Clinical trial NCT02112526
Conditions: Activated B-cell Diffuse Large B-Cell Lymphoma (ABC DLBCL)
Keywords: de Novo Activated B-cell (ABC) Subtype of Diffuse Large B-Cell Lymphoma Diffuse Large B-Cell Lymphoma de Novo Activated B-cell (ABC) de Novo Activated B-cell ABC DLBCL DLBCL Lymphoma B-Cell Immunoproliferative Disorders Immune System Diseases Bruton's tyrosine kinase
Sponsor: Acerta Pharma BV
Start date: 2014-08-07; Completion date: 2024-10-04
Enrollment: 21 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
To characterize the safety profile of acalabrutinib in subjects with relapsed or refractory de Novo Activated B-cell (ABC) Subtype of Diffuse Large B-Cell Lymphoma (DLBCL).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Acalabrutinib
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_004.pdf: 
Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
Acerta Pharma 
Confidential 
Page 1 
PROTOCOL 
TITLE: 
An Open-label, Phase 1b Study of ACP-196 in Subjects with 
Relapsed or Refractory de Novo Activated B-cell (ABC) 
Subtype of Diffuse Large B-Cell Lymphoma 
PROTOCOL NUMBER: 
ACE-LY-002 
STUDY DRUG: 
ACP-196 (acalabrutinib) 
IND NUMBER: 
EUDRACT NUMBER: 
118717 
2014-001341-25 
SPONSOR MEDICAL 
MONITOR: 
Acerta Pharma BV 
Phone:
Email: 
SPONSOR: 
Acerta Pharma BV 
5349 AB Oss 
The Netherlands 
Protocol Date: 
Version 0.0:  26 March 2014 
Amendment 1 Date: 
Version 1.0:  10 June 2014 
Amendment 2 Date: 
Version 2.0:  10 March 2015  
Amendment 3 Date: 
Version 3.0:  13 January 2016 
Amendment 4 Date: 
Version 4.0:  16 March 2020 
Confidentiality Statement 
This document contains proprietary and confidential information of Acerta Pharma BV that 
must not be disclosed to anyone other than the recipient study staff and members of the 
institutional review board/independent ethics committee. This information cannot be used 
for any purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of Acerta Pharma BV.  
PPD
PPD
PPD


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 2 
 
PROTOCOL APPROVAL:  AMENDMENT 4 
I have carefully read Protocol ACE-LY-002 entitled “An Open-label, Phase 1b Study of 
ACP-196 in Subjects with Relapsed or Refractory de Novo Activated B-cell (ABC) Subtype 
of Diffuse Large B-Cell Lymphoma”.  I agree to conduct this study as outlined herein and in 
compliance with Good Clinical Practices (GCP) and all applicable regulatory requirements.  
Furthermore, I understand that the Sponsor, Acerta Pharma, and the Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) must approve any changes to the 
protocol in writing before implementation. 
I agree not to divulge to anyone, either during or after the termination of the study, any 
confidential information acquired regarding the investigational product and processes or 
methods of Acerta Pharma.  All data pertaining to this study will be provided to Acerta 
Pharma.  The policy of Acerta Pharma BV requires that any presentation or publication of 
study data by clinical investigators be reviewed by Acerta Pharma, before release, as 
specified in the protocol. 
 
Principal Investigator’s Signature 
Date 
 
 
Print Name 
 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
Acerta Pharma 
Confidential 
Page 3 
SUMMARY OF AMENDMENT 4 
This protocol is being amended to add Second Primary Malignancy information, add 
rollover protocol language, and align protocol with the Investigator Brochure. 
Inclusion/Exclusion criteria have not been modified because enrollment closed. 
Clarifying edits and typographical changes have been made throughout the protocol.  In 
addition, the following substantive changes were made as part of this amendment. 
Change 
Rationale 
Global Change 
ACP-196 has been changed to acalabrutinib 
as appropriate throughout the document. 
Acalabrutinib is the name of the clinical 
study drug. 
Title Page 
Updated medical monitor. 
Medical Monitor information has been 
updated.  Amendment number and date 
updated. 
Synopsis 
Updated to reflect changes made 
throughout the protocol. 
Updated to ensure consistency between the 
body of the protocol and the synopsis. 
Section 1.3.4 Drug-drug Interaction 
Potential 
Added caution statement when 
coadministering with narrow therapeutic 
index breast cancer resistance protein 
(BCRP) substrates. 
Updated to align with IB update. 
Section 1.4 Clinical Experience 
Added Calquence® approval language. 
Added reference to Investigator Brochure for 
latest information. 
Added Calquence® approval language. 
Deleted detailed information regarding 
pharmacokinetics, pharmacodynamics, and 
clinical experience.   
Added statement to refer to the Investigator 
Brochure for latest information. 
Section 3.1 Description of Study 
Updated rollover language. 
Updated rollover language for acalabrutinib 
studies. 
Section 3.5.3 Administration of Study 
Drug 
Removed language regarding avoiding 
grapefruit juice and Seville oranges. 
Removed text to align with IB update. 
Section 3.6.2 Guideline for Use of CYP 
Inhibiting/Inducing Drugs 
Updated language regarding CYP3A 
inhibitors/inducers. 
Updated to align with IB update, CDS, and 
other protocols. 
Section 3.6.3 Guideline for Use of Drugs 
that Affect Gastric pH 
Updated guidelines. 
Updated to align with IB update, CDS, and 
other protocols. 
Section 3.7.1 Reference Safety 
Information 
Added Reference Safety information. 
Added section to align with IB update. 
Section 3.7.2 Dietary Restrictions 
Updated dietary restriction information. 
Updated to align with IB update. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 4 
Change 
Rationale 
Section 3.7.3 Hemorrhage 
Added hemorrhage information. 
Added section to align with IB update. 
Section 3.7.4 Infections 
Added information regarding infections. 
Added section to align with IB update. 
Section 3.7.4.2 Progressive Multifocal 
Leukoencephalopathy 
Added information regarding progressive 
multifocal leukoencephalopathy (PML). 
Added section to align with IB update. 
Section 3.7.5 Cytopenias 
Added information regarding cytopenias. 
Added section to align with IB update. 
Section 3.7.6 Second Primary 
Malignancies 
Added information regarding second primary 
malignancies. 
Added section to align with IB update. 
Section 3.7.7 Atrial Fibrillation 
Added information on atrial fibrillation. 
Added section to align with IB update. 
Section 3.7.9 Reproductive Toxicity 
Updated definition of women of 
non-reproductive potential.  Updated highly 
effective methods of contraception. 
Updated to align with IB update. 
Section 3.7.10 Overdose Instructions 
Updated overdose information. 
Updated to align with IB update. 
Section 6.1.4 Adverse Events of Special 
Interest 
Added section on adverse events of special 
interest to include ventricular arrhythmias. 
Added section to align with IB update. 
Section 6.2.1 Adverse Event Reporting 
Period 
Updated adverse event reporting period. 
Updated to align with IB update. 
Section 6.2.2 Assessment of Adverse 
Events 
Added information regarding symptomatic 
deterioration. 
Updated to align with IB update 
Section 6.2.3 Second Primary 
Malignancies 
Added section on reporting adverse events 
of second primary malignancies. 
Added section to align with IB update. 
Section 6.2.5 Expedited Reporting 
Requirement for Serious Adverse Events 
Added adverse events of special interest 
(AESI). 
Added AESI to align with IB update 
Section 6.2.7 Hy’s Law 
Added section with information regarding 
Hy’s law. 
Added section to align with IB update. 
Appendix 2 Examples of Coadministered 
Drugs that Need Additional 
Consideration 
Title of the appendix was changed, and 
contents updated. 
Updated to align with IB update, CDS, and 
other protocols. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 5 
Change 
Rationale 
Appendix 5 Actions Required in Cases of 
Increases in Liver Biochemistry and 
Evaluation of Hy’s Law 
Information regarding Hy’s law added. 
Added appendix to align with IB update. 
 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 6 
TABLE OF CONTENTS 
PROTOCOL APPROVAL:  AMENDMENT 4 ........................................................... 2 
SUMMARY OF AMENDMENT 4 .............................................................................. 3 
TABLE OF CONTENTS ........................................................................................... 6 
ABBREVIATIONS .................................................................................................. 10 
STUDY SYNOPSIS ................................................................................................ 13 
1.0 
BACKGROUND INFORMATION ................................................................ 21 
1.1 
Diffuse Large B-Cell Lymphoma ................................................................ 21 
1.2 
Role of Btk in Lymphoid Cancers .............................................................. 23 
1.3 
Preclinical Studies ..................................................................................... 24 
1.3.1 
Chemistry ....................................................................................... 24 
1.3.2 
Efficacy Pharmacology ................................................................... 24 
1.3.3 
Safety Pharmacology ..................................................................... 25 
1.3.4 
Drug-drug Interaction Potential....................................................... 26 
1.3.5 
In Vivo General Toxicology ............................................................ 26 
1.4 
Clinical Experience .................................................................................... 27 
1.5 
Benefit/Risk ............................................................................................... 27 
1.6 
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 Parameters ...................................................................................... 29 
3.2.1 
Efficacy Parameters ....................................................................... 29 
3.2.2 
Safety Parameters .......................................................................... 30 
3.2.3 
Pharmacokinetic and Pharmacodynamic Parameters .................... 30 
3.3 
Rationale for Study Design and Dosing Regimen ...................................... 30 
3.4 
Selection of Study Population .................................................................... 31 
3.4.1 
Inclusion Criteria ............................................................................. 31 
3.4.2 
Exclusion Criteria ........................................................................... 32 
3.4.3 
Replacement 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 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
Acerta Pharma 
Confidential 
Page 7 
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 ................................................................................................ 37 
3.7.1 
Reference Safety Information ......................................................... 37 
3.7.2 
Dietary Restrictions ........................................................................ 38 
3.7.3 
Hemorrhage ................................................................................... 38 
3.7.4 
Infections ........................................................................................ 38 
3.7.4.1 
Hepatitis B Virus Reactivation ......................................... 38 
3.7.4.2 
Progressive Multifocal Leukoencephalopathy .................. 39 
3.7.5 
Cytopenias ..................................................................................... 39 
3.7.6 
Second Primary Malignancies ........................................................ 39 
3.7.7 
Atrial Fibrillation .............................................................................. 39 
3.7.8 
Surgery ........................................................................................... 40 
3.7.9 
Reproductive Toxicity ..................................................................... 40 
3.7.10 Overdose Instructions .................................................................... 41 
3.8 
Stopping Rules .......................................................................................... 42 
3.9 
Data and Safety Monitoring ....................................................................... 43 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS ............................................... 43 
4.1 
Description of Procedures ......................................................................... 44 
4.1.1 
Informed Consent ........................................................................... 44 
4.1.2 
Medical History ............................................................................... 44 
4.1.3 
Adverse Events .............................................................................. 44 
4.1.4 
Concomitant Medications and Therapy .......................................... 44 
4.1.5 
Confirmation of Eligibility ................................................................ 44 
4.1.6 
Archival Tumor Sample .................................................................. 44 
4.1.7 
ECOG Performance Status ............................................................ 44 
4.1.8 
Physical Examination, Vital Signs, Height & Weight ....................... 45 
4.1.9 
Bone Marrow Aspirate and Biopsy ................................................. 45 
4.1.10 Electrocardiogram .......................................................................... 45 
4.1.11 Urine Pregnancy Test ..................................................................... 45 
4.1.12 Hematology .................................................................................... 45 
4.1.13 Serum Chemistry ............................................................................ 46 
4.1.14 Urinalysis ........................................................................................ 46 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 8 
4.1.15 T/B/NK Cell Count .......................................................................... 46 
4.1.16 Serum Immunoglobulin .................................................................. 46 
4.1.17 Hepatitis B and C Testing ............................................................... 46 
4.1.18 Pharmacodynamics ........................................................................ 46 
4.1.19 Pharmacokinetics ........................................................................... 47 
4.1.20 Tumor Assessment ........................................................................ 47 
4.1.21 Routine Clinical Assessments ........................................................ 48 
4.1.22 Study Drug Accountability .............................................................. 49 
4.2 
Investigator’s Assessment of Response to Treatment ............................... 49 
4.3 
Early Termination/Safety Follow-up Visit ................................................... 52 
4.4 
Time-to-Next Treatment ............................................................................. 52 
4.5 
Missed Evaluations .................................................................................... 52 
5.0 
STATISTICAL METHODS OF ANALYSIS .................................................. 53 
5.1 
General Considerations ............................................................................. 53 
5.1.1 
Response Assessment ................................................................... 53 
5.1.2 
Safety Monitoring ........................................................................... 53 
5.2 
Definition of Analysis Sets ......................................................................... 53 
5.3 
Missing Data Handling ............................................................................... 53 
5.4 
Determination of Sample Size ................................................................... 54 
5.5 
Data Analysis ............................................................................................. 54 
5.5.1 
Safety Parameters .......................................................................... 54 
5.5.2 
Demographics and Baseline Characteristics .................................. 54 
5.5.3 
Study Treatment Administration and Compliance .......................... 54 
5.5.4 
Analysis of Efficacy Parameters ..................................................... 55 
5.5.5 
Analysis of Pharmacokinetic/Pharmacodynamic Parameters ........ 56 
5.5.6 
Explorative or Correlative Analyses ................................................ 57 
6.0 
ASSESSMENT OF SAFETY ....................................................................... 57 
6.1 
Definitions .................................................................................................. 57 
6.1.1 
Adverse Events .............................................................................. 57 
6.1.2 
Serious Adverse Event ................................................................... 58 
6.1.3 
Severity .......................................................................................... 58 
6.1.4 
Adverse Events of Special Interest ................................................. 59 
6.2 
Documenting and Reporting of Adverse and Serious Adverse Events ...... 59 
6.2.1 
Adverse Event Reporting Period .................................................... 59 
6.2.2 
Assessment of Adverse Events ...................................................... 60 
6.2.3 
Second Primary Malignancies ........................................................ 60 
6.2.4 
Pregnancy ...................................................................................... 61 
6.2.5 
Expedited Reporting Requirements for Serious Adverse Events ... 61 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 9 
6.2.6 
Type and Duration of Follow-up of Subjects After Adverse 
Events ............................................................................................ 62 
6.2.7 
Hy’s Law ......................................................................................... 62 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS .......... 62 
7.1 
Regulatory and Ethical Compliance ........................................................... 63 
7.2 
Institutional Review Board and Independent Ethics Committee ................ 63 
7.3 
Informed Consent and Protected Subject Health Information 
Authorization ................................................................................. 63 
7.4 
Subject Screening Log ............................................................................... 64 
7.5 
Case Report Forms ................................................................................... 64 
7.6 
Study Monitoring Requirements................................................................. 64 
7.7 
Investigational Study Drug Accountability .................................................. 65 
7.8 
Record Retention ....................................................................................... 66 
7.9 
Protocol Amendments ............................................................................... 66 
7.10 Publication of Study Results ...................................................................... 67 
7.11 Clinical Trial Insurance .............................................................................. 67 
7.12 General Investigator Responsibilities......................................................... 68 
8.0 
REFERENCES ............................................................................................ 69 
9.0 
APPENDICES ............................................................................................. 71 
 
In–Text Tables 
 
Table 1-1.  Assessment of ACP-196 Active-site Occupancy in Fine Needle 
Aspirates of Canine Lymph Node Tumors (N=4) ................................. 25 
Table 3-1.  Drug Discontinuation Actions for Acalabrutinib ..................................... 36 
Table 4-1.  Pharmacokinetic Sample Schedule ...................................................... 47 
Table 4-2.  Response Assessment Criteria for DLBCL (Cheson 2014) .................. 50 
 
Appendices 
 
Appendix 1.  Performance Status Scores ............................................................... 72 
Appendix 2.  Examples of Coadministered Drugs That Need Additional 
Consideration .................................................................................... 73 
Appendix 3.  Adverse Event Assessment of Causality ........................................... 75 
Appendix 4.  Schedule of Assessments ................................................................. 76 
Appendix 5.  Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ...................................................................... 78 
 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 10 
ABBREVIATIONS 
 
Abbreviation 
Definition 
ABC 
activated B-cell (DLBCL subtype) 
ACP-196 
acalabrutinib 
AE(s) 
adverse event(s) 
AESIs 
adverse events of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
hepatitis B core antibody 
ASCO 
American Society of Clinical Oncology 
ASCT 
autologous stem cell transplantation 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BCR 
B-cell receptor 
BCRP 
breast cancer resistance protein 
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 
CHOP 
cyclophosphamide/doxorubicin/vincristine/prednisone 
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 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLBCL 
diffuse large B-cell lymphoma 
DLCO 
diffuse lung capacity for carbon monoxide 
DOR 
duration of response 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 11 
Abbreviation 
Definition 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
FDA 
Food and Drug Administration 
FDG 
[18F]fluorodeoxyglucose 
GCB 
germinal-cell B cell (DLBCL subtype) 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
HNSTD 
highest nonseverely toxic dose 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IPI 
International Prognostic Index 
IRB 
Institutional Review Board 
IVIG 
intravenous immunoglobulins 
LDH 
lactate dehydrogenase 
LTFU 
long-term follow up 
MALT 
mucosa-associated lymphoid tissue (lymphoma) 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHL 
non-Hodgkin lymphoma 
NK 
natural killer (cells) 
ORR 
overall response rate 
OS 
overall survival 
PBMC(s) 
peripheral blood mononuclear cells 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 12 
Abbreviation 
Definition 
PCR 
polymerase chain reaction 
PI3K 
phosphoinositide-3 kinase 
PMBL 
primary mediastinal (thymic) large B-cell lymphoma 
PD 
pharmacodynamics 
PET 
positron-emission tomography 
PFS 
progression-free survival 
PFT 
pulmonary function test 
PK 
pharmacokinetics 
PR 
partial remission (response) 
QD 
once per day (dosing) 
QM 
every month 
QTc 
corrected QT interval 
R-CHOP 
rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone 
R-DHAP 
rituximab/cisplatin/cytarabine/dexamethasone 
R-ICE 
rituximab/ifosamide/etoposide/carboplatin/mesna 
SAE(s) 
serious adverse event(s) 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase (also called AST) 
SGPT 
serum glutamic pyruvic transaminase (also called ALT) 
SPD 
sum of the product of the diameters 
SUSAR 
Suspected Unexpected Serious Adverse Reaction (report) 
t½ 
terminal elimination half-life (whenever possible) 
λz 
terminal elimination rate constant (whenever possible) 
Tmax 
time to maximum drug concentration 
ULN 
upper limit of normal 
WHO 
World Health Organization 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 13 
 
STUDY SYNOPSIS 
Protocol Number: 
ACE-LY-002 
Study Drug: 
ACP-196 (acalabrutinib) 
Protocol Title: 
An Open-label, Phase 1b Study of ACP-196 in Subjects with 
Relapsed or Refractory de Novo Activated B-cell (ABC) 
Subtype of Diffuse Large B-Cell Lymphoma 
Phase: 
Phase 1b 
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 diffuse large B-cell 
lymphoma (DLBCL).  Ibrutinib, a first generation Btk inhibitor, 
has been approved for the treatment of chronic lymphocytic 
leukemia (CLL) and mantle cell lymphoma (MCL).  Interim 
results from a Phase 2 study of ibrutinib 560 mg once per day 
(QD) in subjects with relapsed/refractory GCB and ABC 
DLBCL reported an objective tumor response rate of 41% 
(complete response [CR] 17% and partial response [PR] 24%) 
for subjects with ABC DLBCL versus 5% (no CRs) in subjects 
with germinal-cell B-cell (GCB) DLBCL (de Vos 2013).  Similar 
results were observed with ONO-4059 (160 to 480 mg QD), a 
second generation Btk inhibitor in a Phase 1 dose-escalation 
study in subjects with ABC DLBCL.  In both studies, the Btk 
inhibitors were well tolerated. 
Acerta Pharma BV (Acerta Pharma) has developed a novel 
second generation Btk inhibitor, ACP-196 (also known as 
acalabrutinib), that achieves significant oral bioavailability and 
potency in preclinical models.  Phase 1/2 clinical studies have 
shown that acalabrutinib is an orally bioavailable Btk inhibitor 
with fast absorption and rapid clearance that maintains 
optimal target coverage over 24 hours with a dosage of 
100 mg BID.  Acalabrutinib has been well tolerated in healthy 
volunteers and subjects with CLL or Richter’s syndrome.   
The purpose of this study is to evaluate the safety, 
pharmacokinetics (PK), pharmacodynamics (PD), and activity 
of acalabrutinib administration in subjects with ABC DLBCL.  


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
Acerta Pharma 
Confidential 
Page 14 
Study Design: 
This study is a multicenter, open-label study.  Twenty 
subjects, 10 refractory and 10 relapsed, will be enrolled and 
will take 100 mg of acalabrutinib twice per day (BID).  The 
study will be conducted at approximately 9 sites in up to 
4 countries.   
Relapsed subjects will be defined as subjects who have had a 
PR or better (Cheson 2007 or Cheson 2014 criteria) from the 
previous anticancer therapy and now have progressed.  
Refractory subjects will be defined as subjects whose best 
response to the previous anticancer therapy was stable 
disease or did not respond to therapy.  
Twenty-eight days of study drug administration is 1 cycle.  
Treatment with acalabrutinib may be continued for >28 days 
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 the 
protocol for more information on assessing disease 
progression under these circumstances.  All subjects who 
discontinue study drug will have a safety follow-up visit 
30 (±7) days after the last dose of study drug unless they have 
started another cancer therapy within that timeframe.  
Radiologic tumor assessments will be done at 8- to 12-week 
intervals during the trial. [Note: For sites in Germany, 
radiologic tumor assessments will not include positron 
emission tomography (PET) assessments and radiologic 
tumor assessments will be done at screening and at the end 
of Cycle 2 OR Cycle 4 depending on each subject’s individual 
response; thereafter they will be done at investigator 
discretion].   
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 and monthly thereafter.  
PK/PD testing will be done in Cycle 1 and Cycle 2.   
Refer to protocol for a comprehensive list of study 
assessments and their timing.  Subjects showing clinical 
benefit and who are tolerating acalabrutinib may remain on 
study through the end of Cycle 12.  The end of trial is defined 
as the point when the last subject enrolled completes the end 
of Cycle 12 or withdraws for any reason and completes the 
30-day follow-up visit (if applicable), whichever occurs first.
Subjects who are still on treatment at the end of the study and 
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 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 15 
be transitioned to a separate rollover study or remain within 
this study 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.  
There will be no further data collection other than reporting of 
SAEs per protocol.  Access within this study 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. 
Study Objectives: 
Primary Objective: 
To characterize the safety profile of acalabrutinib in subjects 
with relapsed or refractory ABC DLBCL 
Secondary Objective: 
 
To characterize the PK of acalabrutinib 
 
To evaluate the PD effects of acalabrutinib 
 
To evaluate the activity of acalabrutinib as measured 
by response rate, duration of response, time-to-next 
treatment, and progression-free survival 
Efficacy 
Parameters: 
 
Overall response rate (ORR) 
 
Duration of response 
 
Progression-free survival 
 
Time-to-next treatment 
Safety Parameters: 
Type, frequency, severity, timing of onset, duration, and 
relationship to study drug of any treatment-emergent adverse 
events (AEs) or abnormalities of laboratory tests; serious 
adverse events (SAEs); or AEs leading to discontinuation or 
dose reduction of study treatment. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 16 
Pharmacokinetic 
Parameters: 
The plasma PK of acalabrutinib will be characterized using 
noncompartmental analysis.  The following PK parameters will 
be calculated, whenever possible, from plasma concentrations 
of acalabrutinib: 
 
AUC0-t:  Area under the plasma concentration-time 
curve calculated using linear trapezoidal summation 
from time 0 to time t, 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-∞:  Area under the plasma concentration-time 
curve from 0 to infinity, calculated using the formula: 
AUC0-∞ = AUC0-t + 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 
Pharmacodynamic 
Parameters: 
The occupancy of Btk by acalabrutinib will be measured in 
peripheral blood mononuclear cells (PBMCs) with the aid of a 
biotin-tagged acalabrutinib analogue probe.  The effect of 
acalabrutinib on biologic markers of B-cell function will also be 
evaluated. 
Sample Size: 
Twenty subjects that consist of 10 subjects who are refractory 
to and 10 subjects who have relapsed from the previous 
anticancer therapy.   
Inclusion Criteria: 
 
Men and women ≥ 18 years of age. 
 
Eastern Cooperative Oncology Group (ECOG) 
performance status of ≤ 2. 
 
Pathologically confirmed de novo ABC DLBCL, and 
subjects must have available archival tissue for central 
pathology review to be eligible. 
 
Relapsed or refractory disease, defined as either: 
1) recurrence of disease after a CR, 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 17 
or 2) PR, stable disease (SD), or progressive disease at 
completion of the treatment regimen preceding entry to 
the study (residual disease): 
o Subjects must have previously received a standard 
anthracycline and rituximab-based first-treatment 
regimen (eg, rituximab/cyclophosphamide/ 
doxorubicin/vincristine/prednisone [R-CHOP]). 
o Subjects with suspected residual disease after the 
treatment regimen directly preceding study enrollment 
must have biopsy demonstration of residual DLBCL.  
o Subjects who have not received high-dose 
chemotherapy/autologous stem cell transplantation 
(HDT/ASCT) must be ineligible for HDT/ASCT as 
defined by meeting any of the following criteria: 
 
Age ≥ 70 years 
 
Diffuse lung capacity for carbon monoxide (DLCO) 
< 50% by pulmonary function test (PFT) 
 
Left ventricular ejection fraction (LVEF) < 50% by 
ECHO 
 
Other organ dysfunction or comorbidities 
precluding the use of HDT/ASCT on the basis of 
unacceptable risk of treatment-related morbidity 
 
Subject refusal of HDT/ASCT 
o Subjects who are intolerant to anthracycline-based 
first-line therapy and meet all other eligibility criteria 
including recurrent or refractory disease are also 
eligible. 
 
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).  
 
Agreement to use acceptable forms of contraception 
during the study and for 30 days after the last dose of 
study drug if sexually active and able to bear or beget 
children.  
 
Agreement to refrain from sperm donation during the 
study and for 30 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. 
 
 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 18 
 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: 
 
Transformed DLBCL or DLBCL with coexistent 
histologies (eg, follicular lymphoma [FL] or mucosa-
associated lymphoid tissue [MALT]). 
 
Primary mediastinal (thymic) large B-cell lymphoma 
(PMBL). 
 
Known central nervous system (CNS) lymphoma. 
 
Prior malignancy, except for adequately treated basal 
cell or squamous cell skin cancer, in situ cervical 
cancer, or other cancer from which the subject has 
been disease free for ≥ 2 years or which will not limit 
survival to < 2 years.  Note: these cases must be 
discussed with the medical monitor. 
 
A life-threatening illness, medical condition, or organ 
system dysfunction which, in the investigator’s opinion, 
could compromise the subject’s safety, interfere with 
the absorption or metabolism of acalabrutinib, or put 
the study outcomes at undue risk. 
 
Significant cardiovascular disease such as 
uncontrolled or symptomatic arrhythmias, congestive 
heart failure, or myocardial infarction within 6 months 
of screening, or any Class 3 or 4 cardiac disease as 
defined by the New York Heart Association Functional 
Classification, or 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). 
 
Radio- or toxin-immunoconjugates within 10 weeks of 
the first dose of study drug. 
 
Prior exposure to a B-cell receptor (BCR) inhibitor 
(eg, Btk, phosphoinositide-3 kinase [PI3K], or Syk 
inhibitors) or BCL-2 inhibitors (eg, ABT-199). 
 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 19 
 
Grade ≥ 2 toxicity (other than alopecia) continuing from 
prior anticancer therapy including radiation. 
 
Known history of human immunodeficiency virus (HIV), 
serologic status reflecting active hepatitis B or C 
infection, or any uncontrolled active systemic infection.  
Subjects with hepatitis B core antibody positive who 
are surface antigen negative or who are hepatitis C 
antibody positive will need to have a negative 
polymerase chain reaction (PCR) result before 
enrollment.  Those who are hepatitis B surface antigen 
positive or hepatitis B PCR positive and those who are 
hepatitis C PCR positive will be excluded. 
 
Major surgery within 4 weeks before first dose of study 
drug. 
 
History of stroke or intracranial hemorrhage within 
6 months before the first dose of acalabrutinib. 
 
History of bleeding diathesis (eg, hemophilia or von 
Willebrand disease) 
 
Requires or receiving anticoagulation with warfarin or 
equivalent vitamin K antagonists (eg, phenprocoumon) 
within 28 days of first dose of study drug. 
 
Requires treatment with long-acting proton pump 
inhibitors (eg, omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or 
pantoprazole) 
 
Any of the following laboratory abnormalities:  
o Absolute neutrophil count (ANC) 
< 750 cells/mm3 (0.75 x 109/L).  For subjects 
with documented bone marrow involvement, 
ANC < 500 cells/mm3 (0.50 x 109/L) 
o Platelet count < 50,000 cells/mm3 (50 x 109/L) 
independent of transfusion support.  For 
subjects with documented bone marrow 
involvement, < 30,000 cells/mm3 (30 x 109/L) 
o Serum aspartate transaminase (AST/SGOT) or 
alanine transaminase (ALT/SGPT) 
≥ 3.0 x upper limit of normal (ULN)  
o Creatinine > 2.5 x ULN  
o Total bilirubin > 2.5 x ULN 
 
Breast feeding or pregnant. 
 
Concurrent participation in another therapeutic clinical 
trial. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 20 
Dosage Form and 
Strength: 
Acalabrutinib is provided as 100-mg hard gelatin capsules 
prepared using standard pharmaceutical grade excipients.  
Dose 
Regimen/Route of 
Administration: 
Acalabrutinib is an orally administered product.  Acalabrutinib 
may be administered with or without food.  
Regimen: 
100 mg acalabrutinib (1 x 100-mg capsules) administered 
12 hours apart (BID dosing = 200-mg total daily dose) 
Concomitant 
Medications: 
Use of proton-pump inhibitors, H2-receptor antagonists, or 
antacids while taking acalabrutinib is not recommended due to 
a potential decrease in study treatment exposure.  If treatment 
with a gastric acid reducing agent is required, use of a 
H2-receptor antagonist (2 hours after acalabrutinib) or antacid 
(2 hours before or 2 hours after acalabrutinib) should be 
considered.  Co-administration of acalabrutinib with proton 
pump inhibitors should be avoided.   
The concomitant use of acalabrutinib with breast cancer 
resistance protein (BCRP) substrates (e.g., prazosin, 
glyburide, nitrofurantoin, dipyridamole, statins, and cimetidine) 
may increase exposure to the BCRP substrates by inhibition 
of intestinal BCRP, and therefore should be avoided. 
Concomitant use of strong inhibitors/inducers of CYP3A 
should be avoided when possible.  Subjects requiring 
long-term (>1 week) treatment with a strong CYP3A 
inhibitor/inducer are excluded from the study.  In addition, the 
use of strong or moderate CYP3A inhibitors or inducers within 
7 days of the first dose of study drug is prohibited.  If a subject 
requires short-term treatment (≤7 days) with a strong CYP3A 
inhibitor, acalabrutinib treatment should be interrupted.  If the 
subject requires treatment with a moderate CYP3A inhibitor, 
the acalabrutinib dose should be reduced to 100 mg QD.  
Co-administration of strong CYP3A inducers should be 
avoided.  If a subject requires treatment with a strong CYP3A 
inducer, the acalabrutinib dose should be increased to 200 mg 
BID.   
Statistics: 
No formal statistical tests of hypotheses will be performed as 
is typical for a Phase 1b study.  The trial design is specified 
because of its practical simplicity, use of a biomarker, and not 
because of power 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.   


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 21 
1.0 
BACKGROUND INFORMATION 
1.1 
DIFFUSE LARGE B-CELL LYMPHOMA 
Diffuse large B-cell lymphoma (DLBCL) is the most common of the aggressive NHL in the 
United States, with an annual incidence that has been rising gradually since the 1990s.  
While approximately half of the incremental rise in incidence of DLBCL is attributable to 
identifiable factors—such as the increase in the incidence of HIV-related DLBCL, the 
evolution of more specific diagnostic techniques, and revisions in lymphoma classification 
schemes—much of the rising incidence remains unexplained.  A very aggressive 
malignancy in its untreated natural history, DLBCL is a potentially curable disease, with a 
significant proportion of patients cured with modern standard chemoimmunotherapy.  
Nonetheless, for those patients not cured by standard initial therapy, the prognosis remains 
generally poor, and DLBCL still accounts for the highest number of deaths per year of all 
the NHL histologies. 
Treatment for DLBCL 
Anthracycline-based combination chemotherapy, eg, CHOP (cyclophosphamide, 
doxorubicin, vincristine, and prednisolone), has been the standard approach to initial 
therapy for DLBCL for decades.  While several variants to the CHOP regimen have been 
developed, often varying by the addition of other agents or dose-intensification of the 
agents, a large multi-arm Phase 3 trial demonstrated no differences in disease-free or 
overall survival (OS) with these “second-generation” variants as compared with CHOP 
(Fisher 1993).  The addition of rituximab to CHOP (R-CHOP) or CHOP-like regimens, 
however, has resulted in improvement in both disease-free and OS in DLBCL in 3 large 
randomized Phase 3 trials (Coiffier 2002, Habermann 2006, Pfreundschuh 2006).  
Long-term follow-up of the GELA LNH-98.5 study confirmed that a greater proportion of 
patients are cured using R-CHOP compared with CHOP alone (Coiffier 2010). 
For patients with either residual or recurrent DLBCL following initial therapy, the approach 
of re-induction chemotherapy, followed by high-dose chemotherapy with autologous stem 
cell support (HDT/ASCT) for responding patients, remains the current standard of care.  
Such an approach was demonstrated to result in superior disease-free survival compared 
with re-induction chemotherapy-alone in a randomized Phase 3 trial (Philip 1995).  
However, the results of a more recently reported Phase 3 trial comparing rituximab, 
ifosfamide, carboplatin, and etoposide (R-ICE) to rituximab, cisplatin, cytarabine, and 
dexamethasone (R-DHAP) as re-induction therapy suggests that this standard salvage 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 22 
approach may be less efficacious in the era of rituximab-based first-line therapy, as 3-year 
event-free survival rates were significantly lower for patients who had received 
rituximab-based first-line therapy (Gisselbrecht et al 2010).  In addition, HDT/ASCT is 
associated with considerable treatment-related morbidity and occasional treatment-related 
mortality.  Advanced age and suboptimal baseline pulmonary or cardiac function are risks 
for excessive morbidity during and after HDT/ASCT.  Therefore, effective and tolerable 
therapies are needed in relapsed or refractory DLBCL, particularly in the era of 
rituximab-based initial chemoimmunotherapy.  
Clinical and Molecular Markers of Prognosis 
The major clinical prognostic factors for NHL are well described and have been 
incorporated into the International Prognostic Index (IPI) scoring system.  The specific 
factors are: age > 60 years, stage III or IV disease, performance status ≥ 2, and elevated 
lactate dehydrogenase (LDH) levels.  These factors are combined in the IPI into 
4 categories, with 5-year progression-free survival (PFS) ranging from 40% to 70% and 
5-year OS ranging from 26% to 73% among patients treated with CHOP 
(International Non-Hodgkin’s Lymphoma Prognostic Factors Project, 1993).  Regarding 
applicability of the IPI in the era of modern chemoimmunotherapy (eg, R-CHOP), a recent 
report of a large series of patients treated with rituximab-based regimens found the IPI 
remains predictive for disease-free and overall survival (Ziepert 2010).  
DLBCL is a heterogeneous disease not only clinically, but also morphologically and 
molecularly.  Recent progress has been made in terms of understanding and categorizing 
the molecular heterogeneity of DLBCL.  In a retrospective analysis of a large series of 
patients with DLBCL, The Leukemia and Lymphoma Molecular Profiling Project used DNA 
microarray to identify distinct gene-expression profiles on the basis of hierarchical 
clustering (Rosenwald 2002).  Two principal independent gene-expression subgroups were 
identified: germinal-center B cell (GCB) and activated B cell (ABC).  When outcome after 
standard chemotherapy was analyzed, the GCB and ABC subgroups were not only 
prognostically distinct in direct comparison (with superior outcome in the GCB subgroup), 
but this prognostic distinction was also independent of the IPI.  Therefore, it may be 
possible to distinguish prognostic subgroups of DLBCL on a molecular as well as clinical 
basis. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 23 
1.2 
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 CLL and MCL.  Interim results from a Phase 2 study of 
ibrutinib 560 mg QD in subjects with relapsed/refractory GCB and ABC DLBCL reported an 
objective tumor response rate of 41% (CR 17% and PR 24%) for subjects with ABC DLBCL 
(N=29) versus 5% (no CRs) in subjects with GCB DLBCL (N=20) (de Vos 2013).  In a 
Phase 1 dose-escalation study (160 to 480 mg QD) of ONO-4059, a second generation Btk 
inhibitor, in subjects with ABC DLBCL an ORR of 47% (7/15) was observed (Dyer 2014).  
Also subjects who were refractory to the prior anticancer therapy had an ORR of 33% (3/9) 
compared with an ORR of 67% (4/6) for subjects who had relapsed after the prior therapy.  
In both studies, the Btk inhibitors were well tolerated. 
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 CYP3A4; 
inhibition of CYP3A causes a 29-fold increase in maximum 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 ACP-196 (also known as acalabrutinib), an orally bioavailable, new 
chemical entity that covalently inhibits Btk and shows encouraging activity and acceptable 
safety in nonclinical studies.  Within the class of Btk inhibitors, acalabrutinib is a more 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 24 
selective inhibitor of Btk than ibrutinib.  Key nonclinical differentiators of acalabrutinib 
versus ibrutinib are: 
 
Acalabrutinib has been evaluated against ibrutinib in EGFR expressing cell lines.  
Ibrutinib is a potent covalent inhibitor of EGFR (EC50 = 50 to 70 nM).  Acalabrutinib 
does not inhibit EGFR even at the highest concentration tested (10 μM). 
 
Acalabrutinib has been evaluated against ibrutinib in in vitro antibody-dependent 
cell-mediated cytotoxicity (ADCC) assays.  At physiologic concentrations, ibrutinib, 
but not acalabrutinib, reduced natural killer (NK) cell-mediated lysis of Raji and 
autologous CLL tumor cells and significantly inhibited rituximab-induced NK cell 
cytokine secretion (P<0.05).  
 
Acalabrutinib has been evaluated against ibrutinib in an in vivo thrombus formation 
model.  At physiologic concentrations, ibrutinib, but not acalabrutinib, significantly 
inhibited thrombus formation (P=0.001).  
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.   
1.3 
PRECLINICAL STUDIES 
Summaries of preclinical studies are provided below.  For more detailed information please 
refer to the Investigator Brochure.  
1.3.1 
Chemistry 
Acalabrutinib is an imidazopyrazine analogue with a molecular weight of 465.5 g/mol.  The 
compound has 1 stereogenic center and acalabrutinib is the S-enantiomer.  Acalabrutinib is 
orally bioavailable in humans and is suitable for formulating in capsules.  For clinical 
testing, acalabrutinib has been manufactured and formulated according to current Good 
Manufacturing Practices (cGMP). 
1.3.2 
Efficacy Pharmacology 
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).  ACP-196 is currently being evaluated in an 
ongoing dose-escalation study in canine spontaneous B-cell lymphoma.  Fourteen dogs, all 
of which had DLBCL confirmed by histology, have been treated with ACP-196 for at least 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 25 
2 weeks.  The dosages have ranged from 2.5 to 20 mg/kg QD or BID.  To date, per 
Veterinary Cooperative Oncology Group criteria for assessment of response in peripheral 
nodal lymphoma (Vail 2010), PRs been observed in 4 of 14 dogs (29%) and stable disease 
(SD) has been observed in 8 of 14 dogs (57%) (Gardner 2014).  No ACP-196 related AEs 
have been reported to date in this study.  These findings are preliminary and similar to the 
clinical responses (ie, 1 dog with PR out of 5 dogs treated with suspected or confirmed 
DLBCL) observed with ibrutinib in dogs with spontaneous B-cell lymphoma 
(Honigberg 2010). 
Preliminary results assessing Btk occupancy using a biotin-tagged analogue of ACP-196 
show near complete Btk occupancy over 24 hours with BID versus QD dosing in canine 
tumor tissue (Table 1-1).   
Table 1-1.  Assessment of ACP-196 Active-site Occupancy in Fine Needle Aspirates 
of Canine Lymph Node Tumors (N=4) 
Timing 
Dog Identification and ACP-196 Dosing Regimen 
DL-10 
DL-12 
DL-14 
DL-16 
5 mg/kg QD 
10 mg/kg BID 
20 mg/kg QD 
20 mg/kg QD 
Btk Occupancy (% versus predose) 
Day 1 (3 hours after 
morning dose) 
98% 
99% 
98% 
99% 
Day 7 (before 
morning dose) 
80% 
98% 
77% 
93% 
BID = twice per day; Btk = Bruton tyrosine kinase; ND = not determined; QD = once per 
day 
1.3.3 
Safety Pharmacology 
In vitro and in vivo safety pharmacology studies with ACP-196 have demonstrated a 
favorable nonclinical safety profile.  
When screened at 10 μM in binding assays evaluating interactions with 80 known 
pharmacologic targets such as G-protein-coupled receptors, nuclear receptors, proteases, 
and ion channels, ACP-196 shows significant activity only against the A3 adenosine 
receptor; follow-up dose-response experiments indicated a IC50 of 2.7 µM, suggesting a low 
clinical risk of off-target effects.  ACP-196 at 10 μM showed no inhibition of in vitro 
epidermal growth factor receptor (EGFR) phosphorylation in an A431 human epidermoid 
cancer cell line, whereas ibrutinib had an IC50 of 66 nM.  
The in vitro effect of ACP-196 on human ether-à-go-go-related gene (hERG) channel 
activity was investigated in vitro in human embryonic kidney cells stably transfected with 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 26 
hERG.  ACP-196 inhibited hERG channel activity by 25% at 10 μM, suggesting a low 
clinical risk that ACP-196 would induce clinical QT prolongation as predicted by this assay. 
ACP-196 was well tolerated in standard in vivo Good Laboratory Practices (GLP) studies of 
pharmacologic safety.  A functional observation battery in rats at doses of through 
300 mg/kg (the highest dose level) revealed no adverse effects on neurobehavioral effects 
or body temperature at any dose level.  A study of respiratory function in rats also indicated 
no treatment-related adverse effects at doses through 300 mg/kg (the highest dose level).  
In a cardiovascular function study in awake telemeterized male beagle dogs, single doses 
of ACP-196 at dose levels through 30 mg/kg (the highest dose level) induced no 
meaningful changes in body temperature, cardiovascular, or electrocardiographic (ECG) 
(including QT interval) parameters.  The results suggest that ACP-196 is unlikely to cause 
serious off-target effects or adverse effects on critical organ systems. 
1.3.4 
Drug-drug Interaction Potential 
The in vitro studies suggest CYP-mediated metabolism of ACP-196 appears to be 
catalyzed predominantly by CYP3A4/5.  However, in elimination studies in preclinical 
species, the metabolic fate of ACP-196 is dominated by direct conjugation of ACP-196 with 
glutathione, providing evidence for a significant non-CYP mechanism of elimination.  In a 
healthy volunteer study (ACE-HV-001), the effect of coadministration of a potent CYP3A 
and P-gP inhibitor, itraconazole, on the plasma levels of ACP-196 was evaluated.  The 
mean plasma ACP-196 Cmax and AUC0-last values increased 3.7- and 5.1-fold, respectively, 
in the presence of itraconazole relative to no pretreatment.  In vitro studies also show that 
ACP-196 is a substrate for P-gp.   
ACP-196 is unlikely to be a perpetrator of a drug-drug interaction at the level of inhibition or 
induction of CYP isoforms. 
Results from drug transporter studies suggest that ACP-196 is not anticipated to alter the 
PK of other therapeutic agents that are substrates for MDR1, OATP1B1, OATP1B3, OAT1, 
OAT3 and OCT2.  ACP-196 (200 mg QD) may alter the PK of breast cancer resistance 
protein (BCRP) substrates by inhibition of intestinal BCRP.  Caution should be taken when 
coadministered with narrow therapeutic index BCRP substrates.  
1.3.5 
In Vivo General Toxicology 
To date, the toxicology program has included 28-day GLP evaluations in rats and dogs.  In 
the 28-day study in male and female Sprague-Dawley rats, animals received oral gavage 
ACP-196 dosages of 30, 100, and 300 mg/kg/day.  In the 28-day study in male and female 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 27 
beagle dogs, animals received oral ACP-196 dosages of 3, 10, and 30 mg/kg/day.  Both 
studies had 28-day recovery periods. 
The no observable adverse effect level in the dog was 30 mg/kg/day, which was the 
highest dose evaluated.  In rats, 30 mg/kg/day resulted in minimal inflammation of the 
pancreas in some animals, with reversal, indicating the rat to be the more sensitive 
preclinical species.  The pancreatic effects were minimally increased at 100 mg/kg/day in 
the rat though there was no clinical evidence of toxicity.  Hence, 100 mg/kg/day was 
selected to conservatively represent the highest nonseverely toxic dose (HNSTD).  The 
pancreatic findings were investigated in subsequent rat toxicology studies and found to be 
treatment related, non-adverse at lower doses, and not associated with systemic toxicity or 
changes in biomarkers of pancreatic function.  The islet cell changes resemble a 
spontaneous pancreatic lesion that is described as an age-related finding in male rats of 
this strain.  In dogs at 30 mg/kg/day, no adverse effects on the pancreas were observed; 
there were no microscopic findings in the pancreas, and all clinical biomarkers of 
pancreatic function were normal.  
In rats and dogs, no adverse ECG or histopathologic cardiovascular effects were noted at 
the planned conclusion of the 28-day toxicology studies.  However, in 5 of 6 rats from the 
300-mg/kg group that died early in the study, slight to moderate necrosis of the 
myocardium and/or white blood cell infiltration/inflammation of the myocardium were noted 
on microscopic examination of the hearts.  These findings were most likely incidental 
postmortem changes.  
1.4 
CLINICAL EXPERIENCE 
Calquence® has been approved in the United States and other markets for the treatment of 
adult patients with MCL who have received at least one prior therapy, CLL, and small 
lymphocytic lymphoma (SLL).    
For the latest information for pharmacokinetics and pharmacodynamics and clinical 
experience, see the Investigator Brochure. 
1.5 
BENEFIT/RISK 
Acalabrutinib is a potent, orally available small-molecule inhibitor of Btk.  A PK/PD study 
has been completed with acalabrutinib in healthy volunteers (ACE-HV-001; see Investigator 
Brochure).  The safety results showed no identified safety risks in healthy subjects 
receiving 1 or 2 days of acalabrutinib ≤ 100 mg.  In study ACE-CL-001, a study of 
acalabrutinib in subjects with relapsed/refractory or previously untreated CLL or Richter’s 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 28 
syndrome, no DLTs have been reported at dosages of ≤ 400 mg QD or 100 and 200 mg 
BID.  The overall response rate in the evaluable subjects for this study is currently 94% with 
some subjects obtaining PRs after only 2 cycles of therapy.  Based on these robust results 
in subjects with CLL, the evaluation of acalabrutinib in subjects with relapsed or refractory 
ABC DLBCL is warranted. 
1.6 
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 efficacy 
and safety of other Btk inhibitors (eg, ibrutinib and ONO-4059) in subjects with hematologic 
cancers; and the available nonclinical and clinical information regarding acalabrutinib.  
2.0 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
To characterize the safety profile of acalabrutinib in subjects with relapsed or refractory 
ABC DLBCL 
2.2 
SECONDARY OBJECTIVES: 
 
To characterize the PK of acalabrutinib  
 
To evaluate the PD effects of acalabrutinib 
 
To evaluate the activity of acalabrutinib as measured by response rate, duration of 
response, time-to-next treatment, and progression-free survival 
3.0 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This study is a multicenter and open-label study.  Twenty subjects, 10 relapsed and 
10 refractory, will be enrolled and will take 100 mg of acalabrutinib BID.  The study will be 
conducted at approximately 9 sites in up to 4 countries.   
Relapsed subjects will be defined as subjects who have had a PR or better (Cheson 2014 
or Cheson 2007 criteria) from the previous anticancer therapy and now have progressed.  
Refractory subjects will be defined as subjects whose best response to the previous 
anticancer therapy was SD or did not respond to therapy.  
Treatment with acalabrutinib may be continued for > 28 days until disease progression or 
an unacceptable drug-related toxicity occurs.  Tumor assessments will be performed at 
8- to 12-week intervals during the trial.  Dose modification provisions are provided in 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 29 
Section 3.5.5.  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.  All 
subjects who discontinue study drug will have a safety follow-up visit 30 (±7) days after the 
last dose of study drug unless they have started another cancer therapy within that 
timeframe.  
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 and monthly thereafter.  PK/PD testing will be done in Cycle 1 and 
Cycle 2.   
Refer to Appendix 4 for a comprehensive list of study assessments and their timing.  
Subjects showing clinical benefit and who are tolerating acalabrutinib may remain on study 
through the end of Cycle 12.  The end of trial is defined as the point when the last subject 
enrolled completes the end of Cycle 12 or withdraws for any reason and completes the 
30-day follow-up visit (if applicable), whichever occurs first. 
Subjects who are still on treatment at the end of the study and 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 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.  There will be no further data collection other than 
reporting of SAEs per Section 6.2.5.  Access within this study 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. 
3.2 
STUDY PARAMETERS 
3.2.1 
Efficacy Parameters 
Standardized response and progression criteria have been established for lymphoma 
(Cheson 2014); assessments of acalabrutinib efficacy in this study will be based on these 
Lugano criteria.  Efficacy endpoints will include: 
 
ORR 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 30 
 
Duration of response 
 
Progression-free survival 
 
Time-to-next treatment 
3.2.2 
Safety Parameters 
The safety of acalabrutinib will be characterized by the type, frequency, severity, timing of 
onset, duration, and relationship to study drug of any treatment-emergent AEs or 
abnormalities of laboratory tests; SAEs; or AEs leading to discontinuation or dose reduction 
of study treatment.  
For consistency of interpretation, AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), and the severity of AEs and laboratory abnormalities will 
be graded using the Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.03.  Standard definitions for seriousness will be applied (see Section 6.1). 
3.2.3 
Pharmacokinetic and Pharmacodynamic Parameters 
Standard PK parameters for acalabrutinib in plasma will be evaluated in this study.  A full 
description of the PK parameters is provided in Section 5.5.5. 
The occupancy of Btk by acalabrutinib will be measured in peripheral blood mononuclear 
cells (PBMCs) with the aid of a biotin-tagged acalabrutinib analogue probe.  The effect of 
acalabrutinib on biologic markers of B-cell function will also be evaluated. 
PK/PD assessments will only be done in subjects at sites in the United States only. 
3.3 
RATIONALE FOR STUDY DESIGN AND DOSING REGIMEN 
Preliminary data from the ongoing Phase 1/2 study in subjects with CLL have shown that 
acalabrutinib is well tolerate at dosages of 100 to 400 mg QD and 100 to 200 mg BID.  In 
addition, preliminary PD data from ACE-CL-001 show that Btk occupancy > 95% in 
peripheral blood is observed 4 hours after dosing but decreases to < 95% occupancy at 
24 hours, while with BID dosing complete Btk occupancy (95% to 99%) is maintained over 
24 hours at steady state.  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 increased efficacy and/or decreased 
development of resistance to acalabrutinib.  In addition, having information regarding the 
safety and pharmacology of a BID schedule may support future combination studies with 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 31 
other drugs that are given 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 ABC DLBCL. 
3.4 
SELECTION OF STUDY POPULATION 
3.4.1 
Inclusion Criteria 
Eligible subjects will be considered for inclusion in this study if they meet all of the following 
criteria:  
1. Men and women ≥ 18 years of age. 
2. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 
3. Pathologically confirmed de novo ABC DLBCL, and subjects must have available 
archival tissue for central pathology review to be eligible. 
4. Relapsed or refractory disease, defined as either: 1) recurrence of disease after a 
CR, or 2) PR, SD, or progressive disease at completion of the treatment regimen 
preceding entry to the study (residual disease): 
o Subjects must have previously received a standard anthracycline and 
rituximab-based first-treatment regimen (eg, R-CHOP). 
o Subjects with suspected residual disease after the treatment regimen 
directly preceding study enrollment must have biopsy demonstration of 
residual DLBCL.  
o Subjects who have not received HDT/ASCT must be ineligible for 
HDT/ASCT as defined by meeting any of the following criteria: 
 
Age ≥ 70 years 
 
Diffuse lung capacity for carbon monoxide (DLCO) < 50% by PFT 
 
Left ventricular ejection fraction (LVEF) < 50% by ECHO 
 
Other organ dysfunction or comorbidities precluding the use of 
HDT/ASCT on the basis of unacceptable risk of treatment-related 
morbidity 
 
Subject refusal of HDT/ASCT 
o Subjects who are intolerant to anthracycline-based first-line therapy and 
meet all other eligibility criteria including recurrent or refractory disease are 
also eligible. 
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 CT scan).  
6. Agreement to use acceptable forms of contraception during the study and for 
30 days after the last dose of study drug if sexually active and able to bear or beget 
children.  


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 32 
7. Agreement to refrain from sperm donation during the study and for 30 days after the 
last dose of study drug. 
8. Willing and able to participate in all required evaluations and procedures in this 
study protocol including swallowing capsules without difficulty. 
9. Ability to understand the purpose and risks of the study and provide signed and 
dated informed consent and authorization to use protected health information (in 
accordance with national and local patient privacy regulations). 
3.4.2 
Exclusion Criteria 
Subjects will be ineligible for this study if they meet any of the following criteria: 
1. Transformed DLBCL or DLBCL with coexistent histologies (eg, FL or MALT) 
2. Primary mediastinal (thymic) large B-cell lymphoma (PMBL) 
3. Known central nervous system (CNS) lymphoma 
4. 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. 
5. 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. 
6. Significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of 
screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart 
Association Functional Classification, or QTc > 480 msec. 
7. 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. 
8. Any immunotherapy within 4 weeks of first dose of study drug. 
9. 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). 
10. Radio- or toxin-immunoconjugates within 10 weeks of the first dose of study drug 
11. Prior exposure to a B-cell receptor (BCR) inhibitor (eg, Btk phosphoinositide-3 
kinase [PI3K], or Syk inhibitors) or BCL-2 inhibitors (eg, ABT-199). 
12. Grade ≥ 2 toxicity (other than alopecia) continuing from prior anticancer therapy 
including radiation. 
13. Known history of human immunodeficiency virus (HIV), serologic status reflecting 
active hepatitis B or C infection, or any uncontrolled active systemic infection.  
Subjects with hepatitis B core antibody positive who are surface antigen negative or 
who are hepatitis C antibody positive will need to have a negative PCR result before 
enrollment.  Those who are hepatitis B surface antigen positive or hepatitis B PCR 
positive and those who are hepatitis C PCR positive will be excluded. 
14. Major surgery within 4 weeks before first dose of study drug. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 33 
15. History of stroke or intracranial hemorrhage within 6 months before the first dose of 
acalabrutinib. 
16. History of bleeding diathesis (eg, hemophilia or von Willebrand disease) 
17. Requires or receiving anticoagulation with warfarin or equivalent vitamin K 
antagonists (eg, phenprocoumon) within 28 days of first dose of study drug. 
18. Requires treatment with long-acting proton pump inhibitors (eg, omeprazole, 
esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole) 
19. Any of the following laboratory abnormalities:  
a. Absolute neutrophil count (ANC) < 750 cells/mm3 (0.75 x 109/L).  For 
subjects with documented bone marrow involvement, ANC < 500 cells/mm3 
(0.50 x 109/L) 
b. Platelet count < 50,000 cells/mm3 (50 x 109/L) independent of transfusion 
support.  For subjects with documented bone marrow involvement, < 30,000 
cells/mm3 (30 x 109/L) 
c. Serum AST/SGOT or ALT/SGPT ≥ 3.0 x ULN  
d. Creatinine > 2.5 x ULN  
e. Total bilirubin > 2.5 x ULN 
20. Breast feeding or pregnant. 
21. Concurrent participation in another therapeutic clinical trial.  
3.4.3 
Replacement of Subjects 
Any subject who does not complete Cycle 2 may be replaced at the discretion of the study 
investigator and sponsor.   
3.4.4 
Enrollment Procedures 
Enrollment of a subject into the study will be performed according to the following 
procedure:  
 
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 form is 
faxed/emailed to the sponsor. 
 
An Enrollment Confirmation Form will be completed and faxed/emailed to the study 
center by the sponsor within 24 hours. 
Treatment must begin within the screening window (Section 4.1) and after the site has 
received notification from the sponsor.  Study treatment is not blinded on this study. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 34 
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 should be stored according to the instructions on the label that is affixed to 
the package containing the drug product.   
Acalabrutinib capsules contain100 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 
SAE/Product Complaint Form should be completed and emailed or faxed to the sponsor or 
the sponsor’s representative.   
Refer to the Investigator Brochure for additional information. 
3.5.3 
Administration of Study Drug  
Investigators are prohibited from supplying acalabrutinib to any subjects not properly 
enrolled in this study or to any physicians or scientists except those designated as 
subinvestigators on FDA Form 1572.  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 with 8 ounces (approximately 240 mL) of 
water.  Subjects may take study drug with or without food.  The capsules should be 
swallowed intact and subjects should not attempt to open capsules or dissolve them in 
water.  Dietary restrictions are provided in Section 3.7.1. 
Doses should be taken BID with the second dose 11-13 hours after the first.   
If a dose is missed, it can be taken within 3 hours after the scheduled time with a return to 
the normal schedule with the following dose.  If the time from the scheduled time of 
administration 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. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 35 
3.5.4 
Assuring Subject Compliance 
Subjects will receive their Day 1 and Day 8 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.  Any other clinically important events 
where dose delays may be considered appropriate by the investigator must be discussed 
with the medical monitor.  Study drug may be held for a maximum of 28 consecutive days 
from expected dose due to toxicity.  Study treatment should be discontinued in the event of 
a toxicity lasting > 28 days, unless reviewed and approved by the medical monitor. 
Note: temporary withholding of study drug for as little as 7 days can cause a 
transient worsening of disease and/or of constitutional symptoms.  Refer to 
Section 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: 
 
Grade 4 ANC (< 500/μL) for > 7 days (Neutrophil growth factors are permitted per 
ASCO guidelines [Smith 2006] and use must be recorded on the electronic case 
report form [eCRF]). 
 
Grade 3 platelets in presence of significant bleeding 
 
Grade 4 platelets  


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 36 
 
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  
3rd 
Hold acalabrutinib until recovery to Grade ≤ 1 or baseline; restart at 100 mg 
once daily 
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 Dosage Administration 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, 
alkalinization of urine, and allopurinol or rasburicase per institutional standards before 
initiating treatment. 
3.6.2 
Guideline for Use of CYP Inhibiting/Inducing Drugs 
At the systemic exposure levels expected in this study, acalabrutinib inhibition of CYP 
metabolism is not anticipated.  However, concomitant administration of acalabrutinib with a 
strong CYP3A4 inhibitor increased exposure by approximately 5-fold (see Investigator 
Brochure).  Consequently, the concomitant use of strong inhibitors/inducers of CYP3A4 
(Appendix 2) should be avoided when possible.  Subjects requiring long-term (>1 week) 
treatment with a strong CYP3A inhibitor/inducer are excluded from the study.  In addition, 
the use of strong or moderate CYP3A inhibitors or inducers within 7 days of the first dose of 
study drug is prohibited.  If a subject requires short-term treatment (≤7 days) with a strong 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 37 
CYP3A inhibitor, acalabrutinib treatment should be interrupted.  If the subject requires 
treatment with a moderate CYP3A inhibitor, the acalabrutinib dose should be reduced to 
100 mg QD.  Co-administration of strong CYP3A inducers should be avoided.  If a subject 
requires treatment with a strong CYP3A inducer, the acalabrutinib dose should be 
increased to 200 mg BID.   
3.6.3 
Guideline for Use of Drugs that Affect Gastric pH 
Use of proton-pump inhibitors, H2-receptor antagonists, or antacids while taking 
acalabrutinib is not recommended due to a potential decrease in study treatment exposure.  
If treatment with a gastric acid reducing agent is required, use of a H2-receptor antagonist 
(2 hours after acalabrutinib) or antacid (2 hours before or 2 hours after acalabrutinib) 
should be considered.  Co-administration of acalabrutinib with proton pump inhibitors 
should be avoided.   
The concomitant use of acalabrutinib with BCRP substrates (e.g., prazosin, glyburide, 
nitrofurantoin, dipyridamole, statins, and cimetidine) may increase exposure to the BCRP 
substrates by inhibition of intestinal BCRP, and therefore should be avoided. 
3.6.4 
Prohibited Concomitant Therapy 
Any chemotherapy, immunotherapy, corticosteroids (> 10 mg of prednisone or equivalent), 
kinase inhibitors, bone marrow transplantation, experimental therapy, warfarin, and 
radiotherapy are prohibited.   
3.7 
PRECAUTIONS 
3.7.1 
Reference Safety Information 
For the purpose of reporting AEs and serious adverse events (SAEs): 
The Investigator Brochure contains the Reference Safety Information (RSI) for 
acalabrutinib. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 38 
3.7.2 
Dietary Restrictions 
Acalabrutinib can be taken with or without food.  As acalabrutinib is metabolized by CYP3A, 
subjects should be strongly cautioned against using herbal remedies or dietary 
supplements (in particular, St John’s wort, which is a potent CYP3A inducer).  Otherwise, 
subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting. 
3.7.3 
Hemorrhage 
Serious hemorrhagic events, including fatal events, have occurred in clinical trials with 
acalabrutinib. 
The mechanism for hemorrhage is not well understood.  Subjects receiving antithrombic 
agents may be at increased risk of hemorrhage.  Use caution with antithrombotic agents 
and consider additional monitoring for signs of bleeding when concomitant use is medically 
necessary.  Consider the benefit-risk of withholding acalabrutinib for at least 3 days 
pre- and post-surgery.  Subjects with hemorrhage should be managed per institutional 
guidelines with supportive care and diagnostic evaluations as clinically indicated.  
3.7.4 
Infections    
Serious infections (bacterial, viral, and fungal), including fatal events, have occurred in 
clinical studies with acalabrutinib.  The most frequent reported Grade ≥3 infection was 
pneumonia (preferred term).  
Consider prophylaxis in subjects who are at increased risk for opportunistic infections.  
Subjects should be monitored for signs and symptoms of infection and treated as medically 
appropriate.  Refer to Section 3.7.4.1 and Section 4.1.17 for additional information and 
monitoring guidance for viral hepatitis and Section 3.7.4.2 for additional information and 
management guidance for signs and symptoms of PML. 
3.7.4.1 
Hepatitis B Virus Reactivation 
Serious or life-threatening reactivation of viral hepatitis may occur in subjects treated with 
acalabrutinib.  Therefore, subjects who are hepatitis B core antibody (anti-HBc) positive or 
have a known history of hepatitis B virus (HBV) infection, should be monitored monthly with 
a quantitative PCR test for HBV DNA.  Monthly monitoring should continue until 12 months 
after last dose of acalabrutinib.  Any subject with a rising viral load (above lower limit of 
detection) should discontinue acalabrutinib 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.   


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 39 
3.7.4.2 
Progressive Multifocal Leukoencephalopathy 
Cases of progressive multifocal leukoencephalopathy (PML) have occurred in clinical 
studies with acalabrutinib.  Signs and symptoms of PML may include cognitive and 
behavioral changes, language disturbances, visual disturbances, sensory deficits, 
weakness, and coordination and gait difficulties. 
If PML is suspected, hold further treatment with acalabrutinib treatment until PML is 
excluded.  A diagnostic evaluation may include (but is not limited to): 
 
Neurologic consultation 
 
Brain magnetic resonance imaging (MRI) 
 
PCR analysis for John Cunningham virus DNA in cerebrospinal fluid 
 
If PML is confirmed, permanently discontinue acalabrutinib. 
3.7.5 
Cytopenias 
Grade 3 or 4 cytopenias including neutropenia, anemia, and thrombocytopenia have 
occurred in clinical studies with acalabrutinib.  Monitor blood counts as medically 
appropriate. 
Subjects with cytopenias should be managed according to institutional guidelines with 
maximal supportive care and diagnostic evaluations as clinically indicated.  Subjects should 
be closely monitored as appropriate. 
3.7.6 
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.  For Subjects who develop a second primary malignancy, subjects 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. 
3.7.7 
Atrial Fibrillation 
Events of atrial fibrillation/flutter have occurred in clinical studies with acalabrutinib 
particularly in subjects with cardiac risk factors, hypertension, diabetes mellitus, acute 
infections, or a previous history of atrial fibrillation. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 40 
Monitor for symptoms of atrial fibrillation and atrial flutter (e.g., palpitations, dizziness, 
syncope, chest pain, dyspnea) and obtain an ECG as clinically indicated.  Subjects with 
atrial fibrillation should be managed per institutional guidelines with supportive care and 
diagnostic evaluations as clinically indicated.  
3.7.8 
Surgery 
Susceptibility to bleeding has been observed with the first generation Btk inhibitor, ibrutinib 
(IMBRUVICA® package insert).  As a precaution, it is suggested that acalabrutinib be held 
for 3 days before and after any major surgical procedure. 
3.7.9 
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 post-menopausal 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. 
Highly Effective Methods of Contraception‡  
Highly effective methods of contraception (to be used during heterosexual activity) are 
defined as methods that can achieve a failure rate of <1% per year when used consistently 
and correctly.  Such methods include:  
 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation, which may be oral, intravaginal, or transdermal  
 
Progestogen-only hormonal contraception associated with inhibition of ovulation, which 
may be oral, injectable, or implantable  
 
Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)  
 
Bilateral tubal occlusion  
 
Vasectomy of a female subject’s male partner (with medical assessment and 
confirmation of vasectomy surgical success)  


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 41 
 
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.  
Periodic abstinence† (eg, calendar, ovulation, sympto-thermal, and post-ovulation methods) 
and withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method 
(LAM) are not acceptable methods of contraception.  Female condom and male condom 
should not be used together as an effective method of contraception.  
†Abstinence (relative to heterosexual activity) can only be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle and 
if considered acceptable by local regulatory agencies and IECs/IRBs.  Periodic abstinence 
(eg, calendar, ovulation, sympto-thermal, and post-ovulation methods) and withdrawal are 
not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites 
in this country/region. 
Developmental and reproductive toxicology studies in rats have not identified acalabrutinib-
related toxicities for fertility, reproductive success, embryofetal development, or embryofetal 
survival.  In rabbits, at dose levels which resulted in maternal toxicities, skeletal variations 
were associated with reductions in fetal weights.  Effects on parturition and post-natal 
development are pending.  For additional details, refer to the Acalabrutinib Investigator 
Brochure. 
Subjects should promptly notify the investigator if they, or their partners, become pregnant 
during this period.  Female subjects must also notify the investigator if they become 
pregnant within 2 days after the last dose of acalabrutinib.  If a female subject becomes 
pregnant during the treatment period, she must discontinue acalabrutinib immediately.  
Pregnancy in a female subject or a male subject’s partner must be reported as described in 
Section 6.2.4. 
3.7.10 
Overdose Instructions 
In the event of ingestion of more than the recommended dosage per protocol, additional 
clinical monitoring is recommended by the sponsor.  For any subject experiencing an 
acalabrutinib overdose, observation for any symptomatic side effects should be instituted, 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 42 
and vital signs and biochemical and hematologic parameters should be followed closely 
(consistent with the protocol or more frequently, as needed).  Appropriate supportive 
management to mitigate adverse effects should be initiated.  If the overdose ingestion is 
recent and substantial, and if there are no medical contraindications, use of gastric lavage 
or induction of emesis may be considered. 
The Acerta Pharma medical monitor should be contacted if a study drug overdose occurs.  
3.8 
STOPPING RULES 
All study participants may receive acalabrutinib indefinitely as long as they are safely 
benefitting.  However: 
 
Any subject has the right to withdraw from the study at any time. 
 
Any subject who has objective evidence of definitive DLBCL progression while receiving 
study treatment at the highest individual tolerable dose level allowed in the protocol  
(see Section 3.5.5) should be withdrawn from the study treatment.  Note: If there is 
uncertainty regarding whether there is DLBCL progression, the subject should continue 
study treatment and remain under close observation (eg, evaluated at 4- to 8-week 
intervals) pending confirmation of progression.  In particular, transient worsening of 
disease during temporary interruption of study therapy (eg, for intercurrent illness, 
drug-related toxicity, or surgery) may not indicate disease progression.  In such 
circumstances, and if medically appropriate, subjects may resume therapy and relevant 
clinical, laboratory, and/or radiographic assessment should be done to document 
whether tumor control can be maintained or whether actual disease progression has 
occurred.  
 
Any subject who is unable to tolerate rechallenge with the lowest protocol-described, 
dose-modified levels (see Section 3.5.5) should be withdrawn from the study treatment 
unless continued therapy is permitted by the Acerta Pharma medical monitor. 
 
Any subject whose medical condition substantially changes after entering the study 
should be carefully evaluated by the investigator in consultation with the Acerta Pharma 
medical monitor.  Such subjects should be withdrawn from study treatment if continuing 
would place them at risk.  
 
Any subject who becomes pregnant or begins breastfeeding 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 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 43 
circumstances that increase risk or substantially compromise the interpretation of study 
results. 
 
The investigator, in consultation with the Acerta Pharma medical monitor, may withdraw 
any subject from the study treatment, if, in the investigator’s opinion, it is not in the 
subject’s best interest to continue.  
Subjects who discontinue study therapy will continue on study for safety (Section 4.3) and 
time-to-next therapy (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 or enrolls in an acalabrutinib maintenance study.  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 and also should be described 
on the appropriate eCRF.   
3.9 
DATA AND SAFETY MONITORING 
This trial will be monitored in accordance with the sponsor’s Pharmacovigilance Committee 
procedures.  Adverse events and SAEs will be reviewed internally on an ongoing basis to 
identify safety concerns.  Quarterly conference calls with the investigators will be conducted 
to discuss study progress, obtain investigator feedback and exchange, and discuss 
"significant safety events" (ie, AEs leading to dose reductions, related SAEs, and deaths).   
4.0 
STUDY ACTIVITIES AND ASSESSMENTS 
The schedule of events is provided in Appendix 4.  Descriptions of the scheduled 
evaluations are outlined below and complete information on study drug and dosing is 
provided in Section 3.5. 
Before study entry, throughout the study, and at the follow-up evaluation, various clinical 
and diagnostic laboratory evaluations are required.  The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments.  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. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 44 
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 
standard of care.  Subjects must also grant permission to use protected health information. 
4.1.2 
Medical History 
Collect and record the subject’s complete history through review of medical records and by 
interview.  Concurrent medical signs and symptoms must be documented to establish 
baseline severities.  A disease history, including the date of initial diagnosis and list of all 
prior anticancer treatments, and responses to these treatments, also will be recorded. 
4.1.3 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 6.1.  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.  De-identified copies of all screening radiology results, site pathology report for 
confirming diagnosis of ABC DLBCL, and a list of prior anticancer therapy and best 
responses need to be submitted to the sponsor as part of the enrollment process.   
4.1.6 
Archival Tumor Sample 
All subjects must have available archival tissue for central pathology review.  Either 
unstained slides (minimum of 10 slides) or a paraffin block will be acceptable for central 
pathology review.  Please refer the study manual for a more detailed description of the 
procedures and for information on where to send the archival tissue samples. 
4.1.7 
ECOG Performance Status 
The ECOG performance index is provided in Appendix 1. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 45 
4.1.8 
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, will be done 
during the treatment period and at the safety follow-up visits. 
Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) will be 
assessed after the subject has rested in the sitting position.   
4.1.9 
Bone Marrow Aspirate and Biopsy 
A bone marrow aspirate and biopsy will be done at screening.  Subjects who have a bone 
marrow aspirate and biopsy result since completion of their last therapy for DLBCL may 
use those bone marrow results in lieu of the baseline bone marrow aspirate/biopsy required 
for this study provided the biopsy/aspirate was done within 60 days of 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 complete remission 
(CR).  A bone marrow aspirate and biopsy will also be done at end of Cycle 12.  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.  
4.1.10 
Electrocardiogram 
Subjects should be in supine position and resting for ≥ 10 minutes before study-related 
ECGs.   
4.1.11 
Urine Pregnancy Test 
Pregnancy tests will be required only for women with childbearing potential.  If positive, 
pregnancy must be ruled out by ultrasound.  Testing will be done by the central laboratory. 
4.1.12 
Hematology 
Hematology studies must include complete blood count (CBC) with differential and platelet 
and reticulocyte counts.  Testing will be done by the central laboratory. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 46 
4.1.13 
Serum Chemistry 
Chemistry must include albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood urea 
nitrogen (BUN), calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), 
magnesium, phosphate, potassium, sodium, total bilirubin, total protein, and uric acid.  If an 
unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, magnesium, 
and potassium) must be done to coincide with the ECG testing.  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 IgG, IgM, and IgA will be done by the central laboratory. 
4.1.17 
Hepatitis B and C Testing 
Hepatitis serology testing must include hepatitis B surface antigen (HBsAg), hepatitis B 
surface antibody (HBsAb), anti-HBc, and hepatitis C (HCV) antibody.  Since intravenous 
immunoglobulins (IVIG) may cause false positive hepatitis serology, subjects who are 
receiving prophylactic IVIG and have positive HBsAg or anti-HBc must have negative 
hepatitis B DNA to be eligible.  In addition, any subjects testing positive for any hepatitis 
serology, must have PCR testing (see Appendix 4 and exclusion criterion #13).  Testing will 
be done by local or central laboratory.   
Refer to Section 3.7.4.1 and Appendix 4 regarding monitoring of subjects who are anti-HBc 
positive or have a known history of HBV. 
4.1.18 
Pharmacodynamics 
Blood samples 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. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 47 
4.1.19 
Pharmacokinetics 
Refer to the laboratory manual for instructions on collecting and processing these samples.  
Testing will be performed at a central clinical laboratory.  Leftover plasma samples may be 
used for exploratory acalabrutinib metabolite analyses.  The predose sample can be taken 
up to 1 hour before dosing.   
Table 4-1.  Pharmacokinetic Sample Schedule 
 
HOURS POSTDOSE 
Cycle 
Day Predose 
0.5 
(±5 min) 
1 
(±5 min) 
2 
(±5 min) 
4 
(±10 min) 
6 
(±10 min) 
24 
(±30 min) 
1 
1 
X 
X 
X 
X 
X 
X 
X*before 
Day 2 first 
dose 
 
8 
X 
X 
X 
X 
X 
X 
 
 
15, 
22, 
28 
Predose 
and 1 h 
(±5 min) 
postdose 
and 5 to 
15 min 
before 
electrocar
diogram 
(ECG) 
 
 
 
 
 
 
Note: 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 within 
90 days before the first dose is also required.  Information on extranodal involvement will 
also be recorded.   
During treatment, CT scans with contrast (unless contraindicated) of the chest, abdomen, 
and pelvis and any other disease sites (eg, neck) will be done for tumor assessments at the 
end of Cycle 2 (± 7 days), Cycle 4 (± 7 days), and Cycle 6 (± 7 days); and then every 
3 cycles (12 weeks, ± 7 days) thereafter or more frequently at investigator discretion.  
On-study tumor assessments will also be done by physical exam and laboratory results.  
Bone marrow and PET/CT are only required for confirmation of CR per clinical guidelines 
(see Section 4.2).  


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 48 
Note: For sites in Germany, radiologic tumor assessments will not include PET.  Radiologic 
tumor assessments will be done at Screening and at the end of Cycle 2 (± 7 days) OR 
Cycle 4 (± 7 days) depending each on subjects’ individual response; thereafter they will be 
done at investigator discretion.  On-study tumor assessments will also be done by physical 
exam and laboratory results.   
De-identified copies of all radiology results maybe requested by the sponsor.   
Subjects should have radiographic tumor measurements done at the participating study 
center or an acceptable alternate imaging facility using an identical imaging protocol and 
similar equipment.  The same imaging equipment should be used for all scans whenever 
possible.  The same radiologist should be assigned to read all the scans for a given subject 
throughout the study.  
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.  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. 
4.1.21 
Routine Clinical Assessments 
Routine clinical assessments include physical exams, recording of symptoms, and 
hematologic evaluations to evaluate for both AEs and assessment of disease progression 
at times when the CT and/or PET/CT scan is not obtained.  The investigator should report 
any suspected disease progression to the sponsor or designee via the electronic data 
capturing (EDC) system within 24 hours of discovery.   


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 49 
4.1.22 
Study Drug Accountability 
See Section 7.7. 
4.2 
INVESTIGATOR’S ASSESSMENT OF RESPONSE TO TREATMENT 
The investigator must rate the response of the subject’s response to treatment consistent 
with clinical guidelines (Cheson 2014) as listed in Table 4-2. 
 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 50 
Table 4-2.  Response Assessment Criteria for DLBCL (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 
 
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  
Footnotes appear after the last page of the table. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 51 
 
Table 4-2.  Response Assessment Criteria for DLBCL (Cheson 2014) (continued) 
Response and Site 
PET-CT-Based Response 
CT-Based Response 
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  
 
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, fluorodeoxyglucose; 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 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 52 
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 measureable 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 including disease progression.  Each subject 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 6.2.6) and to document the 
occurrence of any new events, unless the subject receives a new anticancer therapy within 
this timeframe.  Subjects who withdraw consent should still be encouraged to complete the 
safety follow-up assessments, 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 
TIME-TO-NEXT TREATMENT 
Subjects who discontinue study therapy will continue on study for follow-up of safety 
(Section 4.3) and time-to-next DLBCL therapy 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 the 
study and the reason for discontinuation will be recorded and also should be described on 
the appropriate electronic case report form (eCRF).   
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 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 53 
investigator’s opinion, medically unnecessary or unsafe because it is too close in time to 
the next scheduled evaluation.  In that case, the missed evaluation should be abandoned. 
5.0 
STATISTICAL METHODS OF ANALYSIS  
5.1 
GENERAL CONSIDERATIONS 
This proof-of-concept study is designed to assess the safety, PK/PD, and activity of 
acalabrutinib 100 mg BID in subjects with relapsed/refractory de novo ABC DLBCL. 
5.1.1 
Response Assessment 
Response assessments will be done by the investigators. 
5.1.2 
Safety Monitoring 
The safety plan includes quarterly conference calls between Acerta and investigators to 
discuss study-specific issues including adverse events and serious adverse events.   
5.2 
DEFINITION OF ANALYSIS SETS 
The following definitions will be used for the efficacy and safety analysis sets. 
Safety analysis set: All enrolled subjects who receive ≥ 1 dose of study drug. 
Per-protocol (PP) analysis set: All enrolled subjects who receive ≥ 1 dose of study 
drug, have sufficient baseline measurements, and undergo ≥ 1 assessment for the 
endpoint of interest (eg, response and PK/PD parameters) after treatment. 
Intent-to-treat (ITT) population: All subjects who have enrolled in the protocol. 
The safety analysis set will be used for evaluating the safety and efficacy, except duration 
of response, parameters in this study.  The PP and ITT analysis sets will be analyzed for 
efficacy and PK/PD parameters in this study. 
5.3 
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. 
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. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 54 
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.  
5.4 
DETERMINATION OF SAMPLE SIZE 
No formal statistical tests of hypotheses will be performed.  Descriptive statistics (including 
means, standard deviations, and medians for continuous variables and proportions for 
discrete variables) will be used to summarize data as appropriate. 
The trial design is specified because of its practical simplicity, use of a biomarker, and not 
because of power considerations.  The sample size of 20 subjects in a Phase 1b study is 
considered adequate to evaluate the initial safety, PK/PD, and activity of acalabrutinib in 
this patient population. 
5.5 
DATA ANALYSIS 
5.5.1 
Safety Parameters 
Safety summaries will include summaries in the form of tables and listings.  The frequency 
(number and percentage) of treatment emergent AEs will be reported in each treatment 
group by MedDRA System Organ Class and Preferred Term.  Summaries will also be 
presented by the severity of the AE (per CTCAE, v4.03) and by relationship to study drug. 
Laboratory shift tables containing counts and percentages will be prepared by treatment 
assignment, laboratory parameter, and time.  Summary tables will be prepared for each 
laboratory parameter.  Figures of changes in laboratory parameters over time will be 
generated. 
Results of vital sign assessments, ECGs, and physical exams will be tabulated and 
summarized.   
5.5.2 
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. 
5.5.3 
Study Treatment Administration and Compliance 
Descriptive information will be provided regarding the number of acalabrutinib doses 
prescribed, the total number of doses taken, the number of days of treatment, and the 
number and timing of prescribed dose reductions and interruptions.   


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 55 
For each patient, acalabrutinib compliance will be described in terms of the proportion of 
study drug actually taken based on returned pill count relative to the amount that was 
dispensed (taking into account physician-prescribed modifications and interruptions). 
5.5.4 
Analysis of Efficacy Parameters 
Response Rate 
The individual and composite endpoints of response and progression will be determined.  
Tumor control will be documented at each assessment by response category (eg, CR, PR, 
SD, PD) as defined for each response parameter, date that response is first documented, 
and date of DLBCL disease progression. 
Overall response rate will be defined as the proportion of subjects who achieve a CR or 
PR.  Overall response rate will be calculated and the corresponding 97.5% one-sided 
confidence interval will be derived. 
Duration of Response 
The duration of response (DOR) defined as the interval from the first documentation of CR 
or PR to the earlier of the first documentation of definitive disease progression or death 
from any cause.  Kaplan-Meier methods will be used to estimate event-free curves and 
corresponding quantiles (including the median).  Data from surviving, nonprogressing 
subjects will be censored at the earliest of the time of initiation of anticancer treatment other 
than the study treatment or the last time that lack of definitive DLBCL progression was 
objectively documented.  Data from subjects who have DLBCL progression or die after 
≥ 2 consecutive missing tumor assessments will be censored at the last time before the 
missing assessments that lack of DLBCL progression was objectively documented. 
Progression-free Survival 
Progression-free survival (PFS) is defined as the interval from the start of acalabrutinib 
therapy to the earlier of the first documentation of objective DLBCL disease progression or 
death from any cause.  Kaplan-Meier methods will be used to estimate the event-free 
curves and corresponding quantiles (including the median).  Data from surviving, 
non-progressing subjects will be censored at the earliest of the time of initiation of 
anticancer treatment other than the study treatment or the last time that lack of DLBCL 
progression was objectively documented.  Data from subjects who have DLBCL 
progression or die after ≥ 2 consecutive missing tumor assessments will be censored at the 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 56 
last time prior to the missing assessments that lack of FL progression was objectively 
documented. 
Time-to-Next Treatment 
Time-to-next treatment defined as the time from start of acalabrutinib therapy for DLBCL on 
this protocol to the start of the next treatment for DLBCL.  Kaplan-Meier methods will be 
used to estimate the event-free curves and corresponding quantiles (including the median).  
Data from subjects who have not received subsequent therapy for DLBCL will be censored 
at the earliest of death or the last time that lack of administration of a new therapy for 
DLBCL was objectively documented. 
5.5.5 
Analysis of Pharmacokinetic/Pharmacodynamic Parameters  
The plasma PK of acalabrutinib will be characterized using noncompartmental analysis.  
The following PK parameters will be calculated, whenever possible, from plasma 
concentrations of acalabrutinib: 
 
AUC0-t 
Area under the plasma concentration-time curve calculated using 
linear trapezoidal summation from time 0 to time t, 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-∞ 
Area under the plasma concentration-time curve from 0 to infinity, 
calculated using the formula: AUC0-∞ = AUC0-t + 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 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 57 
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.  P-values of 
 0.05 will be considered significant. 
5.5.6 
Explorative or Correlative Analyses 
Additional PK or PD analyses may be performed, as deemed appropriate. 
Correlations between subject characteristics and outcome measures and correlations 
among outcomes measures will be explored using regression models or other appropriate 
techniques. 
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). 
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 DLBCL that were not 
present before the AE reporting period (see Section 6.2.1) 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 58 
 
Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as biopsies) 
 
Preexisting 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) should 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. 
 
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 
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 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 59 
 
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 
 
6.1.4 
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 for reporting instructions), irrespective of 
regulatory seriousness criteria or causality: 
 
Ventricular arrhythmias (e.g., ventricular extrasystoles, ventricular tachycardia, 
ventricular arrhythmia, ventricular fibrillation) 
 
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/Product Compliant form (see Section 6.2.5). 
6.2.1 
Adverse Event Reporting Period 
After the signing of the ICF and prior to the first dose of study drug, all SAEs must be 
reported.  After the first dose of study drug, all AEs/SAEs, irrespective of attribution of 
causality, must be reported.  
All adverse events will be reported until 30 days after the last dose of study drug or the start 
of new anticancer therapy (whichever comes first).  After this period, investigators should 
report serious adverse events or other adverse events of concern that are believed to be 
related to prior treatment with study drug. 
All SAEs that occur during the reporting period should be followed to resolution or until the 
Investigator assesses the subject as stable or until the subject is lost to follow-up or 
withdraws consent.  Resolution/stable means the subject has returned to baseline state of 
health or the investigator does not expect any further improvement or worsening of the 
event. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 60 
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, or detected through physical 
examination, or other means will be recorded in the subject’s medical record and on the AE 
eCRF and, when applicable, on an SAE/Product Compliant form. 
Disease progression itself is not considered an AE; however, signs and symptoms of 
disease progression may be recorded as AEs or SAEs. 
Symptomatic deterioration may occur in some subjects.  Symptomatic deterioration is when 
progression is evident in the subject’s clinical symptoms and the investigator may elect not 
to perform further disease assessments. 
Each recorded AE or SAE will be described by its duration (ie, start and end dates), 
severity, regulatory seriousness criteria, if applicable, suspected relationship to the study 
drug (see following guidance), and any actions taken.  The relationship of AEs to the study 
drug will be assessed by means of the question: ‘Is there a reasonable possibility that the 
event may have been caused by the study drug?’  Answer Yes or No.  
See Appendix 3 for more detail on assessing relationship. 
6.2.3 
Second Primary Malignancies 
Adverse events (AEs) for malignant tumors reported during a study should generally be 
assessed as serious AEs (SAEs).  If no other seriousness criteria apply, the “Important 
Medical Event” criterion should be used.  In certain situations, however, medical judgment 
on an individual event basis should be applied to clarify that the malignant tumor event 
should be assessed and reported as a nonserious AE.  For example, if the tumor is 
included as medical history and progression occurs during the study but the progression 
does not change treatment and/or prognosis of the malignant tumor, the AE may not fulfill 
the attributes for being assessed as serious, although reporting of the progression of the 
malignant tumor as an AE is valid and should occur.  Also, some types of malignant 
tumors, which do not spread remotely after a routine treatment that does not require 
hospitalization, may be assessed as nonserious; examples in adults include Stage 1 basal 
cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 
The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (i.e., it is not the tumor for which entry into the study is a criterion and that 
is being treated by the investigational product [IP] under study and is not the development 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 61 
of new or progression of existing metastasis to the tumor under study).  Malignant tumors 
that—as part of normal, if rare, progression—undergo transformation (e.g., Richter's 
transformation of B cell chronic lymphocytic leukemia into diffuse large B cell lymphoma) 
should not be considered a new malignant tumor.   
6.2.4 
Pregnancy 
The investigator should report all pregnancies in study subjects and in the partners of 
subjects within 24 hours using the Pregnancy Report Form.  This form should be faxed or 
emailed to Acerta Pharma Drug Safety.  Any pregnancy-associated SAE must be reported 
using the SAE report form, according to the usual timelines and directions for SAE 
reporting (Section 6.2.5). 
Any uncomplicated pregnancy that occurs in a study subject or a partner of a treated 
subject during this study will be reported for tracking purposes only, if agreed to by the 
subject or the partner of the subject in this study.  All pregnancies and partner pregnancies 
that are identified during or after this study, wherein the estimated date of conception is 
determined to have occurred from the time of consent to 30 days after the last dose of 
study medication will be reported, followed to conclusion, and the outcome reported, as 
long as the subject or partner is willing to participate in follow-up. 
Pregnancy itself is not regarded as an AE unless there is suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive 
medication.  Likewise, elective abortions without complications are not considered AEs.  
Any SAEs associated with pregnancy (eg, congenital abnormalities/birth 
defects/spontaneous miscarriages or any other serious events) must additionally be 
reported as such using the SAE/Product Complaint form.  
Subjects should be instructed to immediately notify the investigator of any pregnancies.  
Any female subjects 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.   
6.2.5 
Expedited Reporting Requirements for Serious Adverse Events 
All SAEs must be reported within 24 hours of discovery.  All initial SAE/AESI reports and 
follow-up information will be reported using the protocol-specific electronic data capture 
system.  If electronic SAE/AESI reporting is not available, paper SAE/Product Complaint 
forms must be emailed or faxed to Acerta Pharma Drug Safety, or designee.  Acerta 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 62 
Pharma may request follow-up and other additional information from the investigator 
(eg, hospital admission/discharge notes and laboratory results).  
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself.  The primary cause of death on the 
autopsy report should be the term reported.  Autopsy and postmortem reports must be 
forwarded to Acerta Pharma Drug Safety, or designee, as outlined above. 
If study drug is discontinued because of an SAE/AESI, this information must be included in 
the SAE/AESI report. 
An SAE/AESI may qualify for mandatory expedited reporting to regulatory authorities if the 
SAE/AESI is attributable to the investigational product and is not listed in the current 
Investigator Brochure (ie, an unexpected event).  In this case, Acerta Pharma Drug 
Safety/Designee will forward a formal notification describing the SAE/AESI to all 
investigators.  Each investigator must then notify his or her IRB/IEC of the SAE/AESI. 
Drug Safety Contact Information 
Fax: 
Email: 
 
6.2.6 
Type and Duration of Follow-up of Subjects After Adverse Events 
All AEs and SAEs that are encountered during the protocol-specified AE reporting period 
should be followed to resolution, or until the investigator assesses the event as stable, a 
new anticancer therapy is initiated, or the subject is lost to follow-up or withdraws consent. 
6.2.7 
Hy’s Law 
Cases where a subject shows elevations in liver biochemistry may require further 
evaluation, and occurrences of AST or ALT ≥3×ULN together with total bilirubin ≥2×ULN 
may need to be reported as SAEs.  Refer to Appendix 5 for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s law. 
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 
PPD


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 63 
 
Significant or numerous deviations from study protocol requirements, such as failure 
to perform required evaluations on subjects and maintain adequate study records 
 
Inaccurate, incomplete, or late data recording on a recurrent basis 
 
The incidence and/or severity of AEs in this or other studies indicating a potential 
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 ICH Harmonized Tripartite Guidelines for Good Clinical Practices, applicable local 
regulations (including US Code of Federal Regulations Title 21 and European Directive 
2001/20/EC), and the ethical principles laid down in the Declaration of Helsinki. 
7.2 
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE 
The investigator will submit this protocol, the ICF, Investigator Brochure, and any other 
relevant supporting information (eg, all advertising materials) to the appropriate IRB/IEC for 
review and approval before study initiation.  A signed protocol approval page; a letter 
confirming IRB/IEC approval of the protocol and informed consent; and a statement that the 
IRB/IEC is organized and operates according to GCP and the applicable laws and 
regulations; must be forwarded to Acerta Pharma before screening subjects for the study.  
Additionally, sites must forward a signed FDA 1572 form (Statement of Investigator Form) 
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.  In the case of a subject who is incapable of providing 
informed consent, the investigator (or designee) must obtain a signed and dated informed 
consent form from the subject’s legal guardian.  Signed consent forms must remain in each 
subject’s study file and be available for verification by study monitors at any time. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 64 
In accordance with individual local and national patient privacy regulations, the investigator 
or designee must explain to each subject that for the evaluation of study results, the 
subject’s protected health information obtained during the study may be 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 within 5 days of 
each subject’s visit (unless required earlier for SAE reporting).  The investigator will ensure 
that source documents that are required to verify the validity and completeness of data 
transcribed on the eCRFs are never obliterated or destroyed, in accordance with the record 
retention policies described in Section 7.8. 
7.6 
STUDY MONITORING REQUIREMENTS 
Representatives of Acerta Pharma or its designee will monitor this study until completion.  
Monitoring will be conducted through personal visits with the investigator and site staff as 
well as any appropriate communications by mail, fax, email, or telephone.  The purpose of 
monitoring is to ensure compliance with the protocol and the quality and integrity of the 
data.  This study is also subject to reviews or audits by the sponsor, regulatory authorities, 
or ethics committees. 
Every effort will be made to maintain the anonymity and confidentiality of all subjects during 
this clinical study.  However, because of the experimental nature of this treatment, the 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 65 
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 permission form authorizing the use of protected health information. 
7.7 
INVESTIGATIONAL STUDY DRUG ACCOUNTABILITY 
Acalabrutinib capsules must be kept in a locked limited access room.  The study drug must 
not be used outside the context of the protocol.  Under no circumstances should the 
investigator or other site personnel supply acalabrutinib capsules to other investigators, 
subjects, or clinics or allow supplies to be used other than as directed by this protocol 
without prior authorization from Acerta Pharma. 
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 
Re-order Form (provided in the pharmacy binder) must also be included in the site’s drug 
accountability records.   
Contents of each shipment must be visually inspected to verify the quantity and document 
the condition of study drug capsules.  Then 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/emailing 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-002) 
2. 
subject identification number 
3. 
lot number(s) of acalabrutinib dispensed for that subject 
4. 
date and quantity of drug dispensed 
5. 
any unused drug returned by the subject 
 
At study initiation, the monitor will evaluate and approve the site’s procedure for 
investigational product disposal/destruction to ensure that it complies with Acerta Pharma’s 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 66 
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 FDA Form 1572, IRB/IEC approval letters, signed ICFs, 
drug accountability records, SAE forms transmitted to Acerta Pharma, subject files (source 
documentation) that substantiate entries in eCRFs, 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 
return to Acerta Pharma. 
Acerta Pharma must be notified in advance of, and Acerta Pharma must provide express 
written approval of, any change in the maintenance of the foregoing documents if the 
investigator wishes to move study records to another location or assign responsibility for 
record retention to another party.  If the investigator cannot guarantee the archiving 
requirements set forth herein at his or her study site for all such documents, special 
arrangements must be made between the investigator and Acerta Pharma to store such 
documents in sealed containers away from the study site so that they can be returned 
sealed to the investigator for audit purposes. 
7.9 
PROTOCOL AMENDMENTS 
Acerta Pharma will initiate any change to the protocol in a protocol amendment document.  
The amendment will be submitted to the IRB/IEC together with, if applicable, a revised 
model ICF.  If the change in any way increases the risk to the subject or changes the scope 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 67 
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 
Acerta Pharma may use the results of this clinical study in registration documents for 
regulatory authorities in the United States or abroad.  The results may also be used for 
papers, abstracts, posters or other material presented at scientific meetings or published in 
professional journals or as part of an academic thesis by an investigator.  The study is 
being conducted as part of a multicenter clinical trial.  Data from all study centers shall be 
pooled and analyzed for publication in a final report (Primary Publication).  The investigator 
agrees that the Primary Publication, which will be coordinated by Acerta Pharma, will be 
the first publication to present the pooled study results.  After the Primary Publication, or if 
the Primary Publication is not published within 1 year of termination of the study, the 
investigator may freely publish or present the results of his or her work conducted under the 
clinical trial agreement subject to providing Acerta Pharma with the opportunity to review 
the contents of any proposed presentation, abstract or publication about such work, 
including any results of this study, 90 days in advance of any presentation or submission 
for publication.  Within that 90-day period, Acerta Pharma may review the proposed 
publication to identify patentable subject matter and/or any inadvertent disclosure of its 
confidential information, which must be redacted from any final publication or presentation.  
If necessary, to permit the preparation and filing of patent applications, Acerta Pharma may 
elect an additional review period not to exceed 60 days. 
Authorship, in general, will follow the recommendations of the International Committee of 
Medical Journal Editors (International Committee of Medical Journal Editors 2014).   
7.11 CLINICAL 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. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 68 
7.12 GENERAL INVESTIGATOR RESPONSIBILITIES 
The principal investigator must ensure that: 
1. 
He or she will personally conduct or supervise the study. 
2. 
His or her staff and all persons who assist in the conduct of the study clearly 
understand their responsibilities and have their names included in the Study 
Personnel Responsibility/Signature Log. 
3. 
The study is conducted according to the protocol and all applicable regulations. 
4. 
The protection of each subject’s rights and welfare is maintained. 
5. 
Signed and dated informed consent and, when applicable, permission to use 
protected health information are obtained from each subject before conducting 
nonstandard of care study procedures.  If a subject or subject’s legal guardian 
withdraws permission to use protected health information, the investigator will obtain 
a written request from the subject or subject’s legal guardian and will ensure that no 
further data be collected from the subject. 
6. 
The consent process is conducted in compliance with all applicable regulations and 
privacy acts. 
7. 
The IRB/IEC complies with applicable regulations and conducts initial and ongoing 
reviews and approvals of the study. 
8. 
Any amendment to the protocol is submitted promptly to the IRB/IEC. 
9. 
Any significant protocol deviations are reported to Acerta Pharma and the IRB/IEC 
according to the guidelines at each study site. 
10. 
Electronic CRF pages are completed within 5 days of each subject’s visit (unless 
required earlier for SAE reporting). 
11. 
All IND Safety Reports/Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Reports are submitted promptly to the IRB/IEC. 
12. 
All SAEs are reported to Acerta Pharma Drug Safety/Designee within 24 hours of 
knowledge and to the IRB/IEC per their requirements. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 69 
8.0 
REFERENCES 
Bradshaw JM. The Src, Syk, and Tec family kinases: distinct types of molecular switches. 
Cell Signal 2010;22:1175-84.  
Buggy JJ, Elias L. Bruton tyrosine kinase (Btk) and its role in B-cell malignancy. Int Rev 
Immunol 2012;31:119-32. Erratum in: Int Rev Immunol 2012;31:428. 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol 2007;25:579-586. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification. J Clin Oncol 2014;32:3059-3067. 
Coiffier B, Lepage E, Briere J, et al.  CHOP chemotherapy plus rituximab compared with 
CHOP alone in elderly patients with diffuse large-B-cell lymphoma.  NEJM 2002;346:235-
242. 
Coiffier B, Thieblemont C, Van Den Neste E, et al.  Long-term outcome of patients in the 
LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP 
chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de 
l'Adulte.  Blood 2010;116:2040-2045. 
de Vos, S, Wilson W, Gerecitano J, et al.  The Bruton tyrosine kinase (Btk) inhibitor, 
ibrutinib (PCI-32765), has preferential activity in the activated B cell-like (ABC) subtype of 
relapse/refractory (R/R) DLBCL: interim Phase 2 results.  Haematologica 
2013:98(s1):S1180. 
Dyer M, Hutchinson C, Rule S, et al.  The Bruton’s tyrosine kinase (BTK) inhibitor 
ONO-4059: Single-agent activity in patients with relapsed and refractory non-GCB-DLBCL.  
J Clin Oncol 2014;32(5s):S8553. 
Fisher RI, Gaynor ER, Dahlberg S, et al.  Comparison of a standard regimen (CHOP) with 
three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma.  NEJM 
1993;328:1002-1006. 
Gardner HL, Harrington BK, Izumi R, et al.  ACP-196: A second generation Btk inhibitor 
demonstrates biologic activity in a canine model of B-cell non-Hodgkin lymphoma.  AACR 
2014 Annual Meeting Abstract #1744. 
Gisselbrecht C, Glass B, Mounier N, et al.  Salvage regimens with autologous 
transplantation for relapsed large B-cell lymphoma in the rituximab era.  JCO 
2010;28:4184-4190. 
Habermann TM, Weller EA, Morrison VA, et al.  Rituximab-CHOP versus CHOP alone or 
with maintenance rituximab in older patients with diffuse large B-cell lymphoma.  JCO 
2006;24:3121-3127. 
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. 
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals. 2014 Dec.  
Available from: http://www.ICMJE.org.  Accessed February 04, 2015. 
International Non-Hodgkin’s Lymphoma Prognostic Factors Project A predictive model for 
aggressive non-Hodgkin’s lymphoma. NEJM 1993;329:987-994. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 70 
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. 
Pfreundschuh M, Trümper L, Osterborg A, et al.  CHOP-like chemotherapy plus rituximab 
versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-
B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) 
Group.  Lancet Oncol 2006;7:379-391. 
Philip T, Gullielmi C, Hagenbeek A, et al.  Autologous bone marrow transplantation as 
compared with salvage chemotherapy in relapses of chemotherapy-sensitive 
non-Hodgkin's lymphoma.  NEJM 1995:333:1540-1545. 
Rosenwald A, Wright G, Chan WC, et al.  The use of molecular profiling to predict survival 
after chemotherapy for diffuse large-B-cell lymphoma. NEJM 2002;346:1937-1947. 
Smith, TJ, Khatcheressian J, Lyman GH, et al.  2006 update of recommendations for the 
use of white blood cell growth factors: an evidence based clinical practice guideline.  J Clin 
Oncol 2006;24:3187-3205. 
Vail DM, Thamm DH. Spontaneously occurring tumors in companion animals as models for 
drug development. In: Teicher BA, Anders PA, eds. Anticancer Drug Development Guide: 
Preclinical Screening, Clinical Trials, and Approval. 2nd Ed. Totowa, NJ: Human Press; 
2004:259-284. 
Vail DM, Michels GM, Khanna C, Selting KA, London CA; Veterinary Cooperative Oncology 
Group. Response evaluation criteria for peripheral nodal lymphoma in dogs (v1.0)—a 
Veterinary Cooperative Oncology Group (VCOG) consensus document. Vet Comp Oncol 
2010;8:28-37. 
Vihinen M, Mattsson PT, Smith CI. Bruton tyrosine kinase (Btk) in X-linked 
agammaglobulinemia (XLA). Front Biosci 2000;5:D917-D928. 
Ziepert M, Hasenclever D, Kuhnt E, et al.  Standard International Prognostic Index remains 
a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the 
rituximab era.  JCO 2010;28:2372-2380. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 71 
9.0 
APPENDICES 
 
 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 72 
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 August 23, 2013. 
 
 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 73 
Appendix 2.  Examples of Coadministered Drugs That Need Additional Consideration 
The lists of drugs in these tables are not exhaustive.  Any questions about drugs not on this 
list should be addressed to the medical monitor of this study. 
Strong Inhibitors of CYP3A 
Moderate Inhibitors of CYP3A 
boceprevir 
aprepitant 
clarithromycina 
cimetidine 
cobicistata 
ciprofloxacin 
conivaptana 
clotrimazole 
danoprevir and ritonavirb 
crizotinib 
diltiazema 
cyclosporine 
elvitegravir and ritonavirb 
dronedaronea 
grapefruit juice 
erythromycin 
idelalisib 
fluconazole 
indinavir and ritonavirb 
fluvoxamine 
itraconazolea 
imatinib 
ketoconazole 
tofisopam 
lopinavir and ritonavira,b 
verapamila 
nefazodone 
 
nelfinavira 
 
paritaprevir and ritonavir and (ombitasvir 
and/or dasabuvir)b 
 
posaconazole 
 
ritonavira, b 
 
saquinavir and ritonavira, b 
 
telaprevira 
 
tipranavir and ritonavira, b 
 
troleandomycin 
 
voriconazole 
 
a. 
Inhibitor of P-glycoprotein. 
b.  
Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in 
clinical practice. Caution should be used when extrapolating the observed effect of 
ritonavir alone to the effect of combination regimens on CYP3A activities. 
c.  
After discontinuation of the strong or moderate CYP3A inhibitor, wait 3 days before 
resuming ventoclax or acalabrutinib. 
 
Strong Inducers of CYP3A 
Moderate Inducers of CYP3A 
carbamazepine 
bosentan 
enzalutamide 
efavirenz 
mitotane 
etravirine 
phenytoin 
modafinil 
rifampin 
 
St. John’s worta 
 
a. 
The effect of St. John’s wort varies widely and is preparation-dependent. 
 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 74 
P-gp Inhibitors 
BCRP Inhibitors 
Narrow Therapeutic 
Index P-gp Substrates 
amiodarone 
curcumin 
digoxin 
carvedilol 
cyclosporine A 
everolimus 
clarithromycin 
eltrombopag 
sirolimus 
dronedarone 
 
 
itraconazole 
 
 
lapatinib 
 
 
lopinavir and ritonavir 
 
 
propafenone 
 
 
quinidine 
 
 
ranolazine 
 
 
ritonavir 
 
 
saquinavir and ritonavir 
 
 
telaprevir 
 
 
tipranavir and ritonavir 
 
 
verapamil 
 
 
Source:  FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers. Web link Accessed 18 July 2018: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
onsLabeling/ucm093664.htm#inVivo 
 
 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 75 
Appendix 3.  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 
 
 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
 
Confidential 
 
 
Page 76 
Appendix 4.  Schedule of Assessments 
 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycles 5-
12b 
ET/Safety 
Follow Upc 
LTFUs 
 
 
Days (± 2) 
Day(s) (±2) 
Day(s) (±2) Day(s) (±2) Day(s) (±2) 
 
1 
2 
8  
15  
22 
28  
15 
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 
 
ECOG status 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECGf 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Lab assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testg 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Hematologyh 
x 
xt 
 
x 
x  
x 
x 
x  
x 
x 
x 
x 
x 
 
 
Serum chemistryi 
x 
xt 
 
x 
x  
x 
x 
x  
x 
x 
x 
x 
x 
 
 
Urinalysisj 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T/B/NK/monocyte 
 
cell countk 
 
xv 
 
 
 
 
 
 
x 
 
 
Every 6 
mos 
 
 
 
Serum Igl 
 
xv 
 
 
 
 
 
 
x 
 
 
Every 6 
mos 
 
 
 
Bone marrow
 
(aspirate/biopsy)m 
x 
 
 
 
 
 
 
 
 
 
 
For CR 
only 
 
 
Hepatitis serologyu 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV PCRv 
 
 
 
 
 
 
x 
 
x 
x 
x 
QM 
 
QM 
 
Pharmacodynamicsn 
 
x 
x 
x 
 
 
x 
 
x 
 
 
 
x 
 
 
Pharmacokineticso 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
Archival tumor samplep 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acalabrutinib dispensedq 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Study drug compliance 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Tumor assessmentr 
x 
 
 
 
 
 
 
 
x 
 
x 
x 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Time-to-next treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Abbreviations: anti-HBc = hepatitis B core antibody; CR = complete remission; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ET = early 
termination; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; Ig = immunoglobulin; IVIG = 
intravenous immunoglobulins; LTFU = long-term follow-up; mos = months; PCR = polymerase chain reaction; PE = physical exam; QM = every month.  


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
 
Confidential 
 
 
Page 77 
Footnotes for ACE-LY-002 Schedule of Study Activities: 
a.  Screening tests should be performed within 21 days before the first administration of study drug, unless otherwise indicated. 
b. 
Any subjects who have not progressed while receiving study drug treatment, may be eligible to enroll into a long-term follow up study and continue to receive acalabrutinib. 
c. 
An early termination visit will be done for subjects who permanently discontinue study drug early for any reason. A 30-day (± 7 days) safety follow-up visit is required when 
subjects discontinue study drug unless they start another anticancer therapy within that 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, are done thereafter.   
e. 
Vital signs (blood pressure, pulse, respiratory 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.  If positive, pregnancy must be ruled out by ultrasound to be eligible. 
h. 
Cycle 1 Day 1 testing does not need to be repeated if screening hematology was done within 7 days of first dose of study drug.  Hematology includes complete blood count 
with differential and platelet counts. 
i. 
Cycle 1 Day 1 testing does not need to be repeated if screening serum chemistry was done within 7 days of first dose of study drug.  Serum chemistry: albumin, alkaline 
phosphatase, alanine transaminase (ALT), aspartate aminotransferase (AST), bicarbonate, blood urea nitrogen (BUN), calcium, chloride, creatinine, glucose, lactate 
dehydrogenase (LDH), magnesium, phosphate, potassium, sodium, total bilirubin, total protein, and uric acid.  
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 Cycle 5-12, only done end of Cycle 6 and 12. 
l.  
Serum immunoglobulin: IgG, IgM, IgA.  During Cycle 5-12, only done end of Cycle 6 and 12.  
m. A bone marrow aspirate and biopsy will be done at screening.  Subjects who have a bone marrow aspirate and biopsy result since completion of their last therapy for 
DLBCL may use those bone marrow results in lieu of the baseline bone marrow aspirate/biopsy required for this study provided the biopsy/aspirate was done within 60 days 
before the first dose of study drug.  Thereafter, bone marrow aspirate and biopsy will only be required to confirm any complete remission. 
n. 
Pharmacodynamic (PD) assessments will be done on subjects at sites in the United States. On Cycle 1 Day 1 AND Day 8 the PD samples are drawn predose and 4 hours 
(±10 minutes) postdose.  On Cycle 1 Day 2, Cycle 1 Day 28, and Cycle 2 Day 28, the PD samples are drawn up to 10 minutes predose (ie, the first dose of that day). At the 
Safety follow-up visit, a PD sample will be collected. Note: Timepoints are relative to the morning dose. 
o. 
Pharmacokinetic (PK) assessments will be done on subjects at sites in the United States. PK samples for Cycle 1 Day 1 are drawn predose and at 0.5, 1, 2, 4, 6 and 24 h 
(before first dose on Day 2) postdose. Samples for Cycle 1 Day 8 are drawn predose and at 0.5, 1, 2, 4, and 6 h postdose.  On Cycle 1 Day 15, 22, and 28, a PK sample is 
drawn predose and the second PK sample must be drawn 1 hour postdose. Note: Timepoints are relative to the morning dose. 
p. 
Available archival tumor tissue is required to be eligible for this study.  Either unstained slides (a minimum of 10 slides) or a paraffin block will be acceptable for central 
pathology review. 
q. 
Acalabrutinib:  For Cycle 1 Day 1, 2, 8, 15, 22, and 28 study drug (first dose of the day) is administered at the site.   
r. 
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 within 90 days before the first dose is also required. Information on extranodal 
involvement will also be recorded.  During treatment, CT scans with contrast (unless contraindicated) of the chest, abdomen, and pelvis and any other disease sites (eg, 
neck) will be done for tumor assessments at the end of Cycle 2 (± 7 days), Cycle 4 (± 7 days), and Cycle 6 (± 7 days); and then every 3 cycles (12 weeks, ± 7 days) 
thereafter or more frequently at investigator discretion.  At all other visits, tumor assessments will be done by physical exam and laboratory results.  Bone marrow and 
PET/CT are only required for confirmation of CR per clinical guidelines (see Section 4.2). At all other visits tumor assessments will be done by physical exam and laboratory 
results. 
s. 
Subjects who discontinue study therapy will continue on study for follow-up of safety and time-to-next therapy for DLBCL unless they withdraw consent for further follow-up. 
t. 
The indicated samples at this timepoint (Cycle 1 Day 1) must be drawn predose. 
u. 
Hepatitis serology must include hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (anti-HBc), and hepatitis C (HCV) 
antibody.  Subjects who are receiving prophylactic intravenous immunoglobulins (IVIG) and have positive HBsAg or anti-HBc must have negative hepatitis B DNA to be 
eligible.  In addition, any subjects testing positive for any hepatitis serology, must have polymerase chain reaction (PCR) testing (see exclusion criterion #13). 
v. 
Subjects who are anti-HBc positive (or have a known history of HBV infection) should be monitored monthly with a quantitative PCR test for HBV DNA.  Monthly monitoring 
should continue until 12 months after last dose of acalabrutinib.  Any subject with a rising viral load (above lower limit of detection) should discontinue acalabrutinib and 
have antiviral therapy instituted and a consultation with a physician with expertise in managing hepatitis B. 
 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 78 
Appendix 5.  Actions Required in Cases of Increases in Liver Biochemistry and Evaluation 
of Hy’s Law 
 
INTRODUCTION 
This Appendix describes the process to be followed to identify and appropriately report potential 
Hy’s law (PHL) cases and Hy’s law (HL) cases.  It is not intended to be a comprehensive guide to 
the management of elevated liver biochemistries.  
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a subject meets PHL criteria 
at any point during the study.  All sources of laboratory data are appropriate for the determination 
of PHL and HL events; this includes samples taken at scheduled study visits and other visits, 
including central and all local laboratory evaluations, even if collected outside of the study visits 
(e.g., PHL criteria could be met by an elevated ALT from a central laboratory and/or elevated total 
bilirubin from a local laboratory).  The investigator will also review adverse event (AE) data 
(e.g., for AEs that may indicate elevations in liver biochemistry) for possible PHL events. 
The investigator participates with the sponsor in the review and assessment of cases meeting PHL 
criteria to agree whether HL criteria are met.  HL criteria are met if there is no alternative 
explanation for the elevations in liver biochemistry other than drug-induced liver injury (DILI) 
caused by the investigational medicinal product (IMP).  The investigator is responsible for 
recording data pertaining to PHL/HL cases and for reporting AEs and serious adverse events 
(SAEs) according to the outcome of the review and assessment in line with standard 
safety-reporting processes.  
DEFINITIONS 
Potential Hy’s Law  
AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN at any point during the study after the 
start of study drug, irrespective of an increase in alkaline phosphatase.  
Hy’s Law 
AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN, where no reason other than the IMP 
can be found to explain the combination of increases (e.g., elevated alkaline phosphatase 
indicating cholestasis, viral hepatitis, or another drug).   
For PHL and HL, the elevation in transaminases must precede or be coincident with (i.e., on the 
same day) the elevation in total bilirubin, but there is no specified timeframe within which the 
elevations in transaminases and total bilirubin must occur. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 79 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
Laboratory data must be comprehensively reviewed by the investigator for each subject to identify 
laboratory values meeting the following criteria: 
 
ALT ≥3 x ULN 
 
AST ≥3 x ULN 
 
Total bilirubin ≥2 x ULN 
When the identification criteria are met from central or local laboratory results, the investigator will 
perform the following: 
 
Notify the sponsor representative/medical monitor by telephone and report the case as an 
SAE of Potential Hy’s law; seriousness criteria “Important medical event” and causality 
assessment “yes/related” or in accordance with the clinical study protocol as appropriate. 
 
Request a repeat of the test (new blood draw) without delay 
 
Complete the appropriate unscheduled laboratory electronic Case Report Form (eCRF) 
module(s)  
 
Perform follow-up on subsequent laboratory results according to the guidance provided in the 
clinical study protocol, as applicable 
 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
The instructions in this section should be followed by the investigator for all cases where PHL 
criteria are met. 
As soon as possible after the biochemistry abnormality is initially detected, the study medical 
monitor and the investigator will review available data, to agree whether there is an alternative 
explanation for meeting PHL criteria other than DILI caused by the IMP and to ensure that timely 
analysis and reporting to health authorities within 15 calendar days from the date PHL criteria were 
met.   
Where there is an agreed alternative explanation for the ALT or AST and total bilirubin elevations, 
a determination of whether the alternative explanation is an AE will be made and, subsequently, 
whether the AE meets the criteria for an SAE: 
 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF. 


Product: ACP-196 (acalabrutinib) 
Protocol: ACE-LY-002 
 
 
 
Acerta Pharma 
Confidential 
 
Page 80 
 
If the alternative explanation is an AE/SAE, update the previously submitted PHL SAE 
accordingly with the new information (reassessing event term, causality, and seriousness 
criteria) following the sponsor’s standard processes. 
If it is agreed that there is no explanation that would explain the ALT or AST and total bilirubin 
elevations other than the IMP, then: 
 
Send updated SAE (report term “Hy’s law”) according to the sponsor’s standard processes:  
o The “Medically Important” serious criterion should be used if no other serious criteria apply. 
o Because there is no alternative explanation for the HL case, a causality assessment of 
“related” should be assigned. 
If there is an unavoidable delay of over 15 calendar days in obtaining the information necessary to 
assess whether the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until an informed decision can be made: 
 
Provide any further update to the previously submitted SAE of PHL (report term now “Hy’s law 
case”), ensuring causality assessment is related to IMP and seriousness criteria are medically 
important, according to clinical study protocol process. 
 
Continue follow-up and review according to the agreed plan.  After the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met.  Update the previously submitted PHL SAE report following 
the clinical study protocol process, according to the outcome of the review. 
ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S LAW 
This section is applicable when a subject meets PHL criteria while receiving study treatment and 
has already met PHL criteria at a previous on-study treatment visit.  The requirement to conduct 
follow-up, review, and assessment of a repeat occurrence(s) of PHL is based on the nature of the 
alternative cause identified for the previous occurrence.   
 

SAP_001.pdf: 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 1 of 22 
 
Statistical Analysis Plan 
An Open-label, Phase 1b Study of ACP-196 in Subjects with Relapsed or 
Refractory de Novo Activated B-cell (ABC) Subtype of Diffuse Large B-Cell 
Lymphoma 
Protocol Number: ACE-LY-002 
Version: 
Version 2.0 
Date: 
20 March 2018 
Study Statistician: 
 
 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 2 of 22 
TABLE OF CONTENTS 
    
Table of Contents ............................................................................................................ 2 
Table of Abbreviations ..................................................................................................... 4 
1. 
INTRODUCTION .................................................................................................... 5 
2. 
OBJECTIVES ......................................................................................................... 5 
 
Primary Objective ........................................................................................... 5 
 
Secondary Objectives .................................................................................... 5 
3. 
STUDY OVERVIEW ............................................................................................... 5 
 
Study Design .................................................................................................. 5 
 
Sample Size ................................................................................................... 6 
4. 
STUDY ENDPOINTS .............................................................................................. 6 
 
Primary Endpoints .......................................................................................... 6 
 
Secondary Endpoints ..................................................................................... 6 
 
PK and PD Parameters .................................................................................. 7 
5. 
HYPOTHESES AND MULTIPLITCITY .................................................................... 7 
6. 
ANALYSIS SETS .................................................................................................... 7 
 
All-treated Population ..................................................................................... 7 
7. 
INTERIM ANALYSIS AND EARLY STOPPING GUIDELINES ................................ 7 
8. 
FINAL ANALYSIS AND CLINICAL STUDY REPORT ............................................. 7 
9. 
MISSING VALUES ................................................................................................. 7 
 
Missing Safety Data ....................................................................................... 8 
 
Missing Efficacy Data ..................................................................................... 8 
10. 
STATISTICAL METHODS OF ANALYSIS .............................................................. 8 
 General Principles .......................................................................................... 8 
 Subject Accountability .................................................................................... 8 
 Important Protocol Deviations ........................................................................ 9 
 Baseline Data ................................................................................................. 9 
 Demographics ................................................................................... 9 
 Baseline Characteristics .................................................................... 9 
 Baseline Disease Characteristics ...................................................... 9 
 Treatment and Medications .......................................................................... 10 
 Prior Anticancer Therapies .............................................................. 10 
 Prior and Concomitant Medications ................................................. 10 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 3 of 22 
 Exposure to Study Drug .................................................................. 11 
 Analyses of Safety Endpoints ....................................................................... 11 
 Treatment-Emergent Adverse Events (TEAEs) ............................... 11 
 Adverse Events of Clinical Interest .................................................. 12 
 Laboratory Test Results .................................................................. 12 
 Vital Signs ....................................................................................... 12 
 ECOG Performance Score .............................................................. 13 
 Electrocardiogram ........................................................................... 13 
 Analyses of Efficacy Endpoints .................................................................... 13 
 Definitions ....................................................................................... 13 
 Analysis Methods ............................................................................ 14 
11. 
CHANGE FROM PROTOCOL-SPECIFIED ANALYSES ....................................... 14 
12. 
LITERATURE CITATIONS / REFERENCES ........................................................ 14 
13. 
APPENDIX ........................................................................................................... 16 
 Definitions .................................................................................................... 16 
 Study Day ....................................................................................... 16 
 Baseline Value and Post-baseline Value ......................................... 16 
 Duration of Treatment and Time on Study ....................................... 16 
 Average Daily Dose and Relative Dose Intensity ............................. 16 
 Age ................................................................................................. 17 
 Year and Month ............................................................................... 17 
 Treatment-emergent Adverse Events .............................................. 17 
 International Prognostic Index (IPI) and Revised-IPI ....................... 17 
 Extranodal Disease and Bone Marrow Involvement at 
Baseline .......................................................................................... 17 
 Tumor Bulk at Baseline ................................................................... 18 
 Imputation Rules for Partial or Missing Dates ............................................... 18 
 Censoring Rules for Duration of Response .................................................. 20 
 Censoring Rules for Progression-Free Survival ............................................ 21 
 Censoring Rules for Time-to-Next Treatment ............................................... 22 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 4 of 22 
TABLE OF ABBREVIATIONS 
ABC                  activated B-cell  
AE(s) 
adverse event(s) 
BID 
twice per day 
BTK 
CI 
CR 
Bruton's tyrosine kinase 
confidence interval 
complete response 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLBCL 
DOR 
diffuse large B-cell lymphoma 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
IPD 
important protocol deviation 
IPI 
LHD 
MedDRA 
International prognostic index 
lactate dehydrogenase 
Medical Dictionary for Regulatory Activities 
NK 
NCI 
ORR 
natural killer 
National Cancer Institute 
overall response rate 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
PR 
pharmacokinetics 
partial response 
PT 
preferred term 
R-IPI 
R/R 
SAE(s) 
revised international prognostic index 
relapsed or refractory 
serious adverse event(s) 
SAP 
statistical analysis plan 
SD 
SD 
stable disease 
standard deviation 
SOC 
system organ class 
TEAE(s) 
treatment-emergent adverse events 
WHO 
World Health Organization 
 
 
 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 5 of 22 
1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide details of efficacy and 
safety analyses that have been outlined within protocol amendment 3 for study ACE-LY-
002, entitled “An Open-label, Phase 1b Study of ACP-196 in Subjects with Relapsed or 
Refractory de Novo Activated B-cell (ABC) Subtype of Diffuse Large B-Cell Lymphoma” 
dated January 13, 2016.  The original SAP based on same protocol was for interim 
safety clinical study report (CSR) to support the new drug application (NDA).  This SAP 
is updated to include efficacy analysis.  Any changes to the methods described in the 
final SAP will be documented in the clinical study report (CSR). 
Separate reports will be generated for pharmacokinetics (PK) and pharmacodynamics 
(PD) data. 
Hereafter, acalabrutinib (a generic name for ACP-196) will be used in place of ACP-196 
in this document. 
The analysis will be executed by the biometrics department of Acerta Pharma unless 
otherwise specified. 
2. 
OBJECTIVES 
 
Primary Objective 
• 
To characterize the safety profile of acalabrutinib in subjects with relapsed or 
refractory (R/R) ABC subtype of diffuse large B-cell lymphoma (DLBCL). 
 
Secondary Objectives 
• 
To characterize the PK profile of acalabrutinib. 
• 
To evaluate the PD effects of acalabrutinib. 
• 
To evaluate the activity of acalabrutinib as measured by response rate, duration 
of response (DOR), time-to-next treatment, and progression-free survival (PFS). 
3. 
STUDY OVERVIEW 
 
Study Design 
This study is a multicenter and open-label study.  Twenty subjects, 10 relapsed and 10 
refractory, will be enrolled and will take 100 mg of acalabrutinib twice per day (BID).  
Relapsed subjects will be defined as subjects who have had a partial response (PR) or 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 6 of 22 
better (Cheson 2014 or Cheson 2007 criteria) from the previous anticancer therapy and 
have now progressed.  Refractory subjects will be defined as subjects whose best 
response to the previous anticancer therapy was stable disease (SD) or who did not 
respond to therapy. 
Treatment with acalabrutinib may be continued until disease progression or an 
unacceptable drug-related toxicity occurs.  Tumor assessments will be performed at 8- 
to 12-week intervals during the trial.  All subjects who discontinue study drug will have a 
safety follow-up visit 30 (±7) days after the last dose of study drug unless they have 
started another cancer therapy within that timeframe.  
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 and monthly thereafter.  PK and PD testing will be done in Cycle 1 and 
Cycle 2.  Subjects showing clinical benefit and who are tolerating acalabrutinib may 
remain on study through the end of Cycle 12.  The end of trial is defined as the point 
when the last subject enrolled completes the end of Cycle 12 or withdraws for any 
reason and completes the 30-day follow-up visit (if applicable), whichever occurs first. 
 
Sample Size 
The trial design is specified because of its practical simplicity and use of a biomarker, 
rather than power considerations.  The sample size of 20 subjects in a Phase 1b study is 
considered adequate to evaluate the initial safety, PK/PD, and activity of acalabrutinib in 
this patient population. 
4. 
STUDY ENDPOINTS 
 
Primary Endpoints 
Primary endpoints are: 
• 
Frequency and severity of AEs/SAEs. 
• 
Frequency of AEs requiring discontinuation, dose delay or dose modification of 
study drug. 
 
Secondary Endpoints 
Secondary efficacy endpoints are: 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 7 of 22 
• 
Overall response rate (ORR) per Lugano criteria as assessed by investigator; 
• 
DOR per Lugano criteria as assessed by investigator; 
• 
PFS per Lugano criteria as assessed by investigator; 
• 
Time-to-next treatment per Lugano criteria as assessed by investigator. 
Secondary PK/PD endpoints are: 
• 
Plasma PK of acalabrutinib; 
• 
Occupancy of BTK by acalabrutinib in peripheral blood mononuclear cells; 
• 
The effect of acalabrutinib on biologic markers of B-cell function.  
 
PK and PD Parameters 
Refer to separate reports for PK and PD parameters. 
5. 
HYPOTHESES AND MULTIPLITCITY 
No formal statistical hypotheses will be tested.  The clinical hypotheses are that 
acalabrutinib monotherapy is safety and effective in subjects with R/R DLBCL. 
6. 
ANALYSIS SETS 
 
All-treated Population 
All-treated population is defined as all enrolled subjects who receive ≥ 1 dose of study 
drug. All-treated population will be used for evaluating the safety and efficacy unless 
otherwise specified. 
7. 
INTERIM ANALYSIS AND EARLY STOPPING GUIDELINES 
No formal interim analysis will be conducted.  
8. 
FINAL ANALYSIS AND CLINICAL STUDY REPORT 
The final analysis of primary and secondary efficacy endpoint will occur at the end of 
trial.  The end of trial is defined as when last patient enrolled completes the end of Cycle 
12, or withdraws for any reason and completes the 30-day follow-up visit, whichever 
occurs first.  The CSR will be written based on the final analysis.   
9. 
MISSING VALUES  


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 8 of 22 
 
Missing Safety Data  
Conservative imputation rules will be applied in handling partial or missing dates for AE 
onset and stop dates, start and end dates of concomitant medication, start date of 
subsequent anticancer therapy, date of initial diagnosis and death date.  If dates are 
completely missing, no imputation will be made.  The details of imputation algorithm for 
dates are included in Appendix 13.2. 
Missing safety data other than partial dates will not be imputed. 
 
Missing Efficacy Data 
The method of handing missing data and censoring data is described in the definition for 
each of the efficacy endpoints, mentioned at section 13.3, 13.4 and 13.5. 
10. 
STATISTICAL METHODS OF ANALYSIS 
 
General Principles 
Descriptive statistics will be used to summarize disposition, demographics, baseline 
characteristics, disease characteristics, prior anticancer therapy, concomitant 
medication, study drug administration, efficacy and safety outcomes.  Descriptive 
summary of discrete data will be present the sample size and incidence as frequency 
and percentage.  Descriptive summaries of continuous data will be present the sample 
size, group mean, standard deviation, median, and range. 
Confidence intervals (CIs), when presented, will generally be constructed at the 95% 
level.  For binomial variables, the exact method for CIs will be employed unless 
otherwise specified.  
Calculation of time to event or duration of event (e.g., DOR) will be based on actual 
study day of event rather than nominal visit date.  
 
Subject Accountability 
The number of subjects enrolled by site, country will be presented.  Subject disposition 
will be summarized for all enrolled subjects including the following information:  
• 
Subject status on study drug 
• 
Count and reason for study drug discontinuation 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 9 of 22 
• 
Subject status on the study 
• 
Count and reason for study termination 
• 
Time on study (months) 
 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined and managed by the study 
team during the IPD reviews throughout the study before database lock. These 
definitions of IPD categories, sub-category codes, and descriptions will be used during 
the study.  The final IPD list is used to produce the summary of IPDs table and the List of 
IPDs.  
 
Baseline Data 
 
Demographics 
• 
Age (year, continuous) 
• 
Age category (<65 vs. ≥65 years; <= 60 vs. >60 years) 
• 
Gender 
• 
Ethnicity 
• 
Race 
• 
Region (United States, United Kingdom) 
 
Baseline Characteristics  
• 
Eastern Cooperative Oncology Group (ECOG) performance score 
• 
Height (cm, continuous) 
• 
Weight (kg, continuous) 
 
Baseline Disease Characteristics 
• 
Time from initial diagnosis to the first dose of study drug (months, continuous) 
• 
Baseline B symptoms (weight loss, fever, night sweats) (yes, no) 
• 
Number of prior therapy regimens (1-2 vs. >=3 regimens; continuous) 
• 
Autologous stem cell transplant (yes) 
• 
Tumor bulk (<5 cm vs. ≥5 cm) 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 10 of 22 
• 
Bulky disease defined as tumor bulk ≥10 cm (yes, no) 
• 
Ann Arbor stage for lymphoma (stage I, II, III, IV; stage 1-II vs. III-IV) 
• 
Bone marrow involvement (yes, no) 
• 
Extranodal disease (yes, no) 
• 
Number of extranodal sites (0-1 vs. >=2) 
• 
Serum lactate dehydrogenase (LHD) (normal, above normal) 
• 
Baseline QTcF (mean, SD, median, min, max) 
• 
International Prognostic Index (IPI) (low, low-intermediate, high-intermediate, 
high) 
• 
Revised IPI (R-IPI) (very good, good, poor) 
 
Treatment and Medications 
 
Prior Anticancer Therapies  
A prior anticancer therapy is defined as a systemic therapy received by subjects, either 
as a single or combination therapy, for the treatment of DLBCL with a start or end date 
earlier than the date of first dose of study drug.  Therapies given as a consolidation or for 
maintenance of a response or remission will not be considered as a separate regimen.  
Preparatory regimen and transplant will not be considered as separate regimens.  Prior 
number of regimens for DLBCL is the total number of lines of therapy that a subject 
received for DLBCL before he/she entered this study.  The number of lines and type of 
prior therapy for DLBCL will be summarized. 
 
Prior and Concomitant Medications  
Data reported on concomitant medications CRF will be used.  Medications started or 
ended prior to the first dose of study drug will be considered as prior treatment.  
Concomitant medications are defined as all medications used on or after the first dose of 
study drug, through the treatment phase, and through 30 days following the last dose of 
study drug.  Using this definition, a medication can be classified as both prior and 
concomitant medication.  The start date and end date will be imputed based on the rules 
provided in Appendix 13.2.  Medications with completely missing start and stop dates will 
be considered as both prior and concomitant medications. 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 11 of 22 
Except for antineoplastic agents or other systemic therapies for DLBCL after enrollment, 
prior and concomitant medications will be summarized by the World Health Organization 
(WHO) Drug Dictionary therapeutic class and preferred term. 
 
Exposure to Study Drug 
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) will 
be used to summarize: 
• 
Duration of exposure (the interval (months) between first dose date and last dose 
date);  
• 
Actual cumulative dose administered (the total dose administered during the drug 
exposure period) 
• 
Average daily dose (the ratio of actual cumulative dose administered and 
duration of exposure) 
• 
Relative dose intensities (the ratio of actual cumulative dose to the planned 
cumulative dose through the drug exposure period)  
Dose withholding and dose deduction by dose change reasons will be summarized and 
presented as the number and percentage of subjects with non-missing data per 
category.  Dose withholding is defined as missing doses for ≥ 7 consecutive days.  Dose 
reduction is defined as taking lower dose level (100 mg per day) for ≥ 3 consecutive 
days. 
 
Analyses of Safety Endpoints  
 
Treatment-Emergent Adverse Events (TEAEs) 
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all AEs 
to a system organ class (SOC) and a preferred term (PT). The severity of AEs will be 
assessed and graded by the investigator by National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03 or higher.  Treatment 
related AEs are events assessed by investigator as related to study drug. 
Treatment-emergent AEs will be summarized by SOC and PT, and by CTCAE toxicity 
grade.  The drug-related AEs, serious adverse events (SAEs) and drug-related SAEs, 
AEs leading to treatment discontinuation, drug dose delay and dose modification will be 
summarized by PT and by CTCAE toxicity grade.  


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 12 of 22 
Death information is reported in the study exit CRF for all deaths.  Incidences of deaths 
are to be reported, along with the primary cause of death.  A summary table and a listing 
will be provided for death. 
 
Adverse Events of Clinical Interest 
Adverse events of clinical interest (ECI) corresponding search strategy are defined in 
section 8.5.1 of the SAP for acalabrutinib integrated summary of safety dated 
21March2017. 
Subject incidence of ECI will be summarized using the CTCAE Version 4.03 or higher. 
 
Laboratory Test Results 
Laboratory data for hematology, serum chemistry, serum immunoglobulin, and 
T/B/natural killer (NK) cell counts to 30 days after last dose of study drug or up to the 
safety follow-up visit date, whichever is later, will be summarized.  Applicable laboratory 
test results will be graded according to CTCAE Version 4.03 or higher.  Generic normal 
ranges specified in American Medical Association (AMA) Manual of Style 10th Edition 
(2017) will be applied whenever reference ranges are not available.  
Shift from baseline to worst grade during the treatment will be provided as shift tables for 
selected parameters.  Figures of selected parameter will be plotted overtime as 
appropriate.  
All-treated subjects with at least one post-baseline lab test result will be included in the 
tables. 
 
Vital Signs 
Vital signs include systolic blood pressure, diastolic blood pressure, pulse rate, body 
temperature and respiratory rate.  Summary statistics (mean, standard deviation, 
median, minimum and maximum) will be produced for vital signs at baseline, post-
baseline values from the last visit, minimum and maximum post-baseline values, and 
changes of these post-baseline values from baseline. 
All-treated subjects with at least one post-baseline lab test result will be included in the 
tables. 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 13 of 22 
 
ECOG Performance Score 
Shift of ECOG score from baseline to worst post-baseline score during the treatment will 
be provided as a shift table. 
 
Electrocardiogram 
ECG data is collected at screening.  The investigator assessment of clinical significance 
categorized as normal, abnormal but not clinically significant, and abnormal clinically 
significant, will be summarized.  The number of subjects with corrected QT interval 
(QTc) greater than 480 msec will also be provided.  A listing of subjects with abnormal 
and clinically significant baseline ECG results or QTc> 480 msec will be produced. 
 
Analyses of Efficacy Endpoints  
 
Definitions 
• 
Overall Response Rate (ORR) 
ORR is defined as the proportion of subjects who achieve a complete response (CR) or 
partial response (PR) per Lugano criteria as assessed by investigator. 
• 
Duration of Response (DOR) 
DOR is defined as the interval from the first documentation of CR or PR to the earlier of 
the first documentation of definitive DLBCL disease progression or death from any 
cause.  Subjects not meeting the criteria and alive by the analysis data cutoff date will be 
censored and the detail censoring rules for DOR are summarized in Appendix 13.3. 
• 
Progression-Free Survival (PFS) 
PFS is defined as the interval from the start of acalabrutinib therapy to the earlier of the 
first documentation of objective DLBCL disease progression or death from any cause.  
Subjects not meeting the criteria and alive by the analysis data cutoff date will be 
censored and the detail censoring rules for primary and sensitivity analyses of PFS are 
summarized Appendix 13.4. 
• 
Time-to-Next Treatment 
Time-to-next treatment is defined as the time from start of acalabrutinib therapy for 
DLBCL to the start of the next treatment for DLBCL.  Data from subjects who have not 
received subsequent therapy for DLBCL by the analysis data cutoff date will be 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 14 of 22 
censored and the detail of censoring rules for time-to-next treatment are summarized in 
Appendix13.5.  
 
Analysis Methods 
Efficacy analyses will be performed on the R/R cohorts and total.  The analysis of ORR, 
PFS, time-to-next treatment will be conducted on the all-treated population.  The 
analysis of DOR will be conducted on the subset of the all-treated population who 
achieve CR or PR as the best overall response. 
ORR and the corresponding 95% two-sided CI will be calculated using exact binomial 
distribution.  Descriptive statistics will be provided for best overall response.  The order 
of overall response category is: CR>PR>SD>PD.  The number and proportion of 
subjects within each category of overall response as well as the associated 95% CIs will 
be presented.  
The analysis of DOR, PFS, and time-to-next-treatment will be estimated using the 
Kaplan-Meier (KM) method.  KM estimates with 95% CIs will be calculated for event time 
quartiles, and event-free rates will be calculated at selected timepoints.  Given the small 
sample size, listings for DOR, PFS, and time-to-next treatment will be provided in lieu of 
summary statistics as approopriate, including the reason for censoring. 
11. 
CHANGE FROM PROTOCOL-SPECIFIED ANALYSES 
There is no major change from protocol-specified analyses for safety.  
12. 
LITERATURE CITATIONS / REFERENCES 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol 2007; 25:579-586. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification. J Clin Oncol 2014;32:3059-3067. 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0, USDHHS, NIH, 
NCI; publish date May 28, 2009 (v4.03: June 14, 2010). 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 15 of 22 
Laurie H. Sehn, Brian Berry, et al. The revised International Prognostic Index (R-IPI) is a 
better predictor of outcome than standard IPI for patients with diffuse large B-cell 
lymphoma. Blood, 1 March 2007;109:1857-1861. 
The American Medical Association (AMA) Manual of Style, SI Conversion Calculator,  
http://www.amamanualofstyle.com/page/si-conversion-calculator   
Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory 
mantle-cell lymphoma. N Engl J Med 2013 Aug 8;369(6):507-516. 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 16 of 22 
13. 
APPENDIX  
 
Definitions 
 
Study Day 
The study day will be calculated refer to the date of first dose of study drug.  Study day 1 
is defined as the date of first dose of acalabrutinib.  For assessments that occur on or 
after first dose date, study day is defined as (date of assessment – date of first dose + 
1).  For assessments that occur prior to first dose date, study day is defined as (date of 
assessment – date of first dose). 
 
Baseline Value and Post-baseline Value 
Unless otherwise specified, the baseline value is defined as the last measurement taken 
on or prior to the first dose of study drug. 
Change from baseline = Postbaseline Value −Baseline Value 
Percentage change from baseline = ൬Change from baseline
Baseline
൰× 100% 
 
Duration of Treatment and Time on Study 
Duration of treatment will be calculated from the date of the first dose of study drug to 
the date of the last dose of study drug: 
Duration of treatment = (last study drug date −frist study drug date) + 1 
Time on study will be calculated from the date of the first dose of study drug to the date 
of study exit or analysis data cut-off date, whichever is the earliest. 
Time on study = (study exit date or data cut date −first study medication date) + 1 
 
Average Daily Dose and Relative Dose Intensity 
Average daily dose (mg per day) = Total cumulative dose taken (mg)
Duration of treatment
 
and 
Relative dose intensity = ൬Total cumulative dose taken
Total expected dose
൰× 100% 
Where 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 17 of 22 
Total cumulative dose taken =
 sum of actual daily dose taken through the duration of treatment; 
Total expected dose =  duration of treatment × protocol assigned daily dose 
 
Age 
Age in years will be calculated at the date of enrollment. 
 
Year and Month 
One year equals to 365.25 days and 1 month equals to 30.4375 days.  
 
Treatment-emergent Adverse Events 
Treatment-emergent AEs are defined as those events with onset date (actual or imputed 
onset date) on or after the date of first dose of acalabrutinib, through the treatment 
phase to last dose of acalabrutinib, and within 30 days following the last dose of 
acalabrutinib. 
 
International Prognostic Index (IPI) and Revised-IPI 
The IPI will be derived based on baseline value of 5 prognostic risk: age greater than 60 
years; stage III or IV disease; elevated serum LDH; ECOG performance status of 2, 3, or 
4; more than 1 extranodal site.  One point is assigned for each of the above risk.  The 
sum of the points allotted correlates with the following risk groups: low risk (0-1 points); low-
intermediate risk (2 points); high-intermediate risk (3 points); high risk (4-5 points). 
The R-IPI is defined based on IPI as: very good (0 points); good (1, 2 points); poor (3,4,5 
points). 
 
Extranodal Disease and Bone Marrow Involvement at Baseline 
The data of extranodal sites of lymphoma is reported on Disease History CRF.  Subjects 
with any sites/extra nodal notations box checked other than ‘None’, ‘Spleen’ will be 
considered as having extranodal disease at baseline.   
Data reported on ‘Bone Marrow Biopsy and Aspirate’ CRF will be used to derive bone 
marrow involvement.  Subjects with bone marrow biopsy and aspirate result box 
checked ‘Not Involved’ at baseline based on any method of assessment will be 
considered to have no bone marrow involved at baseline.  Subjects with result box 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 18 of 22 
checked ‘involved’, ‘indeterminant’ or ‘other’ will be considered to have bone marrow 
involvement as a conservative approach.   
 
Tumor Bulk at Baseline 
Data reported on Lymph Node Assessment CRF will be used to derive tumor bulk.  
Tumor bulk is defined as the largest diameter of a lymph node by CT scan.  Bulky 
disease is defined as tumor bulk equal to or greater than 10.0 cm. 
 
Imputation Rules for Partial or Missing Dates 
Imputation of partial dates will be made for AE onset and stop dates, start and end dates 
of prior and concomitant medication, start date of subsequent anticancer therapy, date of 
initial diagnosis and death date.  If dates are completely missing, no imputation will be 
made.  For any partial date with missing year, no imputation will be made. 
The general rule for imputation is: 
• 
If only day is missing, then the 15th of the month will be used. 
• 
If only year is present, then June 30th will be used. 
If such imputation date for initial diagnosis is on or after date of first dose, the date of first 
dose – 1 will be used.  If such imputed date for subsequent anticancer therapies is 
before date of last dose, the date of last dose + 1 will be used.  
If the imputed date is for an AE start date and is in the same year and month as the first 
dose date but before the first dose date, the first dose date will be used, or if the imputed 
AE start date is after the AE end date, the AE end date will be used.  If the imputed date 
is for an AE start date and is in the same year and month as but after the last dose date 
+ 30 days, the last dose date + 30 days will be used.  
If the imputed date is for an AE end date and is after the death date, the date of death 
will be used, or if the imputed AE end date is before the AE start date, the AE start date 
will be used. 
If death year and month are available but day is missing: 
• 
If mmyyyy for last contact date = mmyyyy for death date, set death date to the 
day after the last contact date. 
• 
If mmyyyy for last contact date < mmyyyy for death date, set death date to the 
first day of the death month. 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 19 of 22 
• 
If mmyyyy for last contact date > mmyyyy for death date, data error and do not 
impute. 
If both month and day are missing for death date or a death date is totally missing, no 
imputation is made.  
 
 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 20 of 22 
 
Censoring Rules for Duration of Response 
Situation 
Outcome 
Event Description 
or 
Censoring Reason 
Last Analysis 
Date 
Documented disease 
progression before initiation of 
new anticancer therapy or 
on/before data cutoff date, 
whichever occurred first, also no 
more than 1 missing tumor 
assessments before 
documented disease 
progression 
 
Event 
Progressive 
Disease 
Earliest date of 
documented 
disease 
progression 
Death before initiation of new 
anticancer therapy or on/before 
data cutoff date, whichever 
occurred first, and no 
documented disease 
progression with >=2 
consecutive missing tumor 
assessment before death, also 
no more than 1 missing tumor 
assessments before death 
Event 
Death 
Date of Death 
New anticancer therapy 
Initiated before data cutoff date 
and before documented disease 
progression or death  
Censored 
New anti-cancer 
therapy 
Date of last 
adequate tumor 
assessment on or 
prior to initiation of 
new anticancer 
therapy 
New anti-cancer therapy 
before data cutoff date for 
subjects without documented 
disease progression or death  
Censored 
New anti-cancer 
therapy 
Date of last 
adequate tumor 
assessment on or 
prior to initiation of 
new anticancer 
therapy  
No documented disease 
progression, initiation of new 
anticancer therapy or death 
on/before data cutoff date 
Censored 
Data cutoff 
Date of last 
adequate tumor 
assessment on or 
before data cutoff 
date 
Documented disease 
progression or death after ≥ 2 
consecutive missing tumor 
assessments  
 
Censored  
Consecutive 
missing tumor 
assessments  
 
Date of last tumor 
assessment prior 
to the missing 
assessments that 
demonstrate lack 
of disease 
progression  
No post-baseline adequate 
disease assessments 
Censored  
No post-baseline 
adequate disease 
assessments 
Date of first dose 
of study drug 
No baseline disease 
assessments 
Censored  
No baseline 
disease 
assessment 
Date of first  
dose of study 
drug 


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 21 of 22 
 
Censoring Rules for Progression-Free Survival 
Situation 
Outcome 
Event 
Description or 
Censoring 
Reason 
Last Analysis 
Date 
Documented disease progression 
before initiation of new anticancer 
therapy or on/before data cutoff 
date, whichever occurred first, also 
no more than 1 missing tumor 
assessments before documented 
disease progression 
 
Event 
Progressive 
Disease 
Earliest date of 
documented 
disease 
progression 
Death before initiation of new 
anticancer therapy or on/before 
data cutoff date, whichever 
occurred first, and no documented 
disease progression with >=2 
consecutive missing tumor 
assessment before death, also no 
more than 1 missing tumor 
assessments before death 
Event 
Death 
Date of Death 
New anticancer therapy 
Initiated before data cutoff date and 
before documented disease 
progression or death  
Censored 
New anti-cancer 
therapy 
Date of last 
adequate tumor 
assessment on or 
prior to initiation 
of new anticancer 
therapy 
New anti-cancer therapy 
before data cutoff date for subjects 
without documented disease 
progression or death  
Censored 
New anti-cancer 
therapy 
Date of last 
adequate tumor 
assessment on or 
prior to initiation 
of new anticancer 
therapy  
No documented disease 
progression, initiation of new 
anticancer therapy or death 
on/before data cutoff date 
Censored 
Data cutoff 
Date of last 
adequate tumor 
assessment on or 
before data cutoff 
date 
Documented disease progression 
or death after ≥ 2 consecutive 
missing tumor assessments  
 
Censored  
Consecutive 
missing tumor 
assessments  
 
Date of last tumor 
assessment prior 
to the missing 
assessments that 
demonstrate lack 
of disease 
progression  
No post-baseline adequate disease 
assessments 
Censored  
No post-baseline 
adequate disease 
assessments 
Date of first dose 
of study drug 
No baseline disease assessments 
Censored  
No baseline 
disease 
assessment 
Date of first  
dose of study 
drug 
  


 
ACE-LY-002  
Statistical Analysis Plan                                    
Version 2.0 dated:  20 March 2018 
 
 
 
 
 
Acerta Pharma 
Confidential 
Page 22 of 22 
 
Censoring Rules for Time-to-Next Treatment  
Situation 
Outcome 
Event 
Description or 
Censoring 
Reason 
Last Analysis 
Date 
New anticancer therapy on or 
before data cutoff date 
Event 
new anticancer 
therapy 
Initiation of new 
anticancer 
therapy 
New anticancer therapy after data 
cutoff date 
Censored  
new anticancer 
therapy prior to 
cutoff date 
Data cutoff date 
No new anti-cancer therapy 
 
Censored 
No next treatment 
last time prior to 
the missing 
assessments that 
demonstrate lack 
of DLBCL 
progression