Clinical trial NCT02211014
Conditions: Multiple Myeloma (MM)
Keywords: Bruton tyrosine kinase inhibitor Btk Multiple Myeloma MM ACP-196 acalabrutinib Calquence
Sponsor: Acerta Pharma BV
Start date: 2015-02-01; Completion date: 2019-04-26
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To characterize the safety profile of acalabrutinib with and without dexamethasone in subjects with relapsed or refractory Multiple Myeloma (MM)

Detailed description:

Arms: arm 1: Acalabrutinib 100 mg twice daily (bid) continuously arm 2: Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly
Interventions: intervention 1: acalabrutinib
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
Product: ACP-196 (acalabrutinib) 
Date: 13 January 2016 
Protocol: ACE-MY-001
Acerta Pharma 
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Page 1 of 84
PROTOCOL
TITLE:
An Open-label, Phase 1b Study of ACP-196 in Subjects 
with Multiple Myeloma
PROTOCOL NUMBER:
ACE-MY-001
STUDY DRUG:
ACP-196 (acalabrutinib)
IND NUMBER:
118717
EUDRACT NUMBER
2014-003587-21
SPONSOR MEDICAL 
MONITOR:
Acerta Pharma BV
SPONSOR:
Acerta Pharma BV
Kloosterstraat 9
5349 AB Oss
The Netherlands
PROTOCOL DATE:
Version 0.0 - 11 July 2014
AMENDMENT 1 DATE:
Version 1.0 - 20 March 2015
AMENDMENT 2 DATE:
Version 2.0 - 13 January 2016
Confidentiality Statement 
This document contains proprietary and confidential information of Acerta Pharma BV 
that must not be disclosed to anyone other than the recipient study staff and members of 
the institutional review board (IRB)/independent ethics committee (IEC). This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Acerta Pharma BV.




Product: ACP-196 (acalabrutinib) 
Date: 13 January 2016 
Protocol: ACE-MY-001 
 
 
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SUMMARY OF AMENDMENT 2 
This protocol is being amended to add hepatitis serology testing at screening.  For 
subjects who test positive for latent hepatitis B infection at screening (or who have a 
known history of hepatitis B infection), this protocol will now require monthly monitoring 
for potential hepatitis B reactivation.  The reason for this amendment is hepatitis B 
reactivation has occurred in patients treated with Btk inhibitors including 1 subject 
receiving ACP-196 (Ngoma 2015). 
Clarifying edits and typographical changes have been made throughout the protocol. In 
addition, the following substantive changes were made as part of this amendment: 
Change 
Rationale 
In various parts of the protocol, the 
nonproprietary name for ACP-196 was 
introduced. 
The nonproprietary name of acalabrutinib 
was recently approved for use. 
Title Page 
 
Sponsor address changed from: 
 
Molenstraat 110 
5342 CC Oss 
The Netherlands 
 
to new address of: 
 
Kloosterstraat 9 
5349 AB Oss 
The Netherlands 
 
Administrative change 
Synopsis 
 
Updated to reflect changes made 
throughout the protocol. 
To ensure consistency between the body 
of the protocol and the synopsis. 
Section 3.4.2 Exclusion Criteria 
Revised text as follows (bold is new 
text): 
11. Known history of human 
immunodeficiency virus (HIV), 
serologic status reflecting active 
hepatitis B or C infection, or any 
uncontrolled active systemic infection.  
Subjects with hepatitis B core 
antibody positive who are surface 
antigen negative or who are hepatitis 
C antibody positive will need to have a 
negative polymerase chain reaction 
As hepatitis B virus (HBV) reactivation 
has occurred in 1 subject on ACP-196 
treatment, this exclusion criterion was 
further clarified to state that subjects who 
are hepatitis B core antibody positive who 
are surface antigen negative or who are 
hepatitis C antibody positive will need to 
have a negative PCR result before 
enrolling, and subjects who are hepatitis 
B surface antigen positive or hepatitis B 
PCR positive, and those who are hepatitis 
C PCR positive are excluded from the 
study. 


Product: ACP-196 (acalabrutinib) 
Date: 13 January 2016 
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Change 
Rationale 
(PCR) result before enrollment.  Those 
who are hepatitis B surface antigen 
positive or hepatitis B PCR positive 
and those who are hepatitis C PCR 
positive will be excluded. 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. 
 
 
 
 
 
Section 3.7.2 Hepatitis B Virus 
Reactivation 
New section and corresponding language 
was added: 
 
Serious or life-threatening reactivation 
of viral hepatitis may occur in subjects 
treated with ACP-196.  Therefore, 
subjects who are hepatitis B core 
antibody (anti-HBc) positive, or have a 
known history of hepatitis B virus 
(HBV) infection, should be monitored 
monthly with a quantitative PCR test 
for HBV DNA.  Monthly monitoring 
should continue until 12 months after 
last dose of ACP-196.  Any subject 
with a rising viral load (above lower 
limit of detection) should discontinue 
ACP-196 and have antiviral therapy 
instituted and a consultation with a 
physician with expertise in managing 
hepatitis B.  Insufficient data exist 
regarding the safety of resuming 
ACP-196 in subjects who develop HBV 
reactivation.    
 
Section 4.1.16 Hepatitis B and C 
Testing 
New section and corresponding language 
was added: 
 
Hepatitis serology testing must 
include hepatitis B surface antigen 
(HBsAg), hepatitis B surface antibody 
(HBsAb), anti-HBc, and hepatitis C 
(HCV) antibody.  Since intravenous 
immunoglobulins (IVIG) may cause 
false positive hepatitis serology, 
subjects who are receiving 
prophylactic IVIG and have positive 
As HBV reactivation has occurred in 
1 subject on ACP-196 treatment, this 
language is being added to ensure 
adequate monitoring of patients who are 
anti-HBc positive or with a history of HBV. 
 
Subsequent sections were renumbered 
accordingly. 


Product: ACP-196 (acalabrutinib) 
Date: 13 January 2016 
Protocol: ACE-MY-001 
 
 
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Change 
Rationale 
HBsAg or anti-HBc must have 
negative hepatitis B DNA to be 
eligible.  In addition, any subjects 
testing positive for any hepatitis 
serology, must have PCR testing (see 
Appendix 5 and exclusion criterion 
#11).  Testing will be done by local or 
central laboratory.   
Refer to Section 3.7.2 and Appendix 5 
regarding monitoring of subjects who 
are anti-HBc positive or have a known 
history of HBV 
Appendix 5.  Schedule of 
Assessments 
 
The schedule of assessments and 
footnotes were revised, as appropriate, to 
match the body of the protocol as 
described above regarding hepatitis 
serology testing at screening and monthly 
HBV PCR testing. 
Revised to be consistent with this 
amendment. 
 
 


Product: ACP-196 (acalabrutinib) 
Date: 13 January 2016 
Protocol: ACE-MY-001 
 
 
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TABLE OF CONTENTS 
1.0 
BACKGROUND INFORMATION ................................................................ 19 
1.1 
Role of Btk in Lymphoid Cancers ................................................................. 19 
1.2 
Preclinical Studies ....................................................................................... 20 
1.2.1 
Chemistry ....................................................................................... 20 
1.2.2 
Efficacy Pharmacology ................................................................... 21 
1.2.3 
ACP-196 and Thrombus Formation ................................................ 22 
1.2.4 
Safety Pharmacology ..................................................................... 23 
1.2.5 
Drug-drug Interaction Potential....................................................... 24 
1.2.6 
In Vivo General Toxicology ............................................................ 25 
1.3 
Clinical Experience ...................................................................................... 25 
1.3.1 
Pharmacokinetics and Pharmacodynamics of ACP-196 in Healthy 
Volunteers ...................................................................................... 27 
1.3.2 
Clinical Experience of ACP-196 in CLL .......................................... 29 
1.4 
Benefit/Risk .................................................................................................. 33 
1.5 
Summary and Conclusions .......................................................................... 33 
2.0 
STUDY OBJECTIVES ................................................................................. 34 
2.1 
Primary Objective ........................................................................................ 34 
2.2 
Secondary Objectives: ................................................................................. 34 
3.0 
STUDY DESIGN .......................................................................................... 34 
3.1 
Description of Study ..................................................................................... 34 
3.2 
Study Parameters ........................................................................................ 35 
3.2.1 
Safety Parameters .......................................................................... 35 
3.2.2 
Efficacy Parameters ....................................................................... 35 
3.2.3 
Pharmacokinetic and Pharmacodynamic Parameters .................... 36 
3.3 
Rationale for Study Design and Dosing Regimen ........................................ 36 
3.4 
Selection of Study Population ...................................................................... 37 
3.4.1 
Inclusion Criteria ............................................................................. 37 
3.4.2 
Exclusion Criteria ........................................................................... 37 
3.4.3 
Replacement of Subjects ............................................................... 39 
3.4.4 
Enrollment and Randomization Procedures ................................... 39 
3.5 
Study Drug ................................................................................................... 39 
3.5.1 
Premedications ............................................................................... 39 
3.5.2 
Formulation, Packaging, and Storage ............................................ 40 
3.5.2.1 
ACP-196 .................................................................................... 40 
3.5.2.2 
Dexamethasone ....................................................................... 40 
3.5.3 
Administration of Study Drug .......................................................... 40 


Product: ACP-196 (acalabrutinib) 
Date: 13 January 2016 
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3.5.3.1 
ACP-196 .................................................................................... 40 
3.5.3.2 
Dexamethasone ....................................................................... 41 
3.5.4 
Assuring Subject Compliance......................................................... 41 
3.5.5 
Study Treatment Regimen and Dose Modifications ....................... 42 
3.5.5.1 
ACP-196 .................................................................................... 42 
3.5.5.2 
Dexamethasone ....................................................................... 43 
3.6 
Concomitant Therapy................................................................................... 43 
3.6.1 
Permitted Concomitant Therapy ..................................................... 43 
3.6.2 
Guideline for Use of CYP Inhibiting/Inducing Drugs ....................... 43 
3.6.3 
Guideline for Use of Drugs that Affect Gastric pH .......................... 43 
3.6.4 
Prohibited Concomitant Therapy .................................................... 44 
3.7 
Precautions .................................................................................................. 44 
3.7.1 
Dietary Restrictions ........................................................................ 44 
3.7.2 
Hepatitis B Virus Reactivation ........................................................ 44 
3.7.3 
Surgery ........................................................................................... 45 
3.7.4 
Infections ........................................................................................ 45 
3.7.5 
Reproductive Toxicity ..................................................................... 45 
3.7.6 
Overdose Instructions .................................................................... 45 
3.8 
Stopping Rules ............................................................................................ 46 
3.9 
Data and Safety Monitoring ......................................................................... 47 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS ............................................... 47 
4.1 
Description of Procedures ............................................................................ 48 
4.1.1 
Informed Consent ........................................................................... 48 
4.1.2 
Medical History ............................................................................... 48 
4.1.3 
Adverse Events .............................................................................. 48 
4.1.4 
Concomitant Medications and Therapy .......................................... 48 
4.1.5 
Confirmation of Eligibility ................................................................ 48 
4.1.6 
ECOG Performance Status ............................................................ 48 
4.1.7 
Physical Examination, Vital Signs, Height & Weight ....................... 48 
4.1.8 
Bone Marrow Aspirate and Biopsy ................................................. 49 
4.1.9 
Electrocardiogram .......................................................................... 49 
4.1.10 Urine Pregnancy Test ..................................................................... 49 
4.1.11 Hematology .................................................................................... 49 
4.1.12 Serum Chemistry ............................................................................ 49 
4.1.13 Urinalysis ........................................................................................ 50 
4.1.14 T/B/NK Cell Count .......................................................................... 50 
4.1.15 Disease Markers ............................................................................ 50 
4.1.16 Hepatitis B and C Testing ............................................................... 50 
4.1.17 Skeletal Survey .............................................................................. 50 


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4.1.18 Pharmacodynamics ........................................................................ 51 
4.1.19 Pharmacokinetics ........................................................................... 51 
4.1.20 Tumor Assessment ........................................................................ 51 
4.1.21 Study Drug Accountability .............................................................. 52 
4.2 
Investigator’s Assessment of Response to Treatment ................................. 52 
4.3 
Early Termination/Safety Follow-up Visit ..................................................... 54 
4.4 
Missed Evaluations ...................................................................................... 54 
5.0 
STATISTICAL METHODS OF ANALYSIS .................................................. 55 
5.1 
General Considerations ............................................................................... 55 
5.2 
Sample Size Considerations ........................................................................ 55 
5.3 
Definition of Analysis Populations ................................................................ 55 
5.4 
Missing Data Handling ................................................................................. 55 
5.5 
Endpoint Data Analysis ................................................................................ 56 
5.5.1 
Safety Endpoint .............................................................................. 56 
5.5.2 
Demographics and Baseline Characteristics .................................. 56 
5.5.3 
Analysis of Efficacy Parameters ..................................................... 56 
5.5.3.1 
Overall Response Rate ........................................................... 56 
5.5.3.2 
Duration of Response ............................................................. 57 
5.5.3.3 
Clinical Benefit Rate ................................................................ 57 
5.5.3.4 
Disease Control Rate .............................................................. 57 
5.5.3.5 
Progression-free Survival ....................................................... 57 
5.5.4 
Analysis of Pharmacokinetic/Pharmacodynamic Parameters ........ 57 
5.5.5 
Exploratory or Correlative Analyses ............................................... 58 
6.0 
ASSESSMENT OF SAFETY ....................................................................... 58 
6.1 
Definitions .................................................................................................... 59 
6.1.1 
Adverse Events .............................................................................. 59 
6.1.2 
Serious Adverse Event ................................................................... 59 
6.1.3 
Severity .......................................................................................... 60 
6.2 
Documenting and Reporting of Adverse and Serious Adverse Events ........ 61 
6.2.1 
Adverse Event Reporting Period .................................................... 61 
6.2.2 
Assessment of Adverse Events ...................................................... 61 
6.2.3 
Pregnancy ...................................................................................... 61 
6.2.4 
Expedited Reporting Requirements for Serious Adverse Events ... 62 
6.2.5 
Type and Duration of Follow-up of Subjects After Adverse Events 63 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS .......... 63 
7.1 
Regulatory and Ethical Compliance ............................................................. 63 
7.2 
Institutional Review Board and Independent Ethics Committee ................... 64 
7.3 
Informed Consent and Protected Subject Health Information Authorization 64 


Product: ACP-196 (acalabrutinib) 
Date: 13 January 2016 
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7.4 
Subject Screening Log ................................................................................. 65 
7.5 
Case Report Forms ..................................................................................... 65 
7.6 
Study Monitoring Requirements ................................................................... 65 
7.7 
Investigational Study Drug Accountability .................................................... 66 
7.8 
Record Retention ......................................................................................... 67 
7.9 
Protocol Amendments.................................................................................. 67 
7.10 
Publication of Study Results ........................................................................ 68 
7.11 
Clinical Trial Insurance................................................................................. 68 
7.12 
General Investigator Responsibilities ........................................................... 68 
8.0 
REFERENCES ............................................................................................ 70 
9.0 
APPENDICES ............................................................................................. 72 
IN–TEXT TABLES 
Table 1-1.  Assessment of ACP-196 Active-site Occupancy in  Fine Needle Aspirates of 
Canine Lymph Node Tumors (N=4) .......................................................................21 
Table 1-2.  ACP-196 Clinical Studies as of January 2015 ..............................................26 
Table 1-3.  Btk Occupancy in Peripheral Blood of Subjects from ACE-CL-001 (December 
2014) .....................................................................................................................30 
Table 1-4.  Preliminary Day 8 PK Results from ACE-CL-001 (October 2014) ................30 
Table 1-5.  Best Response by Cohort from ACE-CL-001 (23OCT2014) ........................31 
Table 3-1.  Drug Discontinuation Actions for ACP-196 ..................................................42 
Table 4-1.  Pharmacokinetic Sample Schedule .............................................................51 
Table 4-2.  Response Criteria (derived from Rajkumar 2011 and Bladé 1998) ..............52 
 
IN–TEXT FIGURES 
Figure 1-1.  Effect of ACP-196 (1 μM) and Ibrutinib (1 μM) on Thrombus Formation .....23 
Figure 1-2.  Kaplan-Meier Curves for Progression-free Survival by Investigator 
Assessment for ACE-CL-001 (N=75; excludes Richter’s Syndrome Cohort and 
Ibrutinib R/R Cohort) ..............................................................................................31 
Figure 1-3.  Median (95% CI) Change from Baseline in ALC/SPD Over Time ...............33 
 


Product: ACP-196 (acalabrutinib) 
Date: 13 January 2016 
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ABBREVIATIONS 
 
ACP-196 
acalabrutinib 
AE(s) 
adverse event(s) 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
hepatitis B core antibody 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BCR 
B-cell receptor 
BID 
twice a day (dosing) 
Btk 
Bruton tyrosine kinase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum concentration 
CR 
complete remission (response) 
CSSF 
Clinical Supplies Shipping Receipt Form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
FDA 
Food and Drug Administration 
FIH 
first-in-human (trial) 
FLC 
(serum) free light chains 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
HBsAb 
hepatitis B surface antibody 


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Date: 13 January 2016 
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HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
HNSTD 
highest nonseverely toxic dose 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IFE 
immunofixation electrophoresis 
Ig 
immunoglobulin 
IRB 
Institutional Review Board 
IVIG 
intravenous immunoglobulins 
LDH 
lactate dehydrogenase 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
multiple myeloma 
MR 
minimal response 
NHL 
non-Hodgkin lymphoma 
NK 
natural killer (cells) 
ORR 
overall response rate 
PBMC(s) 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PI3K 
phosphoinositide-3 kinase 
PK 
pharmacokinetics 
PR 
partial remission (response) 
QD 
once a day (dosing) 
QM 
every month 
QTc 
corrected QT interval 
SAE(s) 
serious adverse event(s) 
SD 
stable disease 
SFLC 
serum free light chains 
SIFE 
serum immunofixation electrophoresis 
SPD 
sum of the products of the perpendicular diameters (of lymph nodes) 
SPEP 
serum protein electrophoresis 


Product: ACP-196 (acalabrutinib) 
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SUSAR 
Suspected Unexpected Serious Adverse Reaction (report) 
Tmax 
time to maximum drug concentration 
UIFE 
urine immunofixation electrophoresis 
ULN 
upper limit of normal 
UPEP 
urine serum protein electrophoresis 
VGPR 
very good partial response  
WHO 
World Health Organization 


Product: ACP-196 (acalabrutinib) 
Date: 13 January 2016 
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STUDY SYNOPSIS  
Protocol Number: 
ACE-MY-001 
Study Drug: 
ACP-196 (acalabrutinib) 
Protocol Title: 
An Open-label, Phase 1b Study of ACP-196 in Subjects with 
Multiple Myeloma 
Phase: 
Phase 1b 
Comparator: 
None 
Background and 
Rationale for Study 
Clinical studies have shown that targeting the B-cell receptor 
(BCR) signaling pathway by inhibiting Bruton tyrosine kinase (Btk) 
produces significant clinical benefit in patients with non-Hodgkin 
lymphoma (NHL) and chronic lymphocytic leukemia (CLL). 
Preclinical studies have shown that Btk inhibition significantly 
reduces in vivo multiple myeloma (MM) cell growth and MM cell-
induced osteolysis in a murine model (Tai 2012).  Data on the 
utility of Btk targeted therapy in patients with MM is very 
preliminary, but suggests there are subsets of patients with 
malignant plasma cell clones in which Btk is active as evidenced 
by expression of phosphorylated Btk (p-Btk), and that these 
cancers may be particularly responsive to Btk inhibitor therapy. 
Acerta Pharma BV (Acerta Pharma) has developed a novel second 
generation Btk inhibitor, ACP-196, that achieves significant oral 
bioavailability and potency in preclinical models. ACP-196 
monotherapy is currently in multiple Phase 1/2 studies in subjects 
with chronic lymphocytic leukemia (CLL) and other indications.   
The purpose of this study is to evaluate the safety, 
pharmacokinetics (PK), pharmacodynamics (PD), and activity of 
ACP-196 administration with and without dexamethasone in 
subjects with relapsed MM.  The study will explore the concept of 
whether biomarkers may help identify patients with MM that are 
particularly likely to benefit from Btk inhibitor therapy.  
Study Design: 
This study is a multicenter, open-label, randomized, parallel-group 
study to be conducted at approximately 20 sites in 2 countries 
(United Kingdom and United States).  Forty subjects will be equally 
randomized (1:1 ratio) into 2 cohorts to receive ACP-196, with and 
without dexamethasone:  
x 
Cohort 1: ACP-196 100 mg twice per day (BID) continuously 
x 
Cohort 2: ACP-196 100 mg BID continuously and 
dexamethasone 40 mg once weekly  
Twenty-eight days of study drug administration is 1 cycle.  
Treatment may be continued for > 28 days until disease 


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progression or an unacceptable drug-related toxicity occurs.  For 
subjects in Cohort 1, if documented disease progression occurs, 
then dexamethasone can be added to the treatment regimen.  
Additional dose modification provisions are provided in the study 
protocol.  Note: temporary withholding of study drug for as little as 
7 days can cause a transient worsening of disease and/or of 
constitutional symptoms.  Refer to Section 3.8 for more information 
on assessing disease progression under these circumstances.  All 
subjects who discontinue study drug will have a safety follow-up 
visit 30 (±7) days after the last dose of study drug unless they have 
started another cancer therapy within that timeframe.  
All subjects will have hematology, chemistry, and urinalysis safety 
panels done at screening.  Once dosing commences (Day 1), all 
subjects will be evaluated for safety, including serum chemistry 
and hematology, once weekly for the first 4 weeks, every 2 weeks 
in Cycle 2 and monthly thereafter.  PK/PD testing will be done in 
Cycle 1 and Cycle 2. Tumor assessments will be done at 8- to 12-
week intervals during the trial. 
Refer to Appendix 5 for a comprehensive list of study assessments 
and their timing. The end of trial is defined as the point when the 
last subject on the study exits the study for any reason. 
Study Objectives: 
Primary Objective: 
x 
To characterize the safety profile of ACP-196 with and without 
dexamethasone in subjects with relapsed or refractory MM 
Secondary Objectives: 
x 
To characterize the PK profile of ACP-196 with and without 
dexamethasone and the PK profile of dexamethasone with 
concomitant ACP-196 administration 
x 
To evaluate the PD effects of ACP-196 with and without 
dexamethasone 
x 
To evaluate the activity of ACP-196 with and without 
dexamethasone as measured by overall response rate, 
duration of response, clinical benefit rate, disease control rate, 
and progression-free survival 
x 
To explore the relationship between biological markers in MM 
cells and response to therapy 
Safety Parameters: 
Type, frequency, severity, timing of onset, duration, and 
relationship to study drug (ie, ACP-196, dexamethasone, or both) 
of any adverse events (AEs) or abnormalities of laboratory tests; 
serious adverse events (SAEs); or AEs leading to discontinuation 
of study treatment. 


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Efficacy Parameters: 
x 
Overall response rate (ORR) 
x 
Duration of response 
x 
Clinical benefit rate 
x 
Disease control rate 
x 
Progression-free survival 
Pharmacokinetic 
Parameters: 
The plasma PK of ACP-196 will be characterized using 
noncompartmental analysis. The following PK parameters will be 
calculated, whenever possible, from plasma concentrations of 
analytes: 
x 
AUC0-t:  Area under the plasma concentration-time curve 
calculated using linear trapezoidal summation from time 0 to 
time t, where t is the time of the last measurable concentration 
(Ct). 
x 
AUC0-12:  Area under the plasma concentration-time curve from 
0 to 12 hours, calculated using linear trapezoidal summation. 
x 
AUC0-∞:  Area under the plasma concentration-time curve from 
0 to infinity, calculated using the formula: AUC0-∞ = AUC0-t + 
Ct / λz, where λz is the apparent terminal elimination rate 
constant. 
x 
AUC0-24calc:  Area under the plasma concentration-time curve 
from 0 to 24 hours, calculated by doubling the value for 
AUC0-12. 
x 
Cmax:  Maximum observed plasma concentration 
x 
Tmax:  Time of the maximum plasma concentration (obtained 
without interpolation) 
x 
t½:  Terminal elimination half-life (whenever possible) 
x 
λz:  Terminal elimination rate constant (whenever possible) 
x 
CL/F:  Oral clearance 
Pharmacodynamic 
Parameters: 
The occupancy of Btk by ACP-196 will be measured in peripheral 
blood mononuclear cells (PBMCs) and in bone marrow, when 
available, with the aid of a biotin-tagged ACP-196 analogue probe.  
The effect of ACP-196 on biologic markers of B-cell function will 
also be evaluated. 
Sample Size: 
Forty subjects with 20 subjects in each cohort. 
Inclusion Criteria: 
x 
Men and women ≥ 18 years of age. 
x 
A confirmed diagnosis of MM, which has relapsed after, or 
been refractory to ≥ 1 prior therapy for MM, and is progressing 
at the time of study entry. 
x 
Evaluable myeloma at screening, defined as the presence of at 
least one of the following: 
o Serum M-protein ≥ 0.5 g/dL 
o Urine M-protein ≥ 200 mg/24 hours 


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o In subjects without detectable serum or urine M-protein, 
serum free light chain (SFLC) > 100 mg/L (involved light 
chain) and an abnormal serum kappa/lambda ratio 
o For subjects whose disease can only be reliably measured 
by serum quantitative immunoglobulin A (IgA), IgA 
≥ 750 mg/dL (0.75 g/dL)  
x 
Eastern Cooperative Oncology Group (ECOG) performance 
status of ≤ 2. 
x 
Agreement to use acceptable methods of contraception during 
the study and for 30 days after the last dose of study drug if 
sexually active and able to bear or beget children. 
x 
Agreement to refrain from sperm donation during the study and 
for 30 days after the last dose of study drug. 
x 
Willing and able to participate in all required evaluations and 
procedures in this study protocol including swallowing capsules 
without difficulty. 
x 
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: 
x 
Plasma cell leukemia or circulating plasma cells ≥ 2 x 109/L 
x 
Prior malignancy, except for adequately treated basal cell or 
squamous cell skin cancer, in situ cervical cancer, or other 
cancer from which the subject has been disease free for 
≥ 2 years or which will not limit survival to < 2 years. Note: 
these cases must be discussed with the Medical Monitor. 
x 
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 ACP-196, or put the study outcomes at undue 
risk. 
x 
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. 
x 
Malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or small 
bowel, gastric bypass, symptomatic inflammatory bowel 
disease, or partial or complete bowel obstruction. 
x 
Any immunotherapy within 4 weeks of first dose of study drug. 
x 
The time from the last dose of the most recent chemotherapy 
or experimental therapy to the first dose of study drug is 
< 5 times the half-life of the previously administered agent(s). 
x 
 Prior exposure to a B-cell receptor (BCR) inhibitor (eg, Btk, 
phosphoinositide-3 kinase [PI3K], or Syk inhibitors) or BCL-2 
inhibitors (eg, ABT-199). 


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x 
Ongoing immunosuppressive therapy, including systemic or 
enteric corticosteroids for treatment of MM or other conditions. 
Note: Subjects may use topical or inhaled corticosteroids as 
therapy for comorbid conditions. During study participation, 
subjects may receive systemic or enteric corticosteroids as 
needed for MM therapy or treatment-emergent comorbid 
conditions. 
x 
Grade ≥ 2 toxicity (other than alopecia) continuing from prior 
anticancer therapy including radiation. 
x 
Known history of human immunodeficiency virus (HIV), 
serologic status reflecting active hepatitis B or C infection, or 
any uncontrolled active systemic infection.  Subjects with 
hepatitis B core antibody positive who are surface antigen 
negative or who are hepatitis C antibody positive will need to 
have a negative polymerase chain reaction (PCR) result before 
enrollment.  Those who are hepatitis B surface antigen positive 
or hepatitis B PCR positive and those who are hepatitis C PCR 
positive will be excluded. 
x 
Major surgery within 4 weeks before first dose of ACP-196. 
x 
Known history of a bleeding diathesis (eg, hemophilia, von 
Willebrand disease) 
x 
History of stroke or intracranial hemorrhage within 6 months 
before the first dose of ACP-196. 
x 
Requires or receiving anti-coagulation with warfarin or 
equivalent vitamin K antagonist (eg, phenprocoumon) within 
28 days of first dose of study drug.  
x 
Requires treatment with long-acting proton pump inhibitors (eg, 
omeprazole, esomeprazole, lansoprazole, dexlansoprazole, 
rabeprazole, or pantoprazole) 
x 
ANC < 0.75 x 109/L or platelet count < 50 x 109/L.  For subjects 
with > 50% plasma cells in the marrow, ANC < 0.50 x 109/L or 
platelet count < 30 x 109/L. 
x 
Creatinine > 2.5 x institutional upper limit of normal (ULN); total 
bilirubin > 2.5 x ULN; or aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) > 3.0 x ULN. 
x 
Breastfeeding or pregnant. 
x 
Concurrent participation in another therapeutic clinical trial. 
Dosage Form and 
Strength: 
ACP-196 is provided as 100-mg hard gelatin capsules prepared 
using standard pharmaceutical grade excipients.  
Dose Regimen/Route 
of Administration: 
ACP-196 is an orally administered product.  ACP-196 can be 
administered with or without food.  
Regimens: 
x 
Cohort 1 (BID): 100 mg ACP-196 (1 x 100-mg capsule) 
administered 12 hours apart (BID dosing = 200-mg total daily 
dose) 


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x 
Cohort 2 (BID + dexamethasone): 100 mg ACP-196 
(1 x 100-mg capsule) administered 12 hours apart (BID dosing 
= 200-mg total daily dose) plus 40 mg dexamethasone  
administered once weekly (weekly dosing = 40-mg total weekly 
dose) 
Concomitant 
Medications: 
The effect of agents that reduce gastric acidity (eg, proton pump 
inhibitors, H2-receptor antagonists, or antacids) on ACP-196 
absorption is currently being evaluated in a healthy volunteer study 
(ACE-HV-004). Preliminary results from this study suggest 
subjects should avoid the use of calcium carbonate containing 
drugs or supplements (eg, antacids or calcium supplements) and 
short-acting H2-receptor antagonists for a period of at least 
2 hours before and after taking ACP-196.  Use of omeprazole or 
esomeprazole or any other long-acting proton pump inhibitors 
while taking ACP-196 is not permitted due to a potential decrease 
in study drug exposure; however, if a subject requires treatment 
with a long-acting proton pump inhibitor while on study (eg, to treat 
an ulcer), treatment options should be discussed with the Medical 
Monitor. 
Concomitant use of strong inhibitors/inducers of CYP3A should be 
avoided when possible.  If a subject requires a strong CYP3A 
inhibitor while on study, monitor the subject closely for potential 
toxicities. 
Statistics: 
Subjects meeting the stated eligibility requirements will be enrolled 
onto the study. Subjects will be randomized in a 1:1 ratio into the 
2 regimens (ACP-196 with and without dexamethasone).  With a 
sample size of 19 subjects per cohort, the power to detect the 
difference between a null-hypothesis response rate of 15% and an 
alternative response rate of 40% with a 0.025 one-sided 
significance level is 0.69 using a one-group, exact binomial test.  A 
sample size of 19 subjects per cohort will also provide a 97.5% 
one-sided confidence interval centered around an expected ORR 
of 40% that excludes an ORR of 18.6% as a lower bound. 
Descriptive statistics (including means, standard deviations, and 
medians for continuous variables and proportions for discrete 
variables) will be used to summarize data, as appropriate.  
 
 


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1.0 
BACKGROUND INFORMATION 
1.1 
ROLE OF BTK IN LYMPHOID CANCERS 
Bruton tyrosine kinase (Btk) is a non-receptor enzyme of the Tec kinase family that is 
expressed among cells of hematopoietic origin, including B cells, myeloid cells, mast 
cells and platelets, where it regulates multiple cellular processes including proliferation, 
differentiation, apoptosis, and cell migration (Mohamed 2009, Bradshaw 2010). 
Functional null mutations of Btk in humans cause the inherited disease, X-linked 
agammaglobulinemia, which is characterized by a lack of mature peripheral B cells 
(Vihinen 2000). Conversely, Btk activation is implicated in the pathogenesis of several 
B-cell malignancies (Buggy 2012). Taken together, these findings have suggested that 
inhibition of Btk may offer an attractive strategy for treating B-cell neoplasms.  
Ibrutinib (IMBRUVICA™), a first-generation oral, small-molecule Btk inhibitor has been 
approved for the treatment for chronic lymphocytic leukemia (CLL) and mantle cell 
lymphoma (MCL) and is being evaluated for activity in other B-cell neoplasms including 
multiple myeloma (MM).  Preclinical studies have shown that Btk inhibition with ibrutinib 
significantly reduces in vivo multiple myeloma (MM) cell growth and MM cell-induced 
osteolysis in a murine model (Tai 2012).   
While current therapies have provided substantial benefit to patients, MM remains 
incurable; for patients who experience disease relapse after application of existing 
therapies, the prognosis is dismal and new drugs and therapeutic strategies are required 
for continued disease control (Romano 2014).  Inhibition of Btk may simultaneously 
address the MM-related bone complications as well improve patient outcome in MM 
(Edwards 2012). 
While highly potent in inhibiting Btk, ibrutinib has also shown in vitro activity against 
other kinases with a cysteine in the same position as Cys481 in Btk to which the drug 
covalently binds.  The inhibition of epidermal growth factor receptor (EGFR) is also 
observed in cellular assays and may be the cause of ibrutinib-related adverse events 
(AEs) of diarrhea and rash (IMBRUVICA® package insert). In addition, ibrutinib is a 
substrate for CYP3A4; inhibition of CYP3A causes a 29-fold increase in maximum 
concentration (Cmax) and 24-fold increase in area under the curve (AUC) for ibrutinib 
(IMBRUVICA® package insert).  This increases the possibility of drug-drug interactions 
in combination therapies with drugs currently used in management of subjects with 


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cancer.  These liabilities support the development of alternative Btk inhibitors for use in 
the therapy of B-cell malignancies. 
Chemical optimization, pharmacologic characterization, and toxicologic evaluation have 
led to identification of ACP-196 (also known as acalabrutinib), an orally bioavailable, new 
chemical entity that covalently inhibits Btk and shows encouraging activity and 
acceptable safety in nonclinical studies. Within the class of Btk inhibitors, ACP-196 is a 
more selective inhibitor of Btk than ibrutinib.  Key nonclinical differentiators of ACP-196
versus ibrutinib are: 
x
ACP-196 has been evaluated against ibrutinib in EGFR expressing cell lines.  
Ibrutinib is a potent covalent inhibitor of EGFR (EC50 = 50 to 70 nM).  ACP-196
does not inhibit EGFR even at the highest concentration tested (10 μM).
x
ACP-196 has been evaluated against ibrutinib in in vitro antibody-dependent cell-
mediated cytotoxicity (ADCC) assays.  At physiologic concentrations, ibrutinib, 
but not ACP-196, reduced natural killer (NK) cell-mediated lysis of Raji and 
autologous CLL tumor cells and significantly inhibited rituximab-induced NK cell 
cytokine secretion (P<0.05).  
x
ACP-196 has been evaluated against ibrutinib in an in vivo thrombus formation 
model.  At physiologic concentrations, ibrutinib, but not ACP-196, significantly 
inhibited thrombus formation (P=0.001).  
The nonclinical and toxicology results of ACP-196 suggest it may have an improved 
therapeutic window relative to ibrutinib; it may be more readily combined with other 
agents for the treatment of cancer.   
1.2 
PRECLINICAL STUDIES 
Summaries of preclinical studies are provided below. For more detailed information 
please refer to the Investigator’s Brochure.  
1.2.1 
Chemistry 
 ACP-196 is 
orally bioavailable in humans and is suitable for formulating in capsules. For clinical 
testing, ACP-196 has been manufactured and formulated according to current Good 
Manufacturing Practices (cGMP). 


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1.2.2 
Efficacy Pharmacology 
Spontaneous canine B-cell lymphoma shares many characteristics with human NHL, 
including diagnostic classifications and response to Btk inhibition (Honigberg 2010). The 
life expectancy in untreated animals with aggressive disease is ~6 weeks, thus enabling 
rapid assessment of drug efficacy (Vail 2004). ACP-196 is currently being evaluated in 
an ongoing dose-escalation study in canine spontaneous B-cell lymphoma.  Fourteen 
dogs, all of which had diffuse large B-cell lymphoma (DLBCL) confirmed by histology, 
have been treated with ACP-196 for at least 2 weeks. The dosages have ranged from 
2.5 to 20 mg/kg once (QD) or twice (BID) per day.  To date, per Veterinary Cooperative 
Oncology Group criteria for assessment of response in peripheral nodal lymphoma 
(Vail 2010), partial responses (PRs) been observed in 4 of 14 dogs (29%) and stable 
disease has been observed in 8 of 14 dogs (57%).  No ACP-196-related adverse events 
(AEs) have been reported to date in this study.  These findings are preliminary and 
similar to the clinical responses (ie, 1 dog with PR out of 5 dogs treated with suspected 
or confirmed DLBCL) observed with ibrutinib in dogs with spontaneous B-cell lymphoma 
(Honigberg 2010). 
Preliminary results assessing Btk occupancy using a biotin-tagged analogue of ACP-196 
show near complete Btk occupancy over 24 hours with both BID and QD dosing in 
canine tumor tissue (Table 1-1). 
Table 1-1.  Assessment of ACP-196 Active-site Occupancy in  
Fine Needle Aspirates of Canine Lymph Node Tumors (N=4) 
Timing 
Dog Identification and ACP-196 Dosing Regimen 
DL-10 
DL-12 
DL-14 
DL-16 
5 mg/kg BID 
10 mg/kg QD 
20 mg/kg QD 
20 mg/kg QD 
Btk Occupancy (% versus predose) 
Day 1 (3 hours 
after morning 
dose) 
98% 
99% 
98% 
99% 
Day 7 (before 
morning dose) 
80% 
98% 
77 
93% 
BID = twice per day; Btk = Bruton tyrosine kinase; QD = once per day 
These canine data provide nonclinical support for the ability of ACP-196 to target Btk in 
vivo. The role of Btk expression in driving the proliferation and survival of malignant 
plasma cells in multiple myeloma (MM) has been less clear than among other lymphoid 
cancers. However, emerging, unpublished, preclinical data from the laboratory of Sagar 
Lonial (Emory University) suggest that Btk and phosphorylated Btk (p-Btk) expression is 


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present to varying levels in a standard panel of 12 myeloma cell lines, thus providing a 
basis for evaluating Btk inhibition as a therapy for MM. 
1.2.3 
ACP-196 and Thrombus Formation 
Ibrutinib is associated with an increased risk of bleeding (Kamel 2014). Hence, the 
effects of ACP-196 and ibrutinib were evaluated on human platelet-mediated thrombosis 
by using the in vivo human thrombus formation in a VWFHA1 murine model, which has 
been previously described (Chen 2008).  Purified human platelets were preincubated 
with various concentrations of ibrutinib and ACP-196 (0.1 μM, 0.5 μM, or 1 μM for each) 
or DMSO and then administered to VWFHA1 mice followed by laser-induced thrombus 
formation.  Ibrutinib- and ACP-196-treated human platelets were fluorescently labeled 
and infused continuously through a catheter inserted into the femoral artery. Thrombus 
formation in response to laser-induced vascular injury was monitored in real time using 
2-channel confocal intravital microscopy (Furie 2005) (Figure 1-1). Upon induction of 
arteriole injury, untreated platelets rapidly formed thrombi with a mean (± SEM) 
thrombus size of 6450 ± 292 mm2. Similarly, ACP-196 (1 μM) treated platelets formed 
slightly smaller but not significantly different thrombi, with a mean thrombus size of 
5733 ± 393 mm2. In contrast, a significant reduction in thrombus size occurred in 
platelets pretreated with ibrutinib (1 μM); mean thrombus size was 2600 ± 246 mm2, 
representing in a reduction in maximal thrombus size by approximately 61% compared 
with control (P=0.001). Similar results were obtained with platelets pretreated with 
500 nM of ACP-196 or ibrutinib: mean thrombus sizes were 5946 ± 283 mm2 and 
2710 ± 325 mm2, respectively. These preliminary results showing reduced thrombus 
formation for ibrutinib at physiologically relevant concentrations (0.5 to 1 μM) may 
provide some mechanistic background for the Grade ≥ 3 bleeding events (eg, subdural 
hematoma, gastrointestinal bleeding, hematuria, and post procedural hemorrhage) that 
have been reported in ≤ 6% of patients treated with ibrutinib. In addition, bleeding events 
of any grade, including bruising and petechiae, were reported in approximately half of 
patients treated with ibrutinib (IMBRUVICA® package insert). 


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Figure 1-1.  Effect of ACP-196 (1 μM) and Ibrutinib (1 μM) on Thrombus Formation 
 
 
1.2.4 
Safety Pharmacology 
In vitro and in vivo safety pharmacology studies with ACP-196 have demonstrated a 
favorable nonclinical safety profile.  
When screened at 10 μM in binding assays evaluating interactions with 80 known 
pharmacologic targets such as G-protein-coupled receptors, nuclear receptors, 
proteases, and ion channels, ACP-196 shows significant activity only against the 


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A3 adenosine receptor; follow-up dose-response experiments indicated a IC50 of 2.7 μM, 
suggesting a low clinical risk of off-target effects.  ACP-196 at 10 μM showed no 
inhibition of in vitro epidermal growth factor receptor (EGFR) phosphorylation in an A431 
human epidermoid cancer cell line, whereas ibrutinib had an IC50 of 66 nM.  
The in vitro effect of ACP-196 on human ether-à-go-go-related gene (hERG) channel 
activity was investigated in vitro in human embryonic kidney cells stably transfected with 
hERG. ACP-196 inhibited hERG channel activity by 25% at 10 μM, suggesting a low 
clinical risk that ACP-196 would induce clinical QT prolongation as predicted by this 
assay. 
ACP-196 was well tolerated in standard in vivo Good Laboratory Practices (GLP) studies 
of pharmacologic safety. A functional observation battery in rats at doses of through 
300 mg/kg (the highest dose level) revealed no adverse effects on neurobehavioral 
effects or body temperature at any dose level. A study of respiratory function in rats also 
indicated no treatment-related adverse effects at doses through 300 mg/kg (the highest 
dose level). In a cardiovascular function study in awake telemeterized male beagle dogs, 
single doses of ACP-196 at dose levels through 30 mg/kg (the highest dose level) 
induced no meaningful changes in body temperature, cardiovascular, or 
electrocardiographic (ECG) (including QT interval) parameters.  The results suggest that 
ACP-196 is unlikely to cause serious off-target effects or adverse effects on critical 
organ systems. 
1.2.5 
Drug-drug Interaction Potential 
 The in vitro studies suggest CYP-mediated metabolism of ACP-196 appears to be 
catalyzed predominantly by CYP3A4/5.  However, in elimination studies in preclinical 
species, the metabolic fate of ACP-196 is dominated by direct conjugation of ACP-196 
with glutathione, providing evidence for a significant non-CYP mechanism of elimination.  
In a healthy volunteer study (ACE-HV-001), the effect of coadministration of a potent 
CYP3A and P-gP inhibitor, itraconazole, on the plasma levels of ACP-196 was 
evaluated.  The mean plasma ACP-196 Cmax and AUC0-last values increased 3.7- and 
5.1-fold, respectively, in the presence of itraconazole relative to no pretreatment.  In vitro 
studies also show that ACP-196 is a substrate for P-gp.   
ACP-196 is unlikely to be a perpetrator of a drug-drug interaction at the level of inhibition 
or induction of CYP isoforms. 


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Results from drug transporter studies suggest that ACP-196 is not anticipated to alter 
the PK of other therapeutic agents that are substrates for MDR1, OATP1B1, OATP1B3, 
OAT1, OAT3, and OCT2.  ACP-196 (100 mg BID) may alter the PK of BCRP substrates 
by inhibition of intestinal BCRP. 
1.2.6 
In Vivo General Toxicology 
To date, the toxicology program has included 28-day GLP evaluations in rats and dogs. 
In the 28-day study in male and female Sprague-Dawley rats, animals received oral 
gavage ACP-196 dosages of 30, 100, and 300 mg/kg/day. In the 28-day study in male 
and female beagle dogs, animals received oral ACP-196 dosages of 3, 10, and 
30 mg/kg/day. Both studies had 28-day recovery periods. 
The no observable adverse effect level in the dog was 30 mg/kg/day, which was the 
highest dose evaluated. In rats, 30 mg/kg/day resulted in minimal inflammation of the 
pancreas in some animals, with reversal, indicating the rat to be the more sensitive 
preclinical species. The pancreatic effects were minimally increased at 100 mg/kg/day in 
the rat though there was no clinical evidence of toxicity. Hence, 100 mg/kg/day was 
selected to conservatively represent the highest nonseverely toxic dose (HNSTD).  In 
dogs at 30 mg/kg/day, no adverse effects on the pancreas were observed.  In rats and 
dogs, no adverse ECG or histopathologic cardiovascular effects were noted at the 
planned conclusion of the 28-day toxicology studies. However, in 5 of 6 rats from the 
300-mg/kg dose group that died early in the study, slight to moderate necrosis of the 
myocardium and/or white blood cell infiltration/inflammation of the myocardium were 
noted on microscopic examination of the hearts. These findings were most likely 
incidental postmortem changes. 
1.3 
CLINICAL EXPERIENCE 
Table 1-2 lists the studies currently being conducted with ACP-196 monotherapy.   


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Table 1-2.  ACP-196 Clinical Studies as of January 2015 
Protocol 
Design 
Subjects 
Enrolled 
Status 
ACE-CL-001 
(NCT02029443) 
x 
First-in-human 
x 
Open label 
x 
Dose escalation (ACP-196 100-
400 mg QD and 100-200 mg BID) 
x 
Subjects with relapsed/refractory CLL 
x 
Expansion cohorts: 
o treatment-naive subjects 
o subjects with Richter’s syndrome 
o subjects who are intolerant to 
ibrutinib treatment 
o subjects who are 
relapsed/refractory to ibrutinib 
treatment 
125 
x 
Cohort 1 (100 mg QD) 
enrolled and no DLTs 
observed.   
x 
Cohort 2a (175 mg QD) 
enrolled and no DLTs 
observed. 
x 
Cohort 3 (250 mg QD) 
enrolled and no DLTs 
observed. 
x 
Cohort 4a (400 mg QD) 
enrolled and no DLTs 
observed. 
x 
Cohort 2b (100 mg BID 
now enrolling) and no 
DLTs observed. 
x 
Expansion cohorts now 
enrolling. 
ACE-HV-001 
x 
Open label 
x 
Single-dose escalation 
(ACP-196 2.5-50 mg BID and 100 mg 
QD) 
x 
Food effect (ACP-196 75 mg QD) 
x 
Drug-drug interaction with 
itraconazole (ACP-196 50 mg QD) 
x 
Healthy volunteers 
59 
x 
Enrollment completed. 
x 
No adverse laboratory, 
vital signs, or ECGs 
findings observed. 
x 
1 event each of 
constipation, feeling 
cold, somnolence (each 
Grade 1) was reported 
as related to study drug. 
ACE-HV-004 
x 
Open label 
x 
ACP-196 100 mg 
x 
Drug-drug interaction: 
o Calcium carbonate 
o Omeprazole 
o Rifampin 
x 
Healthy volunteers 
72 
x 
Enrollment completed. 
x 
No adverse laboratory, 
vital signs, or ECGs 
findings observed. 
x 
Other analyses 
pending. 
ACE-LY-002 
(NCT02112526) 
x 
Open label 
x 
ACP-196 100 mg BID 
x 
Activated B-cell subtype of diffuse 
large B-cell lymphoma 
 
6 
x 
Enrollment recently 
begun 
ACE-WM-001 
(NCT02180724) 
x 
Open label 
x 
ACP-196 100 mg BID and 200 mg QD 
x 
Waldenström macroglobulinemia 
7 
x 
Enrollment recently 
begun 
ACE-LY-003 
(NCT02180711) 
x 
Open label 
x 
ACP-196 100 mg BID and 200 mg QD 
x 
Follicular lymphoma 
1 
x 
Enrollment recently 
begun 
15-H-0016 
(NIH study) 
x 
Open label 
x 
ACP-196 200 mg QD and 100 mg BID 
x 
CLL 
0 
x 
Enrollment recently 
begun 
ACE-ST-003 
x 
Open label 
x 
ACP-196 100 mg BID ± 
pembrolizumab 200 mg IV Q3W 
x 
Advanced or metastatic pancreatic 
cancer 
0 
x 
Protocol in study start 
up 
 
AE = adverse event; BID = twice per day; CLL = chronic lymphocytic leukemia; DLT = dose-limiting toxicity; 
ECGs = electrocardiograms; QD = once per day 


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Table 1-2.  ACP-196 Clinical Studies as of January 2015 (continued) 
Protocol 
Design 
Subjects 
Enrolled 
Status 
ACE-ST-005 
(NCT02351739) 
x 
Open label 
x 
ACP-196 100 mg BID ± 
pembrolizumab 200 mg IV Q3W 
x 
Advanced or metastatic bladder 
cancer 
 
0 
x 
Protocol in study start 
up 
ACE-LY-004 
(NCT02213926) 
x 
Open label 
x 
ACP-196 100 mg BID 
x 
Mantle cell lymphoma 
0 
x 
Enrollment recently 
begun 
ACE-CL-002 
(NCT02157324) 
x 
Open label 
x 
ACP-196 50 mg BID and ACP-319 
25 mg BID 
x 
CLL 
8 
x 
Enrollment recently 
begun 
ACE-LY-001 
(NCT02328014) 
x 
Open label 
x 
ACP-196 100 mg BID and ACP-319 
25 to 100 mg BID 
x 
B-cell malignancies 
1 
x 
Enrollment recently 
begun 
ACE-CL-003 
(NCT02296918) 
x 
Open label 
x 
ACP-196 200 mg QD and 
Obinutuzumab per label 
x 
CLL 
2 
x 
Enrollment recently 
begun 
ACE-HI-001 
x 
Hepatic impairment study 
x 
ACP-196 50 mg QD 
18 
x 
Enrollment ongoing 
ACE-LY-005 
x 
Open label 
x 
ACP-196 100 mg BID and 
pembrolizumab 2 mg/kg IV Q3W 
x 
B-cell malignancies 
None 
x 
Protocol in study start 
up 
ACE-ST-006 
x 
Open label 
x 
ACP-196 100 mg BID ± 
pembrolizumab 200 mg IV Q3W 
x 
Advanced or metastatic head & neck 
cancer 
0 
x 
Protocol in study start 
up 
ACE-ST-007 
x 
Open label 
x 
ACP-196 100 mg BID ± 
pembrolizumab 200 mg IV Q3W 
x 
Advanced or metastatic non-small cell 
lung cancer 
0 
x 
Protocol in study start 
up 
AE = adverse event; BID = twice per day; CLL = chronic lymphocytic leukemia; DLT = dose-limiting toxicity; 
ECGs = electrocardiograms; IV = intravenous; Q3W = once every 3 weeks; QD = once per day 
 
1.3.1 
Pharmacokinetics and Pharmacodynamics of ACP-196 in 
Healthy Volunteers 
ACE-HV-001 was a dose-ranging, food-effect, and drug-drug interaction study 
evaluating BID and QD dosing for 1 or 2 days in healthy volunteers.  The starting dose 
for ACP-196 was 2.5 mg BID.   This study has been completed and no adverse 
laboratory, vital signs, or ECG findings were observed (2.5 to 50 mg BID; 50 to 100 mg 
QD). Three AEs related to ACP-196 were reported.  Each AE was Grade 1 and resolved 


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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 ACP-196 were evaluated after oral administration of 2 daily 
doses of 2.5 to 50 mg and a single dose of 100 mg.  Of the 30 subjects evaluated, all 
had measurable systemic concentrations of ACP-196.  ACP-196 plasma time to 
maximum concentration (Tmax) values were between 0.5 and 1.0 hour for all dose 
cohorts and independent of the dose level.  The increase in mean maximum 
concentration (Cmax) values was greater than dose proportion based on the increases of 
Cmax from the first dose administered.  When evaluating area under the concentration 
curve (AUC0-12, AUC0-24 or AUC0-inf), the mean values increased in a dose proportional 
manner based on the increases of the total dose administered.  Mean half-life (t1/2) 
values ranged from 0.97 to 2.1 hours, and appeared to decrease as the dose increased.  
The mean calculated oral clearance (CL/F: 165 to 219 L/h) and volume of distribution 
values (Vz/F: 233 to 612 L) appeared to be independent of the dose administered. 
ACP-196 was not detected in the urine of subjects who received the 2.5- or 5.0-mg BID 
doses of ACP-196.  ACP-196 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 ACP-196 (75 mg) after a single oral 
administration was evaluated in 6 men and 6 women.  Median ACP-196 plasma Tmax 
values were increased in the fed state (2.5 hours) relative to the fasted state (0.5 hour).  
The mean plasma ACP-196 Cmax values decreased to 27.3% of the values observed in 
the fasted state.  In contrast, the relative exposure of ACP-196 (AUC) remained mostly 
unchanged in both states. Per FDA guidance on food-effect studies (FDA 2002), this 
decrease in exposure is not clinically significant, and therefore, ACP-196 can be taken 
with or without food. 
In Part 3, after administration of a single dose of ACP-196 (50 mg), the effect of 
itraconazole on the PK was evaluated in 17 subjects.  No difference in ACP-196 Tmax 
values was observed in the presence or absence of itraconazole. 
Mean ACP-196 exposures (as assessed by Cmax, AUC0-last, AUC0-24, and AUC0-inf) 
increased in the presence of itraconazole.  The mean plasma ACP-196 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 


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(CL/F: 217 vs 44 L/h; Vz/F: 1190 vs 184 L).  No differences in half-life values were 
observed (3.3 vs 2.5 hours). 
The pharmacodynamics (PD) profile of ACP-196 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 in the 75- and 100-mg single dose 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 who 
received a second dose of ACP-196 12 hours after the first administration, full Btk target 
occupancy was observed 3 hours after the second dose for the 50 mg dose cohort (Btk 
occupancy 97 ± 4%). 
1.3.2 
Clinical Experience of ACP-196 in CLL 
ACE-CL-001 (NCT02029443), an ongoing Phase 1/2 study in subjects with 
relapsed/refractory or previously untreated CLL or Richter’s syndrome, has a sequential, 
dose-escalation design.  As of 22 January 2015, 125 subjects have received ACP-196 at 
dosages from 100 to 400 mg QD or 100 to 200 mg BID.  
To date, ACP-196 has been well tolerated at all dose levels evaluated.  No dose-limiting 
toxicities (DLTs) have occurred at any dose level.  The MTD was not reached in this 
study; however, per the protocol, dose escalation was stopped once a plateau in PK was 
observed (ie, between 250 and 400 mg).   
Preliminary data from ACE-CL-001 show that Btk occupancy with ACP-196, in peripheral 
blood cells, is > 95% at 4 hours but decreases to < 95% at 24 hours, while with BID 
dosing complete Btk occupancy (97% to 99%) is maintained over 24 hours at steady 
state (Table 1-3). These data suggest that synthesis of de novo Btk may occur within 
24 hours. 


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Table 1-3.  Btk Occupancy in Peripheral Blood of Subjects from ACE-CL-001 
(December 2014) 
Timepoint* 
Subjects with Relapsed/Refractory CLL 
100 mg QD 
(n=8) 
175 mg QD 
(n=8) 
250 mg QD 
(n=6) 
100 mg BID 
(n=17) 
Day 7: 
Median % 
Occupancy 24 h 
89.0 
86.9 
93.5 
97.4 
Day 8: 
Median % 
Occupancy 4 h 
98.6 
98.7 
100 
98.8 
Abbreviations:  BID = twice per day; CLL = chronic lymphocytic leukemia; QD = once per day 
*Note: 24-h timepoint on BID regimen represents 24 hours after first dose and 12 hours after 
second dose on Day 7.  The 4-h timepoint on the BID regimen represents 4 hours after the first 
dose on Day 8.   
 
 
 
Preliminary PK data from Day 8 show dose linearity from 100 to 250 mg and no 
accumulation with repeat dosing (Table 1-4). 
Table 1-4.  Preliminary Day 8 PK Results from ACE-CL-001 (October 2014) 
Cohort 
Mean Cmax ± SD 
(ng/mL) 
Mean AUC0-last ± SD 
(ng•h/mL) 
100 mg QD (N=8) 
529 ± 286 
634 ± 197a 
175 mg QD (N=7) 
800 ± 692 
1240 ± 789 
250 mg QD (N=7) 
1350 ± 933 
2170 ± 1180 
400 mg QD (N=6) 
932 ± 576 
1870 ± 1040 
100 mg BID (N=22) 
716 ± 658 
837 ± 485b 
Timepoints: Predose, 0.25, 0.50, 0.75, 1.0, 2.0, 4.0, and 6.0 postdose. 
a N=7 for AUC calculations in 100 mg QD dose group. 
b BID regimens were not sampled during the second daily dose interval; 0-24 h exposures are 
expected to be approximately 2-fold the AUC0-6 values shown. 
AUC = area under the curve; BID = twice per day; Cmax = maximum concentration; SD = standard 
deviation 
 
To date, 31 subjects have been evaluated for tumor response, by investigators, based 
on International Working Group response criteria (Hallek 2008) as recently updated 
(Cheson 2012) to include partial response with treatment-induced lymphocytosis.  Based 
on preliminary, unaudited data an overall response rate (ORR) of 94% (71% PR + 23% 


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PR with lymphocytosis) has been observed (Table 1-5).  Of the 31 subjects assessed, 
nearly half (15 of 31) have 17p del.  Of the 15 subjects with 17p del, 80% (12/15) have 
PR and 20% (3/15) have PR with lymphocytosis.  The median follow-up for the ACP-196 
subjects evaluated for response is 7.3 cycles (range 3.0 to 10.8) and each cycle is 28 
days.  No primary disease progression has occurred on study (N = 75; Figure 1-2). 
Table 1-5.  Best Response by Cohort from ACE-CL-001 (23OCT2014) 
n (%) 
All 
Cohorts 
(N=31) 
100 mg QD 
(N=8) 
175 mg QD 
(N=8) 
250 mg QD 
(N=7) 
100 mg BID 
(N=3) 
400 mg QD 
(N=5) 
PR 
22 (71) 
7 (88) 
5 (71) 
4 (57) 
3 (100) 
2 (40) 
PR+L 
7 (23) 
0 (0) 
3 (38) 
2 (29) 
0 (0) 
2 (40) 
SD 
2 (6) 
1 (12) 
1 (13) 
0 (0) 
0 (0) 
1 (20) 
PD 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
Median (range) Cycles 
 
7.3 (3.0-10.8) 
10.0 (9.0-10.8) 
8.6 (3.0-8.8) 
7.0 (7.0-7.3) 
5.2 (4.7-5.5) 
5.0 (4.8-5.5) 
BID = twice per day; PD = progressive disease; PR = partial response; PR+L = partial response 
with lymphocytosis; QD = once per day; SD = stable disease 
 
Figure 1-2.  Kaplan-Meier Curves for Progression-free Survival by Investigator 
Assessment for ACE-CL-001 (N=75; excludes Richter’s Syndrome Cohort and 
Ibrutinib R/R Cohort) 
 
 


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These results compare favorably with the Phase 3 results of ibrutinib, the first generation 
Btk inhibitor, when administered at dosages of 420 mg QD in subjects with 
relapsed/refractory CLL (N=195).  In the ibrutinib study, Byrd and colleagues (2014) 
report a PR rate of 43%, a PR with lymphocytosis rate of 20%—for an ORR of 63%─an 
SD rate of 32%, and a progressive disease (PD) rate of 3% (Byrd 2014) based on 
independent review.  The median follow-up time reported for the ibrutinib study was 
9.5 months (range 0.1 to 16.6).   
Figure 1-3 shows the change from baseline in sum of the product of the diameters (SPD) 
(N=31) and in absolute lymphocyte count (ALC) (N=57) over time.  As shown in the 
figure, substantial reductions in lymphadenopathy have been observed despite the fact 
that three-quarters of the evaluable subjects have high-risk cytogenetics (17p del, 11q 
del, or both).  As mentioned above, the observed reductions in lymphadenopathy are 
consistent with the clinical results for ibrutinib (Byrd 2013, Byrd 2014).  However, the 
reduced drug-induced lymphocytosis and the rapid time to resolution of lymphocytosis 
with ACP-196 treatment varies greatly from that reported for ibrutinib.  Per the 
IMBRUVICA package insert, 77% of patients with CLL treated with ibrutinib experienced 
lymphocytosis, which occurred during the first month of therapy and resolved by a 
median of 23 weeks (range 1 to 104+ weeks).  With ACP-196 treatment, the onset of 
lymphocytosis, if it occurs, is within the first week of treatment and resolves by a median 
of 8 weeks (range 0 to 24+ weeks). 


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Figure 1-3.  Median (95% CI) Change from Baseline in ALC/SPD Over Time 
 
 
ALC = absolute lymphocyte count; CI = confidence interval; SPD = sum of the 
products of the perpendicular diameters (of lymph nodes). 
 
 
1.4 
BENEFIT/RISK 
ACP-196 is a potent, orally available small-molecule inhibitor of Btk.  A PK/PD study has 
been completed with ACP-196 in healthy volunteers (ACE-HV-001; Section1.3.1).  The 
safety results showed no identified safety risks in healthy subjects receiving 1 or 2 days 
of ACP-196 ≤ 100 mg.  In study ACE-CL-001, a study of ACP-196 in subjects with 
relapsed/refractory or previously untreated CLL or Richter’s syndrome, no DLTs have 
been reported at dosages of ≤ 400 mg QD or 100 and 200 mg BID.  The overall 
response rate in the evaluable subjects for this study is currently 94% with some 
subjects obtaining PRs after only 2 cycles of therapy.  Based on these robust results in 
subjects with CLL, the evaluation of ACP-196 in subjects with relapsed or refractory MM 
is warranted. 
1.5 
SUMMARY AND CONCLUSIONS 
This study comprises a pilot evaluation of the safety and activity of the potent, second-
generation Btk inhibitor, ACP-196, in patients with relapsed or refractory MM. The design 


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and conduct of this study is supported by an understanding of the natural history and 
current therapies for subjects with lymphoid cancers; knowledge of the efficacy and 
safety of the first-generation BCR inhibitor (eg, ibrutinib) in subjects with hematologic 
cancers; and the available nonclinical and clinical information regarding ACP-196. 
Preclinical studies are ongoing in parallel to identify biomarkers that may be evaluated in 
this clinical trial as correlates of response to Btk-directed therapy and that may permit 
selection of patients who are particularly likely to benefit from ACP-196 treatment for 
MM. 
2.0 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
x 
To characterize the safety profile of ACP-196 with and without dexamethasone in 
subjects with relapsed or refractory MM 
2.2 
SECONDARY OBJECTIVES: 
x 
To characterize the PK profile of ACP-196 with and without dexamethasone and the 
PK profile of dexamethasone with concomitant ACP-196 administration 
x 
To evaluate the PD effects of ACP-196 with and without dexamethasone 
x 
To evaluate the activity of ACP-196 with and without dexamethasone as measured 
by overall response rate, duration of response, clinical benefit rate, disease control 
rate, and progression-free survival 
x 
To explore the relationship between biological markers in MM cells and response to 
therapy 
3.0 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This study is a multicenter, open-label, randomized, parallel-group study to be 
conducted at approximately 20 sites in 2 countries (United Kingdom and United States).  
Forty subjects will be randomized 1:1 into the following 2 cohorts to receive ACP-196, 
with and without dexamethasone: 
x 
Cohort 1: ACP-196 100 mg BID continuously  
x 
Cohort 2: ACP-196 100 mg BID continuously and 40 mg dexamethasone once 
weekly  
Twenty-eight days of study drug administration is 1 cycle.  Treatment may be continued 
for > 28 days until disease progression or an unacceptable drug-related toxicity occurs.  
For subjects in Cohort 1, if documented disease progression occurs, then 
dexamethasone can be added to the treatment regimen.  Additional dose modification 
provisions are provided in Section 3.5.5.  Note: temporary withholding of study drug for 


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as little as 7 days can cause a transient worsening of disease and/or of constitutional 
symptoms.  Refer to Section 3.8 for more information on assessing disease progression 
under these circumstances.  All subjects who discontinue study drug will have a safety 
follow-up visit 30 (±7) days after the last dose of study drug unless they have started 
another cancer therapy within that timeframe.  
All subjects will have standard hematology, chemistry, and urinalysis safety panels 
performed at screening.  Once dosing commences (Day 1), all subjects will be evaluated 
for safety, including serum chemistry and hematology, once weekly for the first 4 weeks, 
every 2 weeks in Cycle 2 and monthly thereafter.  PK/PD testing will be done in Cycle 1 
and Cycle 2. Tumor assessments will be done at 8- to 12-week intervals during the trial. 
Refer to Appendix 5 for a comprehensive list of study assessments and their timing.  The 
end of trial is defined as the point when the last subject on the study exits the study for 
any reason. 
3.2 
STUDY PARAMETERS 
3.2.1 
Safety Parameters 
The safety of ACP-196 with and without dexamethasone will be characterized by the 
type, frequency, severity, timing of onset, duration, and relationship to study drug (ie, 
ACP-196, dexamethasone, or both) of any treatment-emergent AEs or abnormalities of 
laboratory tests; serious adverse events (SAEs); or AEs leading to discontinuation or 
dose reduction of study treatment.  
For consistency of interpretation, AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), and the severity of AEs and laboratory abnormalities 
will be graded using the Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.03. Standard definitions for seriousness will be applied (see Section 6.1). 
3.2.2 
Efficacy Parameters 
Standardized response and progression criteria have been established for MM 
(Rajkumar 2011); assessments of ACP-196 efficacy in this study will be based on these 
criteria. Efficacy endpoints will include: 
x 
Overall response rate (ORR) 
x 
Duration of response 
x 
Clinical benefit rate 
x 
Disease control rate 


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x 
Progression-free survival 
3.2.3 
Pharmacokinetic and Pharmacodynamic Parameters 
Standard PK parameters for ACP-196 and dexamethasone in plasma will be evaluated 
in this study.  A full description of the PK parameters is provided in Section 5.5.4. 
The occupancy of Btk by ACP-196 will be measured in peripheral blood mononuclear 
cells (PBMCs) and bone marrow, when available, with the aid of a biotin-tagged 
ACP-196 analogue probe.  The effect of ACP-196 on biologic markers of B-cell function 
will also be evaluated. 
3.3 
RATIONALE FOR STUDY DESIGN AND DOSING REGIMEN 
As described in Section 1.3, preliminary data from the ongoing Phase 1/2 study in 
subjects with relapsed/refractory or previously untreated CLL have shown that ACP-196 
is well tolerated at dosages of 100 to 400 mg QD and 100 to 200 mg BID.  In addition, 
preliminary PD data from ACE-CL-001 show that Btk occupancy with ACP-196, in 
peripheral blood, is > 95% at 4 hours after QD dosing but decreases to < 95% at 
24 hours with QD dosing, while with BID dosing complete Btk occupancy (95% to 99%) 
is maintained over 24 hours at steady state (Table 1-3).  These data suggest that de 
novo synthesis of Btk can occur within 24 hours in peripheral blood cells.  BID dosing 
may ensure Btk inhibition for the entire 24 hours and thus may be beneficial in terms of 
increasing efficacy and/or decreasing development of resistance to ACP-196.  In 
addition, having information regarding the safety and pharmacology of a BID schedule 
may support future combination studies with other drugs that are administered BID.   
Evaluation of dexamethasone as a combination partner for ACP-196 builds on known 
antineoplastic activity of this drug in patients with MM. Dexamethasone therapy is 
commonly coadministered with targeted agents for MM (Ocio 2014).  The dosing 
regimen of 40 mg weekly to be used in this study has been established based on 
randomized trial data showing the superiority of this method of administration (Rajkumar 
2009). Combined use of ACP-196 and dexamethasone provides an all oral, non-
cytotoxic regimen that may have increased efficacy relative to administration of the 
individual agents alone. While dexamethasone can increase CYP3A4 activity and thus 
might enhance ACP-196 metabolism, it is considered a weak inducer of this isoenzyme 
and has not substantially altered the disposition of other CYP3A4 substrates (eg, 
bortezomib) that are commonly used in the therapy of MM (Hellmann 2011). The 


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randomized design of this pilot study will allow the potential for drug-drug interactions 
between ACP-196 and dexamethasone to be assessed. 
3.4 
SELECTION OF STUDY POPULATION 
3.4.1 
Inclusion Criteria 
Eligible subjects will be considered for inclusion in this study if they meet all of the 
following criteria:  
1. Men and women ≥ 18 years of age. 
2. A confirmed diagnosis of MM, which has relapsed after, or been refractory to 
≥ 1 prior therapy for MM, and is progressing at the time of study entry. 
3. Evaluable myeloma at screening, defined as the presence of at least one of the 
following: 
o Serum M-protein ≥ 0.5 g/dL 
o Urine M-protein ≥ 200 mg/24 hours 
o In subjects without detectable serum or urine M-protein, serum free light 
chain (SFLC) > 100 mg/L (involved light chain) and an abnormal serum 
kappa/lambda ratio 
o For subjects whose disease can only be reliably measured by serum 
quantitative immunoglobulin A (IgA), IgA ≥ 750 mg/dL (0.75 g/dL)  
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 
5. Agreement to use acceptable methods of contraception during the study and for 
30 days after the last dose of study drug if sexually active and able to bear or 
beget children. 
6. Agreement to refrain from sperm donation during the study and for 30 days after 
the last dose of study drug. 
7. Willing and able to participate in all required evaluations and procedures in this 
study protocol including swallowing capsules without difficulty. 
8. Ability to understand the purpose and risks of the study and provide signed and 
dated informed consent and authorization to use protected health information (in 
accordance with national and local patient privacy regulations). 
3.4.2 
Exclusion Criteria 
Subjects will be ineligible for this study if they meet any of the following criteria: 
1. Plasma cell leukemia or circulating plasma cells ≥ 2 x 109/L 
2. Prior malignancy, except for adequately treated basal cell or squamous cell skin 
cancer, in situ cervical cancer, or other cancer from which the subject has been 
disease free for ≥ 2 years or which will not limit survival to < 2 years. Note: these 
cases must be discussed with the Medical Monitor. 
3. A life-threatening illness, medical condition or organ system dysfunction which, in 
the investigator’s opinion, could compromise the subject’s safety, interfere with 


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the absorption or metabolism of ACP-196, or put the study outcomes at undue 
risk. 
4. 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. 
5. Malabsorption syndrome, disease significantly affecting gastrointestinal function, 
or resection of the stomach or small bowel, gastric bypass, symptomatic 
inflammatory bowel disease, or partial or complete bowel obstruction. 
6. Any immunotherapy within 4 weeks of first dose of study drug. 
7. The time from the last dose of the most recent chemotherapy or experimental 
therapy to the first dose of study drug is < 5 times the half-life of the previously 
administered agent(s). 
8. Prior exposure to a B-cell receptor (BCR) inhibitor (eg, Btk, phosphoinositide-3 
kinase [PI3K], or Syk inhibitors) or BCL-2 inhibitors (eg, ABT-199). 
9. Ongoing immunosuppressive therapy, including systemic or enteric 
corticosteroids for treatment of MM or other conditions. Note: Subjects may use 
topical or inhaled corticosteroids as therapy for comorbid conditions. During 
study participation, subjects may also receive systemic or enteric corticosteroids 
as needed for MM therapy or treatment-emergent comorbid conditions. 
10. Grade ≥ 2 toxicity (other than alopecia) continuing from prior anticancer therapy 
including radiation. 
11. Known history of human immunodeficiency virus (HIV), serologic status reflecting 
active hepatitis B or C infection, or any uncontrolled active systemic infection.  
Subjects with hepatitis B core antibody positive who are surface antigen negative 
or who are hepatitis C antibody positive will need to have a negative PCR result 
before enrollment.  Those who are hepatitis B surface antigen positive or 
hepatitis B PCR positive and those who are hepatitis C PCR positive will be 
excluded. 
12. Major surgery within 4 weeks before first dose of ACP-196. 
13. Known history of a bleeding diathesis (eg, hemophilia, von Willebrand disease) 
14. History of stroke or intracranial hemorrhage within 6 months before the first dose 
of ACP-196. 
15. Requires or receiving anti-coagulation with warfarin or equivalent vitamin K 
antagonist (eg, phenprocoumon) within 28 days of first dose of study drug. 
16. Requires treatment with long-acting proton pump inhibitors (eg, omeprazole, 
esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). 
17. ANC < 0.75 x 109/L or platelet count < 50 x 109/L.  For subjects with >50% 
marrow involvement with plasma cells, ANC < 0.50 x 109/L or platelet count 
< 30 x 109/L. 
18. Creatinine > 2.5 x institutional upper limit of normal (ULN); total bilirubin 
> 2.5 x ULN; and aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) > 3.0 x ULN. 
19. Breastfeeding or pregnant. 


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20. Concurrent participation in another therapeutic clinical trial. 
3.4.3 
Replacement of Subjects 
Any subject who does not complete Cycle 2 may be replaced at the discretion of the 
study investigators and sponsor. 
3.4.4 
Enrollment and Randomization Procedures 
Enrollment of a subject into the study will be performed according to the following 
procedure:  
x 
Notify the sponsor when a clinically eligible subject is identified and is ready to 
screen, to ensure enrollment availability on the study. 
x 
After the subject has signed and dated the Informed Consent Form (ICF), all 
screening procedures have been completed, and eligibility has been confirmed, the 
subject can be officially enrolled in the study.  
x 
To enroll a subject, the study center will fax/email a completed Enrollment 
Confirmation Form to the sponsor.  The enrollment date will be the date that the form 
is faxed/emailed to the sponsor. 
x 
An Enrollment Confirmation Form will be completed and faxed/emailed to the study 
center by the sponsor within 24 hours. 
x 
The Enrollment Confirmation Form will contain cohort allocation per the 
randomization scheme generated by the sponsor. 
Treatment must begin within the screening window (Section 4.1) and after the site has 
received the cohort allocation from the sponsor.  Study treatment is not blinded on this 
study. 
3.5 
STUDY DRUG 
3.5.1 
Premedications 
No specific premedications or supporting medications are required in conjunction with 
ACP-196 administration.  


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3.5.2 
Formulation, Packaging, and Storage 
3.5.2.1 
ACP-196 
ACP-196 is manufactured according to cGMP regulations and will be provided to the 
investigational site by Acerta Pharma or designee.  ACP-196 should be stored according 
to the instructions on the label that is affixed to the package containing the drug product.   
ACP-196 capsules is provided as hard gelatin capsules containing 100 mg drug 
substance.  ACP-196 will be provided in white, high-density polyethylene bottles. 
If a drug shipment arrives damaged, or if there are any other drug complaints, a 
SAE/Product Complaint Form should be completed and emailed or faxed to the sponsor 
or the sponsor’s representative.   
Refer to the Investigator’s Brochure for additional information regarding the drug product 
to be used in this trial. 
3.5.2.2 
Dexamethasone 
This study will use commercially available dexamethasone tablets for oral administration.  
The Sponsor will either directly supply sites with dexamethasone or the sites will be 
reimbursed to prescribe dexamethasone; this will be detailed separately in each site’s 
clinical trial agreement.  Per the U.S. dexamethasone package insert (Appendix 4), 
tablets are to be stored at room temperature (20° to 25°C) and protected from moisture 
and light.  Please refer to the appropriate dexamethasone package insert for further 
storage and handling instructions.  
3.5.3 
Administration of Study Drug  
3.5.3.1 
ACP-196 
Investigators are prohibited from supplying ACP-196 to any subjects not properly 
enrolled in this study or to any physicians or scientists except those designated as 
subinvestigators on FDA Form 1572.  The investigator must ensure that subjects receive 
ACP-196 only from personnel who fully understand the procedures for administering the 
drug. 
ACP-196 is intended to be administered orally with 8 ounces (approximately 240 mL) of 
water (avoid grapefruit juice and Seville orange juice due to CYP3A4 inhibition).  ACP-
196 may be taken with or without food. The capsules should be swallowed intact and 
subjects should not attempt to open capsules or dissolve them in water.  . 


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If a dose is missed, it can be taken up to 3 hours after the scheduled time with a return 
to the normal schedule with the following dose.  If it has been greater than 3 hours, the 
dose should not be taken and the subject should take the next dose at the scheduled 
time.  The missed dose will not be made up and must be returned to the site at the next 
scheduled visit. 
3.5.3.2 
Dexamethasone 
This study will use commercially available dexamethasone tablets for oral administration.  
At the time of weekly dexamethasone administration, the subject should take the 
dexamethasone tablets simultaneously with the ACP-196 capsules and with 8 ounces 
(approximately 240 mL) of water.  The dexamethasone tablets should be swallowed 
intact and subjects should not attempt to chew them or dissolve them in water.  
If a dexamethasone dose is missed, it can be taken up to 3.5 days (84 hours) days after 
the scheduled time with a return to the normal schedule the following week.  If the 
interval of missed dosing has been > 3.5 days (84 hours), the dexamethasone dose 
should not be taken and the subject should take the next dose at the scheduled time in 
the following week.  The missed dexamethasone dose will not be made up and must be 
returned to the site at the next scheduled visit. 
3.5.4 
Assuring Subject Compliance 
During cycle 1, subjects will receive their Day 1, 8, 15, 22, and 28 doses (for Cohort 2 
this includes the dexamethasone dose) in the clinic.  For treatments that are taken in the 
clinic, subjects should take the dose from the drug dispensed for them for that particular 
time period.  All other treatments will be taken at home.  Subjects will receive a diary to 
record the specific time each dose was taken and to record reasons for any missed 
doses.   
Subject compliance will be assessed at every visit.  The subject will be instructed to 
bring the diary and any remaining ACP-196 capsules and dexamethasone tablets to the 
clinic at their next visit.  The administrator will review the diary and ask the subject if all 
of the capsules and tablets were administered.  Any remaining or returned capsules and 
tablets will be counted and recorded as described in Section 7.7.  Returned capsules or 
tablets must not be redispensed to another subject. The study staff will resupply the 
subject with the correct number of ACP-196 capsules and dexamethasone tablets 
needed for use until the next visit. 


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3.5.5 
Study Treatment Regimen and Dose Modifications 
3.5.5.1 
ACP-196 
Dose Delays 
Treatment with ACP-196 should be held for any unmanageable, potentially study drug-
related toxicity that is Grade ≥ 3 in severity.  Any other clinically important events where 
dose delays may be considered appropriate by the investigator must be discussed with 
the Medical Monitor.  Study drug may be held for a maximum of 28 consecutive days 
from expected dose due to toxicity.  Study treatment should be discontinued in the event 
of a toxicity lasting > 28 days, unless reviewed and approved by the Medical Monitor. 
Note: temporary withholding of study drug for as little as 7 days can cause a 
transient worsening of disease and/or of constitutional symptoms.  Refer to 
Section 3.8 for more information on assessing disease progression under these 
circumstances. 
Dose Modification and Discontinuation 
The actions in Table 3-1 should be taken for the following toxicities: 
x 
Grade 4 ANC (< 500/μL) for > 7 days (Neutrophil growth factors are permitted 
per ASCO guidelines [Smith 2006] and use must be recorded on the electronic 
case report form [eCRF]). 
x 
Grade 3 platelets in the presence of significant bleeding 
x 
Grade 4 platelets  
x 
Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal 
antiemetic and/or anti-diarrheal therapy 
x 
Any other Grade 4 toxicity or unmanageable Grade 3 toxicity. 
 
Table 3-1.  Drug Discontinuation Actions for ACP-196 
Occurrence 
Action 
1st - 2nd 
Hold ACP-196 until recovery to Grade ≤ 1 or baseline; may restart at 
original dose level  
3rd 
Hold ACP-196 until recovery to Grade ≤ 1 or baseline; restart at 100 mg 
once daily 
4th 
Discontinue ACP-196 
 


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Subjects in Cohort 1 (ACP-196 monotherapy) who do not experience at least an minimal 
response (MR) after 2 cycles of study treatment may have dexamethasone (40 mg once 
weekly) added to their treatment. 
Whenever possible, any dose adjustment of ACP-196, including adding dexamethasone 
to subjects in Cohort 1, should be discussed between the investigator and the Acerta 
Pharma medical monitor before implementation. The appropriate clinic staff should 
dispense the study drug for the new dose level and instruct the subject/caregiver about 
the change in dose level.  Any changes to the dosing regimen must be recorded in the 
appropriate eCRF.   
3.5.5.2 
Dexamethasone 
This study will use commercially available dexamethasone.  Dosing of dexamethasone 
will be 40 mg once weekly.  For subjects who experience intolerable dexamethasone-
related adverse effects, dexamethasone may be reduced to 20 mg once weekly. 
3.6 
CONCOMITANT THERAPY 
3.6.1 
Permitted Concomitant Therapy 
Antiemetics are permitted if clinically indicated.  Standard supportive care medications 
are permitted as per institutional standards.   
For subjects considered at risk for tumor lysis syndrome:  Administer appropriate 
hydration and allopurinol or rasburicase per institutional standards before initiating 
treatment. 
3.6.2 
Guideline for Use of CYP Inhibiting/Inducing Drugs 
At the systemic exposure levels expected in this study, ACP-196 inhibition of CYP 
metabolism is not anticipated.  However, as discussed in Section 1.3.1, concomitant 
administration of ACP-196 with a strong CYP3A4 inhibitor increased exposure by 
approximately 5-fold.  Consequently, the concomitant use of strong inhibitors/inducers of 
CYP3A4 (Appendix 3) should be avoided when possible.  If a subject requires a strong 
CYP3A4 inhibitor while on study, monitor the subject closely for potential toxicities. 
3.6.3 
Guideline for Use of Drugs that Affect Gastric pH 
The effect of agents that reduce gastric acidity (eg, proton pump inhibitors, H2-receptor 
antagonists or antacids) on ACP-196 absorption is currently being evaluated in a healthy 
volunteer study (ACE-HV-004).  Preliminary results from this study suggest subjects 


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should avoid the use of calcium carbonate containing drugs or supplements (eg, 
antacids or calcium supplements) for a period of at least 2 hours before and after taking 
ACP-196.   
Subjects should also avoid the use of H2-receptor antagonists for a period at least 
2 hours before and after taking ACP-196.   Use of omeprazole, esomeprazole, 
lansoprazole or any other long-acting proton pump inhibitors while taking ACP-196 is not 
permitted due to a potential decrease in study drug exposure.  However, if a subject 
requires treatment with a long-acting proton pump inhibitor while on study (eg, to treat an 
ulcer), discuss treatment options with the Medical Monitor. 
3.6.4 
Prohibited Concomitant Therapy 
Any chemotherapy, immunotherapy, kinase inhibitors, bone marrow transplantation, 
experimental therapy, and radiotherapy are prohibited (see Section 3.4.2).   
Administration of live or live, attenuated vaccines is contraindicated in patients receiving 
immunosuppressive doses of corticosteroids, per the dexamethasone package insert 
(Appendix 4). Killed or inactivated vaccines may be administered. However, the 
response to such vaccines cannot be predicted. 
3.7 
PRECAUTIONS 
3.7.1 
Dietary Restrictions 
Because ACP-196 may be metabolized by CYP3A4/3A5 (see Section 1.2.4), subjects 
should be strongly cautioned against excessive consumption of grapefruit, grapefruit 
juice, Seville oranges, or Seville orange juice (which contain potent CYP3A4 inhibitors) 
or using herbal remedies or dietary supplements (in particular, St. John’s Wort, which is 
a potent CYP3A4 inducer). 
ACP-196 may be taken with or without food. 
3.7.2 
Hepatitis B Virus Reactivation 
Serious or life-threatening reactivation of viral hepatitis may occur in subjects treated 
with ACP-196.  Therefore, subjects who are hepatitis B core antibody (anti-HBc) 
positive, or have a known history of hepatitis B virus (HBV) infection, should be 
monitored monthly with a quantitative PCR test for HBV DNA.  Monthly monitoring 
should continue until 12 months after last dose of ACP-196.  Any subject with a rising 
viral load (above lower limit of detection) should discontinue ACP-196 and have antiviral 


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therapy instituted and a consultation with a physician with expertise in managing 
hepatitis B.  Insufficient data exist regarding the safety of resuming ACP-196 in subjects 
who develop HBV reactivation.   
3.7.3 
Surgery 
Susceptibility to bleeding has been observed with the first generation Btk inhibitor, 
ibrutinib [IMBRUVICA package insert].  As a precaution, it is suggested that ACP-196 be 
held for 3 days before and after any major surgical procedure. 
3.7.4 
Infections 
Patients who are on corticosteroids are more susceptible to infections than are healthy 
individuals (dexamethasone package insert, Appendix 4). Corticosteroids may 
exacerbate systemic fungal infections and therefore should not be used in the presence 
of such infections unless they are needed to control life-threatening drug reactions. 
3.7.5 
Reproductive Toxicity 
Definitive reproductive toxicity studies with ACP-196 are pending.  Therefore, subjects 
with reproductive potential who are sexually active must use acceptable methods of 
contraception during the study and for 30 days after the last dose of ACP-196.  
Examples of acceptable methods of contraception include condoms, implants, 
injectables, combined oral contraceptives, intrauterine devices, true sexual abstinence, 
or sterilized partner.  Note that periodic abstinence, eg, calendar, ovulation, 
symptothermal, or postovulation methods, or withdrawal, are not acceptable methods of 
contraception. 
Subjects should promptly notify the investigator if they, or their partner, become 
pregnant during this period. If a female subject becomes pregnant during the treatment 
period, she must discontinue ACP-196 immediately.  Pregnancy in a female subject or a 
male subject’s partner must be reported (see Section 6.2.3). Male subjects must agree 
to refrain from sperm donation during the study and for 30 days after the last dose of 
study drug. 
3.7.6 
Overdose Instructions 
For any subject experiencing an ACP-196 overdose (administration of a dose 
≥ 1.5 times the highest intended dose level in the clinical study protocol), observation for 
any symptomatic side effects should be instituted, and vital signs and biochemical and 
hematologic parameters should be followed closely (consistent with the protocol or more 


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


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x 
Any subject who becomes significantly noncompliant with study drug administration, 
study procedures, or study requirements should be withdrawn from study treatment 
in circumstances that increase risk or substantially compromise the interpretation of 
study results. 
x 
The investigator, in consultation with the Acerta Pharma medical monitor, may 
withdraw any subject from the study treatment, if, in the investigator’s opinion, it is 
not in the subject’s best interest to continue.  
Subjects who discontinue study therapy will continue on study for safety (Section 4.3) 
unless they withdraw consent for further follow-up. Thus, all subjects receiving ≥ 1 dose 
of study drug will be followed during the immediate posttherapy period unless the subject 
withdraws consent for such follow-up to be conducted. The date the subject is withdrawn 
from study treatment or from the study and the reason for discontinuation will be 
recorded and also should be described on the appropriate eCRF.   
3.9 
DATA AND SAFETY MONITORING 
This trial will be monitored in accordance with the sponsor’s Pharmacovigilance 
Committee procedures.  Adverse events and SAEs will be reviewed internally on an 
ongoing basis to identify safety concerns.  Quarterly conference calls with the 
investigators will be conducted to discuss study progress, obtain investigator feedback 
and exchange, and discuss "significant safety events" (ie, AEs leading to dose 
reductions, related SAEs, and deaths).   
4.0 
STUDY ACTIVITIES AND ASSESSMENTS 
The schedule of events is provided in Appendix 5.  Descriptions of the scheduled 
evaluations are outlined below and complete information on study drug and dosing is 
provided in Section 3.5. 
Before study entry, throughout the study, and at the follow-up evaluation, various clinical 
and diagnostic laboratory evaluations are required.  The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments.  
Clinical evaluations and laboratory studies may be repeated more frequently if clinically 
indicated.  Such unscheduled assessments will be captured in the protocol-specific 
database as appropriate. 


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4.1 
DESCRIPTION OF PROCEDURES 
4.1.1 
Informed Consent 
The subject must read, understand and sign the IRB/IEC approved ICF confirming his or 
her willingness to participate in this study before initiating any screening activity that is 
not standard of care.  Subjects must also grant permission to use protected health 
information. 
4.1.2 
Medical History 
The subject’s complete history should be collected and recorded through review of 
medical records and by interview. Concurrent medical signs and symptoms must be 
documented to establish baseline severities. A disease history, including the date of 
initial diagnosis and list of all prior anticancer treatments, and responses and duration of 
response to these treatments, also will be recorded. 
4.1.3 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 6.1  All medical 
occurrences from the time of first dose that meet this definition must be recorded. 
Important additional requirements for reporting SAEs are explained in Section 6.2. 
4.1.4 
Concomitant Medications and Therapy 
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 should be 
documented. 
4.1.5 
Confirmation of Eligibility 
Subject eligibility for enrollment will be assessed per Section 3.4.  All screening 
procedures, unless otherwise indicated, should be completed within 21 days of the first 
dose of study drug. 
4.1.6 
ECOG Performance Status 
The ECOG performance index is provided in Appendix 1. 
4.1.7 
Physical Examination, Vital Signs, Height & Weight 
The screening physical examination will include, at a minimum, the general appearance 
of the subject, height (screening only) and weight, and examination of the skin, eyes, 


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ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous 
system, and lymphatic system. 
Symptom-directed physical exams, including tumor assessments by palpation, will be 
done during the treatment period and at the safety follow-up visits. 
Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) will be 
assessed after the subject has rested in the sitting position.   
4.1.8 
Bone Marrow Aspirate and Biopsy 
A bone marrow aspirate and biopsy will be done at screening or up to 30 days before the 
main screening procedures.  Per the current response criteria (Rajkumar 2011), a bone 
marrow aspirate/biopsy will also be required at any time on study to confirm a complete 
response (CR).  The baseline bone marrow aspirate/biopsy will used for 
immunohistochemistry and/or flow cytometry, cytogenetics, and FISH.  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.  
When available, any unused bone marrow tissue will be used for PD testing.  PD testing 
will be done by the sponsor. 
4.1.9 
Electrocardiogram 
Subjects should be in supine position and resting for ≥ 10 minutes before study-related 
ECGs.   
4.1.10 
Urine Pregnancy Test 
Pregnancy tests will be required only for women of childbearing potential. If positive, 
pregnancy must be ruled out by ultrasound.  Testing will be done by the central 
laboratory. 
4.1.11 
Hematology 
Hematology studies must include complete blood count (CBC) with differential and 
platelet and reticulocyte counts.  Testing will be done by the central laboratory. 
4.1.12 
Serum Chemistry 
Serum chemistry must include albumin, alkaline phosphatase, ALT, AST, bicarbonate, 
blood urea nitrogen (BUN), bone-specific alkaline phosphatase, calcium, chloride, 


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creatinine, C-terminal telopeptide, glucose, lactate dehydrogenase (LDH), magnesium, 
phosphate, potassium, sodium, total bilirubin, total protein, and uric acid.  If an 
unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, 
magnesium, and potassium) must be done to coincide with the ECG testing.  Testing will 
be done by the central laboratory. 
4.1.13 
Urinalysis 
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, N-terminal 
telopeptide, and glucose.  Testing will be done by the central laboratory.  
4.1.14 
T/B/NK Cell Count 
Flow cytometry testing will include CD3+, CD4+, CD8+, CD19+, and CD16/56+ cells.  
Testing will be done by the central laboratory. 
4.1.15 
Disease Markers 
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 the central 
laboratory. 
4.1.16 
Hepatitis B and C Testing 
Hepatitis serology testing must include hepatitis B surface antigen (HBsAg), hepatitis B 
surface antibody (HBsAb), anti-HBc, and hepatitis C (HCV) antibody.  Since intravenous 
immunoglobulins (IVIG) may cause false positive hepatitis serology, subjects who are 
receiving prophylactic IVIG and have positive HBsAg or anti-HBc must have negative 
hepatitis B DNA to be eligible.  In addition, any subjects testing positive for any hepatitis 
serology, must have PCR testing (see Appendix 5 and exclusion criterion #11).  Testing 
will be done by local or central laboratory.   
Refer to Section 3.7.2 and Appendix 5 regarding monitoring of subjects who are 
anti-HBc positive or have a known history of HBV. 
4.1.17 
Skeletal Survey 
Standard lateral radiograph of the skull, anterioposterior and lateral views of the spine, 
and anterioposterior views of the pelvis, ribs, femora, and humeri are required at 
screening or baseline (ie, before the first dose of study drug).  Radiographic imaging and 


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analysis will be performed at the study center’s local laboratory or other clinical 
laboratory listed on the investigator’s form FDA 1572.   
4.1.18 
Pharmacodynamics 
Blood samples and bone marrow, when available, will be used for PD testing (eg, Btk 
occupancy and B-cell activation).  Refer to the laboratory binder for instructions on 
collecting and processing these samples.  Testing will be done by the sponsor. 
4.1.19 
Pharmacokinetics 
Refer to the laboratory binder for instructions on collecting and processing these 
samples. Testing will be performed at the central clinical laboratory.  Leftover plasma 
samples may be used for exploratory ACP-196 metabolite analyses.  The PK sampling 
timepoints are provided in Table 4-1. 
Table 4-1.  Pharmacokinetic Sample Schedule 
 
HOURS POSTDOSE 
Cycle 
Day Predose 
0.5 
(±5 min) 
0.75 
(±5 min) 
1 
(±5 min) 
2 
(±10 min) 
4 
(±10 min) 
6 
(±10 min) 
1 
1 
X 
X 
X 
X 
X 
X 
X 
 
8 
X 
 
 
X 
 
 
 
 
15 
X 
 
 
X 
 
 
 
 
22 
X 
X 
X 
X 
X 
X 
X 
 
28 
X 
 
 
X 
 
 
 
Note: These timepoints are relative to the morning dose. 
 
4.1.20 
Tumor Assessment 
Baseline myeloma assessments will consist of: 
● M-protein determination using both of the following procedures: 
○ serum protein electrophoresis (SPEP) and serum immunofixation 
electrophoresis (SIFE) 
○ Urine protein electrophoresis (UPEP) and urine immunofixation 
electrophoresis (UIFE), all using the same 24-hour urine collection  
● SFLC 


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● Plasmacytoma evaluation 
● Bone marrow to quantify percent myeloma cell involvement (aspirate and 
biopsy required at baseline) 
● Skeletal survey: lateral radiograph of the skull, anterioposterior and lateral 
views of the spine, and anterioposterior views of the pelvis, ribs, femora, and 
humeri 
● β2-microglobulin 
On-study myeloma assessments will consist of: 
● SPEP and/or UPEP (if results were measurable at baseline); quantitative 
immunoglobulins if used to follow disease; immunofixation to confirm a 
complete response 
● SFLC 
● Plasmacytoma evaluation (if only measurable disease at baseline) 
● Bone marrow aspirate and/or trephine bone biopsy (to confirm a complete 
response or if clinically indicated). 
4.1.21 
Study Drug Accountability 
See Section 7.7. 
4.2 
INVESTIGATOR’S ASSESSMENT OF RESPONSE TO TREATMENT 
Subjects will be evaluated by investigator review for disease response and progression 
according to the current guidelines proposed by the International Myeloma Workshop 
Consensus Panel 1 (Rajkumar 2011) and European Group for Blood and Marrow 
Transplant (EBMT; Bladé 1998)as listed below in .  Response categories include sCR, 
CR,  VGPR, PR, SD, and progressive disease. In addition, the number of subjects 
achieving the response category of MR will also be evaluated and reported.  Subjects 
will be considered evaluable for response if they have a baseline and t1 adequate on-
study myeloma assessment obtained t4 weeks from the start of therapy.   
Table 4-2.  Response Criteria (derived from Rajkumar 2011 and Bladé 1998) 
Response Subcategory 
Response Criteriaa 
Complete response (CR) 
x 
Negative immunofixation of serum and urine and 
x 
Disappearance of any soft tissue plasmacytomas and 


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x 
< 5% plasma cells in bone marrowb. 
Stringent complete 
response (sCR) 
x 
CR as defined above plus 
x 
Normal FLC ratio and 
x 
Absence of clonal plasma cells by immunohistochemistry or 2- to 
4-color flow cytometry. 
Very good partial 
response (VGPR) 
x 
Serum and urine M-component detectable by immunofixation but 
not on electrophoresis or 
x 
≥ 90% reduction in serum M-component plus urine M-component 
< 100 mg per 24 h. 
Partial response (PR) 
x 
≥ 50% reduction of serum M-protein and reduction in 24-h urinary 
M-protein by ≥ 90% or to < 200 mg per 24 h 
x 
If the serum and urine M-protein are not measurable, a ≥ 50% 
decrease in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria 
x 
If serum and urine M-protein are not measurable, and serum free 
light assay is also not measurable, ≥ 50% reduction in bone 
marrow plasma cells is required in place of M-protein, provided 
baseline percentage was ≥ 30% 
x 
In addition to the above criteria, if present at baseline, ≥ 50% 
reduction in the size of soft tissue plasmacytomas is also required 
Minimal response (MR) 
x 
Requires all of the following: 
o 
t 25% to d 49% reduction of serum M-protein and 
o 
50% to 89% reduction in 24-hour urine M-protein and 
o 
If present at baseline, 25-49% reduction in the size of soft 
tissue plasmacytomas and 
o 
No increase in size or number of lytic bone lesions 
(development of compression fracture does not exclude 
response). 
Stable disease (SD)  
x 
Not meeting criteria for CR, VGPR, MR, PR or progressive 
disease 
 
Progressive disease 
Any of the following: 
x 
Increase of ≥ 25% from lowest response valuec in: 
o 
Serum M-component (absolute increase must be ≥ 0.5 g/dL)d 
o 
Urine M-component (absolute increase must be 
≥ 200 mg/24 h) 
o 
Only in subjects without measurable serum and urine 
M-protein levels: the difference between involved and 
uninvolved FLC levels (absolute increase must be 
> 10 mg/dL) 
o 
Only in subjects without measurable serum and urine M-
protein levels and without measurable disease by FLC levels 


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bone marrow plasma cell percentage (absolute increase must 
be ≥ 10%) 
x 
Definite development of new bone lesions or soft tissue 
plasmacytomas or definite increase in the size of existing bone 
lesions or soft tissue plasmacytomas 
x 
Development of hypercalcemia (corrected serum calcium 
> 11.5 mg/dL) that can be attributed solely to the plasma cell 
proliferative disorder 
 
Abbreviations:  FLC = (serum) free light chains 
Note: in subjects in whom the only measurable disease is by serum FLC levels, CR requires a 
normal FLC ratio of 0.26-1.65 in addition to negative serum and urine immunofixation. 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 (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments 
made at t4 weeks after the start of study therapy and any time before the institution of any 
new therapy after study therapy; CR, sCR, VGPR, PR, and SD categories also require no 
known evidence of progressive or new bone lesions if radiographic studies were performed. 
VGPR and CR categories require serum and urine studies regardless of whether disease at 
baseline was measurable on serum, urine, both, or neither. Radiographic studies are not 
required to satisfy these response requirements. 
b. Bone marrow assessments need not be confirmed. 
c. Lowest response value does not need to be a confirmed value. 
d. For progressive disease, serum M-component increases of ≥ 1 gm/dL are sufficient to define 
relapse if starting M-component is ≥ 5 g/dL. 
 
4.3 
EARLY TERMINATION/SAFETY FOLLOW-UP VISIT 
An early termination visit is required for any subjects who permanently discontinue study 
drug early for any reason including disease progression.  Each subject should be 
followed for 30 (±7) days after his or her last dose of study drug (ie, the “safety follow-up 
visit”) to monitor for resolution or progression of AEs (see Section 6.2.5) and to 
document the occurrence of any new events; unless, the subject receives a new 
anticancer therapy within this timeframe.  Subjects who withdraw consent should still be 
encouraged to complete the safety follow-up assessments, but these assessments 
cannot be mandated once consent is withdrawn.  The Schedule of Assessments 
(Appendix 5) describes the procedures required for the safety follow-up.  
4.4 
MISSED EVALUATIONS 
Missed evaluations should be rescheduled and performed as close to the original 
scheduled date as possible.  An exception is made when rescheduling becomes, in the 
investigator’s opinion, medically unnecessary or unsafe because it is too close in time to 
the next scheduled evaluation.  In that case, the missed evaluation should be 
abandoned. 


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5.0 
STATISTICAL METHODS OF ANALYSIS  
5.1 
GENERAL CONSIDERATIONS 
Descriptive statistics (including means, standard deviations, and medians for continuous 
variables and proportions for discrete variables) will be used to summarize data as 
appropriate.  Analyses will be done by dosing regimen and overall. 
5.2 
SAMPLE SIZE CONSIDERATIONS 
This study will assess safety, PK, PD, and antitumor activity of ACP-196 alone or in 
combination with dexamethasone.  Subjects will be equally randomized into 1 of the 
2 dosing regimens (ACP-196 monotherapy or ACP-196 + dexamethasone) as an 
efficient method for allocating patients into these regimens. The study is not formally 
designed to compare these regimens but rather to obtain descriptive information that can 
be used in support of further ACP-196 development. 
While the primary objective of this study is to determine the safety in each of the 
2 dosing cohorts, the sample size has been determine to independently evaluate the 
activity of each dosing regimen. The trial seeks to exclude an uninteresting ORR of 
d 15% (ie, the response rate that might be associated with single-agent dexamethasone 
therapy [Anderson 2013]) in favor a target response rate of t 40%.  Considering a 
sample size of 19 subjects per cohort, the power to detect the difference between a null-
hypothesis response rate of 15% and an alternative-hypothesis response rate of 40% 
with a 0.025 one-sided significance level is 69% using a one-group, exact binomial test.  
A sample size of 19 subjects per cohort will also provide a 97.5% 1-sided confidence 
interval centered around an expected ORR of 40% that excludes an ORR of 18.6% as a 
lower bound. 
5.3 
DEFINITION OF ANALYSIS POPULATIONS 
The following definitions will be used for the analysis populations: 
x 
Safety population: All enrolled subjects who receive ≥ 1 dose of study drug. 
x 
Intent-to-treat (ITT) population: All subjects who have been randomized. 
The safety population will be used for evaluating the safety parameters in this study.  
The ITT population will be analyzed for efficacy parameters in this study. 
5.4 
MISSING DATA HANDLING 
General Considerations:  Subjects lost to follow-up (or who dropped out) will be 
included in statistical analyses up to the point of their last evaluation. 


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Duration of Response and Progression-free Survival:  Data for subjects without 
disease progression or death will be censored at the date of the last tumor assessment 
and before the initiation of alternative anticancer therapy. 
Safety:  Missing or partial start and end dates for AEs and concomitant medications will 
be imputed according to prespecified, conservative imputation rules.  No other 
imputation of values for missing data will be performed. 
5.5 
ENDPOINT DATA ANALYSIS 
5.5.1 
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 adverse event (per CTCAE, v4.03) and by 
relationship to study drug. 
Laboratory shift tables containing counts and percentages will be prepared by treatment 
assignment, laboratory parameter, and time.  Summary tables will be prepared for each 
laboratory parameter.  Figures of changes in laboratory parameters over time will be 
generated. 
Results of vital sign assessments and physical exams will be tabulated and summarized.   
5.5.2 
Demographics and Baseline Characteristics 
Additional analyses will include summaries of subject demographics, baseline 
characteristics, compliance, and concurrent treatments. Concomitant medications will be 
coded according to the World Health Organization (WHO) Drug Dictionary and 
tabulated. 
5.5.3 
Analysis of Efficacy Parameters 
5.5.3.1 
Overall Response Rate 
Tumor control will be documented at each assessment by response category (eg, CR, 
sCR, VGPR, PR, MR, SD, and disease progression) as defined for each response 
parameter, date that response is first documented, and date of MM disease progression. 
The overall response rate (ORR) will be defined as the proportion of subjects who 
achieve a CR, sCR, VGPR, or PR. ORR will be calculated and the corresponding 
95% two-sided confidence interval will be derived. 


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5.5.3.2 
Duration of Response 
The duration of response (DOR) defined as the interval from the first documentation of 
CR, sCR, VGPR, or PR to the earlier of the first documentation of definitive disease 
progression or death from any cause.  Kaplan-Meier methods will be used to estimate 
event-free curves and corresponding quantiles (including the median). Data from 
surviving, nonprogressing subjects will be censored at the earliest of the time of initiation 
of anticancer treatment other than the study treatment or the last time that lack of 
definitive MM progression was objectively documented. Data from subjects who have 
MM progression or die after ≥ 2 consecutive missing tumor assessments will be 
censored at the last time before the missing assessments that lack of MM progression 
was objectively documented. 
5.5.3.3 
Clinical Benefit Rate 
Clinical benefit rate (CBR) will be defined as the proportion of subjects who achieve a 
CR, sCR, VGPR, PR, or MR.  CBR will be calculated and the corresponding 95% two-
sided confidence interval will be derived. 
5.5.3.4 
Disease Control Rate 
Disease control rate (DCR) will be defined as the proportion of subjects who achieve a 
CR, sCR, VGPR, PR, MR, or SD.  DCR will be calculated and the corresponding 
95% two-sided confidence interval will be derived. 
5.5.3.5 
Progression-free Survival 
Progression-free survival (PFS) is defined as the interval from the date of randomization 
to the earlier of the first documentation of objective MM disease progression or death 
from any cause.  Kaplan-Meier methods will be used to estimate the event-free curves 
and corresponding quantiles (including the median).  Data from surviving, non-
progressing subjects will be censored at the earliest of the time of initiation of anticancer 
treatment other than the study treatment or the last time that lack of MM progression 
was objectively documented. Data from subjects who have MM progression or die after 
≥ 2 consecutive missing tumor assessments will be censored at the last time prior to the 
missing assessments that lack of MM progression was objectively documented. 
5.5.4 
Analysis of Pharmacokinetic/Pharmacodynamic Parameters  
The plasma PK of ACP-196 and dexamethasone will be characterized using 
noncompartmental analysis. The following PK parameters will be calculated, whenever 
possible, from plasma concentrations of ACP-196: 


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x 
AUC0-t 
Area under the plasma concentration-time curve calculated using linear 
trapezoidal summation from time 0 to time t, where t is the time of the last 
measurable concentration (Ct). 
x 
AUC0-12 
Area under the plasma concentration-time curve from 0 to 12 hours, 
calculated using linear trapezoidal summation. 
x 
AUC0-∞ 
Area under the plasma concentration-time curve from 0 to infinity, 
calculated using the formula: AUC0-∞ = AUC0-t + Ct / λz, where λz is the 
apparent terminal elimination rate constant. 
x 
AUC0-24calc Area under the plasma concentration-time curve from 0 to 24 hours, 
calculated by doubling the value for AUC0-12. 
x 
Cmax 
Maximum observed plasma concentration 
x 
Tmax 
Time of the maximum plasma concentration (obtained without 
interpolation) 
x 
t½ 
Terminal elimination half-life (whenever possible)  
x 
λz 
Terminal elimination rate constant (whenever possible) 
x 
CL/F 
Oral clearance 
Missing dates or times may be imputed for PK and PD samples if the missing values can 
be established with an acceptable level of accuracy based on other information obtained 
during the visit in question. If PK and PD sampling for a given subject is not performed 
according to protocol instructions that subject may be excluded from the PK and PD 
analyses. 
The PK parameters will be tabulated and summarized using descriptive statistics.  
For each PD variable, the concentration at each assessment will be described.  The 
change from baseline to each assessment will be summarized.  The best change from 
baseline during the study will also be summarized.  As appropriate, the on-treatment 
values will be compared with the pretreatment baseline values using paired t-tests.   
5.5.5 
Exploratory or Correlative Analyses 
Additional PK or PD analyses may be performed, as deemed appropriate. 
Correlations between subject characteristics and outcome measures and correlations 
among outcomes measures will be explored using regression models or other 
appropriate techniques.  Such evaluations may assist in determining if baseline 
parameters or early changes in PD biomarkers are predictive of response to Btk 
inhibition. 
6.0 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and recording AEs and SAEs; 
measurements of protocol-specified hematology, clinical chemistry, urinalysis, and other 


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laboratory variables; measurement of protocol-specified vital signs; and other protocol-
specified tests that are deemed critical to the safety evaluation of the study drug(s). 
6.1 
DEFINITIONS 
6.1.1 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational (medicinal) product or other protocol-
imposed intervention, regardless of attribution. 
This includes the following: 
x 
AEs not previously observed in the subject that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with MM that were not 
present before the AE reporting period (see Section 6.2.1) 
x 
Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as biopsies) 
x 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character 
during the protocol-specified AE reporting period. 
Abnormal laboratory values should not be reported as AEs; however, any clinically 
significant laboratory values (defined as requiring treatment, discontinuation from study, 
or dose modification) should be reported as AEs. 
6.1.2 
Serious Adverse Event 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to 
the grade of an AE (see below).  “Serious” is a regulatory definition and is based on 
subject or event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  Seriousness (not severity) serves as the guide 
for defining regulatory reporting obligations from the Sponsor to applicable regulatory 
authorities. 
An AE should be classified as an SAE if it meets any 1 of the following criteria: 
x 
It results in death (ie, the AE actually causes or leads to death). 


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x 
It is life-threatening (ie, the AE, in the view of the investigator, places the subject at 
immediate risk of death.  It does not include an AE that, had it occurred in a more 
severe form, might have caused death). 
x 
It requires or prolongs in-patient hospitalization. 
x 
It results in persistent or significant disability/incapacity (ie, the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
x 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the investigational product. 
x 
It is considered a significant medical event by the investigator based on medical 
judgment (eg, may jeopardize the subject or may require medical/surgical 
intervention to prevent 1 of the outcomes listed above). 
6.1.3 
Severity 
Definitions found in the CTCAE version 4.03 or higher will be used for grading the 
severity (intensity) of AEs. The CTCAE displays Grades 1 through 5 with unique clinical 
descriptions of severity for each referenced AE. Should a subject experience any AE not 
listed in the CTCAE, the following grading system should be used to assess severity: 
x 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities 
x 
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 
x 
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 
x 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to 
be in imminent danger of death 
x 
Grade 5 (Death related to AE) – experiences which result in subject death 


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6.2 
DOCUMENTING AND REPORTING OF ADVERSE AND SERIOUS 
ADVERSE EVENTS 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, as outlined in the prior sections, are recorded on the eCRF.  
All SAEs also must be reported on the SAE/Product Complaint form (see Section 6.2.4). 
6.2.1 
Adverse Event Reporting Period 
The AE reporting period for this study begins when the subject receives the first dose of 
study medication and ends with the safety follow-up visit (or last on-treatment visit if the 
safety follow-up visit is not done), or when the subject receives a new anticancer 
therapy.  An exception to this reporting period is any AE occurring due to a protocol-
defined screening procedure.  Fatal AEs occurring within 30 days after the last dose of 
ACP-196 AND assessed by the investigator as related to ACP-196 must be reported as 
a SAEs. 
6.2.2 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation time 
points during the study.  All AEs and SAEs whether volunteered by the subject, 
discovered by study personnel during questioning, or detected through physical 
examination, or other means will be recorded in the subject’s medical record and on the 
AE eCRF and, when applicable, on an SAE/Product Complaint form. 
Disease progression itself is not considered an adverse event; however, signs and 
symptoms of disease progression may be recorded as AEs or SAEs. 
Each recorded AE or SAE will be described by its duration (ie, start and end dates), 
severity, regulatory seriousness criteria, if applicable, suspected relationship to the study 
drug (ie, ACP-196, dexamethasone, or both; see following guidance), and any actions 
taken.  The relationship of AEs to the study drug will be assessed by means of the 
question: ‘Is there a reasonable possibility that the event may have been caused by the 
study drug?’  Answer Yes or No.  
See Appendix 2 for more detail on assessing relationship. 
6.2.3 
Pregnancy 
The investigator should report all pregnancies in study subjects and in the partners of 
subjects within 24 hours using the Pregnancy Report Form.  This form should be faxed 
or emailed to Acerta Pharma Drug Safety.  Any pregnancy-associated SAE must be 


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reported using the SAE report form, according to the usual timelines and directions for 
SAE reporting (Section 6.2.4). 
Any uncomplicated pregnancy that occurs in a subject or a partner of a treated subject 
during this study will be reported for tracking purposes only, if agreed to by the subject or 
the partner of the subject in this study. All pregnancies and partner pregnancies that are 
identified during or after this study, wherein the estimated date of conception is 
determined to have occurred from the time of consent to 30 days after the last dose of 
study medication will be reported, followed to conclusion, and the outcome reported, as 
long as the subject or partner is willing to participate in follow-up. 
Pregnancy itself is not regarded as an AE unless there is suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Likewise, elective abortions without complications are not 
considered AEs. Any SAEs associated with pregnancy (eg, congenital 
abnormalities/birth defects/spontaneous miscarriages or any other serious events) must 
additionally be reported as such using the SAE/Product Complaint form.  
Subjects should be instructed to immediately notify the investigator of any pregnancies.  
Any female subjects receiving ACP-196 who become pregnant must immediately 
discontinue study drug.  The investigator should counsel the subject, discussing any 
risks of continuing the pregnancy and any possible effects on the fetus.   
6.2.4 
Expedited Reporting Requirements for Serious Adverse 
Events 
All SAEs must be reported within 24 hours of discover.  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/Product Complaint forms 
must be emailed or faxed to Acerta Pharma Drug Safety, or designee.  Acerta Pharma 
may request follow-up and other additional information from the investigator (eg, hospital 
admission/discharge notes and laboratory results).  
All deaths should be reported with the primary cause of death as the AE term, as death 
is typically the outcome of the event, not the event itself. The primary cause of death on 
the autopsy report should be the term reported.  Autopsy and postmortem reports must 
be forwarded to Acerta Pharma Drug Safety, or designee, as outlined above. 
If study drug is discontinued because of an SAE, this information must be included in the 
SAE report. 


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An SAE may qualify for mandatory expedited reporting to regulatory authorities if the 
SAE is attributable to the investigational product and is not listed in the current 
Investigator’s Brochure (ie, an unexpected event). In this case, Acerta Pharma Drug 
Safety/Designee will forward a formal notification describing the SAE to all investigators. 
Each investigator must then notify his or her IRB/IEC of the SAE. 
Drug Safety Contact Information
Fax:
Email:
6.2.5 
Type and Duration of Follow-up of Subjects After Adverse 
Events 
All AEs and SAEs that are encountered during the protocol-specified AE reporting period 
should be followed to resolution, or until the investigator assesses the event as stable, a 
new anticancer therapy is initiated, or the subject is lost to follow-up or withdraws 
consent. 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
Acerta Pharma retains the right to terminate the study and remove all study materials 
from a study site at any time. Specific circumstances that may precipitate such 
termination include: 
x 
Unsatisfactory subject enrollment with regard to quality or quantity 
x 
Significant or numerous deviations from study protocol requirements, such as 
failure to perform required evaluations on subjects and maintain adequate study 
records 
x 
Inaccurate, incomplete or late data recording on a recurrent basis 
x 
The incidence and/or severity of AEs in this or other studies indicating a potential 
health hazard caused by the study treatment 
7.1 
REGULATORY AND ETHICAL COMPLIANCE 
This clinical study was designed and will be implemented in accordance with the 
protocol, the ICH Harmonized Tripartite Guidelines for Good Clinical Practices, 
applicable local regulations (including US Code of Federal Regulations Title 21 and 


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European Directive 2001/20/EC), and the ethical principles laid down in the Declaration 
of Helsinki. 
7.2 
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE 
The investigator will submit this protocol, the ICF, Investigator’s Brochure, and any other 
relevant supporting information (eg, all advertising materials) to the appropriate IRB/IEC 
for review and approval before study initiation.  A signed protocol approval page; a letter 
confirming IRB/IEC approval of the protocol and informed consent; and a statement that 
the IRB/IEC is organized and operates according to GCP and the applicable laws and 
regulations; must be forwarded to Acerta Pharma before screening subjects for the 
study.  Additionally, sites must forward a signed FDA 1572 form (Statement of 
Investigator form) to Acerta Pharma before screening subjects for study enrollment.  
Amendments to the protocol must also be approved by the IRB/IEC and local regulatory 
agencies, as appropriate, before the implementation of changes in this study. 
7.3 
INFORMED CONSENT AND PROTECTED SUBJECT HEALTH 
INFORMATION AUTHORIZATION 
A copy of the IRB/IEC-approved ICF must be forwarded to Acerta Pharma for regulatory 
purposes.  The investigator, or designee (designee must be listed on the Study 
Personnel Responsibility/Signature Log, see Section 7.12), must explain to each subject 
the purpose and nature of the study, the study procedures, the possible adverse effects, 
and all other elements of consent as defined in § 21CFR Part 50, and other applicable 
national and local regulations governing informed consent.  Each subject must provide a 
signed and dated 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 with individual local and national patient privacy regulations, the 
investigator or designee must explain to each subject that for the evaluation of study 
results, the subject’s protected health information obtained during the study may be 
shared with Acerta Pharma and its designees, regulatory agencies, and IRBs/IECs.  As 
the study Sponsor, Acerta Pharma will not use the subject’s protected health information 
or disclose it to a third party without applicable subject authorization.  It is the 
investigator’s or designee’s responsibility to obtain written permission to use protected 


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health information from each subject, or if appropriate, the subject’s legal guardian.  If a 
subject or subject’s legal guardian withdraws permission to use protected health 
information, it is the investigator’s responsibility to obtain the withdrawal request in 
writing from the subject or subject’s legal guardian and to ensure that no further data will 
be collected from the subject.  Any data collected on the subject before withdrawal will 
be used in the analysis of study results. 
7.4 
SUBJECT SCREENING LOG 
The investigator must keep a record that lists all subjects considered for enrollment 
(including those who did not undergo screening) in the study.  For those subjects 
subsequently excluded from enrollment, record the reason(s) for exclusion. 
7.5 
CASE REPORT FORMS 
Authorized study site personnel (see Section 7.12) will complete eCRFs designed for 
this study according to the completion guidelines that will be provided.  The investigator 
will ensure that the eCRFs are accurate, complete, legible, and completed within 5 days 
of each subject’s visit (unless required earlier for SAE reporting).  The investigator will 
ensure that source documents that are required to verify the validity and completeness 
of data transcribed on the eCRFs are never obliterated or destroyed, in accordance with 
the record retention policies in Section 7.8. 
7.6 
STUDY MONITORING REQUIREMENTS 
Representatives of Acerta Pharma or its designee will monitor this study until 
completion.  Monitoring will be conducted through personal visits with the investigator 
and site staff as well as any appropriate communications by mail, fax, email, or 
telephone.  The purpose of monitoring is to ensure compliance with the protocol and the 
quality and integrity of the data.  This study is also subject to reviews or audits by the 
sponsor, regulatory authorities, or ethics committees. 
Every effort will be made to maintain the anonymity and confidentiality of all subjects 
during this clinical study.  However, because of the experimental nature of this 
treatment, the investigator agrees to allow the IRB/IEC, representatives of Acerta 
Pharma, its designated agents, and authorized employees of the appropriate regulatory 
agencies to inspect the facilities used in this study and, for purposes of verification, allow 
direct access to the hospital or clinic records of all subjects enrolled into this study.  This 
includes providing by fax, email, or regular mail de-identified copies of radiology, 


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pathology, and/or laboratory results when requested by the sponsor.  A statement to this 
effect will be included in the informed consent and permission form authorizing the use 
of protected health information. 
7.7 
INVESTIGATIONAL STUDY DRUG ACCOUNTABILITY 
ACP-196 capsules must be kept in a locked limited access room. The study drug must 
not be used outside the context of the protocol. Under no circumstances should the 
investigator or other site personnel supply ACP-196 capsules to other investigators, 
subjects, or clinics or allow supplies to be used other than as directed by this protocol 
without prior authorization from Acerta Pharma. 
Study drug accountability records must be maintained and readily available for 
inspection by representatives of Acerta Pharma and regulatory authorities at any time.  
Each shipment of study drug will contain a Clinical Supplies Shipping Receipt Form 
(CSSF) that must be appended to the site’s drug accountability records. If it is used, the 
Drug Re-order Form (provided in the pharmacy binder) must also be included in the 
site’s drug accountability records.   
Contents of each shipment must be visually inspected to verify the quantity and 
document the condition of study drug capsules.  Then the designated recipient 
completes and signs the CSSF. A copy of the signed CSSF must be faxed or emailed to 
Acerta Pharma at the fax number/emailing address listed on the form. 
An Investigational Drug Accountability Log must be used for drug accountability.  For 
accurate accountability, the following information must be noted when drug supplies are 
used during the study: 
1. 
study identification number (ACE-MY-001) 
2. 
subject identification number 
3. 
lot number(s) of ACP-196 dispensed for that subject 
4. 
date and quantity of drug dispensed 
5. 
any unused drug returned by the subject 
At study initiation, the monitor will evaluate and approve the site’s procedure for 
investigational product disposal/destruction to ensure that it complies with Acerta 
Pharma’s requirements. If the site cannot meet Acerta Pharma’s requirements for 
disposal/destruction, arrangements will be made between the site and Acerta Pharma or 
its representative, for return of unused investigational product.  Before 


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disposal/destruction, final drug accountability and reconciliation must be performed by 
the monitor. 
All study supplies and associated documentation will be regularly reviewed and verified 
by the monitor. 
7.8 
RECORD RETENTION 
The investigator and other appropriate study staff are responsible for maintaining all 
documentation relevant to the study. Mandatory documentation includes copies of study 
protocols and amendments, each FDA Form 1572, IRB/IEC approval letters, signed 
ICFs, drug accountability records, SAE forms transmitted to Acerta Pharma, subject files 
(source documentation) that substantiate entries in eCRFs, and all relevant 
correspondence and other documents pertaining to the conduct of the study. 
An investigator shall retain records for a period of at least 2 years after the date the last 
marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. The investigator must notify Acerta Pharma and obtain 
written approval from Acerta Pharma before destroying any clinical study records at any 
time. Acerta Pharma will inform the investigator of the date that study records may be 
destroyed or returned to Acerta Pharma. 
Acerta Pharma must be notified in advance of, and Acerta Pharma must provide express 
written approval of, any change in the maintenance of the foregoing documents if the 
investigator wishes to move study records to another location or assign responsibility for 
record retention to another party. If the investigator cannot guarantee the archiving 
requirements set forth herein at his or her study site for all such documents, special 
arrangements must be made between the investigator and Acerta Pharma to store such 
documents in sealed containers away from the study site so that they can be returned 
sealed to the investigator for audit purposes. 
7.9 
PROTOCOL AMENDMENTS 
Acerta Pharma will initiate any change to the protocol in a protocol amendment 
document. The amendment will be submitted to the IRB/IEC together with, if applicable, 
a revised model ICF. If the change in any way increases the risk to the subject or 
changes the scope of the study, then written documentation of IRB/IEC approval must 


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be received by Acerta Pharma before the amendment may take effect. Additionally 
under this circumstance, information on the increased risk and/or change in scope must 
be provided to subjects already actively participating in the study, and they must read, 
understand, and sign any revised ICF confirming willingness to remain in the trial. 
7.10 PUBLICATION OF STUDY RESULTS 
Acerta Pharma may use the results of this clinical study in registration documents for 
regulatory authorities in the United States or abroad. The results may also be used for 
papers, abstracts, posters or other material presented at scientific meetings or published 
in professional journals or as part of an academic thesis by an investigator. The study is 
being conducted as part of a multicenter clinical trial. Data from all study centers shall be 
pooled and analyzed for publication in a final report (Primary Publication). The 
investigator agrees that the Primary Publication, which will be coordinated by Acerta 
Pharma, will be the first publication to present the pooled study results. After the Primary 
Publication, or if the Primary Publication is not published within 1 year of termination of 
the study, the investigator may freely publish or present the results of his or her work 
conducted under the clinical trial agreement subject to providing Acerta Pharma with the 
opportunity to review the contents of any proposed presentation, abstract or publication 
about such work, including any results of this study, 90 days in advance of any 
presentation or submission for publication. Within that 90-day period, Acerta Pharma 
may review the proposed publication to identify patentable subject matter and/or any 
inadvertent disclosure of its confidential information, which must be redacted from any 
final publication or presentation. If necessary, to permit the preparation and filing of 
patent applications, Acerta Pharma may elect an additional review period not to exceed 
60 days. 
Authorship, in general, will follow the recommendations of the International Committee of 
Medical Journal Editors (International Committee of Medical Journal Editors 2014).   
7.11 CLINICAL TRIAL INSURANCE 
Clinical trial insurance has been obtained according to the laws of the countries where 
the study will be conducted. An insurance certificate will be made available to the 
participating sites at the time of study initiation. 
7.12 GENERAL INVESTIGATOR RESPONSIBILITIES 
The principal investigator must ensure that: 


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


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8.0 
REFERENCES 
Anderson KC, Alsina M, Bensinger W, et al. Multiple myeloma, version 1.2013. J Natl 
Compr Canc Netw 2013;11:11-17.  
Bladé J, Samson D, Reece D, et al.  Criteria for evaluating disease response and 
progression in patients with multiple myeloma treated by high-dose therapy and 
haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European 
Group for Blood and Marrow Transplant.  Br J Haematol 1998;102:1115-1123. 
Bradshaw JM. The Src, Syk, and Tec family kinases: distinct types of molecular 
switches. Cell Signal 2010;22:1175-1184.  
Buggy JJ, Elias L. Bruton tyrosine kinase (Btk) and its role in B-cell malignancy. Int Rev 
Immunol 2012;31:119-132. Erratum in: Int Rev Immunol 2012;31:428. 
Byrd JC, Furman RR, Coutre SE, Flinn IW, et al. Targeting Btk with ibrutinib in relapsed 
chronic lymphocytic leukemia. NEJM 2013;369:32-42. 
Byrd JC, Brown JR, O’Brien S, et al.  Ibrutinib versus ofatumumab in previously treated 
chronic lymphoid leukemia.  NEJM 2014 May 31 [Epub ahead of print] 
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical 
end points in chronic lymphocytic leukemia. J Clin Oncol 2012;30:2820-2820. 
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical 
end points in chronic lymphocytic leukemia. J Clin Oncol 2012 30:2820-2822. 
Edwards CM, BTK inhibition in myeloma: targeting the seed and soil.  Blood 
2012;120:1757-1759.   
FDA (US Food and Drug Administration). Guidance for industry. Food-Effect 
Bioavailability and Fed Bioequivalence Studies. 2002 Dec. Available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/ucm070241.pdf.  Accessed January 19, 2015. 
Gentile DM, Tomlinson ES, Maggs JL, Park BK, Back DJ. Dexamethasone metabolism 
by human liver in vitro. Metabolite identification and inhibition of 6-hydroxylation. J 
Pharmacol Exp Ther 1996;277:105-12. 
Hallek M, Cheson BD, Catovsky D, et al.  Guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia: a report from the International Workshop on Chronic 
Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 
guidelines. Blood 2008;111:5446-5456. 
Hellmann A, Rule S, Walewski J, et al. Effect of cytochrome P450 3A4 inducers on the 
pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in patients with 
multiple myeloma or non-Hodgkin's lymphoma. Clin Pharmacokinet 2011;50:781-791. 
Honigberg LA, Smith AM, Sirisawad M, et al.  The Bruton tyrosine kinase inhibitor 
PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease 
and B-cell malignancy. PNAS 2010;107:13075-13080. 
IMBRUVICA [package insert].  Horsham, PA: Janssen Biotech, Inc; 2014. 
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals. 2014 Dec.  
Available from: http://www.ICMJE.org.  Accessed February 04, 2015. 


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Mohamed AJ, Yu L, Bäckesjö CM, et al. Bruton's tyrosine kinase (Btk): function, 
regulation, and transformation with special emphasis on the PH domain. Immunol Rev 
2009;228:58-73. 
Ngoma PD, Kabamba B, Dahlgbist G, et al.  Occult HBV reactivation induced by ibrutinib 
treatment: a case report. Acta Gastroenterol Belg. 2015;78:424-426. 
Ocio EM, Richardson PG, Rajkumar SV, et al. New drugs and novel mechanisms of 
action in multiple myeloma in 2013: a report from the International Myeloma Working 
Group (IMWG). Leukemia 2014;28:525-542.   
Rajkumar SV, Harousseau JL, Durie B, et al; International Myeloma Workshop 
Consensus Panel 1. Consensus recommendations for the uniform reporting of clinical 
trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011 
May 5;117(18):4691-5.  
Rajkumar SV, Jacobus S, Callander NS, et a; Eastern Cooperative Oncology Group. 
Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose 
dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label 
randomised controlled trial. Lancet Oncol 2010;11:29-37. Erratum in: Lancet Oncol 
2010;11:14. 
Romano A, Conticello C, Cavalli M, et al. Salvage therapy of multiple myeloma: the new 
generation drugs. Biomed Res Int 2014;2014:456037. Epub 2014 May 19. 
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 2012:120:1877-1887. 
Vail DM, Thamm DH. Spontaneously occurring tumors in companion animals as models 
for drug development. In: Teicher BA, Anders PA, eds. Anticancer Drug Development 
Guide: Preclinical Screening, Clinical Trials, and Approval. 2nd Ed. Totowa, NJ: Human 
Press; 2004:259-284. 
Vail DM, Michels GM, Khanna C, Selting KA, London CA; Veterinary Cooperative 
Oncology Group. Response evaluation criteria for peripheral nodal lymphoma in dogs 
(v1.0)—a Veterinary Cooperative Oncology Group (VCOG) consensus document. Vet 
Comp Oncol 2010;8:28-37. 
Vihinen M, Mattsson PT, Smith CI. Bruton tyrosine kinase (Btk) in X-linked 
agammaglobulinemia (XLA). Front Biosci 2000;5:D917-D928. 


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9.0 
APPENDICES 
 
 
 
 


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Appendix 1. Performance Status Scores  
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, eg, light house 
work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair 
5 
Dead 
As published in Am J Clin Oncol: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin 
Oncol 5:649-655, 1982. 
Credit: Eastern Cooperative Oncology Group Chair: Robert Comis, MD 
Available at: http://www.ecog.org/general/perf_stat.html.  Accessed 23 August 2013. 
 
 


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Appendix 2.  Adverse Event Assessment of Causality 
 
Is there a reasonable possibility that the event may have been caused by study drug?  
No___ Yes___ 
The descriptions provided below will help guide the principal investigator in making the 
decision to choose either “yes” or “no”: 
No = There is no reasonable possibility that the event may have been caused by study 
drug. 
The adverse event: 
x 
may be judged to be due to extraneous causes such as disease or environment 
or toxic factors 
x 
may be judged to be due to the subject’s clinical state or other therapy being 
administered 
x 
is not biologically plausible 
x 
does not reappear or worsen when study drug is re-administered 
x 
does not follow a temporal sequence from administration of study drug 
Yes = There is a reasonable possibility that the event may have been caused by study 
drug. 
The adverse event: 
x 
follows a temporal sequence from administration of study drug 
x 
is a known response to the study drug based on clinical or preclinical data 
x 
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 
x 
disappears or decreases upon cessation or reduction of dose of study drug 
x 
reappears or worsens when study drug is re-administered 


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Appendix 3.  Known Strong in Vivo Inhibitors of CYP3A4 
 
Strong Inhibitors of CYP3Aa 
Strong Inducers of CYP3Ae 
boceprevir 
carbamazepinef 
clarithromycinb 
phenytoinf 
conivaptinb 
rifampinf 
grapefruit juicec 
St John's wortf  
indinavir 
 
itraconazoleb 
 
ketoconazoleb 
 
lopinavir/ritonavirb (combination drug) 
 
mibefradild 
 
nefazodone 
 
nelfinavir 
 
posaconazole 
 
ritonavirb 
 
saquinavir 
 
telaprevir 
 
telithromycin 
 
voriconazole 
 
  
a. 
A strong inhibitor for CYP3A is defined as an inhibitor that increases the AUC of a substrate for CYP3A 
by ≥ 5-fold. 
b. 
In vivo inhibitor of P-glycoprotein. 
c. 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (eg, high dose, double strength) or as a “moderate CYP3A inhibitor” when 
another preparation was used (eg, low dose, single strength). 
d. 
Withdrawn from the United States market because of safety reasons. 
e. 
A strong inducer for CYP3A is defined as an inducer that results in ≥ 80% decrease in the AUC of a 
substrate for CYP3A. 
f. 
In vivo inducer of P-glycoprotein.   
 
Note: The list of drugs in these tables is not exhaustive.  Any questions about drugs not on this list 
should be addressed to the Medical Monitor of the protocol. 
 
Source: 
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers.  Web link 
Accessed 21 January 2015: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabe
ling/ucm093664.htm#inVivo 


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Appendix 4.  Dexamethasone Prescribing Information 
 
The United States label for dexamethasone tablets (Roxane Laboratories 2007) is 
provided for reference.  The United States label will also serve as the Reference Safety 
Information for dexamethasone for this study.  Country-specific labels will be provided to 
investigative sites as appropriate. 
 


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Appendix 5.  Schedule of Assessments 
 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycles 5-12b 
ET/Safety 
Follow Upc 
 
 
Days (± 2) 
Days (± 2) 
Days (± 2) 
Days (± 2) 
Days (± 2) 
 
1 
8 
15 
22 
28 
15 
28 
28 
28 
28 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
x 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
PEd/Vital signse/Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECOG status 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECGf 
x 
x 
x 
Lab assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
testg 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
Hematologyh 
x 
xq 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Serum chemistryi 
x 
xq 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Urinalysisj 
x 
 
 
 
 
x 
 
x 
x 
x 
Every 2 mos 
 
 
T/B/NK cell countk 
 
xq 
x 
x 
 
x 
 
x 
 
 
Every 6 mos 
 
 
Disease markersl 
x 
 
x 
 
x 
 
x 
x 
x 
Every 2 mos 
x 
Bone marrow 
(aspirate/biopsy) 
/Skeletal surveyp 
x 
 
 
 
 
 
 
 
As 
clinically 
indicated 
or to 
confirm a 
CR 
As 
clinically 
indicated 
or to 
confirm a 
CR 
As clinically 
indicated or 
to confirm a 
CR 
 
Hepatitis serologyr 
x 
 
 
 
 
 
 
 
 
 
 
 
HBV PCRs 
 
 
 
 
 
x 
 
x 
x 
x 
QM 
QM 
 
Pharmacodynamics 
 
xm 
xm 
 
 
xn 
 
xn 
 
 
 
x 
 
Pharmacokineticso 
 
x 
x 
x 
x 
x 
 
 
 
 
 
 
ACP-196/ 
dexamethasone 
dispensed 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Study drug compliance 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Tumor assessmentp 
x 
 
 
 
 
x 
 
x 
x 
x 
x 
 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Product: ACP-196 (acalabrutinib)  
Date: 13 January 2016 
Protocol: ACE-MY-001 
 
 
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Abbreviations: anti-HBc = hepatitis B core antibody; CR = complete remission; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ET = 
early termination; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; Ig = 
immunoglobulin; IVIG = intravenous immunoglobulins; mos = months; PCR = polymerase chain reaction; PE = physical exam; QM = every month. 
Footnotes for ACE-MY-001 Schedule of Study Activities: 
a.  Screening tests should be performed within 21 days before the first administration of study drug, unless otherwise indicated. 
b. 
Any subjects who have not progressed while receiving study drug treatment, may be eligible to enroll into a long-term follow up study and continue to receive ACP-
196. 
c. 
An early termination visit is required for any subjects who permanently discontinue study drug early for any reason including disease progression.  A 30-day (± 7 days) 
safety follow-up visit is required when subjects discontinue study drug unless they start another anticancer therapy within that timeframe. 
d. 
The screening physical examination will include, at a minimum, the general appearance of the subject, height (screening only) and weight, and examination of the 
skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system.  Symptom-directed physical exams 
are done thereafter.   
e. 
Vital signs (blood pressure, pulse, respiratory rate, and temperature) will be assessed after the subject has rested in the sitting position.   
f. 
Subjects should be in supine position and resting for ≥ 10 minutes before study-related ECGs.   
g. 
Women of childbearing potential only.  If positive, pregnancy must be ruled out by ultrasound to be eligible. 
h. 
Hematology includes complete blood count with differential and platelet and reticulocyte counts. Cycle 1 Day 1 hematology does not need to be repeated if screening 
hematology was within 5 days. 
i. 
Serum chemistry: albumin, alkaline phosphatase, bone-specific alkaline phosphatase, alanine transaminase (ALT), aspartate aminotransferase (AST), bicarbonate, 
blood urea nitrogen (BUN), calcium, chloride, creatinine, C-terminal telopeptide, glucose, lactate dehydrogenase (LDH), magnesium, phosphate, potassium, sodium, 
total bilirubin, total protein, and uric acid. Cycle 1 Day 1 serum chemistry does not need to be repeated if screening serum chemistry was within 5 days. 
j. 
Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, N-terminal telopeptide, and glucose.  
k. 
T/B/NK cell count (ie, CD3, CD4, CD8, CD19, CD16/56).  During Cycle 5-12, only done at end of Cycle 6 and 12. 
l.  
Refer to Section 4.1 for a list of myeloma disease markers. 
m. Pharmacodynamic samples are drawn predose and 4 hours (±10 minutes) postdose on the days indicated. Note: These timepoints are relative to the morning dose. 
n. 
Pharmacodynamic samples are drawn predose on the days indicated. 
o. 
Pharmacokinetic samples are drawn per Table 4-1. 
p 
Refer to Section 4-2.  Bone marrow aspirate/biopsy and skeletal survey are required at baseline (ie, before the first dose of study drug).  Thereafter they are required 
as indicated in the table above. 
q. 
The indicated samples at this timepoint (Cycle 1 Day 1) must be drawn predose. 
r. 
Hepatitis serology must include hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (anti-HBc), and hepatitis C (HCV) 
antibody.  Subjects who are receiving prophylactic intravenous immunoglobulins (IVIG) and have positive HBsAg or anti-HBc must have negative hepatitis B DNA to 
be eligible.  In addition, any subjects testing positive for any hepatitis serology, must have PCR testing (see exclusion criterion #11). 
s. 
Subjects who are anti-HBc positive (or have a known history of HBV infection) should be monitored monthly with a quantitative PCR test for HBV DNA.  Monthly 
monitoring should continue until 12 months after last dose of ACP-196.  Any subject with a rising viral load (above lower limit of detection) should discontinue 
ACP-196 and have antiviral therapy instituted and a consultation with a physician with expertise in managing hepatitis B. 
 
 


Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
PROTOCOL
TITLE:
An Open-label, Phase 1b Study of ACP-196 in Subjects 
with Multiple Myeloma
PROTOCOL NUMBER:
ACE-MY-001
STUDY DRUG:
ACP-196
IND NUMBER:
118717
EUDRACT NUMBER
2014-003587-21
SPONSOR MEDICAL 
MONITOR:
Acerta Pharma BV
SPONSOR:
Acerta Pharma BV
Molenstraat 110
5342 CC Oss
The Netherlands
PROTOCOL DATE:
Version 0.0 - 11 July 2014
AMENDMENT 1 DATE:
Version 1.0 - 20 March 2015
Confidentiality Statement
This document contains proprietary and confidential information of Acerta Pharma BV
that must not be disclosed to anyone other than the recipient study staff and members of 
the institutional review board (IRB)/independent ethics committee (IEC). This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Acerta Pharma BV.
Acerta Pharma
Confidential
Page 1 of 87




Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
SUMMARY OF AMENDMENT 1
Acerta Pharma is amending this protocol to provide updated background information on 
ACP-196 and to assure consistency in eligibility criteria and other study requirements 
across studies.  
This amendment also reflects the memo to file dated 09 October 2014 clarifying the 
concomitant use of agents that reduce gastric acidity.
Clarifying edits and typographical changes have been made throughout the protocol. In 
addition, the following substantive changes were made as part of this amendment:
Change
Rationale
Title Page:  changed Medical Monitor
Sandeep Inamdar, MBBS, is now the Acerta 
Pharma Medical Monitor for the study.
Synopsis:
Revised text
The synopsis was updated to reflect the 
changes made throughout the protocol.
Section 1.1 Role of BTK in Lymphoid 
Cancers:  
Added background information on ibrutinib
Information added to provide context of 
ACP-196 development compared with other 
BTK inhibitors such as ibrutinib.
Section 1.2.2 Efficacy Pharmacology:
Revised Table 1-1
Table updated to reflect new preclinical data.
Section 1.2.4 ACP-196 and Thrombus 
Formation:
New section added.
An in vivo murine model of human thrombus 
formation showed that the thrombi formed by 
platelets treated with ACP-196 were not 
significantly different than untreated platelets.  
In contrast, ibrutinib-treated platelets showed 
reduced thrombus formation, which may 
provide some mechanistic background for the 
bleeding events seen in patients treated with 
ibrutinib.  
Section 1.2.6 Drug-drug Interaction Potential:
Revised text throughout section
Section updated to reflect new clinical data.
Section 1.3 Clinical Experience:
Revised Table 1-2; updated text and added 
new subsections 1.3.1 Pharmacokinetics and 
Pharmacodynamics of ACP-196 and 1.3.2 
Clinical Experience of ACP-196 in CLL
Section updated to reflect current clinical data
from ACE-CL-001.
Section 1.4 Benefit/Risk:
New section added.  
Section added to summarize the risk/benefit 
to subjects in this study.  
Section 2.2 Secondary Objective:
Added endpoints of clinical benefit rate (CBR) 
and disease control rate (DCR), and deleted 
time-to-next treatment.  
In addition to the endpoint of overall response
rate (ORR), which includes complete 
responses and partial responses, the activity 
of ACP-196 will be evaluated by assessing 
clinical benefit rate (overall response plus 
minimal responses) and disease control rate 
(clinical benefit plus stable disease).  
Time-to-next treatment analysis was 
removed, as subjects who experience 
disease progression on study are expected to 
move quickly on to a new anticancer regimen.  
Section 3.1 Description of Study: Added 
Sites/countries added to clarify study 
Acerta Pharma
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Change
Rationale
number of planned sites and countries and
defined end of trial.  
structure. End of trial defined for reporting 
purposes
Section 3.2.2 Efficacy Parameters:  Added 
clinical benefit rate and disease control rate,
deleted time-to-next treatment.  
Revised to reflect changes in Section 2.2 
Secondary Objectives, as noted above.  
Section 3.3 Rationale for Study Design and 
Dosing Regimen:  updated Btk occupancy 
data.
Updated to reflect current data from ACE-CL-
001.
Section 3.4.1 Inclusion Criteria:  
Added new inclusion criteria:
x
Evaluable myeloma at screening, 
defined as the presence of at least 
one of the following:
o
Serum M-pURWHLQ 0.5 g/dL
o
Urine M-protein 
 200 mg/24 hours
o
In subjects without detectable 
serum or urine M-protein, 
serum free light chain (SFLC) 
> 100 mg/L (involved light 
chain) and an abnormal 
serum kappa/lambda ratio
o
For subjects whose disease 
can only be reliably 
measured by serum 
quantitative immunoglobulin 
A ,J$,J$ 750 mg/dL 
(0.75 g/dL) 
Subjects must have measurable disease at 
screening to allow adequate evaluation of 
response on study.  
Section 3.4.2 Exclusion Criteria:
Added 3 new criteria:
x
Plasma cell leukemia or circulating 
plasma cells  2 x 109/L
x
Known history of a bleeding diathesis 
(eg, hemophilia, von Willebrand 
disease)
x
Requires treatment with long-acting 
proton pump inhibitors (eg, 
omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole,
rabeprazole, or pantoprazole)
Revised exclusion criteria as follows:
x
Removed ECG exclusion criteria, 
except that QTc > 480 msec was 
moved to cardiovascular disease 
exclusion criteria
x
Added gastric bypass
x
Added phosphoinositide-3 kinase 
[PI3K], Syk, and BCL-2 receptors
x
Added vitamin K antagonist 
(phenprocoumon) within 28 days
x
Added specific criteria for absolute 
Subjects with plasma cell leukemia are 
excluded due to the distinct clinical course 
compared to primary multiple myeloma.  
The other exclusion criteria have been 
revised for consistency with other ACP-196
protocols.  
Susceptibility to bleeding has been observed 
with the first generation Btk inhibitor, ibrutinib 
[IMBRUVICA package insert]; therefore, 
subjects with a known history of a bleeding 
diathesis will be excluded from this study.  
Preliminary results from a healthy volunteer 
study suggest subjects should avoid the use 
of calcium carbonate containing drugs or 
supplements (eg, antacids and calcium 
supplements) and short-acting H2 receptor 
antagonists for a period of at least 2 hours 
before and after taking ACP-196. Use of 
omeprazole, esomeprazole, or any other 
long-acting proton pump inhibitors while 
taking ACP-196 is not permitteddue to a 
potential decrease in study drug exposure.  
However, if a subject requires treatment with 
Acerta Pharma
Confidential
Page 4 of 87


Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Change
Rationale
neutrophil count (ANC) and platelet 
count in subjects with bone marrow 
involvement:  ANC < 0.50 x 109/L or 
platelet count < 30 x 109/L 
x
Changed aspartate aminotransferase 
(AST) and alanine aminotransferase 
(ALT) limits from > 2.5 x upper limit of 
normal (ULN) to > 3.0 x ULN and 
removed exception for disease-
related abnormalities for bilirubin and
ALT/AST
a long-acting proton pump inhibitor while on 
study (eg, to treat an ulcer), treatment options 
should be discussed with the Medical Monitor.
Based on the safety results observed in the 
ongoing first-in-human study of ACP-196, the 
ECG exclusion criteria have been narrowed to 
exclude QTc > 480 msec at screening.
Section 3.5.2.1 ACP-196:
Removed 25-mg capsule information; deleted 
inactive excipients and bottle size
This section updated as Acerta Pharma is 
phasing out the 25-mg strength capsule.
Section 3.5.2.2 Dexamethasone:
Added information about supply and storage 
of dexamethasone.
Acerta Pharma will either directly supply sites 
with dexamethasone or the sites will be 
reimbursed to prescribe dexamethasone; this 
will be detailed separately in each site’s 
clinical trial agreement.  
Per the US dexamethasone package insert 
(Appendix 4), tablets are to be stored at room 
temperature (20° to 25°C) and protected from 
moisture and light.  
Section 3.5.5.1 Study Treatment Regimen 
and Dose Modifications, ACP-196:
Revised text and Table 3-1:  
New Section Dose Delays states:
Treatment with ACP-196 should be held for 
any unmanageable, potentially study drug-
related toxicity that is Grade  3 in severity.  
Any other clinically important events where 
dose delays may be considered appropriate 
by the investigator must be discussed with 
the Medical Monitor.  Study drug may be held 
for a maximum of 28 consecutive days from 
expected dose due to toxicity.  Study 
treatment should be discontinued in the event 
of a toxicity lasting > 28 days, unless 
reviewed and approved by the Medical 
Monitor.
Note: temporary withholding of study drug for 
as little as 7 days can cause a transient 
worsening of disease and/or of constitutional 
symptoms.  Refer to Section 3.9 for more 
information on assessing disease progression 
under these circumstances.
New Section Dose Modification and 
Discontinuationstates:
The actions in Table 3-1 should be taken for 
This section is now 2 sections.  
Data from the ongoing study of ACP-196 in 
subjects with CLL (Section1.3.2) suggest full 
Btk occupancy (> 90%) over 24 hours occurs 
with 200 mg QD and 100 mg BID, so dose 
escalation to 200 mg BID is not currently 
supported for this protocol.  Therefore this 
section was revised to remove language that 
allowed escalation to 200 mg BID for subjects 
who were not responding to ACP-196
treatment.
To better allow evaluation of single-agent 
activity of ACP-196, subjects in Cohort 1 must 
have received at least 2 cycles of study 
treatment and not experienced at least an MR 
in order to have dexamethasone added to 
their treatment.  
Acerta Pharma
Confidential
Page 5 of 87


Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Change
Rationale
the following toxicities:
x
Grade 4 absolute neutrophil count 
$1&ȝ/IRU!GD\V
(Neutrophil growth factors are 
permitted per ASCO guidelines 
[Smith 2006] and use must be 
recorded on the electronic case 
report form [eCRF]).
x
Grade 3 platelets in the presence of
significant bleeding
x
Grade 4 platelets 
x
Grade 3 or 4 nausea, vomiting, or 
diarrhea, if persistent despite optimal 
antiemetic and/or anti-diarrheal 
therapy
x
Any other Grade 4 toxicity or 
unmanageable Grade 3 toxicity.
Table 3-1 states:
OccurrenceÆAction
1st - 2ndÆHold ACP-196 until recovery to 
*UDGHRUEDVHOLQHPD\UHVWDUWDWRULJLQDO
dose level 
3rdÆHold ACP-XQWLOUHFRYHU\WR*UDGH
1 or baseline; restart at 100 mg once daily
4thÆDiscontinue ACP-196
Specified that subjects in Cohort 1 (ACP-196
monotherapy) who do not experience at least 
an minimal response (MR) after 2 cycles of 
study treatment may have dexamethasone 
(40 mg once weekly) added to their 
treatment.  
Section 3.6.2 Guideline for Use of CYP 
Inhibiting/Inducing Drugs:
New section added 
Language regarding monitoring of subjects on 
CYP3A inhibitors/inducers was moved 
(formerly appeared under Precautions/Drug-
drug Interactions) and revised for clarity and 
consistency with other studies.  At the 
systemic exposure levels expected in this 
study, ACP-196 inhibition of CYP metabolism 
is not anticipated.  However, as discussed in 
Section 1.3.1, concomitant administration of 
ACP-196 with a strong CYP3A4 inhibitor 
increased exposure by approximately 5-fold.  
Consequently, the concomitant use of strong 
inhibitors/inducers of CYP3A4 (Appendix 3) 
should be avoided when possible.  If a subject 
requires a strong CYP3A4 inhibitor while on 
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Change
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study, monitor the subject closely for potential 
toxicities.
Section 3.6.3 Guideline for Use of Drugs that 
Affect Gastric pH:
New section added
Language regarding the use of drugs that 
affect gastric pH was added to reflect current 
findings on the effect of agents that reduce 
gastric acidity (eg, proton pump inhibitors, H2-
receptor antagonists or antacids) on ACP-196 
absorption in a healthy volunteer study (ACE-
HV-004).  Preliminary results from this study 
suggest subjects should avoid the use of 
calcium carbonate containing drugs or 
supplements (eg, antacids or calcium 
supplements) for a period of at least 2 hours 
before and after taking ACP-196.  
Subjects should also avoid the use of H2-
receptor antagonists for a period at least 2 
hours before and after taking ACP-196.   Use 
of omeprazole, esomeprazole, lansoprazole 
or any other long-acting proton pump 
inhibitors while taking ACP-196 is not 
permitted due to a potential decrease in study 
drug exposure.  However, if a subject requires 
treatment with a long-acting proton pump 
inhibitor while on study (eg, to treat an ulcer), 
discuss treatment options with the Medical 
Monitor.
Section 3.6.4 Prohibited Concomitant 
Therapy:  Added live or live attenuated 
vaccines.  
Per the dexamethasone package insert, 
administration of live or live, attenuated 
vaccines is contraindicated in patients 
receiving immunosuppressive doses of 
corticosteroids. Killed or inactivated vaccines 
may be administered. However, the response 
to such vaccines cannot be predicted.
Section 3.7.1 Dietary Restrictions:
x
Added caution against excessive 
consumption of grapefruit or Seville 
oranges or use of herbal remedies 
such as St. John’s Wort.  
x
Added that ACP-196 can be taken
with or without food.
Because ACP-196 may be metabolized by 
CYP3A4/3A5, subjects are cautioned against 
ingesting these known CYP3A inhibitors and 
inducers.  
Section 3.7.2 Drug-drug Interactions:  Section 
removed.
Information about drug-drug interactions with 
CYP inhibitors/inducers was moved to the 
Concomitant Medications section of the 
protocol (Section 3.6.2).  
Section 3.7.2 Surgery:
New section added.
Susceptibility to bleeding has been observed 
with the first generation Btk inhibitor, ibrutinib 
[IMBRUVICA package insert].  As a 
precaution, it is suggested that ACP-196 be 
held for 3 days before and after any major 
surgical procedure.
Section 3.7.3 Infections:
New section added.
Per the dexamethasone package insert, 
patients who are on corticosteroids are more 
susceptible to infections than are healthy 
individuals. Corticosteroids may exacerbate 
systemic fungal infections and therefore 
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Change
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should not be used in the presence of such 
infections unless they are needed to control 
life-threatening drug reactions.
Section 3.8 Stopping Rules
x
Edited section to clarify the 
assessment of response if there is 
uncertainty regarding whether there 
is cancer progression
x
Revised instruction for 
discontinuation as follows:
Any subject who is unable to tolerate a
second rechallenge with at the lowest 
protocol-described, dose-modified levels (see 
Section 3.5.5) should be withdrawn from the 
study treatment unless continued therapy is 
permitted by the Acerta Pharma medical 
monitor.
Clarified disease assessment in the event that 
transient worsening of disease is observed 
during temporary interruption of study 
therapy.  
Revised instructions for study discontinuation 
to be consistent with the dose modification 
instructions in Section 3.5.5.  
Section 4.1 Description of Procedures:
Revised as noted: 
-
Electrocardiograms (ECGs) – changed 
screening ECG from triplicate to single, 
and added a single ECG to 30-day 
Safety Follow-up visit
-
Tumor Assessments – text added
-
Routine Clinical Assessments – new text 
section added
-
ECG criteria were revised for 
consistency with other protocols
-
Tumor assessment requirements were 
further clarified.
-
Routine Clinical Assessments section 
added to clarify non-radiology 
assessments needed to support overall 
response.
Section 4.2 Investigator’s Assessment of 
Response:  Updated Table 4-1.
Response criteria updated to reflect the latest 
criteria (Rajkumar 2011), including removal of 
near complete response (nCR) category.
Section 4.3 Early Termination/Safety Follow-
up Visit:  Specified that an early termination 
visit is required for any subjects who 
permanently discontinue study drug early for 
any reason including disease progression.  
Clarifying edit.  
Section 5.2 Sample Size Considerations:  
Deleted power calculation based on chi 
square test (no change in power based on 
exact binomial test).  
Clarifying edits; no substantive change in 
sample size calculations.  
Section 5.3 Definition of Analysis 
Populations:
Replaced per-protocol analysis set with
intent-to-treat ITT population for efficacy 
endpoints.
Efficacy analyses will be done on randomized 
subjects (ie, the ITT population) for this study.
PK/PD analyses will be further defined in a 
separate statistical analysis plan.  
Section 5.4 Missing Data Handling:
Revised text
Clarified and specified missing data handling 
procedures for response and safety 
parameters.
Section 5.5.3.1 Overall Response Rate:  
removed nCR and MR from this endpoint;
replaced 97.5% one-sided confidence interval 
with 95% two-sided confidence interval.  
Per the current guidelines (Rajkumar 2011), 
nCR is not defined, and minimal response 
rate should be considered separately from 
ORR.  
Section 5.5.3.2 Duration of Response:  
removed nCR and MR from this endpoint.  
Per the current guidelines (Rajkumar 2011), 
nCR is not defined, and minimal response 
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Change
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rate should be considered separately from 
overall response.  
Section 5.5.3.3 Clinical Benefit Rate:  Added 
new section.
Added endpoint of CBR, defined as the 
proportion of subjects who achieve a CR, 
sCR, VGPR, PR, or MR.
Section 5.5.3.4 Disease Control Rate:  Added 
new section.
Added endpoint of DCR, defined as the 
proportion of subjects who achieve a CR, 
sCR, VGPR, PR, MR, or SD.
Section 5.5.3.5 Progression-free Survival:  
defined start of PFS interval as the date of 
randomization, rather than the start of ACP-
196 therapy.  
As the PFS analysis will be performed on the 
ITT population, the start randomization is a 
more appropriate timepoint for the PFS 
interval.  
Section 5.5.3.4 Time-to-Next Treatment:  
Section deleted; long-term follow-up visits are 
no longer required.  
Time-to-next treatment analysis was 
removed, as subjects who experience 
disease progression on study are expected to 
move quickly on to a new anticancer regimen.  
Section 5.5.4 Analysis of 
Pharmacokinetic/Pharmacodynamic 
Parameters:  Added AUC0-12 analysis and 
defined AUC0-24calc (calculated by doubling the 
value for AUC0-12)
PK parameters revised to be consistent with 
other studies that use BID dosing.
Section 6.2.1 Adverse Event Reporting 
Period:
Added underlined text:  The AE reporting 
period for this study begins when the subject 
receives the first dose of study and ends with 
the safety follow-up visit (or last on-treatment 
visit if the safety follow-up visit is not done) or 
if the subject receives a new anticancer 
therapy.
Added text to clarify the end of the AE 
reporting period.  
Section 6.2.3 Pregnancy:  Revised reporting 
procedures to reflect single-part form
Clarifying edits 
Section 6.2.4 Expedited Reporting 
Requirements for Serious Adverse Events:  
Instructions clarified to emphasize use of the 
electronic reporting system (no substantive 
change in reporting procedures).  
Clarifying edits
Section 7.1 Regulatory and Ethical 
Compliance: 
New section added (with subsequent re-
numbering of sections 7.2-7.12).  New text 
reads:
This clinical study was designed and will be 
implemented in accordance with the protocol, 
the ICH Harmonized Tripartite Guidelines for 
Good Clinical Practices, applicable local 
regulations (including US Code of Federal 
Regulations Title 21 and European Directive 
2001/20/EC), and the ethical principles laid 
down in the Declaration of Helsinki.
Added explicit statement that the study will be 
implemented in accordance with appropriate 
regulatory guidelines.  
Section 7.10 Publication of Study Results:  
Revised text to specify that authorship will 
follow ICMJE recommendations.  
Clarifying edits
Section 8.0 References
Updated to reflect new references throughout 
the protocol.
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
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Appendix 3 Known Strong in Vivo Inhibitors 
and Inducers of CYP3A4:  Replaced table
Replaced with current FDA list of strong 
CYP3A inhibitors/inducers
Appendix 4:  Dexamethasone Prescribing 
Information:  Added new appendix.  
The United States label for dexamethasone 
tablets (Roxane Laboratories 2007) is 
provided for reference.  The United States 
label will also serve as the Reference Safety 
Information for dexamethasone for this study.  
Country-specific labels will be provided to 
investigative sites as appropriate
Appendix 5: Schedule of Assessments:
Revised throughout, including deletion of 
bone marrow requirement at Cycle 2
Schedule updated to reflect changes as 
described above, including deletion of long-
term follow-up visit.  Bone marrow 
assessments were corrected to match the 
existing text (ie, required only at screening 
and as clinically indicated/to confirm a CR).
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
TABLE OF CONTENTS
1.0 
BACKGROUND INFORMATION.....................................................................23 
1.1 
Role of Btk in Lymphoid Cancers .....................................................................23 
1.2 
Preclinical Studies .............................................................................................24 
1.2.1 
Chemistry ............................................................................................24 
1.2.2 
Efficacy Pharmacology .......................................................................25 
1.2.3 
ACP-196 and Thrombus Formation ...................................................26 
1.2.4 
Safety Pharmacology..........................................................................27 
1.2.5 
Drug-drug Interaction Potential ..........................................................28 
1.2.6 
In Vivo General Toxicology.................................................................29 
1.3 
Clinical Experience............................................................................................29 
1.3.1 
Pharmacokinetics and Pharmacodynamics of ACP-196 in Healthy 
Volunteers ...........................................................................................31 
1.3.2 
Clinical Experience of ACP-196 in CLL .............................................33 
1.4 
Benefit/Risk........................................................................................................37 
1.5 
Summary and Conclusions...............................................................................37 
2.0 
STUDY OBJECTIVES......................................................................................38 
2.1 
Primary Objective ..............................................................................................38 
2.2 
Secondary Objectives: ......................................................................................38 
3.0 
STUDY DESIGN...............................................................................................38 
3.1 
Description of Study ..........................................................................................38 
3.2 
Study Parameters..............................................................................................39 
3.2.1 
Safety Parameters ..............................................................................39 
3.2.2 
Efficacy Parameters............................................................................39 
3.2.3 
Pharmacokinetic and Pharmacodynamic Parameters......................40 
3.3 
Rationale for Study Design and Dosing Regimen...........................................40 
3.4 
Selection of Study Population...........................................................................41 
3.4.1 
Inclusion Criteria .................................................................................41 
3.4.2 
Exclusion Criteria ................................................................................41 
3.4.3 
Replacement of Subjects....................................................................43 
3.4.4 
Enrollment and Randomization Procedures ......................................43 
3.5 
Study Drug.........................................................................................................43 
3.5.1 
Premedications....................................................................................43 
3.5.2 
Formulation, Packaging, and Storage ...............................................43 
3.5.2.1 
ACP-196...............................................................................43 
3.5.2.2 
Dexamethasone...................................................................44 
3.5.3 
Administration of Study Drug..............................................................44 
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
3.5.3.1 
ACP-196...............................................................................44 
3.5.3.2 
Dexamethasone...................................................................45 
3.5.4 
Assuring Subject Compliance ............................................................45 
3.5.5 
Study Treatment Regimen and Dose Modifications..........................45 
3.5.5.1 
ACP-196...............................................................................45 
3.5.5.2 
Dexamethasone...................................................................47 
3.6 
Concomitant Therapy........................................................................................47 
3.6.1 
Permitted Concomitant Therapy ........................................................47 
3.6.2 
Guideline for Use of CYP Inhibiting/Inducing Drugs .........................47 
3.6.3 
Guideline for Use of Drugs that Affect Gastric pH.............................47 
3.6.4 
Prohibited Concomitant Therapy........................................................48 
3.7 
Precautions........................................................................................................48 
3.7.1 
Dietary Restrictions.............................................................................48 
3.7.2 
Surgery ................................................................................................48 
3.7.3 
Infections .............................................................................................48 
3.7.4 
Reproductive Toxicity..........................................................................48 
3.7.5 
Overdose Instructions .........................................................................49 
3.8 
Stopping Rules ..................................................................................................49 
3.9 
Data and Safety Monitoring ..............................................................................50 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS...................................................51 
4.1 
Description of Procedures ................................................................................51 
4.1.1 
Informed Consent................................................................................51 
4.1.2 
Medical History....................................................................................51 
4.1.3 
Adverse Events ...................................................................................51 
4.1.4 
Concomitant Medications and Therapy .............................................52 
4.1.5 
Confirmation of Eligibility ....................................................................52 
4.1.6 
ECOG Performance Status ................................................................52 
4.1.7 
Physical Examination, Vital Signs, Height & Weight.........................52 
4.1.8 
Bone Marrow Aspirate and Biopsy.....................................................52 
4.1.9 
Electrocardiogram ...............................................................................53 
4.1.10 
Urine Pregnancy Test .........................................................................53 
4.1.11 
Hematology .........................................................................................53 
4.1.12 
Serum Chemistry ................................................................................53 
4.1.13 
Urinalysis .............................................................................................53 
4.1.14 
T/B/NK Cell Count...............................................................................53 
4.1.15 
Disease Markers .................................................................................53 
4.1.16 
Skeletal Survey ...................................................................................54 
4.1.17 
Pharmacodynamics ............................................................................54 
4.1.18 
Pharmacokinetics................................................................................54 
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
4.1.19 
Tumor Assessment.............................................................................54 
4.1.20 
Study Drug Accountability ..................................................................55 
4.2 
Investigator’s Assessment of Response to Treatment....................................55 
4.3 
Early Termination/Safety Follow-up Visit .........................................................57 
4.4 
Missed Evaluations ...........................................................................................57 
5.0 
STATISTICAL METHODS OF ANALYSIS .....................................................58 
5.1 
General Considerations ....................................................................................58 
5.2 
Sample Size Considerations.............................................................................58 
5.3 
Definition of Analysis Populations ....................................................................58 
5.4 
Missing Data Handling ......................................................................................59 
5.5 
Endpoint Data Analysis.....................................................................................59 
5.5.1 
Safety Endpoint...................................................................................59 
5.5.2 
Demographics and Baseline Characteristics.....................................59 
5.5.3 
Analysis of Efficacy Parameters.........................................................59 
5.5.3.1 
Overall Response Rate .......................................................59 
5.5.3.2 
Duration of Response..........................................................60 
5.5.3.3 
Clinical Benefit Rate ............................................................60 
5.5.3.4 
Disease Control Rate ..........................................................60 
5.5.3.5 
Progression-free Survival ....................................................60 
5.5.4 
Analysis of Pharmacokinetic/Pharmacodynamic Parameters ..........61 
5.5.5 
Exploratory or Correlative Analyses...................................................61 
6.0 
ASSESSMENT OF SAFETY............................................................................62 
6.1 
Definitions ..........................................................................................................62 
6.1.1 
Adverse Events ...................................................................................62 
6.1.2 
Serious Adverse Event .......................................................................62 
6.1.3 
Severity................................................................................................63 
6.2 
Documenting and Reporting of Adverse and Serious Adverse Events..........64 
6.2.1 
Adverse Event Reporting Period........................................................64 
6.2.2 
Assessment of Adverse Events .........................................................64 
6.2.3 
Pregnancy ...........................................................................................64 
6.2.4 
Expedited Reporting Requirements for Serious Adverse Events.....65 
6.2.5 
Type and Duration of Follow-up of Subjects After Adverse Events .66 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS............66 
7.1 
Regulatory and Ethical Compliance .................................................................66 
7.2 
Institutional Review Board and Independent Ethics Committee.....................67 
7.3 
Informed Consent and Protected Subject Health Information Authorization .67 
7.4 
Subject Screening Log......................................................................................68 
7.5 
Case Report Forms...........................................................................................68 
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
7.6 
Study Monitoring Requirements .......................................................................68 
7.7 
Investigational Study Drug Accountability........................................................69 
7.8 
Record Retention ..............................................................................................70 
7.9 
Protocol Amendments.......................................................................................70 
7.10 
Publication of Study Results .............................................................................71 
7.11 
Clinical Trial Insurance......................................................................................71 
7.12 
General Investigator Responsibilities...............................................................71 
8.0 
REFERENCES..................................................................................................73 
9.0 
APPENDICES ...................................................................................................75 
IN–TEXT TABLES
Table 1-1.  Assessment of ACP-196 Active-site Occupancy in  Fine Needle Aspirates of 
Canine Lymph Node Tumors (N=4).....................................................................25 
Table 1-2.  ACP-196 Clinical Studies as of January 2015............................................30 
Table 1-3.  Btk Occupancy in Peripheral Blood of Subjects from ACE-CL-001 (December 
2014)..................................................................................................................34 
Table 1-4.  Preliminary Day 8 PK Results from ACE-CL-001 (October 2014)...............34 
Table 1-5.  Best Response by Cohort from ACE-CL-001 (23OCT2014).......................35 
Table 3-1.  Drug Discontinuation Actions for ACP-196 ................................................46 
Table 4-1.  Pharmacokinetic Sample Schedule...........................................................54 
IN–TEXT FIGURES
Figure 1-1.  Effect of ACP-196 (1 ȝM) and Ibrutinib (1 ȝM) on Thrombus Formation .... 27 
Figure 1-2.  Kaplan-Meier Curves for Progression-free Survival by Investigator 
Assessment for ACE-CL-001 (N=75; excludes Richter’s Syndrome Cohort and 
Ibrutinib R/R Cohort)...........................................................................................35 
Figure 1-3.  Median (95% CI) Change from Baseline in ALC/SPD Over Time ..............37 
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
ABBREVIATIONS
AE(s)
adverse event(s)
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the curve
BCR
B-cell receptor
BID
twice a day (dosing)
Btk
Bruton tyrosine kinase
BUN
blood urea nitrogen
CBC
complete blood count
CFR
Code of Federal Regulations
cGMP
current Good Manufacturing Practices
CLL
chronic lymphocytic leukemia
Cmax
maximum concentration
CR
complete remission (response)
CSSF
Clinical Supplies Shipping Receipt Form
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EGFR
epidermal growth factor receptor
FDA
Food and Drug Administration
FIH
first-in-human (trial)
FLC
(serum) free light chains
GCP
Good Clinical Practice
GLP
Good Laboratory Practices
HBV
hepatitis B virus
HCV
hepatitis C virus
hERG
human ether-à-go-go-related gene
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
HIV
human immunodeficiency virus
HNSTD
highest nonseverely toxic dose
ICF
informed consent form
IEC
Independent Ethics Committee
IFE
immunofixation electrophoresis
Ig
immunoglobulin
IRB
Institutional Review Board
LDH
lactate dehydrogenase
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MM
multiple myeloma
MR
minimal response
NHL
non-Hodgkin lymphoma
NK
natural killer (cells)
ORR
overall response rate
PBMC(s)
peripheral blood mononuclear cells
PD
pharmacodynamics
PI3K
phosphoinositide-3 kinase
PK
pharmacokinetics
PR
partial remission (response)
QD
once a day (dosing)
QTc
corrected QT interval
SAE(s)
serious adverse event(s)
SD
stable disease
SFLC
serum free light chains
SIFE
serum immunofixation electrophoresis
SPD
sum of the products of the perpendicular diameters (of lymph nodes)
SPEP
serum protein electrophoresis
SUSAR
Suspected Unexpected Serious Adverse Reaction (report)
Tmax
time to maximum drug concentration
UIFE
urine immunofixation electrophoresis
ULN
upper limit of normal
UPEP
urine serum protein electrophoresis
VGPR
very good partial response 
WHO
World Health Organization
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
STUDY SYNOPSIS
Protocol Number:
ACE-MY-001
Study Drug:
ACP-196
Protocol Title:
An Open-label, Phase 1b Study of ACP-196 in Subjects with
Multiple Myeloma
Phase:
Phase 1b
Comparator:
None
Background and 
Rationale for Study
Clinical studies have shown that targeting the B-cell receptor 
(BCR) signaling pathway by inhibiting Bruton tyrosine kinase (Btk) 
produces significant clinical benefit in patients with non-Hodgkin 
lymphoma (NHL) and chronic lymphocytic leukemia (CLL).
Preclinical studies have shown that Btk inhibition significantly 
reduces in vivo multiple myeloma (MM) cell growth and MM cell-
induced osteolysis in a murine model (Tai 2012).  Data on the 
utility of Btk targeted therapy in patients with MM is very 
preliminary, but suggests there are subsets of patients with
malignant plasma cell clones in which Btk is active as evidenced 
by expression of phosphorylated Btk (p-Btk), and that these 
cancers may be particularly responsive to Btk inhibitor therapy.
Acerta Pharma BV (Acerta Pharma) has developed a novel second 
generation Btk inhibitor, ACP-196, that achieves significant oral 
bioavailability and potency in preclinical models. ACP-196
monotherapy is currently in multiple Phase 1/2 studiesin subjects 
with chronic lymphocytic leukemia (CLL) and other indications.
The purpose of this study is to evaluate the safety, 
pharmacokinetics (PK), pharmacodynamics (PD), and activity of 
ACP-196 administration with and without dexamethasone in
subjects with relapsed MM. The study will explore the concept of 
whether biomarkers may help identify patients with MM that are 
particularly likely to benefit from Btk inhibitor therapy.
Study Design:
This study is a multicenter, open-label, randomized, parallel-group 
study to be conducted at approximately 20 sites in 2 countries 
(United Kingdom and United States).  Forty subjects will be equally 
randomized (1:1 ratio) into 2 cohorts to receive ACP-196, with and
without dexamethasone:
x
Cohort 1: ACP-196 100 mg twice per day (BID) continuously
x
Cohort 2: ACP-196 100 mg BID continuously and
dexamethasone 40 mg once weekly 
Twenty-eight days of study drug administration is 1 cycle.  
Treatment may be continued for > 28 days until disease 
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
progression or an unacceptable drug-related toxicity occurs. For 
subjects in Cohort 1, if documented disease progression occurs, 
then dexamethasone can be added to the treatment regimen.  
Additional dose modification provisions are provided in the study 
protocol.  Note: temporary withholding of study drug for as little as 
7 days can cause a transient worsening of disease and/or of 
constitutional symptoms.  Refer to Section 3.8 for more information 
on assessing disease progression under these circumstances.  All 
subjects who discontinue study drug will have a safety follow-up
visit 30 (±7) days after the last dose of study drug unless they have 
started another cancer therapy within that timeframe. 
All subjects will have hematology, chemistry, and urinalysis safety 
panels done at screening.  Once dosing commences (Day 1), all 
subjects will be evaluated for safety, including serum chemistry 
and hematology, once weekly for the first 4 weeks, every 2 weeks 
in Cycle 2 and monthly thereafter.  PK/PD testing will be done in 
Cycle 1 and Cycle 2. Tumor assessments will be done at 8- to 12-
week intervals during the trial.
Refer to Appendix 5 for a comprehensive list of study assessments 
and their timing. The end of trial is defined as the point when the 
last subject on the study exits the study for any reason.
Study Objectives:
Primary Objective:
x
To characterize the safety profile of ACP-196 with and without 
dexamethasone in subjects with relapsed or refractory MM
Secondary Objectives:
x
To characterize the PK profile of ACP-196 with and without 
dexamethasone and the PK profile of dexamethasone with 
concomitant ACP-196 administration
x
To evaluate the PD effects of ACP-196 with and without 
dexamethasone
x
To evaluate the activity of ACP-196 with and without 
dexamethasone as measured by overall response rate,
duration of response, clinical benefit rate, disease control rate,
and progression-free survival
x
To explore the relationship between biological markers in MM 
cells and response to therapy
Safety Parameters:
Type, frequency, severity, timing of onset, duration, and 
relationship to study drug (ie, ACP-196, dexamethasone, or both)
of any adverse events (AEs) or abnormalities of laboratory tests; 
serious adverse events (SAEs); or AEs leading to discontinuation 
of study treatment.
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Efficacy Parameters:
x
Overall response rate (ORR)
x
Duration of response
x
Clinical benefit rate
x
Disease control rate
x
Progression-free survival
Pharmacokinetic 
Parameters:
The plasma PK of ACP-196 will be characterized using 
noncompartmental analysis. The following PK parameters will be 
calculated, whenever possible, from plasma concentrations of 
analytes:
x
AUC0-t:  Area under the plasma concentration-time curve 
calculated using linear trapezoidal summation from time 0 to 
time t, where t is the time of the last measurable concentration 
(Ct).
x
AUC0-12:  Area under the plasma concentration-time curve from 
0 to 12 hours, calculated using linear trapezoidal summation.
x
AUC0-:  Area under the plasma concentration-time curve from 
0 to infinity, calculated using the formula: AUC0- = AUC0-t + 
Ct / ȜzZKHUHȜz is the apparent terminal elimination rate 
constant.
x
AUC0-24calc: Area under the plasma concentration-time curve 
from 0 to 24 hours, calculated by doubling the value for 
AUC0-12.
x
Cmax:  Maximum observed plasma concentration
x
Tmax:  Time of the maximum plasma concentration (obtained 
without interpolation)
x
t½:  Terminal elimination half-life (whenever possible)
x
Ȝz: Terminal elimination rate constant (whenever possible)
x
CL/F:  Oral clearance
Pharmacodynamic 
Parameters:
The occupancy of Btk by ACP-196 will be measured in peripheral 
blood mononuclear cells (PBMCs) and in bone marrow, when 
available, with the aid of a biotin-tagged ACP-196 analogue probe.  
The effect of ACP-196 on biologic markers of B-cell function will 
also be evaluated.
Sample Size:
Forty subjects with 20 subjects in each cohort.
Inclusion Criteria:
x
0HQDQGZRPHQ\HDUVRIDJH.
x
A confirmed diagnosis of MM, which has relapsed after, or 
been refractory to  1 prior therapy for MM, and is progressing 
at the time of study entry.
x
Evaluable myeloma at screening, defined as the presence of at 
least one of the following:
o
Serum M-SURWHLQ 0.5 g/dL
o
Urine M-SURWHLQ 200 mg/24 hours
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
o
In subjects without detectable serum or urine M-protein, 
serum free light chain (SFLC) > 100 mg/L (involved light 
chain) and an abnormal serum kappa/lambda ratio
o
For subjects whose disease can only be reliably measured 
by serum quantitative immunoglobulin A (IgA), IgA 
 750 mg/dL (0.75 g/dL) 
x
Eastern Cooperative Oncology Group (ECOG) performance 
status of  2.
x
Agreement to use acceptable methods of contraception during 
the study and for 30 days after the last dose of study drug if 
sexually active and able to bear or beget children.
x
Agreement to refrain from sperm donation during the study and 
for 30 days after the last dose of study drug.
x
Willing and able to participate in all required evaluations and 
procedures in this study protocol including swallowing capsules 
without difficulty.
x
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 subject privacy regulations).
Exclusion Criteria:
x
Plasma cell leukemia or circulating plasma cells  2 x 109/L
x
Prior malignancy, except for adequately treated basal cell or 
squamous cell skin cancer, in situ cervical cancer, or other 
cancer from which the subject has been disease free for 
 2 years or which will not limit survival to < 2 years. Note: 
these cases must be discussed with the Medical Monitor.
x
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 ACP-196, or put the study outcomes at undue 
risk.
x
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.
x
Malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or small 
bowel, gastric bypass, symptomatic inflammatory bowel 
disease, or partial or complete bowel obstruction.
x
Any immunotherapy within 4 weeks of first dose of study drug.
x
The time from the last dose of the most recent chemotherapy 
or experimental therapy to the first dose of study drug is 
< 5 times the half-life of the previously administered agent(s).
x
Prior exposure to a B-cell receptor (BCR) inhibitor (eg, Btk,
phosphoinositide-3 kinase [PI3K], or Syk inhibitors) or BCL-2
inhibitors (eg, ABT-199).
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
x
Ongoing immunosuppressive therapy, including systemic or 
enteric corticosteroids for treatment of MM or other conditions. 
Note: Subjects may use topical or inhaled corticosteroids as 
therapy for comorbid conditions. During study participation, 
subjects may receive systemic or enteric corticosteroids as 
needed for MM therapy or treatment-emergent comorbid 
conditions.
x
*UDGHWR[LFLW\RWKHUWKDQDORSHFLD) continuing from prior 
anticancer therapy including radiation.
x
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.
x
Major surgery within 4 weeks before first dose of ACP-196.
x
Known history of a bleeding diathesis (eg, hemophilia, von 
Willebrand disease)
x
History of stroke or intracranial hemorrhage within 6 months 
before the first dose of ACP-196.
x
Requires or receiving anti-coagulation with warfarin or 
equivalent vitamin K antagonist (eg, phenprocoumon) within 
28 days of first dose of study drug.
x
Requires treatment with long-acting proton pump inhibitors (eg, 
omeprazole, esomeprazole, lansoprazole, dexlansoprazole, 
rabeprazole, or pantoprazole)
x
ANC < 0.75 x 109/L or platelet count < 50 x 109/L.  For subjects 
with > 50% plasma cells in the marrow, ANC < 0.50 x 109/L or 
platelet count < 30 x 109/L.
x
Creatinine > 2.5 x institutional upper limit of normal (ULN); total 
bilirubin > 2.5 x ULN; or aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) > 3.0 x ULN.
x
Breastfeeding or pregnant.
x
Concurrent participation in another therapeutic clinical trial.
Dosage Form and 
Strength:
ACP-196 is provided as 100-mg hard gelatin capsules prepared 
using standard pharmaceutical grade excipients. 
Dose Regimen/Route 
of Administration:
ACP-196 is an orally administered product.  ACP-196 can be
administered with or without food.
Regimens:
x
Cohort 1 (BID): 100 mg ACP-196 (1 x 100-mg capsule)
administered 12 hours apart (BID dosing = 200-mg total daily 
dose)
x
Cohort 2 (BID + dexamethasone): 100 mg ACP-196
(1 x 100-mg capsule) administered 12 hours apart (BID dosing 
= 200-mg total daily dose) plus 40 mg dexamethasone
administered once weekly (weekly dosing = 40-mg total weekly 
dose)
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Concomitant 
Medications:
The effect of agents that reduce gastric acidity (eg, proton pump 
inhibitors, H2-receptor antagonists, or antacids) on ACP-196
absorption is currently being evaluated in a healthy volunteer study 
(ACE-HV-004). Preliminary results from this study suggest 
subjects should avoid the use of calcium carbonate containing 
drugs or supplements (eg, antacids or calcium supplements) and 
short-acting H2-receptor antagonistsfor a period of at least 
2 hours before and after taking ACP-196.  Use of omeprazole or 
esomeprazole or any other long-acting proton pump inhibitors 
while taking ACP-196 is not permitted due to a potential decrease 
in study drug exposure; however, if a subject requires treatment 
with a long-acting proton pump inhibitor while on study (eg, to treat 
an ulcer), treatment options should be discussed with the Medical 
Monitor.
Concomitant use of strong inhibitors/inducers of CYP3A should be 
avoided when possible.  If a subject requires a strong CYP3A 
inhibitor while on study, monitor the subject closely for potential 
toxicities.
Statistics:
Subjects meeting the stated eligibility requirements will be enrolled 
onto the study. Subjects will be randomized in a 1:1 ratio into the
2 regimens (ACP-196 with and without dexamethasone). With a 
sample size of 19 subjects per cohort, the power to detect the 
difference between a null-hypothesis response rate of 15% and an 
alternative response rate of 40% with a 0.025 one-sided 
significance level is 0.69 using a one-group, exact binomial test.  A
sample size of 19 subjects per cohort will also provide a 97.5%
one-sided confidence interval centered around an expected ORR 
of 40% that excludes an ORR of 18.6% as a lower bound.
Descriptive statistics (including means, standard deviations, and 
medians for continuous variables and proportions for discrete 
variables) will be used to summarize data, as appropriate.
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
1.0
BACKGROUND INFORMATION
1.1
ROLE OF BTK IN LYMPHOID CANCERS
Bruton tyrosine kinase (Btk) is a non-receptor enzyme of the Tec kinase family that is 
expressed among cells of hematopoietic origin, including B cells, myeloid cells, mast 
cells and platelets, where it regulates multiple cellular processes including proliferation, 
differentiation, apoptosis, and cell migration (Mohamed 2009, Bradshaw 2010).
Functional null mutations of Btk in humans cause the inherited disease, X-linked 
agammaglobulinemia, which is characterized by a lack of mature peripheral B cells 
(Vihinen 2000). Conversely, Btk activation is implicated in the pathogenesis of several 
B-cell malignancies (Buggy 2012). Taken together, these findings have suggested that 
inhibition of Btk may offer an attractive strategy for treating B-cell neoplasms.
Ibrutinib (IMBRUVICA™), a first-generation oral, small-molecule Btk inhibitor has been 
approved for the treatment for chronic lymphocytic leukemia (CLL) and mantle cell 
lymphoma (MCL) and is being evaluated for activity in other B-cell neoplasms including 
multiple myeloma (MM). Preclinical studies have shown that Btk inhibition with ibrutinib 
significantly reduces in vivo multiple myeloma (MM) cell growth and MM cell-induced 
osteolysis in a murine model (Tai 2012).  
While current therapies have provided substantial benefit to patients, MM remains 
incurable; for patients who experience disease relapse after application of existing 
therapies, the prognosis is dismal and new drugs and therapeutic strategies are required 
for continued disease control (Romano 2014). Inhibition of Btk may simultaneously 
address the MM-related bone complications as well improve patient outcome in MM 
(Edwards 2012).
While highly potent in inhibiting Btk, ibrutinib has also shown in vitro activity against 
other kinases with a cysteine in the same position as Cys481 in Btk to which the drug 
covalently binds.  The inhibition of epidermal growth factor receptor (EGFR) is also 
observed in cellular assays and may be the cause of ibrutinib-related adverse events 
(AEs) of diarrhea and rash (IMBRUVICA® package insert). In addition, ibrutinib is a 
substrate for CYP3A4; inhibition of CYP3A causes a 29-fold increase in maximum 
concentration (Cmax) and 24-fold increase in area under the curve (AUC) for ibrutinib 
(IMBRUVICA® package insert).  This increases the possibility of drug-drug interactions 
in combination therapies with drugs currently used in management of subjects with 
Acerta Pharma
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Page 23 of 87


Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
cancer. These liabilities support the development of alternative Btk inhibitors for use in 
the therapy of B-cell malignancies.
Chemical optimization, pharmacologic characterization, and toxicologic evaluation have 
led to identification of ACP-196, an orally bioavailable, new chemical entity that 
covalently inhibits Btk and shows encouraging activity and acceptable safety in 
nonclinical studies. Within the class of Btk inhibitors, ACP-196 is a more selective 
inhibitor of Btk than ibrutinib.  Key nonclinical differentiators of ACP-196 versus ibrutinib 
are:
x
ACP-196 has been evaluated against ibrutinib in EGFR expressing cell lines.  
Ibrutinib is a potent covalent inhibitor of EGFR (EC50 = 50 to 70 nM).  ACP-196
GRHVQRWLQKLELW(*)5HYHQDWWKHKLJKHVWFRQFHQWUDWLRQWHVWHGȝ0
x
ACP-196 has been evaluated against ibrutinib in in vitro antibody-dependent cell-
mediated cytotoxicity (ADCC) assays.  At physiologic concentrations, ibrutinib, 
but not ACP-196, reduced natural killer (NK) cell-mediated lysis of Raji and 
autologous CLL tumor cells and significantly inhibited rituximab-induced NK cell 
cytokine secretion (P<0.05). 
x
ACP-196 has been evaluated against ibrutinib in an in vivo thrombus formation 
model.  At physiologic concentrations, ibrutinib, but not ACP-196, significantly 
inhibited thrombus formation (P=0.001). 
The nonclinical and toxicology results of ACP-196 suggest it may have an improved 
therapeutic window relative to ibrutinib; it may be more readily combined with other 
agents for the treatment of cancer.  
1.2
PRECLINICAL STUDIES
Summaries of preclinical studies are provided below. For more detailed information 
please refer to the Investigator’s Brochure.  
1.2.1
Chemistry
 ACP-196 is 
orally bioavailable in humans and is suitable for formulating in capsules. For clinical 
testing, ACP-196 has been manufactured and formulated according to current Good 
Manufacturing Practices (cGMP).
Acerta Pharma
Confidential
Page 24 of 87


Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
1.2.2
Efficacy Pharmacology
Spontaneous canine B-cell lymphoma shares many characteristics with human NHL, 
including diagnostic classifications and response to Btk inhibition (Honigberg 2010). The 
life expectancy in untreated animals with aggressive disease is ~6 weeks, thus enabling 
rapid assessment of drug efficacy (Vail 2004). ACP-196 is currently being evaluated in 
an ongoing dose-escalation study in canine spontaneous B-cell lymphoma.  Fourteen 
dogs, all of which had diffuse large B-cell lymphoma (DLBCL) confirmed by histology,
have been treated with ACP-196 for at least 2 weeks. The dosages have ranged from 
2.5 to 20 mg/kg once (QD) or twice (BID) per day.  To date, per Veterinary Cooperative 
Oncology Group criteria for assessment of response in peripheral nodal lymphoma 
(Vail 2010), partial responses (PRs) been observed in 4 of 14 dogs (29%) and stable 
disease has been observed in 8 of 14 dogs (57%).  No ACP-196-related adverse events 
(AEs) have been reported to date in this study.  These findings are preliminary and 
similar to the clinical responses (ie, 1 dog with PR out of 5 dogs treated with suspected 
or confirmed DLBCL) observed with ibrutinib in dogs with spontaneous B-cell lymphoma 
(Honigberg 2010).
Preliminary results assessing Btk occupancy using a biotin-tagged analogue of ACP-196 
show near complete Btk occupancy over 24 hours with both BID and QD dosing in 
canine tumor tissue (Table 1-1).
Table 1-1.  Assessment of ACP-196 Active-site Occupancy in 
Fine Needle Aspirates of Canine Lymph Node Tumors (N=4)
Timing
Dog Identification and ACP-196 Dosing Regimen
DL-10
DL-12
DL-14
DL-16
5 mg/kg BID
10 mg/kg QD
20 mg/kg QD
20 mg/kg QD
Btk Occupancy (% versus predose)
Day 1 (3 hours 
after morning 
dose)
98%
99%
98%
99%
Day 7 (before 
morning dose)
80%
98%
77
93%
BID = twice per day; Btk = Bruton tyrosine kinase; QD = once per day
These canine data provide nonclinical support for the ability of ACP-196 to target Btk in 
vivo. The role of Btk expression in driving the proliferation and survival of malignant 
plasma cells in multiple myeloma (MM) has been less clear than among other lymphoid 
cancers. However, emerging, unpublished, preclinical data from the laboratory of Sagar 
Lonial (Emory University) suggest that Btk and phosphorylated Btk (p-Btk) expression is 
Acerta Pharma
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Page 25 of 87


Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
present to varying levels in a standard panel of 12 myeloma cell lines, thus providing a 
basis for evaluating Btk inhibition as a therapy for MM.
1.2.3
ACP-196 and Thrombus Formation
Ibrutinib is associated with an increased risk of bleeding (Kamel 2014). Hence, the 
effects of ACP-196 and ibrutinib were evaluated on human platelet-mediated thrombosis 
by using the in vivo human thrombus formation in a VWFHA1 murine model, which has 
been previously described (Chen 2008). Purified human platelets were preincubated 
with various concentrations of ibrutinib and ACP-196 (0.1 μM, 0.5 μM, or 1 μM for each) 
or DMSO and then administered to VWFHA1 mice followed by laser-induced thrombus 
formation.  Ibrutinib- and ACP-196-treated human platelets were fluorescently labeled 
and infused continuously through a catheter inserted into the femoral artery. Thrombus 
formation in response to laser-induced vascular injury was monitored in real time using 
2-channel confocal intravital microscopy (Furie 2005) (Figure 1-1). Upon induction of 
arteriole injury, untreated platelets rapidly formed thrombi with a mean (± SEM) 
thrombus size of 6450 ± 292 mm2. Similarly, ACP-ȝ0WUHDWHGSODWHOHWVIRUPHG
slightly smaller but not significantly different thrombi, with a mean thrombus size of 
5733 ± 393 mm2. In contrast, a significant reduction in thrombus size occurred in 
SODWHOHWVSUHWUHDWHGZLWKLEUXWLQLEȝ0; mean thrombus size was 2600 ± 246 mm2,
representing in a reduction in maximal thrombus size by approximately 61% compared 
with control (P=0.001). Similar results were obtained with platelets pretreated with 
500 nM of ACP-196 or ibrutinib: mean thrombus sizes were 5946 ± 283 mm2 and
2710 ± 325 mm2, respectively. These preliminary results showing reduced thrombus 
formation for ibrutinib at physiologically relevant concentrations (0.5 to 1 ȝM) may 
provide some mechanistic background for the Grade  3 bleeding events (eg, subdural 
hematoma, gastrointestinal bleeding, hematuria, and post procedural hemorrhage) that 
have been reported in  6% of patients treated with ibrutinib. In addition, bleeding events 
of any grade, including bruising and petechiae, were reported in approximately half of 
patients treated with ibrutinib (IMBRUVICA® package insert).
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Page 26 of 87


Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Figure 1-1. Effect of ACP-196 (1 ȝM) and Ibrutinib (1 ȝM) on Thrombus Formation
1.2.4
Safety Pharmacology
In vitro and in vivo safety pharmacology studies with ACP-196 have demonstrated a 
favorable nonclinical safety profile. 
:KHQVFUHHQHGDWȝ0LQELQGLQJDVVD\VHYDOXDWLQJLQWHUDFWLRQVZLWKNQRZQ
pharmacologic targets such as G-protein-coupled receptors, nuclear receptors, 
proteases, and ion channels, ACP-196 shows significant activity only against the 
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Page 27 of 87


Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
A3 adenosine receptor; follow-up dose-response experiments indicated a IC50 of 2.7 μM, 
suggesting a low clinical risk of off-target effects.  ACP-DWȝ0VKRZHGQR
inhibition of in vitro epidermal growth factor receptor (EGFR) phosphorylation in an A431 
human epidermoid cancer cell line, whereas ibrutinib had an IC50 of 66 nM. 
The in vitro effect of ACP-196 on human ether-à-go-go-related gene (hERG) channel 
activity was investigated in vitro in human embryonic kidney cells stably transfected with 
hERG. ACP-196 inhibited hERG channel activity by 25% at 10 ȝ0VXJJHVWLQJDORZ
clinical risk that ACP-196 would induce clinical QT prolongation as predicted by this 
assay.
ACP-196 was well tolerated in standard in vivo Good Laboratory Practices (GLP) studies 
of pharmacologic safety. A functional observation battery in rats at doses of through 
300 mg/kg (the highest dose level) revealed no adverse effects on neurobehavioral 
effects or body temperature at any dose level. A study of respiratory function in rats also 
indicated no treatment-related adverse effects at doses through 300 mg/kg (the highest 
dose level). In a cardiovascular function study in awake telemeterized male beagle dogs, 
single doses of ACP-196 at dose levels through 30 mg/kg (the highest dose level) 
induced no meaningful changes in body temperature, cardiovascular, or 
electrocardiographic (ECG) (including QT interval) parameters.  The results suggest that 
ACP-196 is unlikely to cause serious off-target effects or adverse effects on critical 
organ systems.
1.2.5
Drug-drug Interaction Potential
The in vitro studies suggest CYP-mediated metabolism of ACP-196 appears to be 
catalyzed predominantly by CYP3A4/5.  However, in elimination studies in preclinical 
species, the metabolic fate of ACP-196 is dominated by direct conjugation of ACP-196
with glutathione, providing evidence for a significant non-CYP mechanism of elimination.  
In a healthy volunteer study (ACE-HV-001), the effect of coadministration of a potent 
CYP3A and P-gP inhibitor, itraconazole, on the plasma levels of ACP-196 was 
evaluated.  The mean plasma ACP-196 Cmax and AUC0-last values increased 3.7- and 
5.1-fold, respectively, in the presence of itraconazole relative to no pretreatment.  In vitro 
studies also show that ACP-196 is a substrate for P-gp.  
ACP-196 is unlikely to be a perpetrator of a drug-drug interaction at the level of inhibition 
or induction of CYP isoforms.
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Results from drug transporter studies suggest that ACP-196 is not anticipated to alter 
the PK of other therapeutic agents that are substrates for MDR1, OATP1B1, OATP1B3, 
OAT1, OAT3, and OCT2.  ACP-196 (100 mg BID) may alter the PK of BCRP substrates 
by inhibition of intestinal BCRP.
1.2.6
In Vivo General Toxicology
To date, the toxicology program has included 28-day GLP evaluations in rats and dogs. 
In the 28-day study in male and female Sprague-Dawley rats, animals received oral 
gavage ACP-196 dosages of 30, 100, and 300 mg/kg/day. In the 28-day study in male 
and female beagle dogs, animals received oral ACP-196 dosages of 3, 10, and 
30 mg/kg/day. Both studies had 28-day recovery periods.
The no observable adverse effect level in the dog was 30 mg/kg/day, which was the 
highest dose evaluated. In rats, 30 mg/kg/day resulted in minimal inflammation of the 
pancreas in some animals, with reversal, indicating the rat to be the more sensitive 
preclinical species. The pancreatic effects were minimally increased at 100 mg/kg/day in 
the rat though there was no clinical evidence of toxicity. Hence, 100 mg/kg/day was 
selected to conservatively represent the highest nonseverely toxic dose (HNSTD).  In 
dogs at 30 mg/kg/day, no adverse effects on the pancreas were observed.  In rats and 
dogs, no adverse ECG or histopathologic cardiovascular effects were noted at the 
planned conclusion of the 28-day toxicology studies. However, in 5 of 6 rats from the 
300-mg/kg dose group that died early in the study, slight to moderate necrosis of the 
myocardium and/or white blood cell infiltration/inflammation of the myocardium were 
noted on microscopic examination of the hearts. These findings were most likely 
incidental postmortem changes.
1.3
CLINICAL EXPERIENCE
Table 1-2 lists the studies currently being conducted with ACP-196 monotherapy.  
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Table 1-2.  ACP-196 Clinical Studies as of January 2015
Protocol
Design
Subjects 
Enrolled
Status
ACE-CL-001
(NCT02029443)
x
First-in-human
x
Open label
x
Dose escalation (ACP-196 100-
400 mg QD and 100-200 mg BID)
x
Subjects w ith relapsed/refractory CLL
x
Expansion cohorts:
o treatment-naive subjects
o subjects w ith Richter’s syndrome
o subjects w ho are intolerant to 
ibrutinib treatment
o subjects w ho are 
relapsed/refractory to ibrutinib 
treatment
125
x
Cohort 1 (100 mg QD) 
enrolled and no DLTs 
observed.  
x
Cohort 2a (175 mg QD) 
enrolled and no DLTs 
observed.
x
Cohort 3 (250 mg QD) 
enrolled and no DLTs 
observed.
x
Cohort 4a (400 mg QD) 
enrolled and no DLTs 
observed.
x
Cohort 2b (100 mg BID 
now  enrolling) and no 
DLTs observed.
x
Expansion cohorts now  
enrolling.
ACE-HV-001
x
Open label
x
Single-dose escalation
(ACP-196 2.5-50 mg BID and 100 mg 
QD)
x
Food effect (ACP-196 75 mg QD)
x
Drug-drug interaction w ith 
itraconazole (ACP-196 50 mg QD)
x
Healthy volunteers
59
x
Enrollment completed.
x
No adverse laboratory, 
vital signs, or ECGs 
findings observed.
x
1 event each of 
constipation, feeling 
cold, somnolence (each 
Grade 1) w as reported 
as related to study drug.
ACE-HV-004
x
Open label
x
ACP-196 100 mg
x
Drug-drug interaction:
o Calcium carbonate
o Omeprazole
o Rifampin
x
Healthy volunteers
72
x
Enrollment completed.
x
No adverse laboratory, 
vital signs, or ECGs 
findings observed.
x
Other analyses 
pending.
ACE-LY-002
(NCT02112526)
x
Open label
x
ACP-196 100 mg BID
x
Activated B-cell subtype of diffuse 
large B-cell lymphoma
6
x
Enrollment recently 
begun
ACE-WM-001
(NCT02180724)
x
Open label
x
ACP-196 100 mg BID and 200 mg QD
x
Waldenström macroglobulinemia
7
x
Enrollment recently 
begun
ACE-LY-003
(NCT02180711)
x
Open label
x
ACP-196 100 mg BID and 200 mg QD
x
Follicular lymphoma
1
x
Enrollment recently 
begun
15-H-0016
(NIH study)
x
Open label
x
ACP-196 200 mg QD and 100 mg BID
x
CLL
0
x
Enrollment recently 
begun
ACE-ST-003
x
Open label
x
ACP-196 100 mg BID ±
pembrolizumab 200 mg IV Q3W
x
Advanced or metastatic pancreatic 
cancer
0
x
Protocol in study start 
up
AE = adverse event; BID = tw ice per day; CLL = chronic lymphocytic leukemia; DLT = dose-limiting toxicity; 
ECGs = electrocardiograms; QD = once per day
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Table 1-2. ACP-196 Clinical Studies as of January 2015 (continued)
Protocol
Design
Subjects 
Enrolled
Status
ACE-ST-005
(NCT02351739)
x
Open label
x
ACP-196 100 mg BID ±
pembrolizumab 200 mg IV Q3W
x
Advanced or metastatic bladder 
cancer
0
x
Protocol in study start 
up
ACE-LY-004
(NCT02213926)
x
Open label
x
ACP-196 100 mg BID
x
Mantle cell lymphoma
0
x
Enrollment recently 
begun
ACE-CL-002
(NCT02157324)
x
Open label
x
ACP-196 50 mg BID and ACP-319
25 mg BID
x
CLL
8
x
Enrollment recently 
begun
ACE-LY-001
(NCT02328014)
x
Open label
x
ACP-196 100 mg BID and ACP-319
25 to 100 mg BID
x
B-cell malignancies
1
x
Enrollment recently 
begun
ACE-CL-003
(NCT02296918)
x
Open label
x
ACP-196 200 mg QD and 
Obinutuzumab per label
x
CLL
2
x
Enrollment recently 
begun
ACE-HI-001
x
Hepatic impairment study
x
ACP-196 50 mg QD
18
x
Enrollment ongoing
ACE-LY-005
x
Open label
x
ACP-196 100 mg BID and 
pembrolizumab 2 mg/kg IV Q3W
x
B-cell malignancies
None
x
Protocol in study start 
up
ACE-ST-006
x
Open label
x
ACP-196 100 mg BID ±
pembrolizumab 200 mg IV Q3W
x
Advanced or metastatic head & neck 
cancer
0
x
Protocol in study start 
up
ACE-ST-007
x
Open label
x
ACP-196 100 mg BID ±
pembrolizumab 200 mg IV Q3W
x
Advanced or metastatic non-small cell 
lung cancer
0
x
Protocol in study start 
up
AE = adverse event; BID = tw ice per day; CLL = chronic lymphocytic leukemia; DLT = dose-limiting toxicity; 
ECGs = electrocardiograms; IV = intravenous; Q3W = once every 3 w eeks; QD = once per day
1.3.1
Pharmacokinetics and Pharmacodynamics of ACP-196 in
Healthy Volunteers
ACE-HV-001 was a dose-ranging, food-effect, and drug-drug interaction study 
evaluating BID and QD dosing for 1 or 2 days in healthy volunteers.  The starting dose 
for ACP-196 was 2.5 mg BID.  This study has been completed and no adverse 
laboratory, vital signs, or ECG findings were observed (2.5 to 50 mg BID; 50 to 100 mg 
QD). Three AEs related to ACP-196 were reported.  Each AE was Grade 1 and resolved 
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
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 ACP-196 were evaluated after oral administration of 2 daily 
doses of 2.5 to 50 mg and a single dose of 100 mg.  Of the 30 subjects evaluated, all 
had measurable systemic concentrations of ACP-196.  ACP-196 plasma time to 
maximum concentration (Tmax) values were between 0.5 and 1.0 hour for all dose 
cohorts and independent of the dose level.  The increase in mean maximum 
concentration (Cmax) values was greater than dose proportion based on the increases of 
Cmax from the first dose administered.  When evaluating area under the concentration 
curve (AUC0-12, AUC0-24 or AUC0-inf), the mean values increased in a dose proportional 
manner based on the increases of the total dose administered.  Mean half-life (t1/2)
values ranged from 0.97 to 2.1 hours, and appeared to decrease as the dose increased.  
The mean calculated oral clearance (CL/F: 165 to 219 L/h) and volume of distribution 
values (Vz/F: 233 to 612 L) appeared to be independent of the dose administered.
ACP-196 was not detected in the urine of subjects who received the 2.5- or 5.0-mg BID 
doses of ACP-196.  ACP-196 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 ACP-196 (75 mg) after a single oral 
administration was evaluated in 6 men and 6 women.  Median ACP-196 plasma Tmax
values were increased in the fed state (2.5 hours) relative to the fasted state (0.5 hour).  
The mean plasma ACP-196 Cmax values decreased to 27.3% of the values observed in 
the fasted state.  In contrast, the relative exposure of ACP-196 (AUC) remained mostly 
unchanged in both states. Per FDA guidance on food-effect studies (FDA 2002), this 
decrease in exposure is not clinically significant, and therefore, ACP-196 can be taken 
with or without food.
In Part 3, after administration of a single dose of ACP-196 (50 mg), the effect of 
itraconazole on the PK was evaluated in 17 subjects.  No difference in ACP-196 Tmax
values was observed in the presence or absence of itraconazole.
Mean ACP-196 exposures (as assessed by Cmax, AUC0-last, AUC0-24, and AUC0-inf)
increased in the presence of itraconazole.  The mean plasma ACP-196 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 
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
(CL/F: 217 vs 44 L/h; Vz/F: 1190 vs 184 L).  No differences in half-life values were 
observed (3.3 vs 2.5 hours).
The pharmacodynamics (PD) profile of ACP-196 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 
VWXG\)XOO%WNRFFXSDQF\DQGFRPSOHWH&'DQG&'LQKLELWLRQ 90%) 
occurred in the 75- and 100-mg single dose 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 who 
received a second dose of ACP-196 12 hoursafter the first administration, full Btk target 
occupancy was observed 3 hours after the second dose for the 50 mg dose cohort (Btk 
occupancy 97 ± 4%).
1.3.2
Clinical Experience of ACP-196 in CLL
ACE-CL-001 (NCT02029443), an ongoing Phase 1/2 study in subjects with 
relapsed/refractory or previously untreated CLL or Richter’s syndrome, has a sequential, 
dose-escalation design. As of 22 January 2015, 125 subjects have received ACP-196 at 
dosages from 100 to 400 mg QD or 100 to 200 mg BID. 
To date, ACP-196 has been well tolerated at all dose levels evaluated.  No dose-limiting 
toxicities (DLTs) have occurred at any dose level.  The MTD was not reached in this 
study; however, per the protocol, dose escalation was stopped once a plateau in PK was 
observed (ie, between 250 and 400 mg).  
Preliminary data from ACE-CL-001 show that Btk occupancy with ACP-196, in peripheral 
blood cells, is > 95% at 4 hours but decreases to < 95% at 24 hours, while with BID 
dosing complete Btk occupancy (97% to 99%) is maintained over 24 hours at steady 
state (Table 1-3). These data suggest that synthesis of de novo Btk may occur within 
24 hours.
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Table 1-3.  Btk Occupancy in Peripheral Blood of Subjects from ACE-CL-001
(December 2014)
Timepoint*
Subjects with Relapsed/Refractory CLL
100 mg QD
(n=8)
175 mg QD
(n=8)
250 mg QD
(n=6)
100 mg BID
(n=17)
Day 7:
Median %
Occupancy 24 h
89.0
86.9
93.5
97.4
Day 8:
Median %
Occupancy 4 h
98.6
98.7
100
98.8
Abbreviations:  BID = twice per day; CLL = chronic lymphocytic leukemia; QD = once per day
*Note: 24-h timepoint on BID regimen represents 24 hours after first dose and 12 hours after 
second dose on Day 7.  The 4-h timepoint on the BID regimen represents 4 hours after the first 
dose on Day 8.  
Preliminary PK data from Day 8 show dose linearity from 100 to 250 mg and no 
accumulation with repeat dosing (Table 1-4).
Table 1-4.  Preliminary Day 8 PK Results from ACE-CL-001 (October 2014)
Cohort
Mean Cmax ± SD
(ng/mL)
Mean AUC0-last ± SD
(ng•h/mL)
100 mg QD (N=8)
529 ± 286
634 ± 197a
175 mg QD (N=7)
800 ± 692
1240 ± 789
250 mg QD (N=7)
1350 ± 933
2170 ± 1180
400 mg QD (N=6)
932 ± 576
1870 ± 1040
100 mg BID (N=22)
716 ± 658
837 ± 485b
Timepoints: Predose, 0.25, 0.50, 0.75, 1.0, 2.0, 4.0, and 6.0 postdose.
a N=7 for AUC calculations in 100 mg QD dose group.
b BID regimens were not sampled during the second daily dose interval; 0-24 h exposures are 
expected to be approximately 2-fold the AUC0-6 values shown.
AUC = area under the curve; BID = twice per day; Cmax = maximum concentration; SD = standard 
deviation
To date, 31 subjects have been evaluated for tumor response, by investigators, based 
on International Working Group response criteria (Hallek 2008) as recently updated 
(Cheson 2012) to include partial response with treatment-induced lymphocytosis.  Based 
on preliminary, unaudited data an overall response rate (ORR) of 94% (71% PR + 23% 
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
PR with lymphocytosis) has been observed (Table 1-5). Of the 31 subjects assessed, 
nearly half (15 of 31) have 17p del.  Of the 15 subjects with 17p del, 80% (12/15) have 
PR and 20% (3/15) have PR with lymphocytosis.  The median follow-up for the ACP-196 
subjects evaluated for response is 7.3 cycles (range 3.0 to 10.8) and each cycle is 28 
days. No primary disease progression has occurred on study (N = 75; Figure 1-2).
Table 1-5.  Best Response by Cohort from ACE-CL-001 (23OCT2014)
n (%)
All
Cohorts
(N=31)
100 mg QD
(N=8)
175 mg QD
(N=8)
250 mg QD
(N=7)
100 mg BID
(N=3)
400 mg QD
(N=5)
PR
22 (71)
7 (88)
5 (71)
4 (57)
3 (100)
2 (40)
PR+L
7 (23)
0 (0)
3 (38)
2 (29)
0 (0)
2 (40)
SD
2 (6)
1 (12)
1 (13)
0 (0)
0 (0)
1 (20)
PD
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
Median (range) Cycles
7.3 (3.0-10.8)
10.0 (9.0-10.8)
8.6 (3.0-8.8)
7.0 (7.0-7.3)
5.2 (4.7-5.5)
5.0 (4.8-5.5)
BID = twice per day; PD = progressive disease; PR = partial response; PR+L = partial response 
with lymphocytosis; QD = once per day; SD = stable disease
Figure 1-2. Kaplan-Meier Curves for Progression-free Survival by Investigator 
Assessment for ACE-CL-001 (N=75; excludes Richter’s Syndrome Cohort and 
Ibrutinib R/R Cohort)
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
These results compare favorably with the Phase 3 results of ibrutinib, the first generation 
Btk inhibitor, when administered at dosages of 420 mg QD in subjects with 
relapsed/refractory CLL (N=195).  In the ibrutinib study, Byrd and colleagues (2014)
report a PR rate of 43%, a PR with lymphocytosis rate of 20%—for an ORR of 63%ņan
SD rate of 32%, and a progressive disease (PD) rate of 3% (Byrd 2014) based on 
independent review.  The median follow-up time reported for the ibrutinib study was 
9.5 months (range 0.1 to 16.6).  
Figure 1-3 shows the change from baseline in sum of the product of the diameters (SPD) 
(N=31) and in absolute lymphocyte count (ALC) (N=57) over time.  As shown in the 
figure, substantial reductions in lymphadenopathy have been observed despite the fact 
that three-quarters of the evaluable subjects have high-risk cytogenetics (17p del, 11q 
del, or both). As mentioned above, the observed reductions in lymphadenopathy are 
consistent with the clinical results for ibrutinib (Byrd 2013, Byrd 2014).  However, the 
reduced drug-induced lymphocytosis and the rapid time to resolution of lymphocytosis 
with ACP-196 treatment varies greatly from that reported for ibrutinib.  Per the 
IMBRUVICA package insert, 77% of patients with CLL treated with ibrutinib experienced 
lymphocytosis, which occurred during the first month of therapy and resolved by a 
median of 23 weeks (range 1 to 104+ weeks).  With ACP-196 treatment, the onset of 
lymphocytosis, if it occurs, is within the first week of treatment and resolves by a median 
of 8 weeks (range 0 to 24+ weeks).
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Figure 1-3. Median (95% CI) Change from Baseline in ALC/SPD Over Time
ALC = absolute lymphocyte count; CI = confidence interval; SPD = sum of the 
products of the perpendicular diameters (of lymph nodes).
1.4
BENEFIT/RISK
ACP-196 is a potent, orally available small-molecule inhibitor of Btk.  A PK/PD study has 
been completed with ACP-196 in healthy volunteers (ACE-HV-001; Section1.3.1).  The 
safety results showed no identified safety risks in healthy subjects receiving 1 or 2 days 
of ACP- 100 mg.  In study ACE-CL-001, a study of ACP-196 in subjects with 
relapsed/refractory or previously untreated CLL or Richter’s syndrome, no DLTs have 
EHHQUHSRUWHGDWGRVDJHVRI 400 mg QD or 100 and 200 mg BID.  The overall 
response rate in the evaluable subjects for this study is currently 94% with some 
subjects obtaining PRs after only 2 cycles of therapy.  Based on these robust results in 
subjects with CLL, the evaluation of ACP-196 in subjects with relapsed or refractory MM
is warranted.
1.5
SUMMARY AND CONCLUSIONS
This study comprises a pilot evaluation of the safety and activity of the potent, second-
generation Btk inhibitor, ACP-196, in patients with relapsed or refractory MM. The design 
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
and conduct of this study is supported by an understanding of the natural history and 
current therapies for subjects with lymphoid cancers; knowledge of the efficacy and
safety of the first-generation BCR inhibitor (eg, ibrutinib) in subjects with hematologic 
cancers; and the available nonclinical and clinical information regarding ACP-196. 
Preclinical studies are ongoing in parallel to identify biomarkers that may be evaluated in 
this clinical trial as correlates of response to Btk-directed therapy and that may permit 
selection of patients who are particularly likely to benefit from ACP-196 treatment for 
MM.
2.0
STUDY OBJECTIVES
2.1
PRIMARY OBJECTIVE
x
To characterize the safety profile of ACP-196 with and without dexamethasone in 
subjects with relapsed or refractory MM
2.2
SECONDARY OBJECTIVES:
x
To characterize the PK profile of ACP-196 with and without dexamethasone and the 
PK profile of dexamethasone with concomitant ACP-196 administration
x
To evaluate the PD effects of ACP-196 with and without dexamethasone
x
To evaluate the activity of ACP-196 with and without dexamethasone as measured 
by overall response rate, duration of response, clinical benefit rate, disease control 
rate, and progression-free survival
x
To explore the relationship between biological markers in MM cells and response to 
therapy
3.0
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This study is a multicenter, open-label, randomized, parallel-group study to be 
conducted at approximately 20 sites in 2 countries (United Kingdom and United States).
Forty subjects will be randomized 1:1 into the following 2 cohorts to receive ACP-196, 
with and without dexamethasone:
x
Cohort 1: ACP-196 100 mg BID continuously 
x
Cohort 2: ACP-196 100 mg BID continuously and 40 mg dexamethasone once 
weekly 
Twenty-eight days of study drug administration is 1 cycle.  Treatment may be continued 
for > 28 days until disease progression or an unacceptable drug-related toxicity occurs.  
For subjects in Cohort 1, if documented disease progression occurs, then 
dexamethasone can be added to the treatment regimen.  Additional dose modification 
provisions are provided in Section 3.5.5. Note: temporary withholding of study drug for 
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
as little as 7 days can cause a transient worsening of disease and/or of constitutional
symptoms.  Refer to Section 3.8 for more information on assessing disease progression 
under these circumstances. All subjects who discontinue study drug will have a safety 
follow-up visit 30 (±7) days after the last dose of study drug unless they have started 
another cancer therapy within that timeframe. 
All subjects will have standard hematology, chemistry, and urinalysis safety panels 
performed at screening.  Once dosing commences (Day 1), all subjects will be evaluated 
for safety, including serum chemistry and hematology, once weekly for the first 4 weeks, 
every 2 weeks in Cycle 2 and monthly thereafter.  PK/PD testing will be done in Cycle 1
and Cycle 2. Tumor assessments will be done at 8- to 12-week intervals during the trial.
Refer to Appendix 5 for a comprehensive list of study assessments and their timing. The 
end of trial is defined as the point when the last subject on the study exits the study for 
any reason.
3.2
STUDY PARAMETERS
3.2.1
Safety Parameters
The safety of ACP-196 with and without dexamethasone will be characterized by the 
type, frequency, severity, timing of onset, duration, and relationship to study drug (ie, 
ACP-196, dexamethasone, or both) of any treatment-emergent AEs or abnormalities of 
laboratory tests; serious adverse events (SAEs); or AEs leading to discontinuation or 
dose reduction of study treatment. 
For consistency of interpretation, AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), and the severity of AEs and laboratory abnormalities 
will be graded using the Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.03. Standard definitions for seriousness will be applied (see Section 6.1).
3.2.2
Efficacy Parameters
Standardized response and progression criteria have been established for MM
(Rajkumar 2011); assessments of ACP-196 efficacy in this study will be based on these 
criteria. Efficacy endpoints will include:
x
Overall response rate (ORR)
x
Duration of response
x
Clinical benefit rate
x
Disease control rate
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
x
Progression-free survival
3.2.3
Pharmacokinetic and Pharmacodynamic Parameters
Standard PK parameters for ACP-196 and dexamethasone in plasma will be evaluated 
in this study.  A full description of the PK parameters is provided in Section 5.5.4.
The occupancy of Btk by ACP-196 will be measured in peripheral blood mononuclear 
cells (PBMCs) and bone marrow, when available, with the aid of a biotin-tagged 
ACP-196 analogue probe.  The effect of ACP-196 on biologic markers of B-cell function 
will also be evaluated.
3.3
RATIONALE FOR STUDY DESIGN AND DOSING REGIMEN
As described in Section 1.3, preliminary data from the ongoing Phase 1/2 study in 
subjects with relapsed/refractory or previously untreated CLL have shown that ACP-196 
is well tolerated at dosages of 100 to 400 mg QD and 100 to 200 mg BID.  In addition, 
preliminary PD data from ACE-CL-001 show that Btk occupancy with ACP-196, in
peripheral blood, is > 95% at 4 hours after QD dosing but decreases to < 95% at 
24 hours with QD dosing, while with BID dosing complete Btk occupancy (95% to 99%) 
is maintained over 24 hours at steady state (Table 1-3).  These data suggest that de 
novo synthesis of Btk can occur within 24 hours in peripheral blood cells.  BID dosing 
may ensure Btk inhibition for the entire 24 hours and thus may be beneficial in terms of 
increasing efficacy and/or decreasing development of resistance to ACP-196.  In 
addition, having information regarding the safety and pharmacology of a BID schedule 
may support future combination studies with other drugs that are administered BID.  
Evaluation of dexamethasone as a combination partner for ACP-196 builds on known 
antineoplastic activity of this drug in patients with MM. Dexamethasone therapy is
commonly coadministered with targeted agents for MM (Ocio 2014). The dosing 
regimen of 40 mg weekly to be used in this study has been established based on 
randomized trial data showing the superiority of this method of administration (Rajkumar 
2009). Combined use of ACP-196 and dexamethasone provides an all oral, non-
cytotoxic regimen that may have increased efficacy relative to administration of the 
individual agents alone. While dexamethasone can increase CYP3A4 activity and thus 
might enhance ACP-196 metabolism, it is considered a weak inducer of this isoenzyme
and has not substantially altered the disposition of other CYP3A4 substrates (eg, 
bortezomib) that are commonly used in the therapy of MM (Hellmann 2011). The 
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
randomized design of this pilot study will allow the potential for drug-drug interactions 
between ACP-196 and dexamethasone to be assessed.
3.4
SELECTION OF STUDY POPULATION
3.4.1
Inclusion Criteria
Eligible subjects will be considered for inclusion in this study if they meet all of the 
following criteria: 
1. 0HQDQGZRPHQ\HDUVRIDJH.
2. A confirmed diagnosis of MM, which has relapsed after, or been refractory to 
 1 prior therapy for MM, and is progressing at the time of study entry.
3. Evaluable myeloma at screening, defined as the presence of at least one of the 
following:
o
Serum M-SURWHLQ 0.5 g/dL
o
Urine M-SURWHLQ 200 mg/24 hours
o
In subjects without detectable serum or urine M-protein, serum free light 
chain (SFLC) > 100 mg/L (involved light chain) and an abnormal serum 
kappa/lambda ratio
o
For subjects whose disease can only be reliably measured by serum 
quantitative immunoglobulin A ,J$,J$ 750 mg/dL (0.75 g/dL) 
4. Eastern Cooperative Oncology Group (ECOG) performance status of  2.
5. Agreement to use acceptable methods of contraception during the study and for 
30 days after the last dose of study drug if sexually active and able to bear or 
beget children.
6. Agreement to refrain from sperm donation during the study and for 30 days after 
the last dose of study drug.
7. Willing and able to participate in all required evaluations and procedures in this 
study protocol including swallowing capsules without difficulty.
8. 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 subject privacy regulations).
3.4.2
Exclusion Criteria
Subjects will be ineligible for this study if they meet any of the following criteria:
1. 3ODVPDFHOOOHXNHPLDRUFLUFXODWLQJSODVPDFHOOV 2 x 109/L
2. Prior malignancy, except for adequately treated basal cell or squamous cell skin 
cancer, in situ cervical cancer, or other cancer from which the subject has been 
GLVHDVHIUHHIRU\HDUVRUZKLFKZLOOQRWOLPLWVXUYLYDOWR\HDUV1RWHWKHVH
cases must be discussed with the Medical Monitor.
3. A life-threatening illness, medical condition or organ system dysfunction which, in
the investigator’s opinion, could compromise the subject’s safety, interfere with 
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
the absorption or metabolism of ACP-196, or put the study outcomes at undue 
risk.
4. 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.
5. Malabsorption syndrome, disease significantly affecting gastrointestinal function, 
or resection of the stomach or small bowel, gastric bypass, symptomatic 
inflammatory bowel disease, or partial or complete bowel obstruction.
6. Any immunotherapy within 4 weeks of first dose of study drug.
7. The time from the last dose of the most recent chemotherapy or experimental 
therapy to the first dose of study drug is < 5 times the half-life of the previously 
administered agent(s).
8. Prior exposure to a B-cell receptor (BCR) inhibitor (eg, Btk, phosphoinositide-3
kinase [PI3K], or Syk inhibitors) or BCL-2 inhibitors (eg, ABT-199).
9. Ongoing immunosuppressive therapy, including systemic or enteric 
corticosteroids for treatment of MM or other conditions. Note: Subjects may use
topical or inhaled corticosteroids as therapy for comorbid conditions. During 
study participation, subjects may also receive systemic or enteric corticosteroids 
as needed for MM therapy or treatment-emergent comorbid conditions.
10. *UDGHWR[LFLW\RWKHUWKDQDORSHFLD) continuing from prior anticancer therapy 
including radiation.
11. 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.
12. Major surgery within 4 weeks before first dose of ACP-196.
13. Known history of a bleeding diathesis (eg, hemophilia, von Willebrand disease)
14. History of stroke or intracranial hemorrhage within 6 months before the first dose 
of ACP-196.
15. Requires or receiving anti-coagulation with warfarin or equivalent vitamin K
antagonist (eg, phenprocoumon) within 28 days of first dose of study drug.
16. Requires treatment with long-acting proton pump inhibitors (eg, omeprazole, 
esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
17. ANC < 0.75 x 109/L or platelet count < 50 x 109/L.  For subjects with >50% 
marrow involvement with plasma cells, ANC < 0.50 x 109/L or platelet count 
< 30 x 109/L.
18. Creatinine > 2.5 x institutional upper limit of normal (ULN); total bilirubin 
> 2.5 x ULN; and aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) > 3.0 x ULN.
19. Breastfeeding or pregnant.
20. Concurrent participation in another therapeutic clinical trial.
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
3.4.3
Replacement of Subjects
Any subject who does not complete Cycle 2 may be replaced at the discretion of the 
study investigators and sponsor.
3.4.4
Enrollment and Randomization Procedures
Enrollment of a subject into the study will be performed according to the following 
procedure: 
x
Notify the sponsor when a clinically eligible subject is identified and is ready to 
screen, to ensure enrollment availability on the study.
x
After the subject has signed and dated the Informed Consent Form (ICF), all 
screening procedures have been completed, and eligibility has been confirmed, the 
subject can be officially enrolled in the study. 
x
To enroll a subject, the study center will fax/email a completed Enrollment 
Confirmation Form to the sponsor.  The enrollment date will be the date that the form 
is faxed/emailed to the sponsor.
x
An Enrollment Confirmation Form will be completed and faxed/emailed to the study 
center by the sponsor within 24 hours.
x
The Enrollment Confirmation Form will contain cohort allocation per the 
randomization scheme generated by the sponsor.
Treatment must begin within the screening window (Section 4.1) and after the site has 
received the cohort allocation from the sponsor.  Study treatment is not blinded on this 
study.
3.5
STUDY DRUG
3.5.1
Premedications
No specific premedications or supporting medications are required in conjunction with
ACP-196 administration. 
3.5.2
Formulation, Packaging, and Storage
3.5.2.1
ACP-196
ACP-196 is manufactured according to cGMP regulations and will be provided to the 
investigational site by Acerta Pharma or designee.  ACP-196 should be stored according 
to the instructions on the label that is affixed to the package containing the drug product.  
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
ACP-196 capsules is provided as hard gelatin capsules containing 100 mg drug 
substance. ACP-196 will be provided in white, high-density polyethylene bottles.
If a drug shipment arrives damaged, or if there are any other drug complaints, a 
SAE/Product Complaint Form should be completed and emailed or faxed to the sponsor 
or the sponsor’s representative.  
Refer to the Investigator’s Brochure for additional information regarding the drug product 
to be used in this trial.
3.5.2.2
Dexamethasone
This study will use commercially available dexamethasone tablets for oral administration.
The Sponsor will either directly supply sites with dexamethasone or the sites will be 
reimbursed to prescribe dexamethasone; this will be detailed separately in each site’s 
clinical trial agreement.  Per the U.S. dexamethasone package insert (Appendix 4), 
tablets are to be stored at room temperature (20° to 25°C) and protected from moisture 
and light.  Please refer to the appropriate dexamethasone package insert for further 
storage and handling instructions.
3.5.3
Administration of Study Drug
3.5.3.1
ACP-196
Investigators are prohibited from supplying ACP-196 to any subjects not properly 
enrolled in this study or to any physicians or scientists except those designated as 
subinvestigators on FDA Form 1572.  The investigator must ensure that subjects receive 
ACP-196 only from personnel who fully understand the procedures for administering the 
drug.
ACP-196 is intended to be administered orally with 8 ounces (approximately 240 mL) of 
water (avoid grapefruit juice and Seville orange juice due to CYP3A4 inhibition). ACP-
196 may be taken with or without food. The capsules should be swallowed intact and 
subjects should not attempt to open capsules or dissolve them in water.  .
If a dose is missed, it can be taken up to 3 hours after the scheduled time with a return 
to the normal schedule with the following dose.  If it has been greater than 3 hours, the 
dose should not be taken and the subject should take the next dose at the scheduled 
time.  The missed dose will not be made up and must be returned to the site at the next 
scheduled visit.
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3.5.3.2
Dexamethasone
This study will use commercially available dexamethasone tablets for oral administration.
At the time of weekly dexamethasone administration, the subject should take the 
dexamethasone tablets simultaneously with the ACP-196 capsules and with 8 ounces 
(approximately 240 mL) of water.  The dexamethasone tablets should be swallowed 
intact and subjects should not attempt to chew them or dissolve them in water. 
If a dexamethasone dose is missed, it can be taken up to 3.5 days (84 hours) days after 
the scheduled time with a return to the normal schedule the following week.  If the 
interval of missed dosing has been > 3.5 days (84 hours), the dexamethasone dose 
should not be taken and the subject should take the next dose at the scheduled time in 
the following week. The missed dexamethasone dose will not be made up and must be 
returned to the site at the next scheduled visit.
3.5.4
Assuring Subject Compliance
During cycle 1, subjects will receive their Day 1, 8, 15, 22, and 28 doses (for Cohort 2 
this includes the dexamethasone dose) in the clinic.  For treatments that are taken in the 
clinic, subjects should take the dose from the drug dispensed for them for that particular 
time period.  All other treatments will be taken at home.  Subjects will receive a diary to 
record the specific time each dose was taken and to record reasons for any missed 
doses.  
Subject compliance will be assessed at every visit.  The subject will be instructed to 
bring the diary and any remaining ACP-196 capsules and dexamethasone tablets to the 
clinic at their next visit.  The administrator will review the diary and ask the subject if all 
of the capsules and tablets were administered.  Any remaining or returned capsules and
tablets will be counted and recorded as described in Section 7.7.  Returned capsules or 
tablets must not be redispensed to another subject. The study staff will resupply the 
subject with the correct number of ACP-196 capsules and dexamethasone tablets 
needed for use until the next visit.
3.5.5
Study Treatment Regimen and Dose Modifications
3.5.5.1
ACP-196
Dose Delays
Treatment with ACP-196 should be held for any unmanageable, potentially study drug-
related toxicity that is Grade  3 in severity.  Any other clinically important events where 
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dose delays may be considered appropriate by the investigator must be discussed with 
the Medical Monitor.  Study drug may be held for a maximum of 28 consecutive days 
from expected dose due to toxicity.  Study treatment should be discontinued in the event 
of a toxicity lasting > 28 days, unless reviewed and approved by the Medical Monitor.
Note: temporary withholding of study drug for as little as 7 days can cause a 
transient worsening of disease and/or of constitutional symptoms. Refer to 
Section 3.8 for more information on assessing disease progression under these 
circumstances.
Dose Modification and Discontinuation
The actions in Table 3-1 should be taken for the following toxicities:
x
*UDGH$1&ȝ/IRU!GD\V1HXWURSKLOJURZWKIDFWRUVDUHSHUPLWWHG
per ASCO guidelines [Smith 2006] and use must be recorded on the electronic 
case report form [eCRF]).
x
Grade 3 platelets in the presence of significant bleeding
x
Grade 4 platelets 
x
Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal 
antiemetic and/or anti-diarrheal therapy
x
Any other Grade 4 toxicity or unmanageable Grade 3 toxicity.
Table 3-1.  Drug Discontinuation Actions for ACP-196
Occurrence
Action
1st - 2nd
Hold ACP-196 XQWLOUHFRYHU\WR*UDGHRUEDVHOLQHPD\UHVWDUWDW
original dose level
3rd
Hold ACP-196 XQWLOUHFRYHU\WR*UDGHRUEDVHOLQHUHVWart at 100 mg 
once daily
4th
Discontinue ACP-196
Subjects in Cohort 1 (ACP-196 monotherapy) who do not experience at least an minimal
response (MR) after 2 cycles of study treatment may have dexamethasone (40 mg once 
weekly) added to their treatment.
Whenever possible, any dose adjustment of ACP-196, including adding dexamethasone 
to subjects in Cohort 1, should be discussed between the investigator and the Acerta 
Pharma medical monitor before implementation. The appropriate clinic staff should 
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dispense the study drug for the new dose level and instruct the subject/caregiver about 
the change in dose level. Any changes to the dosing regimen must be recorded in the 
appropriate eCRF.  
3.5.5.2
Dexamethasone
This study will use commercially available dexamethasone.  Dosing of dexamethasone 
will be 40 mg once weekly.  For subjects who experience intolerable dexamethasone-
related adverse effects, dexamethasone may be reduced to 20 mg once weekly.
3.6
CONCOMITANT THERAPY
3.6.1
Permitted Concomitant Therapy
Antiemetics are permitted if clinically indicated.  Standard supportive care medications 
are permitted as per institutional standards.  
For subjects considered at risk for tumor lysis syndrome: Administer appropriate 
hydration and allopurinol or rasburicase per institutional standards before initiating 
treatment.
3.6.2
Guideline for Use of CYP Inhibiting/Inducing Drugs
At the systemic exposure levels expected in this study, ACP-196 inhibition of CYP 
metabolism is not anticipated.  However, as discussed in Section 1.3.1, concomitant 
administration of ACP-196 with a strong CYP3A4 inhibitor increased exposure by 
approximately 5-fold.  Consequently, the concomitant use of strong inhibitors/inducers of 
CYP3A4 (Appendix 3) should be avoided when possible.  If a subject requires a strong 
CYP3A4 inhibitor while on study, monitor the subject closely for potential toxicities.
3.6.3
Guideline for Use of Drugs that Affect Gastric pH
The effect of agents that reduce gastric acidity (eg, proton pump inhibitors, H2-receptor 
antagonists or antacids) on ACP-196 absorption is currently being evaluated in a healthy 
volunteer study (ACE-HV-004). Preliminary results from this study suggest subjects 
should avoid the use of calcium carbonate containing drugs or supplements (eg, 
antacids or calcium supplements) for a period of at least 2 hours before and after taking 
ACP-196.  
Subjects should also avoid the use of H2-receptor antagonists for a period at least 
2 hours before and after taking ACP-196.   Use of omeprazole, esomeprazole, 
lansoprazole or any other long-acting proton pump inhibitors while taking ACP-196 is not 
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permitted due to a potential decrease in study drug exposure.  However, if a subject 
requires treatment with a long-acting proton pump inhibitor while on study (eg, to treat an 
ulcer), discuss treatment options with the Medical Monitor.
3.6.4
Prohibited Concomitant Therapy
Any chemotherapy, immunotherapy, kinase inhibitors, bone marrow transplantation,
experimental therapy, and radiotherapy are prohibited (see Section 3.4.2).
Administration of live or live, attenuated vaccines is contraindicated in patients receiving 
immunosuppressive doses of corticosteroids, per the dexamethasone package insert 
(Appendix 4). Killed or inactivated vaccines may be administered. However, the 
response to such vaccines cannot be predicted.
3.7
PRECAUTIONS
3.7.1
Dietary Restrictions
Because ACP-196 may be metabolized by CYP3A4/3A5 (see Section 1.2.4), subjects 
should be strongly cautioned against excessive consumption of grapefruit, grapefruit 
juice, Seville oranges, or Seville orange juice (which contain potent CYP3A4 inhibitors) 
or using herbal remedies or dietary supplements (in particular, St. John’s Wort, which is 
a potent CYP3A4 inducer).
ACP-196 may be taken with or without food.
3.7.2
Surgery
Susceptibility to bleeding has been observed with the first generation Btk inhibitor,
ibrutinib [IMBRUVICA package insert].  As a precaution, it is suggested that ACP-196 be 
held for 3 days before and after any major surgical procedure.
3.7.3
Infections
Patients who are on corticosteroids are more susceptible to infections than are healthy 
individuals (dexamethasone package insert, Appendix 4). Corticosteroids may 
exacerbate systemic fungal infections and therefore should not be used in the presence 
of such infections unless they are needed to control life-threatening drug reactions.
3.7.4
Reproductive Toxicity
Definitive reproductive toxicity studies with ACP-196 are pending.  Therefore, subjects 
with reproductive potential who are sexually active must use acceptable methods of 
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contraception during the study and for 30 days after the last dose of ACP-196.  
Examples of acceptable methods of contraception include condoms, implants, 
injectables, combined oral contraceptives, intrauterine devices, true sexual abstinence, 
or sterilized partner.  Note that periodic abstinence, eg, calendar, ovulation, 
symptothermal, or postovulation methods, or withdrawal, are not acceptable methods of 
contraception.
Subjects should promptly notify the investigator if they, or their partner, become 
pregnant during this period. If a female subject becomes pregnant during the treatment 
period, she must discontinue ACP-196 immediately.  Pregnancy in a female subject or a 
male subject’s partner must be reported (see Section 6.2.3). Male subjects must agree 
to refrain from sperm donation during the study and for 30 days after the last dose of 
study drug.
3.7.5
Overdose Instructions
For any subject experiencing an ACP-196 overdose (administration of a dose 
 1.5 times the highest intended dose level in the clinical study protocol), observation for 
any symptomatic side effects should be instituted, and vital signs and biochemical and 
hematologic parameters should be followed closely (consistent with the protocol or more 
frequently, as needed). Appropriate supportive management to mitigate adverse effects 
should be initiated. If the overdose ingestion is recent and substantial, and if there are no 
medical contraindications, use of gastric lavage or induction of emesis may be 
considered.
The Acerta Pharma Medical Monitor should be contacted if a study drug overdose 
occurs. 
3.8
STOPPING RULES
All study participants may receive ACP-196 indefinitely as long as they are safely 
benefitting. However:
x
Any subject has the right to withdraw from the study at any time.
x
Any subject who has objective evidence of definitive MM progression while receiving 
study treatment at the highest individual tolerable dose level allowed in the protocol 
(see Section 3.5.5) should be withdrawn from the study treatment.  Note: If there is 
uncertainty regarding whether there is MM progression, the subject should continue 
study treatment and remain under close observation (eg, evaluated at 4- to 8-week 
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intervals) pending confirmation of progression. In particular, transient worsening of 
disease during temporary interruption of study therapy (eg, for intercurrent illness,
drug-related toxicity, or surgery) may not indicate definitive disease progression. In 
such circumstances, and if medically appropriate, subjects may resume therapy and 
relevant clinical, laboratory, and/or radiographic assessment should be done to 
document whether tumor control can be maintained or whether actual disease 
progression has occurred. 
x
Any subject who is unable to tolerate rechallenge at the lowest protocol-described, 
dose-modified levels (see Section 3.5.5) should be withdrawn from the study 
treatment unless continued therapy is permitted by the Acerta Pharma medical 
monitor.
x
Any subject whose medical condition substantially changes after entering the study 
should be carefully evaluated by the investigator in consultation with the 
Acerta Pharma medical monitor. Such subjects should be withdrawn from study 
treatment if continuing would place them at risk. 
x
Any subject who becomes pregnant or begins breastfeeding should be removed from 
study treatment.
x
Any subject who becomes significantly noncompliant with study drug administration, 
study procedures, or study requirements should be withdrawn from study treatment 
in circumstances that increase risk or substantially compromise the interpretation of 
study results.
x
The investigator, in consultation with the Acerta Pharma medical monitor, may 
withdraw any subject from the study treatment, if, in the investigator’s opinion, it is 
not in the subject’s best interest to continue. 
Subjects who discontinue study therapy will continue on study for safety (Section 4.3)
unless they withdraw consent for further follow-XS7KXVDOOVXEMHFWVUHFHLYLQJ 1 dose 
of study drug will be followed during the immediate posttherapy period unless the subject 
withdraws consent for such follow-up to be conducted. The date the subject is withdrawn 
from study treatment or from the study and the reason for discontinuation will be 
recorded and also should be described on the appropriate eCRF.
3.9
DATA AND SAFETY MONITORING
This trial will be monitored in accordance with the sponsor’s Pharmacovigilance 
Committee procedures.  Adverse events and SAEs will be reviewed internally on an 
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ongoing basis to identify safety concerns.  Quarterly conference calls with the 
investigators will be conducted to discuss study progress, obtain investigator feedback 
and exchange, and discuss "significant safety events" (ie, AEs leading to dose 
reductions, related SAEs, and deaths).  
4.0
STUDY ACTIVITIES AND ASSESSMENTS
The schedule of events is provided in Appendix 5.  Descriptions of the scheduled 
evaluations are outlined below and complete information on study drug and dosing is 
provided in Section 3.5.
Before study entry, throughout the study, and at the follow-up evaluation, various clinical 
and diagnostic laboratory evaluations are required.  The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments.  
Clinical evaluations and laboratory studies may be repeated more frequently if clinically 
indicated. Such unscheduled assessments will be captured in the protocol-specific 
database as appropriate.
4.1
DESCRIPTION OF PROCEDURES
4.1.1
Informed Consent
The subject must read, understand and sign the IRB/IEC approved ICF confirming his or 
her willingness to participate in this study before initiating any screening activity that is 
not standard of care.  Subjects must also grant permission to use protected health 
information.
4.1.2
Medical History
The subject’s complete history should be collected and recorded through review of 
medical records and by interview. Concurrent medical signs and symptoms must be 
documented to establish baseline severities. A disease history, including the date of 
initial diagnosis and list of all prior anticancer treatments, and responses and duration of 
response to these treatments, also will be recorded.
4.1.3
Adverse Events
The accepted regulatory definition for an AE is provided in Section 6.1 All medical 
occurrences from the time of first dose that meet this definition must be recorded. 
Important additional requirements for reporting SAEs are explained in Section 6.2.
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4.1.4
Concomitant Medications and Therapy
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 should be 
documented.
4.1.5
Confirmation of Eligibility
Subject eligibility for enrollment will be assessed per Section 3.4. All screening
procedures, unless otherwise indicated, should be completed within 21 days of the first 
dose of study drug.
4.1.6
ECOG Performance Status
The ECOG performance index is provided in Appendix 1.
4.1.7
Physical Examination, Vital Signs, Height & Weight
The screening physical examination will include, at a minimum, the general appearance 
of the subject, height (screening only) and weight, and examination of the skin, eyes,
ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous 
system, and lymphatic system.
Symptom-directed physical exams, including tumor assessments by palpation, will be 
done during the treatment period and at the safety follow-up visits.
Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) will be 
assessed after the subject has rested in the sitting position.
4.1.8
Bone Marrow Aspirate and Biopsy
A bone marrow aspirate and biopsy will be done at screening or up to 30 days before the 
main screening procedures. Per the current response criteria (Rajkumar 2011), a bone 
marrow aspirate/biopsy will also be required at any time on study to confirm a complete 
response (CR). The baseline bone marrow aspirate/biopsy will used for 
immunohistochemistry and/or flow cytometry, cytogenetics, and FISH.  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.
When available, any unused bone marrow tissue will be used for PD testing.  PD testing 
will be done by the sponsor.
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4.1.9
Electrocardiogram
Subjects should be in supine pRVLWLRQDQGUHVWLQJIRU 10 minutes before study-related 
ECGs.  
4.1.10
Urine Pregnancy Test
Pregnancy tests will be required only for women of childbearing potential. If positive, 
pregnancy must be ruled out by ultrasound.  Testing will be done by the central 
laboratory.
4.1.11
Hematology
Hematology studies must include complete blood count (CBC) with differential and 
platelet and reticulocyte counts.  Testing will be done by the central laboratory.
4.1.12
Serum Chemistry
Serum chemistry must 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, potassium, sodium, total bilirubin, total protein, and uric acid.  If an 
unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, 
magnesium, and potassium) must be done to coincide with the ECG testing.  Testing will 
be done by the central laboratory.
4.1.13
Urinalysis
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, N-terminal 
telopeptide, and glucose.  Testing will be done by the central laboratory.
4.1.14
T/B/NK Cell Count
Flow cytometry testing will include CD3+, CD4+, CD8+, CD19+, and CD16/56+cells.  
Testing will be done by the central laboratory.
4.1.15
Disease Markers
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 ȕ-microglobulin will be done by the central 
laboratory.
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4.1.16
Skeletal Survey
Standard lateral radiograph of the skull, anterioposterior and lateral views of the spine, 
and anterioposterior views of the pelvis, ribs, femora, and humeri are required at 
screening or baseline (ie, before the first dose of study drug).  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. 
4.1.17
Pharmacodynamics
Blood samples and bone marrow, when available, will be used for PD testing (eg, Btk
occupancy and B-cell activation).  Refer to the laboratory binder for instructions on 
collecting and processing these samples. Testing will be done by the sponsor.
4.1.18
Pharmacokinetics
Refer to the laboratory binder for instructions on collecting and processing these 
samples. Testing will be performed at the central clinical laboratory. Leftover plasma 
samples may be used for exploratory ACP-196 metabolite analyses.  The PK sampling 
timepoints are provided in Table 4-1.
Table 4-1.  Pharmacokinetic Sample Schedule
HOURS POSTDOSE
Cycle
Day Predose
0.5
(±5 min)
0.75
(±5 min)
1
(±5 min)
2
(±10 min)
4
(±10 min)
6
(±10 min)
1
1
X
X
X
X
X
X
X
8
X
X
15
X
X
22
X
X
X
X
X
X
X
28
X
X
Note: These timepoints are relative to the morning dose.
4.1.19
Tumor Assessment
Baseline myeloma assessments will consist of:
Ɣ
M-protein determination using both of the following procedures:
ż
serum protein electrophoresis (SPEP) and serum immunofixation 
electrophoresis (SIFE)
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ż
Urine protein electrophoresis (UPEP) and urine immunofixation 
electrophoresis (UIFE), all using the same 24-hour urine collection 
Ɣ
SFLC
Ɣ
Plasmacytoma evaluation
Ɣ
Bone marrow to quantify percent myeloma cell involvement (aspirate and 
biopsy required at baseline)
Ɣ
Skeletal survey: lateral radiograph of the skull, anterioposterior and lateral 
views of the spine, and anterioposterior views of the pelvis, ribs, femora, and 
humeri
Ɣ
ȕ-microglobulin
On-study myeloma assessments will consist of:
Ɣ
SPEP and/or UPEP (if results were measurable at baseline); quantitative 
immunoglobulins if used to follow disease; immunofixation to confirm a 
complete response
Ɣ
SFLC
Ɣ
Plasmacytoma evaluation (if only measurable disease at baseline)
Ɣ
Bone marrow aspirate and/or trephine bone biopsy (to confirm a complete 
response or if clinically indicated).
4.1.20
Study Drug Accountability
See Section 7.7.
4.2
INVESTIGATOR’S ASSESSMENT OF RESPONSE TO TREATMENT
Subjects will be evaluated by investigator review for disease response and progression 
according to the current guidelines proposed by the International Myeloma Workshop 
Consensus Panel 1 (Rajkumar 2011) and European Group for Blood and Marrow 
Transplant (EBMT; Bladé 1998)as listed belowin .  Response categories include sCR, 
CR,  VGPR, PR, SD, and progressive disease. In addition, the number of subjects
achieving the response category of MR will also be evaluated and reported.  Subjects
will be considered evaluable for response if they have a baseline and t1 adequate on-
study myeloma assessment obtained t4 weeks from the start of therapy.
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Table 4-2. Response Criteria (derived from Rajkumar 2011 and Bladé 1998)
Response Subcategory
Response Criteriaa
Complete response (CR)
x
Negative immunofixation of serum and urine and
x
Disappearance of any soft tissue plasmacytomas and
x
< 5% plasma cells in bone marrowb.
Stringent complete 
response (sCR)
x
CR as defined above plus
x
Normal FLC ratio and
x
Absence of clonal plasma cells by immunohistochemistry or 2- to 
4-color flow cytometry.
Very good partial 
response (VGPR)
x
Serum and urine M-component detectable by immunofixation but 
not on electrophoresis or
x
 90% reduction in serum M-component plus urine M-component 
< 100 mg per 24 h.
Partial response (PR)
x
 50% reduction of serum M-protein and reduction in 24-h urinary 
M-SURWHLQE\ 90% or to < 200 mg per 24 h
x
If the serum and urine M-protein are not measurableD 50% 
decrease in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria
x
If serum and urine M-protein are not measurable, and serum free 
light assay is also not measurable 50% reduction in bone
marrow plasma cells is required in place of M-protein, provided 
EDVHOLQHSHUFHQWDJHZDV 30%
x
,QDGGLWLRQWRWKHDERYHFULWHULDLISUHVHQWDWEDVHOLQH 50% 
reduction in the size of soft tissue plasmacytomas is also required
Minimal response (MR)
x
Requires all of the following:
o
t 25% to d 49% reduction of serum M-protein and
o
50% to 89% reduction in 24-hour urine M-protein and
o
If present at baseline, 25-49% reduction in the size of soft 
tissue plasmacytomas and
o
No increase in size or number of lytic bone lesions 
(development of compression fracture does not exclude 
response).
Stable disease (SD)
x
Not meeting criteria for CR, VGPR, MR, PR or progressive 
disease
Progressive disease
Any of the following:
x
,QFUHDVHRI 25% from lowest response valuec in:
o
Serum M-component (absROXWHLQFUHDVHPXVWEH 0.5 g/dL)d
o
Urine M-component (absolute increase must be 
 200 mg/24 h)
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o
Only in subjects without measurable serum and urine 
M-protein levels: the difference between involved and 
uninvolved FLC levels (absolute increase must be 
> 10 mg/dL)
o
Only in subjects without measurable serum and urine M-
protein levels and without measurable disease by FLC levels 
bone marrow plasma cell percentage (absolute increase must 
EH 10%)
x
Definite development of new bone lesions or soft tissue 
plasmacytomas or definite increase in the size of existing bone 
lesions or soft tissue plasmacytomas
x
Development of hypercalcemia (corrected serum calcium 
> 11.5 mg/dL) that can be attributed solely to the plasma cell 
proliferative disorder
Abbreviations: FLC = (serum) free light chains
Note: in subjects in whom the only measurable disease is by serum FLC levels, CR requires a
normal FLC ratio of 0.26-1.65 in addition to negative serum and urine immunofixation. 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 (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments 
made at t4 weeks after the start of study therapy and any time before the institution of any 
new therapy after study therapy; CR, sCR, VGPR, PR, and SD categories also require no 
known evidence of progressive or new bone lesions if radiographic studies were performed. 
VGPR and CR categories require serum and urine studies regardless of whether disease at 
baseline was measurable on serum, urine, both, or neither. Radiographic studies are not 
required to satisfy these response requirements.
b.
Bone marrow assessments need not be confirmed.
c.
Lowest response value does not need to be a confirmed value.
d.
For progressive disease, serum M-FRPSRQHQWLQFUHDVHVRI 1 gm/dL are sufficient to define 
relapse if starting M-FRPSRQHQWLV 5 g/dL.
4.3
EARLY TERMINATION/SAFETY FOLLOW-UP VISIT
An early termination visit is required for any subjects who permanently discontinue study 
drug early for any reason including disease progression.  Each subject should be 
followed for 30 (±7) days after his or her last dose of study drug (ie, the “safety follow-up
visit”) to monitor for resolution or progression of AEs (see Section 6.2.5) and to 
document the occurrence of any new events; unless, the subject receives a new 
anticancer therapy within this timeframe.  Subjects who withdraw consent should still be 
encouraged to complete the safety follow-up assessments, but these assessments 
cannot be mandated once consent is withdrawn.  The Schedule of Assessments 
(Appendix 5) describes the procedures required for the safety follow-up. 
4.4
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 
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investigator’s opinion, medically unnecessary or unsafe because it is too close in time to 
the next scheduled evaluation.  In that case, the missed evaluation should be 
abandoned.
5.0
STATISTICAL METHODS OF ANALYSIS 
5.1
GENERAL CONSIDERATIONS
Descriptive statistics (including means, standard deviations, and medians for continuous 
variables and proportions for discrete variables) will be used to summarize data as 
appropriate. Analyses will be done by dosing regimen and overall.
5.2
SAMPLE SIZE CONSIDERATIONS
This study will assess safety, PK, PD, and antitumor activity of ACP-196 alone or in 
combination with dexamethasone.  Subjects will be equally randomized into 1 of the 
2 dosing regimens (ACP-196 monotherapy or ACP-196 + dexamethasone) as an 
efficient method for allocating patients into these regimens. The study is not formally 
designed to compare these regimens but rather to obtain descriptive information that can 
be used in support of further ACP-196 development.
While the primary objective of this study is to determine the safety in each of the 
2 dosing cohorts, the sample size has been determine to independently evaluate the 
activity of each dosing regimen. The trial seeks to exclude an uninteresting ORR of 
d 15% (ie, the response rate that might be associated with single-agent dexamethasone 
therapy [Anderson 2013]) in favor a target response rate of t 40%.  Considering a 
sample size of 19 subjects per cohort, the power to detect the difference between a null-
hypothesis response rate of 15% and an alternative-hypothesis response rate of 40%
with a 0.025 one-sided significance level is 69% using a one-group, exact binomial test.  
A sample size of 19 subjects per cohort will also provide a 97.5% 1-sided confidence 
interval centered around an expected ORR of 40% that excludes an ORR of 18.6% as a 
lower bound.
5.3
DEFINITION OF ANALYSIS POPULATIONS
The following definitions will be used for the analysis populations:
x
Safety population: $OOHQUROOHGVXEMHFWVZKRUHFHLYH 1 dose of study drug.
x
Intent-to-treat (ITT) population: All subjects who have been randomized.
The safety population will be used for evaluating the safety parameters in this study.  
The ITT population will be analyzed for efficacy parameters in this study.
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5.4
MISSING DATA HANDLING
General Considerations: Subjects lost to follow-up (or who dropped out) will be 
included in statistical analyses up to the point of their last evaluation.
Duration of Response and Progression-free Survival: Data for subjects without 
disease progression or death will be censored at the date of the last tumor assessment 
and before the initiation of alternative anticancer therapy.
Safety: Missing or partial start and end dates for AEs and concomitant medications will 
be imputed according to prespecified, conservative imputation rules.  No other 
imputation of values for missing data will be performed.
5.5
ENDPOINT DATA ANALYSIS
5.5.1
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 adverse event (per CTCAE, v4.03) and by 
relationship to study drug.
Laboratory shift tables containing counts and percentages will be prepared by treatment 
assignment, laboratory parameter, and time.  Summary tables will be prepared for each 
laboratory parameter.  Figures of changes in laboratory parameters over time will be 
generated.
Results of vital sign assessments and physical exams will be tabulated and summarized.  
5.5.2
Demographics and Baseline Characteristics
Additional analyses will include summaries of subject demographics, baseline 
characteristics, compliance, and concurrent treatments. Concomitant medications will be 
coded according to the World Health Organization (WHO) Drug Dictionary and 
tabulated.
5.5.3
Analysis of Efficacy Parameters
5.5.3.1
Overall Response Rate
Tumor control will be documented at each assessment by response category (eg, CR, 
sCR, VGPR, PR, MR, SD, and disease progression) as defined for each response 
parameter, date that response is first documented, and date of MM disease progression.
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The overall response rate (ORR) will be defined as the proportion of subjects who 
achieve a CR, sCR, VGPR, or PR. ORR will be calculated and the corresponding 
95% two-sided confidence interval will be derived.
5.5.3.2
Duration of Response
The duration of response (DOR) defined as the interval from the first documentation of 
CR, sCR, VGPR, or PR to the earlier of the first documentation of definitive disease 
progression or death from any cause.  Kaplan-Meier methods will be used to estimate 
event-free curves and corresponding quantiles (including the median). Data from 
surviving, nonprogressing subjects will be censored at the earliest of the time of initiation 
of anticancer treatment other than the study treatment or the last time that lack of 
definitive MM progression was objectively documented. Data from subjects who have 
MM SURJUHVVLRQRUGLHDIWHUFRQVHFXWLYHPLVVLQJWXPRUDVVHVVPHQWVZLOOEH
censored at the last time before the missing assessments that lack of MM progression 
was objectively documented.
5.5.3.3
Clinical Benefit Rate
Clinical benefit rate (CBR) will be defined as the proportion of subjects who achieve a 
CR, sCR, VGPR, PR, or MR.  CBR will be calculated and the corresponding 95% two-
sided confidence interval will be derived.
5.5.3.4
Disease Control Rate
Disease control rate (DCR) will be defined as the proportion of subjects who achieve a 
CR, sCR, VGPR, PR, MR, or SD.  DCR will be calculated and the corresponding 
95% two-sided confidence interval will be derived.
5.5.3.5
Progression-free Survival
Progression-free survival (PFS) is defined as the interval from the date of randomization
to the earlier of the first documentation of objective MM disease progression or death 
from any cause.  Kaplan-Meier methods will be used to estimate the event-free curves 
and corresponding quantiles (including the median). Data from surviving, non-
progressing subjects will be censored at the earliest of the time of initiation of anticancer
treatment other than the study treatment or the last time that lack of MM progression 
was objectively documented. Data from subjects who have MM progression or die after 
 2 consecutive missing tumor assessments will be censored at the last time prior to the 
missing assessments that lack of MM progression was objectively documented.
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5.5.4
Analysis of Pharmacokinetic/Pharmacodynamic Parameters
The plasma PK of ACP-196 and dexamethasone will be characterized using 
noncompartmental analysis. The following PK parameters will be calculated, whenever 
possible, from plasma concentrations of ACP-196:
x
AUC0-t
Area under the plasma concentration-time curve calculated using linear 
trapezoidal summation from time 0 to time t, where t is the time of the last 
measurable concentration (Ct).
x
AUC0-12
Area under the plasma concentration-time curve from 0 to 12 hours, 
calculated using linear trapezoidal summation.
x
AUC0-
Area under the plasma concentration-time curve from 0 to infinity, 
calculated using the formula: AUC0-= AUC0-t + Ct ȜzZKHUHȜzis the 
apparent terminal elimination rate constant.
x
AUC0-24calc Area under the plasma concentration-time curve from 0 to 24 hours, 
calculated by doubling the value for AUC0-12.
x
Cmax
Maximum observed plasma concentration
x
Tmax
Time of the maximum plasma concentration (obtained without 
interpolation)
x
t½
Terminal elimination half-life (whenever possible) 
x
Ȝz
Terminal elimination rate constant (whenever possible)
x
CL/F
Oral clearance
Missing dates or times may be imputed for PK and PD samples if the missing values can 
be established with an acceptable level of accuracy based on other information obtained 
during the visit in question. If PK and PD sampling for a given subject is not performed 
according to protocol instructions that subject may be excluded from the PK and PD 
analyses.
The PK parameters will be tabulated and summarized using descriptive statistics. 
For each PD variable, the concentration at each assessment will be described.  The 
change from baseline to each assessment will be summarized.  The best change from 
baseline during the study will also be summarized.  As appropriate, the on-treatment 
values will be compared with the pretreatment baseline values using paired t-tests.  
5.5.5
Exploratory or Correlative Analyses
Additional PK or PD analyses may be performed, as deemed appropriate.
Correlations between subject characteristics and outcome measures and correlations 
among outcomes measures will be explored using regression models or other 
appropriate techniques. Such evaluations may assist in determining if baseline 
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parameters or early changes in PD biomarkers are predictive of response to Btk 
inhibition.
6.0
ASSESSMENT OF SAFETY
Safety assessments will consist of monitoring and recording AEs and SAEs;
measurements of protocol-specified hematology, clinical chemistry, urinalysis, and other 
laboratory variables; measurement of protocol-specified vital signs; and other protocol-
specified tests that are deemed critical to the safety evaluation of the study drug(s).
6.1
DEFINITIONS
6.1.1
Adverse Events
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational (medicinal) product or other protocol-
imposed intervention, regardless of attribution.
This includes the following:
x
AEs not previously observed in the subject that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with MM that were not 
present before the AE reporting period (see Section 6.2.1)
x
Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as biopsies)
x
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character 
during the protocol-specified AE reporting period.
Abnormal laboratory values should not be reported as AEs; however, any clinically 
significant laboratory values (defined as requiring treatment, discontinuation from study,
or dose modification) should be reported as AEs.
6.1.2
Serious Adverse Event
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to 
the grade of an AE (see below).  “Serious” is a regulatory definition and is based on 
subject or event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  Seriousness (not severity) serves as the guide 
for defining regulatory reporting obligations from the Sponsor to applicable regulatory 
authorities.
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An AE should be classified as an SAE if it meets any 1 of the following criteria:
x
It results in death (ie, the AE actually causes or leads to death).
x
It is life-threatening (ie, the AE, in the view of the investigator, places the subject at 
immediate risk of death.  It does not include an AE that, had it occurred in a more 
severe form, might have caused death).
x
It requires or prolongs in-patient hospitalization.
x
It results in persistent or significant disability/incapacity (ie, the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions).
x
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the investigational product.
x
It is considered a significant medical event by the investigator based on medical 
judgment (eg, may jeopardize the subject or may require medical/surgical 
intervention to prevent 1 of the outcomes listed above).
6.1.3
Severity
Definitions found in the CTCAE version 4.03 or higher will be used for grading the 
severity (intensity) of AEs. The CTCAE displays Grades 1 through 5 with unique clinical 
descriptions of severity for each referenced AE. Should a subject experience any AE not 
listed in the CTCAE, the following grading system should be used to assess severity:
x
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities
x
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
x
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
x
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to 
be in imminent danger of death
x
Grade 5 (Death related to AE) – experiences which result in subject death
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6.2
DOCUMENTING AND REPORTING OF ADVERSE AND SERIOUS 
ADVERSE EVENTS
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, as outlined in the prior sections, are recorded on the eCRF.
All SAEs also must be reported on the SAE/Product Complaint form (see Section 6.2.4).
6.2.1
Adverse Event Reporting Period
The AE reporting period for this study begins when the subject receives the first dose of 
study medication and ends with the safety follow-up visit (or last on-treatment visit if the 
safety follow-up visit is not done), or when the subject receives a new anticancer 
therapy.  An exception to this reporting period is any AE occurring due to a protocol-
defined screening procedure.  Fatal AEs occurring within 30 days after the last dose of 
ACP-196 AND assessed by the investigator as related to ACP-196 must be reported as 
a SAEs.
6.2.2
Assessment of Adverse Events
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation time 
points during the study.  All AEs and SAEs whether volunteered by the subject, 
discovered by study personnel during questioning, or detected through physical 
examination, or other means will be recorded in the subject’s medical record and on the 
AE eCRF and, when applicable, on an SAE/Product Complaint form.
Disease progression itself is not considered an adverse event; however, signs and 
symptoms of disease progression may be recorded as AEs or SAEs.
Each recorded AE or SAE will be described by its duration (ie, start and end dates), 
severity, regulatory seriousness criteria, if applicable, suspected relationship to the study 
drug (ie, ACP-196, dexamethasone, or both; see following guidance), and any actions 
taken.  The relationship of AEs to the study drug will be assessed by means of the 
question: ‘Is there a reasonable possibility that the event may have been caused by the 
study drug?’  Answer Yes or No. 
See Appendix 2 for more detail on assessing relationship.
6.2.3
Pregnancy
The investigator should report all pregnancies in study subjects and in the partners of 
subjects within 24 hours using the Pregnancy Report Form.  This form should be faxed 
or emailed to Acerta Pharma Drug Safety. Any pregnancy-associated SAE must be 
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reported using the SAE report form, according to the usual timelines and directions for 
SAE reporting (Section 6.2.4).
Any uncomplicated pregnancy that occurs in a subject or a partner of a treated subject 
during this study will be reported for tracking purposes only, if agreed to by the subject or 
the partner of the subject in this study. All pregnancies and partner pregnancies that are 
identified during or after this study, wherein the estimated date of conception is 
determined to have occurred from the time of consent to 30 days after the last dose of 
study medication will be reported, followed to conclusion, and the outcome reported, as 
long as the subject or partner is willing to participate in follow-up.
Pregnancy itself is not regarded as an AE unless there is suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Likewise, elective abortions without complications are not 
considered AEs. Any SAEs associated with pregnancy (eg, congenital 
abnormalities/birth defects/spontaneous miscarriages or any other serious events) must 
additionally be reported as such using the SAE/Product Complaint form. 
Subjects should be instructed to immediately notify the investigator of any pregnancies.  
Any female subjects receiving ACP-196 who become pregnant must immediately 
discontinue study drug.  The investigator should counsel the subject, discussing any 
risks of continuing the pregnancy and any possible effects on the fetus.  
6.2.4
Expedited Reporting Requirements for Serious Adverse 
Events
All SAEs must be reported within 24 hours of discover.  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/Product Complaint forms 
must be emailed or faxed to Acerta Pharma Drug Safety, or designee. Acerta Pharma
may request follow-up and other additional information from the investigator (eg, hospital 
admission/discharge notes and laboratory results). 
All deaths should be reported with the primary cause of death as the AE term, as death 
is typically the outcome of the event, not the event itself. The primary cause of death on 
the autopsy report should be the term reported.  Autopsy and postmortem reports must 
be forwarded to Acerta Pharma Drug Safety, or designee, as outlined above.
If study drug is discontinued because of an SAE, this information must be included in the 
SAE report.
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An SAE may qualify for mandatory expedited reporting to regulatory authorities if the 
SAE is attributable to the investigational product and is not listed in the current 
Investigator’s Brochure (ie, an unexpected event). In this case, Acerta Pharma Drug 
Safety/Designee will forward a formal notification describing the SAE to all investigators. 
Each investigator must then notify his or her IRB/IEC of the SAE.
Drug Safety Contact Information
Fax:
Email:
6.2.5
Type and Duration of Follow-up of Subjects After Adverse 
Events 
All AEs and SAEs that are encountered during the protocol-specified AE reporting period 
should be followed to resolution, or until the investigator assesses the event as stable, a 
new anticancer therapy is initiated, or the subject is lost to follow-up or withdraws 
consent.
7.0
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS
Acerta Pharma retains the right to terminate the study and remove all study materials 
from a study site at any time. Specific circumstances that may precipitate such 
termination include: 
x
Unsatisfactory subject enrollment with regard to quality or quantity
x
Significant or numerous deviations from study protocol requirements, such as 
failure to perform required evaluations on subjects and maintain adequate study 
records
x
Inaccurate, incomplete or late data recording on a recurrent basis
x
The incidence and/or severity of AEs in this or other studies indicating a potential 
health hazard caused by the study treatment
7.1
REGULATORY AND ETHICAL COMPLIANCE
This clinical study was designed and will be implemented in accordance with the 
protocol, the ICH Harmonized Tripartite Guidelines for Good Clinical Practices, 
applicable local regulations (including US Code of Federal Regulations Title 21 and 
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European Directive 2001/20/EC), and the ethical principles laid down in the Declaration 
of Helsinki.
7.2
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE
The investigator will submit this protocol, the ICF, Investigator’s Brochure, and any other 
relevant supporting information (eg, all advertising materials) to the appropriate IRB/IEC
for review and approval before study initiation.  A signed protocol approval page; a letter 
confirming IRB/IEC approval of the protocol and informed consent; and a statement that 
the IRB/IEC is organized and operates according to GCP and the applicable laws and 
regulations; must be forwarded to Acerta Pharma before screening subjects for the 
study.  Additionally, sites must forward a signed FDA 1572 form (Statement of 
Investigator form) to Acerta Pharma before screening subjects for study enrollment.  
Amendments to the protocol must also be approved by the IRB/IEC and local regulatory 
agencies, as appropriate, before the implementation of changes in this study.
7.3
INFORMED CONSENT AND PROTECTED SUBJECT HEALTH 
INFORMATION AUTHORIZATION
A copy of the IRB/IEC-approved ICF must be forwarded to Acerta Pharma for regulatory 
purposes.  The investigator, or designee (designee must be listed on the Study 
Personnel Responsibility/Signature Log, see Section 7.12), must explain to each subject 
the purpose and nature of the study, the study procedures, the possible adverse effects, 
and all other elements of consent as defined in § 21CFR Part 50, and other applicable 
national and local regulations governing informed consent.  Each subject must provide a 
signed and dated 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 with individual local and national subject privacy regulations, the 
investigator or designee must explain to each subject that for the evaluation of study 
results, the subject’s protected health information obtained during the study may be 
shared with Acerta Pharma and its designees, regulatory agencies, and IRBs/IECs.  As 
the study Sponsor, Acerta Pharma will not use the subject’s protected health information 
or disclose it to a third party without applicable subject authorization.  It is the 
investigator’s or designee’s responsibility to obtain written permission to use protected 
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health information from each subject, or if appropriate, the subject’s legal guardian.  If a 
subject or subject’s legal guardian withdraws permission to use protected health 
information, it is the investigator’s responsibility to obtain the withdrawal request in 
writing from the subject or subject’s legal guardian and to ensure that no further data will 
be collected from the subject.  Any data collected on the subject before withdrawal will 
be used in the analysis of study results.
7.4
SUBJECT SCREENING LOG
The investigator must keep a record that lists all subjects considered for enrollment 
(including those who did not undergo screening) in the study.  For those subjects 
subsequently excluded from enrollment, record the reason(s) for exclusion.
7.5
CASE REPORT FORMS
Authorized study site personnel (see Section 7.12) will complete eCRFs designed for 
this study according to the completion guidelines that will be provided.  The investigator 
will ensure that the eCRFs are accurate, complete, legible, and completed within 5 days 
of each subject’s visit (unless required earlier for SAE reporting).  The investigator will 
ensure that source documents that are required to verify the validity and completeness 
of data transcribed on the eCRFs are never obliterated or destroyed, in accordance with 
the record retention policies in Section 7.8.
7.6
STUDY MONITORING REQUIREMENTS
Representatives of Acerta Pharma or its designee will monitor this study until 
completion.  Monitoring will be conducted through personal visits with the investigator 
and site staff as well as any appropriate communications by mail, fax, email, or 
telephone.  The purpose of monitoring is to ensure compliance with the protocol and the 
quality and integrity of the data.  This study is also subject to reviews or audits by the 
sponsor, regulatory authorities, or ethics committees.
Every effort will be made to maintain the anonymity and confidentiality of all subjects 
during this clinical study.  However, because of the experimental nature of this 
treatment, the investigator agrees to allow the IRB/IEC, representatives of Acerta 
Pharma, its designated agents, and authorized employees of the appropriate regulatory 
agencies to inspect the facilities used in this study and, for purposes of verification, allow 
direct access to the hospital or clinic records of all subjects enrolled into this study. This 
includes providing by fax, email, or regular mail de-identified copies of radiology, 
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pathology, and/or laboratory results when requested by the sponsor.  A statement to this 
effect will be included in the informed consent and permission form authorizing the use 
of protected health information.
7.7
INVESTIGATIONAL STUDY DRUG ACCOUNTABILITY
ACP-196 capsules must be kept in a locked limited access room. The study drug must 
not be used outside the context of the protocol. Under no circumstances should the 
investigator or other site personnel supply ACP-196 capsules to other investigators, 
subjects, or clinics or allow supplies to be used other than as directed by this protocol 
without prior authorization from Acerta Pharma.
Study drug accountability records must be maintained and readily available for 
inspection by representatives of Acerta Pharma and regulatory authorities at any time. 
Each shipment of study drug will contain a Clinical Supplies Shipping Receipt Form 
(CSSF) that must be appended to the site’s drug accountability records. If it is used, the 
Drug Re-order Form (provided in the pharmacy binder) must also be included in the 
site’s drug accountability records.
Contents of each shipment must be visually inspected to verify the quantity and 
document the condition of study drug capsules.  Then the designated recipient 
completes and signs the CSSF. A copy of the signed CSSF must be faxed or emailed to 
Acerta Pharma at the fax number/emailing address listed on the form.
An Investigational Drug Accountability Log must be used for drug accountability.  For 
accurate accountability, the following information must be noted when drug supplies are 
used during the study:
1.
study identification number (ACE-MY-001)
2.
subject identification number
3.
lot number(s) of ACP-196 dispensed for that subject
4.
date and quantity of drug dispensed
5.
any unused drug returned by the subject
At study initiation, the monitor will evaluate and approve the site’s procedure for 
investigational product disposal/destruction to ensure that it complies with Acerta 
Pharma’s requirements. If the site cannot meet Acerta Pharma’s requirements for 
disposal/destruction, arrangements will be made between the site and Acerta Pharma or 
its representative, for return of unused investigational product.  Before
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disposal/destruction, final drug accountability and reconciliation must be performed by 
the monitor.
All study supplies and associated documentation will be regularly reviewed and verified 
by the monitor.
7.8
RECORD RETENTION
The investigator and other appropriate study staff are responsible for maintaining all 
documentation relevant to the study. Mandatory documentation includes copies of study 
protocols and amendments, each FDA Form 1572, IRB/IEC approval letters, signed 
ICFs, drug accountability records, SAE forms transmitted to Acerta Pharma, subject files 
(source documentation) that substantiate entries in eCRFs, and all relevant 
correspondence and other documents pertaining to the conduct of the study.
An investigator shall retain records for a period of at least 2 years after the date the last 
marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. The investigator must notify Acerta Pharma and obtain 
written approval from Acerta Pharma before destroying any clinical study records at any 
time. Acerta Pharma will inform the investigator of the date that study records may be 
destroyed or returned to Acerta Pharma.
Acerta Pharma must be notified in advance of, and Acerta Pharma must provide express 
written approval of, any change in the maintenance of the foregoing documents if the 
investigator wishes to move study records to another location or assign responsibility for 
record retention to another party. If the investigator cannot guarantee the archiving 
requirements set forth herein at his or her study site for all such documents, special 
arrangements must be made between the investigator and Acerta Pharma to store such 
documents in sealed containers away from the study site so that they can be returned 
sealed to the investigator for audit purposes.
7.9
PROTOCOL AMENDMENTS
Acerta Pharma will initiate any change to the protocol in a protocol amendment 
document. The amendment will be submitted to the IRB/IEC together with, if applicable, 
a revised model ICF. If the change in any way increases the risk to the subject or 
changes the scope of the study, then written documentation of IRB/IEC approval must 
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be received by Acerta Pharma before the amendment may take effect. Additionally 
under this circumstance, information on the increased risk and/or change in scope must 
be provided to subjects already actively participating in the study, and they must read, 
understand, and sign any revised ICF confirming willingness to remain in the trial.
7.10
PUBLICATION OF STUDY RESULTS
Acerta Pharma may use the results of this clinical study in registration documents for 
regulatory authorities in the United States or abroad. The results may also be used for 
papers, abstracts, posters or other material presented at scientific meetings or published 
in professional journals or as part of an academic thesis by an investigator. The study is 
being conducted as part of a multicenter clinical trial. Data from all study centers shall be 
pooled and analyzed for publication in a final report (Primary Publication). The 
investigator agrees that the Primary Publication, which will be coordinated by Acerta 
Pharma, will be the first publication to present the pooled study results. After the Primary 
Publication, or if the Primary Publication is not published within 1 year of termination of 
the study, the investigator may freely publish or present the results of his or her work 
conducted under the clinical trial agreement subject to providing Acerta Pharma with the 
opportunity to review the contents of any proposed presentation, abstract or publication 
about such work, including any results of this study, 90 days in advance of any 
presentation or submission for publication. Within that 90-day period, Acerta Pharma 
may review the proposed publication to identify patentable subject matter and/or any 
inadvertent disclosure of its confidential information, which must be redacted from any 
final publication or presentation. If necessary, to permit the preparation and filing of 
patent applications, Acerta Pharma may elect an additional review period not to exceed 
60 days.
Authorship, in general, will follow the recommendations of the International Committee of 
Medical Journal Editors (International Committee of Medical Journal Editors 2014).  
7.11
CLINICAL TRIAL INSURANCE
Clinical trial insurance has been obtained according to the laws of the countries where 
the study will be conducted. An insurance certificate will be made available to the 
participating sites at the time of study initiation.
7.12
GENERAL INVESTIGATOR RESPONSIBILITIES
The principal investigator must ensure that:
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1.
He or she will personally conduct or supervise the study.
2.
His or her staff and all persons who assist in the conduct of the study clearly 
understand their responsibilities and have their names included in the Study 
Personnel Responsibility/Signature Log.
3.
The study is conducted according to the protocol and all applicable regulations.
4.
The protection of each subject’s rights and welfare is maintained.
5.
Signed and dated informed consent and, when applicable, permission to use 
protected health information are obtained from each subject before conducting 
nonstandard of care study procedures.  If a subject or subject’s legal guardian 
withdraws permission to use protected health information, the investigator will 
obtain a written request from the subject or subject’s legal guardian and will 
ensure that no further data be collected from the subject.
6.
The consent process is conducted in compliance with all applicable regulations 
and privacy acts.
7.
The IRB/IEC complies with applicable regulations and conducts initial and 
ongoing reviews and approvals of the study.
8.
Any amendment to the protocol is submitted promptly to the IRB/IEC.
9.
Any significant protocol deviations are reported to Acerta Pharma and the 
IRB/IEC according to the guidelines at each study site.
10.
Electronic CRF pages are completed within 5 days of each subject’s visit (unless 
required earlier for SAE reporting).
11.
All IND Safety Reports/ Suspected Unexpected Serious Adverse Reaction 
(SUSAR) Reports are submitted promptly to the IRB/IEC.
12.
All SAEs are reported to Acerta Pharma Drug Safety/Designee within 24 hours of 
knowledge and to the IRB/IEC per their requirements.
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Protocol: ACE-MY-001
8.0
REFERENCES
Anderson KC, Alsina M, Bensinger W, et al. Multiple myeloma, version 1.2013. J Natl 
Compr Canc Netw 2013;11:11-17. 
Bladé J, Samson D, Reece D, et al.  Criteria for evaluating disease response and 
progression in patients with multiple myeloma treated by high-dose therapy and 
haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European 
Group for Blood and Marrow Transplant. Br J Haematol 1998;102:1115-1123.
Bradshaw JM. The Src, Syk, and Tec family kinases: distinct types of molecular 
switches. Cell Signal 2010;22:1175-1184. 
Buggy JJ, Elias L. Bruton tyrosine kinase (Btk) and its role in B-cell malignancy. Int Rev 
Immunol 2012;31:119-132. Erratum in: Int Rev Immunol 2012;31:428.
Byrd JC, Furman RR, Coutre SE, Flinn IW, et al. Targeting Btk with ibrutinib in relapsed 
chronic lymphocytic leukemia. NEJM 2013;369:32-42.
Byrd JC, Brown JR, O’Brien S, et al.  Ibrutinib versus ofatumumab in previously treated 
chronic lymphoid leukemia.  NEJM 2014 May 31 [Epub ahead of print]
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical 
end points in chronic lymphocytic leukemia. J Clin Oncol 2012;30:2820-2820.
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical 
end points in chronic lymphocytic leukemia. J Clin Oncol 2012 30:2820-2822.
Edwards CM, BTK inhibition in myeloma: targeting the seed and soil.  Blood 
2012;120:1757-1759.  
FDA (US Food and Drug Administration). Guidance for industry. Food-Effect 
Bioavailability and Fed Bioequivalence Studies. 2002 Dec. Available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/ucm070241.pdf.  Accessed January 19, 2015.
Gentile DM, Tomlinson ES, Maggs JL, Park BK, Back DJ. Dexamethasone metabolism
by human liver in vitro. Metabolite identification and inhibition of 6-hydroxylation. J 
Pharmacol Exp Ther 1996;277:105-12.
Hallek M, Cheson BD, Catovsky D, et al.  Guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia: a report from the International Workshop on Chronic 
Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 
guidelines. Blood 2008;111:5446-5456.
Hellmann A, Rule S, Walewski J, et al. Effect of cytochrome P450 3A4 inducers on the
pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in patients with 
multiple myeloma or non-Hodgkin's lymphoma. Clin Pharmacokinet 2011;50:781-791.
Honigberg LA, Smith AM, Sirisawad M, et al.  The Bruton tyrosine kinase inhibitor 
PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease 
and B-cell malignancy. PNAS 2010;107:13075-13080.
IMBRUVICA [package insert].  Horsham, PA: Janssen Biotech, Inc; 2014.
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals. 2014 Dec.  
Available from: http://www.ICMJE.org.  Accessed February 04, 2015.
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Mohamed AJ, Yu L, Bäckesjö CM, et al. Bruton's tyrosine kinase (Btk): function, 
regulation, and transformation with special emphasis on the PH domain. Immunol Rev 
2009;228:58-73.
Ocio EM, Richardson PG, Rajkumar SV, et al. New drugs and novel mechanisms of 
action in multiple myeloma in 2013: a report from the International Myeloma Working 
Group (IMWG). Leukemia 2014;28:525-542.
Rajkumar SV, Harousseau JL, Durie B, et al; International Myeloma Workshop 
Consensus Panel 1. Consensus recommendations for the uniform reporting of clinical 
trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011 
May 5;117(18):4691-5. 
Rajkumar SV, Jacobus S, Callander NS, et a; Eastern Cooperative Oncology Group.
Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose
dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label 
randomised controlled trial. Lancet Oncol 2010;11:29-37. Erratum in: Lancet Oncol
2010;11:14.
Romano A, Conticello C, Cavalli M, et al. Salvage therapy of multiple myeloma: the new 
generation drugs. Biomed Res Int 2014;2014:456037. Epub 2014 May 19.
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 2012:120:1877-1887.
Vail DM, Thamm DH. Spontaneously occurring tumors in companion animals as models 
for drug development. In: Teicher BA, Anders PA, eds. Anticancer Drug Development 
Guide: Preclinical Screening, Clinical Trials, and Approval. 2nd Ed. Totowa, NJ: Human 
Press; 2004:259-284.
Vail DM, Michels GM, Khanna C, Selting KA, London CA; Veterinary Cooperative 
Oncology Group. Response evaluation criteria for peripheral nodal lymphoma in dogs 
(v1.0)—a Veterinary Cooperative Oncology Group (VCOG) consensus document. Vet 
Comp Oncol 2010;8:28-37.
Vihinen M, Mattsson PT, Smith CI. Bruton tyrosine kinase (Btk) in X-linked 
agammaglobulinemia (XLA). Front Biosci 2000;5:D917-D928.
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Product: ACP-196
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9.0
APPENDICES
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Appendix 1. Performance Status Scores 
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, eg, light house 
work, office work
2
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair
5
Dead
As published in Am J Clin Oncol:
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin 
Oncol 5:649-655, 1982.
Credit: Eastern Cooperative Oncology Group Chair: Robert Comis, MD
Available at: http://www.ecog.org/general/perf_stat.html.  Accessed 23 August 2013.
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Protocol: ACE-MY-001
Appendix 2.  Adverse Event Assessment of Causality
Is there a reasonable possibility that the event may have been caused by study drug?  
No___ Yes___
The descriptions provided below will help guide the principal investigator in making the 
decision to choose either “yes” or “no”:
No = There is no reasonable possibility that the event may have been caused by study 
drug.
The adverse event:
x
may be judged to be due to extraneous causes such as disease or environment 
or toxic factors
x
may be judged to be due to the subject’s clinical state or other therapy being 
administered
x
is not biologically plausible
x
does not reappear or worsen when study drug is re-administered
x
does not follow a temporal sequence from administration of study drug
Yes = There is a reasonable possibility that the event may have been caused by study 
drug.
The adverse event:
x
follows a temporal sequence from administration of study drug
x
is a known response to the study drug based on clinical or preclinical data
x
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
x
disappears or decreases upon cessation or reduction of dose of study drug
x
reappears or worsens when study drug is re-administered
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Appendix 3.  Known Strong in Vivo Inhibitors of CYP3A4
Strong Inhibitors of CYP3Aa
Strong Inducers of CYP3Ae
boceprevir
carbamazepinef
clarithromycinb
phenytoinf
conivaptinb
rifampinf
grapefruit juicec
St John's wortf
indinavir
itraconazoleb
ketoconazoleb
lopinavir/ritonavirb (combination drug)
mibefradild
nefazodone
nelfinavir
posaconazole
ritonavirb
saquinavir
telaprevir
telithromycin
voriconazole
a.
A strong inhibitor for CYP3A is defined as an inhibitor that increases the AUC of a substrate for CYP3A 
by  5-fold.
b.
In vivo inhibitor of P-glycoprotein.
c.
The effect of grapefruit juice varies w idely among brands and is concentration-, dose-, and preparation-
dependent. Studies have show n that it can be classified as a “strong CYP3A inhibitor” w hen a certain
preparation w as used (eg, high dose, double strength) or as a “moderate CYP3A inhibitor” w hen 
another preparation w as used (eg, low  dose, single strength).
d.
Withdraw n from the United States market because of safety reasons.
e.
A strong inducer for CYP3A is defined as an inducer that results in  80% decrease in the AUC of a 
substrate for CYP3A.
f.
In vivo inducer of P-glycoprotein.  
Note: The list of drugs in these tables is not exhaustive. Any questions about drugs not on this list 
should be addressed to the Medical Monitor of the protocol.
Source:
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Web link 
Accessed 21 January 2015: 
http://w w w.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabe
ling/ucm093664.htm#inVivo
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Product: ACP-196
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Protocol: ACE-MY-001
Appendix 4. Dexamethasone Prescribing Information
The United States label for dexamethasone tablets (Roxane Laboratories 2007) is
provided for reference.  The United States label will also serve as the Reference Safety 
Information for dexamethasone for this study.  Country-specific labels will be provided to 
investigative sites as appropriate.
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Product: ACP-196
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Appendix 5.  Schedule of Assessments
Screeninga
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycles 5-12b
ET/Safety 
Follow Upc
Days (± 2)
Days (± 2)
Days (± 2)
Days (± 2)
Days (± 2)
1
8
15
22
28
15
28
28
28
28
Informed consent
x
Confirm eligibility
x
Medical history
x
PEd/Vital signse/Weight
x
x
x
x
x
x
x
x
x
x
x
x
ECOG status
x
x
x
x
x
x
x
x
x
x
x
x
ECGf
x
x
x
Lab assessments:
Urine pregnancy 
testg
x
x
Hematologyh
x
xq
x
x
x
x
x
x
x
x
x
x
Serum chemistryi
x
xq
x
x
x
x
x
x
x
x
x
x
Urinalysisj
x
x
x
x
x
Every 2 mos
T/B/NK cell countk
xq
x
x
x
x
Every 6 mos
Disease markersl
x
x
x
x
x
x
Every 2 mos
x
Bone marrow
(aspirate/biopsy)
/Skeletal surveyp
x
As 
clinically 
indicated 
or to 
confirm a 
CR
As 
clinically 
indicated 
or to 
confirm a 
CR
As clinically 
indicated or
to confirm a 
CR
Pharmacodynamics
xm
xm
xn
xn
x
Pharmacokineticso
x
x
x
x
x
ACP-196/
dexamethasone
dispensed
x
x
x
x
x
x
x
x
x
x
Study drug compliance
x
x
x
x
x
x
x
x
x
x
Tumor assessmentp
x
x
x
x
x
x
Concomitant 
medications
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
Abbreviations: CR = complete remission; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ET + early termination; Ig = immunoglobulin; 
mos = months; PE = physical exam;
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Product: ACP-196
Date: 20 March 2015
Protocol: ACE-MY-001
Footnotes for ACE-MY-001 Schedule of Study Activities:
a. 
Screening tests should be performed w ithin 21 days before the first administration of study drug, unless otherwise indicated.
b.
Any subjects who have not progressed while receiving study drug treatment, may be eligible to enroll into a long-term follow  up study and continue to receive ACP-
196.
c.
An early termination visit is required for any subjects who permanently discontinue study drug early for any reason including disease progression.  A 30-day (± 7 days) 
safety follow-up visit is required when subjects discontinue study drug unless they start another anticancer therapy within that timeframe.
d.
The screening physical examination w ill include, at a minimum, the general appearance of the subject, height (screening only) and w eight, and examination of the 
skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system.  Symptom-directed physical exams 
are done thereafter.  
e.
Vital signs (blood pressure, pulse, respiratory rate, and temperature) will be assessed after the subject has rested in the sitting position.  
f.
Subjects should be in supine poVLWLRQDQGUHVWLQJIRU10 minutes before study-related ECGs.  
g.
Women of childbearing potential only.  If positive, pregnancy must be ruled out by ultrasound to be eligible.
h.
Hematology includes complete blood count w ith differential and platelet and reticulocyte counts. Cycle 1 Day 1 hematology does not need to be repeated if screening 
hematology w as within 5 days.
i.
Serum chemistry: albumin, alkaline phosphatase, bone-specific alkaline phosphatase, alanine transaminase (ALT), aspartate aminotransferase (AST), bicarbonate, 
blood urea nitrogen (BUN), calcium, chloride, creatinine, C-terminal telopeptide, glucose, lactate dehydrogenase (LDH), magnesium, phosphate, potassium, sodium, 
total bilirubin, total protein, and uric acid. Cycle 1 Day 1 serum chemistry does not need to be repeated if screening serum chemistry w as within 5 days.
j.
Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, N-terminal telopeptide, and glucose. 
k.
T/B/NK cell count (ie, CD3, CD4, CD8, CD19, CD16/56).  During Cycle 5-12, only done at end of Cycle 6 and 12.
l.
Refer to Section 4.1 for a list of myeloma disease markers.
m.
Pharmacodynamic samples are draw n predose and 4 hours (±10 minutes) postdose on the days indicated. Note: These timepoints are relative to the morning dose.
n.
Pharmacodynamic samples are draw n predose on the days indicated.
o.
Pharmacokinetic samples are draw n per Table 4-1.
p
Refer to Section 4-2. Bone marrow  aspirate/biopsy and skeletal survey are required at baseline (ie, before the first dose of study drug).  Thereafter they are required 
as indicated in the table above.
q.
The indicated samples at this timepoint (Cycle 1 Day 1) must be draw n predose.
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Product: ACP-196
Date: 11 July 2014 
Protocol: ACE-MY-001
Acerta Pharma 
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Page 1 of 64
PROTOCOL
TITLE:
An Open-label, Phase 1b Study of ACP-196 in Subjects 
with Multiple Myeloma
PROTOCOL NUMBER:
ACE-MY-001
STUDY DRUG:
ACP-196
IND NUMBER:
118717
SPONSOR MEDICAL 
MONITOR:
Acerta Pharma BV
SPONSOR:
Acerta Pharma BV
Molenstraat 110
5342 CC Oss
The Netherlands
PROTOCOL DATE:
11 July 2014
Confidentiality Statement 
This document contains proprietary and confidential information of Acerta Pharma BV
that must not be disclosed to anyone other than the recipient study staff and members of 
the institutional review board (IRB)/independent ethics committee (IEC). This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Acerta Pharma BV.




Product: ACP-196 
Date: 11 July 2014 
Protocol: ACE-MY-001 
 
 
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TABLE OF CONTENTS 
1.0 
BACKGROUND INFORMATION ................................................................ 15 
1.1 
Role of Btk in Lymphoid Cancers ................................................................. 15 
1.2 
Preclinical Studies ....................................................................................... 15 
1.2.1 
Chemistry ....................................................................................... 16 
1.2.2 
Efficacy Pharmacology ................................................................... 16 
1.2.3 
Safety Pharmacology ..................................................................... 17 
1.2.4 
Drug-drug Interaction Potential....................................................... 18 
1.2.5 
In Vivo General Toxicology ............................................................ 18 
1.3 
Clinical Experience ...................................................................................... 19 
1.4 
Summary and Conclusions .......................................................................... 22 
2.0 
STUDY OBJECTIVES ................................................................................. 22 
2.1 
Primary Objective ........................................................................................ 22 
2.2 
Secondary Objectives: ................................................................................. 22 
3.0 
STUDY DESIGN .......................................................................................... 23 
3.1 
Description of Study ..................................................................................... 23 
3.2 
Study Parameters ........................................................................................ 23 
3.2.1 
Safety Parameters .......................................................................... 23 
3.2.2 
Efficacy Parameters ....................................................................... 24 
3.2.3 
Pharmacokinetic and Pharmacodynamic Parameters .................... 24 
3.3 
Rationale for Study Design and Dosing Regimen ........................................ 24 
3.4 
Selection of Study Population ...................................................................... 25 
3.4.1 
Inclusion Criteria ............................................................................. 25 
3.4.2 
Exclusion Criteria ........................................................................... 25 
3.4.3 
Replacement of Subjects ............................................................... 26 
3.4.4 
Enrollment and Randomization Procedures ................................... 26 
3.5 
Study Drug ................................................................................................... 27 
3.5.1 
Premedications ............................................................................... 27 
3.5.2 
Formulation, Packaging, and Storage ............................................ 27 
3.5.2.1 
ACP-196 .......................................................................... 27 
3.5.2.2 
Dexamethasone............................................................... 28 
3.5.3 
Administration of Study Drug .......................................................... 28 
3.5.3.1 
ACP-196 .......................................................................... 28 
3.5.3.2 
Dexamethasone............................................................... 28 
3.5.4 
Assuring Subject Compliance......................................................... 29 
3.5.5 
Study Treatment Regimen and Dose Modifications ....................... 29 
3.5.5.1 
ACP-196 .......................................................................... 29 


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3.5.5.2 
Dexamethasone............................................................... 30 
3.6 
Concomitant Therapy................................................................................... 31 
3.6.1 
Permitted Concomitant Therapy ..................................................... 31 
3.6.2 
Prohibited Concomitant Therapy .................................................... 31 
3.7 
Precautions .................................................................................................. 31 
3.7.1 
Dietary Restrictions ........................................................................ 31 
3.7.2 
Drug-drug Interactions .................................................................... 31 
3.7.3 
Reproductive Toxicity ..................................................................... 32 
3.7.4 
Overdose Instructions .................................................................... 32 
3.8 
Stopping Rules ............................................................................................ 33 
3.9 
Data and Safety Monitoring ......................................................................... 34 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS ............................................... 34 
4.1 
Description of Procedures ............................................................................ 35 
4.1.1 
Informed Consent ........................................................................... 35 
4.1.2 
Medical History ............................................................................... 35 
4.1.3 
Adverse Events .............................................................................. 35 
4.1.4 
Concomitant Medications and Therapy .......................................... 35 
4.1.5 
Confirmation of Eligibility ................................................................ 35 
4.1.6 
ECOG Performance Status ............................................................ 35 
4.1.7 
Physical Examination, Vital Signs, Height & Weight ....................... 35 
4.1.8 
Bone Marrow Aspirate and Biopsy ................................................. 36 
4.1.9 
Electrocardiogram .......................................................................... 36 
4.1.10 Urine Pregnancy Test ..................................................................... 36 
4.1.11 Hematology .................................................................................... 36 
4.1.12 Serum Chemistry ............................................................................ 37 
4.1.13 Urinalysis ........................................................................................ 37 
4.1.14 T/B/NK Cell Count .......................................................................... 37 
4.1.15 Disease Markers ............................................................................ 37 
4.1.16 Skeletal Survey .............................................................................. 37 
4.1.17 Pharmacodynamics ........................................................................ 37 
4.1.18 Pharmacokinetics ........................................................................... 38 
4.1.19 Tumor Assessment ........................................................................ 38 
4.1.20 Study Drug Accountability .............................................................. 39 
4.2 
Investigator’s Assessment of Response to Treatment ................................. 39 
4.3 
Safety Follow-up Visit .................................................................................. 41 
4.4 
Missed Evaluations ...................................................................................... 41 
5.0 
STATISTICAL METHODS OF ANALYSIS .................................................. 42 
5.1 
General Considerations ............................................................................... 42 


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5.2 
Sample Size Considerations ........................................................................ 42 
5.3 
Definition of Analysis Sets ........................................................................... 42 
5.4 
Missing Data Handling ................................................................................. 43 
5.5 
Endpoint Data Analysis ................................................................................ 43 
5.5.1 
Safety Endpoint .............................................................................. 43 
5.5.2 
Demographics and Baseline Characteristics .................................. 43 
5.5.3 
Analysis of Efficacy Parameters ..................................................... 43 
5.5.3.1 
Response Rate ........................................................................ 43 
5.5.3.2 
Duration of Response ............................................................. 44 
5.5.3.3 
Progression-free Survival ....................................................... 44 
5.5.3.4 
Time-to-Next Treatment .......................................................... 44 
5.5.4 
Analysis of Pharmacokinetic/Pharmacodynamic Parameters ........ 44 
5.5.5 
Explorative or Correlative Analyses ................................................ 45 
6.0 
ASSESSMENT OF SAFETY ....................................................................... 45 
6.1 
Definitions .................................................................................................... 46 
6.1.1 
Adverse Events .............................................................................. 46 
6.1.2 
Serious Adverse Event ................................................................... 46 
6.1.3 
Severity .......................................................................................... 47 
6.2 
Documenting and Reporting of Adverse and Serious Adverse Events ........ 48 
6.2.1 
Adverse Event Reporting Period .................................................... 48 
6.2.2 
Assessment of Adverse Events ...................................................... 48 
6.2.3 
Pregnancy ...................................................................................... 48 
6.2.4 
Expedited Reporting Requirements for Serious Adverse Events ... 49 
6.2.5 
Type and Duration of Follow-up of Subjects After Adverse Events 50 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS .......... 50 
7.1 
Institutional Review Board and Independent Ethics Committee ................... 51 
7.2 
Informed Consent and Protected Subject Health Information Authorization 51 
7.3 
Subject Screening Log ................................................................................. 52 
7.4 
Case Report Forms ..................................................................................... 52 
7.5 
Study Monitoring Requirements ................................................................... 52 
7.6 
Investigational Study Drug Accountability .................................................... 53 
7.7 
Record Retention ......................................................................................... 54 
7.8 
Protocol Amendments.................................................................................. 54 
7.9 
Publication of Study Results ........................................................................ 55 
7.10 
Clinical Trial Insurance................................................................................. 55 
7.11 
General Investigator Responsibilities ........................................................... 56 
8.0 
REFERENCES ............................................................................................ 57 
9.0 
APPENDICES ............................................................................................. 59 


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In–text Tables 
Table 1-1.  Assessment of ACP-196 Active-site Occupancy in  Fine Needle Aspirates of 
Canine Lymph Node Tumors (N=4) .......................................................................17 
Table 1-2.  ACP-196 Clinical Studies .............................................................................19 
Table 1-3.  Btk Occupancy in Peripheral Blood of Subjects from ACE-CL-001 ..............20 
Table 3-1.  ACP-196 Dose Levels for Cohort 1 and Cohort 2 ........................................29 
Table 4-1.  Pharmacokinetic Sample Schedule .............................................................38 
 


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ABBREVIATIONS 
 
AE(s) 
adverse event(s) 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
 
 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BCR 
B-cell receptor 
BID 
twice a day (dosing) 
Btk 
Bruton tyrosine kinase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
Cmax 
maximum concentration 
CLL 
chronic lymphocytic leukemia 
 
 
CR 
complete remission (response) 
CSSF 
Clinical Supplies Shipping Receipt Form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
 
 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
FDA 
Food and Drug Administration 
FIH 
first-in-human (trial) 
FLC 
(serum) free light chains 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 


Product: ACP-196 
Date: 11 July 2014 
Protocol: ACE-MY-001 
 
 
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HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
HNSTD 
highest nonseverely toxic dose 
ICF 
informed consent form 
 
 
IEC 
Independent Ethics Committee 
IFE 
immunofixation electrophoresis 
Ig 
immunoglobulin 
IRB 
Institutional Review Board 
LDH 
lactate dehydrogenase 
LTFU 
long-term follow up 
 
 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
multiple myeloma 
MR 
minor response 
NHL 
non-Hodgkin lymphoma 
NK 
natural killer (cells) 
ORR 
overall response rate 
PBMC(s) 
peripheral blood mononuclear cells 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PR 
partial remission (response) 
QD 
once a day (dosing) 
QTc 
corrected QT interval 
SAE(s) 
serious adverse event(s) 
SD 
stable disease 
SFLC 
serum free light chains 
SIFE 
serum immunofixation electrophoresis 
SPD 
sum of the products of the perpendicular diameters (of lymph nodes) 
SPEP 
serum protein electrophoresis 
SUSAR 
Suspected Unexpected Serious Adverse Reaction (report) 
Tmax 
time to maximum drug concentration 


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Date: 11 July 2014 
Protocol: ACE-MY-001 
 
 
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UIFE 
urine immunofixation electrophoresis 
ULN 
upper limit of normal 
UPEP 
urine serum protein electrophoresis 
VGPR 
very good partial response  
 
 
WHO 
World Health Organization 


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Date: 11 July 2014 
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STUDY SYNOPSIS  
Protocol Number: 
ACE-MY-001 
Study Drug: 
ACP-196 
Protocol Title: 
An Open-label, Phase 1b Study of ACP-196 in Subjects with 
Multiple Myeloma 
Phase: 
Phase 1b 
Comparator: 
None 
Background and 
Rationale for Study 
Clinical studies have shown that targeting the B-cell receptor 
(BCR) signaling pathway by inhibiting Bruton tyrosine kinase (Btk) 
produces significant clinical benefit in patients with non-Hodgkin 
lymphoma (NHL) and chronic lymphocytic leukemia (CLL). 
Preclinical studies have shown that Btk inhibition significantly 
reduces in vivo multiple myeloma (MM) cell growth and MM cell-
induced osteolysis in a murine model (Tai 2012).  Data on the 
utility of Btk targeted therapy in patients with MM is very 
preliminary, but suggests there are subsets of patients with 
malignant plasma cell clones in which Btk is active as evidenced 
by expression of phosphorylated Btk (p-Btk), and that these 
cancers may be particularly responsive to Btk inhibitor therapy. 
Acerta Pharma BV (Acerta Pharma) has developed a novel second 
generation Btk inhibitor, ACP-196, that achieves significant oral 
bioavailability and potency in preclinical models. ACP-196 
monotherapy is currently in Phase 1 studies in subjects with 
chronic lymphocytic leukemia (CLL) and in healthy volunteers.   
The purpose of this study is to evaluate the safety, 
pharmacokinetics (PK), pharmacodynamics (PD), and activity of 
2 different schedules of ACP-196 administration in subjects with 
relapsed MM.  The study will explore the concept of whether 
biomarkers may help identify patients with MM that be particularly 
benefit from Btk inhibitor therapy.  
Study Design: 
This study is a multicenter, open-label, randomized, parallel-group 
study.  Forty subjects will be equally randomized (1:1 ratio) into 
2 cohorts to receive ACP-196, without or without dexamethasone:  
x 
Cohort 1: ACP-196 100 mg twice per day (BID) continuously 
x 
Cohort 2: ACP-196 100 mg BID continuously and 
dexamethasone 40 mg once weekly  
Twenty-eight days of study drug administration is 1 cycle.  
Treatment may be continued for > 28 days until disease 
progression or an unacceptable drug-related toxicity occurs.  For 
subjects in Cohort 1, if documented disease progression occurs, 


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then dexamethasone can be added to the treatment regimen.  
Additional dose modification provisions are provided in the study 
protocol.  All subjects who discontinue study drug will have a 
safety follow-up visit 30 (±7) days after the last dose of study drug 
unless they have started another cancer therapy within that 
timeframe.  
All subjects will have hematology, chemistry, and urinalysis safety 
panels done at screening.  Once dosing commences (Day 1), all 
subjects will be evaluated for safety, including serum chemistry 
and hematology, once weekly for the first 4 weeks, every 2 weeks 
in Cycle 2 and monthly thereafter.  PK/PD testing will be done in 
Cycle 1. Tumor assessments will be done at 8- to 12-week 
intervals during the trial. 
Refer to Appendix 4 for a comprehensive list of study assessments 
and their timing.  
Study Objectives: 
Primary Objective: 
x 
To characterize the safety profile of ACP-196 with and without 
dexamethasone in subjects with relapsed or refractory MM 
Secondary Objectives: 
x 
To characterize the PK profile of ACP-196 with and without 
dexamethasone and the PK profile of dexamethasone with 
concomitant ACP-196 administration 
x 
To evaluate the PD effects of ACP-196 with and without 
dexamethasone 
x 
To evaluate the activity of ACP-196 with and without 
dexamethasone as measured by response rate, duration of 
response, time-to-next treatment, and progression-free survival 
x 
To explore the relationship between biological markers in MM 
cells and response to therapy 
Safety Parameters: 
Type, frequency, severity, timing of onset, duration, and 
relationship to study drug (ie, ACP-196, dexamethasone, or both) 
of any adverse events (AEs) or abnormalities of laboratory tests; 
serious adverse events (SAEs); or AEs leading to discontinuation 
of study treatment. 
Efficacy Parameters: 
x 
Overall response rate (ORR) 
x 
Duration of response 
x 
Progression-free survival 
x 
Time-to-next treatment 


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Pharmacokinetic 
Parameters: 
The plasma PK of ACP-196 will be characterized using 
noncompartmental analysis. The following PK parameters will be 
calculated, whenever possible, from plasma concentrations of 
analytes: 
x 
AUC(0-t):  Area under the plasma concentration-time curve 
calculated using linear trapezoidal summation from time 0 to 
time t, where t is the time of the last measurable concentration 
(Ct). 
x 
AUC(0-24):  Area under the plasma concentration-time curve 
from 0 to 24 hours, calculated using linear trapezoidal 
summation. 
x 
AUC(0-∞):  Area under the plasma concentration-time curve from 
0 to infinity, calculated using the formula: AUC(0-∞) = AUC(0-t) + 
Ct / λz, where λz is the apparent terminal elimination rate 
constant. 
x 
Cmax:  Maximum observed plasma concentration 
x 
Tmax:  Time of the maximum plasma concentration (obtained 
without interpolation) 
x 
t½:  Terminal elimination half-life (whenever possible) 
x 
λz:  Terminal elimination rate constant (whenever possible) 
x 
Cl/F:  Oral clearance 
Pharmacodynamic 
Parameters: 
The occupancy of Btk by ACP-196 will be measured in peripheral 
blood mononuclear cells (PBMCs) and in bone marrow, when 
available, with the aid of a biotin-tagged ACP-196 analogue probe.  
The effect of ACP-196 on biologic markers of B-cell function will 
also be evaluated. 
Sample Size: 
Forty subjects with 20 subjects in each cohort. 
Inclusion Criteria: 
x 
Men and women ≥ 18 years of age. 
x 
A confirmed diagnosis of MM, which has relapsed after, or 
been refractory to ≥ 1 prior therapy for MM, and is progressing 
at the time of study entry. 
x 
Eastern Cooperative Oncology Group (ECOG) performance 
status of ≤ 2. 
x 
Agreement to use acceptable methods of contraception during 
the study and for 30 days after the last dose of study drug if 
sexually active and able to bear or beget children. 
x 
Agreement to refrain from sperm donation during the study and 
for 30 days after the last dose of study drug. 
x 
Willing and able to participate in all required evaluations and 
procedures in this study protocol including swallowing capsules 
without difficulty. 
x 
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 


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national and local subject privacy regulations). 
Exclusion Criteria: 
x 
Prior malignancy, except for adequately treated basal cell or 
squamous cell skin cancer, in situ cervical cancer, or other 
cancer from which the subject has been disease free for 
≥ 2 years or which will not limit survival to < 2 years. Note: 
these cases must be discussed with the Medical Monitor. 
x 
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 ACP-196, or put the study outcomes at undue 
risk. 
x 
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 
x 
Malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or small 
bowel, symptomatic inflammatory bowel disease, or partial or 
complete bowel obstruction. 
x 
Any immunotherapy within 4 weeks of first dose of study drug. 
x 
The time from the last dose of the most recent chemotherapy 
or experimental therapy to the first dose of study drug is 
< 5 times the half-life of the previously administered agent(s). 
x 
Relapsed or refractory to prior Btk inhibitor therapy. 
x 
Ongoing immunosuppressive therapy, including systemic or 
enteric corticosteroids for treatment of MM or other conditions. 
Note: Subjects may use topical or inhaled corticosteroids as 
therapy for comorbid conditions. During study participation, 
subjects may receive systemic or enteric corticosteroids as 
needed for MM therapy or treatment-emergent comorbid 
conditions. 
x 
Grade ≥ 2 toxicity (other than alopecia) continuing from prior 
anticancer therapy including radiation. 
x 
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. 
x 
Major surgery within 4 weeks before first dose of study drug. 
x 
History of stroke or intracranial hemorrhage within 6 months 
before the first dose of study drug. 
x 
Requires anti-coagulation with warfarin or a vitamin K 
antagonist.  
x 
ANC < 0.75 x 109/L or platelet count < 50 x 109/L unless 
associated with >50% plasma cells in the marrow. 
x 
Creatinine > 2.5 x institutional upper limit of normal (ULN); total 
bilirubin > 2.5 x ULN (unless due to Gilbert’s disease); and 
aspartate aminotransferase (AST) or alanine aminotransferase 


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(ALT) > 2.5 x ULN unless disease related. 
x 
Significant screening electrocardiogram (ECG) abnormalities 
including left bundle-branch block, 2nd-degree AV block type II, 
3rd-degree block, Grade t 2 bradycardia, or QTc > 480 msec. 
x 
Breastfeeding or pregnant. 
x 
Concurrent participation in another therapeutic clinical trial. 
Dosage Form and 
Strength: 
ACP-196 is provided as 25- and 100-mg hard gelatin capsules 
prepared using standard pharmaceutical grade excipients.  
Dose Regimen/Route 
of Administration: 
ACP-196 is an orally administered product.  ACP-196 will be 
administered on an empty stomach defined as no food 2 hours 
before and 1 hour after dosing.  
Regimens: 
x 
Cohort 1 (BID): 100 mg ACP-196 (1 x 100-mg capsule) 
administered 12 hours apart (BID dosing = 200-mg total daily 
dose) 
x 
Cohort 2 (BID + dexamethasone): 100 mg ACP-196 
(1 x 100-mg capsule) administered 12 hours apart (BID dosing 
= 200-mg total daily dose) plus 40 mg dexamethasone (1 x 
40-mg capsule) administered once weekly (weekly dosing = 
40-mg total weekly dose) 
Statistics: 
Subjects meeting the stated eligibility requirements will be enrolled 
onto the study. Subjects will be equally randomized into 1 of 
2 regimens (ACP-196 with or without dexamethasone).  With a 
sample size of 19 subjects per cohort, the power to detect the 
difference between a null-hypothesis response rate of 15% and an 
alternative response rate of 40% with a 0.025 one-sided 
significance level is 0.84 using a one-group, chi-square test and 
0.69 using a one-group, exact binomial test.  A sample size of 
19 subjects per cohort will also provide a 97.5% one-sided 
confidence interval centered around an expected ORR of 40% that 
excludes an ORR of 18.6% as a lower bound. 
Descriptive statistics (including means, standard deviations, and 
medians for continuous variables and proportions for discrete 
variables) will be used to summarize data, as appropriate.  
 
 


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1.0 
BACKGROUND INFORMATION 
1.1 
ROLE OF BTK IN LYMPHOID CANCERS 
Bruton tyrosine kinase (Btk) is a non-receptor enzyme of the Tec kinase family that is 
expressed among cells of hematopoietic origin, including B cells, myeloid cells, mast 
cells and platelets, where it regulates multiple cellular processes including proliferation, 
differentiation, apoptosis, and cell migration (Mohamed 2009, Bradshaw 2010). 
Functional null mutations of Btk in humans cause the inherited disease, X-linked 
agammaglobulinemia, which is characterized by a lack of mature peripheral B cells 
(Vihinen 2000). Conversely, Btk activation is implicated in the pathogenesis of several 
B-cell malignancies (Buggy 2012). Taken together, these findings have suggested that 
inhibition of Btk may offer an attractive strategy for treating B-cell neoplasms. Ibrutinib 
(IMBRUVICA™), a first-generation oral, small-molecule Btk inhibitor has been approved 
for the treatment for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma 
(MCL) and is being evaluated for activity in other B-cell neoplasms including multiple 
myeloma (MM).  Preclinical studies have shown that Btk inhibition with ibrutinib 
significantly reduces in vivo multiple myeloma (MM) cell growth and MM cell-induced 
osteolysis in a murine model (Tai 2012).  While current therapies have provided 
substantial benefit to patients, MM remains incurable; for patients who experience 
disease relapse after application of existing therapies, the prognosis is dismal and new 
drugs and therapeutic strategies are required for continued disease control (Romano 
2014).  Inhibition of Btk may simultaneously address the MM-related bone complications 
as well improve patient outcome in MM (Edwards 2012). 
1.2 
PRECLINICAL STUDIES 
Knowledge of the critical importance of Btk in tumor biology and the clinical profile 
observed with ibrutinib has encouraged the development of second-generation Btk 
inhibitors as a therapy for lymphoid cancers. Acerta Pharma, a pharmaceutical company 
with sites in San Carlos, CA, USA and in Oss, The Netherlands, has identified novel 
compounds that selectively inhibit Btk. Chemical optimization, pharmacologic 
characterization, and toxicologic evaluation have led to identification of ACP-196, an 
orally bioavailable, new chemical entity that covalently inhibits Btk and shows 
encouraging activity and acceptable safety in nonclinical studies. ACP-196 may offer an 
improved therapeutic index relative to ibrutinib and may be more readily combined with 
other agents active in the therapy of lymphoid cancers.  Summaries of preclinical studies 


Product: ACP-196
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Protocol: ACE-MY-001
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are provided below. For more detailed information please refer to the Investigator’s 
Brochure.  
1.2.1 
Chemistry 
 ACP-196 is 
orally bioavailable in animals and is suitable for formulating in capsules. For clinical 
testing, ACP-196 has been manufactured and formulated according to current Good 
Manufacturing Practices (cGMP). 
1.2.2 
Efficacy Pharmacology 
Spontaneous canine B-cell lymphoma shares many characteristics with human NHL, 
including diagnostic classifications and response to Btk inhibition (Honigberg 2010). The 
life expectancy in untreated animals with aggressive disease is ~6 weeks, thus enabling 
rapid assessment of drug efficacy (Vail and Thamm, 2004). ACP-196 is currently being 
evaluated in an ongoing dose-escalation study in canine spontaneous B-cell lymphoma.  
Fourteen dogs, all of which had diffuse large B-cell lymphoma (DLBCL) confirmed by 
histology, have been treated with ACP-196 for at least 2 weeks. The dosages have 
ranged from 2.5 to 20 mg/kg once (QD) or twice (BID) per day.  To date, per Veterinary 
Cooperative Oncology Group criteria for assessment of response in peripheral nodal 
lymphoma (Vail 2010), partial responses (PRs) been observed in 4 of 14 dogs (29%) 
and stable disease has been observed in 8 of 14 dogs (57%).  No ACP-196-related 
adverse events (AEs) have been reported to date in this study.  These findings are 
preliminary and similar to the clinical responses (ie, 1 dog with PR out of 5 dogs treated 
with suspected or confirmed DLBCL) observed with ibrutinib in dogs with spontaneous 
B-cell lymphoma (Honigberg 2010). 
Preliminary results assessing Btk occupancy using a biotin-tagged analogue of ACP-196
show near complete Btk occupancy over 24 hours with both BID and QD dosing in 
canine tumor tissue (Table 1-1). 


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Table 1-1.  Assessment of ACP-196 Active-site Occupancy in  
Fine Needle Aspirates of Canine Lymph Node Tumors (N=4) 
Timing 
Dog Identification and ACP-196 Dosing Regimen 
DL-12 
DL-14 
DL-15 
DL-16 
10 mg/kg BID 
20 mg/kg QD 
20 mg/kg QD 
20 mg/kg QD 
Btk Occupancy (% versus predose) 
Day 1 (3 hours 
after morning 
dose) 
99% 
98% 
87% 
99% 
Day 7 (before 
morning dose) 
98% 
77% 
ND 
93% 
BID = twice per day; Btk = Bruton tyrosine kinase; ND = not determined; QD = once per 
day 
These canine data provide nonclinical support for the ability of ACP-196 to target Btk in 
vivo. The role of Btk expression in driving the proliferation and survival of malignant 
plasma cells in multiple myeloma (MM) has been less clear than among other lymphoid 
cancers. However, emerging, unpublished, preclinical data from the laboratory of Sagar 
Lonial (Emory University) suggest that Btk and phosphorylated Btk (p-Btk) expression is 
present to varying levels in a standard panel of 12 myeloma cell lines, thus providing a 
basis for evaluating Btk inhibition as a therapy for MM. 
1.2.3 
Safety Pharmacology 
In vitro and in vivo safety pharmacology studies with ACP-196 have demonstrated a 
favorable nonclinical safety profile.  
When screened at 10 μM in binding assays evaluating interactions with 80 known 
pharmacologic targets such as G-protein-coupled receptors, nuclear receptors, 
proteases, and ion channels, ACP-196 shows significant activity only against the 
A3 adenosine receptor; follow-up dose-response experiments indicated a IC50 of 2.7 μM, 
suggesting a low clinical risk of off-target effects.  ACP-196 at 10 μM showed no 
inhibition of in vitro epidermal growth factor receptor (EGFR) phosphorylation in an A431 
human epidermoid cancer cell line, whereas ibrutinib had an IC50 of 66 nM.  
The in vitro effect of ACP-196 on human ether-à-go-go-related gene (hERG) channel 
activity was investigated in vitro in human embryonic kidney cells stably transfected with 
hERG. ACP-196 inhibited hERG channel activity by 25% at 10 μM, suggesting a low 
clinical risk that ACP-196 would induce clinical QT prolongation as predicted by this 
assay. 


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ACP-196 was well tolerated in standard in vivo Good Laboratory Practices (GLP) studies 
of pharmacologic safety. A functional observation battery in rats at doses of through 
300 mg/kg (the highest dose level) revealed no adverse effects on neurobehavioral 
effects or body temperature at any dose level. A study of respiratory function in rats also 
indicated no treatment-related adverse effects at doses through 300 mg/kg (the highest 
dose level). In a cardiovascular function study in awake telemeterized male beagle dogs, 
single doses of ACP-196 at dose levels through 30 mg/kg (the highest dose level) 
induced no meaningful changes in body temperature, cardiovascular, or 
electrocardiographic (ECG) (including QT interval) parameters.  The results suggest that 
ACP-196 is unlikely to cause serious off-target effects or adverse effects on critical 
organ systems. 
1.2.4 
Drug-drug Interaction Potential 
In vitro metabolism studies using mouse, rat, dog, rabbit, monkey, and human 
hepatocytes incubated with 14C-labelled ACP-196 indicated 2 mono-oxidized metabolites 
and a glutathione conjugate. No unique human metabolite was identified. Preliminary 
evaluations of metabolism in the plasma, bile, and urine of rats, dogs, and monkeys 
indicated metabolic processes of oxidation, glutathione binding, and hydrolysis. It was 
shown that ACP-196 binds to glutathione but does not deplete glutathione in vitro. 
In vitro experiments evaluating loss of parent drug as catalyzed by cytochrome P450 
enzymes (CYPs) indicated that ACP-196 is metabolized by CYP3A4. Drugs potentially 
altering activity of this isoenzyme may alter ACP-196 disposition (see Section 1.3).  
Nonclinical CYP interaction studies data indicate that ACP-196 is very unlikely to cause 
clinical drug-drug interactions through alteration of the metabolism of drugs that are 
substrates for CYPs. 
1.2.5 
In Vivo General Toxicology 
To date, the toxicology program has included 28-day GLP evaluations in rats and dogs. 
In the 28-day study in male and female Sprague-Dawley rats, animals received oral 
gavage ACP-196 dosages of 30, 100, and 300 mg/kg/day. In the 28-day study in male 
and female beagle dogs, animals received oral ACP-196 dosages of 3, 10, and 
30 mg/kg/day. Both studies had 28-day recovery periods. 
The no observable adverse effect level in the dog was 30 mg/kg/day, which was the 
highest dose evaluated. In rats, 30 mg/kg/day resulted in minimal inflammation of the 


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pancreas in some animals, with reversal, indicating the rat to be the more sensitive 
preclinical species. The pancreatic effects were minimally increased at 100 mg/kg/day in 
the rat though there was no clinical evidence of toxicity. Hence, 100 mg/kg/day was 
selected to conservatively represent the highest nonseverely toxic dose (HNSTD).  In 
dogs at 30 mg/kg/day, no adverse effects on the pancreas were observed.  In rats and 
dogs, no adverse ECG or histopathologic cardiovascular effects were noted at the 
planned conclusion of the 28-day toxicology studies. However, in 5 of 6 rats from the 
300-mg/kg dose group that died early in the study, slight to moderate necrosis of the 
myocardium and/or white blood cell infiltration/inflammation of the myocardium were 
noted on microscopic examination of the hearts. These findings were most likely 
incidental postmortem changes. 
1.3 
CLINICAL EXPERIENCE 
Table 1-2 lists the studies currently being conducted with ACP-196 monotherapy.   
Table 1-2.  ACP-196 Clinical Studies 
Protocol 
Design 
Subjects 
Enrolled 
Status 
ACE-CL-001 
(NCT02029443) 
x 
First-in-human 
x 
Open label 
x 
Dose escalation (100-450 mg QD) 
x 
Subjects with relapsed/refractory 
CLL 
24 
x 
1st cohort (100 mg 
QD) enrolled and 
no DLTs observed.   
x 
2nd cohort (175 mg 
QD) enrolled and 
no DLTs observed. 
x 
3rd cohort (250 mg 
QD) enrolled and 
no DLTs observed. 
ACE-HV-001 
x 
Open label 
x 
Single-dose escalation 
(2.5-50 mg BID and 100 mg QD) 
x 
Food effect (75 mg QD) 
x 
Drug-drug interaction (50 mg QD) 
x 
Healthy volunteers 
59 
x 
Enrollment 
completed. 
x 
No adverse 
laboratory, vital 
signs, or ECGs 
findings observed. 
x 
1 event each of 
constipation, 
feeling cold, 
somnolence (each 
Grade 1) was 
reported as related 
to study drug. 
AE = adverse event; BID = twice per day; CLL = chronic lymphocytic leukemia; DLT = dose-
limiting toxicity; QD = once per day 
 
ACE-CL-001 (NCT02029443), an ongoing FIH study in subjects with relapsed/refractory 
CLL, has a sequential, dose-escalation design. The starting dosage for ACP-196 is 
100 mg QD and the DLT observation period is 28 days (ie, 1 cycle of treatment).  To 


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date, ACP-196 has been well tolerated with no DLTs observed from 100 to 250 mg QD. 
PD data from the first 2 cohorts in this study show that Btk occupancy with ACP-196, in 
peripheral blood cells, is > 95% at 4 hours after dosing but decreases to < 90% 24 hours 
after QD dosing (Table 1-3).  
Table 1-3.  Btk Occupancy in Peripheral Blood of Subjects from ACE-CL-001 
 
Percent Btk Occupancy Versus Day 1 Predose 
  
100 mg QD 
175 mg QD 
Timing 
Mean Std Dev 
N 
Mean 
Std Dev 
N 
Day 1: 4 h postdose 
96.0 
3.2 
8 
97.4 
2.4 
8 
Day 1: 24 h postdose 
84.4 
9.8 
8 
80.2 
10.7 
8 
Day 8: predose 
87.6 
5.0 
8 
87.0 
10.5 
7 
Day 8: 4 h postdose 
98.0 
1.8 
8 
96.6 
5.1 
7 
Btk = Bruton tyrosine kinase; std dev = standard deviation; QD = once per day 
 
To date, 16 subjects have been evaluated for tumor response in the 100- and 175-mg 
cohorts after 56 days of treatment; a response rate of 81% (13 of 16 subjects) has been 
observed based on International Working Group response criteria (Halleck 2008) as 
recently updated (Cheson 2012).  Of the 16 evaluable subjects, 15 (94%) have 
experienced reductions in lymphadenopathy, with 7 subjects achieving PRs, 6 subjects 
experiencing a ≥ 50% decrease in lymphadenopathy with lymphocytosis (ie, PR with 
lymphocytosis), and 3 subjects having stable disease (SD) (Figure 1-1).  As shown in the 
figure, substantial response has been observed even among subjects with the adverse 
prognostic indicator of del17p in CLL cells. ACP-196 has been well tolerated in all 
subjects. 


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Figure 1-1.  Changes in the SPDs of Lymph Nodes at Week 8  
of ACP-196 Therapy as Documented by CT Scans 
(Evaluable CLL Subjects, N=16) 
 
CLL = chronic lymphocytic leukemia; CT= computed tomography; PR = partial response; 
PR+L = partial response with lymphocytosis; SD = stable disease; SPD = sum of the 
products of the perpendicular diameters (of lymph nodes). 
 
ACE-HV-001 is a dose-ranging, food-effect, and drug-drug interaction study evaluating 
BID and QD dosing for 1 day in healthy volunteers.  The starting dose for ACP-196 was 
2.5 mg BID.  The healthy volunteer study has completed and no adverse laboratory, vital 
signs, or ECG findings were observed (2.5 to 50 mg BID; 50 to 100 mg QD). Three AEs 
related to study drug were reported.  Each AE was Grade 1 and resolved without 
treatment.  The AEs were constipation (2.5 mg BID), feeling cold (75 mg QD), and 
somnolence (75 mg QD). 
The food-effect evaluation indicated that there was no difference in area under the curve 
(AUC) between the fed and fasted states; however, there was an approximately 3-fold 
decrease in the mean maximum concentration (Cmax) in the fed state. Therefore, 
ACP-196 should be administered on an empty stomach as outlined in Section 3.5.3.   


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The effect of coadministration of a potent CYP3A4 inhibitor, itraconazole, on the plasma 
levels of ACP-196 was also evaluated.  The mean plasma ACP-196 Cmax and AUClast 
values increased 4.1- and 5.3-fold, respectively, in the presence of itraconazole relative 
to no pretreatment. Please refer to Section 3.7.2 for more information on drug-drug 
interactions. 
1.4 
SUMMARY AND CONCLUSIONS 
This study comprises a pilot evaluation of the safety and activity of the potent, second-
generation Btk inhibitor, ACP-196, in patients with relapse or refractory MM. The design 
and conduct of this study is supported by an understanding of the natural history and 
current therapies for subjects with lymphoid cancers; knowledge of the activity and 
safety of the first-generation BCR inhibitor (eg, ibrutinib) in subjects with hematologic 
cancers; and the available nonclinical and clinical information regarding ACP-196. 
Preclinical studies are ongoing in parallel to identify biomarkers that may be evaluated in 
this clinical trial as correlates of response to Btk-directed therapy and that may permit 
selection of patients who are particularly likely to benefit from ACP-196 treatment for 
MM. 
2.0 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
x 
To characterize the safety profile of ACP-196 with and without dexamethasone in 
subjects with relapsed or refractory MM 
2.2 
SECONDARY OBJECTIVES: 
x 
To characterize the PK profile of ACP-196 with and without dexamethasone and the 
PK profile of dexamethasone with concomitant ACP-196 administration 
x 
To evaluate the PD effects of ACP-196 with and without dexamethasone 
x 
To evaluate the activity of ACP-196 with and without dexamethasone as measured 
by response rate, duration of response, time-to-next treatment, and progression-free 
survival 
x 
To explore the relationship between biological markers in MM cells and response to 
therapy 


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3.0 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This study is a multicenter, open-label, randomized, parallel-group study.  Forty subjects 
will be randomized 1:1 into the following 2 cohorts to receive ACP-196, with or without 
dexamethasone: 
x 
Cohort 1: ACP-196 100 mg BID continuously  
x 
Cohort 2: ACP-196 100 mg BID continuously and 40 mg dexamethasone once 
weekly  
Twenty-eight days of study drug administration is 1 cycle.  Treatment may be continued 
for > 28 days until disease progression or an unacceptable drug-related toxicity occurs.  
For subjects in Cohort 1, if documented disease progression occurs, then 
dexamethasone can be added to the treatment regimen.  Additional modification 
provisions are provided in Section 3.5.5.  All subjects who discontinue study drug will 
have a safety follow-up visit 30 (±7) days after the last dose of study drug unless they 
have started another cancer therapy within that timeframe.  
All subjects will have standard hematology, chemistry, and urinalysis safety panels 
performed at screening.  Once dosing commences (Day 1), all subjects will be evaluated 
for safety, including serum chemistry and hematology, once weekly for the first 4 weeks, 
every 2 weeks in Cycle 2 and monthly thereafter.  PK/PD testing will be done in Cycle 1. 
Tumor assessments will be done at 8- to 12-week intervals during the trial. 
Refer to Appendix 4 for a comprehensive list of study assessments and their timing. 
3.2 
STUDY PARAMETERS 
3.2.1 
Safety Parameters 
The safety of ACP-196 with and without dexamethasone will be characterized by the 
type, frequency, severity, timing of onset, duration, and relationship to study drug (ie, 
ACP-196, dexamethasone, or both) of any treatment-emergent AEs or abnormalities of 
laboratory tests; serious adverse events (SAEs); 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. Standard definitions for seriousness will be applied (see Section 6.1). 


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3.2.2 
Efficacy Parameters 
Standardized response and progression criteria have been established for MM (Durie 
2006); assessments of ACP-196 efficacy in this study will be based on these criteria. 
Efficacy endpoints will include: 
x 
Overall response rate (ORR) 
x 
Duration of response 
x 
Progression-free survival 
x 
Time-to-next treatment 
3.2.3 
Pharmacokinetic and Pharmacodynamic Parameters 
Standard PK parameters for ACP-196 and dexamethasone in plasma will be evaluated 
in this study.  A full description of the PK parameters is provided in Section 5.5.4. 
The occupancy of Btk by ACP-196 will be measured in peripheral blood mononuclear 
cells (PBMCs) and bone marrow, when available, with the aid of a biotin-tagged 
ACP-196 analogue probe.  The effect of ACP-196 on biologic markers of B-cell function 
will also be evaluated. 
3.3 
RATIONALE FOR STUDY DESIGN AND DOSING REGIMEN 
As described in Section 1.3, preliminary data from the ongoing FIH study in subjects with 
relapsed/refractory CLL have shown that ACP-196 is well tolerated at dosages of 
100 and 250 mg QD.  In addition, preliminary PD data from the first 2 cohorts in the FIH 
study suggest full Btk occupancy (96% to 98%) in peripheral blood is observed 4 hours 
after dosing but decreases to < 90% occupancy at 24 hours (Table 1-3).  These data 
suggest that de novo synthesis of Btk can occur within 24 hours in peripheral blood cells.  
BID dosing may ensure Btk inhibition for the entire 24 hours and thus may be beneficial 
in terms of increasing efficacy and/or decreasing development of resistance to ACP-196.  
In addition, having information regarding the safety and pharmacology of a BID schedule 
may support future combination studies with other drugs that are administered BID.   
Evaluation of dexamethasone as a combination partner for ACP-196 builds on known 
antineoplastic activity of this drug in patients with MM. Dexamethasone therapy is 
commonly coadministered with targeted agents for MM (Ocio 2014).  The dosing 
regimen of 40 mg weekly to be used in this study has been established based on 
randomized trial data showing the superiority of this method of administration (Rajkumar 
2009). Combined use of ACP-196 and dexamethasone provides an all oral, non-
cytotoxic regimen that may have increased efficacy relative to administration of the 


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individual agents alone. While dexamethasone can increase CYP3A4 activity and thus 
might enhance ACP-196 metabolism, it is considered a weak inducer of this isoenzyme 
and has not substantially altered the disposition of other CYP3A4 substrates (eg, 
bortezomib) that are commonly used in the therapy of MM (Hellmann 2011). The 
randomized design of this pilot study will allow the potential for drug-drug interactions 
between ACP-196 and dexamethasone to be assessed. 
3.4 
SELECTION OF STUDY POPULATION 
3.4.1 
Inclusion Criteria 
Eligible subjects will be considered for inclusion in this study if they meet all of the 
following criteria:  
1. Men and women ≥ 18 years of age. 
2. A confirmed diagnosis of MM, which has relapsed after, or been refractory to 
≥ 1 prior therapy for MM, and is progressing at the time of study entry. 
3. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 
4. Agreement to use acceptable methods of contraception during the study and for 
30 days after the last dose of study drug if sexually active and able to bear or beget 
children. 
5. Agreement to refrain from sperm donation during the study and for 30 days after the 
last dose of study drug. 
6. Willing and able to participate in all required evaluations and procedures in this study 
protocol including swallowing capsules without difficulty. 
7. 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 subject privacy regulations). 
3.4.2 
Exclusion Criteria 
Subjects will be ineligible for this study if they meet any of the following criteria: 
1. Prior malignancy, except for adequately treated basal cell or squamous cell skin 
cancer, in situ cervical cancer, or other cancer from which the subject has been 
disease free for ≥ 2 years or which will not limit survival to < 2 years. Note: these 
cases must be discussed with the Medical Monitor. 
2. A life-threatening illness, medical condition or organ system dysfunction which, in the 
investigator’s opinion, could compromise the subject’s safety, interfere with the 
absorption or metabolism of ACP-196, 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. 


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4. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or 
resection of the stomach or small bowel, symptomatic inflammatory bowel disease, 
or partial or complete bowel obstruction. 
5. Any immunotherapy within 4 weeks of first dose of study drug. 
6. The time from the last dose of the most recent chemotherapy or experimental 
therapy to the first dose of study drug is < 5 times the half-life of the previously 
administered agent(s). 
7. Relapsed after or refractory to prior Btk inhibitor therapy. 
8. Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids 
for treatment of MM or other conditions. Note: Subjects may use topical or inhaled 
corticosteroids as therapy for comorbid conditions. During study participation, 
subjects may also receive systemic or enteric corticosteroids as needed for MM 
therapy or treatment-emergent comorbid conditions. 
9. Grade ≥ 2 toxicity (other than alopecia) continuing from prior anticancer therapy 
including radiation. 
10. Known history of human immunodeficiency virus (HIV) or active infection with 
hepatitis C virus (HCV) or hepatitis B virus (HBV) or any uncontrolled active systemic 
infection.  
11. Major surgery within 4 weeks before first dose of study drug. 
12. History of stroke or intracranial hemorrhage within 6 months before the first dose of 
study drug. 
13. Requires anti-coagulation with warfarin or a vitamin K antagonist. 
14. ANC < 0.75 x 109/L or platelet count < 50 x 109/L unless >50% marrow involvement 
with plasma cells are present. 
15. Creatinine > 2.5 x institutional upper limit of normal (ULN); total bilirubin > 2.5 x ULN 
(unless due to Gilbert’s disease); and aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) > 2.5 x ULN unless disease related. 
16. Significant screening ECG abnormalities including left bundle-branch block, 
2nd-degree AV block type II, 3rd-degree block, Grade t 2 bradycardia, or 
QTc > 480 msec. 
17. Breastfeeding or pregnant. 
18. Concurrent participation in another therapeutic clinical trial. 
3.4.3 
Replacement of Subjects 
Any subjects who do not complete Cycle 2 may be replaced at the discretion of the study 
investigators and sponsor. 
3.4.4 
Enrollment and Randomization Procedures 
Enrollment of a subject into the study will be performed according to the following 
procedure:  


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x 
Notify the sponsor when a clinically eligible subject is identified and is ready to 
screen, to ensure enrollment availability on the study. 
x 
After the subject has signed and dated the Informed Consent Form (ICF), all 
screening procedures have been completed, and eligibility has been confirmed, the 
subject can be officially enrolled in the study.  
x 
To enroll a subject, the study center will fax/email a completed Enrollment 
Confirmation Form to the sponsor.  The enrollment date will be the date that the form 
is faxed/emailed to the sponsor. 
x 
An Enrollment Confirmation Form will be completed and faxed/emailed to the study 
center by the sponsor within 24 hours. 
x 
The Enrollment Confirmation Form will contain cohort allocation per the 
randomization scheme generated by the sponsor. 
Treatment must begin within the screening window (Section 4.1) and after the site has 
received the cohort allocation from the sponsor.  Study treatment is not blinded on this 
study. 
3.5 
STUDY DRUG 
3.5.1 
Premedications 
No specific premedications or supporting medications are required in conjunction with 
ACP-196 administration.  
3.5.2 
Formulation, Packaging, and Storage 
3.5.2.1 
ACP-196 
ACP-196 should be stored according to the instructions on the label that is affixed to the 
package containing the drug product.   
ACP-196 capsules are available in 2 dose strengths: 25 and 100 mg. The 25-mg 
capsules are Swedish orange in color; the 100-mg capsules are grey in color.  Capsules 
also include the following inactive excipients: microcrystalline cellulose, gelatin, and 
globally acceptable colorant.  ACP-196 will be provided in white, high-density 
polyethylene bottles; each bottle contains 30 capsules. 
If a drug shipment arrives damaged, or if there are any other drug complaints, a 
SAE/Product Complaint Form should be completed and emailed or faxed to the sponsor 
or the sponsor’s representative.   


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Refer to the Investigator’s Brochure for additional information. 
3.5.2.2 
Dexamethasone 
This study will use commercially available dexamethasone.  Please refer to the 
appropriate dexamethasone package insert for storage and handling instructions. 
3.5.3 
Administration of Study Drug  
3.5.3.1 
ACP-196 
Investigators are prohibited from supplying ACP-196 to any subjects not properly 
enrolled in this study or to any physicians or scientists except those designated as 
subinvestigators on FDA Form 1572.  The investigator must ensure that subjects receive 
ACP-196 only from personnel who fully understand the procedures for administering the 
drug. 
ACP-196 is intended to be administered orally with 8 ounces (approximately 240 mL) of 
water.  Subjects should be instructed to take each dose of study drug on an empty 
stomach defined as no food 2 hours before and 1 hour after dosing. The capsules 
should be swallowed intact and subjects should not attempt to open capsules or dissolve 
them in water.  Dietary restrictions are provided in Section 3.7.1. 
If a dose is missed, it can be taken up to 6 hours after the scheduled time with a return 
to the normal schedule the following day.  If it has been greater than 6 hours, the dose 
should not be taken and the subject should take the next dose at the 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. 
3.5.3.2 
Dexamethasone 
This study will use commercially available dexamethasone tablets for oral administration.  
At the time of weekly dexamethasone administration, the subject should take the 
dexamethasone tablets simultaneously with the ACP-196 capsules and with 8 ounces 
(approximately 240 mL) of water.  The dexamethasone tablets should be swallowed 
intact and subjects should not attempt to chew them or dissolve them in water.  
If a dexamethasone dose is missed, it can be taken up to 3.5 days (84 hours) days after 
the scheduled time with a return to the normal schedule the following week.  If the 
interval of missed dosing has been > 3.5 days (84 hours), the dexamethasone dose 
should not be taken and the subject should take the next dose at the scheduled time in 


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the following week.  The missed dexamethasone dose will not be made up and must be 
returned to the site at the next scheduled visit. 
3.5.4 
Assuring Subject Compliance 
During cycle 1, subjects will receive their Day 1, 8, 15, 22, and 28 doses (for Cohort 2 
this includes the dexamethasone dose) in the clinic because predose PK/PD 
measurements are required.  For treatments that are taken in the clinic, subjects should 
take the dose from the drug dispensed for them for that particular time period.  All other 
treatments will be taken at home.  Subjects will receive a diary to record the specific time 
each dose was taken and to record reasons for any missed doses.   
Subject compliance will be assessed at every visit.  The subject will be instructed to 
bring the diary and any remaining ACP-196 capsules and dexamethasone tablets to the 
clinic at their next visit.  The administrator will review the diary and ask the subject if all 
of the capsules and tablets were administered.  Any remaining or returned capsules and 
tablets will be counted and recorded as described in Section 7.6.  Returned capsules or 
tablets must not be redispensed to another subject. The study staff will resupply the 
subject with the correct number of ACP-196 capsules and dexamethasone tablets 
needed for use until the next visit. 
3.5.5 
Study Treatment Regimen and Dose Modifications 
3.5.5.1 
ACP-196 
ACP-196 dose levels and capsule numbers are shown in Table 3-1.  Lower dose levels 
are provided should individual subjects require an ACP-196 dose reduction for drug-
related toxicity.  A higher dose level is provided should an individual subject warrant a 
dose escalation for lack of response or for disease progression. 
Table 3-1.  ACP-196 Dose Levels for Cohort 1 and Cohort 2 
Dose 
Level 
Dosage 
Twice per Day 
(mg) 
Capsule 
Strength 
(mg) 
Capsule 
Number per 
Dose 
Total Daily 
Dosage 
(mg) 
+1 
200 
100 
2 
400 
Starting 
100 
100 
1 
200 
-1 
50 
25 
2 
100 
-2 
25 
25 
1 
50 
 
 
 
Subjects should be followed closely for AEs or laboratory abnormalities that might 
indicate ACP-196-related toxicity and for disease response to ACP-196 therapy.  If a 
subject experiences an ACP-196-related adverse event requiring dose modification 


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during the course of ACP-196 therapy, then study drug administration should be held, as 
necessary, until the AE resolves or stabilizes to an acceptable degree.  As appropriate, 
certain laboratory abnormalities may warrant more frequent monitoring (eg, once per 
week) until abnormalities have recovered to Grade d 1. Thereafter, ACP-196 may be 
reinstituted at the current dose or at a lower dose, based on the judgment of the 
investigator. Successive adjustments to progressively lower dose levels can be done as 
outlined in Table 3-1. 
After a dose is reduced for apparent drug-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 ACP-196 for ≥ 4 weeks then the ACP-196 dose may 
be increased to the next higher dose level, at the discretion of the investigator.  Such re-
escalation may be particularly warranted if further evaluation reveals that the AE that led 
to the dose reduction was not study drug-related.  Successive adjustments to 
progressively higher dose levels, as outlined in the tables above, can be made at 4-week 
intervals.   
Individual subjects who are tolerating the current dose level of ACP-196 therapy may 
have the dose escalated, as outlined in the tables above, if the investigator feels that a 
dose escalation is medically warranted to maximize therapeutic benefit (eg, for lack of 
response or for disease progression in a subject who is tolerating the current dose level 
of ACP-196 therapy).  In addition, subjects in Cohort 1 who have reached the highest 
dose level allowed by the protocol and show lack of response or disease progression 
may have dexamethasone (40 mg once weekly) added to their treatment. 
Whenever possible, any dose adjustment of ACP-196, including adding dexamethasone 
to subjects in Cohort 1, should be discussed between the investigator and the Acerta 
Pharma medical monitor before implementation. The appropriate clinic staff should 
dispense the study drug for the new dose level and instruct the subject/caregiver about 
the change in dose level. 
3.5.5.2 
Dexamethasone 
This study will use commercially available dexamethasone.  Dosing of dexamethasone 
will be 40 mg once weekly.  For subjects who experience intolerable dexamethasone-
related adverse effects, dexamethasone may be reduced to 20 mg once weekly. 


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3.6 
CONCOMITANT THERAPY 
3.6.1 
Permitted Concomitant Therapy 
Antiemetics are permitted if clinically indicated.  Standard supportive care medications 
are permitted as per institutional standards.   
For subjects considered at risk for tumor lysis syndrome:  Administer appropriate 
hydration and allopurinol or rasburicase per institutional standards before initiating 
treatment. 
3.6.2 
Prohibited Concomitant Therapy 
Any chemotherapy, immunotherapy, kinase inhibitors, bone marrow transplantation, 
experimental therapy, and radiotherapy are prohibited (see Section 3.4.2).   
3.7 
PRECAUTIONS 
3.7.1 
Dietary Restrictions 
There are no dietary restrictions on this protocol. 
Subjects should be encouraged to follow instructions relating to eating relative to study 
drug administration (Section 3.5.3). 
3.7.2 
Drug-drug Interactions 
At the systemic exposure levels expected in this study, ACP-196 inhibition of CYP-
mediated metabolism of other drugs is not anticipated.  However, ACP-196 is 
metabolized in part by CYP3A4. In a clinical drug-drug interaction study, 
coadministration of the potent CYP3A4 inhibitor, itraconazole, increased the mean 
plasma exposures of ACP-196 by > 4-fold (see Section 1.3). Dexamethasone is also 
metabolized by CYP3A4 (Gentile 1996). These data indicate that coadministration of 
inhibitors of CYP3A4 could increase ACP-196 and dexamethasone exposure while 
coadministration of inducers of these enzymes could decrease ACP-196 or 
dexamethasone exposure. Thus, there is the potential that subjects receiving inhibitors 
of these enzymes might have exaggerated pharmacological or toxic responses to 
ACP-196 or dexamethasone or that those receiving inducers of these enzymes might 
have reduced ACP-196 or dexamethasone activity. A list of inhibitors or inducers of 
CYP3A4 is provided in Appendix 3.  Subjects receiving concomitant medications that are 
inhibitors or inducers of these isoenzymes should have therapeutically equivalent drugs 
that do not inhibit these enzymes substituted if possible (particularly if the 


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coadministered agents are strong inhibitors or inducers).  If substitution is not possible, 
investigators should carefully monitor for toxicity or loss of ACP-196 activity and 
appropriately alter ACP-196 administration consistent with protocol recommendations for 
dose modification in response to ACP-196-related adverse events (see Section 3.5.3). 
The study medical monitor should be consulted if there are questions regarding the 
potential for drug-drug interactions with ACP-196. 
3.7.3 
Reproductive Toxicity 
Reproductive toxicity studies have not been done with ACP-196.  Therefore, subjects 
with reproductive potential who are sexually active must use acceptable methods of 
contraception during the study and for 30 days after the last dose of ACP-196.  
Examples of acceptable methods of contraception include condoms, implants, 
injectables, combined oral contraceptives, intrauterine devices, true sexual abstinence, 
or sterilized partner.  Note that periodic abstinence, eg, calendar, ovulation, 
symptothermal, postovulation methods or withdrawal, are not acceptable methods of 
contraception. 
Subjects should promptly notify the investigator if they, or their partner, become 
pregnant during this period. If a female subject becomes pregnant during the treatment 
period, she must discontinue ACP-196 immediately.  Pregnancy in a female subject or a 
male subject’s partner must be reported (see Section 6.2.3). Male subjects must agree 
to refrain from sperm donation during the study and for 30 days after the last dose of 
study drug. 
3.7.4 
Overdose Instructions 
For any subject experiencing an ACP-196 overdose (administration of a dose 
≥ 1.5 times the highest intended dose level in the clinical study protocol), observation for 
any symptomatic side effects should be instituted, and vital signs, biochemical and 
hematologic parameters should be followed closely (consistent with the protocol or more 
frequently, as needed). Appropriate supportive management to mitigate adverse effects 
should be initiated. If the overdose ingestion is recent and substantial, and if there are no 
medical contraindications, use of gastric lavage or induction of emesis may be 
considered. 
The Acerta Pharma Medical Monitor should be contacted if a study drug overdose 
occurs.  


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3.8 
STOPPING RULES 
All study participants may receive ACP-196 indefinitely as long as they are safely 
benefitting. However: 
x 
Any subject has the right to withdraw from the study at any time. 
x 
Any subject who has objective evidence of definitive MM progression while receiving 
study treatment at the highest individual tolerable dose level allowed in the protocol 
(total dose = 400 mg of ACP-196 plus dexamethasone) (see Section 3.5.5) should 
be withdrawn from the study treatment.  Note: If there is uncertainty regarding 
whether there is MM progression, the subject should continue study treatment and 
remain under close observation (eg, evaluated at 4- to 8-week intervals) pending 
confirmation of progression. In particular, worsening of constitutional symptoms in 
the absence of objective evidence of worsening MM will not be considered definitive 
disease progression; in such subjects, both MM-related and non-MM-related causes 
for the constitutional symptoms should be considered. Transient worsening of 
disease during temporary interruption of study therapy (eg, for intercurrent illness) 
may also not indicate definitive disease progression. In these instances, relevant 
clinical, laboratory, and/or radiographic assessment should be attempted to 
document whether definitive disease progression has occurred. If subsequent 
evaluations suggest that the subject has experienced persistent definitive disease 
progression, then the date of progression will be the timepoint at which progression 
was first objectively documented. 
x 
Any subject is unable to tolerate a second rechallenge with protocol-described, dose-
modified levels (see Section 3.5.5) should be withdrawn from the study treatment 
unless continued therapy is permitted by the Acerta Pharma medical monitor. 
x 
Any subject whose medical condition substantially changes after entering the study 
should be carefully evaluated by the investigator in consultation with the 
Acerta Pharma medical monitor. Such subjects should be withdrawn from study 
treatment if continuing would place them at risk.  
x 
Any subject who becomes pregnant or begins breastfeeding should be removed from 
study treatment. 
x 
Any subject who becomes significantly noncompliant with study drug administration, 
study procedures, or study requirements should be withdrawn from study treatment 


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in circumstances that increase risk or substantially compromise the interpretation of 
study results. 
x 
The investigator, in consultation with the Acerta Pharma medical monitor, may 
withdraw any subject from the study treatment, if, in the investigator’s opinion, it is 
not in the subject’s best interest to continue.  
Subjects who discontinue study therapy will continue on study for follow-up of safety 
(Section 4.3) and time-to-next therapy for MM unless they withdraw consent for further 
follow-up. Thus, all subjects receiving ≥ 1 dose of study drug will be followed during the 
immediate posttherapy and long-term follow-up assessments unless the subject 
withdraws consent for such follow-up to be conducted. The date the subject is withdrawn 
from study treatment or from the study (including long-term follow-up) and the reason for 
discontinuation will be recorded and also should be described on the appropriate 
electronic case report form (eCRF).   
3.9 
DATA AND SAFETY MONITORING 
This trial will be monitored in accordance with the sponsor’s Pharmacovigilance 
Committee procedures.  Adverse events and SAEs will be reviewed internally on an 
ongoing basis to identify safety concerns.  Quarterly conference calls with the 
investigators will be conducted to discuss study progress, obtain investigator feedback 
and exchange, and discuss "significant safety events" (ie, AEs leading to dose 
reductions, related SAEs, and deaths).   
4.0 
STUDY ACTIVITIES AND ASSESSMENTS 
The schedule of events is provided in Appendix 4.  Descriptions of the scheduled 
evaluations are outlined below and complete information on study drug and dosing is 
provided in Section 3.5. 
Before study entry, throughout the study, and at the follow-up evaluation, various clinical 
and diagnostic laboratory evaluations are 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. 


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4.1 
DESCRIPTION OF PROCEDURES 
4.1.1 
Informed Consent 
The subject must read, understand and sign the IRB/IEC approved ICF confirming his or 
her willingness to participate in this study before initiating any screening activity that is 
not standard of care.  Subjects must also grant permission to use protected health 
information. 
4.1.2 
Medical History 
The subject’s complete history should be collected and recorded through review of 
medical records and by interview. Concurrent medical signs and symptoms must be 
documented to establish baseline severities. A disease history, including the date of 
initial diagnosis and list of all prior anticancer treatments, and responses and duration of 
response to these treatments, also will be recorded. 
4.1.3 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 6.1  All medical 
occurrences from the time of first dose that meet this definition must be recorded. 
Important additional requirements for reporting SAEs are explained in Section 6.2. 
4.1.4 
Concomitant Medications and Therapy 
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 should be 
documented. 
4.1.5 
Confirmation of Eligibility 
Subject eligibility for enrollment will be assessed per Section 3.4.  All screening 
procedures, unless otherwise indicated, should be completed within 21 days of the first 
dose of study drug. 
4.1.6 
ECOG Performance Status 
The ECOG performance index is provided in Appendix 1. 
4.1.7 
Physical Examination, Vital Signs, Height & Weight 
The screening physical examination will include, at a minimum, the general appearance 
of the subject, height (screening only) and weight, and examination of the skin, eyes, 


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ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous 
system, and lymphatic system. 
Symptom-directed physical exams, including tumor assessments by palpation, will be 
done during the treatment period and at the safety follow-up visits. 
Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) will be 
assessed after the subject has rested in the sitting position.   
4.1.8 
Bone Marrow Aspirate and Biopsy 
A bone marrow aspirate and biopsy will be done at screening or up to 30 days before the 
main screening procedures.  Per the current response criteria (Durie 2006), a bone 
marrow aspirate/biopsy will also be required at any time on study to confirm a complete 
response (CR).  The baseline bone marrow aspirate/biopsy will used for 
immunohistochemistry and/or flow cytometry, cytogenetics, and FISH.  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.  
When available, any unused bone marrow tissue will be used for PD testing.  PD testing 
will be done by the sponsor. 
4.1.9 
Electrocardiogram 
Subjects should be in supine position and resting for ≥ 10 minutes before study-related 
ECGs.  At screening, results from the sites ECG machine (12-lead; triplicates taken 
≥ 1 minute apart) will be averaged to determine eligibility and must meet the eligibility 
criteria of QTc ≤ 480 msec.   
4.1.10 
Urine Pregnancy Test 
Pregnancy tests will be required only for women with childbearing potential. If positive, 
pregnancy must be ruled out by ultrasound.  Testing will be done by a central laboratory 
as listed on the investigator’s form FDA 1572. 
4.1.11 
Hematology 
Hematology studies must include complete blood count (CBC) with differential and 
platelet and reticulocyte counts.  Testing will be done by a central laboratory as listed on 
the investigator’s form FDA 1572. 


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4.1.12 
Serum Chemistry 
Serum chemistry must 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, potassium, sodium, total bilirubin, total protein, and uric acid.  If an 
unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, 
magnesium, and potassium) must be done to coincide with the ECG testing.  Testing will 
be done by a central laboratory as listed on the investigator’s form FDA 1572. 
4.1.13 
Urinalysis 
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, N-terminal 
telopeptide, and glucose.  Testing will be done by a central laboratory as listed on the 
investigator’s form FDA 1572.  
4.1.14 
T/B/NK Cell Count 
Flow cytometry testing for CD3+, CD4+, CD8+, CD19+, and CD16/56+ cells.  Testing will 
be done by a central laboratory as listed on the investigator’s form FDA 1572. 
4.1.15 
Disease Markers 
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 central laboratory 
as listed on the investigator’s form FDA 1572. 
4.1.16 
Skeletal Survey 
Standard lateral radiograph of the skull, anterioposterior and lateral views of the spine, 
and anterioposterior views of the pelvis, ribs, femora, and humeri are required at 
screening or baseline (ie, before the first dose of study drug).  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.   
4.1.17 
Pharmacodynamics 
Blood samples and bone marrow, when available, will be used for PD testing (eg, Btk 
occupancy and B-cell activation).  Refer to the laboratory binder for instructions on 
collecting and processing these samples.  Testing will be done by the sponsor. 


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4.1.18 
Pharmacokinetics 
Refer to the laboratory binder for instructions on collecting and processing these 
samples. Testing will be performed at a central clinical laboratory.  The PK sampling 
timepoints are provided in Table 4-1. 
Table 4-1.  Pharmacokinetic Sample Schedule 
 
HOURS POSTDOSE 
Cycle 
Day Predose 
0.5 
(±5 min) 
0.75 
(±5 min) 
1 
(±5 min) 
2 
(±10 min) 
4 
(±10 min) 
6 
(±10 min) 
1 
1 
X 
X 
X 
X 
X 
X 
X 
 
8 
X 
 
 
X 
 
 
 
 
15 
X 
 
 
X 
 
 
 
 
22 
X 
X 
X 
X 
X 
X 
X 
 
28 
X 
 
 
X 
 
 
 
Note: These timepoints are relative to the morning dose. 
 
4.1.19 
Tumor Assessment 
Baseline myeloma assessments will consist of: 
● M-protein determination using both of the following procedures: 
○ SPEP and SIFE 
○ UPEP and UIFE (all using the same 24-hour urine collection)  
● SFLC 
● Plasmacytoma evaluation 
● Bone marrow to quantify percent myeloma cell involvement (aspirate and 
biopsy required at baseline) 
● Skeletal survey: lateral radiograph of the skull, anterioposterior and lateral 
views of the spine, and anterioposterior views of the pelvis, ribs, femora, and 
humeri 
● β2-microglobulin 


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On-study myeloma assessments will consist of: 
● SPEP and/or UPEP (if results were measurable at baseline); quantitative 
immunoglobulins if used to follow disease; immunofixation to confirm a 
complete response 
● SFLC 
● Plasmacytoma evaluation (if only measurable disease at baseline) 
● Bone marrow aspirate and/or trephine bone biopsy (to confirm a complete 
response or if clinically indicated). 
4.1.20 
Study Drug Accountability 
See Section 7.6. 
4.2 
INVESTIGATOR’S ASSESSMENT OF RESPONSE TO TREATMENT 
Subjects will be evaluated by investigator review for disease response and progression 
according to the International Myeloma Working Group (IMWG; Durie 2006) and 
European Group for Blood and Marrow Transplant (EBMT; Bladé 1998) criteria as listed 
below.  Response categories include sCR, CR, nCR, VGPR, PR, SD, and progressive 
disease. In addition, the number of subjects achieving the response category of MR will 
also be evaluated and reported.   Subjects will be considered evaluable for response if 
they have a baseline and t1 adequate on-study anti-myeloma assessment obtained 
t4 weeks from the start of therapy.   
Table 4-1.  Response Criteria (incorporating EBMT [Bladé 1998] and IMWG [Durie 
2006]) 
Response Subcategory 
Response Criteria a 
Complete response (CR) 
x 
Negative immunofixation on the serum and urine and 
x 
Disappearance of any soft tissue plasmacytomas and 
x 
< 5% plasma cells in bone marrowb. 
Stringent complete 
response (sCR) 
x 
CR as defined above plus 
x 
Normal FLC ratio and 
x 
Absence of clonal cells in bone marrowb by immunohistochemistry 
or immunofluorescencec. 
Near complete response 
(nCR) 
x 
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. 


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Very good partial 
response (VGPR) 
x 
Serum and urine M-component detectable by immunofixation but 
not on electrophoresis or 
x 
≥ 90% reduction in serum M-component plus urine M-component 
< 100 mg per 24 h. 
Partial response (PR) 
x 
≥ 50% reduction of serum M-protein and reduction in 24-h urinary 
M-protein by ≥ 90% or to < 200 mg per 24 h 
x 
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 
x 
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% 
x 
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) 
x 
MR includes subjects in whom some, but not all, criteria for PR are 
fulfilled providing the remaining criteria satisfy the requirements for 
MR. 
x 
Requires all of the following: 
o 
t 25% to d 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 
25-49% 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 
time to progression 
estimates) 
x 
Not meeting criteria for CR, VGPR, MR, PR or progressive 
disease 
 
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: 
x 
Increase of ≥ 25% from lowest response value in serum M-
component and/or (the absolute increase must be ≥ 0.5 g/dL)e. 
x 
Urine M-component and/or (the absolute increase must be 
≥200 mg/24 h). 
x 
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. 
x 
Bone marrow plasma cell percentage: the absolute % must be 
≥ 10%c. 
x 
Definite development of new bone lesions or soft tissue 


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plasmacytomas or definite increase in the size of existing bone 
lesions or soft tissue plasmacytomas. 
 
Abbreviations:  EBMT = European Group for Blood and Marrow Transplant; IMWG = International 
Myeloma Working Group; FLC = (serum) free light chains 
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 t4 weeks after the start 
of study therapy and anytime 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 anytime 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. 
 
4.3 
SAFETY FOLLOW-UP VISIT 
Each subject should be followed for 30 (±7) days after his or her last dose of study drug 
(ie, the “safety follow-up visit”) to monitor for resolution or progression of AEs (see 
Section 6.2.5) and to document the occurrence of any new events; unless, the subject 
receives a new anticancer therapy within this timeframe.  Subjects who withdraw 
consent should still be encouraged to complete the safety follow-up assessments, but 
these assessments cannot be mandated once consent is withdrawn.  The Schedule of 
Assessments (Appendix 4) describes the procedures required for the safety follow-up.  
4.4 
MISSED EVALUATIONS 
Missed evaluations should be rescheduled and performed as close to the original 
scheduled date as possible.  An exception is made when rescheduling becomes, in the 
investigator’s opinion, medically unnecessary or unsafe because it is too close in time to 
the next scheduled evaluation.  In that case, the missed evaluation should be 
abandoned. 


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5.0 
STATISTICAL METHODS OF ANALYSIS  
5.1 
GENERAL CONSIDERATIONS 
Descriptive statistics (including means, standard deviations, and medians for continuous 
variables and proportions for discrete variables) will be used to summarize data as 
appropriate.  Analyses will be done by dosing regimen and overall. 
5.2 
SAMPLE SIZE CONSIDERATIONS 
This study will assess safety, PK, PD, and antitumor activity of ACP-196 alone or in 
combination with dexamethasone.  Subjects will be equally randomized into 1 of the 
2 dosing regimens (ACP-196 monotherapy or ACP-196 + dexamethasone) as an 
efficient method for allocating patients into these regimens. The study is not formally 
designed to compare these regimens but rather to obtain descriptive information that can 
be used in support of further ACP-196 development. 
While the primary objective of this study is to determine the safety in each of the 
2 dosing cohorts, the sample size has been determine to independently evaluate the 
activity of each dosing regimen. The trial seeks to exclude an uninteresting ORR of 
d 15% (ie, the response rate that might be associated with single-agent dexamethasone 
therapy [Anderson 2013]) in favor a target response rate of t 40%.  Considering a 
sample size of 19 subjects per cohort, the power to detect the difference between a null-
hypothesis response rate of 15% and an alternative-hypothesis response rate of 40% 
with a 0.025 one-sided significance level is 84% using a one-group, chi-square test and 
69% using a one-group, exact binomial test.  A sample size of 19 subjects per cohort will 
also provide a 97.5% 1-sided confidence interval centered around an expected ORR of 
40% that excludes an ORR of 18.6% as a lower bound. 
5.3 
DEFINITION OF ANALYSIS SETS 
The following definitions will be used for the efficacy and safety analysis sets. 
x 
Safety analysis set: All enrolled subjects who receive ≥ 1 dose of study drug. 
x 
Per-protocol (PP) analysis set: All enrolled subjects who receive ≥ 1 dose of study 
drug, have sufficient baseline measurements, and undergo ≥ 1 assessment for the 
endpoint of interest (eg, response and PK/PD parameters) after treatment. 
The safety analysis set will be used for evaluating the safety and efficacy parameters in 
this study (with the exception of assessment of duration of response).  The PP analysis 
sets will be analyzed for efficacy and PK/PD parameters in this study. 


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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 adverse event (per CTCAE, v4.03) and by 
relationship to study drug. 
Laboratory shift tables containing counts and percentages will be prepared by treatment 
assignment, laboratory parameter, and time.  Summary tables will be prepared for each 
laboratory parameter.  Figures of changes in laboratory parameters over time will be 
generated. 
Results of vital sign assessments and physical exams will be tabulated and summarized.   
5.5.2 
Demographics and Baseline Characteristics 
Additional analyses will include summaries of subject demographics, baseline 
characteristics, compliance, and concurrent treatments. Concomitant medications will be 
coded according to the World Health Organization (WHO) Drug Dictionary and 
tabulated. 
5.5.3 
Analysis of Efficacy Parameters 
5.5.3.1 
Response Rate 
The individual and composite endpoints of response and progression will be determined. 
Tumor control will be documented at each assessment by response category (eg, CR, 
sCR, nCR, VGPR, PR, MR, SD, and disease progression) as defined for each response 
parameter, date that response is first documented, and date of MM disease progression. 
ORR will be defined as the proportion of subjects who achieve a CR, sCR, nCR, VGPR, 
PR, or MR. ORR will be calculated and the corresponding 97.5% one-sided confidence 
interval will be derived. 


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5.5.3.2 
Duration of Response 
The duration of overall response defined as the interval from the first documentation of 
CR, sCR, nCR, VGPR, PR, or MR to the earlier of the first documentation of definitive 
disease progression or death from any cause.  Kaplan-Meier methods will be used to 
estimate event-free curves and corresponding quantiles (including the median). Data 
from surviving, nonprogressing subjects will be censored at the earliest of the time of 
initiation of antitumor treatment other than the study treatment or the last time that lack 
of definitive MM progression was objectively documented. Data from subjects who have 
MM progression or die after ≥ 2 consecutive missing tumor assessments will be 
censored at the last time before the missing assessments that lack of MM progression 
was objectively documented. 
5.5.3.3 
Progression-free Survival 
Progression-free survival is defined as the interval from the start of ACP-196 therapy to 
the earlier of the first documentation of objective MM disease progression or death from 
any cause.  Kaplan-Meier methods will be used to estimate the event-free curves and 
corresponding quantiles (including the median).  Data from surviving, non-progressing 
subjects will be censored at the earliest of the time of initiation of antitumor treatment 
other than the study treatment or the last time that lack of MM progression was 
objectively documented. Data from subjects who have MM progression or die after 
≥ 2 consecutive missing tumor assessments will be censored at the last time prior to the 
missing assessments that lack of MM progression was objectively documented. 
5.5.3.4 
Time-to-Next Treatment 
Time-to-next treatment defined as the time from start of ACP-196 therapy for MM on this 
protocol to the start of the next treatment for MM. Kaplan-Meier methods will be used to 
estimate the event-free curves and corresponding quantiles (including the median). Data 
from subjects who have not received subsequent therapy for MM will be censored at the 
earliest of death or the last time that lack of administration of a new therapy for MM was 
objectively documented. 
5.5.4 
Analysis of Pharmacokinetic/Pharmacodynamic Parameters  
The plasma PK of ACP-196 and dexamethasone will be characterized using 
noncompartmental analysis. The following PK parameters will be calculated, whenever 
possible, from plasma concentrations of ACP-196: 


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x 
AUC(0-t) 
Area under the plasma concentration-time curve calculated using linear 
trapezoidal summation from time 0 to time t, where t is the time of the last 
measurable concentration (Ct). 
x 
AUC(0-24) 
Area under the plasma concentration-time curve from 0 to 24 hours, 
calculated using linear trapezoidal summation. 
x 
AUC(0-∞) 
Area under the plasma concentration-time curve from 0 to infinity, 
calculated using the formula: AUC(0-∞) = AUC(0-t) + Ct / λz, where λz is the 
apparent terminal elimination rate constant. 
x 
Cmax 
Maximum observed plasma concentration 
x 
Tmax 
Time of the maximum plasma concentration (obtained without 
interpolation) 
x 
t½ 
Terminal elimination half-life (whenever possible)  
x 
λz 
Terminal elimination rate constant (whenever possible) 
x 
Cl/F 
Oral clearance 
Missing dates or times may be imputed for PK and PD samples if the missing values can 
be established with an acceptable level of accuracy based on other information obtained 
during the visit in question. If PK and PD sampling for a given subject is not performed 
according to protocol instructions that subject may be excluded from the PK and PD 
analyses. 
The PK parameters will be tabulated and summarized using descriptive statistics.  
For each PD variable, the concentration at each assessment will be described.  The 
change from baseline to each assessment will be summarized.  The best change from 
baseline during the study will also be summarized.  As appropriate, the on-treatment 
values will be compared with the pretreatment baseline values using paired t-tests.  
P-values of d 0.05 will be considered significant. 
5.5.5 
Explorative or Correlative Analyses 
Additional PK or PD analyses may be performed, as deemed appropriate. 
Correlations between subject characteristics and outcome measures and correlations 
among outcomes measures will be explored using regression models or other 
appropriate techniques.  Such evaluations may assist in determining if baseline 
parameters or early changes in PD biomarkers are predictive of response to Btk 
inhibition. 
6.0 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and recording AEs and SAEs; 
measurements of protocol-specified hematology, clinical chemistry, urinalysis, and other 


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laboratory variables; measurement of protocol-specified vital signs; and other protocol-
specified tests that are deemed critical to the safety evaluation of the study drug(s). 
6.1 
DEFINITIONS 
6.1.1 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational (medicinal) product or other protocol-
imposed intervention, regardless of attribution. 
This includes the following: 
x 
AEs not previously observed in the subject that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with MM that were not 
present before the AE reporting period (see Section 6.2.1) 
x 
Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as biopsies) 
x 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character 
during the protocol-specified AE reporting period. 
Abnormal laboratory values should not be reported as AEs; however, any clinical 
consequences of the abnormality (eg, withdrawal from study) should be reported as 
AEs. 
6.1.2 
Serious Adverse Event 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to 
the grade of an AE (see below).  “Serious” is a regulatory definition and is based on 
subject or event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  Seriousness (not severity) serves as the guide 
for defining regulatory reporting obligations from the Sponsor to applicable regulatory 
authorities. 
An AE should be classified as an SAE if it meets any 1 of the following criteria: 
x 
It results in death (ie, the AE actually causes or leads to death). 


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x 
It is life-threatening (ie, the AE, in the view of the investigator, places the subject at 
immediate risk of death.  It does not include an AE that, had it occurred in a more 
severe form, might have caused death). 
x 
It requires or prolongs in-patient hospitalization. 
x 
It results in persistent or significant disability/incapacity (ie, the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
x 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the investigational product. 
x 
It is considered a significant medical event by the investigator based on medical 
judgment (eg, may jeopardize the subject or may require medical/surgical 
intervention to prevent 1 of the outcomes listed above). 
6.1.3 
Severity 
Definitions found in the CTCAE version 4.03 or higher will be used for grading the 
severity (intensity) of AEs. The CTCAE displays Grades 1 through 5 with unique clinical 
descriptions of severity for each referenced AE. Should a subject experience any AE not 
listed in the CTCAE, the following grading system should be used to assess severity: 
x 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities 
x 
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 
x 
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 
x 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to 
be in imminent danger of death 
x 
Grade 5 (Death related to AE) – experiences which result in subject death 


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6.2 
DOCUMENTING AND REPORTING OF ADVERSE AND SERIOUS 
ADVERSE EVENTS 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, as outlined in the prior sections, are recorded on the eCRF.  
All SAEs also must be reported on the SAE/Product Complaint form (see Section 6.2.4). 
6.2.1 
Adverse Event Reporting Period 
The AE reporting period for this study begins when the subject receives the first dose of 
study medication and ends with the safety follow-up visit.  An exception to this reporting 
period is any AE occurring due to a protocol-defined screening procedure.  Fatal AEs 
occurring 30 days after the last dose of ACP-196 AND assessed by the investigator as 
related to ACP-196 must be reported as an SAE. 
6.2.2 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation time 
points during the study.  All AEs and SAEs whether volunteered by the subject, 
discovered by study personnel during questioning, or detected through physical 
examination, or other means will be recorded in the subject’s medical record and on the 
AE eCRF and, when applicable, on an SAE/Product Complaint form. 
Disease progression itself is not considered an adverse event; however, signs and 
symptoms of disease progression may be recorded as AEs or SAEs. 
Each recorded AE or SAE will be described by its duration (ie, start and end dates), 
severity, regulatory seriousness criteria, if applicable, suspected relationship to the study 
drug (ie, ACP-196, dexamethasone, or both; see following guidance), and any actions 
taken.  The relationship of AEs to the study drug will be assessed by means of the 
question: ‘Is there a reasonable possibility that the event may have been caused by the 
study drug?’  Answer Yes or No.  
See Appendix 2 for more detail on assessing relationship. 
6.2.3 
Pregnancy 
The investigator should report all pregnancies and pregnancies in the partners of 
subjects within 24 hours using the Pregnancy Report Form Part I.  This form should be 
faxed or emailed to Acerta Pharma Drug Safety.  Any pregnancy-associated SAE must 
be reported using the SAE report form, according to the usual timelines and directions 
for SAE reporting (Section 6.2.4). 


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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 30 days after the 
last dose of study medication will be reported, followed to conclusion, and the outcome 
reported. 
Monitoring of the pregnancy should continue until conclusion of the pregnancy at which 
point the Pregnancy Report Form Part II must be completed and submitted to Acerta 
Drug Safety.  If a viable baby is born, then 2 months postpartum the Pregnancy Report 
Form Part III must be completed and submitted. 
Pregnancy itself is not regarded as an AE unless there is suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Likewise, elective abortions without complications are not 
considered AEs. Any SAEs associated with pregnancy (eg, congenital 
abnormalities/birth defects/spontaneous miscarriages or any other serious events) must 
additionally be reported as such using the SAE report form.  
Subjects should be instructed to immediately notify the investigator of any pregnancies.  
Any female subjects receiving ACP-196 who become pregnant must immediately 
discontinue study drug.  The investigator should counsel the subject, discussing any 
risks of continuing the pregnancy and any possible effects on the fetus.   
6.2.4 
Expedited Reporting Requirements for Serious Adverse 
Events 
All SAEs (initial and follow-up information) will be reported on an SAE/Product Complaint 
form.  Paper SAE/Product Complaint forms must be emailed or faxed to Acerta Pharma 
Drug Safety, or designee, within 24 hours of the discovery of the event or information. 
Alternatively, electronic SAE reporting may be available through the protocol-specific 
electronic data capture system.  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 (eg, hospital admission/discharge notes and laboratory 
results).  
All deaths should be reported with the primary cause of death as the AE term, as death 
is typically the outcome of the event, not the event itself. The primary cause of death on 


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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 and is not listed in the current 
Investigator’s Brochure (ie, an unexpected event). In this case, Acerta Pharma Drug 
Safety/Designee will forward a formal notification describing the SAE to all investigators. 
Each investigator must then notify his or her IRB/IEC of the SAE. 
Drug Safety Contact Information
Fax:
Email:
6.2.5 
Type and Duration of Follow-up of Subjects After Adverse 
Events 
All AEs and SAEs that are encountered during the protocol-specified AE reporting period 
should be followed to resolution, or until the investigator assesses the subject as stable, 
a new anticancer therapy is initiated, or the subject is lost to follow-up or withdraws 
consent. 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
Acerta Pharma retains the right to terminate the study and remove all study materials 
from a study site at any time. Specific circumstances that may precipitate such 
termination are: 
x 
Unsatisfactory subject enrollment with regard to quality or quantity 
x 
Significant or numerous deviations from study protocol requirements, such as 
failures to perform required evaluations on subjects and maintain adequate study 
records 
x 
Inaccurate, incomplete and/or late data recording on a recurrent basis 
x 
The incidence and/or severity of AEs in this or other studies indicating a potential 
health hazard caused by the study treatment 


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7.1 
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE 
The investigator will submit this protocol, the informed consent, Investigator’s Brochure, 
and any other relevant supporting information (eg, all advertising materials) to the 
appropriate IRB/IEC for review and approval before study initiation.  A signed protocol 
approval page; a letter confirming IRB/IEC approval of the protocol and informed 
consent; and a statement that the IRB/IEC is organized and operates according to GCP 
and the applicable laws and regulations; must be forwarded to Acerta Pharma before 
screening subjects for the study.  Additionally, sites must forward a signed FDA 1572 
form (Investigator Obligation Form) 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.  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 subject privacy regulations, the 
investigator or designee must explain to each subject that for the evaluation of study 
results, the subject’s protected health information obtained during the study may be 
shared with Acerta Pharma and its designees, regulatory agencies, and IRBs/IECs.  As 
the study Sponsor, Acerta Pharma will not use the subject’s protected health information 
or disclose it to a third party without applicable subject authorization.  It is the 
investigator’s or designee’s responsibility to obtain written permission to use protected 
health information from each subject, or if appropriate, the subject’s legal guardian.  If a 


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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 eCRFs designed for 
this study according to the completion guidelines that will be provided.  The investigator 
will ensure that the eCRFs are accurate, complete, legible, and completed within 5 days 
of each subject’s visit (unless required earlier for SAE reporting).  The investigator will 
ensure that source documents that are required to verify the validity and completeness 
of data transcribed on the eCRFs are never obliterated or destroyed. 
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 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. 


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7.6 
INVESTIGATIONAL STUDY DRUG ACCOUNTABILITY 
ACP-196 capsules must be kept in a locked limited access room. The study drug must 
not be used outside the context of the protocol. Under no circumstances should the 
investigator or other site personnel supply ACP-196 capsules to other investigators, 
subjects, or clinics or allow supplies to be used other than as directed by this protocol 
without prior authorization from Acerta Pharma. 
Study drug accountability records must be maintained and readily available for 
inspection by representatives of Acerta Pharma 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.  Then the designated recipient 
completes and signs the CSSF. A copy of the signed CSSF must be faxed or emailed to 
Acerta Pharma at the fax number/emailing address listed on the form. 
An Investigational Drug Accountability Log must be used for drug accountability.  For 
accurate accountability, the following information must be noted when drug supplies are 
used during the study: 
1. 
study identification number (ACE-MY-001) 
2. 
subject identification number 
3. 
lot number(s) of ACP-196 dispensed for that subject 
4. 
date and quantity of drug dispensed 
5. 
any unused drug returned by the subject 
At study initiation, the monitor will evaluate and approve the site’s procedure for 
investigational product disposal/destruction to ensure that it complies with Acerta 
Pharma’s requirements. If the site cannot meet Acerta Pharma’s requirements for 
disposal/destruction, arrangements will be made between the site and Acerta Pharma or 
its representative, for return of unused investigational product.  Before 
disposal/destruction, final drug accountability and reconciliation must be performed by 
the monitor. 


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All study supplies and associated documentation will be regularly reviewed and verified 
by the monitor. 
7.7 
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 FDA Form 1572, IRB/IEC approval letters, signed 
ICFs, drug accountability records, SAE forms transmitted to Acerta Pharma, subject files 
(source documentation) that substantiate entries in eCRFs, all relevant correspondence 
and other documents pertaining to the conduct of the study. 
An investigator shall retain records for a period of at least 2 years after the date the last 
marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. The investigator must notify Acerta Pharma and obtain 
written approval from Acerta Pharma before destroying any clinical study records at any 
time. Acerta Pharma will inform the investigator of the date that study records may be 
destroyed or return to Acerta Pharma. 
Acerta Pharma must be notified in advance of, and Acerta Pharma must provide express 
written approval of, any change in the maintenance of the foregoing documents if the 
investigator wishes to move study records to another location or assign responsibility for 
record retention to another party. If the investigator cannot guarantee the archiving 
requirements set forth herein at his or her study site for all such documents, special 
arrangements must be made between the investigator and Acerta Pharma to store such 
documents in sealed containers away from the study site so that they can be returned 
sealed to the investigator for audit purposes. 
7.8 
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 amendment may take effect. Additionally 
under this circumstance, information on the increased risk and/or change in scope must 


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be provided to subjects already actively participating in the study, and they must read, 
understand, and sign any revised ICF confirming willingness to remain in the trial. 
7.9 
PUBLICATION OF STUDY RESULTS 
Acerta Pharma may use the results of this clinical study in registration documents for 
regulatory authorities in the United States or abroad. The results may also be used for 
papers, abstracts, posters or other material presented at scientific meetings or published 
in professional journals or as part of an academic thesis by an investigator. The study is 
being conducted as part of a multicenter clinical trial. Data from all study centers shall be 
pooled and analyzed for publication in a final report (Primary Publication). The 
investigator agrees that the Primary Publication, which will be coordinated by Acerta 
Pharma, will be the first publication to present the pooled study results. After the Primary 
Publication, or if the Primary Publication is not published within 1 year of termination of 
the study, the investigator may freely publish or present the results of his or her work 
conducted under the clinical trial agreement subject to providing Acerta Pharma with the 
opportunity to review the contents of any proposed presentation, abstract or publication 
about such work, including any results of this study, 90 days in advance of any 
presentation or submission for publication. Within that 90-day period, Acerta Pharma 
may review the proposed publication to identify patentable subject matter and/or any 
inadvertent disclosure of its confidential information, which must be redacted from any 
final publication or presentation. If necessary, to permit the preparation and filing of 
patent applications, Acerta Pharma may elect an additional review period not to exceed 
60 days. 
In most cases, the principal investigators at the sites with the highest accruals of eligible 
subjects, who have provided significant intellectual input into the study design, shall be 
listed as lead authors on manuscripts and reports of study results. The Medical Monitor, 
study director and/or lead statistician may also be included in the list of authors. This 
custom can be adjusted upon mutual agreement of the authors and Acerta Pharma. 
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. 


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


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8.0 
REFERENCES 
Anderson KC, Alsina M, Bensinger W, et al. Multiple myeloma, version 1.2013. J Natl 
Compr Canc Netw 2013;11:11-17.  
Bladé J, Samson D, Reece D, et al.  Criteria for evaluating disease response and 
progression in patients with multiple myeloma treated by high-dose therapy and 
haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European 
Group for Blood and Marrow Transplant.  Br J Haematol 1998;102:1115-1123. 
Bradshaw JM. The Src, Syk, and Tec family kinases: distinct types of molecular 
switches. Cell Signal 2010;22:1175-1184.  
Buggy JJ, Elias L. Bruton tyrosine kinase (Btk) and its role in B-cell malignancy. Int Rev 
Immunol 2012;31:119-132. Erratum in: Int Rev Immunol 2012;31:428. 
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical 
end points in chronic lymphocytic leukemia. J Clin Oncol 2012;30:2820-2820. 
Durie BG, Harousseau JL, Miguel JS et al.  International uniform response criteria for 
multiple myeloma.  Leukemia 2006;20:1467-1473. 
Edwards CM, BTK inhibition in myeloma: targeting the seed and soil.  Blood 
2012;120:1757-1759.   
Gentile DM, Tomlinson ES, Maggs JL, Park BK, Back DJ. Dexamethasone metabolism 
by human liver in vitro. Metabolite identification and inhibition of 6-hydroxylation. J 
Pharmacol Exp Ther 1996;277:105-12. 
Hallek M, Cheson BD, Catovsky D, et al.  Guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia: a report from the International Workshop on Chronic 
Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 
guidelines. Blood 2008;111:5446-5456. 
Hellmann A, Rule S, Walewski J, et al. Effect of cytochrome P450 3A4 inducers on the 
pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in patients with 
multiple myeloma or non-Hodgkin's lymphoma. Clin Pharmacokinet 2011;50:781-791. 
Honigberg LA, Smith AM, Sirisawad M, et al.  The Bruton tyrosine kinase inhibitor 
PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease 
and B-cell malignancy. PNAS 2010;107:13075-13080. 
Mohamed AJ, Yu L, Bäckesjö CM, et al. Bruton's tyrosine kinase (Btk): function, 
regulation, and transformation with special emphasis on the PH domain. Immunol Rev 
2009;228:58-73. 
Ocio EM, Richardson PG, Rajkumar SV, et al. New drugs and novel mechanisms of 
action in multiple myeloma in 2013: a report from the International Myeloma Working 
Group (IMWG). Leukemia 2014;28:525-542.   
Rajkumar SV, Jacobus S, Callander NS, et a; Eastern Cooperative Oncology Group. 
Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose 
dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label 
randomised controlled trial. Lancet Oncol 2010;11:29-37. Erratum in: Lancet Oncol 
2010;11:14. 
Romano A, Conticello C, Cavalli M, et al. Salvage therapy of multiple myeloma: the new 
generation drugs. Biomed Res Int 2014;2014:456037. Epub 2014 May 19. 


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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 2012:120:1877-1887. 
Vail DM, Thamm DH. Spontaneously occurring tumors in companion animals as models 
for drug development. In: Teicher BA, Anders PA, eds. Anticancer Drug Development 
Guide: Preclinical Screening, Clinical Trials, and Approval. 2nd Ed. Totowa, NJ: Human 
Press; 2004:259-284. 
Vail DM, Michels GM, Khanna C, Selting KA, London CA; Veterinary Cooperative 
Oncology Group. Response evaluation criteria for peripheral nodal lymphoma in dogs 
(v1.0)—a Veterinary Cooperative Oncology Group (VCOG) consensus document. Vet 
Comp Oncol 2010;8:28-37. 
Vihinen M, Mattsson PT, Smith CI. Bruton tyrosine kinase (Btk) in X-linked 
agammaglobulinemia (XLA). Front Biosci 2000;5:D917-D928. 


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9.0 
APPENDICES 
 
 
 
 


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Appendix 1. Performance Status Scores  
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, eg, light house 
work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair 
5 
Dead 
As published in Am J Clin Oncol: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin 
Oncol 5:649-655, 1982. 
Credit: Eastern Cooperative Oncology Group Chair: Robert Comis, MD 
Available at: http://www.ecog.org/general/perf_stat.html.  Accessed 23 August 2013. 
 
 


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Appendix 2.  Adverse Event Assessment of Causality 
 
Is there a reasonable possibility that the event may have been caused by study drug?  
No___ Yes___ 
The descriptions provided below will help guide the principal investigator in making the 
decision to choose either “yes” or “no”: 
No = There is no reasonable possibility that the event may have been caused by study 
drug. 
The adverse event: 
x 
may be judged to be due to extraneous causes such as disease or environment 
or toxic factors 
x 
may be judged to be due to the subject’s clinical state or other therapy being 
administered 
x 
is not biologically plausible 
x 
does not reappear or worsen when study drug is re-administered 
x 
does not follow a temporal sequence from administration of study drug 
Yes = There is a reasonable possibility that the event may have been caused by study 
drug. 
The adverse event: 
x 
follows a temporal sequence from administration of study drug 
x 
is a known response to the study drug based on clinical or preclinical data 
x 
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 
x 
disappears or decreases upon cessation or reduction of dose of study drug 
x 
reappears or worsens when study drug is re-administered 


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Appendix 3.  Inhibitors of CYP3A4 
Inhibitors 
Strong (t5-fold  
Increase in AUC) 
Moderate (2- to 5-fold  
Increase in AUC) 
Weak (1.25- to  <2-fold 
Increase in AUC) 
Boceprevir 
Chloramphenicol 
Clarithromycin 
Cobicistat 
Conivaptan 
Indinavir 
Itraconazole 
Ketoconazole 
Lopinavir 
Mibefradil 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Suboxone 
Telaprevir 
Telithromycin 
Voriconazole 
Amprenavir 
Aprepitant 
Atazanavir 
Ciprofloxacin 
Darunavir 
Diltiazem 
Erythromycin 
Fluconazole 
Fosamprenavir 
Grapefruit juice1 
Imatinib 
Verapamil 
Alprazolam 
Amiodarone 
Amlodipine 
Atorvastatin 
Bicalutamide 
Buprenorphine 
Cilostazol 
Cimetidine 
Cyclosporine 
Fluoxetine 
Fluvoxamine 
Ginkgo1  
Goldenseal1  
Isoniazid 
Nilotinib 
Oral contraceptives 
Ranitidine 
Ranolazine 
Tipranavir 
Zileuton 
Inducers 
Strong (t80%  
Decrease in AUC) 
Moderate (50 to 80% 
Decrease in AUC) 
Weak (20 to 50% 
Decrease in AUC) 
Avasimibe 
Carbamazepine 
Phenytoin 
Rifampin 
St. John’s wort1 
Bosentan 
Efavirenz 
Etravirine 
Modafinil 
Nafcillin 
Amprenavir 
Aprepitant 
Armodafinil 
Echinacea1 
Pioglitazone 
Prednisone 
Rufinamide 
1. 
Food or herbal product 
2. 
Primary reference: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm0
93664.htm 
 
 
 
 


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Appendix 4.  Schedule of Assessments 
 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycles 5-12b 
Follow Upc 
LTFUq 
 
 
Days (± 2) 
Days (± 2) 
Days (± 2) 
Days (± 2) 
Days (± 2) 
Days (± 2) 
 
1 
8 
15 
22 
28 
15 
28 
28 
28 
28 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
PEd/Vital signse/Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECOG status 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECGf 
x 
x 
 
Lab assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
testg 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Hematologyh 
x 
xr 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Serum chemistryi 
x 
xr 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Urinalysisj 
x 
 
 
 
 
x 
 
x 
x 
x 
Every 2 mos 
 
 
 
T/B/NK cell countk 
 
xr 
x 
x 
 
x 
 
x 
 
 
Every 6 mos 
 
 
 
Disease markersl 
x 
 
x 
 
x 
 
x 
x 
x 
Every 2 mos 
x 
 
Bone marrow 
(aspirate/biopsy) 
/Skeletal surveyp 
x 
 
 
 
 
 
 
Bone 
Marrow 
only 
As 
clinically 
indicated 
or to 
confirm a 
CR 
As 
clinically 
indicated 
or to 
confirm a 
CR 
As clinically 
indicated or to 
confirm a CR 
 
 
 
Pharmacodynamics 
 
xm 
xm 
 
 
xn 
 
xn 
 
 
 
x 
 
 
Pharmacokineticso 
 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
ACP-196/ 
dexamethasone 
dispensed 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Study drug compliance 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Tumor assessmentp 
x 
 
 
 
 
x 
 
x 
x 
x 
x 
 
 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Time-to-next treatment 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Abbreviations: CR = complete remission; ECG = electrocardiogram, ECOG = Eastern Cooperative Oncology Group, Ig = immunoglobulin; mos = months; PE = 
physical exam; LTFU = long-term follow up 


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Footnotes for ACE-MY-001 Schedule of Study Activities: 
a.  Screening tests should be performed within 21 days before the first administration of study drug, unless otherwise indicated. 
b. 
Any subjects who have not progressed while receiving study drug treatment, may be eligible to enroll into a long-term follow up study and continue to receive ACP-196. 
c. 
A 30-day (± 7 days) safety follow-up visit is required when subjects discontinue study drug unless they start another anticancer therapy within that timeframe. 
d. 
The screening physical examination will include, at a minimum, the general appearance of the subject, height (screening only) and weight, and examination of the skin, 
eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system.  Symptom-directed physical exams are done 
thereafter.   
e. 
Vital signs (blood pressure, pulse, respiratory rate, and temperature) will be assessed after the subject has rested in the sitting position.   
f. 
Subjects should be in supine position and resting for ≥ 10 minutes before study-related ECGs.  12-lead electrocardiogram (ECG) will be done in triplicate (≥ 1 minute apart) 
at screening.  The calculated QTc average of the 3 ECGs must be ≤ 480 ms for eligibility.  
g. 
Women of childbearing potential only.  If positive, pregnancy must be ruled out by ultrasound to be eligible. 
h. 
Hematology includes complete blood count with differential and platelet and reticulocyte counts. Cycle 1 Day 1 hematology does not need to be repeated if screening 
hematology was within 5 days. 
i. 
Serum chemistry: albumin, alkaline phosphatase, bone-specific alkaline phosphatase, alanine transaminase (ALT), aspartate aminotransferase (AST), bicarbonate, blood 
urea nitrogen (BUN), calcium, chloride, creatinine, C-terminal telopeptide, glucose, lactate dehydrogenase (LDH), magnesium, phosphate, potassium, sodium, total bilirubin, 
total protein, and uric acid. Cycle 1 Day 1 serum chemistry does not need to be repeated if screening hematology was within 5 days. 
j. 
Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, N-terminal telopeptide, and glucose.  
k. 
T/B/NK cell count (ie, CD3, CD4, CD8, CD19, CD16/56).  During Cycle 5-12, only done at end of Cycle 6 and 12. 
l.  
Refer to Sectin 4.1 for a list of myeloma disease markers. 
m. Pharmacodynamic samples are drawn predose and 4 hours (±10 minutes) postdose on the days indicated. Note: These timepoints are relative to the morning dose. 
n. 
Pharmacodynamic samples are drawn predose on the days indicated. 
o. 
Pharmacokinetic samples are drawn per Table 4-1. 
p 
Refer to Section 4-2.  Bone marrow aspirate/biopsy and skeletal survey are required at baseline (ie, before the first dose of study drug).  Thereafter they are required as 
indicated in the table above. 
q. 
Subjects who discontinue study therapy will continue on study for follow-up of safety and time-to-next therapy for myeloma unless they withdraw consent for further follow-
up. 
r. 
The indicated samples at this timepoint (Cycle 1 Day 1) must be drawn predose. 
 

SAP_001.pdf: 


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Statistical Analysis Plan 
An Open-label, Phase 1b Study of ACP-196 in Subjects with Multiple Myeloma 
Protocol Number: ACE-MY-001 
Version: 
Version 2.0 
Date: 
20 September, 2018 
Study Statistician: 
 
 


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TABLE OF CONTENTS 
 
Table of Contents ............................................................................................................ 2 
Table of Abbreviations ..................................................................................................... 4 
1. 
INTRODUCTION .................................................................................................... 5 
2. 
OBJECTIVES ......................................................................................................... 5 
 
Primary Objective ........................................................................................... 5
 
Secondary Objectives .................................................................................... 5
3. 
STUDY OVERVIEW ............................................................................................... 5
 
Study Design .................................................................................................. 6
 
Sample Size ................................................................................................... 6
4. 
STUDY ENDPOINTS .............................................................................................. 7
 
Safety Endpoints ............................................................................................ 7
 
Efficacy Endpoints  ......................................................................................... 7
 
Pharmacokinetic and Pharmacodynamic Parameters .................................... 7
5. 
HYPOTHESES AND MULTIPLICITY ...................................................................... 7
6. 
ANALYSIS SETS .................................................................................................... 7
 
All-Treated Population .................................................................................... 8
 
Treatment Cohorts ......................................................................................... 8
7. 
INTERIM ANSLYSIS AND EARLY STOPPING GUIDELINES ................................ 8 
8. 
FINAL ANALYSIS AND CLINICAL STUDY REPORT ............................................. 8 
9. 
MISSING VALUES ................................................................................................. 8 
 
Missing Safety Data ....................................................................................... 8
 
Missing Efficacy Data ..................................................................................... 8
10. 
STATISTICAL METHODS OF ANALYSIS .............................................................. 8 
 General Principles .......................................................................................... 9
 Subject Disposition ......................................................................................... 9
 Important Protocol Deviations ........................................................................ 9
 Baseline Data ................................................................................................. 9
 Demographics ................................................................................. 10
 Baseline Characteristics .................................................................. 10
 Baseline Disease Characteristics .................................................... 10
 Treatment and Medications .......................................................................... 11
 Prior Anticancer Therapies .............................................................. 11


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 Prior and Concomitant Medications Received for Indications 
Other Than MM ............................................................................... 11
 Exposure to Study Drugs ................................................................ 12
 Analyses of Safety Endpoints ....................................................................... 12
 Adverse Events of Clinical Interest .................................................. 13
 Laboratory Abnormality ................................................................... 14
 Vital Signs ....................................................................................... 15
 ECOG Performance Score .............................................................. 15
 Electrocardiogram ........................................................................... 16
 Analyses of Efficacy Endpoints .................................................................... 16
 Definitions ....................................................................................... 16
 Analysis Methods ............................................................................ 17
11. 
DISEASE BIOMARKERS ..................................................................................... 17 
12. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES .................................... 17 
13. 
LITERATURE CITATIONS  REFERENCES ........................................................ 18 
14. 
APPENDICES....................................................................................................... 19 
 Definitions .................................................................................................... 19
 Study Day ....................................................................................... 19
 Imputation Rules .......................................................................................... 19
 Partial or Missing Dates .................................................................. 19
 Censoring Rules for Duration of Response and Progression-Free Survival .. 20
 Events of Clinical Interest ............................................................................. 20


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TABLE OF ABBREVIATIONS 
AE(s) 
adverse event(s) 
Bid 
CBR 
twice per day 
clinical benefit rate 
CR 
complete response 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
DOR 
disease control rate 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
Ex-US 
Ig 
IRC 
Excluding United States of America 
immunoglobulin 
independent review committee 
IPD 
important protocol deviation 
ISS 
MedDRA 
International Staging System 
Medical Dictionary for Regulatory Activities 
MM 
MR 
NCI 
multiple myeloma 
minimal response 
National Cancer Institute 
PD 
pharmacodynamics 
PFS 
progression-free survival 
PK 
PR 
pharmacokinetics 
partial response 
PT 
preferred term 
SAE(s) 
serious adverse event(s) 
SAP 
sCR 
SD 
statistical analysis plan 
stringent complete response 
stable disease 
TEAE(s) 
VGPR 
treatment-emergent adverse events 
very good partial response 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide details of the safety and 
efficacy analyses that have been outlined within Protocol Amendment 2 for 
Study ACE-MY-001, which is entitled “An Open-label, Phase 1b Study of ACP-196 in 
Subjects with Multiple Myeloma” dated January 13, 2016.  The original SAP based on 
same protocol was for interim safety clinical study report (CSR) to support the new drug 
application (NDA) in relapsed and refractory mantle cell lymphoma.  This SAP is 
updated to include efficacy analysis.  Any change to the planned analyses  described in 
the final SAP will be documented in the clinical study report (CSR). 
Separate reports will be generated for pharmacokinetic (PK) and pharmacodynamic 
(PD) data. 
From here on, acalabrutinib (generic name for formerly ACP-196) will be used in place of 
ACP-196 in this document. 
2. 
OBJECTIVES 
 
Primary Objective 
x 
To characterize the safety profile of acalabrutinib with and without 
dexamethasone in subjects with relapsed or refractory (R/R) multiple myeloma 
(MM).  
 
Secondary Objectives 
x 
To characterize the PK profile of acalabrutinib with and without dexamethasone 
and the PK profile of dexamethasone with concomitant acalabrutinib 
administration 
x 
To evaluate the PD effects of acalabrutinib with and without dexamethasone 
x 
To evaluate the activity of acalabrutinib with and without dexamethasone as 
measured by overall response rate (ORR), duration of response (DOR), clinical 
benefit rate, disease control rate, and progression-free survival (PFS).  
x 
To explore the relationship between biological markers in MM cells and response 
to therapy 
3. 
STUDY OVERVIEW 


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Study Design 
This study is a multicenter, open-label, randomized, parallel-group study to be 
conducted at approximately 20 sites in 2 countries (United Kingdom and United States).  
Forty subjects are planned to be randomized 1:1 into the following 2 cohorts to receive 
acalabrutinib, with or without dexamethasone: 
x 
Cohort 1 (acalabrutinib monotherapy): acalabrutinib 100 mg bid continuously 
x 
Cohort 2 (acalabrutinib + dexamethasone): acalabrutinib 100 mg bid continuously 
and 40 mg dexamethasone once weekly 
Due to limited evidence of efficacy of acalabrutinib monotherapy in R/R MM subjects in 
this study, in a memo dated March 15, 2016 to all study sites, the enrollment was 
discontinued immediately and subjects who were randomized to receive acalabrutinib 
monotherapy were permitted to crossover to receive acalabrutinib + dexamethasone 
treatment. 
One cycle is defined as a 28-day study treatment period.  Treatment may be continued 
until disease progression (PD) or an unacceptable drug-related toxicity occurs.  All 
subjects who discontinue study drug will have a safety follow-up visit 30 (±7) days after 
the last dose of study drug unless they have started another cancer therapy within that 
timeframe.  
All subjects will have hematology, serum chemistry, and urinalysis safety panels done at 
screening.  Once dosing commences (Day 1), all subjects will be evaluated for safety, 
including serum chemistry, and hematology, once weekly for the first 4 weeks, every 2 
weeks in Cycle 2 and monthly thereafter.  PK/PD testing will be done in Cycle 1 and 
Cycle 2.  The end of trial is defined as the point when the last subject on the study exits 
the study for any reason. 
 
Sample Size 
The trial seeks to exclude an uninteresting ORR of 15% (i.e., the response rate that 
might be associated with single-agent dexamethasone therapy [Anderson 2013]) in favor 
a target response rate of 40%.  Considering a sample size of 19 subjects per cohort, 
the power to detect the difference between a null hypothesis response rate of 15% and 
an alternative-hypothesis response rate of 40% with a 0.025 one-sided significance level 
is 69% using a one-group, exact binomial test.  A sample size of 19 subjects per cohort 


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will also provide a 97.5% 1-sided confidence interval centered around an expected ORR 
of 40% that excludes an ORR of 18.6% as a lower bound. 
4. 
STUDY ENDPOINTS 
 
Safety Endpoints  
The safety of acalabrutinib with and without dexamethasone will be characterized by the 
type, frequency, severity, and relationship to study drug(s) of any treatment-emergent 
adverse events (AEs) or incidence of abnormalities of laboratory tests; serious adverse 
events (SAEs); or AEs leading to dose modification/delay or discontinuation of study 
treatment.  
 
Efficacy Endpoints  
Assessments of acalabrutinib efficacy in this study will be based on the criteria of 
standardized tumor response and disease progression for MM ([Rajkumar 2011] and 
[Blade 1998]). 
x 
Overall response rate (ORR) 
x 
Duration of response (DOR) 
x 
Clinical benefit rate (CBR) 
x 
Disease control rate (DCR) 
x 
Progression-free survival (PFS) 
 
Pharmacokinetic and Pharmacodynamic Parameters  
Refer to separate reports for PK and PD parameters. 
5. 
HYPOTHESES AND MULTIPLICITY 
No formal statistical hypotheses will be tested.  The clinical hypotheses are that 
acalabrutinib monotherapy and acalabrutinib + dexamethasone is safety and effective in 
subjects with R/R MM. 
6. 
ANALYSIS SETS 


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All-Treated Population 
All-treated population is GHILQHGDVDOOHQUROOHGVXEMHFWVZKRUHFHLYHGRse of any 
study drug.  All-treated population will be used for evaluating the safety and efficacy 
unless otherwise specified. 
Treatment Cohorts 
Subjects are randomized with the ratio of 1:1 into 2 treatment cohorts to receive 
acalabrutinib, with or without dexamethasone: 
x
Cohort 1 (acalabrutinib monotherapy): acalabrutinib 100 mg bid continuously
x
Cohort 2 (acalabrutinib + dexamethasone): acalabrutinib 100 mg bid continuously
and 40 mg dexamethasone once weekly

INTERIM AN$LYSIS AND EARLY STOPPING GUIDELINES
No formal interim analysis will be conducted.

FINAL ANALYSIS AND CLINICAL STUDY REPORT
The final analysis of primary and secondary efficacy endpoints will occur when last
patient enrolled completes the end of Cycle 12, or withdraws for any reason and
completes the 30-day follow-up visit, whichever occurs first.  The CSR will be written
based on the final analysis.  The addendum of CSR will be written at the end of trial.

MISSING VALUES
Missing Safety Data
Conservative imputation rules will be applied partial dates for AE onset and stop dates, 
start and end dates of concomitant medication, start date of subsequent anticancer 
therapy, date of initial diagnosis, and death date.  The algorithm for the imputation in 
Appendices 14.2 will be used. If dates are completely missing, no imputation will be 
made.  Missing safety data other than partial or missing dates will not be imputed. 
Missing Efficacy Data 
The method of handing missing data and censoring data is described in the definition for 
the efficacy endpoints, mentioned at section 14.3. 
10.
STATISTICAL METHODS OF ANALYSIS


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General Principles 
Descriptive statistics will be used to summarize disposition, demographics, baseline 
characteristics, disease characteristics, prior anticancer therapy, concomitant 
medication, study drug administration, efficacy and safety outcomes.  Descriptive 
summary of discrete data will be present the sample size and incidence as frequency 
and percentage.  Descriptive summaries of continuous data will be present the sample 
size, group mean, standard deviation, median, and range. 
Confidence intervals (CIs), when presented, will generally be constructed at the 95% 
level.  For binomial variables, the exact method for CIs will be employed unless 
otherwise specified.  
Calculation of time to event or duration of event (e.g., DOR) will be based on actual 
study day of event rather than nominal visit date.  
 
Subject Disposition  
Subjects are enrolled from 11 study sites of 2 countries. The number of subjects enrolled 
by region, country, and site will be presented.  Subject disposition will be summarized for 
all enrolled subjects including the following information: 
x 
Subject status on acalabrutinib 
x 
Primary reasons for acalabrutinib discontinuation  
x 
Subject status on the study 
x 
Primary reasons for study discontinuation 
x 
Time on the study 
 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined and managed by the study 
team during the IPD reviews throughout the study before database lock. These 
definitions of IPD categories, sub-category codes, and descriptions will be used during 
the course of the study.  The final IPD list is used to produce the Summary of IPDs table.   
 
Baseline Data 
Summaries of demographics and baseline characteristics will be presented for subjects 
in the All-treated population. For continuous variables, n, mean, standard deviation, 


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median, minimum, and maximum values will be provided. For categorical variables, the 
number and percentage of subjects in each category will be summarized. 
 Demographics  
x 
Sex (Male, Female) 
x 
Age (year, continuous) 
x 
Age category (<65 versus  years)  
x 
Ethnicity  
x 
Hispanic or Latino  
x 
Not Hispanic or Latino  
x 
Not Reported 
x 
Race 
x 
American Indian or Alaska Native 
x 
Asian 
x 
Black or African American 
x 
Native Hawaiian or Other Pacific Islander 
x 
White 
x 
Other  
x 
Not Reported 
x 
Country 
x 
Unites States  
x 
United Kingdom  
 Baseline Characteristics  
x 
Eastern Cooperative Oncology Group (ECOG) performance score  
x 
0 = fully active.  
x 
1 = restricted in physically strenuous activity  
x 
2 = incapable of any work activity  
x 
3 = limited self-care  
x 
4 = completely disabled 
x 
Height (cm) 
x 
Weight (kg) 
 Baseline Disease Characteristics 
x 
Time from initial diagnosis to first dose of acalabrutinib (months) 


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x 
Prior anticancer therapy regimens  
x 
Number of regimens (mean, standard deviation, median, minimum, 
maximum) 
x 
Number of subjects with regimens (1-3 regimens, >=4 regimens) 
x 
Prior stem cell transplant 
x 
MM stage by International Staging System (ISS) (stage I, II, III [Greipp 2005]) 
x 
MM subtypes  
x 
heavy chain subtypes 
x 
light chain subtypes 
x 
6HUXPȕ-microglobulin (<2.5, >=2.5 mg/L) 
x 
Serum creatinine (<2,  2 mg/dL) 
x 
Serum Hemoglobin (mean, standard deviation, median, min, max) 
x 
Serum calcium (12, >12 g/dL) 
x 
IgG (mean, median, min, max)  
x 
IgA (mean, median, min, max)  
x 
Bone marrow cellularity  
x 
Hypercellular 
x 
Normocellular 
x 
Hypocellular 
 
Treatment and Medications 
 
Prior Anticancer Therapies 
A prior anticancer therapy is defined as a systemic therapy subjects received, either as a 
single or combination therapy, for the treatment of MM with an end date occurring before 
the date of first dose of study treatment. Therapies given as a consolidation or for 
maintenance of a response or remission will not be considered as a separate regimen. 
The prior anticancer therapy regimens will be summarized.  
 
Prior and Concomitant Medications Received for Indications Other Than 
MM 
Concomitant therapy is defined as all medications used on or after the first dose of study 
drug, through the treatment phase, and through 30 days following the last dose of study 
drug. Data reported on concomitant medications CRF pages will be used. Medications 


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started prior to first dose of study drug will be consider as prior treatment. Using this 
definition, a medication can be classified as both prior and concomitant. The start date 
and end date will be based on the rules provided in Appendices 14.2.1. Medications with 
completely missing start and stop dates will be considered as both prior and concomitant 
medications. Prior and concomitant medications other than antineoplastic agents or 
other systemic therapies for MM after enrollment will be coded by the World Health 
Organization (WHO) Drug Dictionary and summarized by Anatomic Therapeutic 
Chemical Classification System (ATC) level 2 (therapeutic subgroup) and level 5 
(preferred term/chemical ingredient).  
 
Exposure to Study Drugs 
Separate analysis will be performed for acalabrutinib and dexamethasone. Descriptive 
statistics (n, mean, standard deviation, median, minimum and maximum values) will be 
used to summarize:    
x 
Duration of exposure (the interval between first dose date and last dose date) 
x 
Actual cumulative dose administered 
x 
Average dose (the ratio of actual cumulative dose administered and Duration of 
exposure): daily dose for acalabrutinib and weekly dose for dexamethasone 
x 
Relative dose intensities (the percentage of actual cumulative dose to the 
planned cumulative dose)  
 
The reasons for acalabrutinib dose withholding and reduction will be summarized and 
presented as the number and percentage of subjects with non-missing data per 
category. 
x 
Dose withholding of acalabrutinib LVGHILQHGDVPLVVLQJGRVHIRUFRQVHFXWLYH
days.  
x 
Dose reduction defined as taking lower dose level (100 mg per day) for 
acalabrutinib for 3 consecutive days. 
 
Analyses of Safety Endpoints 
Safety analyses will be performed on All-treated population by treatment cohort.  
Analyses of adverse events (AEs) will be performed on treatment-emergent AE (TEAE) 
data, unless otherwise specified. TEAEs are defined as those events with onset or 


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worsen date on or after the date of first dose of acalabrutinib, through the treatment 
phase to last dose of acalabrutinib, and within 30 days following the last dose of 
acalabrutinib, whichever is later. Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.03 or higher is used for AE grading. 
Treatment-emergent AEs will be summarized in 3 groups: (1) acalabrutinib 
monotherapy, (2) acalabrutinib + dexamethasone, and (3) crossover from monotherapy 
to acalabrutinib + dexamethasone therapy. By this grouping method, AEs among 
subjects assigned to acalabrutinib monotherapy will be reported in group 1 when AEs 
occurred before crossover, and AEs occurred on/after crossover will be reported in 
group 3. Treatment-emergent AEs occurred on or after crossover will be summarized in 
the crossover group. Treatment-emergent AEs occurred before crossover will be 
summarized in the monotherapy group. All AE terms will be coded by Medical Dictionary 
for Regulatory Activities (MedDRA) Version 19.1 and will be presented by system organ 
class (SOC) and preferred term (PT). Treatment-emergent AEs will be summarized by 
SOC and PT and by CTCAE toxicity grade.  The drug-related AEs, serious adverse 
events (SAEs) and drug-related SAEs, AEs leading to treatment discontinuation, dose 
delay and dose modification will be summarized by PT by CTCAE toxicity grade. 
Death will be reported in a listing and summarized. A table will be provided for grade 5 
AE and the relationship with any study drug.  
 
Adverse Events of Clinical Interest 
In addition to general analyses of adverse events, analyses will be conducted on 
selected AEs of clinical interest. The following are event of clinical interests (ECIs): 
cardiac events (including atrial fibrillation), anemia, cytopenias, hemorrhage including 
major hemorrhage, hepatic events, hypertension, infections, interstitial lung disease and 
pneumonitis, second primary malignancies, and tumor lysis syndrome.  Details of ECIs 
is summarized in the Appendices of this SAP.  
AEs of clinical interest are defined in section 14.4 of the appendices. 
Subject incidence rates of AEs of clinical interest will be tabulated by treatment cohorts 
and all-treated population.  


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Laboratory Abnormality 
All of the laboratory tests are performed in central laboratory and/or in local laboratory. 
Analyses will be performed for laboratory test data collected at baseline and from first 
exposure to acalabrutinib to 30 days after last dose of acalabrutinib or up to the safety 
follow-up visit date, whichever is later. Laboratory test for hematology, serum chemistry, 
and T/B/NK cell count up will be performed in central laboratory with reference range 
and the results will be reported in standard international units or conventional units when 
appropriate. Applicable laboratory test results will be graded according to CTCAE 
Version 4.03 or higher. AMA (American Medical Association (AMA) Manual of Style 10th 
Edition 2017) laboratory values will be applied whenever reference ranges are not 
available (e.g., local laboratory data). 
For selected laboratory test parameters, summary statistics (mean, standard deviation, 
median, minimum and maximum) will be produced at baseline, post-baseline values 
from the last visit, minimum and maximum post-baseline values, and changes of these 
post-baseline values from baseline. Post-baseline toxicity grade greater than baseline 
grade will be presented in the treatment-emergent laboratory abnormality table. Shift 
from baseline to the worst grade from first exposure to acalabrutinib to 30 days after last 
dose of acalabrutinib or up to the safety follow-up visit date, whichever is later, will be 
provided as shift tables for selected parameters. 
To be included in the summary table, a subject must have at least one post-baseline 
value for the given time point.  
x 
Lymphocytosis 
Lymphocytosis is defined as an elevation in absolute lymphocyte count (ALC) RI
compared to baseline and a post-baseline assessment >5x109/L (Wang 2013). The 
number of subjects with at least one occurrence of lymphocytosis will be summarized. 
For subjects with lymphocytosis, resolution of lymphocytosis is defined as 1) a decrease 
of ALC value to the baseline level or lower, or 2)  a decrease of ALC value that is below 
5x109/L, whichever occurs first. Duration of lymphocytosis (DOL) is defined as the 
duration of time from the earliest date on which the ALC value met the lymphocytosis 
criteria at a post-baseline assessment to the earliest date on which a subsequent ALC 
value met the resolution criteria. 


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DOL = Earliest date of meeting resolution criteria -Earliest date of meeting lymphocytosis 
criteria + 1. 
Subjects who developed lymphocytosis but whose lymphocytosis was not resolved prior 
to the analysis cutoff date will be censored at the last sample date with non-missing ALC 
value at or prior to the analysis cutoff date. 
Summary statistics will be provided for time to lymphocytosis.  KM estimates for DOL will 
be provided. 
x 
Hepatitis B Test 
Subjects with a history of hepatitis B virus (HBV) infection should be monitored monthly 
with a quantitative polymerase chain reaction (PCR) test for HBV DNA. Monthly 
monitoring should last until 12 months after last dose of acalabrutinib. Any subject with a 
rising viral load (above lower limit of detection) should discontinue study drug and have 
antiviral therapy instituted and a consultation with a physician with expertise in managing 
hepatitis B.  A listing of subjects with any hepatitis B test will be provided. 
 
Vital Signs 
Analyses will be performed for vital sign safety data collected at baseline and from first 
exposure to acalabrutinib to 30 days after last dose of acalabrutinib or up to the safety 
follow-up visit date, whichever is later. Summary statistics (mean, standard deviation, 
median, minimum and maximum) will be produced for vital signs at baseline, post-
baseline values from the last visit, minimum and maximum post-baseline values, and 
changes of these post-baseline values from baseline. In addition, blood pressure is 
graded and the maximum post-baseline grade will be presented. Systolic Blood 
Pressure is graded by CTCAE as Grade 0 (<= 119 mm Hg), Grade 1 (120-139 mm Hg), 
Grade 2 (140 – 159 mm Hg), Grade 3 (>= 160 mm Hg). Diastolic Blood Pressure is 
grade as Grade 0 (<= 79 mm Hg), Grade 1 (80 -89 mm Hg), Grade 2 (90 – 99 mm Hg), 
Grade 3 (>= 100 mm Hg). In order to be included in the table, a subject must have at 
least one post-baseline value for the given time point. 
 
ECOG Performance Score 
Change of ECOG score from baseline to the worst score during the period from first 
exposure to acalabrutinib to 30 days after last dose of acalabrutinib or up to the safety 
follow-up visit date, whichever is later will be provided as shift tables. 


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Electrocardiogram 
ECG data are collected at screening. The investigator assessment of clinical 
significance categorized as normal, abnormal but not clinically significant, and abnormal 
clinically significant will be summarized. The number of subjects with corrected QT 
interval (QTc) greater than 480 msec will also be provided. A listing of subjects with 
abnormal and clinically significant baseline ECG results or QTc> 480 msec will be 
provided. 
 
Analyses of Efficacy Endpoints  
 
Definitions 
Study treatment response will be assessed according to response criteria of 
standardized tumor response and disease progression for MM ([Rajkumar 2011] and 
[Blade 1998]) including stringent complete response (sCR), complete response (CR), 
very good partial response (VGPR), partial response (PR), minimal response (MR), 
stable disease (SD), and disease progression. Overall response data will be 
summarized as follows:  
x 
Overall Response Rate 
ORR is defined as the proportion of subjects who achieve a sCR, CR, VGPR, or PR.   
x 
Clinical Benefit Rate 
Clinical benefit rate (CBR) is defined as the proportion of subjects who achieve a sCR, 
CR, VGPR, PR, or MR. 
x 
Disease Control Rate  
Disease control rate (DCR) is defined as the proportion of subjects who achieve a sCR, 
CR, VGPR, PR, MR, or SD. 
x 
Duration of Response (DOR) 
DOR is defined as the interval from the first documentation of sCR, CR, VGPR or PR to 
the first documentation of definitive disease progression or death from any cause. Data 
from surviving, non-progressing subjects will be censored at the earliest of the time of 
initiation of anticancer treatment other than the study treatment or the last time that lack 
of definitive MM progression was objectively documented. Data from subjects who have 


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MM progreVVLRQRUGLHDIWHUFRQVHFXWLYHPLVVLQJWXPRUDVVHVVPHQWVZLOOEH
censored at the last time before the missing assessments that lack of MM progression 
was objectively documented. The censoring rules for analyses of DOR are summarized 
in Appendix 14.3. 
x 
Progression-free Survival (PFS) 
PFS is defined as the interval between the date of randomization to any study cohort 
and the first documentation of objective MM disease progression or death from any 
cause. Data from surviving, non-progressing subjects will be censored at the earliest of 
the time of initiation of anticancer treatment other than the study treatment or the last 
time that lack of MM progression was objectively documented. Subjects who have MM 
SURJUHVVLRQRUGLHDIWHUFRQVHFXWLYHPLVVLQJWXPRUDVVHVVPHQWVZLOOEHFHQVRUHGDW
the last time that lack of MM progression was objectively documented before the missing 
assessments. The censoring rules for analyses of PFS are summarized in Appendix 
14.3.  
 
Analysis Methods 
The analysis of ORR, CBR, DCR, and PFS will be conducted on the All-treated 
Population. The analysis of DOR will be conducted on the subset of the All-treated 
Population who achieve sCR, CR, VGPR or PR as their best overall response.  
ORR, CBR, DCR will be calculated and the corresponding 95% two-sided confidence 
intervals will be derived. DOR and PFS will be estimated using the Kaplan-Meier (KM) 
method. KM estimates with 95% CIs will be calculated for event time quartiles, including 
median. In addition, listings for DOR and PFS will be provided, including the reason for 
censoring. 
11. 
DISEASE BIOMARKERS 
The relationship between biological markers in MM cells and response to therapy will not 
be explored, due to the fact that a very small number of subjects has responded to study 
treatment.  
12. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES  
There is no major change from protocol-specified analyses.  


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Due to the fact that a very small number of subjects has responded to study treatment, 
there will not be an exploration of drug response and biological markers. 
13. 
LITERATURE CITATIONS  REFERENCES 
The American Medical Association (AMA) Manual of Style, SI Conversion Calculator,  
http://www.amamanualofstyle.com/page/si-conversion-calculator   
Anderson KC, Alsina M, Bensinger W, et al. Multiple myeloma, version 1.2013. J Natl 
Compr Canc Netw 2013;11:11-17.  
Bladé J, Samson D, Reece D, et al. Criteria for evaluating disease response and 
progression in patients with multiple myeloma treated by high-dose therapy and 
haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European 
Group for Blood and Marrow Transplant. Br J Haematol 1998;102:1115-1123. 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol 2007; 25:579-586. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification. J Clin Oncol 2014;32:3059-3067. 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0, USDHHS, NIH, 
NCI; publish date May 28, 2009 (v4.03: June 14, 2010). 
Rajkumar SV, Harousseau JL, Durie B, et al; International Myeloma Workshop 
Consensus Panel 1. Consensus recommendations for the uniform reporting of clinical 
trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011 
May 5;117(18):4691-5. 
Greipp PR, Miguel JS, Durie BGM, Crowley JJ,  Barlogie B, et al; International Staging 
System for Multiple Myeloma: Journal of Clinical Oncology 2005 23:15, 3412-3420. 
Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory 
mantle-cell lymphoma. N Engl J Med 2013 Aug 8;369(6):507-516.   


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14. 
APPENDICES  
 
Definitions 
Study Day
The study day will be calculated in reference to the date of first dose date.  Study Day 1  
is defined as the date of first dose of acalabrutinib.  For assessments that occur on or 
after first dose date, study day is defined as (date of assessment – date of first dose + 
1).  For assessments that occur prior to first dose date, study day is defined as (date of 
assessment – date of first dose).  There is no Study Day 0. 
 
Imputation Rules  
 
  Partial or Missing Dates 
Imputation of partial dates will be made for AE onset and stop dates, start and end dates 
of concomitant medication, start date of subsequent anticancer therapy, date of initial 
diagnosis and death date.  If dates are completely missing, no imputation will be made. 
For any partial date with missing year, no imputation will be made. 
 
The general rule for imputation is: 
x 
If only day is missing, then the 15th of the month will be used. 
x 
If only year is present, then June 30th will be used. 
 
If such imputation date for initial diagnosis is on or after date of first dose, the date of first 
dose – 1 will be used.  If such imputed date for subsequent anticancer therapies is 
before date of last dose, the date of last dose + 1 will be used.  
If the imputed date is for an AE start date and is in the same year and month as the first 
dose date but before the first dose date, the first dose date will be used, or if the imputed 
AE start date is after the AE end date, the AE end date will be used.  If the imputed date 
is for an AE start date and is in the same year and month as but after the last dose date 
+ 30 days, the last dose date + 30 days will be used.  
 
If the imputed date is for an AE end date and is after the death date, the date of death 
will be used, or if the imputed AE end date is before the AE start date, the AE start date 
will be used. 
 
If death year and month are available but day is missing: 


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x 
If mmyyyy for last contact date = mmyyyy for death date, set death date to the 
day after the last contact date. 
x 
If mmyyyy for last contact date < mmyyyy for death date, set death date to the 
first day of the death month. 
x 
If mmyyyy for last contact date > mmyyyy for death date, data error and do not 
impute. 
 
If both month and day are missing for death date or a death date is totally missing, no 
imputation is made.  
 
Censoring Rules for Duration of Response and Progression-Free 
Survival 
 
Situation 
Outcome 
Event 
Description or 
Censoring 
Reason 
Last Analysis 
Date 
Documented disease progression 
before initiation of new anticancer 
therapy or on/before data cutoff 
date, whichever occurred first, also 
no more than 1 missing tumor 
assessments before documented 
disease progression 
 
Event 
Progressive 
Disease 
Earliest date of 
documented 
disease 
progression 
Death before initiation of new 
anticancer therapy or on/before 
data cutoff date, whichever 
occurred first 
Event 
Death
Date of Death
New anticancer therapy 
Initiated before data cutoff date and 
before documented disease 
progression or death  
Censored 
New anti-cancer 
therapy 
Date of last 
adequate tumor 
assessment prior 
to initiation of new 
anticancer 
therapy 
New anti-cancer therapy 
before data cutoff date for subjects 
without documented disease 
progression or death  
Censored 
New anti-cancer 
therapy 
Date of last 
adequate tumor 
assessment prior 
to initiation of new 
anticancer 
therapy  
No documented disease 
progression, initiation of new 
anticancer therapy or death 
on/before data cutoff date 
Censored 
Data cutoff 
Date of last 
adequate tumor 
assessment on or 
before data cutoff 
date 
No post-baseline adequate disease 
assessments 
Censored  
No post-baseline 
adequate disease 
assessments 
Date of first dose 
of study drug 
 
Events of Clinical Interest 
The Events of Clinical Interest (ECIs) have been identified based on preclinical findings, 
emerging data from clinical studies relating to acalabrutinib, and pharmacological effects 


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of approved BTK inhibitor. The AEs selected for dedicated analysis were evaluated 
using Standardized MedDRA Queries (SMQs), where available, by SOC, or by sponsor 
defined baskets of MedDRA Adverse Event Grouped Terms. 
Category 
name 
Sub-
category 
name 
Definition for SAP 
Additional Criteria for Narratives 
Cardiac events 
 
SOC Cardiac disorders 
No additional criteria  
 
Atrial 
fibrillation 
PT Atrial fibrillation 
PT Atrial flutter 
Any 
Cytopenias-
Anemia 
 
SMQ Haematopoietic 
erytheropenia [narrow + broad] 
No additional criteria 
Cytopenias-
Leukopenia 
 
SMQ Haematopoietic 
leukopenia [narrow + broad] 
No additional criteria 
 
Neutropenia 
x PT Febrile neutropenia 
x PT Neutropenia 
x PT Neutropenic infection 
x PT Neutropenic sepsis 
x PT Neutrophil count 
decreased 
x PT Neutrophil percentage 
No additional criteria 
 
Other 
Leukopenia 
SMQ Haematopoietic 
leukopenia [narrow + broad] 
excluding PTs for neutropenia 
above 
No additional criteria 
Cytopenias - 
Thrombocytop
enia 
 
SMQ Haemorrhage terms 
(excluding laboratory terms) 
No additional criteria 
 
Major 
Hemorrhage 
As per Acerta definition 
(Appendences)  
Any 
Hepatic Events 
 
x SMQ [narrow] Hepatic 
failure, fibrosis and cirrhosis 
and other liver damage 
related conditions 
x SMQ [narrow] Liver related 
investigation signs 
x SMQ [narrow] Hepatitis, non-
infectious 
PTs of Grade 3 as below 
x 
Alanine aminotransferase 
abnormal  
x 
Alanine  aminotransferase 
increased  
x 
Aspartate aminotransferase 
abnormal  
x 
Aspartate aminotransferase 
increased 
x 
Hepatic enzyme abnormal 
x 
Hepatic enzyme increased 
x 
Hypertransminasemia 


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x 
Liver function test abnormal 
x 
Liver function test increase 
x 
Transaminases abnormal 
x 
Transaminases increased 
Subjects who fulfill biochemical Hy’s 
law criteria defined as below: 
 3 x ULN AST or  
 3 x ULN ALT and  
 2 x ULN total bilirubin 
At the same visit 
Hypertension 
 
x SMQ Hypertension [narrow] 
No additional criteria 
Infections 
 
x SOC Infections and 
infestations 
No additional criteria 
Interstitial lung 
disease/Pneu
monitis 
 
x SMQ [narrow] Interstitial lung 
disease 
No additional criteria 
Second 
primary 
malignancies 
 
x SMQ Malignant or 
unspecified tumors and 
SMQ Myelodysplastic 
syndrome (narrow), 
excluding skin (i.e. exclude 
SMQ Skin neoplasms, 
malignant and unspecified) 
Any 
Tumor lysis 
syndrome 
 
x PT Tumor lysis syndrome  
Any 
MedDRA version 19.1 
x 
No additional criteria means only SAE, AE leading to study drug discontinuation, and deaths within 
specified window will be selected for narratives.  
x 
‘Any’ means any subject with a PT in the category will be selected for narratives.