz 
terminal elimination rate constant 
5PS 
5-point scale 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE(s) 
adverse event(s) 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-12 
area under the plasma concentration-time curve from time 0 to the 
12-hour time point 
AUC0-24 
area under the plasma concentration-time curve from time 0 to the 
24-hour time point 
AUC0-24calc 
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 time 0 to infinity 
AUC0-last 
area under the plasma concentration-time curve from time 0 to time t, 
where t is the last measurable concentration 
BCR 
B-cell receptor 
BID 
twice per day (dosing) 
BTK 
Bruton tyrosine kinase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
CL/F 
oral clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CR 
complete remission (response) 
CSSF 
Clinical Supplies Shipping Receipt Form 
CT 
computed tomography 
Ct 
measurable concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DFU  
discontinuation follow-up 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 

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Abbreviation 
Definition 
DOR 
duration of response 
EC50 
effective concentration 50% (concentration causing half maximal effect) 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
 
FcR 
Fc receptor 
FDA 
Food and Drug Administration 
FDG 
[18F]fluorodeoxyglucose 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IHC 
immunohistochemistry 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITK 
interleukin-2-inducible T-cell kinase 
LDH 
lactate dehydrogenase 
LDi 
longest transverse diameter of a lesion 
LTFU 
long-term follow up 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MRD 
minimal residual disease 
NDA 
New Drug Application 
NHL 
non-Hodgkin lymphoma 
NK 
natural killer (cells) 
NR 
not reached 
ORR 
overall response rate 
OS 
overall survival 
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Abbreviation 
Definition 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics  
PE 
physical exam 
PET 
positron-emission topography 
PFS 
progression-free survival 
PI3K 
phosphoinositide-3 kinase 
PK 
pharmacokinetics 
PML 
progressive multifocal leukoencephalopathy  
PPD 
cross product of the LDi and perpendicular diameter 
PR 
partial remission (response) 
PRL 
partial response with lymphocytosis 
 
QD 
once per day (dosing) 
 
Q3M 
every 3 months 
QTc 
corrected QT interval 
R/R 
relapsed/refractory 
SAE(s) 
serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SDi 
shortest axis perpendicular to the LDi 
SPD 
sum of the product of the perpendicular diameters for multiple lesions 
SUSAR 
suspected unexpected serious adverse reaction  
t½   
terminal elimination half-life 
Tmax 
time of the maximum plasma concentration 
 
ULN 
upper limit of normal 
US 
United States 
Vz/F 
oral volume of distribution 
WHO 
World Health Organization 
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STUDY SYNOPSIS 
Protocol 
Number: 
ACE-LY-004 
Study Drug: 
Acalabrutinib (ACP-196) 
Protocol Title: 
An Open-label, Phase 2 Study of ACP-196 in Subjects with 
Mantle Cell Lymphoma 
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 (NHL), including mantle cell lymphoma (MCL).  
Ibrutinib, a first-generation BTK inhibitor, has been approved for 
the treatment of chronic lymphocytic leukemia (CLL) and MCL.  
The pivotal study of ibrutinib for the treatment of MCL showed that 
75 of the 111 subjects (68%; 95% confidence interval [CI] 58% to 
76%) had a reduction of ≥ 50% in lymphadenopathy (Wang 2013).  
Acerta Pharma BV (Acerta Pharma) has developed a highly 
selective BTK inhibitor, acalabrutinib (also known as ACP-196 
and Calquence®), that achieves significant oral bioavailability and 
potency in preclinical models.   
The purpose of this study is to evaluate the activity, safety, 
pharmacokinetics (PK), and pharmacodynamics (PD) of 
acalabrutinib administration in subjects with MCL. 
Study Design: 
This clinical trial is a Phase 2, multicenter, (approximately 
70 global centers), open-label study in subjects with histologically 
documented MCL, who have relapsed after, or were refractory to, 
≥ 1 (but not > 5) prior treatment regimens.  Subjects will be 
enrolled and will take 100 mg of acalabrutinib twice per day (BID) 
in repeated 28-day cycles.   
Treatment with acalabrutinib may be continued until disease 
progression or an unacceptable drug-related toxicity occurs.  
Dose modification provisions are provided in the study protocol.  
Note: temporary withholding of study drug for as little as 7 days 
can cause a transient worsening of disease and/or of 
constitutional symptoms.  Refer to Section 3.8 for more 
information on assessing disease progression under these 
circumstances.  An early termination visit is required for any 
subjects who permanently discontinue study drug for any reason 
(except for death, lost to follow up or withdrawal of consent), 
including disease progression.  In addition to the early termination 
visit, all subjects who discontinue study drug will have a safety 

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follow-up visit 30 (+ 7) days after his or her last dose of 
acalabrutinib.  
All subjects will have 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, once weekly for the first 4 weeks, every 2 weeks 
in Cycle 2, every 4 weeks in Cycles 3 to 12, and every 24 weeks 
thereafter.  PK/PD testing will be done in Cycles 1 and 2.  Tumor 
assessments will be completed at 8- to 24-week intervals during 
the trial.   
Refer to Appendix 4 for a comprehensive list of study 
assessments and their timing.  The end of study is defined as the 
last subject last visit date.   
Study 
Objectives: 
Primary Objective: 
To determine the activity of acalabrutinib in subjects with 
relapsed/refractory (R/R) MCL as measured primarily by response 
rate.  In addition, activity of acalabrutinib will be evaluated using 
duration of response, progression-free survival, and overall 
survival. 
Secondary Objective: 
• 
To characterize the safety profile of acalabrutinib 
• 
To characterize the PK profile of acalabrutinib 
• 
To evaluate the PD effects of acalabrutinib 
Study Endpoints:  Primary Endpoint: 
The primary endpoint of the study is the overall response rate 
(ORR), defined as the proportion of subjects achieving either a 
partial remission (response) (PR) or complete response (CR) 
according to the Lugano Classification for NHL (Cheson 2014) as 
assessed by investigators.   
Secondary Endpoints: 
Efficacy: 
• 
Duration of response (DOR)  
• 
Progression-free survival (PFS) 
• 
Overall survival (OS) 
• 
Independent Review Committee (IRC)-assessed ORR, 
DOR, and PFS per Lugano Classification 
Safety: 
• 
Frequency and severity of adverse events (AEs) 
• 
Frequency of AEs requiring discontinuation of study drug 
or dose reductions 
• 
Effect of acalabrutinib on peripheral T/B/natural killer (NK) 
cell counts 
• 
Effect of acalabrutinib on serum immunoglobulin levels 

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Pharmacokinetics: 
• 
Plasma pharmacokinetics of acalabrutinib  
Exploratory Endpoints:  
 
  
 
 
 
 
 
 
 
 
Sample Size: 
The planned sample size for this study is 117 subjects.   
Inclusion 
Criteria: 
• 
Men and women ≥ 18 years of age. 
• 
Pathologically confirmed MCL, with documentation of 
monoclonal B cells that have a chromosome translocation 
t(11;14)(q13;q32) and/or overexpress cyclin D1. 
• 
Disease has relapsed after or been refractory to ≥ 1 prior 
therapy for MCL and now requires further treatment. 
• 
Documented failure to achieve at least PR with, or 
documented disease progression after, the most recent 
treatment regimen. 
• 
Presence of radiographically measurable lymphadenopathy or 
extranodal lymphoid malignancy (defined as the presence of 
≥ 1 lesion that measures ≥ 2.0 cm in the longest dimension 
and ≥ 1.0 cm in the longest perpendicular dimension as 
assessed by computed tomography [CT] scan). 
• 
At least 1, but no more than 5, prior treatment regimens for 
MCL.  (Note: Subjects having received ≥ 2 cycles of prior 
treatment with bortezomib or any other commercially available 
proteasome inhibitor, either as single agent or as part of a 
combination therapy regimen, will be considered to be 
proteasome inhibitor exposed). 
• 
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 study drug.  
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• 
Men who are sexually active and can beget children must 
agree to use highly effective forms of contraception, and to 
refrain from sperm donation, during the study and for 2 days 
after the last dose of study drug. 
• 
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 Acerta Pharma 
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 
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, gastric bypass, symptomatic inflammatory bowel 
disease, or partial or complete bowel obstruction. 
• 
Any immunotherapy within 4 weeks of first dose of study drug. 
• 
The time from the last dose of the most recent chemotherapy 
or experimental therapy to the first dose of study drug is 
< 5 times the half-life of the previously administered agent(s). 
• 
Prior exposure to a B-cell receptor (BCR) inhibitor (eg, BTK, 
phosphoinositide-3 kinase [PI3K], or SYK inhibitors) or BCL-2 
inhibitor (eg, ABT-199). 
• 
Ongoing immunosuppressive therapy, including systemic or 
enteric corticosteroids for treatment of MCL 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. 

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• 
Grade ≥ 2 toxicity (other than alopecia) continuing from prior 
anticancer therapy including radiation. 
• 
Known history of human immunodeficiency virus (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 
acalabrutinib. 
• 
Uncontrolled autoimmune hemolytic anemia or idiopathic 
thrombocytopenia purpura. 
• 
Known history of a bleeding diathesis (eg, 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 (eg, phenprocoumon) within 
7 days of first dose of study drug. 
• 
Requires treatment with proton-pump inhibitors (eg, 
omeprazole, esomeprazole, lansoprazole, dexlansoprazole, 
rabeprazole, or pantoprazole).   
• 
Absolute neutrophil count (ANC) < 0.75 × 109/L or platelet 
count < 50 × 109/L; for subjects with disease involvement in 
the bone marrow, ANC < 0.50 × 109/L or platelet count 
< 30 × 109/L. 
• 
Creatinine > 2.5 × institutional upper limit of normal (ULN); 
total bilirubin > 2.5 × ULN; and aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) > 3.0 × ULN. 
• 
Breastfeeding or pregnant. 
• 
Concurrent participation in another therapeutic clinical trial. 
• 
Known central nervous system (CNS) lymphoma or 
leptomeningeal disease. 
• 
Requires treatment with a strong cytochrome P450 3A 
(CYP3A) inhibitor/inducer. 
• 
Presence of a gastrointestinal ulcer diagnosed by endoscopy 
within 3 months prior to screening. 
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.  
Starting Dose Regimen: 
100 mg acalabrutinib administered 12 hours apart (BID dosing = 
200 mg total daily dose) 
Concomitant 
Medications: 
The effect of agents that reduce gastric acidity (antacids or 
proton-pump inhibitors) on acalabrutinib absorption was evaluated 

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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. 
The concomitant use of strong inhibitors/inducers of CYP3A with 
acalabrutinib 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 acalabrutinib with a strong inducer 
of CYP3A has the potential to decrease exposure to acalabrutinib 
and could reduce efficacy.  
For more information on potential drug interactions with 
acalabrutinib, refer to the Acalabrutinib Investigator’s Brochure 
(IB). 
Statistical 
Methods: 
Approximately 117 subjects meeting the stated eligibility 
requirements will be enrolled onto the study.   
A one-sample Chi-square test with a 0.025 1-sided significance 
level will have more than 99% power to test the null hypothesis 
that ORR will be ≤ 20% (not considered clinically compelling) 
versus the alternative hypothesis that ORR will be ≥ 40%.  The 
sample size will provide adequate estimation utility for safety and 
other secondary analyses.  In particular, with a sample size of 
117 subjects, the probability of observing 1 or more instances of a 
specific AE with a true incidence rate of 1%, 2% or 5% is 69.1%, 
90.6% or 99.8%, respectively.  This provides reasonable 
assurance that events that occurring at ≥ 1% frequency can be 
identified in this Phase 2 study. 
The final analysis of primary and secondary efficacy endpoints will 
occur approximately 14 months after the last subject has been 
enrolled.   
A follow-up analysis will be performed 24 months after the last 
subject has been enrolled, and close-out analysis will be 
performed approximately 54 months after enrollment of the last 
subject. 

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1.0 
BACKGROUND INFORMATION 
1.1 
ROLE OF BTK IN LYMPHOID CANCERS 
Bruton tyrosine kinase (BTK) is a non-receptor enzyme of the Tec kinase family that is 
expressed among cells of hematopoietic origin, including B cells, myeloid cells, mast 
cells and platelets, where it regulates multiple cellular processes including proliferation, 
differentiation, apoptosis, and cell migration (Mohamed 2009, Bradshaw 2010). 
Functional null mutations of BTK in humans cause the inherited disease, X-linked 
agammaglobulinemia, which is characterized by a lack of mature peripheral B cells 
(Vihinen 2000).  Conversely, BTK activation is implicated in the pathogenesis of several 
B-cell malignancies (Buggy 2012).  Taken together, these findings have suggested that 
inhibition of BTK may offer an attractive strategy for treating B-cell neoplasms. 
Ibrutinib (IMBRUVICA®), a first-generation oral, small-molecule BTK inhibitor has been 
approved for the treatment for of several B-cell malignancies, including chronic 
lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).  The pivotal study of 
ibrutinib for the treatment of MCL showed that 75 of the 111 treated subjects (68%) had 
a reduction of ≥ 50% in lymphadenopathy (Wang 2013). 
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 adverse events 
(AEs) of diarrhea and rash (IMBRUVICA package insert).  In addition, ibrutinib is a 
substrate for CYP3A; inhibition of CYP3A causes a 29-fold increase in maximum 
observed plasma concentration (Cmax) and 24-fold increase in area under the curve 
(AUC) for ibrutinib (IMBRUVICA package insert).  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 and Calquence®), an orally 
administered, 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: 

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• 
Acalabrutinib has been evaluated against ibrutinib in EGFR-expressing cell lines.  
Ibrutinib is a potent covalent inhibitor of EGFR (inhibitory concentration 50% 
[IC50] = 5.3 nM).  Ibrutinib inhibited EGFR activation in epithelial cell lines 
(effective concentration [EC50] = 71 nM]), whereas acalabrutinib did not inhibit 
EGFR even at the highest concentration tested (10 μM). 
• 
Acalabrutinib has been evaluated against ibrutinib in natural killer (NK) cell 
functional assays.  While ibrutinib inhibited 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 
MANTLE CELL LYMPHOMA 
MCL is a distinct sub-type of non-Hodgkin lymphoma (NHL) comprising approximately 
7% of all adult NHL, with a moderately aggressive clinical course and poor outcome.  
The primary cell of origin of MCL is thought to be a naive B cell of pregerminal center 
origin within the mantle zone of the lymph node.  The incidence of MCL increases with 
age and an increase in incidence has been observed over time (Zhou 2008).   
Although high response rates have been reported in the front-line setting with 
combination chemotherapy and stem-cell transplant, most of these patients eventually 
relapse and die from their disease (Romaguera 2010).  Median overall survival (OS) 
from initial diagnosis varies from 18 to 61 months depending on prognostic risk category 
at baseline (Hoster 2008).  Median progression-free survival (PFS) for relapsed MCL 
varies from 4 to 14 months (Wang 2013; Goy 2013).  Effective therapy for relapsed MCL 
is therefore an unmet medical need.  

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1.3 
THERAPEUTIC OPTIONS FOR PREVIOUSLY-TREATED MANTLE 
CELL LYMPHOMA 
BTK inhibition is a promising therapeutic intervention for the treatment of MCL.  Ibrutinib, 
a first-in-class BTK inhibitor, has demonstrated substantial efficacy in patients with 
relapsed MCL based on data from a single-arm Phase 2 study of 111 patients (Wang 
2013).  In this study, which had an estimated median follow up of 15.3 months, the 
median PFS was 13.9 months (95% CI: 7.0-not reached [NR]) and ORR was 68% (CR: 
21%; PR: 47%).  The ORR was comparable between the bortezomib-naive and 
bortezomib-treated cohort of subjects, while median PFS was longer in the bortezomib-
treated cohort (16.6 months) compared to the bortezomib-naive cohort (7.4 months).  
The most frequently reported AEs in the study were diarrhea (50%, Grade 3: 6%), 
fatigue (41%, Grade 3: 5%), and nausea (31%, no Grade 3 AEs).  Grade 3 and 4 
hematologic AEs included neutropenia (in 16% of patients), thrombocytopenia (in 11%), 
and anemia (in 10%).  Grade 3 bleeding AEs were reported in 5 patients, and 4 patients 
had subdural hematomas.  
Other therapeutic agents that have received regulatory approval in relapsed MCL 
include bortezomib and lenalidomide.  The ORR reported with both these agents is 
notably lower than that reported in the ibrutinib Phase 2 study.  In a single arm, 
open-label study of lenalidomide in 134 patients with MCL who had relapsed after or 
were refractory to bortezomib (or a bortezomib-containing regimen), the ORR was 26% 
(1% CR) (REVLIMID® package insert).  The efficacy of bortezomib was evaluated in a 
single-arm open label study of 155 patients with relapsed MCL (after at least 1 prior 
therapy); the ORR was 31% (6% CR).   
1.4 
PRECLINICAL STUDIES 
Summaries of preclinical studies are provided below.  For more detailed information 
please refer to the Acalabrutinib Investigator’s Brochure (IB).  
1.4.1 
Chemistry 
  
  
Acalabrutinib is orally administered in humans and is suitable for formulating in capsules.  
For clinical testing, acalabrutinib has been manufactured and formulated according to 
current Good Manufacturing Practices (cGMP). 
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Acalabrutinib is an investigational product.  Acalabrutinib (Calquence) has been 
approved in the United States and other markets for the treatment of adult patients with 
MCL who have received at least 1 prior therapy, CLL, and small lymphocytic lymphoma. 
1.4.2 
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 IB.   
1.4.3 
Dog Lymphoma Study 
Spontaneous canine B-cell lymphoma shares many characteristics with human NHL, 
including diagnostic classifications and response to BTK inhibition (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 clinical trial and treated with acalabrutinib at dosages 
of 2.5 to 20 mg/kg every 12 or 24 hours.  Acalabrutinib was generally well tolerated, with 
adverse events 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 NHL.  These findings are similar to the clinical responses (ie, 1 dog with PR 
out of 5 dogs treated with suspected or confirmed diffuse large B-cell lymphoma 
[DLBCL]) observed with ibrutinib in dogs with spontaneous B-cell lymphoma (Honigberg 
2010). 
1.4.4 
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 (FcR)-stimulated NK cell function including calcium mobilization, granule 
release, and overall ADCC.  Anti-CD20 antibodies are standard of care drugs, often as 

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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. 
Figure 1-1.  NK Cell Natural Cytotoxicity 
 
Peripheral blood mononuclear cells were cultured with 51Cr labelled K562 targets at an Effector:Target 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 1µM, 
other acalabrutinib doses not statistically different from control condition). 
1.4.5 
Acalabrutinib and Thrombus Formation 
Ibrutinib is associated with an increased risk of bleeding (Kamel 2015; Shatzel 2017).  
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 
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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(n=5), CLL patients treated with 420 mg once per day (QD) ibrutinib (n=5) or CLL 
patients 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 patients, but not of those from CLL patients treated 
with acalabrutinib (Byrd 2016).   
Figure 1-2.  In Vivo Thrombus Formation 
 
Platelets from patients treated with ibrutinib 420 mg once per day (QD) (n=5) or acalabrutinib 100 mg twice 
per day (BID) (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). 
1.4.6 
Safety Pharmacology and Toxicology 
In vitro and in vivo safety pharmacology and toxicology studies with acalabrutinib have 
demonstrated a favorable nonclinical safety profile; please refer to Acalabrutinib IB for 
additional details.  
1.4.7 
Drug-drug Interaction Potential 
For more detailed information on drug-drug interaction potential for acalabrutinib, refer to 
the Acalabrutinib IB.  
Please refer to Section 3.6 for guidance that may cause drug-drug interactions. 

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1.5 
CLINICAL STUDIES 
1.5.1 
Pharmacokinetics and Pharmacodynamics of Acalabrutinib in 
Healthy Volunteers 
Acalabrutinib has a short PK half-life with a long-lasting PD effect due to covalent 
binding to BTK.  In a first-in-human study in healthy subjects, acalabrutinib plasma time 
to maximum concentration (Tmax) values was between 0.5 and 1.0 hour for all dose 
cohorts (2.5 mg BID to 100 mg QD), and mean half-life ranged from 0.97 to 2.1 hours.  
Acalabrutinib has an absolute oral bioavailability of 25%, is best taken with water, can be 
taken with or without food and does not accumulate in plasma upon repeat-dose 
administration.  In healthy subjects, exposure was generally linear over the dose range 
of 15 mg to 100 mg and slightly greater than proportional between 100 mg and 400 mg.  
Variability in exposure to acalabrutinib is mainly due to a combination of pH-dependent 
dissolution and absorption, and predominantly CYP3A-mediated metabolism. 
For more detailed information on acalabrutinib clinical pharmacology studies, please 
refer to the Acalabrutinib IB.   
1.5.2 
Clinical Experience 
Acerta Pharma is developing acalabrutinib for the treatment of patients with cancer or 
autoimmune disorders.  The safety data of acalabrutinib monotherapy are consistent 
among studies.  Preliminary data as of 01 June 2016, based on 134 subjects with 
relapsed and refractory CLL, have been evaluated for tumor response based on 
International Working Group response criteria (Hallek 2008) as updated (Cheson 2012) 
to include PR with treatment-induced lymphocytosis (PRL).  With a median follow up of 
15.5 months, an ORR of 96.9% has been observed.  Preliminary data through 01 June 
2016 are also available on the first 99 sequentially enrolled subjects with previously 
untreated CLL.  With a median follow up of 14.8 months, the ORR is 97.9% in subjects 
with previously untreated CLL.  Overall in the ACE-CL-001 relapsed and refractory and 
treatment-naive cohorts, as of the 01 June 2016 data cut-off date, few subjects have 
experienced disease progression.  
Preliminary data through 01 June 2016 are also available on the first 124 sequentially 
enrolled subjects with relapsed/refractory MCL who were treated with acalabrutinib on 
this protocol (ACE-LY-004).  With a median follow up of 6.9 months, the ORR is 80.6%, 
with CR in 31.5% of subjects. 
For detailed information on acalabrutinib clinical experience, refer to the Acalabrutinib IB. 

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1.6 
BENEFITS/RISKS 
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 1.5).  The safety results showed no identified safety risks in healthy subjects 
receiving 1 or 2 days of acalabrutinib ≤ 100 mg.  In ACE-CL-001, a study of acalabrutinib 
in subjects with relapsed/refractory or previously untreated CLL or Richter’s syndrome, 
no dose-limiting toxicities (DLTs) have been reported at dosages of ≤ 400 mg QD or 
100 mg and 200 mg BID.  With a median follow up of 15.5 months, an ORR of 96.9% 
has been observed in subjects with relapsed/refractory CLL.  Based on these robust 
results in subjects with CLL, the evaluation of acalabrutinib in subjects with 
relapsed/refractory MCL is warranted.  
1.7 
SUMMARY AND CONCLUSIONS 
The design and conduct of this study is supported by an understanding of the natural 
history and current therapies for subjects with lymphoid cancers, knowledge of the 
activity 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 activity of acalabrutinib in subjects with R/R MCL as measured 
primarily by response rate.  In addition, activity of acalabrutinib will be assessed by 
duration of response, progression-free survival, and overall survival. 
2.2 
SECONDARY OBJECTIVES: 
• 
To characterize the safety profile of acalabrutinib 
• 
To characterize the pharmacokinetic (PK) profile of acalabrutinib  
• 
To evaluate the PD effects of acalabrutinib 
3.0 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This clinical trial is a Phase 2, multicenter, open-label study in subjects with histologically 
documented MCL who have relapsed after, or were refractory to, ≥ 1 (but not > 5) prior 

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treatment regimens.  Subjects will be enrolled and will take 100 mg of acalabrutinib BID 
in repeated 28-day cycles.  
Treatment with acalabrutinib may be continued until disease progression or 
unacceptable drug-related toxicity, whichever occurs first.  Dose modification provisions 
are outlined in 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.  An early termination visit is required for any subjects who permanently 
discontinue study drug for any reason (except for death, lost to follow up or withdrawal of 
consent), including disease progression.  In addition to the early termination visit, all 
subjects who discontinue study drug will have a safety follow-up visit 30 (+ 7) days after 
his or her last dose of study drug.  
All subjects will have 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 once weekly for the first 4 weeks, every 
2 weeks in Cycle 2, every 4 weeks in Cycles 3 to 12, and every 24 weeks thereafter.  
Tumor assessments will be performed at 8- to 24-week intervals throughout the study. 
This study will enroll approximately 117 subjects.   
Refer to Appendix 4 for a comprehensive list of study assessments and their timing.  The 
end of study is defined as the last subject last visit date.   
The primary efficacy analyses will be based on investigator assessment.  An 
Independent Review Committee (IRC) will assess the efficacy endpoints in accordance 
with the IRC charter provided separately from this document. 
Subjects who are still on treatment at the time of close-out analysis and are deriving 
clinical benefit from acalabrutinib treatment may continue treatment.  At the time of the 
final data cutoff (DCO) and database closure, subjects who remain in this study may be 
transitioned to a separate rollover study or remain within this study protocol for continued 
access to study drug.  Once all active subjects are eligible to continue to receive 
acalabrutinib after database closure, there will be no further data collection other than 
reporting of SAEs per Section 6.2.  Access to study treatment within this study protocol 
will enable continued treatment with visit assessments per standard of care, whereas the 
separate rollover study will enable treatment continuation with visit assessments and 
data collection per the rollover study protocol. 

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3.2 
STUDY ENDPOINTS AND PARAMETERS 
3.2.1 
Efficacy Endpoints 
Primary Endpoint: 
The primary endpoint of the study is the ORR, defined as the proportion of subjects 
achieving either a PR or CR according to the Lugano Classification for NHL 
(Cheson 2014) as assessed by investigators.   
Secondary Endpoints: 
Efficacy: 
• 
Duration of response (DOR)  
• 
Progression-free survival (PFS) 
• 
Overall survival (OS) 
• 
IRC-assessed ORR, DOR, and PFS per Lugano Classification 
Safety: 
• 
Frequency and severity of adverse events (AEs) 
• 
Frequency of AEs requiring discontinuation of study drug or dose reductions 
• 
Effect of acalabrutinib on peripheral T/B/NK cell counts 
• 
Effect of acalabrutinib on serum immunoglobulin levels 
Pharmacokinetics: 
• 
Plasma pharmacokinetics of acalabrutinib 
Exploratory Endpoints: 
 
 
 
 
 
 
 
  
3.3 
RATIONALE FOR STUDY DESIGN AND DOSING REGIMEN 
As described in Section 1.5, preliminary data from the ongoing Phase 1/2 study in 
subjects with relapsed/refractory or previously untreated CLL have shown that 
CCI
CCI
CCI
CCI

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acalabrutinib is well tolerated at dosages of 100 mg to 400 mg QD and 100 mg to 
200 mg BID.  In addition, preliminary PD data from ACE-CL-001 show that BTK 
occupancy with acalabrutinib, in peripheral blood, is > 95% at 4 hours after QD dosing 
but decreases to < 95% at 24 hours with QD dosing, while with BID dosing complete 
BTK occupancy (95% to 99%) is maintained over 24 hours at steady state (Byrd 2016).  
These data suggest that de novo synthesis of BTK can occur within 24 hours in 
peripheral blood cells.  BID dosing may ensure BTK inhibition for the entire 24 hours, 
and thus may be beneficial in terms of increasing efficacy and/or decreasing 
development of resistance to acalabrutinib.  In addition, having information regarding the 
safety and pharmacology of a BID schedule may support future combination studies with 
other drugs that are administered BID; therefore, this study has been designed to 
evaluate the safety, PK, PD, and activity of dosing with 100 mg BID dosing in subjects 
with MCL. 
Approximately 117 subjects will be enrolled to this trial to receive acalabrutinib100 mg 
BID dose.  Subjects enrolled into this trial must have received ≥ 1 appropriate treatment 
regimen for MCL.  A maximum of 5 prior regimens is allowed.   
3.4 
SELECTION OF STUDY POPULATION 
3.4.1 
Inclusion Criteria 
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. Pathologically confirmed MCL, with documentation of monoclonal B cells that have a 
chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1. 
3. Disease has relapsed after or been refractory to ≥ 1 prior therapy for MCL and now 
requires further treatment. 
4. Documented failure to achieve at least PR with, or documented disease progression 
after, the most recent treatment regimen. 
5. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid 
malignancy (defined as the presence of ≥ 1 lesion that measures ≥ 2.0 cm in the 
longest dimension and ≥ 1.0 cm in the longest perpendicular dimension as assessed 
by computed tomography [CT] scan). 
6. At least 1, but no more than 5, prior treatment regimens for MCL. (Note: Subjects 
having received ≥ 2 cycles of prior treatment with bortezomib or any other 
commercially available proteasome inhibitor, either as single agent or as part of a 
combination therapy regimen, will be considered to be proteasome inhibitor 
exposed). 
7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 

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8. 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 
study drug.  
9. Men who are sexually active and can beget children must agree to use highly 
effective forms of contraception, and to refrain from sperm donation, during the study 
and for 2 days after the last dose of study drug. 
10. Willing and able to participate in all required evaluations and procedures in this study 
protocol including swallowing capsules without difficulty. 
11. 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 screening, or any 
Class 3 or 4 cardiac disease as defined by the New York Heart Association 
Functional Classification, or corrected QT interval (QTc) > 480 msec. 
4. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or 
resection of the stomach or small bowel, 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. The time from the last dose of the most recent chemotherapy or experimental 
therapy to the first dose of study drug is < 5 times the half-life of the previously 
administered agent(s). 
7. Prior exposure to a BCR inhibitor (eg, BTK, phosphoinositide-3 kinase [PI3K], or 
SYK inhibitors) or BCL-2 inhibitor (eg, ABT-199). 
8. Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids 
for treatment of MCL 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 human immunodeficiency virus (HIV) or active infection with 
hepatitis C virus (HCV) or hepatitis B virus (HBV) or any uncontrolled active systemic 
infection.  

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11. Major surgery within 4 weeks before first dose of study drug. 
12. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura. 
13. Known history of a bleeding diathesis (eg, hemophilia, von Willebrand disease). 
14. History of stroke or intracranial hemorrhage within 6 months before the first dose of 
study drug. 
15. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonist 
(eg, phenprocoumon) within 7 days of first dose of study drug. 
16. Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). 
17. ANC < 0.75 × 109/L or platelet count < 50 × 109/L; for subjects with disease 
involvement in the bone marrow, ANC < 0.50 × 109/L or platelet count < 30 × 109/L. 
18. Creatinine > 2.5 × institutional upper limit of normal (ULN); total bilirubin > 2.5 × ULN; 
and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
> 3.0 × ULN. 
19. Breastfeeding or pregnant. 
20. Concurrent participation in another therapeutic clinical trial. 
21. Known central nervous system (CNS) lymphoma or leptomeningeal disease. 
22. Requires treatment with a strong CYP3A inhibitor/inducer. 
23. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months prior to 
screening. 
3.4.3 
Numbers of Subjects 
This study will enroll approximately 117 subjects.  
3.4.4 
Enrollment Procedures 
Enrollment of a subject into the study will be performed according to the following 
procedures:  
• 
The study center will notify the sponsor when a clinically eligible subject is identified 
and is 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. 

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• 
The sponsor will aim to fax/email a completed Enrollment Confirmation Form to the 
study center within 24 hours.  Refer to the Pre-Screening and Enrollment Process 
Instructions for further details. 
Treatment must begin within the screening window (Section 4.1).  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 cGMP 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 drug product is provided as hard gelatin capsules containing 100 mg 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 IB for additional information regarding the drug product to be 
used in this trial. 
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 is intended to be administered orally BID (with the second daily dose 
11 hours to 13 hours after first dose) with 8 ounces (approximately 240 mL) of water.  
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.   

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If a dose is missed, it can be taken up to 3 hours after the scheduled time with a return 
to the normal schedule for the next dose.  If it has been > 3 hours, the dose should not 
be taken, and the subject should take the next dose at the scheduled time.  The missed 
dose will not be made up and must be returned to the site at the next scheduled visit.  
3.5.4 
Assuring Subject Compliance 
Subjects undergoing PK sampling, will receive their morning Cycle 1 Day 1, Day 8, 
Day 15, Day 22, and Day 28 doses in the clinic.  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.  The medical monitor may be contacted 
to discuss dose delays related to clinically important events.  Study drug may be held for 
a maximum of 28 consecutive days from expected dose.  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 3-1 should be taken for the following toxicities: 

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• 
Grade 4 neutrophil count decreases (ANC < 500/μL) for > 7 days (Neutrophil 
growth factors are permitted per American Society of Clinical Oncology [ASCO 
guidelines; Smith 2015] and use must be recorded on the electronic case report 
form [eCRF]). 
• 
Grade 3 platelet count decreases in the presence of significant bleeding 
• 
Grade 4 platelet count 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 3-1.  Drug Discontinuation Actions for Acalabrutinib 
Occurrence 
Action 
1st - 2nd 
Hold acalabrutinib until recovery to Grade 1 or baseline; may restart at 
original dose level (100 mg BID) 
3rd 
Hold acalabrutinib until recovery to Grade 1 or baseline; restart at 
100 mg QD 
4th 
Discontinue acalabrutinib 
Whenever possible, any dose adjustment of acalabrutinib should be discussed between 
the investigator and the Acerta Pharma medical monitor before implementation.  The 
appropriate clinic staff should dispense the study drug for the new dose level and 
instruct the subject/caregiver about the change in dose level.  Any changes to the dosing 
regimen must be recorded in the appropriate eCRF. 
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 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.  The concomitant use of strong inhibitors/inducers of 
CYP3A (Appendix 3) with acalabrutinib should be avoided when possible.  If a subject 

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requires a strong or moderate CYP3A inhibitor while on study, monitor the subject 
closely for potential toxicities.  Conversely, concomitant administration of acalabrutinib 
with a strong inducer of CYP3A has the potential to decrease exposure to acalabrutinib 
and could reduce efficacy. 
For more information on potential drug interactions with acalabrutinib, refer to the 
Acalabrutinib IB. 
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 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.   
For more information on potential drug interactions with acalabrutinib, refer to the 
Acalabrutinib IB. 
3.6.4 
Prohibited Concomitant Therapy 
Any chemotherapy, anticancer immunotherapy, corticosteroids (at dosages equivalent to 
prednisone > 10 mg/day), experimental therapy, or radiotherapy for treating MCL are 
prohibited. 
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 (eg, phenprocoumon) are prohibited. 

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3.7 
PRECAUTIONS 
3.7.1 
Risks Associated with Acalabrutinib Treatment 
The following summarizes the experience with acalabrutinib in hematological cancer 
studies.  Full details regarding the clinical safety of acalabrutinib are presented in 
Sections 5 and 6 of the Acalabrutinib IB. 
Hemorrhage 
Bleeding events, some fatal, including central nervous system, respiratory, and 
gastrointestinal hemorrhage, have been reported in patients treated with acalabrutinib.  
Patients 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.  
Patients with hemorrhage should be managed per institutional guidelines or as clinically 
indicated. 
Infections 
Serious infections, including fatal events, have been reported in patients treated with 
acalabrutinib.  Consider prophylaxis in subjects who are at increased risk for 
opportunistic infections.  Patients should be monitored for signs and symptoms of 
infection and treated as medically appropriate.  Refer to the sections below for additional 
information and monitoring guidance for viral hepatitis and additional information and 
management guidance for signs and symptoms of progressive multifocal 
leukoencephalopathy (PML). 
Hepatitis B Virus Reactivation 
Cases of hepatitis B virus (HBV) reactivation have been reported in patients treated with 
acalabrutinib with 1 case resulting in liver failure and death. Subjects who are anti-HBc 
positive or have a known history of hepatitis B virus (HBV) infection should be monitored 
every 3 months with a quantitative PCR test for HBV DNA.  Monitoring for HBV in these 
subjects 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.   

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Progressive Multifocal Leukoencephalopathy 
Cases of 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 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. 
Cytopenias 
Grade 3 or 4 events of cytopenias, including neutropenia, anemia, and 
thrombocytopenia have occurred in patients treated with acalabrutinib.  Monitor blood 
counts as specified in the schedule of assessments and as medically appropriate.  
Please refer to Section 3.5.6 for study drug modification guidance. Patients with 
cytopenias should be managed according to institutional guidelines or as clinically 
indicated. 
Second Primary Malignancies 
Second primary malignancies, including solid tumors and skin cancers, have been 
reported in patients treated with acalabrutinib.  The most frequent second primary 
malignancy was skin cancer (basal cell carcinoma).  Subjects should be monitored for 
signs and symptoms of malignancy.  Subjects who develop a second primary 
malignancy should be managed according to institutional guidelines with diagnostic 
evaluations as clinically indicated, and it may be necessary for subjects to permanently 
discontinue study treatment.  Continuation of acalabrutinib treatment should be 
discussed with the medical monitor.  Please refer to Section 6.2.3 for second primary 
malignancy reporting guidance. 
Atrial Fibrillation 
Monitor for symptoms of atrial fibrillation and atrial flutter (eg, palpitations, dizziness, 
syncope, chest pain, dyspnea) and obtain an ECG as clinically indicated.  Subjects with 

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atrial fibrillation should be managed per institutional guidelines with supportive care and 
diagnostic evaluations as clinically indicated.  
Reference Safety Information 
See the Reference Safety Information (RSI) in the Acalabrutinib IB for assessment of 
expectedness of serious adverse reactions. 
3.7.2 
Dietary Restrictions 
Because acalabrutinib is metabolized by CYP3A (see Section 1.4.7), subjects should be 
strongly cautioned against using herbal remedies or dietary supplements that contain 
potent CYP3A inhibitors or CYP3A inducers (in particular, St. John’s wort, which is a 
potent CYP3A inducer). 
Acalabrutinib may be taken with or without food. 
3.7.3 
Reproductive Toxicity 
Definition of women of non-reproductive potential:  
Women will be considered of non-reproductive potential if they are either:  
1) Postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy.  In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) Have a congenital or acquired condition that prevents childbearing. 
Women who are sexually active and can bear children must use highly effective forms of 
contraception during the study and for 2 days after the last dose of acalabrutinib.  Men 
who are sexually active and can beget children must agree to use highly effective forms 
of contraception during the study and for 2 days after the last dose of acalabrutinib. 
Examples of highly effective methods of contraception are defined below. 

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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 (IUS)  
• 
Bilateral tubal occlusion  
• 
Vasectomy of a female subject’s male partner (with medical assessment and 
confirmation of vasectomy surgical success)  
• 
Sexual abstinence (only if refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments)†  
Hormonal contraception may be susceptible to interaction with study or other drugs, 
which may reduce the efficacy of the contraception method.  
†Abstinence (relative to heterosexual activity) can 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 (eg, calendar, ovulation, sympto-thermal, and post-ovulation methods) and 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method 
(LAM) are not acceptable methods of contraception.  Female condom and male condom 
should not be used together as an effective method of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for subjects participating at 
sites in this country/region. 
Subjects should promptly notify the investigator if they, or their partner, become 
pregnant during this study, or within 2 days after the last dose of acalabrutinib.  If a 
female subject 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 (see Section 6.2.5).  Men must also refrain from donating sperm during 
the study and for 2 days after the last dose of acalabrutinib. 
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 

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maternal toxicities skeletal variations were associated with reductions in fetal weights.  
Effects on parturition and post-natal development are pending.  For additional details, 
refer to the Acalabrutinib IB. 
3.7.4 
Overdose Instructions 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or incorrect administration of study drug is not 
an adverse event unless it results in untoward medical effects. 
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF. 
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
serious criteria, the event should be reported to the sponsor immediately (ie, no more 
than 24 hours after learning of the event). 
For any subject experiencing an acalabrutinib overdose, 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. 
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 lasting 
> 28 days, unless reviewed and approved by the medical monitor.   
• 
Any subject who starts new chemotherapy or chemoimmunotherapy for the 
treatment of MCL should be withdrawn from study treatment. 

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• 
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 cancer progression, the subject may 
continue study treatment and remain under close observation (eg, evaluated at 
4-week intervals) pending objective confirmation of progression.  In particular, 
transient worsening of disease early in therapy or during temporary interruption 
of study therapy (eg, 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, 
and/or radiographic 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.   
Subjects who discontinue study therapy will continue on study for safety (Section 4.3) 
and survival (Section 4.4) unless they withdraw consent for further follow-up.  Thus, all 
subjects receiving ≥ 1 dose of study drug will be followed during the immediate 
post-therapy and long-term follow-up assessments unless the subject withdraws consent 
for such follow-up to be conducted.  The date the subject is withdrawn from study 
treatment or from the study (including long-term follow-up) and the reason for 
discontinuation will be recorded on the appropriate CRF. 
3.9 
REASONS FOR STUDY EXIT 
Reasons for study exit could be: 
• 
Subject’s withdrawal of consent from study 
• 
Decision by sponsor to terminate the study 
• 
Subject lost to follow-up 

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• 
Death 
3.10 DATA AND SAFETY MONITORING 
This trial will be monitored in accordance with the sponsor’s pharmacovigilance 
procedures.  AEs, serious adverse events (SAEs), and any subject safety questions or 
potential safety issues raised by the sites will be reviewed internally on an ongoing basis 
to identify safety concerns.  The sponsor also will initiate ad hoc interactions (eg, emails, 
conference calls or direct contact) with investigators to obtain investigator feedback and 
exchange and to discuss "significant safety events" (ie, AEs leading to dose reductions, 
related SAEs and deaths), as well as, to discuss study progress. 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS 
The schedule of events is provided in Appendix 4.  See Appendix 6 for management of 
study procedures during pandemic.  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.  
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 IRB/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 

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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, will also be recorded. 
4.1.3 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 6.1.1.  All medical 
occurrences from the time of first dose that meet this definition must be recorded. 
Important additional requirements for reporting SAEs are explained in Section 6.2. 
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 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status 
The ECOG performance index is provided in Appendix 1. 
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. 
Symptom-directed physical exams, including tumor assessments by palpation and 
attention to neurologic signs and symptoms of PML, will be done during the treatment 
period and at the safety follow-up visits. 
Vital signs (blood pressure, heart rate, and body temperature) will be assessed after the 
subject has rested in the sitting position. 
4.1.8 
 
 
 
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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.  Per the current response criteria (Cheson 2014), a bone 
marrow aspirate/biopsy will also be required at any time on study to confirm CR (if bone 
marrow was involved by lymphoma at baseline) and in some cases to confirm PR.  
Testing will be performed at the study center’s local laboratory or other clinical laboratory 
listed on the investigator’s Form FDA 1572.  De-identified copies of all bone marrow 
biopsy/aspirate results may be requested by the sponsor. 
For only the subjects from whom PD samples will be collected:  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 supine and resting for ≥ 10 minutes before any study-related 
electrocardiograms (ECGs).   
4.1.11 
Urine Pregnancy Test 
Urine pregnancy tests will be required only for women of childbearing potential.  Urine 
pregnancy tests will be performed at Screening; on Cycle 1 Day 1; on Day 28 of 
Cycles 1-12; on Day 28 of Cycles 15, 18, 21, and 24, then every 24 weeks; and at the 
early termination or safety follow-up visit. 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 (CBC) with differential and 
platelet counts.  Testing will be done by the central laboratory. 
4.1.13 
Serum Chemistry 
Chemistry must include albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood 
urea nitrogen (BUN), bone-specific alkaline phosphatase, calcium, chloride, creatinine, 
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C-terminal telopeptide, glucose, lactate dehydrogenase (LDH), magnesium, 
phosphate/phosphorus, potassium, sodium, total bilirubin, total protein, and uric acid.  
Testing will be done by the central laboratory. 
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  
Testing for immunoglobulin G (IgG), IgM, and IgA will be done by the central laboratory. 
4.1.17 
HBV PCR Testing 
Refer to Section 3.7.1 and Appendix 4 for information on the required HBV PCR testing 
for subjects with a history of HBV infection.  Testing will be done by local laboratories. 
4.1.18 
Pharmacodynamics 
PD assessments will be done on up to 24 bortezomib-naive subjects and up to 
24 bortezomib-exposed subjects.  Blood samples and bone marrow, when available, will 
be used for PD testing (eg, 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 up to 24 bortezomib-naive subjects and up to 
24 bortezomib-exposed subjects.  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 4-1. 

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Table 4-1.  Pharmacokinetic Sample Schedule 
 
HOURS POSTDOSE 
Cycle 
Day Predose 
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 
Tumor Assessment 
A pretreatment CT scan with contrast (unless contraindicated) is required of the chest, 
abdomen, and pelvis and any other disease sites (eg, neck) within 30 days before the 
first dose of study drug.  A pretreatment positron-emission tomography (PET)/CT scan is 
required within 60 days of first dose of study drug.  Information on extranodal 
involvement will also be recorded. 
On-study tumor assessments will be done by physical exam, radiographic examination, 
and bone marrow assessment.  Bone marrow assessments are required for confirmation 
of CR per clinical guidelines (see Section 4.2).  Likewise, endoscopy is mandatory to 
confirm CR for any subjects with a documented history of gastrointestinal involvement. 
During treatment, CT scans with contrast (unless contraindicated) of the chest, 
abdomen, and pelvis and any other disease sites (eg, neck) will be performed for tumor 
assessments at the end of Cycle 2 (± 7 days), Cycle 4 (± 7 days), and Cycle 6; and then 
every 6 cycles (24 weeks) thereafter or more frequently at investigator discretion.  For 
Cycles ≥ 6, CT and PET/CT scans may be performed within an imaging window of up to 
21 days before and up to 7 days after the scheduled study visit date.  During treatment, 
PET/CT scans will be performed at the end of Cycle 2 (± 7 days) and Cycle 6 and are 
required to confirm CR or as clinically indicated.  Subjects with confirmed CR are not 
required to undergo further PET/CT scans on study unless there is suspicion of 
progressive disease.   
Subjects should have radiographic tumor measurements done at the participating study 
center or an acceptable alternate imaging facility using an identical imaging protocol and 
similar equipment.  The same imaging equipment should be used for all scans whenever 

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possible.  The same radiologist should be assigned to read all the scans for a given 
subject throughout the study.  
In the event disease progression is suspected due to physical examination or laboratory 
test, a CT and PET/CT scan must be performed to confirm disease progression.  It is 
recommended that disease progression identified by PET/CT alone be confirmed by an 
alternative imaging modality (eg, diagnostic quality CT) or by biopsy.  There must be 
radiographically measurable disease at Screening (≥ 1 lymph node > 2.0 cm in the 
longest diameter).  If the sole lesion lies within the field of prior radiotherapy, there must 
be evidence of disease progression in that lesion. 
Up to 6 measurable lymph nodes (only target lesions > 1.5 cm in the longest diameter 
may be assessed), clearly measurable in 2 perpendicular dimensions, will be followed as 
target lesions for each subject.  Measurable sites of disease should be chosen such that 
they are representative of the subject’s disease.  In addition, selection of target lesions 
should be from as disparate regions of the body as possible when these areas are 
significantly involved.  If additional lesions are present but are not included in the target 
lesion assessment, they can be added as non-target lesions followed throughout the 
study.  The cranial-caudal measurement of the spleen and longest diameter of the liver 
will be assessed at screening and all subsequent response evaluations. 
A central imaging vendor will be used to provide independent radiologic assessments for 
the purposes of confirming disease progression, while investigator assessment will be 
used for confirming the primary endpoint.  The measurements from the central imaging 
vendor will not be reported back to the site. 
The CT portion of a PET/CT may be submitted in lieu of a dedicated CT; however, 
certain radiographic requirements are needed for acceptance, as described in the Site 
Radiology Manual, provided separately from this protocol.  Magnetic resonance imaging 
(MRI) may be used for subjects who are either allergic to CT contrast media or have 
renal insufficiency that per institutional guidelines restricts the use of CT contrast media.  
If MRI is used, 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.  
De-identified copies of all radiology results may be requested by the sponsor. 

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Minimal Residual Disease (MRD) Testing 
MRD testing will be performed on peripheral blood samples by a central laboratory.  A 
blood sample is to be collected every 24 weeks (ie, every 6 cycles), aligned with CT 
scan schedule, and again at the Early Termination visit.  Baseline (pretreatment) tissue 
from each subject (ie, diagnostic/predose archival lymph node, bone marrow or tumor 
tissue) will be requested from the sites and used for baseline calibration measurements 
for comparison with on-treatment samples.  MRD determination will be an exploratory 
analysis for correlation with outcome on trial, and the MRD testing results will not be 
used for making any treatment decisions on study.  Refer to the laboratory manual for 
processing and shipping of samples. 
4.1.21 
Study Drug Accountability 
See Section 7.7. 
4.1.22 
Routine Clinical Assessments 
Routine clinical assessments include physical exams, recording of symptoms, including 
B symptoms, and hematologic evaluations to evaluate for both AEs and assessment of 
disease progression.  If a subject shows signs of progression, the subject may continue 
treatment until objective progression is confirmed.  The investigator should report any 
suspected disease progression to the sponsor or designee.  Subjects should continue to 
be followed and adhere to study-related procedures until objective progression, 
regardless of the administration of subsequent anticancer therapy.  New anticancer 
therapy should be withheld if clinically appropriate in the absence of objective 
progressive disease.  
4.2 
INVESTIGATOR’S ASSESSMENT OF RESPONSE TO TREATMENT 
The investigator must rate the response of the subject’s MCL to treatment consistent 
with clinical guidelines (Cheson 2014) as listed in Table 4-2. 
Overall response assessments will include evaluation of physical exams, bone marrow 
assessments, and radiographic evaluations per the Schedule of Assessments 
(Appendix 4).  Subjects who have signs and symptoms of progression outside of the 
scheduled assessment should be evaluated by the investigator with a physical exam and 
laboratory assessments to determine if disease progression is present.  Any suspected 
case of disease progression should be confirmed with a CT and/or PET/CT scan, if one 
was not obtained, and should be reported to the sponsor or designee.  It is 

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recommended that disease progression identified by PET/CT alone be confirmed by an 
alternative imaging modality (eg, diagnostic quality CT) or by biopsy.  Subjects may 
continue study treatment until progression is confirmed by a serial exam at least 2 weeks 
later.  In addition, when clinically appropriate, based on investigator-perceived 
risk/benefit assessment, a subject may continue treatment until objective progression is 
confirmed. New anticancer therapy should be withheld if clinically appropriate in the 
absence of objectively confirmed progressive disease.  
Table 4-2.  Response Assessment Criteria for MCL (Cheson 2014) 
Response and Site 
PET-CT-Based Response 
CT-Based Response 
Complete 
Complete metabolic response 
Complete radiologic response (all of 
the following)  
 Lymph nodes and 
extra lymphatic sites 
Score 1, 2, or 3* with or without a 
residual mass on 5PS 
It is recognized that in Waldeyer’s ring 
or extranodal sites with high physiologic 
uptake or with activation within spleen 
or marrow (eg, with chemotherapy or 
myeloid colony-stimulating factors), 
uptake may be greater than normal 
mediastinum and/or liver. In this 
circumstance, complete metabolic 
response may be inferred if uptake at 
sites of initial involvement is no greater 
than surrounding normal tissue even if 
the tissue has high physiologic uptake 
Target nodes/nodal masses must 
regress to ≤1.5 cm in LDi 
No extralymphatic sites of disease  
 
Nonmeasured lesion 
Not applicable 
Absent 
 
Organ enlargement  
Not applicable 
Regress to normal 
 
New lesions 
None 
None 
 
Bone marrow 
No evidence of FDG-avid disease in the 
marrow 
Normal by morphology; if 
indeterminate, IHC negative  
Partial 
Partial metabolic response 
Partial remission (all of the following)  
 
Lymph nodes and 
extra lymphatic sites 
Score 4 or5 with reduced uptake 
compared with baseline and residual 
mass(es) of any size 
At interim, these findings suggest 
responding disease  
 
At end of treatment, these findings 
indicate residual disease 
≥ 50% decrease in SPD of up to 6 
target measurable nodes and 
extranodal sites 
 
When a lesion is too small to 
measure on CT, assign 
5 mm × 5 mm as the default value 
When no longer visible, 0 × 0mm 
For a node > 5 mm × 5 mm, but 
smaller than the normal, use actual 
measurement for calculation 
 
Nonmeasured 
lesions  
Not applicable  
Absent/normal, regressed, but no 
increase  
 
Organ enlargement 
Not applicable  
Spleen must have regressed by 
> 50% in length beyond normal 
 
New lesions 
None 
None 

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Table 4-2.  Response Assessment Criteria for MCL (Cheson 2014) 
Response and Site 
PET-CT-Based Response 
CT-Based Response 
 
Bone marrow 
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline (diffuse uptake 
compatible with reactive changes from 
chemotherapy allowed). If there are 
persistent focal changes in the marrow 
in the context of a nodal response, 
consideration should be given to further 
evaluation with MRI or biopsy or an 
interval scan  
Not applicable  
No response or stable 
disease 
No metabolic response  
Stable disease  
 
Target nodes/nodal 
masses, extranodal 
lesions  
Score 4 or 5 with no significant change 
in FDG uptake from baseline at interim 
or end of treatment 
< 50% decrease from baseline in 
SPD of up to 6 dominant, 
measurable nodes and extranodal 
sites; no criteria for progressive 
disease are met 
 
Nonmeasured 
lesions 
Not applicable 
No increase consistent with 
progression 
 
Organ enlargement  
Not applicable 
No increase consistent with 
progression 
 
New lesions 
None 
None 
 
Bone marrow 
No change from baseline 
Not applicable  
Progressive disease 
Progressive metabolic disease  
Progressive disease requires at 
least 1 of the following  
 
Individual target 
nodes/nodal masses 
Score 4 or 5 with increase in intensity of 
uptake from baseline and/or 
 
PPD progression: 
 
Extranodal lesions 
New FDG-avid foci consistent with 
lymphoma at interim or end-of-
treatment assessment 
An individual node/lesion must be 
abnormal with: 
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir 
and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤ 2cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the 
splenic length must increase by 
> 50% of the extent of its prior 
increase beyond baseline (eg, a 15-
cm spleen must increase to >16 
cm). If no prior splenomegaly, must 
increase by at least 2 cm from 
baseline 
New or recurrent splenomegaly 
 
Nonmeasured 
lesions 
None 
New or clear progression of 
preexisting nonmeasured lesions  

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Table 4-2.  Response Assessment Criteria for MCL (Cheson 2014) 
Response and Site 
PET-CT-Based Response 
CT-Based Response 
 
New lesions 
New FDG-avid foci consistent with 
lymphoma rather than another etiology 
(eg, infection, inflammation). If 
uncertain regarding etiology of new 
lesions, biopsy or interval scan may be 
considered 
Regrowth of previously resolved 
lesions 
A new node > 1.5 cm in any axis 
A new extranodal site >1.0 cm in 
any axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to 
lymphoma 
 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement  
Abbreviations: 5PS=5-point scale; CT=computed tomography; FDG=[18F]fluorodeoxyglucose; 
GI=gastrointestinal; IHC=immunohistochemistry; LDi=longest transverse diameter of a lesion; 
MRI=magnetic resonance imaging; PET=positron emission tomography; PPD=cross product of 
the LDi and perpendicular diameter; SDi=shortest axis perpendicular to the LDi; SPD=sum of the 
product of the perpendicular diameters for multiple lesions. 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at 
the time of an interim scan. However, in trials involving PET where de-escalation is investigated, 
it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). 
Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and 
extranodal lesions selected to be clearly measurable in two diameters. Nodes should preferably 
be from disparate regions of the body and should include, where applicable, mediastinal and 
retroperitoneal areas. Non-nodal lesions include those in solid organs (eg, liver, spleen, kidneys, 
and lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured 
lesions: Any disease not selected as measured, dominant disease and truly assessable disease 
should be considered not measured. These sites include any nodes, nodal masses, and 
extranodal sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, which is any 
site of suspected disease that would be difficult to follow quantitatively with measurement, 
including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, 
and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in 
extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the 
mediastinum with complete metabolic response but should be no higher than surrounding normal 
physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid growth 
factors).  
PET 5PS: 1, no uptake above background; 2. Uptake ≤ mediastinum; 3, uptake > mediastinum 
but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; 
X, new areas of uptake unlikely to be related to lymphoma.  
 
4.3 
EARLY TERMINATION/SAFETY FOLLOW-UP VISIT 
An early termination visit is required for any subjects who permanently discontinue study 
drug early for any reason (except for death, lost to follow up or withdrawal of consent), 
including disease progression.   

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In addition, all subjects should be followed for 30 (+ 7) days after his or her last dose of 
study drug (ie, the “safety follow-up visit”) to monitor for resolution or progression of AEs 
(see Section 6.2.7), 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.  Subjects who withdraw consent should still be 
encouraged to complete the safety follow-up assessments before withdrawing consent, 
but these assessments cannot be mandated once consent is withdrawn.  The Schedule 
of Assessments (Appendix 4) describes the procedures required for the safety follow-up.  
4.4 
FOLLOW-UP FOR PROGRESSION AND SURVIVAL 
Discontinuation Follow-up (DFU) 
Subjects who discontinue for reasons other than progressive disease will be followed 
approximately every 24 weeks from the end of study treatment until disease progression 
or the start of alternative anticancer therapy, whichever occurs first, to assess survival 
and the use of alternative anticancer therapy.  During this period, scans will be done 
approximately every 24 weeks. 
Long Term Follow-up (LTFU) 
Once subjects progress or start use of alternative anticancer therapy—for all subjects 
who have not withdrawn consent—they will be contacted approximately every 24 weeks 
by clinic visit or telephone, to assess survival and the use of alternative anticancer 
therapy until death or lost to follow up.  At the time of the planned final analysis and 
additional milestone analyses, a survival sweep may be conducted.  All subjects who are 
on study and not known to have died before the survival sweep may be contacted at that 
time. 
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. 

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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.   
Response Assessment 
Response assessments will be done by the investigators and independently assessed 
by the IRC.  The IRC will conduct response evaluations in accordance with the IRC 
charter (provided separately from this protocol). The response and disease progression 
criteria are provided in Section 4.2.  
5.2 
SAMPLE SIZE CONSIDERATIONS 
The study will enroll approximately 117 subjects.  
A one-sample Chi-square test with a 0.025 1-sided significance level will have more than 
99% power to test the null hypothesis that ORR will be ≤ 20% (not considered clinically 
compelling) versus the alternative hypothesis that ORR will be ≥ 40%.  The sample size 
will also provide adequate estimation utility for safety and other secondary analyses.  In 
particular, with a sample size of 117 subjects, the probability of observing 1 or more 
instances of a specific AE with a true incidence rate of 1%, 2%, or 5% is 69.1%, 90.6%, 
or 99.8%, respectively.  This provides reasonable assurance that events that occurring 
at ≥ 1% frequency can be identified in this Phase 2 study.   
EAST6 (Version 6.3.1) was employed to conduct the sample size calculation. 
5.3 
DEFINITION OF ANALYSIS POPULATION 
The safety analyses and primary efficacy analyses for all efficacy endpoints (except for 
DOR and 
 will be performed on the All-treated population, defined as all enrolled 
subjects who receive ≥ 1 dose of study drug.  The analysis of DOR and 
 will be 
conducted on the subset of the All-treated population who achieve CR or PR as their 
best overall response. 
5.4 
MISSING DATA HANDLING 
General Considerations:  Subjects lost to follow-up (or who dropped out) will be 
included in statistical analyses up to the point of their last evaluation. 
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Duration of Response and Progression-free Survival:  Data for subjects without 
disease progression or death will be censored at the date of the last tumor assessment 
and before the initiation of alternative anticancer therapy.  The censoring rules details 
will be provided in the Statistical Analysis Plan (SAP). 
Overall Survival:  Data for subjects who have not died will be censored at the date of 
the last date known to be alive.   
Safety:  Missing or partial start and end dates for AEs and concomitant medications will 
be imputed according to prespecified, conservative imputation rules.  No other 
imputation of values for missing data will be performed.  
5.5 
ENDPOINT DATA ANALYSIS 
5.5.1 
Demographics and Baseline Characteristics 
Additional analyses will include summaries of subject demographics, baseline 
characteristics, compliance, and concurrent treatments.  Concomitant medications will 
be coded according to the World Health Organization (WHO) Drug Dictionary and 
tabulated. 
5.5.2 
Study Treatment Administration  
Descriptive information will be provided regarding the duration of study treatment 
exposure, average daily dose, and relative dose intensity.   
For each subject, acalabrutinib relative dose intensity will be described in terms of the 
proportion of study drug actually taken relative to the amount that was planned during 
the treatment exposure period. 
5.5.3 
Analysis of Efficacy Parameters 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the ORR as assessed by investigators.  The ORR is 
defined as the proportion of subjects achieving either a PR or CR, according to the 
Lugano Classification for NHL (Cheson 2014), as assessed by investigators.  The 
corresponding 95% two-sided confidence interval will be derived.  

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Secondary Efficacy Endpoints 
Duration of Response 
The DOR is defined as the interval from the first documentation of CR or PR to the 
earlier of the first documentation of objective MCL disease progression or death from 
any cause.  Kaplan-Meier methods will be used to estimate event-free curves and 
corresponding quantiles (including the median).   
Progression-free Survival 
PFS is defined as the interval from the start of acalabrutinib therapy to the earlier of the 
first documentation of objective MCL disease progression per investigator assessment 
or death from any cause. Kaplan-Meier methods will be used to estimate the event-free 
curves and corresponding quantiles (including the median).   
Overall Survival 
The duration of OS will be measured from the time of first study drug administration until 
the date of death.  Subjects who are known to be alive as of their last known status will 
be censored at their last date known to be alive.  Kaplan-Meier methodology will be used 
to estimate overall survival curves and corresponding quantiles (including the median). 
IRC-assessed Endpoints per Lugano Classification 
ORR, DOR, and PFS assessed by the IRC per Lugano Classification will be analyzed 
using the same analysis methods described for investigator-assessed endpoints.  The 
discordant responses assessed by the investigator and IRC using Lugano Classification 
will be provided. 
5.5.4 
Analysis of Safety Endpoints 
Safety summaries will be included in the form of tables and listings.  The frequency 
(number and percentage) of treatment emergent AEs will be reported by Medical 
Dictionary for Regulatory Activities (MedDRA) System Organ Class and Preferred Term.  
Summaries will also be presented by the severity of the AE (per Common Terminology 
Criteria for Adverse Events [CTCAE], v4.03 or higher) and by relationship to study drug. 
Laboratory shift tables containing counts and percentages will be prepared by laboratory 
parameter.  Figures of changes in laboratory parameters over time will be generated. 
Results of vital sign assessments will be tabulated and summarized. 

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5.5.5 
Analysis of Pharmacokinetic/Pharmacodynamic Endpoints 
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 t 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 
 
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 concentration at each assessment will be described.  The 
change from baseline to each assessment will be summarized.  The best change from 
baseline during the study will also be summarized.  As appropriate, the on-treatment 
values will be compared with the pretreatment baseline values using paired t-tests.   
5.5.6 
Explorative or Correlative Analyses 
 
 
 
 
CCI

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5.5.7 
 
 
 
 
 
 
 
 
5.5.8 
 
 
 
 
  
5.5.9 
 
 
 
 
   
5.6 
FINAL AND FOLLOW-UP ANALYSES 
The final analysis of primary and secondary efficacy endpoints will occur approximately 
14 months after the last subject has been enrolled.  A follow-up analysis will be 
performed 24 months after the last subject has been enrolled, and close-out analysis will 
be performed approximately 54 months after enrollment of the last subject. 
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(s). 
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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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 or other 
protocol-imposed intervention, regardless of attribution. 
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with MCL that were not 
present before the AE reporting period (see Section 6.2.1). 
Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as biopsies). 
• 
Pre-existing medical conditions (other than the condition being studied) judged by 
the investigator to have worsened in severity or frequency or changed in character 
during the protocol-specified AE reporting period. 
Abnormal laboratory values should not be reported as AEs; however, any clinically 
significant laboratory values (defined as requiring treatment, discontinuation from the 
study, or dose modification) will be reported as AEs. 
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 (ie, the AE actually causes or leads to death). 
• 
It is life-threatening (ie, 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. 

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• 
It results in persistent or significant disability/incapacity (ie, the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the investigational product. 
• 
It is considered a significant medical event by the investigator based on medical 
judgment (eg, 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 adverse events of special interest (AESIs) and must be 
reported to the sponsor expeditiously (see Section 6.2.6 for reporting instructions), 
irrespective of regulatory seriousness criteria or causality: 
• 
Ventricular arrhythmias (eg, ventricular extrasystoles, ventricular tachycardia, 
ventricular arrhythmia, ventricular fibrillation) 
 
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 activity, and require systemic drug 
therapy or other treatment 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject 
to be in imminent danger of death 
• 
Grade 5 (Death related to AE) – experiences which result in subject death 

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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 eCRF.  
All SAEs also must be reported on the SAE form (see Section 6.2.6). 
6.2.1 
Adverse Event Reporting Period 
The AE reporting period for this study begins when the subject receives the first dose of 
study drug and ends with the safety follow-up visit (or last on-treatment visit if the safety 
follow-up visit is not done).  After the signing of the ICF and prior to the first dose of 
study drug, all SAEs must be reported.  After the first dose of study drug, all AEs/SAEs, 
irrespective of attribution of causality, must be reported.  If a fatal AE occurs beyond 
30 days after the last dose of acalabrutinib AND it is assessed by the investigator as 
related to acalabrutinib, it must be reported as an SAE. 
All AEs will be reported until 30 days after the last dose of study drug or the start of new 
anticancer therapy (whichever comes first).  After this period, investigators should report 
SAEs or other adverse events of concern that are believed to be related to prior 
treatment with study drug.   
All SAEs that occur during the reporting period should be followed to resolution or until 
the investigator assesses the subject as stable, or 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 tests (ie, requiring change in study drug 
dose or discontinuation of study drug or any other medical intervention), or other means, 
will be recorded in the subject’s medical record and on the AE eCRF. 
Disease progression itself is not considered an AE; however, signs and symptoms of 
disease progression may be recorded as AEs or SAEs. 

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Each recorded AE or SAE will be described by its duration (ie, start and end dates), 
severity, regulatory seriousness criteria, if applicable, suspected relationship to the study 
drug (see following guidance), and any actions taken.  The causality of AEs to the study 
drug will be assessed by means of the question: ‘Is there a reasonable possibility that 
the event may have been caused by the study drug?’ per FDA guidance on safety 
reporting requirements (FDA Guidance 2012). 
See Appendix 2 for more detail on assessing causality. 
6.2.3 
Second Primary Malignancies 
Adverse events for malignant tumors reported during a study should generally be 
assessed as SAEs.  If no other seriousness criteria apply, the “Important Medical Event” 
criterion should be used.  In certain situations, however, medical judgment on an 
individual event basis should be applied to clarify that the malignant tumor event should 
be assessed and reported as a nonserious AE.  For example, if the tumor is included as 
medical history and progression occurs during the study but the progression does not 
change treatment and/or prognosis of the malignant tumor, the AE may not fulfill the 
attributes for being assessed as serious, although reporting of the progression of the 
malignant tumor as an AE is valid and should occur.  Also, some types of malignant 
tumors, which do not spread remotely after a routine treatment that does not require 
hospitalization, may be assessed as nonserious; examples in adults include Stage 1 
basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 
The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (ie, it is not the tumor for which entry into the study is a criterion and 
that is being treated by the investigational product (IP) under study and is not the 
development of new or progression of existing metastasis to the tumor under study).  
Malignant tumors that—as part of normal, if rare, progression—undergo transformation 
(eg, Richter's transformation of B cell chronic lymphocytic leukemia into diffuse large B 
cell lymphoma) should not be considered a new malignant tumor. 
6.2.4 
Hy’s Law 
Cases in which a subject shows elevations in liver biochemistry may require further 
evaluation, and occurrences of AST or ALT ≥3 × ULN together with total bilirubin 
≥2 × ULN may need to be reported as SAEs.  Refer to Appendix 5 for further instruction 
on cases of increases in liver biochemistry and evaluation of Hy’s law. 

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6.2.5 
Pregnancy 
The investigator should report all pregnancies in study subjects and the partners of study 
subjects within 24 hours of notification using the Pregnancy Report Form.  This form 
should be sent to the AstraZeneca Representative.  Any pregnancy-associated SAE 
must be reported using the SAE form, according to the usual timeline and direction for 
SAE reporting as described below. 
Any uncomplicated pregnancy that occurs in a study subject or a partner of a treated 
subject during this study will be reported for tracking purposes only, if agreed to by the 
subject or the partner of the subject in this study.  All pregnancies and partner 
pregnancies that are identified during or after this study will be reported.  All pregnancies 
and partner pregnancies that are identified during or after this study, wherein the 
estimated date of conception is determined to have occurred from the time of consent to 
2 days after the last dose of acalabrutinib will be reported, followed to conclusion, and 
the outcome reported, as long as the subject or partner has consented to participate in 
follow-up.  
The pregnancy itself is not regarded as an AE, unless there is suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Likewise, elective abortions without complications are not 
considered AEs.  Any SAEs associated with pregnancy (eg, congenital 
abnormalities/birth defects/spontaneous miscarriage or any other serious events) must 
additionally be reported as such using the SAE form. 
Subject should be instructed to immediately notify the investigator of any pregnancies.  
Any women 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 the AstraZeneca Representative. 
6.2.6 
Expedited Reporting Requirements for Serious Adverse 
Events 
All SAEs must be reported within 24 hours of discovery.  All initial SAE reports and 
follow-up information will be reported using the protocol-specific electronic data capture 
system.  If electronic SAE reporting is not available, paper SAE forms must be sent to 
the AstraZeneca Representative.  The AstraZeneca Representative may request 

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follow-up and other additional information from the investigator (eg, hospital 
admission/discharge notes and laboratory results). 
Whenever possible, AEs/SAEs 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 the AstraZeneca Representative, as outlined above. 
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 and is not listed in the current 
Acalabrutinib IB (ie, an unexpected event).  In this case, Acerta Pharma will forward a 
formal notification describing the suspected unexpected serious adverse reaction 
(SUSAR) to all investigators.  Each investigator must then notify his or her IRB/IEC of 
the SUSAR. 
6.2.7 
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, 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 

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• 
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 or severity of AEs in this or other studies indicating a potential 
health hazard caused by the study treatment 
7.1 
REGULATORY AND ETHICAL COMPLIANCE 
This clinical study was designed and will be implemented in accordance with the 
protocol, the International Council for Harmonisation (ICH) Harmonised Tripartite 
Guidelines for Good Clinical Practices, applicable local regulations (including US Code 
of Federal Regulations (CFR) 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, IB, and any other relevant supporting 
information (eg, all advertising materials) to the appropriate IRB/IEC for review and 
approval before study initiation.  A signed protocol approval page, a letter confirming 
IRB/IEC approval of the protocol and informed consent, and a statement that the 
IRB/IEC is organized and operates according to GCP and the applicable laws and 
regulations must be forwarded to Acerta Pharma before screening subjects for the 
study.  Additionally, sites must forward a signed Form FDA 1572 (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 § 21CFR 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 

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representative may sign the informed consent form 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 in order to evaluate study 
results, the subject’s protected health information obtained during the study may be 
shared with Acerta Pharma and its designees, regulatory agencies, and IRBs/IECs.  As 
the study sponsor, Acerta Pharma will not use the subject’s protected health information 
or disclose it to a third party without applicable subject authorization.  It is the 
investigator’s or designee’s responsibility to obtain written permission to use protected 
health information from each subject, or if appropriate, the subject’s legal guardian.  If a 
subject or subject’s legal guardian withdraws permission to use protected health 
information, it is the investigator’s responsibility to obtain the withdrawal request in 
writing from the subject or subject’s legal guardian and to ensure that no further data will 
be collected from the subject.  Any data collected on the subject before withdrawal will 
be used in the analysis of study results. 
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 eCRFs designed for 
this study according to the completion guidelines that will be provided.  The investigator 
will ensure that the eCRFs are accurate, complete, legible, and completed promptly.  
Refer to Section 7.8 for record retention requirements.  
7.6 
STUDY MONITORING REQUIREMENTS 
Representatives of Acerta Pharma or its designee will monitor this study until 
completion.  Monitoring will be conducted through 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. 

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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, 
pathology, and/or laboratory results when requested by the sponsor.  A statement to this 
effect will be included in the informed consent and a permission form authorizing the use 
of protected health information will also be included. 
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) that must be appended to the site’s drug accountability records.  If it is used, the 
Drug Reorder 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 the receipt of study drug, the 
designated recipient completes and signs the CSSF.  A copy of the signed CSSF must 
be faxed or emailed to Acerta Pharma at the fax number/email address listed on the 
form. 
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-LY-004) 
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 
 

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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. 
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 Form 1572, IRB/IEC approval letters, signed ICFs, 
drug accountability records, SAE forms transmitted to Acerta Pharma, subject files 
(source documentation) that substantiate eCRF entries, 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. 

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7.9 
PROTOCOL AMENDMENTS 
Acerta Pharma will initiate any change to the protocol in a protocol amendment 
document.  Protocol amendments will be submitted to the IRB/IEC together with, if 
applicable, a revised model ICF.  If the change in any way increases the risk to the 
subject or changes the scope of the study, then written documentation of IRB/IEC 
approval must be received by Acerta Pharma before the amendment may take effect. 
Additionally, under this circumstance, information on the increased risk and/or change in 
scope must be provided to subjects already actively participating in the study, and they 
must read, understand, and sign any revised ICF confirming willingness to remain in the 
trial. 
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 2016).   
7.11 CLINICAL TRIAL INSURANCE 
Clinical trial 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. 

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9. Any significant protocol deviations are reported to Acerta Pharma and the IRB/IEC 
according to the guidelines at each study site. 
10. Electronic CRF pages are completed promptly. 
11. All IND Safety Reports and SUSAR Reports are submitted promptly to the IRB/IEC. 
12. All SAEs are reported to the AstraZeneca Representative within 24 hours of 
knowledge and to the IRB/IEC per their requirements. 

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8.0 
REFERENCES 
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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, et al. Modifying murine von Willebrand factor A1 domain for in 
vivo assessment of human platelet therapies. Nat Biotechnol 2008; 26(1):114-9. 
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end points in chronic lymphocytic leukemia. J Clin Oncol 2012;30:2820-22. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
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Covey T, Barf T, Gulrajani M, et al. ACP-196: a novel covalent Bruton’s tyrosine kinase 
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lymphocytic leukemia (CLL) patients. In: Proceedings of the 106th Annual Meeting of the 
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Philadelphia (PA): AACR; 2015. Abstract #2596. 
FDA Guidance 2012 (US Food and Drug Administration). Guidance for Industry and 
Investigators:  Safety Reporting Requirements for INDs and BA/BE Studies (December 
2012). Available at: http://www.fda.gov/downloads/Drugs/.../Guidances/UCM227351.pdf, 
accessed on:  28January2016. 
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. 
Hoster E, Dreyling M, Klapper W, et al.  A new prognostic index (MIPI) for patients with 
advanced-stage mantle cell lymphoma.  Blood 2008;111(2):558. 
Goy A, Sinha R, Williams ME, et al.  Single-agent lenalidomide in patients with mantle-
cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase 
II MCL-001 (EMERGE) study.  J Clin Oncol 2013;31(29):3688-95.  
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals. 2016 Dec.  
Available from: http://www.ICMJE.org.  Accessed 02 March 2017. 
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Kamel S, Horton L, Ysebaert L, et al.  Ibrutinib inhibits collagen-mediated but not 
ADP-mediated platelet aggregation. Leukemia 2015;29(4):783-7. 
Kohrt HE, Sagiv-Barfi I, Rafiq S, Herman SEM, Butchar JP, Cheney C, et al. Ibrutinib 
antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood 2014;123: 1957–
60. 
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. 
Romaguera JE, Fayad LE, Feng L, et al.  Ten-year follow-up after intense 
chemoimmunotherapy with Rituximab-HyperCVAD alternating with Rituximab-high dose 
methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with 
untreated aggressive mantle cell lymphoma.  Br J Haematol 2010;150(2):200-8. 
Shatzel JJ, Olsen SR, Tao DL, McCarty OJ, Danilov AV, DeLoughery TG.  Ibrutinib-
associated bleeding: pathogenesis, management, and risk reduction strategies.  
J Thromb Haemost. 2017 Feb 9. doi: 10.1111/jth.13651. [Epub ahead of print]. 
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 2015b;33(28):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, et al. 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. 
Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory 
mantle-cell lymphoma. NEJM 2013;369(6):507-16. 
Zhou Y, Wang H, Fang W, et al.  Incidence trends of mantle cell lymphoma in the United 
States between 1992 and 2004.  Cancer 2008;113(4):791-8.  

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9.0 
APPENDICES 
 
 
 
 
 

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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, eg, 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 (eg, high dose, double strength) or as a “moderate CYP3A inhibitor” when 
another preparation was used (eg, 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 
Cycle 4 
Cycles 5-12 
Cycles 15, 
18, 21, 
≥ 24b 
ET/Safety 
Follow Upc 
DFUr 
LTFUs 
 
 
Days (± 2) 
Days (± 2) 
Days (± 2) 
Days (± 2) 
Days (± 2) 
Days (± 2) 
+ 7 days 
± 7 days 
± 7 days 
 
1 
8 
15 
22 
28 
15 
28 
28 
28 
28 
28 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PEd/Vital 
signse/Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
B symptoms 
x 
x 
 
 
 
 
x 
 
x 
x 
x 
x 
x 
 
 
ECOG status 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
ECGf 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lab assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
testg 
x 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
 
 
Hematologyh 
x 
xt 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x (every 24 
weeks) 
x 
 
 
Serum chemistryi 
x 
xt 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x (every 24 
weeks) 
x 
 
 
Urinalysisj 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T/B/NK cell countk 
 
xt 
 
 
 
 
 
x 
 
 
Cycle 6 and 
12 
Cycle 18 
and 24, 
then every 
24 weeks 
x 
 
 
Serum Igl 
 
xt 
 
 
 
 
 
x 
 
 
Cycle 6 and 
12 
Cycle 18 
and 24, 
then every 
24 weeks 
x 
 
 
Bone marrow 
(aspirate/biopsy)p 
x 
 
 
 
 
 
 
 
 
 
To confirm 
CR 
To confirm 
CR 
 
 
 
 HBV PCRv 
 
 
 
 
 
 
 
 
x 
 
Q3M 
x (Q3M) 
 
Q3M 
Q3M 
Response 
assessmentsq 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT 
x 
 
 
 
 
 
 
x 
 
x 
Cycle 6 and 
12 
Cycle 18 
and 24, 
then every 
24 weeks (6 
cycles) 
 
x 
 
PET/CT 
x 
 
 
 
 
 
 
x 
 
 
Cycle 6 & to 
confirm CR  
To confirm 
CR  
 
 
 

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Screeninga 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycles 5-12 
Cycles 15, 
18, 21, 
≥ 24b 
ET/Safety 
Follow Upc 
DFUr 
LTFUs 
 
 
Days (± 2) 
Days (± 2) 
Days (± 2) 
Days (± 2) 
Days (± 2) 
Days (± 2) 
+ 7 days 
± 7 days 
± 7 days 
 
1 
8 
15 
22 
28 
15 
28 
28 
28 
28 
28 
 
 
 
MRDw 
x 
 
 
 
 
 
 
 
 
 
 
x (every 24 
weeks/6 
cycles) 
x 
 
 
Pharmacodynamics 
 
xm 
xm 
 
 
xn 
 
xn 
 
 
 
 
xz 
 
 
Pharmacokineticso 
 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
Acalabrutinib 
dispensed 
 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
 
 
 
Study drug 
compliance 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Adverse eventsx 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Survival statusy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CR = complete remission; 
CT = computed tomography; DFU = discontinuation follow-up; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ET = early termination; 
HBV = hepatitis B virus; Ig = immunoglobulin; LDH = lactate dehydrogenase; LTFU = long-term follow-up; mos = months; MRD = minimal residual disease; 
PCR = polymerase chain reaction; PD = pharmacodynamic; PE = physical exam; PET = positron-emission tomography; PK = pharmacokinetic; 
 
 Q3M = every 3 months; SAE = serious adverse event. 
Footnotes for ACE-LY-004 Schedule of Study Activities: 
a.  Screening tests should be performed within 21 days before the first administration of study drug, unless otherwise indicated. 
b. 
Treatment with acalabrutinib may be continued until disease progression or unacceptable drug-related toxicity, whichever occurs first.  After Cycle 24, subjects will 
continue to have scheduled visits every 24 weeks as outlined on the schedule of assessments.   
c. 
An early termination visit will be done for subjects who permanently discontinue study drug early for any reason (except for death, lost to follow up or withdrawal of 
consent).  In addition, a 30-day (+ 7 days) safety follow-up visit is required for all subjects after his or her last dose of study drug to monitor for AEs, regardless of 
whether the subject receives a new anticancer therapy or demonstrates disease progression within this timeframe.   
d. 
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 
exams, including tumor assessments by palpation and attention to neurologic signs and symptoms of progressive multifocal leukoencephalopathy, are done 
thereafter.  
e. 
Vital signs (blood pressure, heart rate, and temperature) will be assessed after the subject has rested in the sitting position.   
f. 
Subjects should be in supine position and resting for ≥ 10 minutes before study-related ECGs.   
g. 
Women of childbearing potential only.  Urine pregnancy tests will be performed at Screening, on Cycle 1 Day 1; on Day 28 of Cycles 1-12; on Day 28 of Cycles 15, 
18, 21, and 24, then every 24 weeks; and at the early termination or safety follow-up visit.  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.  
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h. 
Hematology includes complete blood count with differential and platelet counts.  Cycle 1 Day 1 hematology does not need to be repeated if screening hematology 
was within 5 days. 
i. 
Serum chemistry: albumin, alkaline phosphatase, alanine transaminase (ALT), aspartate aminotransferase (AST), bicarbonate, blood urea nitrogen (BUN), 
bone-specific alkaline phosphatase, calcium, chloride, creatinine, c-terminal telopeptide, glucose, lactate dehydrogenase (LDH), magnesium, 
phosphate/phosphorus, 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. 
j. 
Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.  
k. 
T/B/NK cell count (ie, CD3, CD4, CD8, CD19, CD16/56).  During Cycles ≥ 5, only done at the end of Cycles 6, 12, 18, and 24, then every 24 weeks thereafter. 
l.  
Serum immunoglobulin: IgG, IgM, IgA.  During Cycles ≥ 5, only done at the end of Cycles 6, 12, 18, and 24, then every 24 weeks thereafter.  
m. Pharmacodynamic (PD) assessments will be done on up to 24 bortezomib-naive subjects and up to 24 bortezomib-exposed subjects.  PD samples are drawn 
predose and 4 hours (± 10 minutes) postdose on the days indicated (relative to the morning dose). 
n. 
Pharmacodynamic (PD) assessments will be done on up to 24 bortezomib-naive subjects and up to 24 bortezomib-exposed subjects.  PD samples are drawn 
predose on the days indicated  
o. 
Pharmacokinetic (PK) assessments will be done on up to 24 bortezomib-naive subjects and up to 24 bortezomib-exposed subjects.  PK samples are drawn per 
Table 4-1, and timepoints are relative to the morning dose.   
p. 
Bone marrow are required for confirmation of CR (if bone marrow was involved by lymphoma at baseline) per clinical guidelines (see Section 4.2).   
q. 
A pretreatment computed tomography (CT) scan with contrast (unless contraindicated) is required of the chest, abdomen, and pelvis and any other disease sites 
(eg, neck) within 30 days before the first dose of study drug.  A pretreatment positron-emission tomography (PET)/CT scan within 60 days from first dose of study 
drug is also required.  During treatment, CT scans with contrast (unless contraindicated) will be performed for tumor assessments at the end of Cycle 2 (± 7 days), 
Cycle 4 (± 7 days), and Cycle 6; and then every 6 cycles (24 weeks) thereafter, or more frequently at the investigator’s discretion.  For Cycles ≥ 6, CT and PET/CT 
scans may be performed within an imaging window of up to 21 days before and up to 7 days after the scheduled study visit date.  During treatment, PET/CT scans 
will be performed at the end of Cycle 2 (± 7 days) and Cycle 6 as well as any time to confirm CR or as clinically indicated.  Subjects with confirmed CR are not 
required to undergo further PET/CT scans on study unless there is suspicion of progressive disease.  Endoscopy is mandatory to confirm CR for any subjects with 
a documented history of gastrointestinal involvement.  
r. 
Subjects who discontinue will be followed approximately every 24 weeks from the date of last dose until study exit to assess survival and the use of alternative 
anticancer therapy.  During this period, CT scans will be done approximately every 24 weeks until disease progression or until the start of alternative anticancer 
therapy. 
s. 
Subjects who progress or start alternative anticancer therapy will be followed approximately every 24 weeks until study exit to assess survival and the use of 
alternative anticancer therapy.  
t. 
The indicated samples at this timepoint (Cycle 1 Day 1) must be drawn predose. 
u. 
 
  
v. 
Subjects who are hepatitis B core antibody positive (or have a known history of HBV infection) should be monitored Q3M with a quantitative PCR test for HBV 
DNA.  HBV monitoring should last until 12 months after last dose of study drug.  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. 
w. MRD testing will be performed on peripheral blood samples and pretreatment archival tissue by a central laboratory.  A blood sample is to be collected every 
24 weeks (6 cycles) for all subjects; this sample should be collected at the same visit (schedule) as the CT scan (if an MRD sample was missed due to alignment 
with the CT scan visit, an unscheduled sample should be collected and then return to the protocol schedule with the next visit). For those subjects who 
permanently discontinued early, a blood sample is to be collected at the ET visit.  An archival tissue sample is to be collected (ie, tumor tissue in form of lymph 
node, peripheral blood or bone marrow sample) before study drug administration to identify the malignant clone and calibrate measurements for comparison with 
on-treatment samples.   
x. 
After the signing of the ICF and prior to the first dose of study drug, all SAEs must be reported.  After the first dose of study drug, all AEs/SAEs, irrespective of 
attribution of causality, must be reported.  After the end of the protocol-defined adverse event reporting period (see Section 6.2.1), only serious adverse events 
considered related to study drug(s) or study procedures are required to be collected. 
y. 
Survival status should be assessed at the time of the planned final analysis and additional milestone analyses as applicable. 
z. 
Pharmacodynamics to be assessed at the ET visit for patients who permanently discontinued early.  
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Appendix 5. Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law 
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 (eg, PHL criteria could be met by an elevated alanine 
aminotransferase (ALT) from a central laboratory and/or elevated total bilirubin from a 
local laboratory).  The investigator will also review adverse event (AE) data (eg, 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  
Aspartate aminotransferase (AST) or ALT ≥3 × the upper limit of normal (ULN) together 
with total bilirubin ≥2 × 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 × ULN together with total bilirubin ≥2 × ULN, where no reason other than 
the IMP can be found to explain the combination of increases (eg, elevated alkaline 
phosphatase indicating cholestasis, viral hepatitis, or another drug).   

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For PHL and HL, the elevation in transaminases must precede or be coincident with (ie, 
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 × ULN 
• 
AST ≥3 × ULN 
• 
Total bilirubin ≥2 × 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 PHL 
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.   

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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. 
• 
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 
SAEreport 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 

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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 (eg, 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 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. 
 

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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 (ANA) 
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/Guida
nces/UCM174090.pdf  
 

Product: Acalabrutinib (ACP-196) 
Protocol: ACE-LY-004 
 
 
 
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Appendix 6. Management of Study Procedures During Pandemic 
This appendix consolidates guidance for subject safety and ongoing access to medical 
care and investigational product during the global COVID-19 pandemic.  The measures 
detailed below will be implemented across Acerta Pharma studies on a temporary basis 
until the pandemic is considered resolved by governmental and public health 
organizations, as applicable.  
Regardless of the guidance below, please consider public health advice in your local 
market and individual risk/benefit in treatment decisions for subjects at your study site 
during the pandemic.  Please also consider logistical requirements such as the ability of 
subjects to travel to the study site, accessibility of public transport, etc. 
If the subject is unable or unwilling to visit the study site due to COVID-19 related 
reasons, investigators may ask enrolled subjects to use healthcare facilities local to the 
subject to ensure safety and efficacy measures are done per protocol. If a study 
assessment is not done at either the site or a facility local to the subject, then its 
absence should be documented as a protocol deviation.  Any protocol deviations 
resulting from the COVID-19 situation should be recorded and prefixed with COVID-19. 
Study Subject Participation 
Conduct of Telephone Visits 
Due to the current pandemic, it is conceivable that not all subject visit commitments may 
be able to be fulfilled.  If a subject is unable or unwilling to attend a study visit, 
adaptation of the onsite visit to a telephone visit is recommended to ensure continuity of 
study care (as an interim measure; eg, telephone contacts instead of visits, shipping 
study medication to the subject).  Priority should be given to maintaining ongoing safety 
follow-up (even if this is conducted by telephone contacts).  Study sites should speak 
with their site monitor before performing a telephone visit so he or she may provide 
guidance regarding logistics that may need consideration.  Also, study sites should 
speak with the site monitor if the subject cannot attend more than one onsite visit in 
succession, because multiple incomplete visits may have the potential to impact 
evaluation of study endpoints. 
Acalabrutinib Dose Modification Recommendation for COVID-19 
The sponsor recognizes that coronavirus 2019-nCoV (COVID-19) presents an increased 
risk for all subjects.  Due to the potential impact of COVID-19 on multiple organ systems, 
the sponsor recommends the following dose modification and management plan for 

Product: Acalabrutinib (ACP-196) 
Protocol: ACE-LY-004 
 
 
 
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subjects with confirmed or suspected COVID-19 while receiving treatment with 
acalabrutinib.  
First and foremost, the following safety reporting guidelines are required:  
All confirmed or suspected COVID-19-related adverse events (AEs) must be recorded in 
the eCRF. All dose modifications should be based on the worst Common Terminology 
Criteria for Adverse Events (CTCAE) grade.  All interruptions or modifications must be 
recorded on the AE and drug administration eCRFs.  The CTCAE general grading 
criteria should be used to evaluate COVID-19.  
If an event is suspected to be COVID -19 infection, the sponsor recommends 
interrupting acalabrutinib and testing for COVID-19 per local guidance.  
• 
If COVID-19 is ruled out, standard clinical practice and the study protocol 
procedures should be followed regarding any dose modifications required for 
management of severe infections.  
• 
If COVID-19 is confirmed or diagnosis is suspected after evaluation, COVID-19 
infection should be managed per local guidance until the subject achieves full 
recovery, defined as no signs or symptoms.  
 
In case of COVID-19 positivity, the investigator must determine the risk and benefit of 
interruption versus continuation of acalabrutinib and whether to resume it at full or 
modified doses or discontinue treatment.  
Please contact the study medical monitor for further discussion.  
Comparator Drugs or Drugs Used in Combination with Acalabrutinib: 
• 
 Please refer to guidance from the manufacturer.  
 
Drug-drug interactions (DDI) may occur with some of the drugs being used as best 
supportive care (eg, drugs that are strong inducers or inhibitors of cytochrome P450 
[CYP]3A). Guidance is provided below:  
Drug-Drug Interaction Guidance for Investigators with Subjects Enrolled in an 
Acalabrutinib Clinical Study who are COVID-19 Positive:  
• 
The potential combination with chloroquine or 8-8-OH-chloroquine (8-OH-CHQ) and 
azithromycin are not predicted to have a pharmacokinetic DDI with acalabrutinib.  
However, both agents are known to cause cardiovascular risk of QT-prolongation.  
Therefore, the benefit-risk of initiating 8-OH-CHQ + azithromycin should be 
discussed with the medical monitor.  

Product: Acalabrutinib (ACP-196) 
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• 
Many antivirals and antibiotics are considered strong CYP3A4 inhibitors or inducers 
and are therefore likely to cause complex DDIs with acalabrutinib.  The risk-benefit 
balance of acalabrutinib use in the setting of COVID-19 treatment should be 
discussed between the investigator and the medical monitor.  
• 
 Remdesivir is rapidly metabolized to a pharmacologically active metabolite, 
GS-443902.  Based on published and publicly available data, remdesivir does not 
appear to inhibit CYP isoforms and will likely not interact in a meaningful way with 
drug transport systems.  Remdesivir does not prolong QTc interval.  
• 
Systemic steroids and acalabrutinib may impair the ability of the body to fight 
infection; it is best to avoid high-dose systemic steroids while taking acalabrutinib.  
• 
The study protocol and investigator brochure should be referenced for other DDI 
information.  
 
COVID-19 Specific Data Entry Instructions for Investigational Sites 
Adverse Event Recording: 
Currently no changes to normal data capture procedures are required for COVID-19 
data in the eCRF.  For subjects who have confirmed or who are suspected of having 
coronavirus infection, the infection should be documented as an AE or serious adverse 
event (SAE), in line with instructions for safety reporting documented in the clinical study 
protocol.  Either “COVID-19 Confirmed” or “COVID-19 Suspected” should be used 
when reporting the event as follows: 
• 
If test is positive, “COVID-19 confirmed” should be recorded in the AE field. 
• 
If test is negative, AE/SAE signs and symptoms and/or other diagnosis should be 
recorded in the AE field(s). 
• 
If test is not available and signs and symptoms, as judged by the investigator, are 
highly suspicious of COVID-19 infection, record “COVID-19 suspected” in the AE 
field. 
 
Details of any testing or procedure to determine the status of COVID-19 infection should 
be documented on the Concomitant Procedure Form if available or on the appropriate 
eCRF page in the study. 
For fatal SAEs, the Death Information Form, End of Study Treatment Form, and Study 
Exit Form should be completed.  
Study Treatment Recording: 
If an AE or SAE is associated with COVID-19, the investigator should determine whether 
the subject’s treatment with investigational product should continue, be interrupted, or be 
discontinued in accordance with the clinical study protocol. 

Product: Acalabrutinib (ACP-196) 
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For dosing interruptions, where applicable, the following guidelines should be used: 
• 
Related to AE:  
On the Dose Administration Forms(s), dose change/missed should be indicated 
with AE as the reason. The dosing stop date must correlate to the AE/SAE 
start/stop dates. 
• 
Related to Logistics:  
For subjects who have missed a study treatment due to an inability to travel to 
the clinic or for some other logistical reason, on the Dose Administration Form(s) 
dose change/missed should be indicated with Other as the reason, and “Logistic” 
as Other, Specify. 
  
If these options are not available in the eCRF, then either dose discontinuation should 
be recorded (if permanently stopped) or a protocol deviation should be recorded, 
prefixed COVID19. 
For dosing discontinuations, where applicable, the dosing discontinuation guidelines 
should be followed, and the End of Treatment Form(s) completed. 
Capturing telephone contacts with subjects: 
If a telephone visit is substituted for an onsite study visit, the following are guidelines for 
data capture: 
1. 
If the visit is specified as a phone visit as per protocol, no additional action is 
required.  
2. 
If the visit is listed as on-site but the subject will be contacted by phone, data should 
be completed as per a normal visit (ie, using the relevant eCRF pages to capture a 
phone Visit Date, and any possible assessment that can be obtained remotely 
should be captured, such as AEs, study drug administration and/or concomitant 
medications, and any additional safety information).  All assessments that cannot be 
performed should be marked as not done or eCRF inactivated/marked Blank.  A 
protocol deviation should be recorded in the clinic notes prefixed COVID19 detailing 
the use of a phone visit in place of an onsite visit.   
3. 
If the visit requires procedures that cannot be performed via telephone contact (eg, 
MRI or CT Scan), this should be discussed with the site monitor because this 
procedure may impact primary efficacy or safety analyses. 
 
Acalabrutinib Site-to-Subject Drug Shipment Instructions During Pandemic 
Containment or in Case of Force Majeure 
If a subject is definitively unable to physically go to the study site or unable to be 
represented by a third person because of pandemic containment or other force majeure, 

Product: Acalabrutinib (ACP-196) 
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the study site's pharmacy may ship the study drug to the home of the subject following 
approval by the sponsor.  
For such a shipment, the following conditions must be met: 
• 
The sponsor is responsible for delivery of the study drug to the study site. Any 
shipments made from the site to the subject will be the responsibility of the study 
site. 
• 
The subject is informed about the shipment method, confirms the address for receipt 
of the drug, and agrees that his or her personal information (ie, name and address) 
may be given to a professional carrier. 
• 
The pharmacy securely packages the drug for shipment.  
• 
A professional carrier is used by the pharmacy to ship the drug securely and 
maintain chain of custody, with evidence provided. Acalabrutinib must be stored and 
shipped at room temperature (15°C to 30°C). The professional carrier must ensure 
that temperature monitoring is conducted for all shipments. 
• 
To respect subject confidentiality, the carrier should only be given the name and 
address of the subject. The sponsor should not receive any personal information 
about the subject. 
• 
A procedure is defined with the carrier to confirm the receipt of the drug by the 
subject and that it is received in good condition. 
• 
The site contacts the subject to confirm the receipt and integrity of the drug and gives 
instructions about the drug administration. 
• 
The pharmacy completes its accountability with each shipment made directly to a 
subject.