A Phase 1b/2 Proof-of-Concept Study of the Combination of ACP-196 (Acalabrutinib) and Pembrolizumab in Subjects With Hematologic Malignancies
Phase: PHASE1
Conditions: Follicular Lymphoma (FL), CLL, Small Lymphocytic Lymphoma (SLL), Richter's Syndrome, Mantle Cell Lymphoma (MCL), Indolent Non Hodgkin Lymphoma, Waldenström Macroglobulinemia, Multiple Myeloma, Hodgkin Lymphoma, Burkitt Lymphoma, Marginal Zone Lymphomas, Mediastinal Large B Cell Lymphoma, Hairy Cell Leukemia
Sponsor: Acerta Pharma BV

Product: Acalabrutinib (ACP-196) 
Protocol: ACE-LY-005 
 
 
 
Acerta Pharma 
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PROTOCOL 
TITLE: 
A Phase 1b/2 Proof-of-Concept Study of the Combination of 
ACP-196 and Pembrolizumab in Subjects with Hematologic 
Malignancies 
PROTOCOL NUMBER: 
ACE-LY-005 
STUDY DRUG: 
CALQUENCE® (acalabrutinib / ACP-196) and  
KEYTRUDA® (pembrolizumab) 
IND NUMBER: 
118717 
SPONSOR MEDICAL 
MONITOR: 
 
 
Phone:  
 
Email:  
 
SPONSOR: 
Acerta Pharma B.V. 
 
5349 AB Oss 
The Netherlands 
PROTOCOL DATE: 
Version 0.0 – 25 October 2014 
AMENDMENT 1: 
Version 1.0 – 14 August 2015 
AMENDMENT 2: 
Version 2.0 – 21 January 2016 
AMENDMENT 3: 
Version 3.0 – 23 May 2016 
AMENDMENT 4: 
Version 4.0 – 16 May 2017 
AMENDMENT 5: 
Version 5.0 – 30 May 2018 
AMENDMENT 6: 
Version 6.0 – 14 March 2019 
AMENDMENT 7: 
Version 7.0 – 18 February 2020 
 
Confidentiality Statement 
This document contains proprietary and confidential information of Acerta Pharma B.V. that 
must not be disclosed to anyone other than the recipient study staff and members of the 
institutional review board (IRB)/independent ethics committee (IEC).  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Acerta Pharma B.V.  
PPD
PPD
PPD
PPD
PPD

Product: Acalabrutinib (ACP-196) 
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PROTOCOL APPROVAL 
 
Version 7.0 
 
I have carefully read Protocol ACE-LY-005 entitled “A Phase 1b/2 Proof-of-Concept Study of 
the Combination of ACP-196 and Pembrolizumab in Subjects with Hematologic 
Malignancies” (Amendment 7.0, dated 18 February 2020).  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 IRB/ IEC must approve any changes to the protocol in writing before implementation. 
I agree not to divulge to anyone, either during or after the termination of the study, any 
confidential information acquired regarding the investigational product and processes or 
methods of Acerta Pharma.  All data pertaining to this study will be provided to Acerta 
Pharma.  The policy of Acerta Pharma 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 Signature 
 
 
Print Name of Principal Investigator 
 
Date (DD Month YYYY) 
 

Product: Acalabrutinib (ACP-196) 
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SUMMARY OF AMENDMENT 7 
This protocol has been amended to align with new safety language in the most current 
acalabrutinib Investigator Brochure, and to update the medical monitor.  Clarifying edits and 
typographical changes have been made throughout the protocol.  The following substantive 
changes were made as part of this amendment:  
Description of Change 
Sections 
Sponsor medical monitor was changed  
• 
TITLE page 
Current protocol number/version was updated to v7.0 
• 
Throughout 
CALQUENCE® marketing approval in the United States 
and other markets has been expanded to include treatment 
of chronic lymphocytic leukemia and small lymphocytic 
lymphoma.  
• 
Section 1.2 
Updated/added language regarding continued access to 
study treatment and details for transitioning subjects from 
Study ACE-LY-005 to a rollover study  
• 
Section 3.6 
Guidelines for use of CYP-inhibiting/inducing drugs 
updated to reflect new language added in Section 3.10 
• 
Section 3.9.2 
Details regarding concomitant use of strong CYP3A 
inducers/inhibitors were consolidated within Section 3.10.7 
(Guidelines for use of CYP-inhibiting/inducing drugs)  
• 
Section 3.9.4 
Language was updated and/or details were added to the 
following Warnings and Precautions for acalabrutinib:  
• 
Hemorrhage  
• 
Infections 
• 
Cytopenias 
• 
Second primary malignancies 
• 
Atrial fibrillation 
• 
Section 3.10.1.2 
Language was updated and/or details were added to the 
following Risks Associated with acalabrutinib:   
 
• 
Progressive multifocal leukoencephalopathy 
• 
Section 3.10.3 
• 
Hepatitis B reactivation  
• 
Section 3.10.5 
• 
Drug-drug interactions 
• 
Section 3.10.7 
Additional details were provided in the Guidance and 
Definitions related to highly effective methods of 
contraception.  
• 
Section 3.10.9.2 
Hepatitis testing language was updated to match 
Section 3.10.5 
• 
Section 4.1.14 
Language regarding the AE reporting period was updated 
to align with Acerta Pharma standard protocol language 
• 
Section 4.3 

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Description of Change 
Sections 
Language regarding the Adverse Event Reporting Period 
was updated to align with Acerta Pharma standard protocol 
language. 
• 
Section 6.2.1 
Second Primary Malignancies section added with reporting 
guidelines for AEs for malignant tumors; subsequent 
sections were renumbered 
• 
Section 6.2.3 
Appendix 7“Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law” was updated to 
align with Acerta Pharma standard protocol language. 
• 
Appendix 7 
 

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TABLE OF CONTENTS 
1.0 
BACKGROUND INFORMATION ................................................................. 29 
1.1 
A Case for Combination BTK and Checkpoint Blockade For Treatment of 
Hematologic Malignancies ........................................................................... 29 
1.2 
Acalabrutinib ................................................................................................ 31 
1.2.1 
Mechanism of Action ...................................................................... 32 
1.2.2 
Spontaneous Canine B-cell Lymphoma .......................................... 32 
1.2.3 
Acalabrutinib and Antibody-dependent Cell-mediated Cytotoxicity . 32 
1.2.4 
Acalabrutinib and Thrombus Formation .......................................... 33 
1.2.5 
Safety Pharmacology ...................................................................... 34 
1.2.6 
Drug-drug Interaction Potential ....................................................... 35 
1.2.7 
In Vivo General Toxicology ............................................................. 35 
1.3 
Pembrolizumab ............................................................................................ 36 
1.4 
Clinical Experience ....................................................................................... 36 
1.4.1 
Pharmacokinetics and Pharmacodynamics of Acalabrutinib .......... 36 
1.4.2 
Safety of Acalabrutinib .................................................................... 39 
1.4.2.1 
Safety of Acalabrutinib in Combination with Pembrolizumab 
for Subjects with B-Cell Malignancies (ACE-LY-005) .... 39 
1.4.3 
Efficacy of Acalabrutinib ................................................................. 41 
1.5 
Benefit/Risk of Acalabrutinib ........................................................................ 41 
2.0 
STUDY OBJECTIVES  ................................................................................ 41 
2.1 
Primary Objective ......................................................................................... 41 
2.2 
Secondary Objective .................................................................................... 41 
2.3 
Exploratory Objectives ................................................................................. 41 
3.0 
STUDY DESIGN .......................................................................................... 42 
3.1 
Study Parameters ........................................................................................ 47 
3.1.1 
Safety Parameters .......................................................................... 47 
3.1.2 
Pharmacodynamic and Biomarker Parameters .............................. 47 
3.1.3 
Efficacy Parameters ........................................................................ 47 
3.2 
Rationale for Study Design and Dosing Regimen ........................................ 48 
3.3 
Selection of Study Population ...................................................................... 50 
3.3.1 
Inclusion Criteria ............................................................................. 50 
3.3.2 
Exclusion Criteria ............................................................................ 53 
3.3.3 
Replacement of Subjects ................................................................ 56 
3.3.4 
Enrollment Procedures ................................................................... 56 
3.4 
Study Drugs ................................................................................................. 56 

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3.4.1 
Premedications ............................................................................... 56 
3.4.2 
Formulation, Packaging, and Storage ............................................. 57 
3.4.3 
Administration of Study Drug .......................................................... 57 
3.4.4 
Assuring Subject Compliance ......................................................... 58 
3.5 
Study Drug Dosing ....................................................................................... 59 
3.6 
Duration of Therapy ..................................................................................... 59 
3.7 
Assessment of Dose-Limiting Toxicity .......................................................... 60 
3.8 
Dosing Delays and Modifications ................................................................. 60 
3.8.1 
Dose Modifications for Acalabrutinib ............................................... 61 
3.8.2 
Dose Modifications and Toxicity Management for Immune-
Related AEs Associated with Pembrolizumab ................................ 62 
3.8.3 
Supportive Care Guidelines for Pembrolizumab ............................. 66 
3.9 
Concomitant Therapy ................................................................................... 70 
3.9.1 
Permitted Concomitant Therapy ..................................................... 70 
3.9.2 
Guidelines for Use of CYP Inhibiting/Inducing Drugs...................... 71 
3.9.3 
Guideline for Use of Drugs that Affect Gastric pH .......................... 71 
3.9.4 
Prohibited or Restricted Concomitant Therapy ............................... 72 
3.10 
Risks Associated with Study Treatment ....................................................... 72 
3.10.1 Risks Associated with Acalabrutinib ............................................... 72 
3.10.1.1 Contraindications ............................................................. 72 
3.10.1.2 Warnings and Precautions ............................................... 72 
3.10.2 Risks Associated with Pembrolizumab ........................................... 74 
3.10.2.1 Contraindications ............................................................. 74 
3.10.2.2 Warnings and Precautions ............................................... 74 
3.10.3 Progressive Multifocal Leukoencephalopathy ................................. 77 
3.10.4 Transaminase Elevations for Acalabrutinib in Combination with 
Pembrolizumab ............................................................................... 77 
3.10.5 Hepatitis B Reactivation .................................................................. 77 
3.10.6 Dietary Restrictions ......................................................................... 78 
3.10.7 Drug-Drug Interactions ................................................................... 78 
3.10.8 Surgery ........................................................................................... 79 
3.10.9 Reproductive Toxicity ..................................................................... 79 
3.10.9.1 Reproductive Toxicity Summaries for Study Drugs .......... 79 
3.10.9.2 Guidance and Definitions ................................................. 80 
3.10.10 Overdose Instructions ..................................................................... 82 
3.11 
Withdrawal of Subjects From Study Treatment ............................................ 83 
3.12 
Reasons for Study Exit ................................................................................. 83 
3.13 
Data and Safety Monitoring .......................................................................... 83 

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4.0 
STUDY ACTIVITIES AND ASSESSMENTS ...............................................  84 
4.1 
Description of Procedures ............................................................................ 84 
4.1.1 
Informed Consent ........................................................................... 84 
4.1.2 
Medical History ............................................................................... 84 
4.1.3 
Adverse Events............................................................................... 85 
4.1.4 
Concomitant Medications and Therapy .......................................... 85 
4.1.5 
Confirmation of Eligibility ................................................................ 85 
4.1.6 
ECOG Performance Status ............................................................ 85 
4.1.7 
Physical Examination, Vital Signs, Height, and Weight .................. 85 
4.1.8 
Bone Marrow Aspirate and Biopsy.................................................. 86 
4.1.9 
Electrocardiogram ........................................................................... 86 
4.1.10 Urine or Serum Pregnancy Test ..................................................... 86 
4.1.11 Hematology .................................................................................... 86 
4.1.12 Serum Chemistry ............................................................................ 87 
4.1.13 Thyroid Panel ................................................................................. 87 
4.1.14 Hepatitis B and C Testing ............................................................... 87 
4.1.15 Urinalysis ........................................................................................ 88 
4.1.16 T/B/NK Cell Count .......................................................................... 88 
4.1.17 Serum Immunoglobulin ................................................................... 88 
4.1.18 Disease Markers for Subjects with MM, WM, and MF .................... 88 
4.1.19 Skeletal Survey for MM Subjects .................................................... 89 
4.1.20 Pharmacodynamics and Biomarker Studies ................................... 89 
4.1.21 
 ....................................................................... 89 
4.1.22 Follow-up Post Allogenic Stem Cell Transplant .............................. 92 
4.1.23 Myeloproliferative Neoplasm Symptom Assessment Form Total 
Symptom Score .............................................................................. 92 
4.1.24 Early Termination Visit .................................................................... 92 
4.1.25 Study Drug Accountability ............................................................... 92 
4.2 
Investigator’s Assessment of Response to Treatment ................................. 92 
4.3 
Safety Follow-up Visit ................................................................................. 103 
4.4 
Time-to-Next Treatment and Survival ........................................................ 104 
4.5 
Missed Evaluations .................................................................................... 104 
5.0 
STATISTICAL METHODS OF ANALYSIS ................................................ 104 
5.1 
General Considerations ............................................................................. 104 
5.2 
Sample Size Justification ........................................................................... 104 
5.3 
Definition of Analysis Populations .............................................................. 107 
5.4 
Missing Data Handling ............................................................................... 108 
CCI

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5.5 
Endpoint Data Analysis .............................................................................. 108 
5.5.1 
Safety Endpoint ............................................................................ 108 
5.5.2 
Demographics and Baseline Characteristics ................................ 108 
5.5.3 
Study Treatment Administration and Compliance ......................... 109 
5.5.4 
Analysis of Efficacy Parameters ................................................... 109 
5.5.5 
PD or Biomarker Analyses ............................................................ 110 
6.0 
ASSESSMENT OF SAFETY ..................................................................... 110 
6.1 
Definitions .................................................................................................. 111 
6.1.1 
Adverse Events............................................................................. 111 
6.1.2 
Serious Adverse Events ............................................................... 112 
6.1.3 
Severity ......................................................................................... 113 
6.2 
Documenting and Reporting of Adverse and Serious Adverse Events ...... 113 
6.2.1 
Adverse Event Reporting Period .................................................. 114 
6.2.2 
Assessment of Adverse Events .................................................... 114 
6.2.3 
Second Primary Malignancies ...................................................... 115 
6.2.4 
Pregnancy .................................................................................... 115 
6.2.5 
Expedited Reporting Requirements for Serious Adverse Events .. 116 
6.2.6 
Reporting Events of Clinical Interest ............................................. 117 
6.2.7 
Type and Duration of Follow-up of Subjects after Adverse Events118 
6.2.8 
Other Safety Issues Requiring Expedited Reporting..................... 118 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ......... 118 
7.1 
Institutional Review Board and Independent Ethics Committee ................. 119 
7.2 
Informed Consent and Protected Subject Health Information Authorization119 
7.3 
Subject Screening Log ............................................................................... 120 
7.4 
Case Report Forms .................................................................................... 120 
7.5 
Study Monitoring Requirements ................................................................. 120 
7.6 
Investigational Study Drug Accountability .................................................. 121 
7.7 
Record Retention ....................................................................................... 122 
7.8 
Protocol Amendments ................................................................................ 122 
7.9 
Publication of Study Results ....................................................................... 123 
7.10 
Clinical Trial Insurance ............................................................................... 123 
7.11 
General Investigator Responsibilities ......................................................... 123 
8.0 
REFERENCES ........................................................................................... 125 
9.0 
APPENDICES ............................................................................................ 128 

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IN–TEXT TABLES 
 
Table 1 
Pembrolizumab Clinical Supplies ......................................................................57 
Table 2 
Drug Discontinuation Actions for Acalabrutinib .................................................61 
Table 3 
Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab ................................................................63 
Table 4 
Infusion Reaction Treatment Guidelines a .........................................................69 
Table 5 
Response Assessment Criteria for Lymphoma .................................................93 
Table 6 
Response Assessment Criteria for CLL/SLL .....................................................96 
Table 7 
Response Assessment Criteria for WM ............................................................98 
Table 8 
Response Criteria for MM (incorporating EBMT and IMWG) .............................99 
Table 9 
Response Assessment Criteria for MF ............................................................ 101 
Table 10 
Two-Sided Exact 90% CIs for Response Rate in Initial Group in Part 3 
(N=12) ............................................................................................................ 105 
Table 11 
Two-Sided Exact 90% CIs for Response Rate in Expansion Cohorts in 
Part 2 and Part 3 (N=30) ................................................................................. 107 
Table 12 
Acerta Pharma Drug Safety Contact Information ............................................ 117 
Table 13 
Laboratory Tests to Aid in Assessing Potential Hy’s Law / Hy’s Law ............... 144 
 
IN–TEXT FIGURES 
 
Figure 1 
Acalabrutinib Enhances the Antitumor Effects of α-PD-L1 in the Orthotopic 
CT26 Colon Cancer Model ...............................................................................31 
Figure 2 
NK Cell Natural Cytotoxicity ..............................................................................33 
Figure 3 
In Vivo Thrombus Formation .............................................................................34 
Figure 4 
Study Schema ..................................................................................................46 
 

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ABBREVIATIONS  
Term 
Definition 
5PS 
5-point scale 
ABC 
activated B-cell 
ACP-196 
acalabrutinib 
ADCC 
antibody-dependent cellular cytotoxicity 
AE 
adverse event 
ALC 
absolute lymphocyte count 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
anti-HBc 
hepatitis B core antibody 
anti-HBs 
hepatitis B surface antibody 
AST 
aspartate aminotransferase 
ASXL1 
Additional Sex Combs-Like 1 
AUC 
area under the curve 
AUC0-last 
area under the concentration-time curve, from time 0 to last quantifiable 
concentration 
AUC0-inf 
area under the concentration-time curve, from time 0 to infinity 
AUC0-24 
area under the concentration-time curve, from time 0 to 24-hour timepoint 
AUC0-12 
area under the concentration-time curve, from time 0 to 12-hour timepoint 
BID 
twice per day (dosing) 
BTK 
Bruton tyrosine kinase 
BUN 
blood urea nitrogen 
CAL-R 
calreticulin 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
CI 
confidence interval, or clinical improvement (response) 
CL/F 
oral clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CR 
complete remission (response) 
CRF 
case report form 
CRi 
CR with incomplete blood count recovery 
CSSF 
Clinical Supplies Shipping Receipt Form 

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Term 
Definition 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated antigen-4 
CYP 
cytochrome P450 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
EBMT 
European Group for Blood and Marrow Transplant 
EC50 
concentration of a drug that gives half-maximal response 
ECG 
electrocardiogram 
ECI 
event of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EFD 
embryofetal development  
EGFR 
epidermal growth factor receptor 
EMH 
extramedullary hematopoiesis 
FDA 
Food and Drug Administration 
FDG 
[18F]fluorodeoxyglucose 
FL 
follicular lymphoma 
FLC 
free light chains 
FSH 
follicle stimulating hormone 
GCB 
germinal center B-cell 
GCP 
Good Clinical Practices 
GI 
gastrointestinal  
GLP 
Good Laboratory Practices 
GVHD 
graft-versus-host disease 
Hb 
hemoglobin 
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 
HL 
Hy’s law 
HSCT 
hematopoietic stem cell transplantation 
IB 
Investigator Brochure 
ICF 
informed consent form 
IC50 
half-maximal inhibitory concentration  

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Term 
Definition 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IHC 
immunohistochemistry 
IMWG 
International Myeloma Working Group 
IMP 
investigational medicinal product 
iNHL 
indolent non-Hodgkin lymphoma 
irAE 
immune-related adverse event 
ITK 
interleukin-2-inducible kinase 
IUD 
intrauterine device 
IV 
intravenous 
IVIG 
intravenous immunoglobulins 
IRB 
Institutional Review Board 
JAK2 
Janus kinase 2 
LCM 
left costal margin 
LDH 
lactate dehydrogenase 
LDi 
longest transverse diameter of a lesion 
LFT 
liver function test 
mAb 
monoclonal antibody 
MCL 
mantle cell lymphoma 
 
 
MM 
multiple myeloma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
myelofibrosis 
MPD 
myeloproliferative disease 
MPN-SAF TSS 
Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom 
Score 
MR 
minor response 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
nCR 
near complete response  
NHL 
non-Hodgkin lymphoma 
NK 
natural killer (cells) 
NOAEL 
no observable adverse effect level 
non-GCB 
non-germinal center B-cell 
nPR 
nodular remission 
NSAIDS 
nonsteroidal anti-inflammatory drugs 
CCI
CCI

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Term 
Definition 
ORR 
overall response rate 
 
 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics or progressive disease 
PD-1 
programmed death-1 (receptor) 
PD-L1 
programmed death ligand-1 
PET 
positron-emission topography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetics 
PML 
progressive multifocal leukoencephalopathy 
PO 
per os (oral) 
PHL 
potential Hy’s law 
PPD 
cross product of the LDi and perpendicular diameter 
PR 
partial remission (response) 
PRL 
partial remission (response) and lymphocytosis 
Q3W 
every 3 weeks 
QD 
once per day (dosing) 
QM 
every month 
QTc 
corrected QT interval 
R/R 
relapsed/refractory 
RS 
Richter’s syndrome 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sCR 
stringent complete remission (response) 
SCT 
stem cell transplant 
SFLC 
serum-free light chains 
SDi 
shortest axis perpendicular to the LDi 
SD 
stable disease or standard deviation 
SIFE 
serum immunofixation electrophoresis  
SLL 
small lymphocytic lymphoma 
SPD 
sum of the product of the diameters 
SPEP 
serum protein electrophoresis  
SUSAR 
Suspected Unexpected Serious Adverse Reaction (report) 
t½ 
terminal elimination half-life 
CCI
CCI

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Term 
Definition 
T3 
triiodothyronine 
T4 
free thyroxine  
T1DM 
Type 1 diabetes mellitus 
Tmax 
time to maximum drug concentration 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
UIFE 
urine immunofixation electrophoresis  
UNL 
upper normal limit 
UPEP 
urine serum protein electrophoresis  
VGPR 
very good partial response 
Vz/F 
volume of distribution values 
WBC 
white blood cell (count) 
WHO 
World Health Organization 
WM 
Waldenström macroglobulinemia 
WOCBP 
women of childbearing potential 
 
 
 

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STUDY SYNOPSIS 
Protocol Number: 
ACE-LY-005 
Study Drugs: 
CALQUENCE®/acalabrutinib (also known as ACP-196) 
KEYTRUDA® (pembrolizumab) 
Protocol Title: 
A Phase 1b/2 Proof-of-Concept Study of the Combination of 
ACP-196 and Pembrolizumab in Subjects with Hematologic 
Malignancies 
Phase: 
Phase 1b/2 
Comparator: 
None 
Background and 
Rationale for Study 
Decades of research across various oncologic diseases support the 
fact that multidrug regimens produce higher and more durable 
complete response (CR) rates than single-agent chemotherapy.  
However, these benefits are often outweighed with the increased 
toxicity associated with multidrug regimens.  The high risk:benefit 
ratio of multidrug regimens means these regimens are less likely to 
be used in elderly patients or patients with comorbid conditions.  The 
advent of highly selective, targeted agents to treat cancer, such as 
Bruton tyrosine kinase (BTK) inhibitors, has changed the risk:benefit 
paradigm traditionally associated with chemotherapy agents.   
However, the proportion of patients with CR when treated with single-
agent BTK inhibitors is low compared with traditional 
polychemotherapy or chemoimmunotherapy.  Also, in more 
aggressive histologies, the median duration of response can be brief 
(<12 months).  The question remains as to whether “targeted 
combination” therapy can produce more durable responses and 
potentially more CRs than single agents without an associated 
increase in toxicity.   
Acerta Pharma, B.V. is developing acalabrutinib as a 2nd generation, 
orally administered, small-molecule inhibitor of BTK.  Preclinical data 
indicate that acalabrutinib may offer greater potency, improved 
selectivity, better pharmaceutical properties, and less potential for 
drug-drug interactions than the 1st generation compound, ibrutinib 
(IMBRUVICA®).  Acalabrutinib has shown clinical activity in an 
ongoing Phase 1/2 study in subjects with chronic lymphocytic 
leukemia (CLL) (NCT02029443). 
Improved understanding of the molecular mechanisms governing the 
host response to tumors has led to the identification of checkpoint 
signaling pathways involved in limiting the anticancer immune 
response.  A critical checkpoint pathway responsible for mediating 
tumor-induced immune suppression is the programmed death-1 

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(PD-1) pathway (McDermott and Atkins 2013).  This proof-of-concept 
study will assess the clinical potential of combined BTK inhibition and 
checkpoint blockade by evaluating the safety, pharmacodynamics 
(PD), and efficacy of acalabrutinib and pembrolizumab in hematologic 
malignancies.   
To determine whether there is potential synergy between BTK 
inhibition and PD-1 blockade, Acerta has conducted a nonclinical 
study of acalabrutinib in combination with an anti-PD ligand 1 (anti-
PD-L1) antibody in an orthotopic colon cancer murine model.  
Treatment with anti-PD-L1 as a single agent reduced tumor growth, 
but tumor regression was not observed.  However, combined anti-
PD-L1 and acalabrutinib treatment showed a further reduction in 
tumor growth and 6 of 9 animals displayed tumor regression (see 
Figure 1). These results suggest the combination therapy of BTK 
inhibition, and PD-1 blockade leads to greater benefit compared with 
PD-1 blockade alone. 
Study Design: 
This is a Phase 1b/2, open-label, nonrandomized study that will be 
conducted in 2 stages.  In the first stage, Part 1 of the study will 
determine the safety and preliminary efficacy of acalabrutinib and 
pembrolizumab in a limited group of B-cell malignancies.  In the 
second stage, Part 2 allows for possible expansion cohorts into a 
wider range of B-cell malignancies, and Part 3 (enrolled concurrently 
with Part 2) will evaluate the combination in subjects with 
myelofibrosis (MF). 
Part 1 
Six subjects will be enrolled to receive acalabrutinib in combination 
with pembrolizumab.  If the combination is safe with ≤1 dose-limiting 
toxicity (DLT) (6-week observation period) in the first 6 subjects, the 
cohort will be expanded to up to 24 subjects to obtain additional 
safety information and to assess the efficacy of the combination.   
Part 1 of the study will include adult subjects with the following 
disease types: 
• 
Non-germinal center B-cell (non-GCB) diffuse large B-cell 
lymphoma (DLBCL) 
• 
Follicular lymphoma (FL) 
• 
CLL/small lymphocytic lymphoma (SLL) 
Part 2 
Part 2 will consist of expansion groups of up to 30 subjects per 
histology provided the safety and efficacy results from Part 1 of the 
study indicate that further evaluation of the combination is warranted.  

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The possible expansion groups for Part 2 may include adult subjects 
with the following disease types: 
• 
Non-GCB DLBCL 
• 
Germinal center B-cell (GCB) DLBCL 
• 
Richter’s syndrome (RS)  
• 
Mantle cell lymphoma (MCL) 
• 
Indolent non-Hodgkin lymphoma (iNHL) 
o FL 
o Waldenström macroglobulinemia (WM) 
o CLL/SLL 
• 
Multiple myeloma (MM) 
• 
Other B-cell malignancy (including but not limited to: Hodgkin’s 
lymphoma, Burkitt lymphoma, marginal zone lymphomas, 
mediastinal large B-cell lymphoma, and hairy cell leukemia) 
Under Amendment 3 of this protocol, subjects with MCL or iNHL 
(including FL, WM, and CLL/SLL) are no longer enrolled.   
Under Amendment 4 of this protocol, subjects with RS are no longer 
enrolled. 
Part 3 
Part 3 includes up to 30 subjects with primary MF, post-polycythemia 
vera MF, or post-essential thrombocythemia MF with 
thrombocytopenia or anemia.  Part 3 will run in parallel with Part 2.  
Subjects with MF will receive a run-in of 6 weeks of acalabrutinib 
alone.  Subjects who are demonstrating a clinically meaningful 
response, in the opinion of the investigator, may continue on 
acalabrutinib monotherapy; those who are not will receive 
combination therapy with acalabrutinib and pembrolizumab.   
In Part 3, safety and response data will be reviewed after the initial 
12 subjects have completed 24 weeks of treatment (i.e., the Week 25 
visit) or have discontinued treatment before Week 25.  The first 
12 subjects will be evaluated regardless of the length of treatment 
with acalabrutinib alone or in combination with pembrolizumab.  If 
<2 subjects who received acalabrutinib monotherapy or the 
combination with pembrolizumab have achieved a response of 
“clinical improvement” or better (see Table 9), the MF group will not 
be expanded.  The decision to expand the study is multifactorial and 
will take into consideration the nature and quality of response, safety, 
and evolving competitive landscape.  If the safety and response data 
indicate that further evaluation is warranted, up to 18 additional 

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subjects with MF (for a total of up to 30 subjects) will be treated on 
the same adaptive regimen as was given to the first 12 subjects. 
Under Amendment 3 of this protocol, Part 3 is closed to enrollment. 
Treatment with acalabrutinib may be continued until disease 
progression or an unacceptable drug-related toxicity occurs as 
defined in the protocol.  Treatment with acalabrutinib can continue 
until the end of trial, defined as 48 months after the last subject is 
enrolled.  Subjects who are still on treatment at the end of the study 
and deriving clinical benefit from acalabrutinib treatment may be 
eligible to enroll in a separate rollover study.  Treatment with 
pembrolizumab may continue for 24 months (103 weeks) from first 
dose of pembrolizumab provided subjects are tolerating the drug and 
not progressing.  In addition, pembrolizumab treatment can end for 
subjects with confirmed CR (or stringent CR [sCR] for MM) if 
treatment has been administered for at least 24 weeks and 2 doses 
of pembrolizumab have been administered after confirmation of 
CR/sCR.  Subjects who have confirmed progressive disease will 
come off treatment.  Note: If there is uncertainty regarding whether 
there is cancer progression, the subject may continue study 
treatment and remain under close observation (e.g., evaluated at 
4- to 8-week intervals) pending confirmation of progression.  In 
particular, transient worsening of disease during temporary 
interruption of study therapy (e.g., for drug-related toxicity or 
intercurrent illness) may not indicate disease progression.  In such 
circumstances, and if medically appropriate, subjects may resume 
therapy and relevant clinical, laboratory, and/or radiographic 
assessments should be done to document whether tumor control can 
be maintained or whether actual disease progression has occurred. 
All subjects will have bone marrow biopsy, hematology, chemistry, 
thyroid, and urinalysis safety panels performed at screening.  Once 
dosing commences (Day 1), all subjects will be evaluated for safety, 
including serum chemistry, hematology, and thyroid function tests 
once weekly for the first 8 weeks, followed by a Week 10 visit and 
then every 3 weeks thereafter (every 6 weeks thereafter for thyroid 
function tests) through Week 103.  For subjects who discontinue 
pembrolizumab at Week 103, the Week 103 visit will be followed by 
Week 106 and Week 109 visits, at which time the investigator will 
determine eligibility to continue single-agent acalabrutinib treatment.  
Subjects remaining on study treatment after Week 103 will have a 
Week 103 and Week 115 visit, and then visits for safety and tumor 
response assessments every 24 weeks starting at Week 127 through 
3 years (for subjects with CLL/SLL histologies) or 5 years (for 
subjects with non-CLL/SLL histologies [i.e., DLBCL/Hodgkin 
lymphoma]), and then every 52 weeks thereafter (all histologies).   
Subjects who permanently discontinue pembrolizumab at any time 
during study participation must have a minimum of 2 consecutive 

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study visits, 3 weeks apart, after the last dose of pembrolizumab for 
safety evaluation. The study visits will be scheduled as follows: 
• 
For all subjects except MM and CLL subjects 
o If a subject discontinued pembrolizumab prior to 
completing 37 weeks on study and is on acalabrutinib 
alone, study visits will be held every 3 weeks until 
Week 37. After Week 37, study visits will be held every 
12 weeks.  
o If a subject discontinued pembrolizumab after completing 
37 weeks on study and is on acalabrutinib alone, 
2 consecutive study visits will be held 3 weeks apart (e.g., 
Week 40 and 43), after which study visits will be held 
every 12 weeks.  
o It is acknowledged that the discontinuation timepoint of 
pembrolizumab (if applicable) is unique per subject. To 
synchronize the every 12-week study visit schedule with 
the radiologic tumor assessment schedule, the first 
2 study visits after pembrolizumab discontinuation should 
be 3 and 6 weeks after pembrolizumab discontinuation 
and then scheduled to align with the nearest radiological 
timepoint. 
• 
For CLL subjects 
o If a subject discontinued pembrolizumab prior to 
completing 37 weeks on study and is on acalabrutinib 
alone, study visits will be held every 3 weeks until 
Week 37. After Week 37, study visits will be held every 
12 weeks.  
o If a subject discontinued pembrolizumab after completing 
37 weeks on study and is on acalabrutinib alone, study 
visits will be held every 12 weeks. 
o It is acknowledged that the discontinuation timepoint of 
pembrolizumab (if applicable) is unique per subject. To 
synchronize the every 12-week study visit schedule with 
the radiologic tumor assessment schedule, the first study 
visit should be scheduled to align with the nearest 
radiological timepoint.   
In addition, subjects who permanently discontinue pembrolizumab for 
any reason (e.g., pembrolizumab toxicity, adverse event (AE), or 
completing the 103-week course of pembrolizumab) and remain on 
acalabrutinib alone at any time during study participation must have a 
thyroid test done every 6 weeks for 6 months after pembrolizumab 
discontinuation.  Thyroid testing may be discontinued at 6 months if 
1) testing that was performed at 6 months was normal and 2) testing 
that was performed 6 weeks prior to the 6-month timepoint was 
normal (for a total of 2 consecutive normal test results).  Otherwise, 
thyroid testing will continue as scheduled until 2 consecutive normal 
test results. 

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Refer to Appendix 5 and Appendix 6 for comprehensive lists of study 
assessments and their timing.  A study schema is provided in Figure 
4. 
Definition of Dose-
limiting Toxicity: 
For Part 1, a DLT will be defined as the occurrence of any of the 
following study drug-related AEs (note: AEs clearly related to disease 
progression or the subject’s current medical history and associated 
comorbidities will not be considered DLTs): 
1. Any Grade ≥3 non-hematologic toxicity (except Grade 3 nausea, 
vomiting, or diarrhea that respond to supportive therapy).  
2. Any of the following hematologic toxicities: 
a. Grade 4 neutropenia lasting >7 days.  
b. Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with 
bleeding, or any requirement for platelets transfusion.  
c. Grade ≥3 febrile neutropenia (temperature ≥38.5°C).  
d. Grade 4 anemia, unexplained by underlying disease.  
3. Dosing delay due to toxicity for >28 consecutive days. 
Study Objectives: 
Primary Objective: 
To characterize the safety profile of acalabrutinib and pembrolizumab 
in subjects with hematologic malignancies 
Secondary Objective: 
To evaluate the activity of acalabrutinib and pembrolizumab as 
measured by overall response rate (ORR), duration of response, 
progression-free survival (PFS), overall survival, and time-to-next 
treatment 
Exploratory Objectives: 
CCI

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Safety Parameters: 
Type, frequency, severity, timing of onset, duration, and relationship 
to study drug of any treatment-emergent AEs or abnormalities of 
laboratory tests; serious AEs (SAEs); events of clinical interest 
(ECIs), or AEs leading to discontinuation of study treatment. 
Pharmacodynamic 
and Biomarker 
Parameters: 
Efficacy Parameters: 
• 
ORR 
• 
Duration of response 
• 
Progression-free survival 
• 
Overall survival 
• 
Time-to-next treatment 
In addition, for Part 3 subjects with MF, an overall response will be 
defined as clinical improvement or better (clinical improvement, 
partial response [PR], or CR) as shown in Table 9. Under 
Amendment 3 of this protocol, Part 3 is closed to enrollment. 
Sample Size: 
Part 1: Up to 24 subjects  
Part 2: Up to 270 subjects  
Part 3: Up to 30 subjects 
Note: Under Amendment 3 of this protocol, Part 3 is closed to 
enrollment. 
Inclusion Criteria: 
Part 1: 
• 
Diagnosis of non-GCB DLBCL or iNHL as documented by 
medical records and with histology based on criteria established 
by the World Health Organization (WHO). 
o If a subject has DLBCL, it is characterized as de novo 
non-GCB DLBCL (Hans et al 2004; Choi et al 2009).   
o If the subject has iNHL, the histology shows one of the 
following subtypes: 
 
FL Grade 1, 2, or 3a 
 
CLL/SLL 
• 
Prior treatment for lymphoid malignancy (applies to Part 1 and 
Part 2): 
o If the subject has DLBCL, there is no curative option with 
conventional therapy and the prior treatment included 
CCI

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≥1 prior combination chemoimmunotherapy regimen (e.g., 
anthracycline based therapy with rituximab). 
o If the subject has MCL or iNHL, the prior treatment 
comprised any of the following: 
 
≥1 regimen containing an anti-CD20 antibody 
administered for ≥2 doses, and/or 
 
≥1 regimen containing ≥1 cytotoxic agent (e.g., 
bendamustine, chlorambucil, cyclophosphamide, 
cytarabine, doxorubicin) administered for 
≥2 cycles, and/or 
 
≥1 regimen containing yttrium90-ibritumomab 
tiuxetan (ZEVALIN®) or iodine131-tositumomab 
(BEXXAR®). 
• 
Presence of radiographically measurable lymphadenopathy or 
extranodal lymphoid malignancy (defined as the presence of a 
≥2.0 cm lesion, as measured in the longest dimension by 
computed tomography [CT] scan).  Note:  Not applicable to 
subjects with WM and MM. 
• 
Absolute neutrophil count (ANC) ≥1.5×109/L and platelet count 
≥100×109/L unless due to disease involvement in the bone 
marrow (Part 1 only). 
 
Part 2:  
• 
ANC ≥0.5×109/L and platelet count ≥50×109/L unless due to 
disease involvement in the bone marrow (Part 2 only). 
 
Additional Part 2 disease entry criteria including those listed in 
Part 1 above: 
• 
DLBCL (GCB):  Confirmed diagnosis of DLBCL with disease 
characterized as GCB subtype by immunohistochemistry 
(Hans et al 2004; Choi et al 2009) and meeting the rest of the 
criteria as defined above, including characterization as de novo 
DLBCL. 
• 
If the subject has MCL, it is characterized by documentation of 
monoclonal B-cell that have a chromosome translocation 
t(11;14)(q13;q32) and/or overexpression of cyclin D1 
• 
Richter’s syndrome:  Confirmed diagnosis of and biopsy-proven 
DLBCL due to Richter transformation and meeting the rest of the 
criteria as defined above. 
• 
WM: Confirmed diagnosis of WM, which has relapsed after, or 
been refractory to ≥1 prior therapy for WM, and is progressing at 
the time of study entry and meeting the rest of the criteria as 
defined above.  Must be able to provide archival or newly 
obtained bone marrow aspirate/biopsy material for biomarker 
analysis. 

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• 
MM: Confirmed diagnosis of MM, which has relapsed after, or 
been refractory to ≥3 prior therapies for MM, and is progressing at 
the time of study entry and meeting the rest of the criteria as 
defined above.  Must be able to provide archival or newly 
obtained bone marrow aspirate/biopsy material for biomarker 
analysis. 
• 
Other B-cell malignancy (including but not limited to: Hodgkin’s 
lymphoma, Burkitt lymphoma, marginal zone lymphomas, 
mediastinal large B-cell lymphoma, and hairy cell leukemia): 
Confirmed diagnosis of previously treated B-cell malignancy and 
meeting the rest of the criteria as defined above. 
 
Part 3 (Under Amendment 3 of this protocol, Part 3 is closed to 
enrollment.): 
• 
Diagnosis of primary MF, post-polycythemia vera MF, or post-
essential thrombocythemia MF. 
• 
Intermediate-1, intermediate-2, or high-risk MF per 
Passamonti 2010 criteria and must have failed therapy with 
ruxolitinib. 
• 
Thrombocytopenia (platelet count ≤100×109/L at any time after 
signing informed consent) OR anemia (hemoglobin ≤8.0 g/dL). 
Subjects who are platelet or red blood cell transfusion-dependent 
are eligible; platelet counts must be ≥30×109/L during the 
screening period. 
• 
Palpable splenomegaly ≥5 cm on physical examination. 
• 
Total Symptom Score ≥13 on the Myeloproliferative Neoplasm 
Symptom Assessment Form (MPN-SAF TSS), not including the 
inactivity question. 
• 
No splenic irradiation within 6 months before first study dose. 
• 
No myelofibrosis therapy, including any erythropoietic or 
thrombopoietic agents, within 2 weeks before first study dose. 
• 
ANC ≥0.5×109/L. 
• 
Bone marrow blasts <10%.   
 
All Parts: 
• 
Men and women ≥18 years of age on day of signing informed 
consent.  
• 
Documented active disease. 
• 
Eastern Cooperative Oncology Group (ECOG) performance 
status of ≤1. 
• 
Completion of all therapy (including surgery, radiotherapy, 
chemotherapy, immunotherapy, or investigational therapy) for the 
treatment of cancer ≥4 weeks before the start of study therapy 
(Parts 1 and 2) and recovered (i.e., Grade ≤1 or baseline) from 

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AEs associated with prior cancer therapy (all subjects).  Note:  
Subjects with Grade ≤2 neuropathy or Grade ≤2 alopecia are an 
exception to the latter criterion and may qualify for the study. 
• 
Women who are sexually active and can bear children must 
agree to use highly effective methods of contraception during the 
study and for 2 days after the last dose of acalabrutinib or 
120 days after the last dose of pembrolizumab, whichever is 
longer.  Note:  Highly effective methods of contraception are 
defined in Section 3.10.9. 
• 
Men who are sexually active and can beget children must agree 
to use highly effective methods of contraception during the study 
and for 120 days after the last dose of pembrolizumab.  Highly 
effective methods of contraception are defined in Section 3.10.9. 
• 
Men must agree to refrain from sperm donation during the study 
and for 120 days after the last dose of pembrolizumab. 
• 
Able to provide tissue, if available, from either an archived or 
newly obtained tumor sample (most recent biopsy) for biomarker 
and correlative analysis as appropriate for a given histology. 
• 
Willing and able to participate in all required evaluations and 
procedures in this study protocol including swallowing capsules 
without difficulty. 
• 
Ability to understand the purpose and risks of the study and 
provide signed and dated informed consent and authorization to 
use protected health information (in accordance with national and 
local patient privacy regulations). 
Exclusion Criteria: 
All Parts: 
• 
Prior malignancy, except for adequately treated basal cell or 
squamous cell skin cancer, in situ cancer, or other cancer from 
which the subject has been disease free for ≥2 years. 
• 
A life-threatening illness, medical condition or organ system 
dysfunction which, in the investigator’s opinion, could compromise 
the subject’s safety, interfere with the absorption or metabolism of 
acalabrutinib, or put the study outcomes at undue risk. 
• 
Significant cardiovascular disease such as uncontrolled or 
symptomatic arrhythmias, congestive heart failure, or myocardial 
infarction within 6 months of screening, or any Class 3 or 4 
cardiac disease as defined by the New York Heart Association 
Functional Classification, or corrected QT interval (QTc) 
>480 msec at screening. 
• 
Malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach, or extensive 
small bowel resection that is likely to affect absorption, 
symptomatic inflammatory bowel disease, partial or complete 
bowel obstruction, or gastric restrictions and bariatric surgery, 
such as gastric bypass. 

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• 
Central nervous system (CNS) involvement by 
lymphoma/leukemia 
• 
Any therapeutic antibody within 4 weeks of first dose of study 
drug. 
• 
Any prior irreversible BTK inhibitor therapy.  Note:  Prior treatment 
with reversible, noncovalent BTK inhibitors is not excluded on this 
protocol. 
• 
Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD ligand 2 
(anti-PD-L2), anti-CD137, or anti-cytotoxic T-lymphocyte-
associated antigen-4 (CTLA-4) antibody (including ipilimumab, 
tremelimumab, or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways). 
• 
Receiving ongoing immunosuppressive therapy, including 
systemic or enteric corticosteroids except for minimally 
systemically absorbed treatments (such as inhaled or topical 
steroid therapy for asthma, chronic obstructive pulmonary 
disease, or allergic rhinitis) within 7 days before the first dose of 
pembrolizumab. 
• 
Active autoimmune disease that has required systemic treatment 
in past 2 years (i.e., with use of disease modifying agents, 
corticosteroids or immunosuppressive drugs).  Note:  
Replacement therapy (e.g., thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary 
insufficiency) is not considered a form of systemic treatment. 
• 
History of interstitial lung disease or non-infectious pneumonitis 
that required steroids or current pneumonitis.  
• 
History of severe allergic, anaphylactic, or other hypersensitivity 
reactions to chimeric or humanized antibodies or fusion proteins. 
• 
History of bleeding diathesis (e.g., hemophilia or von Willebrand 
disease).  
• 
Active bleeding that requires hospitalization during the screening 
period. 
• 
Prior allogeneic hematopoietic stem cell transplantation within the 
last 5 years. 
• 
Requires treatment with a strong cytochrome P450 3A (CYP3A) 
inhibitor/inducer. 
• 
Requires or receiving anticoagulation with warfarin or equivalent 
vitamin K antagonists (e.g., phenprocoumon) within 7 days of first 
dose of study drug. 
• 
Requires treatment with a proton-pump inhibitor (e.g., 
omeprazole, esomeprazole, lansoprazole, dexlansoprazole, 
rabeprazole, or pantoprazole). 
• 
Known history of human immunodeficiency virus (HIV) or active 
infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) or 
any uncontrolled active systemic infection.  

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• 
Major surgery within 28 days of first dose of study drug.  Note: If a 
subject had major surgery, they must have recovered adequately 
from any toxicity and/or complications from the intervention before 
the first dose of study drug. 
• 
Has received a live vaccine within 30 days of planned start of 
study therapy. 
• 
History of stroke or intracranial hemorrhage within 6 months 
before the first dose of study drug. 
• 
Total bilirubin >1.5× institutional upper limit of normal (ULN); 
aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) >3.0× ULN. 
• 
Estimated creatinine clearance of <30 mL/min, calculated using 
the formula of Cockcroft and Gault [(140−Age) • Mass (kg)/(72 • 
Creatinine mg/dL); multiply by 0.85 if female]. 
• 
Breastfeeding or pregnant or expecting to conceive or father 
children within the projected duration of the trial, starting with the 
screening visit through 120 days after the last dose of trial 
treatment. 
• 
Is currently participating in a clinical trial and receiving study 
therapy or has participated in a study of an investigational agent 
and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
• 
Immediate family members of the sponsor personnel or site staff 
directly involved with the conduct of this protocol are excluded 
from participating on this study. 
• 
Presence of a gastrointestinal ulcer diagnosed by endoscopy 
within 3 months before screening. 
• 
Active or known tuberculosis infection.  Note: Tuberculosis testing 
is not required for this protocol. 
• 
Serologic status reflecting active hepatitis B or C infection:   
o Subjects who are hepatitis B core antibody (anti-HBc) 
positive and who are surface antigen negative will 
need to have a negative polymerase chain reaction 
(PCR) result before enrollment.  Those who are 
hepatitis B surface antigen (HBsAg) positive or 
hepatitis B PCR positive will be excluded. 
o Subjects who are hepatitis C antibody-positive will 
need to have a negative PCR result before enrollment.  
Those who are hepatitis C PCR positive will be 
excluded. 
Dose Regimen/Route 
of Administration: 
Acalabrutinib is provided as hard gelatin capsules for oral 
administration. 
KEYTRUDA® (pembrolizumab) for injection is provided as a 
100 mg/4 mL (25 mg/mL) solution in a single-use vial or as a 

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lyophilized powder for reconstitution 50 mg/vial).  It is administered as 
an intravenous infusion over 30 minutes. 
Regimen (Combination Therapy): 
• 
Acalabrutinib 100 mg twice a day (BID) continuous oral 
dosing; and  
• 
Pembrolizumab 200 mg by intravenous (IV) infusion every 
3 weeks (Q3W) 
 
Note:  In Part 3, subjects with MF will receive a run-in of 6 weeks of 
acalabrutinib alone (100 mg BID).  Subjects who are demonstrating a 
clinically meaningful response, in the opinion of the investigator, may 
continue on acalabrutinib monotherapy; those who are not will 
receive combination therapy with acalabrutinib (100 mg BID) and 
pembrolizumab (200 mg Q3W) as described above.  Under 
Amendment 3 of this protocol, Part 3 is closed to enrollment. 
Concomitant 
Medications: 
The concomitant use of strong inhibitors/inducers of CYP3A with 
acalabrutinib should be avoided when possible.   
The effect of agents that reduce gastric acidity (e.g., antacids or 
proton-pump inhibitors,) on acalabrutinib absorption was evaluated in 
a healthy volunteer study (ACE-HV-004). Results from this completed 
study indicate subjects should avoid the use of calcium 
carbonate-containing drugs or supplements for a period of at least 
2 hours before and at least 2 hours after taking acalabrutinib.  Use of 
omeprazole, lansoprazole or esomeprazole or any other proton-pump 
inhibitors while taking acalabrutinib is not recommended due to a 
potential decrease in study drug exposure. However, the decision to 
treat with proton-pump inhibitors during the study is at the 
investigator’s discretion, with an understanding of the potential 
benefit to the subject’s gastrointestinal condition and a potential risk 
of decreased exposure to acalabrutinib. Although the effect of H2-
receptor antagonists (such as famotidine or ranitidine) on 
acalabrutinib absorption has not been evaluated, if treatment with an 
H2-receptor antagonist is required, the H2-receptor antagonist should 
be taken approximately 2 hours after an acalabrutinib dose. 
Statistics: 
Descriptive statistics (including means, standard deviations, and 
medians for continuous variables and proportions and confidence 
intervals [CIs] for discrete variables) will be used to summarize data 
as appropriate. 
Depending on Part 1 and the expansion cohorts opened in Parts 2 
and 3, a total of 6 to 324 evaluable subjects will be enrolled in this 
study.  Under Amendment 4 of this protocol, the planned total 
enrollment is approximately 160 evaluable subjects. 
In Part 1 (DLT review), enrollment of 6 subjects for DLT review is 
consistent with sample sizes used in oncology studies for 

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determination of maximum tolerated dose (MTD).  The trial employs 
the standard National Cancer Institute definition of MTD (dose 
associated with DLT in <33.3% of subjects).  Provided ≤1 DLT occurs 
during the DLT review, then expansion will occur in Part 1 to include 
up to 24 subjects in a select group of histologies (as described in 
Section 3.0).  The safety and preliminary efficacy results from Part 1 
will be used to determine opening Part 2 and Part 3 of the protocol. 
In Part 2, expansion groups of up to 30 subjects per disease type will 
be enrolled.  In Part 3, safety and response data will be reviewed 
after the initial 12 subjects have completed 24 weeks of treatment 
(i.e., the Week 25 visit) or have discontinued treatment before 
Week 25.  The first 12 subjects will be evaluated regardless of the 
length of treatment with acalabrutinib alone or in combination with 
pembrolizumab.  If <2 subjects who received acalabrutinib 
monotherapy or the combination with pembrolizumab have achieved 
a response of “clinical improvement” or better, the MF group will not 
be expanded.  The decision to expand the study is multifactorial and 
needs to take into consideration the nature and quality of response, 
safety, and evolving competitive landscape.  If the safety and 
response data indicate that further evaluation is warranted, up to 
18 additional subjects with MF (for a total of up to 30 subjects) will be 
treated on the same adaptive regimen as was given to the first 
12 subjects. 
In Part 2 (expansion groups), enrollment of 30 subjects per group 
offers the opportunity to determine if there is sufficient antitumor 
activity to warrant further development in the selected tumor types. 
An ORR of ≥20% is considered the minimum value of potential 
interest in each of the selected indications in Part 2.  If ≤2 subjects in 
a group experience an objective response, the probability is >0.90 
that an ORR of ≥20% will be excluded for that cancer.  If 2 subjects in 
a group experience an objective response, the upper bound of a 
1-sided exact binomial 90% CI is 16.8%. 
In Part 3 (if MF group is expanded), enrollment of 30 subjects offers 
the opportunity to determine if there is sufficient antitumor activity to 
warrant further development in MF.  An overall response rate (clinical 
improvement, PR, or CR) of ≥25% within the sample size of 
30 subjects with MF is considered the minimum value of potential 
interest in this highly unmet medical need population of MF patients 
with thrombocytopenia or anemia.  To reject the null hypothesis of 
response rate ≤5% in favor of an alternative hypothesis that the 
response rate is ≥25%, 30 subjects will preserve approximately 90% 
power to detect the difference at a 0.05 level of significance by 
1-sided exact test for single proportion.  Under Amendment 3 of this 
protocol, Part 3 is closed to enrollment. 

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BACKGROUND INFORMATION 
1.1 
A CASE FOR COMBINATION BTK AND CHECKPOINT BLOCKADE 
FOR TREATMENT OF HEMATOLOGIC MALIGNANCIES 
Through decades of clinical experience, the use of multidrug regimens has been shown to 
produce higher CR rates and more durable responses, resulting in improved survival in most 
oncology indications.  However, these benefits are often outweighed with the increased 
toxicity associated with multidrug regimens.  This high risk-benefit ratio limits the use of 
many effective multidrug regimens in elderly patients or patients with comorbid conditions.   
The advent of highly selective, targeted agents such as BTK inhibitors has changed the 
risk-benefit paradigm traditionally associated with cytotoxic chemotherapy regimens.  For 
example, ibrutinib, a first-generation oral, small-molecule BTK inhibitor, has been approved 
for the treatment for CLL and MCL (IMBRUVICA Package Insert).  In addition, ibrutinib has 
shown clinical efficacy in other NHL histologies, including FL (Advani 2013), DLBCL (De 
Vos 2013), and in WM (Treon 2013).  Preliminary data suggests that patients with MM with 
high BTK activity, as evidenced by phosphorylated BTK, may be particularly responsive to 
BTK inhibitor therapy (Liu 2014).  In nonclinical studies, BTK inhibition significantly reduced 
MM cell growth and tumor-induced osteolysis in a murine model (Tai 2012).  Despite these 
significant advances, the investigation of additional treatment regimens is essential to 
improve outcomes in hematologic malignances.  A low proportion of patients achieve CR 
when treated with single-agent BTK inhibitors compared with conventional chemotherapy or 
chemoimmunotherapy regimens.  Moreover, the median duration of response can be brief 
(<12 months) in aggressive histologies.   
Chemical optimization, pharmacologic characterization, and toxicologic evaluation have led 
to identification of acalabrutinib, an orally administered, new chemical entity that covalently 
inhibits BTK and shows encouraging activity and acceptable safety in nonclinical studies.  
Within the class of BTK inhibitors, acalabrutinib is a more selective inhibitor of BTK than 
ibrutinib.  Key nonclinical differentiators of acalabrutinib versus ibrutinib are: 
• 
Acalabrutinib has been evaluated against ibrutinib in epidermal growth factor receptor 
(EGFR) expressing cell lines.  Ibrutinib is a potent covalent inhibitor of EGFR 
(EC50=5.3 nM).  Acalabrutinib did not inhibit EGFR, even at the highest concentration 
tested (10 μM). 

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• 
Acalabrutinib and ibrutinib have been evaluated in natural killer (NK) cell functional 
assays.  While ibrutinib inhibits NK cell functions including antibody-dependent cellular 
cytotoxicity (ADCC), lytic granule release and cytokine production (Kohrt 2014), the 
in vitro functional activity of acalabrutinib-treated NK cells was preserved.  
• 
Acalabrutinib has been evaluated against ibrutinib in an in vivo thrombus formation 
model.  Platelets from CLL patients treated with acalabrutinib had similar thrombus 
formation dynamics as platelets from healthy volunteers, while platelets from 
ibrutinib-treated CLL patients had impaired thrombus formation.  
 
The nonclinical and toxicology results of acalabrutinib suggest it may have an improved 
therapeutic window relative to ibrutinib; it may be more readily combined with other agents 
for the treatment of cancer including monoclonal antibodies that activate effector cells.   
Improved understanding of the molecular mechanisms governing the host response to 
tumors has led to the identification of checkpoint signaling pathways involved in limiting the 
anticancer immune response (Topalian 2011).  A critical checkpoint pathway responsible for 
mediating tumor-induced immune suppression is the PD-1 pathway 
(McDermott and Atkins 2013).  This proof-of-concept study will assess the clinical potential 
of combined BTK inhibition and checkpoint blockade by evaluating the safety, PD, and 
efficacy of acalabrutinib and pembrolizumab in hematologic malignancies. 
To determine whether there is potential synergy between BTK inhibition and PD-1 blockade, 
Acerta conducted a nonclinical study of acalabrutinib in combination with an anti–PD-L1 
antibody in an orthotopic colon cancer murine model.  Mice were inoculated with syngeneic 
CT26 colorectal cancer cells on Day 0; anti–PD-L1 (150 μg on Days 6, 9, 12, 15) and 
acalabrutinib (15 mg/kg BID) treatment was initiated on Day 6, when the tumor was well 
established.  Treatment of mice with ACP-196 alone did not substantially diminish tumor 
growth.  In comparison, there was a significant reduction in tumor volume in mice treated 
with the PD-L1 antibody (mean + SD of 621 +349 mm3) or the combination of ACP-196 + 
PD-L1 antibody (mean + SD of 491 +489 mm3) compared to tumor sizes in the untreated 
group (mean + SD of 2667 +1222 mm3, p<0.0001) or ACP-196 only group (mean + SD of 
2449 +1149 mm3, p=0.0004) (see Figure 1).  On Day 14, the average tumor growth was not 
significantly different between mice treated with the PD-L1 antibody or the combination of 
ACP-196 + PD-L1 antibody (see Figure 1).  Interestingly, in the combination group, 5 of 

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10 tumors appeared to be smaller than any of those in the PD-L1 antibody-treated group 
(see Figure 1).  Additionally, there were 2 complete regressions (CRs) in the 
combination-treated group but not in the PD-L1 antibody group (see Figure 1). 
Figure 1 
Acalabrutinib Enhances the Antitumor Effects of α-PD-L1 in the 
Orthotopic CT26 Colon Cancer Model 
 
ACP-196=acalabrutinib; CR=complete regression; PD-L1=programmed death ligand-1. 
Effects of ACP-196 or anti-PD-L1 antibody alone or in combination were evaluated in the CT26 
colorectal tumor model in Balb/c mice.  A) Treatment effects on tumor growth, and B) Treatment effects 
on Day 14. Data were available from 9 mice in the ACP-196 group and10 mice in the other groups on 
Day 14.  Data analyzed by one-way analysis of variance (ANOVA) with Sidak’s multiple comparison test 
(***p=0.0002 to ACP-196, ****p<0.0001 to Untreated). 
 
Summaries of other nonclinical and clinical studies for acalabrutinib are provided below.  For 
more detailed information refer to the acalabrutinib Investigator Brochure (IB).  For detailed 
information on pembrolizumab refer to the pembrolizumab (MK-3475) IB. 
1.2 
ACALABRUTINIB 
Acalabrutinib is an imidazopyrazine analogue with a molecular weight of 465.5 g/mol.  The 
compound has 1 stereogenic center and acalabrutinib is the S-enantiomer.  Acalabrutinib is 
orally administered and is suitable for formulating in capsules.  For clinical testing, 
acalabrutinib has been manufactured and formulated according to current Good 
Manufacturing Practices (cGMP). 

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Acalabrutinib (CALQUENCE®) is an investigational product.  CALQUENCE® has been 
approved in the United States and other markets for the treatment of adult patients with 
mantle cell lymphoma (MCL) who have received at least one prior therapy, chronic 
lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL). 
1.2.1 
Mechanism of Action 
Acalabrutinib is a highly selective, potent, covalent inhibitor of BTK.  In kinase activity 
assays and wide kinome screens, acalabrutinib was more selective than ibrutinib 
(Covey 2015).  For additional details, refer to the acalabrutinib IB.  
1.2.2 
Spontaneous Canine B-cell Lymphoma 
Spontaneous canine B-cell lymphoma shares many characteristics with human NHL, 
including diagnostic classifications and response to BTK inhibition (Honigberg 2010).  The 
life expectancy in untreated animals with aggressive disease is ~6 weeks, thus enabling 
rapid assessment of drug efficacy (Vail 2004).  Acalabrutinib was evaluated in a dose-
escalation study in canine spontaneous B-cell lymphoma (Harrington 2016).  Twenty dogs 
were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20 mg/kg 
every 12 or 24 hours.  Acalabrutinib was generally well tolerated, with AEs consisting 
primarily of Grade 1 or 2 anorexia, weight loss, vomiting, diarrhea, and lethargy.  Per 
Veterinary Cooperative Oncology Group criteria for assessment of response in peripheral 
nodal lymphoma (Vail 2010), the ORR was 25% (5/20) with a median progression-free 
survival of 22.5 days.  Clinical benefit was observed in 30% (6/20) of dogs.  These findings 
suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients 
and support the use of canine lymphoma as a relevant model for human NHL.  These 
findings are similar to the clinical responses observed with ibrutinib in dogs with 
spontaneous B-cell lymphoma (Honigberg 2010). 
1.2.3 
Acalabrutinib and Antibody-dependent Cell-mediated Cytotoxicity 
As acalabrutinib is not an inhibitor of interleukin-2-inducible kinase (ITK), it is expected to 
have less activity against non-malignant cells that require ITK for development and 
functional activation, such as T and NK cells.  ITK kinase is required for FcR-stimulated NK 
cell functions including calcium mobilization, lytic granule release (Khurana 2007), and 
overall ADCC.  Anti-CD20 antibodies are standard of care drugs, often as part of 
combination regimens, for the treatment of CD20+ B-cell malignancies; obinutuzumab has 

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been specifically designed to increase Fc interactions and promote ADCC and phagocytosis 
of malignant CD20+ cells.  Ibrutinib has been evaluated for effects on NK activity, including 
ADCC, using in vitro assays of cytokine release, lytic granule release, and cellular 
cytotoxicity (Kohrt 2014).  In contrast to more specific BTK inhibitors, ibrutinib inhibited all 
these NK cell functions, and impaired NK activity against rituximab-coated autologous CLL 
cells and in mouse tumor models requiring Fc-mediated effector functions (Kohrt 2014).  
Acalabrutinib was tested in ADCC and natural cytotoxicity assays, using cells from healthy 
donors.  In these in vitro tests, NK cell function was preserved with acalabrutinib treatment, 
whereas ibrutinib inhibited functional activity, including natural cytotoxicity against K562 
cells.  
Figure 2 NK Cell Natural Cytotoxicity 
 
Peripheral blood mononuclear cells were cultured with 51Cr labelled K562 targets at an effector-to-target 
(E:T) ratio of 100:1 for 4 hours.  Cytotoxicity was evaluated by scintillation counting of supernatants.  
Treatment, dose, and interaction effect were significant in 2-way analysis of variance (ANOVA) 
(n=5 healthy donors; ibrutinib versus acalabrutinib p<0.0001; all ibrutinib doses p<0.0001 compared 
with control; p=0.0117 for control versus acalabrutinib 1 µM, other acalabrutinib doses not statistically 
different from control condition). 
 
1.2.4 
Acalabrutinib and Thrombus Formation 
Ibrutinib is associated with an increased risk of bleeding (Kamel 2015).  Hence, the effects 
of acalabrutinib and ibrutinib were evaluated on human platelet-mediated thrombus 
formation by using the in vivo human thrombus formation in VWFHA1 murine model, which 
has been previously described (Chen 2008).  The in vivo function of platelets isolated from 
C o n tr o l 0 .2 5  u M
0 .5  u M
1  u M
0
5 0
1 0 0
K 5 6 2  C y to to x ic ity  (%  L y s is )
A c a la b ru tin ib
Ib ru tin ib

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blood of healthy volunteers (n=5), CLL patients treated with 420 mg once per day (QD) 
ibrutinib (n=5), or CLL patients treated with 100 mg BID acalabrutinib (n=3) was evaluated in 
the VWFHA1 model.  Results from this study showed a reduction in platelet-vessel wall 
interactions of platelets from ibrutinib-treated CLL patients, but not of those from CLL 
patients treated with acalabrutinib (Byrd 2016). 
Figure 3 In Vivo Thrombus Formation 
 
 
Platelets from patients treated with ibrutinib 420 mg once per day (QD) (n=5) or acalabrutinib 100 mg twice per 
day (BID) (n=3) were evaluated for their ability to support thrombus formation in laser injured arterioles of 
VWFHA1 mice.  Freshly isolated platelets from healthy volunteers (n=5) were used as non-drug treated controls.  
A minimum of 4 arterioles per mouse was used to assess thrombus formation for each patient/volunteer sample.  
Thrombus size as a function of time is provided in the figure (shading denotes standard error of the median). 
 
1.2.5 
Safety Pharmacology 
In vitro and in vivo safety pharmacology studies with acalabrutinib have demonstrated a 
favorable nonclinical safety profile.  
When screened at 10 μM in binding assays evaluating interactions with 80 known 
pharmacologic targets such as G-protein–coupled receptors, nuclear receptors, proteases, 
and ion channels, acalabrutinib shows significant activity only against the A3 adenosine 

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receptor; follow-up dose-response experiments indicated a half-maximal inhibitory 
concentration (IC50) of 4.6 µM, suggesting a low clinical risk of off-target effects.  
The in vitro effect of acalabrutinib on human ether-à-go-go-related gene (hERG) channel 
activity was investigated in vitro in human embryonic kidney cells stably transfected with 
hERG.  Acalabrutinib inhibited hERG channel activity by ~25% at 10 μM, suggesting a low 
clinical risk that acalabrutinib would induce clinical QT prolongation as predicted by this 
assay (see the acalabrutinib IB for a summary of the thorough QT study in humans). 
Acalabrutinib was well tolerated in standard in vivo Good Laboratory Practices (GLP) 
studies of pharmacologic safety.  A functional observation battery in rats at doses through 
300 mg/kg (the highest dose level) revealed no adverse effects on neurobehavioral effects 
or body temperature.  A study of respiratory function in rats also indicated no treatment-
related adverse effects at doses through 300 mg/kg (the highest dose level).  In a 
cardiovascular function study in awake telemeterized male beagle dogs, single doses of 
acalabrutinib at dose levels through 30 mg/kg (the highest dose level) induced no 
meaningful changes in body temperature, cardiovascular, or electrocardiographic (including 
QT interval) parameters.  The results suggest that acalabrutinib is unlikely to cause serious 
off-target effects or adverse effects on critical organ systems. 
1.2.6 
Drug-drug Interaction Potential 
For more detailed information on drug-drug interaction potential for acalabrutinib, refer to the 
acalabrutinib IB. 
Please refer to Section 3.10.7 for guidance on drugs that may cause drug-drug interactions. 
1.2.7 
In Vivo General Toxicology 
The systemic toxicity of acalabrutinib has been fully investigated in repeat-dose sub-chronic 
studies in mice, rats, and dogs.  The pivotal GLP studies were 28- and 91-day repeat-dose 
studies in rats and dogs, each with recovery periods to assess the reversibility of observed 
changes. 
In rats, 100 mg/kg/day was selected initially to represent the highest non-severely toxic 
dose; however, in subsequent studies the 100 mg/kg/day dose level was determined to be a 
no observable adverse effect level (NOAEL).  In rats, the target organs of toxicity were the 
kidney, liver, and heart.   

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The NOAEL in the dog was 30 mg/kg/day; dose levels higher than 30 mg/kg/day were not 
tolerated.  In dogs, the target organs of toxicity, observed only at doses exceeding the MTD, 
were the kidney and liver.  Heart findings were also observed in 2 dogs with kidney toxicity, 
which were interpreted as possibly secondary to uremia, as has been reported for this 
species. 
In rats and dogs, no adverse electrocardiogram (ECG) or histopathologic cardiovascular 
effects were noted at the planned conclusion of the sub-chronic studies or in the rat chronic 
toxicity study.  However, in 5 of 6 rats from the 4-week study that died early, slight to 
moderate necrosis of the myocardium and/or white blood cell infiltration/inflammation of the 
myocardium were noted on microscopic examination of the hearts.   
1.3 
PEMBROLIZUMAB 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction with 
PD-L1 and PD-L2.  Based on nonclinical in vitro data, pembrolizumab has high affinity and 
potent receptor blocking activity for PD-1.  Pembrolizumab has an acceptable nonclinical 
safety profile and is in clinical development as an IV immunotherapy for advanced 
malignancies.  KEYTRUDA® (pembrolizumab) is indicated for the treatment of patients 
across a number of indications.  For more details on specific indications refer to the 
pembrolizumab IB. 
1.4 
CLINICAL EXPERIENCE 
Acalabrutinib has been studied in a broad range of clinical studies, including subjects with 
hematologic malignancies and solid tumors.  No new safety concerns were identified for 
acalabrutinib monotherapy based on safety data available to date.  The safety data of 
acalabrutinib monotherapy are consistent among studies.  For more detailed and updated 
information on the clinical experience for acalabrutinib, refer to the acalabrutinib IB.  See the 
KEYTRUDA package insert for details about clinical experience with pembrolizumab. 
1.4.1 
Pharmacokinetics and Pharmacodynamics of Acalabrutinib 
ACE-HV-001 was a pharmacokinetic (PK)/PD, dose-ranging, food-effect, and drug-drug 
interaction study evaluating BID and QD dosing for 1 or 2 days in healthy volunteers.  This 
study evaluated the PK/PD of acalabrutinib at various dose levels and regimens.  The 
starting dose for acalabrutinib was 2.5 mg BID.  This study has been completed and no 

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adverse laboratory, vital signs, or ECG findings were observed (2.5 to 50 mg BID; 50 to 
100 mg QD).  Three AEs related to study drug were reported.  Each AE was Grade 1 and 
resolved without treatment.  The AEs were constipation (2.5 mg BID), feeling cold (75 mg 
QD), and somnolence (75 mg QD). 
In Part 1, PK properties of acalabrutinib were evaluated after oral administration of 2 daily 
divided doses of 2.5 to 50 mg and a single dose of 100 mg.  Of the 30 subjects evaluated, 
all observed systemic concentrations of acalabrutinib.  Acalabrutinib plasma time to 
maximum concentration (Tmax) values were between 0.5 and 1.0 hour for all dose cohorts 
and were independent of dose level.  The increase in mean maximum observed plasma 
concentration (Cmax) values was greater than dose proportion based on the increases of 
Cmax from the first dose administered.  When evaluating area under the curve from time 0 to 
12-hour timepoint (AUC0-12), from time 0 to 24-hour timepoint (AUC0-24), or from time 0 to 
infinity (AUC0-inf) the mean values increased in a dose-proportional manner based on the 
increases of the total dose administered.  Mean half-life (t1/2) values ranged from 0.97 to 
2.1 hours and appeared to decrease as the dose increased.  The mean calculated oral 
clearance (CL/F: 165 to 219 L/h) and volume of distribution values (Vz/F: 233 to 612 L) 
appeared to be independent of the dose administered. 
Acalabrutinib was not detected in the urine of subjects receiving the 2.5- or 5.0-mg BID 
doses of acalabrutinib.  Acalabrutinib was detected in urine of other subjects (0.4% to 0.6% 
of dose) and amounts increased in a dose-dependent manner. 
In Part 2, the effect of food on the PK of acalabrutinib (75 mg) after a single oral 
administration was evaluated in 6 men and 6 women.  Median acalabrutinib plasma Tmax 
values were increased in the fed state (2.5 hours) relative to the fasted state (0.5 hour).  The 
mean plasma acalabrutinib Cmax fed values decreased to 27.3% of the Cmax values observed 
in the fasted state.  In contrast, the relative AUC exposure of acalabrutinib remained mostly 
unchanged in both states.  This decrease in exposure is not clinically significant; therefore, 
acalabrutinib can be taken without regard to meals. 
In Part 3, the effect of itraconazole on the PK of acalabrutinib (50 mg) after a single oral 
administration was evaluated in 17 subjects.  No difference in acalabrutinib Tmax values was 
observed in the presence or absence of itraconazole. 

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Mean acalabrutinib exposures (as assessed by Cmax, AUC0-last, AUC0-24, and AUC0-inf) 
increased in the presence of itraconazole.  The mean plasma acalabrutinib Cmax values 
increased 3.7-fold in the presence of itraconazole.  The mean plasma AUC0-last, AUC0-24, and 
AUC0-inf values also increased between 4.9- to 5.1-fold in the presence of itraconazole.  
Mean CL/F and Vz/F values decreased in the presence of itraconazole (CL/F: 217 vs 44 L/h; 
Vz/F: 1190 vs 184 L).  No differences in t1/2 were observed (3.3 vs 2.5 hours). 
The PD of acalabrutinib was evaluated using a BTK occupancy assay and correlated with a 
functional assay that determines the level of BTK inhibition by measuring expression of 
CD69 and CD86 on B cells.  A dose-dependent increase in BTK occupancy and 
corresponding decrease in CD69/86 expression was observed in this study.  Full BTK 
occupancy (≥90%) and complete CD86 and CD69 inhibition (≥90%) occurred at the 75- and 
100-mg single dosed cohorts 1 to 3 hours after administration.  However, only the 100-mg 
cohort maintained high BTK occupancy (91.5%) and high BCR functional inhibition 
(CD86: 86 ±3% and CD69: 78 ±8%) at 24 hours.  For subjects receiving a second dose of 
acalabrutinib 12 hours after the first administration, full BTK target occupancy was observed 
3 hours after the second dose for the 50-mg dosed cohort (BTK occupancy 97 ±4%). 
ACE-HV-004 was a 3-part drug interaction study.  Each part was conducted as an 
open-label, 2-period, fixed sequence study under fasting conditions.  The study design was 
as follows: 
• 
Part 1:  In Period 1, a single oral dose of acalabrutinib (100 mg) was administered 
followed by PK sampling for 24 hours.  In Period 2, a single oral dose of calcium 
carbonate (1 g) was coadministered with a single oral dose of acalabrutinib (100 mg) 
followed by PK sampling for 24 hours.  
• 
Part 2:  In Period 1, a single oral dose of acalabrutinib (100 mg) was administered 
followed by PK sampling for 24 hours.  In Period 2, oral doses of omeprazole (40 mg) 
were administered QD for 5 consecutive days with a single oral dose of acalabrutinib 
(100 mg) coadministered on Day 5.  PK sampling for acalabrutinib and omeprazole were 
done for 24 hours after dosing on Day 5. 
• 
Part 3:  In Period 1, a single oral dose of acalabrutinib (100 mg) was administered 
followed by PK sampling for 24 hours.  In Period 2, oral doses of rifampin (600 mg) were 
administered QD for 9 consecutive days with a single oral dose of acalabrutinib (100 mg) 

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coadministered on Day 1 and Day 9.  PK sampling for acalabrutinib and rifampin were 
done for 24 hours after dosing on Day 1 and Day 9.  
Seventy-two healthy volunteers enrolled in the study.  Acalabrutinib administration was well 
tolerated.  Three AEs were reported as related to study drug.  These were generalized 
pruritus, dyspepsia, and abdominal pain.  All were considered mild and resolved without 
treatment.  No drug-related AEs led to discontinuation from the study.  No severe AEs or 
SAEs occurred on this study. 
Coadministration of the gastric pH-modifiers calcium carbonate or omeprazole decreased 
mean Cmax to 25% and 21% and AUC to 47% and 43%, respectively, of values obtained with 
acalabrutinib dosed alone.  Rifampin dosed at 600 mg QD for 9 days decreased AUC to 
23% of values obtained with acalabrutinib dosed alone.  Results from Part 1 of this study 
suggest that subjects should avoid the use of calcium carbonate-containing drugs or 
supplements (e.g., antacids and calcium supplements) for a period of at least 2 hours before 
and after taking the study drug.   
1.4.2 
Safety of Acalabrutinib  
This section includes preliminary safety in Study ACE-LY-005.  Additional safety details in 
studies with healthy subjects and in subjects with malignancies are available in the 
acalabrutinib IB. 
1.4.2.1 
Safety of Acalabrutinib in Combination with Pembrolizumab for 
Subjects with B-Cell Malignancies (ACE-LY-005) 
Study ACE-LY-005 is a Phase 1b/2, multicenter, open-label proof-of-concept study in 
subjects with B-cell malignancies.  Safety data from 161 subjects are available as of the 
data cutoff date of 03 September 2017.  Median exposure was 3.4 months (range 0.2 to 
30.2 months).  
All 161 subjects (100.0%) experienced at least 1 AE of any grade.  The most frequently 
reported AEs were diarrhea (44.1%), headache (35.4%), fatigue (33.5%), cough (26.7%), 
nausea (26.7%), decreased appetite (24.8%), and vomiting (22.4%).   
Nine subjects (5.6%) had Grade 5 (fatal) events, including 2 subjects with Grade 5 sepsis 
and 3 subjects with Grade 5 respiratory failure.  One subject with DLBCL had Grade 5 
neutropenic sepsis, which was considered by the investigator to be related to acalabrutinib.  

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Two other subjects had Grade 5 events of respiratory failure and sepsis which were 
considered by the investigator to be related to pembrolizumab.  
SAEs were reported for 73 subjects (45.3%).  The most commonly reported SAEs were 
sepsis (5 subjects [3.1%]) and lung infection and AST increased (4 subjects [2.5%] each).  
Five subjects had SAEs reported by the investigator as related to only acalabrutinib of 
lymphoma, tumor flare, neutropenic sepsis (fatal event described above), nausea, and 
syncope.   
Fifteen subjects had SAEs that were attributed to both acalabrutinib and pembrolizumab 
treatment.  Of these 15 subjects, 1 subject experienced multiple related events of mental 
status change, pyrexia, lactic acidosis, and AST increased (Grade 3).  Other SAEs related to 
both acalabrutinib and pembrolizumab were hypotension, dehydration, septic shock, 
systemic inflammatory response syndrome, ALT increased, Herpes zoster, lymphadenitis, 
cytokine release syndrome, lymphocyte count decreased, platelet count decreased, 
pancreatitis, pneumonitis, lymphoma, gastrointestinal hemorrhage, retroperitoneal mass, 
anemia, hyponatremia, upper gastrointestinal hemorrhage, enteritis, and neck pain.   
Sixteen subjects had SAEs reported by the investigator to be related to only pembrolizumab, 
including AST increased, anemia, bronchitis, vertigo, orthostatic hypotension, drug-induced 
liver injury, platelet count decreased, sepsis, lung infection, pneumonitis, respiratory failure, 
respiratory distress, colitis, hyponatremia, pyrexia, tubulointerstitial nephritis, and systemic 
inflammatory response syndrome.  The AE of drug-induced liver injury was attributed to 
pembrolizumab due to the known risk for pembrolizumab of immune-mediated hepatitis, and 
occurred in a subject in whom initial corticosteroid therapy was likely not adequate.  The 
event improved when corticosteroids were again administered per guidance in the 
pembrolizumab prescribing information (Immune-Mediated Hepatitis, pembrolizumab 
prescribing information). 
A total of 40 subjects (24.8%) had AEs that led to study drug discontinuation, the most 
frequent of which included ALT increased (8 subjects [5.0%]) and AST increased (7 subjects 
[4.3%]).  One subject discontinued study drug due to an AE of lymphoma, considered by the 
investigator to be related to acalabrutinib only. Five subjects discontinued study drug due to 
AEs considered to be related to both acalabrutinib and pembrolizumab, including ALT 
increased in 2 subjects, and cytokine release syndrome, pneumonitis, and AST increased in 
1 subject each.  Thirteen subjects discontinued treatment due to AEs considered related 

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only to pembrolizumab, including 1 or more AEs of ALT increased, AST increased, 
pneumonitis, deafness neurosensory, neutropenia, bursitis, pneumonitis, colitis, and 
diarrhea. 
1.4.3 
Efficacy of Acalabrutinib  
Preliminary efficacy data as of 03 April 2017 have been evaluated for subjects with CLL, 
including subjects with R/R CLL (N=134), treatment-naive subjects (N=99), ibrutinib-
intolerant subjects (N=33), and subjects with Richter’s syndrome or PLL transformation 
(N=29).  The ORRs for the 4 populations were 96.9%, 99.0%, 80.6%, and 37.0%, 
respectively.  Efficacy data through 28 February 2017 are also available on the first 
124 sequentially enrolled subjects with R/R MCL who were treated with acalabrutinib 
monotherapy.  With a median follow-up of 15.2 months, the ORR was 80.6%, with CR in 
39.5% of subjects.  See the acalabrutinib IB for details. 
1.5 
BENEFIT/RISK OF ACALABRUTINIB 
Acalabrutinib is a potent, orally administered small-molecule inhibitor of BTK.  Preliminary 
efficacy and safety data from ongoing studies suggest that acalabrutinib is well tolerated and 
has robust activity as monotherapy and combination therapy.   
 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
To characterize the safety profile of acalabrutinib and pembrolizumab in subjects with 
hematologic malignancies. 
2.2 
SECONDARY OBJECTIVE 
To evaluate the activity of acalabrutinib and pembrolizumab as measured by response rate, 
duration of response, progression-free survival, overall survival, and time to next treatment. 
2.3 
EXPLORATORY OBJECTIVES 
CCI

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STUDY DESIGN 
This is a Phase 1b/2, open-label, nonrandomized study that will be conducted in 2 stages.  
In the first stage, Part 1 of the study will determine the safety and preliminary efficacy of 
acalabrutinib and pembrolizumab in a limited group of B-cell malignancies.  In the second 
stage, Part 2 allows for possible expansion cohorts into a wider range of B-cell 
malignancies, and Part 3 (enrolled concurrently with Part 2) will evaluate the combination in 
subjects with myelofibrosis (see Figure 4). 
Part 1 
Six subjects will be enrolled to receive acalabrutinib in combination with pembrolizumab.  If 
the combination is safe with ≤1 DLT (6-week observation period) in the first 6 subjects, the 
cohort will be expanded up to 24 subjects to obtain additional safety information and to 
assess the efficacy of the combination.   
Part 1 of the study will include adult subjects with the following disease types: 
• 
Non-GCB DLBCL 
• 
FL 
• 
CLL/SLL 
 
Part 2 
Part 2 consists of expansion groups of up to 30 subjects per histology provided the safety 
and efficacy results from Part 1 of the study indicate that further evaluation of the 
combination is warranted.  The possible expansion groups for Part 2 could include adult 
subjects with the following disease types: 
• 
Non-GCB DLBCL 
• 
GCB DLBCL  
• 
Richter syndrome 
• 
MCL 
CCI

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• 
iNHL 
o FL 
o WM 
o CLL/SLL 
• 
MM 
• 
Other B-cell malignancy (including but not limited to: Hodgkin’s lymphoma, Burkitt 
lymphoma, marginal zone lymphomas, mediastinal large B-cell lymphoma, and hairy 
cell leukemia) 
Under Amendment 3 of this protocol, subjects with MCL or iNHL (including FL, WM, and 
CLL/SLL) are no longer enrolled.  Under Amendment 4, subjects with RS are no longer 
enrolled. 
Part 3 
Part 3 includes up to 30 subjects with primary MF, post-polycythemia vera MF, or 
post-essential thrombocythemia MF with thrombocytopenia or anemia.  Part 3 will run in 
parallel with Part 2.  Subjects with MF will receive a run-in of 6 weeks of acalabrutinib alone.  
Subjects who are demonstrating a clinically meaningful response, in the opinion of the 
investigator, may continue on acalabrutinib monotherapy; those who are not will be treated 
with combination therapy with acalabrutinib and pembrolizumab.   
In Part 3, safety and response data will be reviewed after the initial 12 subjects have 
completed 24 weeks of treatment (i.e., the Week 25 visit) or have discontinued treatment 
before Week 25.  The first 12 subjects will be evaluated regardless of the length of treatment 
with acalabrutinib alone or in combination with pembrolizumab.  If <2 subjects who received 
acalabrutinib monotherapy or the combination with pembrolizumab have achieved a 
response of “clinical improvement” or better (see Table 9), the MF group will not be 
expanded.  The decision to expand the study is multifactorial and will take into consideration 
the nature and quality of response, safety, and evolving competitive landscape.  If the safety 
and response data indicate that further evaluation is warranted, up to 18 additional subjects 
with MF (for a total of up to 30 subjects) will be treated on the same adaptive regimen as 
was given to the first 12 subjects. 
Under Amendment 3 of this protocol, Part 3 is closed to enrollment. 

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All Parts 
Treatment with acalabrutinib may be continued until disease progression or an unacceptable 
drug-related toxicity occurs as defined in the protocol.  Treatment with acalabrutinib can 
continue until the end of trial, defined as 48 months after the last subject is enrolled.  
Subjects who are still on treatment at the end of the study and deriving clinical benefit from 
acalabrutinib treatment may be eligible to enroll in a separate rollover study of acalabrutinib 
monotherapy.  In the event that a rollover or safety extension study is available at the time of 
the final data cutoff and database closure, subjects who remain in Study ACE-LY-005 may 
be transitioned to such a study.  Once all active subjects are eligible for and move to a 
rollover or safety extension study, Study ACE-LY-005 would be considered closed.  The 
rollover or safety extension study would ensure treatment continuation, with visit 
assessments per the rollover or extension protocol.  Any subject who would be proposed to 
move to a rollover or safety extension study would be asked to sign an Informed Consent 
Form (ICF) for the rollover or safety extension study. 
Treatment with pembrolizumab may continue for 24 months (103 weeks) from first dose of 
pembrolizumab, provided subjects are tolerating the drug and not progressing.  In addition, 
pembrolizumab treatment can end for subjects with confirmed CR (or sCR for MM) if 
treatment has been administered for at least 24 weeks and 2 doses of pembrolizumab have 
been administered after confirmation of CR/sCR.  Subjects who have confirmed 
progressive disease will come off treatment.  Note:  If there is uncertainty regarding whether 
there is cancer progression, the subject may continue study treatment and remain under 
close observation (e.g., evaluated at 4- to 8-week intervals) pending confirmation of 
progression.  In particular, transient worsening of disease during temporary interruption of 
study therapy (e.g., for drug-related toxicity or intercurrent illness) may not indicate disease 
progression.  In such circumstances, and if medically appropriate, subjects may resume 
therapy and relevant clinical, laboratory, and/or radiographic assessments should be done 
to document whether tumor control can be maintained or whether actual disease 
progression has occurred. 
All subjects will have bone marrow biopsy, hematology, chemistry, thyroid, and urinalysis 
safety panels performed at screening.  Once dosing commences (Day 1), all subjects will be 
evaluated for safety, including serum chemistry, hematology, and thyroid function tests, 
once weekly for the first 8 weeks, followed by a Week 10 visit and then every 3 weeks 

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thereafter (every 6 weeks thereafter for thyroid function tests) through Week 103.  For 
subjects who discontinue pembrolizumab at Week 103, the Week 103 visit will be followed 
by Week 106 and Week 109 visits, at which time, the investigator will determine eligibility to 
continue single-agent acalabrutinib treatment.  Subjects remaining on study treatment after 
Week 103 will have a Week 103 and Week 115 visit, and then visits for safety and tumor 
response assessments every 24 weeks starting at Week 127 through 3 years (for subjects 
with CLL/SLL histologies) or 5 years (for subjects with non-CLL/SLL histologies [i.e., 
DLBCL/Hodgkin lymphoma]), and then every 52 weeks thereafter (all histologies). 
Subjects who permanently discontinue pembrolizumab at any time during study participation 
must have a minimum of 2 consecutive study visits, 3 weeks apart, after the last dose of 
pembrolizumab for safety evaluation. The study visits will be scheduled as follows: 
• 
For all subjects except MM and CLL subjects 
o If a subject discontinued pembrolizumab prior to completing 37 weeks on 
study and is on acalabrutinib alone, study visits will be held every 3 weeks 
until Week 37.  After Week 37, study visits will be held every 12 weeks.  
o If a subject discontinued pembrolizumab after completing 37 weeks on study 
and is on acalabrutinib alone, 2 consecutive study visits will be held 3 weeks 
apart (e.g., Week 40 and 43), after which study visits will be held every 
12 weeks.  
o It is acknowledged that the discontinuation timepoint of pembrolizumab (if 
applicable) is unique per subject.  To synchronize the every 12-week study 
visit schedule with the radiologic tumor assessment schedule, the first 
2 study visits after pembrolizumab discontinuation should be 3 and 6 weeks 
after pembrolizumab discontinuation and then scheduled to align with the 
nearest radiological timepoint. 
 
• 
For CLL subjects 
o If a subject discontinued pembrolizumab prior to completing 37 weeks on 
study and is on acalabrutinib alone, study visits will be held every 3 weeks 
until Week 37.  After Week 37, study visits will be held every 12 weeks.  
o If a subject discontinued pembrolizumab after completing 37 weeks on study 
and is on acalabrutinib alone, study visits will be held every 12 weeks. 
o It is acknowledged that the discontinuation timepoint of pembrolizumab (if 
applicable) is unique per subject.  To synchronize the every 12-week study 

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visit schedule with the radiologic tumor assessment schedule, the first study 
visit should be scheduled to align with the nearest radiological timepoint. 
 
In addition, subjects who permanently discontinue pembrolizumab for any reason (e.g., 
pembrolizumab toxicity, AE, or completing the 103-week course of pembrolizumab) and 
remain on acalabrutinib alone at any time during study participation must have a thyroid test 
done every 6 weeks for 6 months after pembrolizumab discontinuation.  Thyroid testing may 
be discontinued at 6 months if 1) testing that was performed at 6 months was normal and 2) 
testing that was performed 6 weeks prior to the 6-month timepoint was normal (for a total of 
2 consecutive normal test results). Otherwise, thyroid testing will continue as scheduled until 
2 consecutive normal test results. 
Refer to Appendix 5 and Appendix 6 for a comprehensive list of study assessments and 
their timing. 
Figure 4 Study Schema 
 
ACP-196=acalabrutinib; BID=twice per day; CLL/SLL= chronic lymphocytic leukemia/small lymphocytic 
lymphoma; DLT=dose-limiting toxicity; FL= follicular lymphoma; GCB=germinal center B-cell diffuse 
large B-cell lymphoma; iNHL=indolent non-Hodgkin lymphoma; IV=intravenous; MF=myelofibrosis (per 
Amendment 3, Part 3, MF was not opened for this study); MM=multiple myeloma; non-GCB 
DLBCL=non-germinal center B-cell diffuse large B-cell lymphoma; PO=oral; Q3W=every 3 weeks; 
RS=Richter’s syndrome (under Amendment 4, subjects with RS are no longer enrolled); 
WM=Waldenström macroglobulinemia. 

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3.1 
STUDY PARAMETERS 
3.1.1 
Safety Parameters 
The safety of acalabrutinib and pembrolizumab will be characterized by the type, frequency, 
severity, timing of onset, duration, and relationship to study drug(s) of any 
treatment-emergent AEs or abnormalities of laboratory tests; SAEs; ECIs, or AEs leading to 
discontinuation 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 
or higher. Standard definitions for seriousness will be applied (see Section 6.1). 
3.1.2 
Pharmacodynamic and Biomarker Parameters 
3.1.3 
Efficacy Parameters 
Standardized response and progression criteria have been established for B-cell 
malignancies including WM (Bladé 1998; Durie 2006; Hallek 2008; Owen 2013; 
Tefferi 2013; Cheson 2014); assessments of acalabrutinib and pembrolizumab efficacy in 
this study will be based on these criteria.  Efficacy endpoints will include: 
• 
ORR 
• 
Duration of response 
• 
Progression-free survival 
• 
Overall survival 
• 
Time-to-next treatment 
 
For Part 3 subjects with MF, an overall response will be defined as clinical improvement or 
better (clinical improvement, PR, or CR) see Table 9.  An additional analysis will evaluate 
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response when defined as CR + PR only.  Under Amendment 3 of this protocol, Part 3 is 
closed to enrollment. 
3.2 
RATIONALE FOR STUDY DESIGN AND DOSING REGIMEN 
As described in Section 1.4, acalabrutinib is currently being evaluated in a Phase 1/2 study 
in subjects with CLL (ACE-CL-001).  In this study, subjects have received oral dosages of 
100 to 400 mg QD and 100 to 200 mg BID of acalabrutinib.  All tested dose levels have 
been well tolerated and, to date, no DLTs have been observed.  Robust clinical responses 
have been observed with dosages as low as 100 mg QD.  Preliminary PK data from 
ACE-CL-001 suggests a plateauing of exposure after 250 mg QD.  PD results from this 
study also show 100 mg BID has the highest BTK occupancy at 24 hours of all the regimens 
evaluated.  Therefore, 100 mg BID maintains full target coverage over 24 hours, while 
lowering the Cmax and AUC of acalabrutinib suggesting this regimen is preferred when 
acalabrutinib is being administered with other agents to lower the potential risk of drug-drug 
interactions.  Therefore, based on PK/PD and efficacy results of the Phase 1/2 study, a 
200-mg total daily dose, administered 100 mg BID, will be evaluated in this protocol. 
Because acalabrutinib has not yet been evaluated in subjects with MF, an adaptive regimen 
will be used in Part 3.  Preliminary data in CLL suggest that responses to acalabrutinib occur 
rapidly; in study ACE-CL-001, some subjects obtained PRs after only 2 cycles (8 weeks) of 
therapy.  Thus, subjects in Part 3 will receive at least 6 weeks run-in with acalabrutinib alone 
before beginning combination therapy with pembrolizumab.  The adaptive dosing regimen 
allows for the reasonable possibility that robust activity will be seen in MF using 
acalabrutinib as a single agent, while providing combination therapy of acalabrutinib plus 
pembrolizumab for subjects who do not show a clinically meaningful response to 
acalabrutinib alone.  Under Amendment 3 of this protocol, Part 3 is closed to enrollment. 
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W.  The dose 
recently approved in the United States and several other countries for treatment of 
melanoma subjects is 2 mg/kg Q3W.  Information on the rationale for selecting 200 mg Q3W 
is summarized below. 
KEYNOTE-001 was an open-label Phase 1 study conducted to evaluate the safety, 
tolerability, PK and PD, and anti-tumor activity of pembrolizumab when administered as 
monotherapy.  The dose escalation portion of this trial evaluated 3 dose levels, 1 mg/kg, 

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3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) and dose expansion cohorts 
evaluated 2 mg/kg Q3W and 10 mg/kg Q3W in subjects with advanced solid tumors.  All 
dose levels were well tolerated and no DLTs were observed.  This first-in-human study of 
pembrolizumab showed evidence of target engagement and objective evidence of tumor 
size reduction at all dose levels.  No MTD has been identified.  In addition, 2 randomized 
cohort evaluations of melanoma subjects receiving pembrolizumab at a dose of 2 mg/kg 
versus 10 mg/kg Q3W have been completed, and 1 randomized cohort evaluating 10 mg/kg 
Q3W versus 10 mg/kg Q2W has also been completed.  The clinical efficacy and safety data 
demonstrate a lack of important differences in efficacy or safety profile across doses.  
An integrated body of evidence suggests that 200 mg Q3W is expected to provide similar 
response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg Q2W.  Previously, a flat 
pembrolizumab exposure-response relationship for efficacy and safety has been found in 
subjects with melanoma in the range of doses between 2 mg/kg and 10 mg/kg.  Exposures 
of 200 mg Q3W are expected to lie within this range and will be close to those obtained with 
the 2 mg/kg Q3W dose.   
A population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed.  The PK profile of pembrolizumab is 
consistent with that of other humanized monoclonal antibodies, which typically have a low 
clearance and a limited volume of distribution.  The distribution of exposures from the 
200 mg fixed dose is predicted to considerably overlap those obtained with the 2 mg/kg 
dose and importantly will maintain individual patient exposures within the exposure range 
established in melanoma as associated with maximal clinical response.  PK properties of 
pembrolizumab, and specifically the weight-dependency in clearance and volume of 
distribution are consistent with no meaningful advantage to weight-based dosing relative to 
fixed dosing. 
In translating to other tumor indications, similarly flat exposure-response relationships for 
efficacy and safety as observed in subjects with melanoma can be expected, as the 
anti-tumor effect of pembrolizumab is driven through immune system activation rather than 
through a direct interaction with tumor cells, rendering it independent of the specific tumor 
type.  In addition, available PK results in subjects with melanoma, NSCLC, and other tumor 
types support a lack of meaningful difference in PK exposures obtained at tested doses 

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among tumor types.  Thus the 200 mg Q3W fixed-dose regimen is considered an 
appropriate fixed dose for other tumor indications as well.   
A fixed-dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed-dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage.  The existing data suggest 
200 mg Q3W as the appropriate dose for pembrolizumab.  
As described in Section 1.1, Acerta Pharma has conducted a nonclinical study to evaluate 
the potential synergy of BTK inhibition with PD-1 blockade and has seen encouraging 
results which warrant testing the hypothesis in a clinical trial.   
3.3 
SELECTION OF STUDY POPULATION 
3.3.1 
Inclusion Criteria 
Eligible subjects will be considered for inclusion in this study if they meet all of the following 
criteria:  
Part 1 
1) Diagnosis of non-GCB DLBCL or iNHL as documented by medical records and with 
histology based on criteria established by the WHO. 
a) If the subject has DLBCL, it is characterized as de novo non-GCB DLBCL 
(Hans 2004; Choi 2009).  
b) If the subject has iNHL, the histology shows one of the following subtypes: 
i) FL Grade 1, 2, or 3a 
ii) CLL/SLL 
2) Prior treatment for lymphoid malignancy (applies to Part 1 and Part 2 of the protocol): 
a) If the subject has DLBCL, there is no curative option with conventional therapy and 
the prior treatment included ≥1 prior combination chemoimmunotherapy regimen 
(e.g., anthracycline based therapy with rituximab). 
b) If the subject has MCL or iNHL, the prior treatment comprised any of the following: 
i) ≥1 regimen containing an anti-CD20 antibody administered for ≥2 doses, and/or 
ii) ≥1 regimen containing ≥1 cytotoxic agent (e.g., bendamustine, chlorambucil, 
cyclophosphamide, cytarabine, doxorubicin) administered for ≥2 cycles, and/or 

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iii) ≥1 regimen containing yttrium90-ibritumomab tiuxetan (ZEVALIN®) or 
iodine131-tositumomab (BEXXAR®). 
3) Presence of radiographically measurable lymphadenopathy or extranodal lymphoid 
malignancy (defined as the presence of a ≥2.0-cm lesion as measured in the longest 
dimension by CT scan).  Note:  Not applicable to subjects with WM and MM. 
4) ANC ≥1.5×109/L or platelet count ≥100×109/L unless due to disease involvement in the 
bone marrow (Part 1 only). 
Part 2 
5) ANC ≥0.5×109/L and platelet count ≥50×109/L unless due to disease involvement in the 
bone marrow (Part 2 only). 
Additional Part 2 disease entry criteria including those listed in Part 1 above 
6) DLBCL (GCB):  Confirmed diagnosis of DLBCL with disease characterized as GCB 
subtype by immunohistochemistry (Hans 2004; Choi 2009) and meeting the rest of the 
criteria as defined above, including characterization as de novo DLBCL. 
7) If the subject has MCL, it is characterized by documentation of monoclonal B cells that 
have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1. 
8) Richter’s syndrome:  Confirmed diagnosis of and biopsy-proven DLBCL due to Richter 
transformation and meeting the rest of the criteria as defined above. 
9) MM:  Confirmed diagnosis of MM, which has relapsed after, or been refractory to 
≥3 prior therapies for MM, and is progressing at the time of study entry and meeting the 
rest of the criteria as defined above.  Must be able to provide archival or newly obtained 
bone marrow aspirate/biopsy material for biomarker analysis. 
10) WM:  Confirmed diagnosis of WM, which has relapsed after, or been refractory to 
≥1 prior therapy for WM, and is progressing at the time of study entry and meeting the 
rest of the criteria as defined above.  Must be able to provide archival or newly obtained 
bone marrow aspirate/biopsy material for biomarker analysis. 
11) Other B-cell malignancy (including but not limited to Hodgkin’s lymphoma, Burkitt 
lymphoma, marginal zone lymphomas, mediastinal large B-cell lymphoma, and hairy 
cell leukemia):  Confirmed diagnosis of previously treated B-cell malignancy and 
meeting the rest of the criteria as defined above. 

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Part 3 (Under Amendment 3 of this protocol, Part 3 is closed to enrollment.) 
12) Diagnosis of primary MF, post-polycythemia vera MF, or post-essential 
thrombocythemia MF. 
13) Intermediate-1, intermediate-2, or high-risk MF per Passamonti 2010 criteria and must 
have failed therapy with ruxolitinib. 
14) Thrombocytopenia (platelet count ≤100×109/L at any time after signing informed 
consent) OR anemia (hemoglobin ≤8.0 g/dL).  Subjects who are platelet or red blood 
cell transfusion-dependent are eligible; platelet counts must be ≥30×109/L during the 
screening period.   
15) Palpable splenomegaly ≥5 cm on physical examination. 
16) Total Symptom Score ≥13 on the MPN-SAF TSS, not including the inactivity question. 
17) No splenic irradiation within 6 months before first study dose. 
18) No myelofibrosis therapy, including any erythropoietic or thrombopoietic agents, within 
2 weeks before first study dose. 
19) ANC ≥0.5×109/L. 
20) Bone marrow blasts <10%. 
All Parts 
21) Men and women ≥18 years of age on day of signing informed consent. 
22) Documented active disease. 
23) ECOG performance status of ≤1. 
24) Completion of all therapy (including surgery, radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of cancer ≥4 weeks before 
the start of study therapy (Parts 1 and 2) and recovered (i.e., Grade ≤1 or baseline) 
from AEs associated with prior cancer therapy (all subjects).  Note:  Subjects with 
Grade ≤2 neuropathy or Grade ≤2 alopecia are an exception to the latter criterion and 
may qualify for the study. 
25) Women who are sexually active and can bear children must agree to use highly 
effective methods of contraception during the study and for 2 days after the last dose of 

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acalabrutinib or 120 days after the last dose of pembrolizumab, whichever is longer.  
Note:  Highly effective methods of contraception are defined in Section 3.10.9. 
26) Men who are sexually active and can beget children must agree to use highly effective 
methods of contraception during the study and for 120 days after the last dose of 
pembrolizumab.  Note: Highly effective methods of contraception are defined in 
Section 3.10.9. 
27) Men must agree to refrain from sperm donation during the study and for 120 days after 
the last dose of pembrolizumab. 
28) Able to provide tissue, if available, from either an archived or newly obtained tumor 
sample (most recent biopsy) for biomarker and correlative analysis as appropriate for a 
given histology. 
29) Willing and able to participate in all required evaluations and procedures in this study 
protocol including swallowing capsules without difficulty. 
30) 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). 
 
3.3.2 
Exclusion Criteria 
Subjects will be ineligible for this study if they meet any of the following criteria: 
All Parts 
1) 
Prior malignancy, except for adequately treated basal cell or squamous cell skin 
cancer, in situ cancer, or other cancer from which the subject has been disease free for 
≥2 years.  
2) 
A life-threatening illness, medical condition or organ system dysfunction which, in the 
investigator’s opinion, could compromise the subject’s safety, interfere with the 
absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk. 
3) 
Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
congestive heart failure, or myocardial infarction within 6 months of screening, or any 
Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional 
Classification, or QTc >480 msec at screening. 

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4) 
Malabsorption syndrome, disease significantly affecting gastrointestinal function, or 
resection of the stomach, or extensive small bowel resection that is likely to affect 
absorption, symptomatic inflammatory bowel disease, partial or complete bowel 
obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. 
5) 
CNS involvement by lymphoma/leukemia. 
6) 
Any therapeutic antibody within 4 weeks of first dose of study drug. 
7) 
Any prior irreversible BTK inhibitor therapy.  Note:  Prior treatment with reversible, 
noncovalent BTK inhibitors is not excluded on this protocol. 
8) 
Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody (including ipilimumab, tremelimumab, or any other antibody or drug 
specifically targeting T-cell co-stimulation or checkpoint pathways). 
9) 
Receiving ongoing immunosuppressive therapy, including systemic or enteric 
corticosteroids except for minimally systemically absorbed treatments (such as inhaled 
or topical steroid therapy for asthma, chronic obstructive pulmonary disease, or allergic 
rhinitis) within 7 days before the first dose of pembrolizumab. 
10) Active autoimmune disease that has required systemic treatment in past 2 years (i.e., 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).  
Note:  Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a form of 
systemic treatment. 
11) History of interstitial lung disease or non-infectious pneumonitis that required steroids 
or current pneumonitis. 
12) History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric 
or humanized antibodies or fusion proteins. 
13) History of bleeding diathesis (e.g., hemophilia or von Willebrand disease). 
14) Prior allogeneic hematopoietic stem cell transplantation (HSCT) within the last 5 years. 
15) Requires treatment with a strong CYP3A inhibitor/inducer. 
16) Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists 
(e.g., phenprocoumon) within 7 days of first dose of study drug. 
17) Requires treatment with a proton-pump inhibitor (e.g., omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). 
18) Known history of HIV or active infection with HCV or HBV or any uncontrolled active 
systemic infection.  

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19) Major surgery within 28 days of first dose of study drug.  Note:  If a subject had major 
surgery, they must have recovered adequately from any toxicity and/or complications 
from the intervention before the first dose of study drug. 
20) Has received a live vaccine within 30 days of planned start of study therapy. 
21) History of stroke or intracranial hemorrhage within 6 months before the first dose of 
study drug. 
22) Active bleeding that requires hospitalization during the screening period. 
23) Total bilirubin >1.5×ULN; AST or ALT >3.0×ULN. 
24) Estimated creatinine clearance of <30 mL/min, calculated using the formula of 
Cockcroft and Gault [(140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 if 
female]. 
25) Breastfeeding or pregnant or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of trial treatment. 
26) Is currently participating in a clinical trial and receiving study therapy or has 
participated in a study of an investigational agent and received study therapy or used 
an investigational device within 4 weeks of the first dose of treatment. 
27) Immediate family members of the sponsor personnel or site staff directly involved with 
the conduct of this protocol are excluded from participating on this study. 
28) Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before 
screening. 
29) Active or known tuberculosis infection.  Note:  Tuberculosis testing is not required for 
this protocol. 
30) Serologic status reflecting active hepatitis B or C infection: 
a) Subjects who are anti-HBc positive and who are surface antigen negative will need 
to have a negative PCR result before enrollment.  Those who are HBsAg positive or 
hepatitis B PCR positive will be excluded. 
b) Subjects who are hepatitis C antibody-positive will need to have a negative PCR 
result before enrollment.  Those who are hepatitis C PCR positive will be excluded. 

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3.3.3 
Replacement of Subjects 
Subjects will not be replaced on this study except if needed to complete the DLT 
assessment in Part 1 (N=6).  However, subjects who discontinue from the study due to a 
DLT during the DLT assessment period will not be replaced.  
3.3.4 
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 (ICF), all screening procedures have been 
completed, and eligibility has been confirmed, the subject can be officially enrolled into 
the study.  
• 
To enroll a subject, the study center will fax/email a completed Enrollment Confirmation 
Form to the sponsor.  The enrollment date will be the date that the sponsor confirms 
enrollment. 
• 
The sponsor will aim to fax/email a completed Enrollment Confirmation Form to the 
study center within 24 hours.  
Treatment must begin within the screening window (see Section 4.1) and after the site has 
received the Enrollment Confirmation Form from the sponsor.   
3.4 
STUDY DRUGS 
3.4.1 
Premedications 
No specific premedications or supporting medications are required in conjunction with 
acalabrutinib or pembrolizumab administration.  
Events of tumor lysis syndrome, consistent with disease-related events, have been reported 
in subjects exposed to acalabrutinib in both monotherapy and in combination with other 
agents (acalabrutinib IB).  Whether there could be an increased likelihood of tumor lysis 
syndrome when co-administering acalabrutinib and pembrolizumab is unknown. 
Investigators are at liberty to consider additional monitoring and prophylaxis for tumor lysis 
syndrome according to local practices (see Section 3.9).  

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As general precautions considering the subject population, institution of antibiotic 
prophylaxis for Pneumocystis (carinii) jiroveci and use of intravenous immunoglobulin (Ig) 
may be considered in selected study subjects (see Section 3.9.1). 
3.4.2 
Formulation, Packaging, and Storage 
Acalabrutinib 
Acalabrutinib is manufactured according to cGMP regulations and will be provided to the 
investigational site by Acerta Pharma or designee.  Acalabrutinib should be stored according 
to the instructions on the label that is affixed to the package of the drug product.  
Acalabrutinib will be provided in white, high-density polyethylene bottles.   
If a drug shipment arrives damaged, or if there are any other drug complaints, a Product 
Complaint Form should be completed and emailed or faxed to the sponsor or the sponsor’s 
representative.  Refer to the acalabrutinib IB for additional information regarding the drug 
products to be used in this trial. 
Pembrolizumab 
Pembrolizumab clinical supplies will be provided by the sponsor as summarized in Table 1. 
Table 1 
Pembrolizumab Clinical Supplies 
Product Name and Potency 
Dosage Form 
MK-3475 50 mg 
Lyophilized Powder for Injection 
MK-3475 100 mg/ 4mL 
Solution for Injection 
 
Information on the formulation, packaging and storage of pembrolizumab is provided in the 
pembrolizumab Pharmacy Manual and the pembrolizumab (MK-3475) Investigator 
Brochure. 
3.4.3 
Administration of Study Drug  
Investigators are prohibited from supplying acalabrutinib to any subjects not properly 
enrolled in this study.  The investigator must ensure that subjects receive acalabrutinib or 
pembrolizumab only from personnel who fully understand the procedures for administering 
the drugs. 

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Acalabrutinib 100 mg is intended to be administered orally BID with 8 ounces (approximately 
240 mL) of water (avoid grapefruit juice and Seville orange juice due to CYP3A inhibition).  
Doses should be administered 12 hours apart (a window of ±1 hour is allowed).  
Acalabrutinib can be taken with or without food.  The capsules should be swallowed intact.  
Subjects should not attempt to open capsules or dissolve them in water.   
If a dose is not taken within the allowed window, it can be taken up to 3 hours after the 
scheduled time with a return to the normal schedule the same or following day.  If it has 
been >3 hours, the dose should not be taken and the subject should take the next dose at 
the next scheduled time the next day.  The missed dose will not be made up and must be 
returned to the site at the next scheduled visit. 
Guidance on co-administration of acalabrutinib with agents that affect gastric pH is provided 
in Section 3.10.7. 
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion.  
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a window 
between -5 minutes and +10 minutes is permitted (i.e., infusion time is 
30 minutes -5 minutes/ +10 minutes).  Detailed information on preparation of pembrolizumab 
for infusion is provided in the pembrolizumab (MK-3475) Pharmacy Manual.  
3.4.4 
Assuring Subject Compliance 
For treatments that are taken in the clinic, subjects should take the dose from the drug 
dispensed for them for that particular time period.  All other acalabrutinib treatments will be 
taken at home.  Subjects will receive a drug diary to record the specific time each dose was 
taken and to record reasons for any missed doses.   
Pembrolizumab infusions will be administered only at the clinics per the study schedule. 
Missed doses of pembrolizumab should not be made up, with the next dose occurring in 
agreement with the original schedule (from the first dose of drug administered to the subject) 
for this agent (every 3 weeks). 
Subject compliance with acalabrutinib dosing 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 study staff 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 

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described in Section 7.6.  Returned capsules must not be redispensed.  Only a sufficient 
quantity of capsules will be dispensed to reach the next protocol-specified visit unless 
approved by the medical monitor.  Subjects on treatment who are on yearly visits (see 
Appendix 5) may return to the clinic to receive a 6-month supply between yearly visits, if 
they are unable to get a 1-year supply at a time.  
3.5 
STUDY DRUG DOSING 
Acalabrutinib 100 mg BID will be orally administered.  Pembrolizumab 200 mg will be 
administered every 3 weeks by IV infusion.  In Part 3, subjects with MF will receive a run-in 
of 6 weeks with acalabrutinib alone (100 mg BID).  Subjects who are demonstrating a 
clinically meaningful response, in the opinion of the investigator, may continue on 
acalabrutinib monotherapy; those who are not will receive combination therapy with 
acalabrutinib (100 mg BID) and pembrolizumab (200 mg Q3W) as described above.   
3.6 
DURATION OF THERAPY 
Subjects may continue to receive acalabrutinib treatment until disease progression or an 
unacceptable drug-related toxicity occurs as defined in the protocol.  Treatment with 
acalabrutinib can continue until the end of trial, defined as 48 months after the last subject is 
enrolled.  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 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 (see Section 6.2).  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. 
Treatment with pembrolizumab may continue for 24 months (103 weeks) from first dose of 
pembrolizumab provided subjects are tolerating the drug and not progressing.  In addition, 
pembrolizumab treatment can end for subjects with confirmed CR (or sCR for MM) if 
treatment has been administered for at least 24 weeks and 2 doses of pembrolizumab have 
been administered after confirmation of CR/sCR.  Subjects who have confirmed 

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progressive disease will come off treatment.  Note: If there is uncertainty regarding whether 
there is cancer progression, the subject may continue study treatment and remain under 
close observation (e.g., evaluated at 4- to 8-week intervals) pending confirmation of 
progression.  In particular, transient worsening of disease during temporary interruption of 
study therapy (e.g., for drug-related toxicity or intercurrent illness) may not indicate disease 
progression.  In such circumstances, and if medically appropriate, subjects may resume 
therapy and relevant clinical, laboratory, and/or radiographic assessments should be done 
to document whether tumor control can be maintained or whether actual disease 
progression has occurred. 
3.7 
ASSESSMENT OF DOSE-LIMITING TOXICITY 
In Part 1 the first 6 subjects enrolled will be evaluated for DLT.  The DLT review period is the 
first 6 weeks on treatment.  A DLT will be defined as the occurrence of any of the following 
study-drug-related AEs (note: AEs clearly related to disease progression or the subject’s 
current medical history and associated comorbidities will not be considered DLTs): 
1. Any Grade ≥3 non-hematologic toxicity (except Grade 3 nausea, vomiting, or diarrhea 
that respond to supportive therapy)  
2. Any of the following hematologic toxicities: 
a. Grade 4 neutropenia lasting >7 days.  
b. Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding, or any 
requirement for platelets transfusion.  
c. Grade ≥3 febrile neutropenia (temperature ≥38.5°C).  
d. Grade 4 anemia, unexplained by underlying disease.  
3. Dosing delay due to toxicity for >28 consecutive days. 
3.8 
DOSING DELAYS AND MODIFICATIONS 
Subjects should be followed closely for AEs or laboratory abnormalities that might indicate 
acalabrutinib- or pembrolizumab-related toxicity.  If a subject experiences a 
treatment-related DLT or other intolerable AE during the course of therapy, then 
acalabrutinib, pembrolizumab, or both drugs should be held, as necessary, until the AE 
resolves or stabilizes to an acceptable degree.  In cases where pembrolizumab is held, 
pembrolizumab should be restarted in agreement with its original dosing schedule 

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(every 3 weeks).  As appropriate, certain laboratory abnormalities may warrant more 
frequent monitoring (e.g., once per week) until abnormalities have recovered to Grade ≤1. 
Whenever possible, please discuss plans for delays or dose modifications with the medical 
monitor before implementation.  
Note:  Temporary withholding of study treatment for as little as 7 days can cause a transient 
worsening of disease and/or of constitutional symptoms. Refer to Section 3.6 for more 
information on assessing disease progression under these circumstances.  
3.8.1 
Dose Modifications for Acalabrutinib  
After the DLT review is cleared, the actions in Table 2 should be followed for the following 
toxicities: 
• 
Grade 4 neutropenia (<500/μL) for >7 days (neutrophil growth factors are permitted per 
American Society of Clinical Oncology [ASCO] guidelines [Smith 2015] and use must be 
recorded on the case report form [CRF]). 
• 
Grade 3 thrombocytopenia in presence of significant bleeding. 
• 
Grade 4 thrombocytopenia.  
• 
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 2 
Drug Discontinuation Actions for Acalabrutinib 
Occurrence 
Action 
1st – 2nd 
Hold acalabrutinib until recovery to Grade ≤1 or baseline; may restart at 
original dose level 
3rd 
Hold acalabrutinib until recovery to Grade ≤1 or baseline; restart at one 
dose level lower (100 mg QD) 
4th 
Discontinue acalabrutinib 
 
If acalabrutinib is reduced for apparent treatment-related toxicity, the dose need not be 
re-escalated, even if there is minimal or no toxicity with the reduced dose.  However, if the 
subject tolerates a reduced dose of acalabrutinib for ≥28 days then the dose may be 
increased to the next higher dose level, at the discretion of the investigator.  Such 

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re-escalation may be particularly warranted if further evaluation reveals that the AE that led 
to the dose reduction was not treatment-related.  However, the maximum dose of 
acalabrutinib is 100 mg BID for this protocol. 
Treatment with acalabrutinib should be withheld 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 withheld 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. 
For treatment-emergent hepatotoxicity in the combination arm only:  Important 
guidelines for treatment-emergent hepatotoxicity are provided in Section 3.8.2 for 
pembrolizumab.  In the combination arm, treatment with acalabrutinib should be withheld for 
Grade 3 or 4 hepatitis.  For Grade 4 events, acalabrutinib may be restarted only after 
discussion with the medical monitor.  For Grade 3 events, treatment with acalabrutinib can 
be considered after the liver function test (LFT) laboratory values have returned to Grade ≤1 
or to baseline. 
3.8.2 
Dose Modifications and Toxicity Management for Immune-Related 
AEs Associated with Pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology.  
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously.  Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab, administration of corticosteroids and/or 
other supportive care.  For suspected irAEs, ensure adequate evaluation to confirm etiology 
or exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, 
skin biopsy may be included as part of the evaluation.  Based on the severity of irAEs, 
withhold or permanently discontinue pembrolizumab and administer corticosteroids.  Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab 
are provided in Table 3. 
 

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Table 3 
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with 
Pembrolizumab 
General Instructions 
1. 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0  
and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last 
dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive 
treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-related 
AEs 
Toxicity Grade 
or Conditions 
(CTCAE v4.0) 
Action Taken to 
Pembrolizumab 
irAE Management with 
Corticosteroid and/or Other 
Therapies  
Monitor and Follow-up  
Pneumonitis  
Grade 2 
Withhold  
Administer corticosteroids (initial 
dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper 
 
Monitor participants for signs and symptoms 
of pneumonitis 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
Add prophylactic antibiotics for opportunistic 
infections 
Grade 3 or 4,  
or recurrent 
Grade 2 
Permanently 
discontinue 
Diarrhea / colitis  
Grade 2 or 3 
Withhold 
Administer corticosteroids (initial 
dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper 
 
Monitor participants for signs and symptoms 
of enterocolitis (i.e., diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (i.e., peritoneal signs 
and ileus). 
Participants with Grade ≥2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to rule 
out colitis.  
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
Grade 4 
Permanently 
discontinue 

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Table 3 
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with 
Pembrolizumab 
Immune-related 
AEs 
Toxicity Grade 
or Conditions 
(CTCAE v4.0) 
Action Taken to 
Pembrolizumab 
irAE Management with 
Corticosteroid and/or Other 
Therapies 
Monitor and Follow-up 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
Administer corticosteroids (initial 
dose of 0.5 to 1 mg/kg prednisone 
or equivalent) followed by taper 
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
Administer corticosteroids (initial 
dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper 
T1DM or 
hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
β-cell failure 
Withhold 
Initiate insulin replacement therapy 
for participants with T1DM  
Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.   
 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue a  
Hyperthyroidism  
Grade 2 
Continue  
Treat with non-selective beta-
blockers (e.g., propranolol) or 
thionamides as appropriate  
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue a 
Hypothyroidism 
Grade 2 to 4 
Continue  
Initiate thyroid replacement 
hormones (e.g., levothyroxine or 
liothyroinine) per standard of care 
Monitor for signs and symptoms of thyroid 
disorders.  
 

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Table 3 
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with 
Pembrolizumab 
Immune-related 
AEs 
Toxicity Grade 
or Conditions 
(CTCAE v4.0) 
Action Taken to 
Pembrolizumab 
irAE Management with 
Corticosteroid and/or Other 
Therapies 
Monitor and Follow-up 
Nephritis and 
renal dysfunction 
Grade 2 
Withhold  
Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper. 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
Based on type and severity of AE 
administer corticosteroids  
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events 
that require 
discontinuation 
include and not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
a 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; 
GI=gastrointestinal; irAE=immune-related AE; IV=intravenous; T1DM=Type 1 diabetes mellitus. 
Note:  For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to Grade ≤2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   

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3.8.3 
Supportive Care Guidelines for Pembrolizumab 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined below.  Note that several courses of steroid tapering 
may be necessary as symptoms may worsen when the steroid dose is decreased.  For each 
disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the investigator determines the events to be related 
to pembrolizumab.  
Note:  If after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below).  Refer to Section 3.8.2 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
• 
Pneumonitis 
o For Grade 2 events, treat with systemic corticosteroids.  When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3 to 4 (or recurrent Grade 2) events, permanently discontinue 
pembrolizumab; immediately treat with IV steroids.  Administer additional 
anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
• 
Diarrhea/Colitis 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider gastrointestinal consultation and endoscopy to confirm or rule 
out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  

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o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Type 1 Diabetes Mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
Grade ≥3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
o For T1DM or Grade 3 to 4 hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3 to 4 hyperglycemia associated with metabolic acidosis or 
ketonuria.  
 
Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
• 
Hypophysitis 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks.  Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3 to 4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids.  When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks.  Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
• 
Hyperthyroidism or Hypothyroidism 
Thyroid disorders can occur at any time during treatment.  Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
o Grade 2 hyperthyroidism events (and Grade 2 to 4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g., propranolol) are 
suggested as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3 to 4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 

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• 
Hepatic 
o For Grade 2 events, treatment with pembrolizumab should be withheld.  
Administer corticosteroids (initial dose of 0.5 to 1 mg/kg/day prednisone or 
equivalent) (KEYTRUDA package insert).  When LFT laboratory values resolve 
to baseline or return to Grade ≤1, then taper the corticosteroids over no fewer 
than 4 weeks while continuing to monitor LFTs at least weekly.  Further 
treatment with pembrolizumab can be considered after the LFT laboratory 
values have returned to Grade ≤1 or to baseline either during the steroid taper or 
after stopping corticosteroids. 
o For Grade 3 to 4 events, permanently discontinue pembrolizumab.  Treat with 
corticosteroids (initial dose 1 to 2 mg/kg/day prednisone or equivalent) 
(KEYTRUDA package insert) until LFT laboratory values resolve to baseline or 
return to Grade ≤1, and then taper the corticosteroids over no fewer than 
4 weeks while continuing to monitor LFTs at least weekly.  
• 
Renal Failure or Nephritis 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3 to 4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
• 
Management of Infusion Reactions 
o Signs and symptoms usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion.  
o Table 4 shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab. 

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Table 4 
Infusion Reaction Treatment Guidelines a 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hours 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
• IV fluids 
• Antihistamines 
• NSAIDS 
• Acetaminophen 
• Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the original 
infusion rate (e.g., from 100 mL/hr to 
50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the 
subject should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
Subject may be 
premedicated 1.5 hours 
(±30 minutes) prior to 
infusion of pembrolizumab 
with: 
• Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
• Acetaminophen 500 to 
1000 mg po (or 
equivalent dose of 
antipyretic). 

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Table 4 
Infusion Reaction Treatment Guidelines a 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
• IV fluids 
• Antihistamines 
• NSAIDS 
• Acetaminophen 
• Narcotics 
• Oxygen 
• Pressors 
• Corticosteroids 
• Epinephrine 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
Hospitalization may be indicated. 
Subject is permanently 
discontinued from further trial 
treatment administration. 
No subsequent dosing 
a 
Appropriate resuscitation equipment should be available in the room and a physician readily available during 
the period of drug administration. 
IV=intravenous; NCI-CTCAE=National Cancer Institute–Common Terminology Criteria for Adverse Events; 
NSAIDS=nonsteroidal anti-inflammatory drugs; po=by mouth.  
3.9 
CONCOMITANT THERAPY 
3.9.1 
Permitted Concomitant Therapy 
Antiemetics are permitted if clinically indicated. Standard supportive care medications are 
permitted as per institutional standards.   
For subjects considered at risk for tumor lysis syndrome:  Administer appropriate hydration and 
allopurinol or rasburicase per institutional standards before initiating treatment. 
For subjects at risk for pneumonitis:  In selected subjects (e.g., those with a history of recurrent 
pneumonias), anti-infectious prevention should be considered. Initiation of antibiotic prophylaxis 
against pneumocystis infection (e.g., with trimethoprim-sulfamethoxazole, dapsone, aerosolized 
pentamidine, or atovaquone) beginning before study drug administration may be warranted.  
Such support may also offer the benefit of reducing the risk for other bacterial infections 
(Stern 2014).  Prophylaxis with IV immunoglobulins (IVIG) may be appropriate in subjects with 

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low Ig levels (Raanani 2009).  Local practices or guidelines regarding infection prophylaxis may 
be followed.   
For subjects at risk for infections:  Bacterial/viral/fungal prophylaxis is allowed per institutional 
standards. 
3.9.2 
Guidelines for Use of CYP Inhibiting/Inducing Drugs 
At the systemic exposure levels expected in this study, acalabrutinib inhibition of CYP 
metabolism is not anticipated.  However, as discussed in Section 1.4.1, concomitant 
administration of acalabrutinib with a strong CYP3A inhibitor increased exposure by 
approximately 5-fold.  Conversely, concomitant administration of acalabrutinib with a strong 
CYP3A inducer has the potential to decrease acalabrutinib exposure and could reduce efficacy.  
Consequently, the concomitant use of strong inhibitors or inducers of CYP3A (see Appendix 2) 
should be avoided when possible.  If a subject requires treatment with a strong/moderate 
CYP3A inhibitor or strong CYP3A inducer while on-study, follow the acalabrutinib 
treatment/dosing instructions described in Section 3.10.7 and monitor the subject closely for 
potential toxicities.   
3.9.3 
Guideline for Use of Drugs that Affect Gastric pH 
The effect of agents that reduce gastric acidity (e.g., antacids or proton-pump inhibitors) on 
acalabrutinib absorption was evaluated in a healthy volunteer study (ACE-HV-004).  Results 
from this completed study indicate that subjects should avoid the use of calcium carbonate 
containing drugs or supplements for a period of at least 2 hours before and at least 2 hours after 
taking acalabrutinib.   
Use of omeprazole, esomeprazole, lansoprazole or any other proton pump inhibitors while 
taking acalabrutinib is not recommended due to a potential decrease in study drug exposure.  
However, the decision to treat with proton-pump inhibitors during the study is at the 
investigator’s discretion, with an understanding of the potential benefit to the subject’s 
gastrointestinal condition and a potential risk of decreased exposure to acalabrutinib. 
Although the effect of H2-receptor antagonists (such as famotidine or ranitidine) on acalabrutinib 
absorption has not been evaluated, if treatment with an H2-receptor antagonist is required, the 
H2-receptor antagonist should be taken approximately 2 hours after an acalabrutinib dose. 

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3.9.4 
Prohibited or Restricted Concomitant Therapy 
Any chemotherapy, anticancer immunotherapy, corticosteroids (at dosages equivalent to 
prednisone >20 mg/day), warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon), 
experimental therapy, and radiotherapy are prohibited.  
At study entry, subjects may be using topical or inhaled corticosteroids or low-dose steroids 
(≤10 mg of prednisone or equivalent per day) as therapy for comorbid conditions but use of 
corticosteroids as therapy of the lymphoid cancer is not permitted.  During study participation, 
subjects may also receive systemic or enteric corticosteroids at any required dosage as needed 
for treatment-emergent immune-mediated adverse reactions associated with pembrolizumab 
therapy (see Section 3.8).  
Live vaccines within 30 days before the first dose of trial treatment and while participating in the 
trial are prohibited.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine.  
Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed.  
However, intranasal influenza vaccines (e.g., FLUMIST®) are live attenuated vaccines and are 
not allowed. 
Use of calcium carbonate-containing drugs or supplements and short-acting H2-receptor 
antagonists should be avoided for at least 2 hours before or after acalabrutinib administration 
(see Section 3.10.7).For additional information on drugs with potential drug-drug interactions, 
refer to Section 3.10.7. 
3.10 
RISKS ASSOCIATED WITH STUDY TREATMENT 
3.10.1 
Risks Associated with Acalabrutinib 
The following summarizes the experience with acalabrutinib in hematological cancer studies.  
Full details regarding the clinical safety of acalabrutinib are presented in the acalabrutinib IB. 
3.10.1.1 
Contraindications 
No contraindications are known for acalabrutinib. 
3.10.1.2 
Warnings and Precautions 
• 
Hemorrhage 
Serious hemorrhagic events, including fatal events, have occurred in clinical trials with 
acalabrutinib.  

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Subjects receiving antithrombotic agents may be at increased risk of hemorrhage.  Use 
caution with antithrombotic agents and consider additional monitoring for signs of 
bleeding when concomitant use is medically necessary.  As a precaution, it is suggested 
that acalabrutinib be withheld for at least 3 days pre- and post-surgery (see 
Section 3.10.8).  
Subjects with hemorrhage should be managed per institutional guidelines with 
supportive care and diagnostic evaluations or as clinically indicated. 
• 
Infections  
Serious infections (bacterial, viral, and fungal), including fatal events, have occurred in 
clinical studies with acalabrutinib.  The most frequent reported Grade ≥3 infection was 
pneumonia (preferred term).  Consider prophylaxis in subjects who are at increased risk 
for opportunistic infections.  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.   
HBV reactivation and progressive multifocal leukoencephalopathy (PML) have occurred 
in clinical studies with acalabrutinib; see Section 3.10.5 and Section 4.1.14 for additional 
information and monitoring guidance for viral hepatitis, and see Section 3.10.3 for 
additional information and management guidance for signs and symptoms of PML.   
• 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias, including neutropenia, anemia, and 
thrombocytopenia, have occurred in clinical studies with acalabrutinib.  Blood counts 
should be monitored as specified in the Schedule of Assessments (Appendix 5 and 
Appendix 6) and as medically appropriate.  Refer to Section 3.8 for study drug 
modification guidance.  Subjects with cytopenias should be managed according to 
institutional guidelines with maximal supportive care and diagnostic evaluations as 
clinically indicated.  
• 
Second Primary Malignancies 
Second primary malignancies, including solid tumors and skin cancers, have been 
reported in patients treated with acalabrutinib.  The most frequent second primary 
malignancy was skin cancer (basal cell carcinoma).  Subjects should be monitored for 
signs and symptoms of malignancy.  Subjects who develop a second primary 
malignancy should be managed according to institutional guidelines with diagnostic 

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evaluations as clinically indicated, and it may be necessary for subjects to permanently 
discontinue study treatment.  Continuation of acalabrutinib treatment should be 
discussed with the medical monitor.  Please refer to Section 6.2.3 for second primary 
malignancy reporting guidance. 
• 
Atrial Fibrillation 
Atrial fibrillation or flutter have occurred in clinical studies with acalabrutinib, particularly 
in subjects with cardiac risk factors, hypertension, diabetes mellitus, acute infections, 
and a previous history of atrial fibrillation.  Monitor for symptoms of atrial fibrillation and 
atrial flutter (e.g., palpitations, dizziness, syncope, chest pain, dyspnea) and obtain an 
ECG as appropriate.  Subjects with atrial fibrillation should be managed per institutional 
guidelines with supportive care and diagnostic evaluation as clinically indicated.   
3.10.2 
Risks Associated with Pembrolizumab 
The following summarizes significant risks with pembrolizumab based on KEYTRUDA 
Prescribing Information Contraindications and Warnings & Precautions.  For additional 
information, please refer to the KEYTRUDA Prescribing Information. 
3.10.2.1 
Contraindications 
No contraindications are known for pembrolizumab. 
3.10.2.2 
Warnings and Precautions 
• 
Immune-Mediated Pneumonitis 
Pembrolizumab can cause immune-mediated pneumonitis, including fatal cases. Monitor 
subjects for signs and symptoms of pneumonitis. Evaluate subjects with suspected 
pneumonitis with radiographic imaging and follow the treatment guidance in 
Section 3.8.3.  
• 
Immune-Mediated Colitis 
Pembrolizumab can cause immune-mediated colitis.  Monitor subjects for signs and 
symptoms of colitis and follow the treatment guidance in Section 3.8.3.   
• 
Immune-Mediated Hepatitis 
Pembrolizumab can cause immune-mediated hepatitis.  Monitor subjects for changes in 
liver function and follow the treatment guidance in Section 3.8.3. 

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• 
Immune-Mediated Endocrinopathies  
o Hypophysitis:  Pembrolizumab can cause hypophysitis.  Monitor subjects for 
signs and symptoms of hypophysitis (including hypopituitarism and adrenal 
insufficiency) and follow the treatment guidance in Section 3.8.3. 
o Thyroid disorders:  Pembrolizumab can cause thyroid disorders, including 
hyperthyroidism, hypothyroidism and thyroiditis.  Monitor subjects for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders, and follow the treatment guidance in Section 3.8.3. 
o Type 1 diabetes mellitus:  Pembrolizumab can cause type 1 diabetes mellitus, 
including diabetic ketoacidosis.  Monitor subjects for hyperglycemia or other 
signs and symptoms of diabetes and follow the treatment guidance in 
Section 3.8.3.   
 
• 
Immune-Mediated Nephritis and Renal Dysfunction 
Pembrolizumab can cause immune-mediated nephritis.  Monitor subjects for changes in 
renal function and follow the treatment guidance in Section 3.8.3. 
• 
Immune-Mediated Skin Adverse Reactions 
Immune-mediated rashes, including Stevens-Johnson syndrome, toxic epidermal 
necrolysis (some cases with fatal outcome), exfoliative dermatitis, and bullous 
pemphigoid can occur.  Monitor subjects for suspected severe skin reactions and 
exclude other causes.  Based on the severity of the adverse reaction, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids.  For signs or 
symptoms of Stevens-Johnson syndrome or toxic epidermal necrolysis, withhold 
pembrolizumab and refer the subject for specialized care for assessment and treatment. 
If Stevens-Johnson syndrome or toxic epidermal necrolysis is confirmed, permanently 
discontinue pembrolizumab. 
• 
Other Immune-Mediated Adverse Reactions 
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any 
organ system or tissue in patients receiving pembrolizumab.  While immune-mediated 
adverse reactions usually occur during treatment with PD-1/PD-L1 blocking antibodies, 
they may occur after discontinuation of treatment.  For suspected immune-mediated 
adverse reactions, ensure adequate evaluation to confirm etiology or exclude other 
causes.  Based on the severity of the adverse reaction, withhold pembrolizumab and 
administer corticosteroids.  Upon improvement to Grade 1 or less, initiate corticosteroid 

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taper and continue to taper over at least 1 month.  Based on limited data from clinical 
studies in subjects whose immune-related adverse reactions could not be controlled with 
corticosteroid use, administration of other systemic immunosuppressants can be 
considered.  Resume pembrolizumab when the immune-mediated adverse reaction 
remains at Grade 1 or less following corticosteroid taper.  Permanently discontinue 
pembrolizumab for any Grade 3 immune-mediated adverse reaction that recurs and for 
any life-threatening immune-mediated adverse reaction.  In organ transplant recipients, 
consider the benefit of treatment with pembrolizumab versus the risk of possible organ 
rejection.  
• 
Infusion-Related Reactions 
Pembrolizumab can cause severe or life-threatening infusion-related reactions, including 
hypersensitivity and anaphylaxis.  Monitor subjects for signs and symptoms of infusion-
related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, 
hypoxemia, and fever. Follow the treatment guidance in Section 3.8.3. 
• 
Complications of Allogeneic HSCT 
Allogeneic HSCT after treatment with pembrolizumab:  Immune-mediated complications, 
including fatal events, occurred in patients who underwent HSCT after being treated with 
pembrolizumab.  Monitor for hepatic veno-occlusive disease, Grade 3 or 4 acute graft-
versus-host disease (GVHD) including hyperacute GVHD, steroid-requiring febrile 
syndrome, and other immune-mediated adverse reactions.  Transplant-related mortality 
has occurred. 
Allogeneic HSCT prior to treatment with pembrolizumab: In patients with a history of 
allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment 
with pembrolizumab.  Patients who experienced GVHD after their transplant procedure 
may be at increased risk for GVHD after treatment with pembrolizumab.  In subjects with 
a history of allogeneic HSCT, consider the benefit of treatment with pembrolizumab 
versus the risk of GVHD. 
• 
Increased Mortality in Patients with Multiple Myeloma When Pembrolizumab is Added 
to a Thalidomide Analogue and Dexamethasone 
Treatment of subjects with multiple myeloma with a PD-1 or PD-L1 blocking antibody in 
combination with a thalidomide analogue plus dexamethasone is not recommended 
outside of controlled clinical trials.  

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• 
Embryo-Fetal Toxicity 
Based on its mechanism of action, pembrolizumab can cause fetal harm when 
administered to a pregnant woman. Advise women of reproductive potential of the 
potential risk to a fetus and to use effective method of contraception during treatment 
and for 120 days after the last dose of pembrolizumab (see Section 3.10.9). 
3.10.3 
Progressive Multifocal Leukoencephalopathy  
Cases of PML have occurred in clinical studies with acalabrutinib.  Signs and symptoms of PML 
may include cognitive and behavioral changes, language disturbances, visual disturbances, 
sensory deficits, weakness, and coordination and gait difficulties.  If PML is suspected, hold 
further treatment with acalabrutinib until PML is excluded. A diagnostic evaluation may include 
(but is not limited to): 
• 
Neurologic consultation 
• 
Brain magnetic resonance imaging (MRI) 
• 
PCR analysis for JC virus DNA in cerebrospinal fluid 
If PML is confirmed, permanently discontinue acalabrutinib. 
3.10.4 
Transaminase Elevations for Acalabrutinib in Combination with 
Pembrolizumab 
Serum transaminase elevations (including elevations of AST and/or ALT) may be increased in 
severity and frequency in subjects exposed to the combination of acalabrutinib and 
pembrolizumab, as compared with subjects exposed to pembrolizumab monotherapy and 
subjects exposed to acalabrutinib monotherapy. Routine monitoring for serum transaminase 
elevations must follow the Schedule of Assessments (serum chemistry laboratory assessments 
in Appendix 5 and Appendix 6).  Dosing delays and modifications for subjects with serum 
transaminase elevations must follow guidance provided in Section 3.8.  
3.10.5 
Hepatitis B Reactivation 
Cases of hepatitis B virus (HBV) reactivation have occurred in clinical studies with acalabrutinib.  
Therefore, subjects with a history of HBV infection should be monitored every 3 months with a 
quantitative PCR test for HBV DNA.  Monitoring every 3 months should continue until 12 months 
after the last dose of acalabrutinib.  Any subject with a rising viral load (above lower limit of 
detection) should discontinue study drug and have antiviral therapy instituted and a consultation 

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with a physician with expertise in managing hepatitis B.  Insufficient data exist regarding the 
safety of resuming acalabrutinib in subjects who develop HBV reactivation.  
3.10.6 
Dietary Restrictions 
Acalabrutinib can be taken with or without food.  Because acalabrutinib is metabolized by 
CYP3A, subjects should be strongly cautioned against excessive consumption of grapefruit, 
grapefruit juice, or Seville orange juice (which contain potent CYP3A inhibitors) or using herbal 
remedies or dietary supplements (in particular, St John’s wort, which is a potent CYP3A 
inducer). 
Otherwise subjects should maintain a normal diet unless modifications are required to manage 
an AE such as diarrhea, nausea, or vomiting. 
3.10.7 
Drug-Drug Interactions 
At the systemic exposure levels expected in this study, acalabrutinib inhibition of CYP 
metabolism is not anticipated.  However, acalabrutinib is metabolized by CYP3A.  Concomitant 
administration of acalabrutinib with a strong CYP3A and P-glycoprotein (P-gp) inhibitor, 
itraconazole increased exposure by approximately 5-fold.  Conversely, concomitant 
administration of acalabrutinib with a strong CYP3A inducer, rifampin, decreases acalabrutinib 
exposure and could reduce efficacy.  Consequently, the concomitant use of strong 
inhibitors/inducers of CYP3A (see Appendix 2) should be avoided when possible.   
If a subject requires short-term treatment with a strong or moderate CYP3A inhibitor (such as 
anti-infectives for up to 7 days), interrupt acalabrutinib treatment.   
If a subject requires treatment with a strong CYP3A inducer, increase the acalabrutinib dose to 
200 mg BID during concomitant administration with the strong inducer and return to 
recommended dose of 100 mg BID after stopping the strong CYP3A inducer.  See Appendix 2 
for a list of strong CYP3A inhibitors/inducers. 
Based on these considerations, subjects who require therapy with drugs listed in Appendix 2 
should not be enrolled into the study.  If medically justified, subjects may be enrolled if such 
inhibitors or inducers can be discontinued or alternative drugs that do not affect these enzymes 
can be substituted within 7 days before first dose of study drug.  If a subject requires a strong 
CYP3A inhibitor while on study, monitor the subject closely for potential drug-related toxicities.   
The effect of agents that reduce gastric acidity (e.g., antacids or proton-pump inhibitors,) on 
acalabrutinib absorption was evaluated in a healthy volunteer study (ACE-HV-004).  Results 

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from this completed study suggest subjects should avoid the use of calcium carbonate-
containing drugs or supplements for a period of at least 2 hours before and at least 2 hours after 
taking acalabrutinib.   
Use of omeprazole, lansoprazole or esomeprazole or any other proton-pump inhibitors while 
taking acalabrutinib is not recommended due to a potential decrease in study drug exposure.  
However, the decision to treat with proton-pump inhibitors during the study is at the 
investigator’s discretion, with an understanding of the potential benefit to the subject’s 
gastrointestinal condition and a potential risk of decreased exposure to acalabrutinib.  
Although the effect of H2-receptor antagonists (such as famotidine or ranitidine) on acalabrutinib 
absorption has not been evaluated, if treatment with an H2-receptor antagonist is required, the 
H2-receptor antagonist should be taken approximately 2 hours after an acalabrutinib dose. 
No formal PK drug interaction studies have been conducted with pembrolizumab. 
3.10.8 
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. 
3.10.9 
Reproductive Toxicity 
3.10.9.1 
Reproductive Toxicity Summaries for Study Drugs 
Acalabrutinib 
Acalabrutinib has been evaluated in a combined definitive fertility and embryofetal development 
(EFD) study in rats.  Effects of acalabrutinib on embryofetal development was also evaluated in 
a definitive EFD study in rabbits.  No effects on fertility or EFD were observed in rats at 
exposures 16 times the human exposure at the recommended dose.  In rabbits, acalabrutinib 
was not teratogenic at any dose level.  Decreased fetal body weight and delayed ossification 
were observed at exposure levels that produced maternal toxicity, which were approximately 
4-fold greater than the human exposure levels at the recommended dose.  Refer to the current 
acalabrutinib IB for further details. 
There has been one reported pregnancy in a subject exposed to acalabrutinib; the subject was 
exposed during the first trimester.  Acalabrutinib was discontinued, and the subject gave birth to 
a live, full-term male infant by cesarean section. 

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The potential for acalabrutinib to be excreted in breast milk of nursing mothers is unknown.  In 
studies of lactating rats, acalabrutinib and its metabolite ACP-5862 were measured in milk and 
in the plasma of nursing pups on Postnatal Day 12. 
There have been no positive genotoxicity findings during development of acalabrutinib.  In 
addition, based on modeled estimates of fetal exposures to active product ingredient levels in 
ejaculated material using assumptions for small molecules, direct embryofetal exposure (i.e., 
female partner exposure following a vaginal dose of estimated seminal concentration) and 
male-mediated developmental risk with acalabrutinib treatment is considered to be very low, 
and risk mitigation measures for male-mediated developmental risk are therefore not required 
for acalabrutinib.   
Pembrolizumab 
Based on its mechanism of action, pembrolizumab can cause fetal harm when administered to a 
pregnant woman.  There are no available human data informing the risk of embryo-fetal toxicity. 
In animal models, the PD-1/PD-L1 signaling pathway is important in the maintenance of 
pregnancy through induction of maternal immune tolerance to fetal tissue (see KEYTRUDA 
Prescribing Information). Human IgG4 (immunoglobulins) are known to cross the placenta; 
therefore, pembrolizumab has the potential to be transmitted from the mother to the developing 
fetus.   
3.10.9.2 
Guidance and Definitions 
Guidance 
For acalabrutinib:  Women of childbearing potential (WOCBP) must use highly effective forms 
of contraception while in the study and for 2 days after the last dose of acalabrutinib.  For male 
subjects with a pregnant or non-pregnant WOCBP partner, no contraception measures or 
restrictions are required with regard to acalabrutinib. Contraception measures and restrictions 
on sperm donation are not required for male subjects who are treated with acalabrutinib only. 
For pembrolizumab:  WOCBP must use highly effective forms of contraception while in the 
study and for 120 days after the last dose of pembrolizumab.  Male subjects must use highly 
effective forms of contraception with the addition of a barrier method (condom) during the study 
and for 120 days after the last dose of pembrolizumab.  Even with medical confirmation of 
vasectomy surgical success, vasectomized male subjects should still use a barrier method 
(condom) with WOCBP partners during the same timeframe, to prevent possible direct exposure 

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of a developing fetus to pembrolizumab in seminal fluid.  Sperm donation is not permitted during 
the same timeframe. 
Subjects in clinical studies should promptly notify the investigator if they or their partner become 
pregnant during the study or within 2 days after the last dose of acalabrutinib, or 120 days after 
the last dose of pembrolizumab, whichever is longer.  If a female subject becomes pregnant 
during the treatment period, she must discontinue acalabrutinib.  Pregnancy in a subject or a 
male subject’s partner must be reported as outlined in Section 6.2.4. 
Definitions for WOCBP and for Subjects of Non-Reproductive Potential 
WOCBP are women who are fertile following menarche and until becoming postmenopausal 
unless permanently sterile; permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women will be considered of non-reproductive potential if they meet any of the following criteria:  
1) 
Postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women <45 years of age a high follicle stimulating hormone [FSH] level 
in the postmenopausal range may be used to confirm a postmenopausal 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);  
2) 
Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or 
bilateral tubal ligation/occlusion at least 6 weeks prior to screening;  
3) 
Have a congenital or acquired condition that prevents childbearing. 
Men are considered to be of non-reproductive potential if they are permanently sterile due to 
bilateral orchidectomy. 
Definition for 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 

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• 
Intrauterine device (IUD) or intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Vasectomy of a female subject’s sole male partner (with medical assessment and 
confirmation of vasectomy surgical success) 
• 
Sexual abstinence (only if refraining from heterosexual intercourse during the entire period 
of risk associated with the study treatments) 
 
Hormonal contraception may be susceptible to interaction with study or other drugs, which may 
reduce the efficacy of the contraception method. 
Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
only if it is consistently employed during the entire period of risk associated with the study 
treatments and reflects the subject’s preferred and usual lifestyle.  Periodic abstinence (e.g., 
calendar, ovulation, sympto-thermal, and post-ovulation methods) and withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods 
of contraception.  Female condom and male condom should not be used together as an 
effective method of contraception.   
If a contraceptive method is restricted by local regulations/guidelines, then it does not qualify as 
an acceptable highly effective method of contraception for subjects participating at sites in the 
relevant country/region. 
3.10.10 
Overdose Instructions 
Study drug overdose is the accidental or intentional use of the drug in an amount higher than 
the dose being studied.  An overdose or incorrect administration of study drug is not an AE 
unless it results in untoward medical effects.  Any study drug overdose or incorrect 
administration of study drug should be noted on the Study Drug Administration eCRF.  All AEs 
associated with an overdose or incorrect administration of study drug should be recorded on the 
Adverse Event eCRF.  If the associated AE fulfills serious criteria, the event should be reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event). 
For any subject experiencing an acalabrutinib overdose, observation for any symptomatic side 
effects should be instituted, and vital signs, 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 

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ingestion is recent and substantial, and if there are no medical contraindications, use of gastric 
lavage or induction of emesis may be considered. 
There is no information on over dosage with KEYTRUDA (refer to KEYTRUDA Prescribing 
Information). 
3.11 
WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT  
Subjects may be withdrawn from study treatment for the following reasons: 
• 
Progressive disease 
• 
Completed treatment 
• 
Start of alternative anticancer therapy 
• 
Pregnancy 
• 
Adverse event 
• 
Investigator decision 
• 
Subject’s withdrawal of consent from the study 
• 
Decision by sponsor to terminate the study 
• 
Subject lost to follow-up 
• 
Death 
• 
Other 
3.12 
REASONS FOR STUDY EXIT 
Reasons for study exit are: 
• 
Subject’s withdrawal of consent from study 
• 
Decision by sponsor to terminate the study 
• 
Subject lost to follow-up 
• 
Death 
3.13 
DATA AND SAFETY MONITORING 
This trial will be monitored in accordance with the sponsor’s pharmacovigilance procedures.  
AEs and SAEs will be reviewed internally on an ongoing basis to identify safety concerns.  

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Periodic conference calls with the investigators and applicable site staff will be conducted to 
discuss study progress, obtain investigator feedback and exchange, and discuss "significant 
safety events" (i.e., AEs leading to dose reductions, related SAEs, and deaths).  In addition, in 
Part 1, a mandatory safety teleconference will occur before Part 1 is expanded to up to 
24 subjects.  In Part 2, teleconferences with investigators and applicable site staff will be 
conducted or written communications sent to discuss study progress, obtain investigator 
feedback and exchange, and discuss “significant safety events” (i.e., AEs leading to dose 
reductions, related SAEs, and deaths) on an as needed basis. 
 
STUDY ACTIVITIES AND ASSESSMENTS 
The schedule of events is provided in Appendix 5 for Parts 1 and 2, and Appendix 6 for Part 3.  
Descriptions of the scheduled evaluations are outlined below and complete information on study 
drug and dosing is provided in Section 3.4. 
Before study entry, throughout the study, and at the follow-up evaluation, various clinical and 
diagnostic laboratory evaluations are outlined.  The purpose of obtaining these detailed 
measurements is to ensure adequate safety and tolerability assessments.  Clinical evaluations 
and laboratory studies may be repeated more frequently if clinically indicated.  This study will 
primarily use central laboratory testing for safety laboratory evaluations.  Samples from sites’ 
local laboratories will be used if central laboratory testing is unavailable. 
4.1 
DESCRIPTION OF PROCEDURES 
4.1.1 
Informed Consent 
The subject must read, understand and sign the IRB/IEC approved ICF confirming his or her 
willingness to participate in this study before initiating any screening activity that is not 
considered standard of care by institutional standards.  Subjects must also grant permission to 
use protected health information if required by local regulations. 
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, responses, and duration of response to these treatments also will be recorded. 

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4.1.3 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 6.1.  The AE reporting period 
is described in Section 6.2.1.  Important additional requirements for reporting SAEs are 
explained in Section 6.2. 
4.1.4 
Concomitant Medications and Therapy 
Document all concomitant medications and procedures from within 28 days before the start of 
study drug administration through 30 days after the last dose of study drug. 
For subjects with MF, record all transfusions of blood products (e.g., red blood cells or platelets) 
within 12 weeks before the first study dose and throughout the study period.   
4.1.5 
Confirmation of Eligibility 
Subject eligibility for enrollment will be assessed as described in Section 3.3.  All screening 
procedures, unless otherwise indicated, should be completed within 28 days of the first dose of 
study drug. 
4.1.6 
ECOG Performance Status 
The ECOG performance index is provided in Appendix 1. 
4.1.7 
Physical Examination, Vital Signs, Height, and 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. 
Physical examinations will be done during the treatment period and at the safety follow-up visits.  
For all subjects except those with MM or MF, the following B symptoms will be collected at each 
examination:   
• 
Unintentional weight loss of normal body weight over a period of ≤6 months 
• 
Disease-associated intermittent fevers ≥38°C 
• 
Drenching sweats, especially at night 
Vital signs (blood pressure, heart rate, and body temperature) will be assessed after the subject 
has rested in the sitting position.   

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4.1.8 
Bone Marrow Aspirate and Biopsy 
A bone marrow aspirate and biopsy will be done at screening or up to 60 days before the first 
dose of study drugs for all subjects.  Per the current response criteria (Bladé 1998; Durie 2006; 
Hallek 2008; Owen 2013; Tefferi 2013; Cheson 2014), a bone marrow aspirate/biopsy will also 
be required at any time on study to confirm a CR, and may be used to confirm a PR in some 
cases (see Section 4.2).  A bone marrow aspirate and biopsy will also be done at Week 52 and 
as clinically indicated.  Note that the Tefferi criteria for response in MF (see Table 9) require 
that, for all response categories, the benefit must last for ≥12 weeks to qualify as a response; 
thus, a second bone marrow evaluation must be done ≥12 weeks later to confirm CR or bone 
marrow PR response.  For subjects with MF it might only be possible to obtain a bone marrow 
biopsy as sometimes excessive fibrosis prevents bone marrow aspiration.  Bone marrow 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.  
With subject consent, biomarker and correlative studies on excess bone marrow (if available) 
will be done by the sponsor or designee; per the protocol, bone marrow will be collected at 
screening, on study, and at Week 52.  Refer to the study manual for sample handling and 
shipment instructions. 
4.1.9 
Electrocardiogram  
Subjects should be in supine position and resting for at least 10 minutes before the Screening 
ECG.  If an unscheduled ECG is done at any time, then an electrolyte panel (i.e., calcium, 
magnesium, and potassium) must be done to coincide with the ECG testing. 
4.1.10 
Urine or Serum Pregnancy Test 
Pregnancy tests will be required only for women of childbearing potential.  Women of 
childbearing potential must have a negative urine or serum pregnancy testing within 72 hours 
prior to receiving the first dose of study medication.  If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test is required.  Testing will be done by a local or 
central laboratory as listed on the investigator’s Form FDA 1572. 
4.1.11 
Hematology 
Hematology studies must include complete blood count (CBC) with peripheral blood smear and 
differential, including, but not limited to white blood cell (WBC) count, hemoglobin, hematocrit, 

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platelet count, ANC, and absolute lymphocyte count (ALC).  Testing will be done by a local or 
central laboratory as listed on the investigator’s Form FDA 1572. 
4.1.12 
Serum Chemistry 
Chemistry will include albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood urea 
nitrogen (BUN), bone-specific alkaline phosphatase, calcium, chloride, creatinine, c-terminal 
telopeptide, glucose, lactate dehydrogenase (LDH), magnesium, phosphate/phosphorus, 
potassium, sodium, total bilirubin, total protein, and uric acid.  If an unscheduled ECG is done at 
any time, then an electrolyte panel (i.e., calcium, magnesium, and potassium) must be done to 
coincide with the ECG testing.  Testing will be done by a local or central laboratory as listed on 
the investigator’s Form FDA 1572. 
4.1.13 
Thyroid Panel 
The thyroid panel will include total triiodothyronine (T3), free thyroxine (T4), and thyroid 
stimulating hormone (TSH).  Testing will be done by a local or central laboratory as listed on the 
investigator’s Form FDA 1572. 
4.1.14 
Hepatitis B and C Testing 
Hepatitis serology testing must include HBsAg, hepatitis B surface antibody (anti-HBs), 
anti-HBc, and hepatitis C antibody.  In addition, any subjects testing positive for any hepatitis 
serology must have PCR testing during screening and on study (see Appendix 5 and 
Appendix 6 and exclusion criterion #30).  Testing will be done by a local or central laboratory.   
Subjects who are anti-HBc positive (or have a known history of HBV) should have quantitative 
PCR testing for HBV DNA performed during screening and every 3 months as described in 
Section 3.10.5.  Following study drug discontinuation, monitoring should continue every 
3 months until 12 months after last dose of study drug(s).  Any subject with a rising viral load 
(above lower limit of detection) should discontinue study drug and have antiviral therapy 
instituted and a consultation with a physician with expertise in managing hepatitis B.  Because 
IVIGs may cause false positive hepatitis serology, monthly PCR testing is not required in 
subjects who are currently receiving or received prophylactic IVIG within 3 months before study 
enrollment and have a documented negative anti-HBc test before the initiation of IVIG therapy.  
Additional PCR testing should be performed when clinically indicated (e.g., in the setting of 
rising transaminase levels).   

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Subjects with a known history of hepatitis C or who are hepatitis C antibody-positive should 
have quantitative PCR test for HCV DNA performed during screening and at Weeks 13 and 25.  
No further testing beyond Week 25 is necessary if PCR results are negative.   
Refer to Section 3.10.5, Appendix 5, and Appendix 6 regarding monitoring of subjects who are 
anti-HBc positive or hepatitis C antibody-positive, or who have a known history of HBV or HCV 
infection. 
4.1.15 
Urinalysis 
Urinalysis includes pH, ketones, specific gravity, bilirubin, N-terminal telopeptide, protein, blood, 
and glucose.  Testing will be done by a local or central laboratory as listed on the investigator’s 
Form FDA 1572.  
4.1.16 
T/B/NK Cell Count 
Flow cytometry testing for CD3+, CD4+, CD8+, CD19+, and CD16/56+ cells.  Testing will be 
done by a local or central laboratory as listed on the investigator’s Form FDA 1572. 
4.1.17 
Serum Immunoglobulin  
Testing for IgG, IgM, and IgA will be done by a local or central laboratory as listed on the 
investigator’s Form FDA 1572. 
4.1.18 
Disease Markers for Subjects with MM, WM, and MF 
MM Subjects 
Testing for serum M-protein levels (by serum protein electrophoresis [SPEP] and serum 
immunofixation electrophoresis [SIFE]), serum-free light chains (SFLC), urine M-protein levels 
(by urine serum protein electrophoresis [UPEP] and urine immunofixation electrophoresis 
[UIFE]), and serum β2-microglobulin will be done by a local or central laboratory as listed on the 
investigator’s Form FDA 1572. 
WM Subjects 
Serum M-protein levels (by SPEP and SIFE) will be done by a local or central laboratory as 
listed on the investigator’s Form FDA 1572. 
MF Subjects 
Molecular disease markers (Janus kinase 2 [JAK2], calreticulin [CAL-R], and Additional Sex 
Combs-Like 1 [ASXL1]) to be done at baseline and repeated as clinically indicated (at the 

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investigator’s discretion) to assess molecular response (see Section 4.2).  Testing will be done 
by a local or central laboratory as listed on the investigator’s Form FDA 1572. 
4.1.19 
Skeletal Survey for MM Subjects 
Standard lateral radiograph of the skull, anterioposterior and lateral views of the spine, and 
anterioposterior views of the pelvis, ribs, femur, and humerus are required at screening or 
baseline (i.e., before the first dose of study drug), at Week 52, and as clinically indicated.  
Radiographic imaging and analysis will be performed at the study center’s local laboratory or 
other clinical laboratory listed on the investigator’s Form FDA 1572.   
4.1.20 
Pharmacodynamics and Biomarker Studies 
4.1.21 
 
CCI
CCI
CCI

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CCI

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CCI

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4.1.22 
Follow-up Post Allogenic Stem Cell Transplant 
For subjects who have an allogeneic stem cell transplant (SCT) within 24 months of last dose of 
pembrolizumab, transplant parameters will be collected, and specific events will be collected for 
18 months from the date of the allogeneic transplant, to include graft-versus-host-disease (acute 
and/or chronic), veno-occlusive disease, febrile syndrome (a steroid-requiring febrile illness 
without an infectious cause), and encephalitis, for all grades, and regardless of relationship to 
study drug.  Additional medically important adverse events post-allogeneic SCT may be 
submitted at the investigator’s discretion.  If available and relevant to an event post-allogeneic 
SCT, concomitant medications and/or laboratory results may also be reported. 
4.1.23 
Myeloproliferative Neoplasm Symptom Assessment Form Total 
Symptom Score  
MPN-SAF TSS will be assessed for subjects with MF (Part 3 only) on the same schedule as 
MRI/CT scans (i.e., at the end of Week 6, end of Week 15, end of Week 24, every 9 weeks 
through Week 52, and every 12 weeks thereafter, or more frequently at investigator discretion).  
Please refer to the MPN-SAF TSS Manual for this study for instructions on administering this 
questionnaire. 
4.1.24 
Early Termination Visit 
An early termination visit is required for safety assessments as outlined in the Schedules of 
Assessments (see Appendix 5 and Appendix 6).  The early termination visit is not required for 
subjects who discontinue from the study within 10 days after a scheduled study visit. 
4.1.25 
Study Drug Accountability 
See Section 7.6. 
4.2 
INVESTIGATOR’S ASSESSMENT OF RESPONSE TO TREATMENT 
The investigator must rate the response of the subjects as outlined below: 
• 
NHL, Hodgkin lymphoma, or RS refer to Table 5 
• 
CLL/SLL refer to Table 6 
• 
WM refer to Table 7 
• 
MM refer to Table 8 
• 
MF refer to Table 9 

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Table 5 
Response Assessment Criteria for Lymphoma  
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 (e.g., 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 or 5+ 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 mm×0 mm 
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  

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Table 5 
Response Assessment Criteria for Lymphoma  
Response and Site 
PET-CT-Based Response 
CT-Based Response 
 
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  
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 one 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 ≤2 cm 
1.0 cm for lesions >2 cm 
In the setting of splenomegaly, 
the splenic length must increase 

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Table 5 
Response Assessment Criteria for Lymphoma  
Response and Site 
PET-CT-Based Response 
CT-Based Response 
by >50% of the extent of its prior 
increase beyond baseline (e.g., 
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 (e.g., 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  
Cheson 2014. 
5PS=5-point scale; CT=computed tomography; FDG=fluorodeoxyglucose; GI=gastrointestinal ; 
IHC=immunohistochemistry; LDi=longest transverse diameter of a lesion; MRI=magnetic resonance imaging; 
PET=positron emission tomography; PPD=cross product of the LDi and perpendicular diameter; SDi=shortest axis 
perpendicular to the LDi; SPD=sum of the product of the perpendicular diameters for multiple lesions. 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to consider 
a score of 3 as inadequate response (to avoid undertreatment). Measured dominant lesions: Up to six of the 
largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two diameters. 
Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal 
and retroperitoneal areas. Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI 
involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not selected as 
measured, dominant disease and truly assessable disease should be considered not measured. These sites 
include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not 
meet the requirements for measurability but are still considered abnormal, as well as truly assessable disease, 
which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including 
pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot 
be confirmed and followed by imaging. In Waldeyer’s ring or in extranodal sites (e.g., 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 (e.g., 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.  

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Table 6 
Response Assessment Criteria for CLL/SLL  
Response 
Lymphocytes 
Bone Marrow 
Physical Examination b (Nodes, 
Liver, Spleen) 
Peripheral Blood 
CR a 
Lymphocytes <4×109/L 
Normocellular 
<30% lymphocytes 
No B-lymphoid nodules 
Normal (e.g., no lymph nodes 
>1.5 cm) 
ANC >1.5×109/L c 
Platelets >100×109/L c 
Hemoglobin >11.0 g/dL 
(untransfused) b 
CRi 
Lymphocytes <4×109/L 
Hypocellular 
<30% lymphocytes 
Normal (e.g., no lymph nodes 
>1.5 cm) 
Persistent anemia, 
thrombocytopenia, or neutropenia 
related to drug toxicity 
nPR 
CR with the presence of lymphoid nodules in the bone marrow which reflect residual disease 
PR a 
Lymphocytes <5×109/L  
Or 
≥50% decrease from baseline 
 
Not assessed 
≥50% reduction in lymphadenopathy d 
and/or in spleen or liver enlargement 
ANC >1.5×109/L 
Or 
Platelets >100×109/L or 
≥50% improvement over baseline b 
Or 
Hemoglobin >11.0 g/dL or 
≥50% improvement over baseline 
(untransfused) c 
PRL a 
Lymphocytes ≥5×109/L 
And 
<50% decrease from baseline 
 
 
Not assessed 
≥50% reduction in lymphadenopathy d 
and/or in spleen or liver enlargement 
ANC >1.5×109/L 
Or 
Platelets >100×109/L or 
≥50% improvement over baseline c 
Or 
Hemoglobin >11.0 g/dL or 
≥50% improvement over baseline 
(untransfused) c 

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Table 6 
Response Assessment Criteria for CLL/SLL  
Response 
Lymphocytes 
Bone Marrow 
Physical Examination b (Nodes, 
Liver, Spleen) 
Peripheral Blood 
SD 
Absence of PD and failure to achieve at least a PR 
PD a 
Lymphocytes ≥50% increase 
over baseline  
 
Not assessed (except 
to confirm PD as 
assessed by 
progressive 
cytopenias) 
Appearance of any new lesion or de 
novo appearance of hepatomegaly or 
splenomegaly 
Or 
Increase ≥50% in lymphadenopathy 
Or 
Increase ≥50% in hepatomegaly 
Or  
Increase ≥50% in splenomegaly 
Platelets decrease of ≥50% from 
baseline secondary to CLL or 
<100,000 µL and worsening bone 
marrow due to CLL 
Or 
Hemoglobin decrease of >2 g/dL 
from baseline secondary to CLL or 
decrease to <100 g/L and 
worsening bone marrow due to 
CLL 
Modified From Hallek 2008. 
ANC=absolute neutrophil count; CLL= chronic lymphocytic leukemia; CR=complete remission (response); CRi=CR with incomplete bone marrow recovery; 
nPR=nodular partial response; PD=progressive disease; PR=partial remission (response); PRL=partial remission (response) with lymphocytosis; SD=stable 
disease. 
a 
CR: all of the above CR criteria have to be met, and patients have to lack disease-related constitutional symptoms; PR: at least two of the above PR criteria 
for lymphadenopathy, splenomegaly, hepatomegaly, or lymphocytes plus one of the criteria for ANC, platelets or hemoglobin have to be met; PRL: presence 
of lymphocytosis, plus ≥50% reduction in lymphadenopathy and/or in spleen or liver enlargement, plus one of the criteria for ANC, platelets or hemoglobin 
have to be met; PD: at least one of the above PD criteria has to be met or transformation to a more aggressive histology (e.g., Richter’s syndrome).  For PD 
as assessed by progressive cytopenias, a bone marrow biopsy is required for confirmation.  Note: Isolated elevation of treatment-related lymphocytosis by 
itself will not be considered PD unless patient becomes symptomatic from this per Cheson 2012. 
b 
Computed tomography (CT) scan of abdomen, pelvis, and thorax may be used if previously abnormal. 
c 
Without need for exogenous growth factors. 
d 
In the sum products of ≤6 lymph nodes or in the largest diameter of the enlarged lymph node(s) detected before therapy and no increase in any lymph node or 
new enlarged lymph nodes. 
 

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Table 7 
Response Assessment Criteria for WM  
Response 
Definition 
Complete 
response 
(CR) 
• 
Absence of serum monoclonal IgM protein by immunofixation 
• 
Normal serum IgM level 
• 
Complete resolution of extramedullary disease, i.e., lymphadenopathy and 
splenomegaly if present at baseline 
• 
Morphologically normal bone marrow aspirate and trephine biopsy 
Very good 
partial 
response 
(VGPR) 
• 
Monoclonal IgM protein is detectable 
• 
≥90% reduction in serum IgM level from baseline a 
• 
Complete resolution of extramedullary disease i.e., 
lymphadenopathy/splenomegaly if present at baseline 
• 
No new signs or symptoms of active disease 
Partial 
response 
(PR) 
• 
Monoclonal IgM protein is detectable 
• 
≥50% but <90% reduction in serum monoclonal IgM level from baseline a 
• 
Reduction in extramedullary disease i.e., lymphadenopathy/splenomegaly if 
present at baseline 
• 
No new signs for symptoms of active disease 
Minor 
response 
(MR) 
• 
Monoclonal IgM protein is detectable 
• 
≥25% but <50% reduction in serum monoclonal IgM level from baseline a 
• 
No new signs for symptoms of active disease 
Stable 
disease (SD) 
• 
Monoclonal IgM protein is detectable 
• 
<25% reduction and <25% increase in serum monoclonal IgM level from 
baseline*  
• 
No progression in extramedullary disease i.e., 
lymphadenopathy/splenomegaly 
• 
No new signs for symptoms of active disease 
Progressive 
disease 
• 
≥25% increase in serum IgM level a from lowest nadir (requires confirmation on 
≥2 consecutive measurements at least 4 weeks apart). 
AND 
• 
Progression of clinical features attributable to the disease per Owen 2013. 
Owen 2013. 
IgM=immunoglobulin M; WM=Waldenström macroglobulinemia.  
a 
Sequential changes in IgM levels may be determined either by M protein quantitation or total serum IgM 
quantitation by nephelometry.  
 

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Table 8 
Response Criteria for MM (incorporating EBMT and IMWG) 
Response Subcategory 
Response Criteriaa 
Complete response (CR) 
• 
Negative immunofixation on the serum and urine and 
• 
Disappearance of any soft tissue plasmacytomas and 
• 
<5% plasma cells in bone marrowb. 
Stringent complete 
response (sCR) 
• 
CR as defined above plus 
• 
Normal FLC ratio and 
• 
Absence of clonal cells in bone marrowb by immunohistochemistry 
or immunofluorescencec. 
Near complete response 
(nCR) 
• 
Meeting the criteria for CR, except that the persistence of original 
monoclonal protein by immunofixation while absence of 
monoclonal protein on serum or urine protein electrophoresis. 
Very good partial 
response (VGPR) 
• 
Serum and urine M-component detectable by immunofixation but 
not on electrophoresis or 
• 
≥90% reduction in serum M-component plus urine M-component 
<100 mg/24 h. 
Partial response (PR) 
• 
≥50% reduction of serum M-protein and reduction in 24-h urinary 
M-protein by ≥90% or to <200 mg/24 h 
• 
If the serum and urine M-protein are unmeasurable at baseline, a 
≥50% decrease in the difference between involved and uninvolved 
FLC levels is required in place of the M-protein criteria 
• 
If serum and urine M-protein are unmeasurable at baseline, and 
serum free light assay is also unmeasurable, ≥50% reduction in 
plasma cells is required in place of M-protein, provided baseline 
bone marrow plasma cell percentage was ≥30% 
• 
In addition to the above listed criteria, if present at baseline, a 
≥50% reduction in the size of soft tissue plasmacytomas is also 
required 
Minor response (MR) 
• 
MR includes subjects in whom some, but not all, criteria for PR are 
fulfilled providing the remaining criteria satisfy the requirements for 
MR. 
• 
Requires all of the following: 
o 
≥25% to ≤49% reduction in the level of serum monoclonal 
protein for ≥2 determinations 6 weeks apart. 
o 
If present, a 50% to 89% reduction in 24-hour light chain 
excretion, which still exceeds 200 mg/24 h, for 
≥2 determinations 6 weeks apart. 
o 
25% to 49% reduction in the size of plasmacytomas (by 
clinical or radiographic examination) for ≥6 weeks. 
o 
No increase in size or number of lytic bone lesions 
(development of compression fracture does not exclude 
response). 
Stable disease - SD (not 
recommended for use as 
an indicator of response; 
stability of disease is best 
described by providing the 
• 
Not meeting criteria for CR, VGPR, MR, PR or progressive 
disease 
 

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Table 8 
Response Criteria for MM (incorporating EBMT and IMWG) 
Response Subcategory 
Response Criteriaa 
time to progression 
estimates) 
Progression 
Subcategory  
Progression Criteriad  
Progressive diseasea — 
To be used for calculation 
of duration of response 
and progression-free 
survival end points for all 
subjects including those in 
CR (includes primary 
progressive disease and 
disease progression on or 
off therapy)g 
Laboratory or biochemical relapse or progressive disease: requires the 
occurrence of ≥1 of any of the following: 
• 
Increase of ≥25% from lowest response value in serum M-
component and/or (the absolute increase must be ≥0.5 g/dL)e. 
• 
Urine M-component and/or (the absolute increase must be 
≥200 mg/24 h). 
• 
Only in subjects without measurable serum and urine M-protein 
levels: the difference between involved and uninvolved FLC levels. 
The absolute increase must be >10 mg/dL. 
• 
Bone marrow plasma cell percentage: the absolute % must be 
≥10%f. 
• 
Definite development of new bone lesions or soft tissue 
plasmacytomas or definite increase in the size of existing bone 
lesions or soft tissue plasmacytomas. 
EBMT: Bladé 1998; IMWG: Durie 2006. 
EBMT=European Group for Blood and Marrow Transplant; FLC=(serum) free light chains; IMWG=International 
Myeloma Working Group; MM=multiple myeloma. 
Note: * Note clarification to IMWG criteria for coding CR and VGPR in subjects in whom the only measurable disease 
is by serum FLC levels: CR in such subjects a normal FLC ratio of 0.26-1.65 in addition to CR criteria listed above. 
VGPR in such subjects is defined as a >90% decrease in the difference between involved and uninvolved free light 
chain FLC levels 
a. 
All response categories require 2 consecutive assessments made at ≥4 weeks after the start of study therapy 
and any time before the institution of any new therapy after study therapy; CR and PR and SD categories also 
require no known evidence of progressive or new bone lesions if radiographic studies were performed. 
Radiographic studies are not required to satisfy these response requirements. 
b. 
Confirmation with repeat bone marrow biopsy not needed 
c. 
Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An 
abnormal ratio reflecting presence of an abnormal clone is kappa/lambda of >4:1 or <1:2.  
d. 
All relapse categories require 2 consecutive assessments made at any time before classification as relapse or 
disease progression and/or the institution of any new therapy. 
e. 
For progressive disease, serum M-component increases of ≥1 gm/dL are sufficient to define relapse if starting 
M-component is ≥5 g/dL. 
f. 
Relapse from CR has the 5% cutoff versus 10% for other categories of relapse. 
g. 
For purposes of calculating time to progression and progression-free survival, CR subjects should also be 
evaluated using criteria listed above for progressive disease. 
 

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Table 9 
Response Assessment Criteria for MF  
Response 
Categories 
Required Criteria  
(for all response categories, benefit must last  
for ≥12 weeks to qualify as a response) 
Complete 
response (CR) 
• 
Bone marrow:* Age-adjusted normocellularity; <5% blasts; Grade ≤1 
MF† and 
• 
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count 
≥1×109/L and <UNL; 
• 
Platelet count ≥100×109/L and <UNL; <2% immature myeloid cells‡ and 
• 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; 
no evidence of EMH 
Partial 
response (PR) 
• 
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count 
≥1×109/L and <UNL; platelet count ≥100×109/L and <UNL; <2% 
immature myeloid cells‡ and 
• 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; 
no evidence of EMH or 
• 
Bone marrow:* Age-adjusted normocellularity; <5% blasts; Grade <1 
MF†, and peripheral blood: Hemoglobin ≥85 but <100 g/L and <UNL; 
neutrophil count ≥1×109/L and <UNL; platelet count ≥50, but 
<100×109/L and <UNL; <2% immature myeloid cells‡ and 
• 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; 
no evidence of EMH 
Clinical 
improvement 
(CI) 
• 
The achievement of anemia, spleen or symptoms response without 
progressive disease or increase in severity of anemia, 
thrombocytopenia, or neutropenia§ 
Anemia 
response 
• 
Transfusion-independent patients: a ≥20 g/L increase in hemoglobin 
level|| 
• 
Transfusion-dependent patients: becoming transfusion-independent{ 
Spleen 
response 
• 
A baseline splenomegaly that is palpable at 5 to 10 cm, below the LCM, 
becomes not palpable# or 
• 
A baseline splenomegaly that is palpable at >10 cm, below the LCM, 
decreases by ≤50%# 
• 
A baseline splenomegaly that is palpable at <5 cm, below the LCM, is 
not eligible for spleen response 
• 
A spleen response requires confirmation by MRI or computed 
tomography showing ≥35% spleen volume reduction** 
Symptoms 
response 
• 
A ≥50% reduction in the MPN-SAF TSS†† 

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Table 9 
Response Assessment Criteria for MF  
Response 
Categories 
Required Criteria  
(for all response categories, benefit must last  
for ≥12 weeks to qualify as a response) 
Progressive 
disease 
• 
Appearance of a new splenomegaly that is palpable at least 5 cm below 
the LCM or‡‡ 
• 
A ≥100% increase in palpable distance, below LCM, for baseline 
splenomegaly of 5-10 cm or‡‡ 
• 
A 50% increase in palpable distance, below LCM, for baseline 
splenomegaly of >10 cm or‡‡ 
• 
Leukemic transformation confirmed by a bone marrow blast count of 
≥20% or 
• 
A peripheral blood blast content of ≥20% associated with an absolute 
blast count of ≥1×109/L that lasts for at least 2 weeks 
Stable disease 
• 
Belonging to none of the above listed response categories 
Relapse 
• 
No longer meeting criteria for at least CI after achieving CR, PR, or CI, 
or 
• 
Loss of anemia response persisting for at least 1 month or 
• 
Loss of spleen response persisting for at least 1 month 
Recommendations for assessing treatment-induced cytogenetic and molecular changes 
Cytogenetic 
remission 
• 
At least 10 metaphases must be analyzed for cytogenetic response 
evaluation and 
• 
requires confirmation by repeat testing within 6 months window 
• 
CR: eradication of a pre-existing abnormality 
• 
PR: ≥50% reduction in abnormal metaphases 
• 
(partial response applies only to patients with at least ten abnormal 
metaphases at baseline) 
Molecular 
remission 
• 
Molecular response evaluation must be analyzed in peripheral blood 
granulocytes and 
• 
requires confirmation by repeat testing within 6 months window 
• 
CR: Eradication of a pre-existing abnormality 
• 
PR: ≥50% decrease in allele burden 
• 
(partial response applies only to patients with at least 20% mutant allele 
burden at baseline) 
Cytogenetic/
molecular 
relapse 
• 
Re-emergence of a pre-existing cytogenetic or molecular abnormality 
that is confirmed by repeat testing 
Tefferi 2013. 
EMH=extramedullary hematopoiesis (no evidence of EMH implies the absence of pathology- or imaging study-proven 
nonhepatosplenic EMH); LCM=left costal margin; UNL=upper normal limit. 
* 
Baseline and posttreatment bone marrow slides are to be interpreted at one sitting by a central review process. 
Cytogenetic and molecular responses are not required for CR assignment. 
† 
Grading of MF is according to the European classification 
 
Thiele et al. European consensus on grading bone marrow fibrosis and assessment of cellularity. 
Haematologica. 2005;90:1128. 

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It is underscored that the consensus definition of a CR bone marrow is to be used only in those patients in which 
all other criteria are met, including resolution of leukoerythroblastosis. 
 
It should also be noted that it was a particularly difficult task for the working group to reach a consensus 
regarding what represents a complete histologic remission. 
‡ 
Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + nucleated red blood 
cells. In splenectomized patients, <5% immature myeloid cells is allowed. 
§ 
See above for definitions of anemia response, spleen response, and progressive disease.  Increase in severity of 
anemia constitutes the occurrence of new transfusion dependency or a ≥20 g/L decrease in hemoglobin level 
from pretreatment baseline that lasts for at least 12 weeks. Increase in severity of thrombocytopenia or 
neutropenia is defined as a 2-grade decline, from pretreatment baseline, in platelet count or absolute neutrophil 
count, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. In addition, 
assignment to CI requires a minimum platelet count of ≥25 000×109/L and absolute neutrophil count of 
≥0.5×109/L. 
|| 
Applicable only to patients with baseline hemoglobin of <100 g/L. In patients not meeting the strict criteria for 
transfusion dependency at the time of study enrollment (see as follows), but have received transfusions within 
the previous month, the pretransfusion hemoglobin level should be used as the baseline. 
{ 
Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of packed red 
blood cells (PRBC), in the 12 weeks prior to study enrollment, for a hemoglobin level of <85 g/L, in the absence 
of bleeding or treatment-induced anemia. In addition, the most recent transfusion episode must have occurred in 
the 28 days prior to study enrollment. Response in transfusion-dependent patients requires absence of any 
PRBC transfusions during any consecutive “rolling” 12-week interval during the treatment phase, capped by a 
hemoglobin level of ≥85 g/L. 
# 
In splenectomized patients, palpable hepatomegaly is substituted with the same measurement strategy. 
** 
Spleen or liver responses must be confirmed by imaging studies where a ≥35% reduction in spleen volume, as 
assessed by MRI or CT, is required. Furthermore, a ≥35% volume reduction in the spleen or liver, by MRI or CT, 
constitutes a response regardless of what is reported with physical examination. 
†† Symptoms are evaluated by the MPN-SAF TSS (Emanuel 2012). The MPN-SAF TSS is assessed by the 
patients themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone 
pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst 
imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores 
(0-100 scale). Symptoms response requires ≥50% reduction in the MPN-SAF TSS. 
‡‡ Progressive disease assignment for splenomegaly requires confirmation my MRI or computed tomography 
showing a ≥25% increase in spleen volume from baseline. 
Baseline values for both physical examination and imaging studies refer to pretreatment baseline and not to 
posttreatment measurements. 
 
4.3 
SAFETY FOLLOW-UP VISIT 
Each subject should be followed for 30 days (+7) after his or her last dose of study drug (i.e., 
the “safety follow-up visit”) to monitor for resolution or progression of AEs (see Section 6.2.7) 
and to document the occurrence of any new events, regardless of whether the subject receives 
a new anticancer therapy or demonstrates disease progression within this timeframe; after this 
period, investigators should report SAEs or other AEs of concern that are believed to be related 
to prior treatment with acalabrutinib (see Section 6.2.1).  Subjects who withdraw consent for 
study treatment should still be encouraged to complete the safety follow-up assessments, but 
these assessments cannot be mandated if subject consent for further study participation is 
withdrawn.  The Schedules of Assessments (Appendix 5 and Appendix 6) describe the 
procedures required for safety follow-up.  

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4.4 
TIME-TO-NEXT TREATMENT AND SURVIVAL 
Subjects who discontinue study therapy will continue to be followed for assessment of 
time-to-next therapy unless they withdraw consent for further follow-up.  After discontinuing 
study therapy, subjects will also be contacted approximately every 12 weeks until death, 
withdrawal of consent by subject, loss to follow-up, or study termination by the sponsor, 
whichever comes first.  
4.5 
MISSED EVALUATIONS 
Missed evaluations should be rescheduled and performed as close to the original scheduled 
date as possible.  An exception is made when rescheduling becomes, in the investigator’s 
opinion, medically unnecessary or unsafe because it is too close in time to the next scheduled 
evaluation.  In that case, the missed evaluation should be abandoned. 
 
STATISTICAL METHODS OF ANALYSIS  
5.1 
GENERAL CONSIDERATIONS 
Descriptive statistics (including means, standard deviations, and medians for continuous 
variables and proportions and CIs for discrete variables) will be used to summarize data as 
appropriate.  As appropriate, analyses will be performed by cancer type or overall.  Depending 
on Part 1 and the number of expansion cohorts opened in Parts 2 and 3, a total of 6 to 324 
evaluable subjects will be enrolled in this study.  Under Amendment 4 of this protocol, the 
planned total enrollment was approximately 160 evaluable subjects; enrollment was closed in 
May 2017 with a total of 161 evaluable subjects. 
5.2 
SAMPLE SIZE JUSTIFICATION 
In Part 1 (DLT review), enrollment of 6 subjects for DLT review is consistent with sample sizes 
used in oncology studies for determination of MTD.  The trial employs the standard National 
Cancer Institute definition of MTD (dose associated with DLT in <33.3% of subjects).  Provided 
≤1 DLT occurs during the DLT review, then expansion will occur in Part 1 to include up to 
24 subjects in a select group of histologies (as described in Section 3.0).  The safety and 
preliminary efficacy results from Part 1 will be used to determine opening Part 2 and Part 3 of 
the protocol. 
In Part 2 (expansion groups), enrollment of 30 subjects per group offers the opportunity to 
determine if there is sufficient antitumor activity to warrant further development in the selected 
tumor types.  An ORR of ≥20% is considered the minimum value of potential interest in each of 

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the selected indications. If <2 subjects per cohort experience an objective response, the 
probability is >0.90 that an ORR of ≥20% will be excluded for that cancer.  If 2 subjects in a 
group experience an objective response, the upper bound of a 1-sided exact binomial 
90% CI=16.8%. 
In Part 3, safety and response data will be reviewed after the initial 12 subjects have completed 
24 weeks of treatment (i.e., the Week 25 visit) or have discontinued treatment before Week 25.  
The first 12 subjects will be evaluated regardless of the length of treatment with acalabrutinib 
alone or in combination with pembrolizumab.  If <2 subjects who received acalabrutinib 
monotherapy or the combination with pembrolizumab have achieved a response of “clinical 
improvement” or better (see Table 9), the MF group will not be expanded.  The decision to 
expand the study is multifactorial and needs to take into consideration the nature and quality of 
response, safety, and evolving competitive landscape.  If the safety and response data indicate 
that further evaluation is warranted, up to 18 additional subjects with MF (for a total of up to 
30 subjects) will be treated on the same adaptive regimen as was given to the first 12 subjects. 
Table 10 shows the 2-sided exact 90% binomial CIs on the true response rate for the range of 
all possible values for the observed response rate in the initial group of 12 subjects. 
Table 10 
Two-Sided Exact 90% CIs for Response Rate in Initial Group in Part 3 
(N=12) 
Responses, n 
Response Rate, % 
90%CI 
Lower Bound 
Upper Bound 
0 
0% 
0% 
22% 
1 
8% 
0% 
34% 
2 
17% 
3% 
44% 
3 
25% 
7% 
53% 
4 
33% 
12% 
61% 
5 
42% 
18% 
68% 
6 
50% 
25% 
75% 
7 
58% 
32% 
82% 
8 
67% 
39% 
88% 
9 
75% 
47% 
93% 
10 
83% 
56% 
97% 
11 
92% 
66% 
100% 
12 
100% 
78% 
100% 
CI=confidence interval. 
 
If the MF group is expanded, enrollment of 30 subjects offers the opportunity to determine if 
there is sufficient antitumor activity to warrant further development in MF.  A response rate 

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(clinical improvement, PR, or CR) of ≥25% within the sample size of 30 subjects with MF is 
considered the minimum value of potential interest in this highly unmet medical need population 
of MF patients with thrombocytopenia or anemia.  To reject the null hypothesis of response rate 
≤5% in favor of an alternative hypothesis that the response rate is ≥25%, 30 subjects will 
preserve approximately 90% power to detect the difference at a 0.05 level of significance by 
1-sided exact test for single proportion. 
Considering the planned expansion cohort size of 30 subjects, Table 11 shows the 2-sided 
exact 90% binomial CIs on the true response rate for the range of all possible values for the 
observed response rate.  

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Table 11 
Two-Sided Exact 90% CIs for Response Rate in Expansion Cohorts in 
Part 2 and Part 3 (N=30) 
Responses, n 
Response Rate, % 
90%CI 
Lower Bound 
Upper Bound 
0 
0% 
0% 
10% 
1 
3% 
0% 
15% 
2 
7% 
1% 
20% 
3 
10% 
3% 
24% 
4 
13% 
5% 
28% 
5 
17% 
7% 
32% 
6 
20% 
9% 
36% 
7 
23% 
11% 
39% 
8 
27% 
14% 
43% 
9 
30% 
17% 
47% 
10 
33% 
19% 
50% 
11 
37% 
22% 
53% 
12 
40% 
25% 
57% 
13 
43% 
28% 
60% 
14 
47% 
31% 
63% 
15 
50% 
34% 
66% 
16 
53% 
37% 
69% 
17 
57% 
40% 
72% 
18 
60% 
43% 
75% 
19 
63% 
47% 
78% 
20 
67% 
50% 
81% 
21 
70% 
53% 
83% 
22 
73% 
57% 
86% 
23 
77% 
61% 
89% 
24 
80% 
64% 
91% 
25 
83% 
68% 
93% 
26 
87% 
72% 
95% 
27 
90% 
76% 
97% 
28 
93% 
80% 
99% 
29 
97% 
85% 
100% 
30 
100% 
90% 
100% 
CI=confidence interval. 
5.3 
DEFINITION OF ANALYSIS POPULATIONS 
The following definitions will be used for the efficacy and safety analysis populations. 
• 
All-treated population: All enrolled subjects who receive ≥1 dose of any study drug (either 
acalabrutinib or pembrolizumab). The safety analyses and primary efficacy analyses will be 
performed on the All-treated population. 

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• 
Efficacy-evaluable population: All subjects in the All-treated population who have ≥1 
evaluable response assessment after the first dose of study drug (either acalabrutinib or 
pembrolizumab). Sensitivity analyses for efficacy will be carried out on the 
Efficacy-evaluable population. 
• 
PD analysis population:  A subset of subjects from the All-treated population who have 
sufficient baseline measurements and undergo ≥1 PD assessment after treatment.  This 
analysis set will be used for PD parameters.  
5.4 
MISSING DATA HANDLING 
No imputation of values for missing data will be performed except that missing or partial start 
and end dates for AEs and concomitant medication will be imputed according to prespecified, 
conservative imputation rules.  Subjects lost to follow-up (or drop out) will be included in 
statistical analyses to the point of their last evaluation. 
5.5 
ENDPOINT DATA ANALYSIS 
5.5.1 
Safety Endpoint 
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 or higher) and by relationship to study drug (e.g., 
either acalabrutinib, pembrolizumab, or both). 
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 examinations 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 and tabulated 
according to the WHO Drug Dictionary. 

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5.5.3 
Study Treatment Administration and Compliance 
Descriptive information will be provided regarding the number of acalabrutinib and 
pembrolizumab 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.   
For each subject, acalabrutinib and pembrolizumab compliance will be described in terms of the 
relative dose intensity. 
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 (see Section 4.2) 
as defined for each response parameter, date that response is first documented, and date of 
disease progression. 
ORR will be defined as the proportion of subjects who achieve a response of PR or CR (see 
Section 4.2).  For Part 3 subjects with MF, ORR will be defined as the proportion of subjects 
who achieve a response of clinical improvement or better (clinical improvement, PR, or CR) as 
shown in Table 9.  ORR will be calculated and the corresponding exact 2-sided 90% and 95% 
CIs will be derived.  
In addition, for subjects with CLL/SLL in Parts 1 and 2, a response will be assessed according 
to Table 6, which reflects modified International Working Group response criteria (Hallek 2008) 
as recently updated (Cheson 2012) to include PRL.  For the purpose of this analysis, 
lymphocytosis at a given timepoint will be defined as absolute lymphocyte count which is above 
normal limits and is not ≥50% decreased from baseline.   
For Part 3 subjects with MF, an additional analysis will evaluate response when defined as 
CR + PR only.  A descriptive analysis will be done on the subgroups of subjects with MF who 
receive acalabrutinib alone or the combination of acalabrutinib and pembrolizumab.   
Duration of Response 
The duration of overall response defined as the interval from the first documentation of 
response to the earlier of the first documentation of definitive disease progression or death from 
any cause.  Kaplan-Meier methods will be used to estimate event-free curves and 
corresponding quartiles (including the median).  Data from surviving, non-progressing subjects 

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will be censored and detailed censoring rules will be specified in the statistical analysis plan 
(SAP). 
Progression-free Survival 
Progression-free survival is defined as the interval from the first dose date of 
acalabrutinib or pembrolizumab to the earlier of the first documentation of objective disease 
progression or death from any cause.  Kaplan-Meier methods will be used to estimate the 
event-free curves and corresponding quartiles (including the median).  Data from surviving, 
non-progressing subjects will be censored, and detailed censoring rules will be specified in the 
SAP. 
Time-to-Next Treatment 
Time-to-next treatment defined as the time from the first dose date of acalabrutinib or 
pembrolizumab to the start of the next treatment other than the study treatment.  Kaplan-Meier 
methods will be used to estimate the event-free curves and corresponding quartiles (including 
the median).  Data from subjects who have not received subsequent therapy will be censored at 
the earliest of death or the last time that lack of administration of a new therapy was objectively 
documented. 
Overall Survival 
Overall survival is defined as the time from the first dose date of acalabrutinib or pembrolizumab 
until date of death due to any cause.  Subjects who are known to be alive or whose survival 
status is unknown will be censored at the date last known to be alive.  The analysis methods for 
overall survival will be similar to those described for progression-free survival.  
5.5.5 
PD or Biomarker Analyses 
 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and recording AEs and SAEs; measurements of 
protocol-specified hematology, clinical chemistry (including thyroid function), urinalysis, and 
other laboratory variables; measurement of protocol-specified vital signs; and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study drug(s). 
CCI

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6.1 
DEFINITIONS 
6.1.1 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational medicinal product (IMP), 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 the primary hematologic 
malignancy that were not present before the AE reporting period (see Section 6.2.1). 
• 
Pre-existing medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
• 
Abnormal laboratory values considered clinically significant by the investigator should be 
reported as AEs. 
The following are NOT considered an AE: 
• 
Pre-existing condition that has not worsened: A pre-existing condition (documented on 
the medical history CRF) is not considered an AE unless the severity, frequency, or 
character of the event worsens during the study period. 
• 
Preplanned hospitalization: A hospitalization planned before signing the ICF is not 
considered an SAE, but rather a therapeutic intervention.  However, if during the preplanned 
hospitalization an event occurs, which prolongs the hospitalization or meets any other SAE 
criteria, the event will be considered an SAE.  Surgeries or interventions that were under 
consideration, but not performed before signing the ICF, will not be considered serious if 
they are performed after signing the ICF for a condition that has not changed from its 
baseline level.  Elective hospitalizations for social reasons, solely for the administration of 
chemotherapy, or due to long travel distances are also not SAEs.  
• 
Diagnostic testing and procedures: Testing and procedures should not be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported.  If a test or 
procedure is done to rule out a diagnosis, the sign or symptom leading to the test/procedure 
should be the event term, and the event term should only be updated to the diagnosis 
if/when the diagnosis is confirmed.  Testing and procedures performed solely as screening 

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measures (e.g., routine screening mammography or colonoscopy) should not be reported as 
AEs or SAEs. 
• 
Abnormal laboratory results:  Abnormal laboratory results are not AEs unless they are 
clinically significant.  For example, a clinically significant laboratory result is one that requires 
treatment (for example, a blood transfusion for low hemoglobin) or requires a change in 
study drug (e.g., lowering the dose or withholding study drug while the laboratory finding 
resolves or stabilizes). 
• 
Progression of underlying malignancy:  Progression of underlying malignancy will not be 
reported as an AE if it is clearly consistent with the suspected progression of the underlying 
cancer.  Hospitalization due solely to the progression of underlying malignancy should NOT 
be reported as an SAE.  Clinical symptoms of progression may be reported as AEs if the 
symptoms cannot be determined as exclusively due to the progression of the underlying 
malignancy, or if they do not fit the expected pattern of progression for the disease under 
study. 
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.  
If there is any uncertainty about an AE being due only to the disease under study, it should be 
reported as an AE or SAE. 
6.1.2 
Serious Adverse Events 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to the grade 
of an AE (see below).  “Serious” is a regulatory definition and is based on subject or event 
outcome or action criteria usually associated with events that pose a threat to a subject’s life or 
functioning.  Seriousness (not severity) serves as the guide for defining regulatory reporting 
obligations from the sponsor to applicable regulatory authorities. 
An AE should be classified as an SAE if it meets any one of the following criteria: 
• 
It results in death (i.e., the AE actually causes or leads to death). 
• 
It is life-threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death.  It does not include an AE that, had it occurred in a more severe 
form, might have caused death). 
• 
It requires or prolongs in-patient hospitalization. 

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• 
It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to the investigational product. 
• 
It is considered a significant medical event by the investigator based on medical judgment 
(e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one 
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 nonhematologic and hematologic AEs. The CTCAE v4.03 displays Grades 1 
through 5 with unique clinical descriptions of severity for each referenced AE. Should a subject 
experience any AE not listed in the CTCAE, the following grading system should be used to 
assess severity: 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special treatment, 
and not interfering with the subject’s daily activities 
• 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures 
• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be in 
imminent danger of death 
• 
Grade 5 (Death related to AE) – experiences which result in subject death. 
6.2 
DOCUMENTING AND REPORTING OF ADVERSE AND SERIOUS 
ADVERSE EVENTS 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, as outlined in the prior sections, are recorded on the CRF.  All SAEs must be 
reported on the SAE form or clinical database. 

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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.  
For acalabrutinib, all AEs will be reported until 30 days after the last dose of acalabrutinib or the 
start of new anticancer therapy (whichever comes first).  After this period, investigators should 
report SAEs or other AEs of concern that are believed to be related to prior treatment with 
acalabrutinib.   
For pembrolizumab, all AEs must be reported through 30 days after the last dose of 
pembrolizumab; any SAEs, or follow-up to an SAE, including death due to any cause other than 
progression of the cancer under study, must be reported through 90 days after the last dose or 
30 days after the last dose of pembrolizumab if the subject initiates a new anticancer therapy 
within the 90-day posttreatment timeframe.   
SAEs considered related to study drug(s) or study procedures occurring after the end of the AE 
reporting period (as defined above) must be reported.   
All AEs and SAEs that occur during the reporting period should be followed to resolution or until 
the investigator assesses the subject as stable, the subject is lost to follow-up or withdraws 
consent.  Resolution/stable means the subject has returned to baseline state of health or the 
investigator does not expect any further improvement or worsening of the event. 
6.2.2 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation timepoints 
during the study.  All AEs and SAEs whether volunteered by the subject, discovered by study 
personnel during questioning, or detected through physical examination, or other means, that 
occur to any subject from the time of first dose through 30 days following the cessation of study 
drug(s), and all SAEs that occur to any subject receiving pembrolizumab from the time of first 
dose through 90 days following cessation of pembrolizumab, or 30 days following cessation of 
pembrolizumab if the subject initiates new anticancer therapy (whichever is earlier) will be 
recorded in the subject’s medical record and on the AE CRF.  
Disease progression itself is not considered an AE unless it is considered to be drug-related by 
the investigator; however, signs and symptoms of disease progression may be recorded as AEs 
or SAEs. 

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Each recorded AE or SAE will be described by its diagnostic term, duration (e.g., start and end 
dates), severity, regulatory seriousness criteria, if applicable, suspected relationship to the study 
drugs (see following guidance), and any actions taken.  The causality of AEs to the study drugs 
will be assessed by means of the question: ‘Is there a reasonable possibility that the event may 
have been caused by the study drugs?’ per FDA guidance on safety reporting requirements 
(FDA Drug Safety Communication 2012).  
See Appendix 3 for more detail on assessing causality. 
6.2.3 
Second Primary Malignancies  
AEs for malignant tumors reported during a study should generally be assessed as SAEs.  If no 
other seriousness criteria apply, the “Important Medical Event” criterion should be used.  In 
certain situations, however, medical judgment on an individual event basis should be applied to 
clarify that the malignant tumor event should be assessed and reported as a nonserious AE.  
For example, if the tumor is included as medical history and progression occurs during the study 
but the progression does not change treatment and/or prognosis of the malignant tumor, the AE 
may not fulfil 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 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 and pregnancies in the partners of subjects within 
24 hours using the Pregnancy Report Form.  This form should be faxed or emailed to Acerta 
Pharma Drug Safety.  Any pregnancy-associated SAE must be reported to Acerta Pharma, 
according to the usual timelines and directions for SAE reporting (see Section 6.2.4). 

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Any uncomplicated pregnancy that occurs with the subject or with the partner of a treated 
subject during this study will be reported.  All pregnancies and partner pregnancies that are 
identified during or after this study, wherein the estimated date of conception is determined to 
have occurred from the time of consent to 2 days after the last dose of acalabrutinib, or within 
120 days after the last dose of pembrolizumab or 30 days after the last dose of pembrolizumab 
if the subject initiates a new anticancer therapy (whichever is earlier of the pembrolizumab 
dosing situations) will be reported, followed to conclusion, and the outcome reported, as long as 
the subject or partner is willing to participate in follow-up. 
A pregnancy itself is not regarded as an AE unless there is suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication.  
Likewise, elective abortions without complications are not considered AEs.  Any SAEs 
associated with pregnancy (e.g., congenital abnormalities/birth defects/spontaneous 
miscarriage or any other serious events) must additionally be reported as such using the SAE 
form. 
Subjects should be instructed to immediately notify the investigator of any pregnancies.  Any 
female subjects receiving study drug who become pregnant must immediately discontinue study 
drug.  The investigator should counsel the subject, discussing any risks of continuing the 
pregnancy and any possible effects on the fetus. 
Upon completion of the pregnancy, additional information on the mother, pregnancy, and baby 
will be collected and sent to 
 
6.2.5 
Expedited Reporting Requirements for Serious Adverse Events 
All SAEs must be reported within 24 hours of discovery.  All initial SAE reports and follow-up 
information will be reported using the protocol-specific electronic data capture system.  If 
electronic SAE reporting is not available, paper SAE forms must be emailed or faxed to Acerta 
Pharma Drug Safety (see Table 12), or designee.  These must also be completed within 
24 hours of the discovery of the SAE. Acerta Pharma may request follow-up and other 
additional information from the investigator (e.g., hospital admission/discharge notes and 
laboratory results).  
Whenever possible, AEs/SAEs should be reported by diagnosis term, not as a constellation of 
symptoms.   
Death due to disease progression should be recorded on the appropriate form in the electronic 
data capture system.  If the primary cause of death is disease progression, the death due to 
PPD

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disease progression should not be reported as an SAE. If the primary cause of death is 
something other than disease progression, then the death should be reported as an SAE with 
the primary cause of death as the event term, as death is typically the outcome of the event, not 
the event itself.  The primary cause of death on the autopsy report should be the term reported.  
Autopsy and postmortem reports must be forwarded to Acerta Pharma Drug Safety, or 
designee, as outlined above. 
If study drug is discontinued because of an SAE, this information must be included in the SAE 
report. 
An SAE may qualify for mandatory expedited reporting to regulatory authorities if the SAE is 
attributable to the investigational product (or if a causality assessment is not provided for the 
SAE, in which case the default of ‘related’ must be used for expedited reporting purposes) and 
the SAE is not listed in the current acalabrutinib IB (i.e., an unexpected event).  In this case, 
Acerta Pharma Drug Safety/Designee will forward a formal notification describing the suspected 
unexpected serious adverse reaction (SUSAR) to all investigators.  Each investigator must then 
notify his or her IRB/IEC of the SUSAR. 
Table 12 
Acerta Pharma Drug Safety Contact Information 
Drug Safety Contact Information 
Fax 
United States 
 
Outside United States 
 
Email 
 
 
6.2.6 
Reporting Events of Clinical Interest 
Selected non-serious and serious AEs are also known as ECIs and must be reported to the 
sponsor. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the sponsor if it causes the subject to be excluded from the trial, or is 
the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 30 days following 
cessation of treatment, any ECI, or follow up to an ECI, whether or not related to study drug 
PPD
PPD
PPD

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must be reported within 24 hours to the sponsor either by electronic media or paper as 
described in Section 6.2.5.   
Events of Clinical Interest for this trial include: 
1) 
An overdose of study drug (overdose is defined in Section 3.10.10) that is not associated 
with clinical symptoms or abnormal laboratory results.  
2) 
An elevated AST or ALT lab value that is ≥3 times the ULN and an elevated total bilirubin 
value that is ≥2 times ULN and, at the same time, an alkaline phosphatase value that is 
<2 times the ULN, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing. a 
3) 
Ventricular arrhythmias (e.g., ventricular extrasystoles, ventricular tachycardia, ventricular 
arrhythmia, ventricular fibrillation). 
a 
These criteria are based upon available regulatory guidance documents.  The purpose of the criteria is to specify 
a threshold of abnormal hepatic tests that may require an additional evaluation for an underlying etiology.  The 
guidance for assessment and follow-up of these criteria for potential drug-induced liver injury can be found in 
Appendix 7. 
 
6.2.7 
Type and Duration of Follow-up of Subjects after Adverse Events 
All AEs and SAEs that are encountered during the protocol-specified AE reporting period should 
be followed to resolution, or until the investigator assesses the subject as stable or the subject is 
lost to follow-up or withdraws consent. 
6.2.8 
Other Safety Issues Requiring Expedited Reporting 
For studies being conducted in Europe expedited reporting is required for safety issues that 
might materially alter the current benefit-risk assessment of an investigational medicinal product 
or that would be sufficient to consider changes in the investigational medicinal products 
administration or in the overall conduct of the trial.  For a detailed description of safety issues 
that may qualify for expedited reporting please refer to the European Commission guidance 
titled, “Detailed guidance on the collection, verification and presentation of adverse reaction 
reports arising from clinical trials on medicinal products for human use – April 2006” available at 
http://ec.europa.eu/health/files/eudralex/vol-10/21_susar_rev2_2006_04_11_en.pdf. 
 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
Acerta Pharma retains the right to terminate the study and remove all study materials from a 
study site at any time. Specific circumstances that may precipitate such termination are: 
• 
Unsatisfactory subject enrollment with regard to quality or quantity 

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• 
Significant or numerous deviations from study protocol requirements, such as failures to 
perform required evaluations on subjects and maintain adequate study records 
• 
Inaccurate, incomplete and/or late data recording on a recurrent basis 
• 
The incidence and/or severity of AEs in this or other studies indicating a potential health 
hazard caused by the study treatment 
7.1 
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE 
The investigator will submit this protocol, the informed consent, Investigator Brochure, and any 
other relevant supporting information (e.g., all advertising materials) to the appropriate IRB/IEC 
for review and approval before study initiation.  A signed protocol approval page; a letter 
confirming IRB/IEC approval of the protocol and informed consent; and a statement that the 
IRB/IEC is organized and operates according to GCP and the applicable laws and regulations; 
must be forwarded to Acerta Pharma before screening subjects for the study.  Additionally, 
sites must forward a signed Form FDA 1572 (Investigator Obligation 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 agency, as appropriate, before the 
implementation of changes in this study. 
7.2 
INFORMED CONSENT AND PROTECTED SUBJECT HEALTH 
INFORMATION AUTHORIZATION 
A copy of the IRB/IEC-approved informed consent must be forwarded to Acerta Pharma for 
regulatory purposes.  The investigator, or designee (designee must be listed on the Study 
Personnel Responsibility/Signature Log, see Section 7.11), 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 form.  Each subject must provide a signed and 
dated informed consent before enrollment into this study.  In the case of a subject who is 
incapable of providing informed consent, the investigator (or designee) must obtain a signed 
and dated informed consent form from the subject’s legal guardian.  Signed consent forms must 
remain in each subject’s study file and be available for verification by study monitors at any 
time. 
In accordance to individual local and national patient privacy regulations, the investigator or 
designee must explain to each subject that for the evaluation of study results, the subject’s 
protected health information obtained during the study may be shared with Acerta Pharma and 

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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. 
7.3 
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. 
7.4 
CASE REPORT FORMS 
Authorized study site personnel (see Section 7.11) will complete CRFs designed for this study 
according to the completion guidelines that will be provided within the clinical database.  The 
investigator will ensure that the CRFs are accurate, complete, legible, and completed promptly.  
The investigator will ensure that source documents that are required to verify the validity and 
completeness of data transcribed on the CRFs are never obliterated or destroyed.  Refer to 
Section 7.7 for record retention requirements. 
7.5 
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. 
Every effort will be made to maintain the anonymity and confidentiality of all subjects during this 
clinical study.  However, because of the experimental nature of this treatment, the investigator 
agrees to allow the IRB/IEC, representatives of Acerta Pharma, its designated agents, and 
authorized employees of the appropriate regulatory agencies to inspect the facilities used in this 
study and, for purposes of verification, allow direct access to the hospital or clinic records of all 
subjects enrolled into this study.  This includes providing by fax, email, or regular mail 

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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. 
7.6 
INVESTIGATIONAL STUDY DRUG ACCOUNTABILITY 
Acalabrutinib and pembrolizumab must be kept in a locked limited access cabinet or space.  
The study drug must not be used outside the context of the protocol. 
Study drug accountability records must be maintained and readily available for inspection by 
representatives of Acerta Pharma and are open to inspections by regulatory authorities at any 
time.  
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.  Additionally, a Drug Re-order Form 
for requesting more study drug is provided in the pharmacy binder.  If it is used, then the Drug 
Re-order Form 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.  The designated recipient completes and signs the CSSF. A 
copy of the signed CSSF must be faxed or emailed to AstraZeneca at the fax number/email 
address listed on the form. 
An Investigational Drug Accountability Log must be used for drug accountability.  For accurate 
accountability, the following information must be noted when drug supplies are used during the 
study: 
1) 
Study identification number (ACE-LY-005) 
2) 
Subject identification number 
3) 
Lot number(s) of acalabrutinib and pembrolizumab dispensed for that subject 
4) 
Date and quantity of drug dispensed 
5) 
Any unused drug returned by the subject 
 
At study initiation, the monitor will evaluate and approve the site’s procedure for investigational 
product disposal/destruction to ensure that it complies with Acerta Pharma’s requirements.  If 
the site cannot meet Acerta Pharma’s requirements for disposal/destruction, arrangements will 
be made between the site and Acerta Pharma or its designee, for return of unused 

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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.  Returned capsules must not be redispensed.  Only a sufficient quantity of capsules will 
be dispensed to reach the next protocol-specified visit unless approved by the medical monitor.   
7.7 
RECORD RETENTION 
The investigator and other appropriate study staff are responsible for maintaining all 
documentation relevant to the study.  Mandatory documentation includes copies of study 
protocols and amendments, each Form FDA 1572, IRB/IEC approval letters, signed ICFs, drug 
accountability records, SAE information transmitted to Acerta Pharma, subject files (source 
documentation) that substantiate entries in CRFs, all relevant correspondence and other 
documents pertaining to the conduct of the study. 
An investigator shall retain records for a period of at least 2 years after the date the last 
marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and regulatory authorities have 
been notified.  The investigator must notify Acerta Pharma and obtain written approval from 
Acerta Pharma before destroying any clinical study records at any time.  Acerta Pharma will 
inform the investigator of the date that study records may be destroyed or returned to Acerta 
Pharma. 
Acerta Pharma must be notified in advance of, and Acerta Pharma must provide express written 
approval of, any change in the maintenance of the foregoing documents if the investigator 
wishes to move study records to another location or assign responsibility for record retention to 
another party.  If the investigator cannot guarantee the archiving requirements set forth herein at 
his or her study site for all such documents, special arrangements must be made between the 
investigator and Acerta Pharma to store such documents in sealed containers away from the 
study site so that they can be returned sealed to the investigator for audit purposes. 
7.8 
PROTOCOL AMENDMENTS 
Acerta Pharma will initiate any change to the protocol in a protocol amendment document.  The 
amendment will be submitted to the IRB/IEC together with, if applicable, a revised model ICF.  If 
the change in any way increases the risk to the subject or changes the scope of the study, then 
written documentation of IRB/IEC approval must be received by Acerta Pharma before the 

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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. 
7.9 
PUBLICATION OF STUDY RESULTS 
Authorship, in general, will follow the recommendations of the International Committee of 
Medical Journal Editors (2014). 
7.10 
CLINICAL TRIAL INSURANCE 
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted.  An insurance certificate will be made available to the participating sites 
at the time of study initiation. 
7.11 
GENERAL INVESTIGATOR RESPONSIBILITIES 
The principal investigator must ensure that: 
1) 
He or she will conduct or supervise the study. 
2) 
His or her staff and all persons who assist in the conduct of the study clearly understand 
their responsibilities and have their names included in the Study Personnel 
Responsibility/Signature Log. 
3) 
The study is conducted according to the protocol and all applicable regulations. 
4) 
The protection of each subject’s rights and welfare is maintained. 
5) 
Signed and dated informed consent and, when applicable, permission to use protected 
health information are obtained from each subject before conducting nonstandard of care 
study procedures.  If a subject or subject’s legal guardian withdraws permission to use 
protected health information, the investigator will obtain a written request from the subject 
or subject’s legal guardian and will ensure that no further data be collected from the 
subject. 
6) 
The consent process is conducted in compliance with all applicable regulations and privacy 
acts. 
7) 
The IRB/IEC complies with applicable regulations and conducts initial and ongoing reviews 
and approvals of the study. 
8) 
Any amendment to the protocol is submitted promptly to the IRB/IEC. 
9) 
Any significant protocol deviations are reported to Acerta Pharma and the IRB/IEC 
according to the guidelines at each study site. 
10) CRF pages are completed promptly. 

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11) All Investigational New Drug Safety Reports/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 via the clinical database and to the IRB/IEC per their requirements. 
 
 

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Kamel S, Horton L, Ysebaert L, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated 
platelet aggregation. Leukemia 2015;29(4):783-7. 
Khurana D, Arneson LN, Schoon RA, et al. Differential regulation of human NK cell-mediated 
cytotoxicity by the tyrosine kinase Itk. J Immunol 2007;178:3575-82. 
Kohrt HE, Sagiv-Barfi I, Rafiq S, et al. Ibrutinib antagonizes rituximab-dependent NK 
cell-mediated cytotoxicity. Blood 2014;123(12):1957-60. 
Liu Y, Dong Y, Jiang QL, et al. Bruton's tyrosine kinase: potential target in human multiple 
myeloma. Leuk Lymphoma 2014;55:177-81. 
McDermott DF, Atkins MB. PD-1 as a potential target in cancer therapy. Cancer Med 
2013;2(5):662-73. 
Owen RG, Kyle RA, Stone MJ, et al. Response assessment in Waldenström 
macroglobulinaemia: update from the VIth International Workshop. Br J Haematol 
2013;160(2):171-6. 
Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict 
survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for 
Myeloproliferative Neoplasms Research and Treatment). Blood 2010;115(9):1703-8.  
Raanani P, Gafter-Gvili A, Paul M, et al. Immunoglobulin prophylaxis in chronic lymphocytic 
leukemia and multiple myeloma: systematic review and meta-analysis. Leuk Lymphoma 
2009;50(5):764-72. 
Scherber et al. The Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom 
Score (MPN-SAF TSS): prospective international assessment of an abbreviated symptom 
burden scoring system among 1408 MPN patients. Available at: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872304/bin/supp_JCO.2012.42.3863_data_sup
plement_JCO.2012.42.3863.pdf. Accessed   
http://jco.ascopubs.org/content/suppl/2012/10/15/JCO.2012.42.3863.DC1/data_supplement_JC
O.2012.42.3863.pdf, accessed on: 14 August 2015. 
Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the Use of WBC Growth Factors: 
American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 
2015;33(28):3199-212. 
Stern A, Green H, Paul M, Vidal L, Leibovici L. Prophylaxis for Pneumocystis pneumonia (PCP) 
in non-HIV immunocompromised patients. Cochrane Database Syst Rev 2014;(10):CD005590. 

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Tai YT, Chang, BY, Kong SY, et al. Bruton tyrosine kinase inhibition is a novel therapeutic 
strategy targeting tumor in the bone marrow microenvironment in multiple myeloma. Blood 
2012;120(9):1877-1887. 
Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International 
Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and 
European LeukemiaNet (ELN) consensus report. Blood 2013;122(8):1395-8.  
Topalian SL, Weiner GJ, Pardoll DM.  Cancer immunotherapy comes of age. J Clin Oncol 
2011;29(36):4828-4836. 
Treon SP, Tripsas CK, Yang G, et al. A prospective multicenter study of the Bruton’s tyrosine 
kinase inhibitor ibrutinib in patients with relapsed or refractory Waldenstrom’s 
macroglobulinemia. Blood 2013;122:251. 
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(1):28-37. 
 
 

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APPENDICES 
 
 

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Appendix 1 
Performance Status Scores  
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, office 
work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair 
5 
Dead 
 
Source:  Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55. 
Credit: Eastern Cooperative Oncology Group Chair: Robert Comis, MD 
Available at: http://www.ecog.org/general/perf_stat.html.  Accessed 23 August 2013. 
 
 

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

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Appendix 3 
Adverse Event Assessment of Causality 
Is there a reasonable possibility that the event may have been caused by study drugs?   
No___  
Yes___ 
The descriptions provided below will help guide the principal investigator in making the decision 
to choose either “No” or “Yes”: 
No=There is no reasonable possibility that the event may have been caused by study drugs.  
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 drugs.  
The adverse event: 
• 
Follows a temporal sequence from administration of study drug 
• 
Is a known response to the study drug based on clinical or nonclinical data 
• 
Could not be explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other therapy administered to the subject 
• 
Disappears or decreases upon cessation or reduction of dose of study drug 
• 
Reappears or worsens when study drug is re-administered 
 

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Appendix 4 
Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom 
Score  
Symptom 
1 to 10 (0 if absent) Ranking 
1 is most favorable and 10 least favorable 
Please rate your fatigue 
(weariness, tiredness) by circling 
the one number that best 
describes your WORST level of 
fatigue during past 24 hours 
(No Fatigue) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Circle the one number that describes how, during the past week how much difficulty you 
have had with each of the following symptoms 
Filling up quickly when you eat  
(early satiety)  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Abdominal discomfort  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Inactivity  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Problems with concentration - 
Compared to prior to my 
myeloproliferative disease (MPD) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Night sweats  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Itching (pruritus)  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Bone pain (diffuse not joint pain or 
arthritis) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Fever (>100° F)  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Daily) 
Unintentional weight loss last 
6 months  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Source:  Scherber et al. The Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score 
(MPN-SAF TSS):  prospective international assessment of an abbreviated symptom burden scoring system among 
1408 MPN patients. Available at: http://jco.ascopubs.org/content/suppl/2012/10/15/JCO.2012.42.3863.DC1/ 
data_supplement_JCO.2012.42.3863.pdf. Accessed on: 14 August 2015. 
 
Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom assessment form total 
symptom score: prospective international assessment of an abbreviated symptom burden scoring system among 
patients with MPNs. J Clin Oncol 2012;30(33):4098-103. 
 
 

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Appendix 5 
Schedule of Assessments – Parts 1 and 2 
 
Treatment Phaseb 
Safety 
Follow-up 
Visitc 
Follow-
up 
Phased 
Study Weeks  
Screeninga 
Weeks  
Wks 10-103 
(Q3W) aa 
Wks >103 
(Q24W/ 
Q52W)aa 
ET 
+30 days 
after last 
dose 
Q12W 
1 
2 
3 
4 
5 
6 
7 
8 
Study Window 
-28 days 
 
±3 days 
±3 days 
±10 days 
+3 days 
+7 days 
±10 days 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
PEe/Vital signsf/Weight 
x 
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 
x 
 
ECGg 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lab assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine or serum pregnancy 
testh 
x 
xr,u 
 
 
x 
 
 
x 
 
x 
x 
x 
x 
 
 
Hematology (w/smear)i 
x 
xr 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Serum chemistryj 
x 
xr 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Thyroid panelk 
x 
xr 
x 
x 
x 
x 
x 
x 
x 
xk 
xk 
x 
x 
 
 
Hepatitis serologyv 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV PCRw 
x 
 
 
 
x 
 
 
 
x 
Week 12 then 
Q4W 
Q3Mw 
 
 
Q3Mw 
HCV PCRx 
x 
 
 
 
 
 
 
 
 
Week 13 and 25 
 
 
 
 
 
Urinalysisl 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T/B/NK cell countm 
 
xr 
 
 
 
 
x 
 
x 
Week 19 then 
Q12W 
xm 
 
 
 
 
Serum Ign 
 
xr 
 
 
 
 
x 
 
x 
Week 19 then 
Q12W 
xn 
 
 
 
 
Disease markerso,q (MM and 
WM only) 
x 
xr 
 
x 
 
 
x 
 
x 
x 
x 
 
 
 
 
Tumor tissuep 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skeletal survey (MM only)q 
x 
As clinically indicated, and at Week 52 
 
 
 
Acalabrutinib 100 mg BID 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Pembrolizumab 200 mg Q3W 
 
x 
 
 
x 
 
 
x 
 
x 
x 
 
 
 
Study drug compliance 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Radiologic assessmentsq 
x 
 
 
 
 
 
 
 
xq 
Week 19 then 
Q12Wq 
xq 
 
 
 
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Treatment Phaseb 
Safety 
Follow-up 
Visitc 
Follow-
up 
Phased 
Study Weeks  
Screeninga 
Weeks  
Wks 10-103 
(Q3W) aa 
Wks >103 
(Q24W/ 
Q52W)aa 
ET 
+30 days 
after last 
dose 
Q12W 
1 
2 
3 
4 
5 
6 
7 
8 
Study Window 
-28 days 
 
±3 days 
±3 days 
±10 days 
+3 days 
+7 days 
±10 days 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse eventsz 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Follow-up post-allogenic stem 
cell transplantation data 
collectiony 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Time-to-next treatment 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
AE=adverse event; anti-HBc=hepatitis B core antibody; anti-HBs=hepatitis B surface antibody; BID=twice per day; CLL=chronic lymphocytic leukemia; CR=complete 
remission; CT=computed tomography; ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, ET=early termination; HBsAg=hepatitis B surface 
antigen; HBV=hepatitis B virus; Ig=immunoglobulin; IVIG =intravenous immunoglobulins; MM=multiple myeloma; PCR=polymerase chain reaction; 
 PE=physical examination; PET=positron-emission tomography; PR=partial response; Q12W=every 12 weeks; Q3W=every 3 weeks; 
Q4W=every 4 weeks; SAE=serious adverse event; SCT=stem cell transplantation; SLL=small lymphocytic lymphoma; WM=Waldenström macroglobulinemia. 
Footnotes for Appendix 5 ACE-LY-005 Schedule of Study Activities – Parts 1 and 2 
a 
Screening tests should be performed within 28 days before the first administration of study drug, unless otherwise indicated. 
b 
Treatment with acalabrutinib may be continued until disease progression or an unacceptable drug-related toxicity occurs as defined in the protocol.  Treatment with 
pembrolizumab may continue for 24 months (103 weeks) from first dose of pembrolizumab, provided subject is tolerating the drug and not progressing.  Treatment 
may be stopped earlier for confirmed CR as described in the protocol.  Treatment with acalabrutinib can continue until the end of trial, defined as 48 months after 
the last subject is enrolled, for subjects who are tolerating therapy and not progressing.   
c 
A 30-day (+7 days) safety follow-up visit is required when subjects discontinue study drug. 
d 
Subjects who discontinue study therapy will continue on study to measure survival unless they withdraw consent, are lost to follow up, die, or the sponsor ends the 
study.  
e 
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.  Physical examinations are 
done thereafter.  For all subjects except those with MM, the following B symptoms will be collected at each examination.  Unintentional weight loss of normal body 
weight over a period of ≤6 months; disease associated intermittent fevers ≥38°C; drenching sweats especially at night. 
f 
Vital signs (blood pressure, pulse and temperature) will be assessed after the subject has rested in the sitting position.   
g 
Subjects should be in supine position and resting for ≥10 minutes before study-related ECGs.   
h 
Women of childbearing potential must have a negative urine or serum pregnancy testing within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required.  
i 
Hematology includes complete blood count with peripheral blood smear and differential, and platelet and reticulocyte counts. Week 1 hematology does not need to 
be repeated if screening hematology was done within 7 days. 
j 
Serum chemistry: albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bicarbonate, blood urea nitrogen, bone-specific alkaline 
phosphatase, calcium, chloride, creatinine, c-terminal telopeptide, glucose, lactate dehydrogenase, magnesium, phosphate/phosphorus, potassium, sodium, total 
bilirubin, total protein, and uric acid. Week 1 serum chemistry does not need to be repeated if screening chemistry was within 7 days. 
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k 
Thyroid panel: total triiodothyronine, free thyroxine, and thyroid stimulating hormone.  Week 1 thyroid panel does not need to be repeated if screening thyroid panel 
was within 7 days.  Thyroid function tests will be performed once weekly for the first 8 weeks, followed by a Week 10 visit and then every 6 weeks until 6 months 
after the last dose of pembrolizumab. For subjects who permanently discontinue pembrolizumab, i.e., before completing 103 weeks, thyroid tests must be 
completed every 6 weeks after the last dose of pembrolizumab for 6 months until 1) testing that was performed at 6 months was normal, and 2) testing that was 
performed 6 weeks prior to the 6-month timepoint was normal (for a total of 2 consecutive normal test results).  Otherwise, thyroid testing will continue as 
scheduled until 2 consecutive normal test results.  Subjects who complete pembrolizumab through 103 weeks will have a thyroid panel collected at Week 106 and 
Week 109 only, and every 6 weeks thereafter. Thyroid testing may be discontinued at 6 months after pembrolizumab discontinuation if 1) testing that was 
performed at 6 months was normal and 2) testing that was performed 6 weeks prior to the 6-month timepoint was normal (for a total of 2 consecutive normal test 
results).  Otherwise, thyroid testing will continue every 6 weeks until 2 consecutive normal test results. 
l 
Urinalysis: pH, ketones, specific gravity, bilirubin, N-terminal telopeptide, protein, blood, and glucose.   
m 
T/B/NK cell count (i.e., CD3, CD4, CD8, CD19, CD16/56), conducted at Week 1, Week 6, Week 8, and Week 19, and then every 12 weeks through Week 103, 
thereafter collected every 24 weeks starting at Week 127 through 3 years (for subjects with CLL/SLL histologies) or 5 years (for subjects with non-CLL/SLL 
histologies [i.e., DLBCL/Hodgkin lymphoma]), and then every 52 weeks thereafter (all histologies).   
n 
Serum immunoglobulin: IgG, IgM, IgA, conducted at Week 1, Week 6, Week 8, and Week 19, and then every 12 weeks through Week 103, thereafter collected 
every 24 weeks starting at Week 127 through 3 years (for subjects with CLL/SLL histologies) or 5 years (for subjects with non-CLL/SLL histologies [i.e., DLBCL/ 
Hodgkin lymphoma]), and then every 52 weeks thereafter (all histologies). 
o 
Refer to Section 4.1.18 for a list of MM and WM disease markers.  For MM, serum samples should be drawn approximately 1 hour before or 1 hour after the end of 
the 24-hour urine collection.   
p 
Provide tissue (if available) from either an archived or newly obtained tumor sample (most recent biopsy) for biomarker and correlative analysis. 
r 
The indicated samples at this timepoint must be drawn predose. 
t 
This peripheral blood sample will be collected if treatment termination is due to disease progression. 
u 
This urine or serum pregnancy test is to be performed on Week 1 Day 1 (- 3 days) and at each visit for subjects with childbearing potential. 
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v 
Hepatitis serology must include HBsAg, anti-HBs, anti-HBc, and hepatitis C antibody.  In addition, any subjects testing positive for any hepatitis serology, must 
have PCR testing (see exclusion criterion #30). 
w 
Subjects who are anti-HBc positive (or have a known history of HBV) should have a quantitative PCR test for HBV DNA performed during screening and while on 
study treatment.  These subjects should have a quantitative PCR test performed monthly while on combination treatment and every 3 months while on 
acalabrutinib monotherapy. Following study drug discontinuation, monitoring should continue every 3 months until 12 months after last dose of study drug(s).  Any 
subject with a rising viral load (above lower limit of detection) should discontinue study drug(s) and have antiviral therapy instituted and a consultation with a 
physician with expertise in managing hepatitis B.  As IVIG may cause false positive serology, monthly PCR testing is not required in subjects who are currently 
receiving or received prophylactic IVIG within 3 months before study enrollment and have a documented negative anti-HBc test before the initiation of IVIG 
therapy.  Additional PCR testing should be performed when clinically indicated (e.g., in the setting of rising transaminase levels).     
x 
Subjects with a known history of hepatitis C or who are hepatitis C antibody-positive should have quantitative PCR testing for HCV DNA performed during 
screening and at Weeks 13 and 25.  No further testing beyond Week 25 is necessary if PCR results are negative.    
y 
For subjects who have an allogeneic SCT within 24 months of last dose of pembrolizumab, transplant parameters will be collected, and specific events will be 
collected for 18 months from the date of the allogeneic transplant, to include graft-versus-host-disease (acute and/or chronic), veno-occlusive disease, febrile 
syndrome (a steroid-requiring febrile illness without an infectious cause), and encephalitis, for all grades, and regardless of relationship to study drug.  Additional 
medically important adverse events post-allogeneic SCT may be submitted at the investigator’s discretion. If available and relevant to an event post-allogeneic 
SCT, concomitant medications and/or laboratory results may also be reported. 
z 
After the end of the protocol-defined AE reporting period, only SAEs considered related to study drug(s) or study procedures are required to be collected. 
aa All subjects continuing single-agent acalabrutinib treatment after Week 103 will have a Week 103 and Week 115 visit, and then every 24 weeks thereafter 
beginning at Week 127 through 3 years (for subjects with CLL/SLL histologies) or 5 years (for subjects with non-CLL/SLL histologies [i.e., DLBCL/Hodgkin 
lymphoma]), and then every 52 weeks thereafter (all histologies).  Subjects who discontinue pembrolizumab at Week 103 must also have visits at Week 106 and 
Week 109.  Subjects who discontinue pembrolizumab before Week 103 must continue visits every 3 weeks until Week 37, after which time visits are every 
12 weeks through 104 weeks, and thereafter every 24 or 52 weeks as described above. However, it is noted that because the discontinuation timepoint of 
pembrolizumab (if applicable) is unique per subject, the first every 12-week visit for these subjects will be scheduled to align with the radiologic tumor assessment 
timepoint nearest to the 12-week interval.  
 
 

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Appendix 6 
Schedule of Assessments – Part 3 (Myelofibrosis) 
 
Treatment Phaseb 
Safety 
Follow-
up Visitc 
Follow
-up 
Phase
d 
Study Weeks 
Screeninga 
Weeks 
Wks 13-52 
(Q3W) 
Wks >52 
(Q3W) 
ET 
+30 days 
after last 
dose 
Q12W 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Study Window 
-28 days 
 
±3 days 
±3 d 
±3 d 
+3 d 
+7 d 
±10 d 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PEe/Vital signsf/Weight 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
x 
 
ECGg 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lab assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Urine or serum 
pregnancy testh 
x 
xr,y 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
 
 
 
 Hematology (w/ smear)i 
x 
xr 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 Serum chemistryj 
x 
xr 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 Hepatitis serologyz 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 HBV PCRaa 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
Q4W 
Q4W 
 
 
Q4W 
 Thyroid panelk 
x 
xr 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 Urinalysisl 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Serum Ign 
 
xr 
 
 
 
 
x 
 
 
 
 
 
 
Wks 16 & 25, 
+ Q9W 
Q12W 
 
 
 
 Disease markerso 
x 
As clinically indicated 
 
 
 
Acalabrutinib 100 mg BID 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Pembrolizumab 200 mg 
Q3Wt 
 
 
 
 
 
 
 
xt 
 
 
xt 
 
 
xt 
xt 
 
 
 
Study drug compliance 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
MRI/CT of spleenw 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
Wks 16 & 25, 
+ Q9W 
Q12W 
 
 
 
MPN-SAF TSSu 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
Wks 16 & 25, 
+ Q9W 
Q12W 
 
 
 
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Treatment Phaseb 
Safety 
Follow-
up Visitc 
Follow
-up 
Phase
d 
Study Weeks 
Screeninga 
Weeks 
Wks 13-52 
(Q3W) 
Wks >52 
(Q3W) 
ET 
+30 days 
after last 
dose 
Q12W 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Study Window 
-28 days 
 
±3 days 
±3 d 
±3 d 
+3 d 
+7 d 
±10 d 
Concomitant medications 
(including transfusions)v 
x 
x 
x 
x 
x 
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 
x 
x 
x 
x 
Time-to-next treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Footnotes for Appendix 6 ACE-LY-005 Schedule of Study Activities – Part 3 (Myelofibrosis): 
Anti-HBc=hepatitis B core antibody; anti-HBs=hepatitis B surface antibody; BID=twice per day; CR=complete remission; CT=computed tomography; d=days; 
ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, ET=early termination; F/U=follow-up; HBsAg=hepatitis B surface antigen; HBV=hepatitis B 
virus; Ig=immunoglobulin; IVIG =intravenous immunoglobulins; JAK=Janus kinase; MF=myelofibrosis; MPN-SAF TSS=Myeloproliferative Neoplasm Symptom 
Assessment Form Total Symptom Score; MRI=magnetic resonance imaging; PCR=polymerase chain reaction; 
 PE=physical examination; 
PR=partial response; Q3W=every 3 weeks; Q4W=every 4 weeks; Q9W=every 9 weeks; Q12W=every 12 weeks; QM=every month   
a 
Screening tests should be performed within 28 days before the first administration of study drug, unless otherwise indicated. 
b 
Treatment with acalabrutinib may be continued until disease progression or an unacceptable drug-related toxicity occurs as defined in the protocol.  Treatment with 
pembrolizumab may continue for 24 months (103 weeks) from first dose of pembrolizumab, provided subjects are tolerating the drug and not progressing.  
Treatment may be stopped earlier for confirmed CR as described in the protocol.  Treatment with acalabrutinib can continue until the end of trial, defined as 
48 months after the last subject is enrolled, for subjects who are tolerating therapy and not progressing.   
c 
A 30-day (+7 days) safety follow-up visit is required when subjects discontinue study drug. 
d 
Subjects who discontinue study therapy will continue on study until withdrawal of consent, loss to follow-up, death, or study termination by the sponsor. 
e 
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.  As part of tumor assessment, 
Physical examinations, including presence and degree of splenomegaly and hepatomegaly (where appropriate) by palpation, are done thereafter.    
f 
Vital signs (blood pressure, pulse, and temperature) will be assessed after the subject has rested in the sitting position.   
g 
Subjects should be in supine position and resting for ≥10 minutes before study-related ECGs.   
h 
Women of childbearing potential must have a negative urine or serum pregnancy testing within 72 hours prior to receiving the first dose of study medication. If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required.  
i 
Hematology includes complete blood count with peripheral blood smear and differential, and platelet and reticulocyte counts. Week 1 hematology does not need to 
be repeated if screening hematology was done within 7 days. 
j 
Serum chemistry: albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bicarbonate, blood urea nitrogen, bone-specific alkaline 
phosphatase, calcium, chloride, creatinine, c-terminal telopeptide, glucose, lactate dehydrogenase, magnesium, phosphate, potassium, sodium, total bilirubin, total 
protein, and uric acid. Week 1 serum chemistry does not need to be repeated if screening chemistry was within 7 days. 
k 
Thyroid panel:  total triiodothyronine, free thyroxine, and thyroid stimulating hormone.  Week 1 thyroid panel does not need to be repeated if screening thyroid 
panel was within 7 days. Thyroid function tests will be performed once weekly for the first 8 weeks, followed by a Week 10 visit and then every 6 weeks thereafter 
until the 6-month timepoint. Thyroid testing may be discontinued at 6 months if 1) testing that was performed at 6 months was normal and 2) testing that was 
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performed 6 weeks prior to the 6-month timepoint was normal (for a total of 2 consecutive normal test results).  Otherwise, thyroid testing will continue beyond the 
6-month timepoint as scheduled until 2 consecutive normal test results. 
l 
Urinalysis: pH, ketones, specific gravity, bilirubin, N-terminal telopeptide, protein, blood, and glucose.  
n 
Serum immunoglobulin: IgG, IgM, IgA.   
o 
Molecular disease markers to be done at baseline and repeated as clinically indicated (at the investigator’s discretion) to assess molecular response (see 
Section 4.2) 
p 
(Footnote not applicable for Part 3) 
r 
The indicated samples at this timepoint must be drawn predose. 
t 
Subjects with MF will receive a run-in of 6 weeks of acalabrutinib alone.  Subjects who are demonstrating a clinically meaningful response, in the opinion of the 
investigator, may continue on acalabrutinib monotherapy; those who are not will receive combination therapy thereafter.   
u 
MPN-SAF TSS will be assessed at the end of Week 6 (±7 days), end of Week 15 (±7 days), end of Week 24 (±7 days), every 9 weeks (±10 days) through 
Week 52, and every 12 weeks (±14 days) thereafter, or more frequently at investigator discretion.   
v 
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. For subjects with MF, record all transfusions of blood products (e.g., red blood cells or platelets) within 12 weeks before the first study dose and 
throughout the study period.    
w 
A pretreatment MRI or CT scan to measure spleen volume is required within 30 days of the first dose; this baseline MRI/CT scan must be done at least 2 weeks 
after the last dose of any JAK inhibitors.  MRI is the preferred modality; the same modality (either MRI or CT) should be used for all timepoints for a given subject.  
On-treatment MRIs or CT scans will be done for spleen measurements at the end of Week 6 (±7 days), end of Week 15 (±7 days), end of Week 24 (±7 days), 
every 9 weeks (±10 days) through Week 52, and every 12 weeks (±14 days) thereafter, or more frequently at investigator discretion.    
x 
This peripheral blood sample will be collected if treatment termination is due to disease progression. 
y 
This urine or serum pregnancy test is to be performed on Cycle 1 Day 1 (- 3 days). 
z 
Hepatitis serology must include HBsAg, anti-HBs, anti-HBc, and hepatitis C antibody.  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 
exclusion criterion #30). 
aa Subjects who are anti-HBc positive (or have a known history of HBV) should be monitored every 3 months with a quantitative PCR test for HBV DNA and this 
testing is recommended to continue until 12 months after last dose of study drug(s).  Any subject with a rising viral load (above lower limit of detection) should 
discontinue study drug(s) and have antiviral therapy instituted and a consultation with a physician with expertise in managing hepatitis B. 
 
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Appendix 7 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law  
INTRODUCTION 
This Appendix describes the process to be followed in order 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 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× ULN together with total bilirubin ≥2× ULN at any point during the study after the 
start of study drug, irrespective of an increase in alkaline phosphatase.  
Hy’s Law  
AST or ALT ≥3× ULN together with total bilirubin ≥2× ULN, where no other reason other than the 
IMP can be found to explain the combination of increases (e.g., elevated alkaline phosphatase 
indicating cholestasis, viral hepatitis, or another drug).   
For PHL and HL, the elevation in transaminases must precede or be coincident with (i.e., on the 
same day) the elevation in total bilirubin, but there is no specified timeframe within which the 
elevations in transaminases and total bilirubin must occur. 

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IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
Laboratory data must be comprehensively reviewed by the investigator for each subject to 
identify laboratory values meeting the following criteria:  
• 
ALT ≥3× ULN 
• 
AST ≥3× ULN 
• 
Total bilirubin ≥2× ULN 
 
When the identification criteria are met from central or local laboratory results, the investigator 
will perform the following: 
• 
Notify the sponsor representative/medical monitor by telephone and report the PHL case as 
an SAE of Potential Hy’s law: seriousness criteria “important medical event” and causality 
assessment “yes/related” or in accordance with the clinical study protocol as appropriate. 
• 
Request a repeat of the test (new blood draw) without delay 
• 
Complete the appropriate unscheduled laboratory electronic Case Report Form (eCRF) 
module(s)  
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in the 
clinical study protocol, as applicable 
 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
The instructions in this section should be followed by the investigator for all cases where PHL 
criteria are met. 
As soon as possible after the biochemistry abnormality is initially detected, the study medical 
monitor and the investigator will review available data to agree whether there is an alternative 
explanation for meeting PHL criteria other than DILI caused by the IMP and to ensure that timely 
analysis and reporting to health authorities within 15 calendar days from the date PHL criteria 
were met.     
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 
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• 
If the alternative explanation is an AE/SAE, update the previously submitted PHL SAE and 
AE eCRFs 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 or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until an informed decision can be made: 
• 
Provide any further update to the previously submitted SAE of PHL (report term now “Hy’s 
law case”), ensuring causality assessment is related to IMP and seriousness criteria are 
medically important, according to clinical study protocol process.  
• 
Continue follow-up and review according to the agreed plan.  After the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met.  Update the previously submitted PHL SAE report following 
the clinical study protocol process, according to the outcome of the review.  
 
ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S LAW 
This section is applicable when a subject meets PHL criteria while receiving study treatment and 
has already met PHL criteria at a previous on-study treatment visit.  The requirement to conduct 
follow-up, review, and assessment of a repeat occurrence(s) of PHL is based on the nature of 
the alternative cause identified for the previous occurrence.   
The investigator should determine the cause for the previous occurrence of PHL and answer the 
following question: 

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Was the alternative cause for the previous occurrence of PHL determined to be the 
disease under study (e.g., chronic or progressing malignant disease, severe infection, or 
liver disease)? 
If the answer is No: 
Follow the process described in “Potential Hy’s Law Criteria Met” in this Appendix for 
reporting PHL as an SAE. 
If the answer is Yes:  
Determine whether there has been a significant change in the subject’s condition 
compared with the previous occurrence of PHL.  Note:  A “significant” change in the 
subject’s condition refers to a clinically relevant change in any of the individual liver 
biochemistry parameters (ALT, AST, or total bilirubin) in isolation or in combination or a 
clinically relevant change in associated symptoms.  The determination of whether there 
has been a significant change will be at the discretion of the investigator; this may be in 
consultation with the study medical monitor if there is any uncertainty. 
o If there is no significant change, no action is required. 
o If there is a significant change, follow the process described in “Potential Hy’s Law 
Criteria Met” in this Appendix for reporting PHL as an SAE.  
 
LABORATORY TESTS 
Table 13 represents the standard comprehensive list of follow-up tests that may aid in assessing 
PHL/HL.  
Test results used to assess PHL/HL should be recorded on the appropriate eCRF.   
 

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Table 13 
Laboratory Tests to Aid in Assessing Potential Hy’s Law / Hy’s Law  
Additional standard chemistry 
and coagulation tests 
GGT 
LDH 
Prothrombin time 
INR 
Viral hepatitis 
IgM anti-HAV  
IgM and IgG anti-HBc 
HBsAg 
HBV DNA 
IgM and IgG anti-HCV 
HCV RNA 
IgM anti-HEV 
HEV RNA 
Other viral infections 
IgM and IgG anti-CMV 
IgM and IgG anti-HSV 
IgM and IgG anti-EBV 
Alcoholic hepatitis 
Carbohydrate deficient transferrin (CD-transferrin) 
Autoimmune hepatitis 
Antinuclear antibody (ANA) 
Anti-Liver/Kidney Microsomal Ab (Anti-LKM) 
Anti-Smooth Muscle Ab (ASMA) 
Metabolic diseases 
alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin 
Transferrin saturation 
 
Reference 
FDA Guidance for Industry (issued July 2009). Drug-induced liver injury: premarketing clinical 
evaluation. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation 
/Guidances/UCM174090.pdf