A Phase 2 Study of the Efficacy and Safety of ACP-196 in Subjects With Relapsed/Refractory CLL and Intolerant of Ibrutinib Therapy
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia
Sponsor: Acerta Pharma BV

 
Product: Acalabrutinib (ACP-196) 
Protocol: ACE-CL-208 
 
 
 
 
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PROTOCOL 
TITLE: 
A Phase 2 Study of the Efficacy and Safety of ACP-196 in 
Subjects with Relapsed/Refractory CLL and Intolerant of 
Ibrutinib Therapy 
PROTOCOL NUMBER: 
ACE-CL-208 
STUDY DRUG: 
Acalabrutinib (ACP-196) 
IND NUMBER: 
118717 
EUDRACT NUMBER: 
2015-005317-68 
SPONSOR MEDICAL 
MONITOR: 
 
 
Phone:
Email: 
 
SPONSOR: 
Acerta Pharma BV 
 
5349 AB Oss 
The Netherlands 
ORIGINAL PROTOCOL: 
Version 0.0 – 21 September 2015 
AMENDMENT 1 DATE: 
Version 1.0 – 14 January 2016 
AMENDMENT 2 DATE: 
Version 2.0 – 16 August 2016 
AMENDMENT 3 DATE: 
Version 3.0 – 01 December 2017 
AMENDMENT 4 DATE: 
Version 4.0 – 24 February 2020 
AMENDMENT 5 DATE: 
Version 5.0 – 25 June 2020 
 
 
Confidentiality Statement 
This document contains proprietary and confidential information of Acerta Pharma BV that 
must not be disclosed to anyone other than the recipient study staff and members of the 
institutional review board (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. 
PPD
PPD
PPD
PPD
PPD

 
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PROTOCOL APPROVAL PAGE 
Version 5.0 
I have carefully read Protocol ACE-CL-208 entitled “A Phase 2 Study of the Efficacy and 
Safety of ACP-196 in Subjects with Relapsed/Refractory CLL and Intolerant of Ibrutinib 
Therapy”.  I agree to conduct this study as outlined herein and in compliance with Good 
Clinical Practices (GCP) and all applicable regulatory requirements.  Furthermore, I 
understand that the sponsor, Acerta Pharma, and the IRB/ IEC must approve any 
changes to the protocol in writing before implementation. 
I agree not to divulge to anyone, either during or after the termination of the study, any 
confidential information acquired regarding the investigational product and processes or 
methods of Acerta Pharma.  All data pertaining to this study will be provided to Acerta 
Pharma.  The policy of Acerta Pharma requires that any presentation or publication of 
study data by clinical investigators be reviewed by Acerta Pharma, before release, as 
specified in the protocol. 
 
Principal Investigator’s Signature 
Date 
 
 
Print Name 
 
 
 
 

 
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SUMMARY OF AMENDMENT 5.0 
This protocol is being amended to clarify the definition of the end of the study and 
the time point for the final analysis.  
The substantive changes that were made as part of this amendment are as follows: 
Sections Impacted 
Rationale 
STUDY SYNOPSIS 
Updated the Synopsis to reflect 
changes in the protocol. 
Section 3.1 End of Study 
Section 3.7 Duration of Therapy 
Appendix 1 Schedule of Assessments 
(footnote “a”) 
The definition of the end of study has 
been changed to “the date of the last 
subject’s last visit.” 
Section 3.1 End of Study 
 
The time point for the final analysis was 
clarified to occur no earlier than the 
date the last subject has completed the 
end of Cycle 36 or has been withdrawn 
for any reason and completed the 30-
day SFU visit (if applicable), whichever 
occurs first.   
Section 3.9.2 Prohibited or Restricted 
Concomitant Therapies 
Reference to Section 3.10.9 (dietary 
restrictions) was added to the 
paragraph on concomitant use of strong 
inhibitors/inducers of CYP3A, to alert to 
the prohibition of St John’s wort, an 
herbal product that is also a strong 
CYP3A inducer described in the dietary 
restrictions section and listed in 
Appendix 4. 
 

 
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TABLE OF CONTENTS 
1.0 
BACKGROUND INFORMATION ............................................................. 20 
1.1 
Chronic Lymphocytic Leukemia ............................................................... 20 
1.2 
Bruton Tyrosine Kinase Inhibition in CLL ................................................. 20 
1.3 
Acalabrutinib ............................................................................................ 22 
1.3.1 
Mechanism of Action .................................................................. 22 
1.3.2 
Safety Pharmacology ................................................................. 22 
1.3.3 
Drug-Drug Interaction Potential .................................................. 23 
1.4 
Clinical Experience – Acalabrutinib .......................................................... 23 
1.5 
Benefit/Risk .............................................................................................. 23 
2.0 
STUDY OBJECTIVES ............................................................................. 25 
2.1 
Primary Objective: ................................................................................... 25 
2.2 
Secondary Objective: ............................................................................... 25 
2.3 
Exploratory Objectives: ............................................................................ 25 
3.0 
STUDY DESIGN ...................................................................................... 25 
3.1 
End of Study ............................................................................................ 26 
3.2 
Study Endpoints ....................................................................................... 27 
3.2.1 
Efficacy Endpoints ...................................................................... 27 
3.2.2 
Safety Endpoints ........................................................................ 27 
3.2.3 
 27 
3.3 
Rationale for Study Design and Dosing Regimen .................................... 27 
3.3.1 
Dose Selection Rationale ........................................................... 27 
3.3.2 
Selection of the Patient Population ............................................. 28 
3.4 
Selection of Study Population .................................................................. 28 
3.4.1 
Inclusion Criteria ......................................................................... 28 
3.4.2 
Exclusion Criteria ....................................................................... 30 
3.4.3 
Replacement of Subjects ........................................................... 31 
3.4.4 
Enrollment Procedures ............................................................... 31 
3.5 
Study Drug ............................................................................................... 32 
3.5.1 
Premedications ........................................................................... 32 
3.5.2 
Formulation, Packaging, and Storage ........................................ 32 
3.5.3 
Administration of Study Drug ...................................................... 32 
3.5.4 
Assuring Subject Compliance..................................................... 33 
3.6 
Study Treatment Schedule ...................................................................... 33 
3.7 
Duration of Therapy ................................................................................. 33 
3.8 
Dosing Delays and Modifications ............................................................. 33 
3.8.1 
Dose Delays and Modifications of Acalabrutinib......................... 33 
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3.9 
Concomitant Therapy............................................................................... 35 
3.9.1 
Permitted Concomitant Therapy ................................................. 35 
3.9.2 
Prohibited or Restricted Concomitant Therapy ........................... 35 
3.10 
Risks Associated with Acalabrutinib Treatment ....................................... 36 
3.10.1 Hemorrhage ............................................................................... 36 
3.10.2 Infections .................................................................................... 36 
3.10.3 Hepatitis B Virus Reactivation .................................................... 36 
3.10.4 Progressive Multifocal Leukoencephalopathy ............................ 37 
3.10.5 Cytopenias ................................................................................. 37 
3.10.6 Second Primary Malignancies .................................................... 37 
3.10.7 Atrial Fibrillation .......................................................................... 38 
3.10.8 Reference Safety Information ..................................................... 38 
3.10.9 Dietary Restrictions .................................................................... 38 
3.10.10 Drug-Drug Interactions ............................................................... 38 
3.10.11 Reproductive Toxicity ................................................................. 39 
3.10.12 Overdose Instructions ................................................................ 41 
3.11 
Withdrawal of Subjects From Study Treatment ........................................ 41 
3.12 
Reasons for Study Exit ............................................................................ 42 
3.13 
Data and Safety Monitoring ..................................................................... 42 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS ............................................ 43 
4.1 
Description of Procedures ........................................................................ 43 
4.1.1 
Informed Consent ....................................................................... 43 
4.1.2 
Medical History ........................................................................... 43 
4.1.3 
Adverse Events .......................................................................... 43 
4.1.4 
Concomitant Medications and Therapy ...................................... 44 
4.1.5 
Confirmation of Eligibility ............................................................ 44 
4.1.6 
ECOG Performance Status ........................................................ 44 
4.1.7 
Physical Examination, Vital Signs, Height and Weight, and 
Disease-Related Symptoms ....................................................... 44 
4.1.8 
Electrocardiogram ...................................................................... 45 
4.1.9 
Urine or Serum Pregnancy Test ................................................. 45 
4.1.10 Hematology ................................................................................ 45 
4.1.11 Serum Chemistry ........................................................................ 45 
4.1.12 Urinalysis .................................................................................... 45 
4.1.13 
 45 
4.1.14 Hepatitis B and C Testing ........................................................... 46 
4.1.15 Serum Immunoglobulin .............................................................. 46 
4.1.16 
 46 
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4.1.17 
 47 
4.1.18 Bone Marrow Aspirate and Biopsy ............................................. 47 
4.1.19 CT Scans ................................................................................... 47 
4.1.20 Routine Clinical Assessments .................................................... 49 
4.1.21 Overall Response Evaluations ................................................... 49 
4.2 
Treatment Termination and Safety Follow-up Visits ................................ 49 
4.3 
Follow-up for Progression ........................................................................ 50 
4.3.1 
Post-Treatment Disease Follow-Up ............................................ 50 
4.3.2 
Long-Term Follow-Up ................................................................. 50 
4.4 
Missed Evaluations .................................................................................. 50 
5.0 
STATISTICAL METHODS OF ANALYSIS ............................................... 51 
5.1 
General Considerations ........................................................................... 51 
5.2 
Rationale for Sample Size ....................................................................... 51 
5.3 
Analysis Populations ................................................................................ 52 
5.4 
Missing Data Handling ............................................................................. 52 
5.5 
Endpoint Data Analysis ............................................................................ 52 
5.5.1 
Demographics and Baseline Characteristics .............................. 52 
5.5.2 
Study Treatment Administration and Compliance ...................... 52 
5.5.3 
Analysis of Efficacy Endpoints.................................................... 52 
5.5.3.1 
Primary Efficacy Endpoint ............................................ 52 
5.5.3.1 
Secondary Efficacy Endpoints ..................................... 53 
5.5.4 
Safety Endpoint .......................................................................... 53 
5.5.5 
 54 
6.0 
ASSESSMENT OF SAFETY ................................................................... 54 
6.1 
Definitions ................................................................................................ 54 
6.1.1 
Adverse Events .......................................................................... 54 
6.1.2 
Serious Adverse Event ............................................................... 56 
6.1.3 
Severity ...................................................................................... 57 
6.1.4 
Adverse Events of Special Interest ............................................. 57 
6.2 
Documenting and Reporting of Adverse and Serious Adverse Events .... 57 
6.2.1 
Adverse Event Reporting Period ................................................ 57 
6.2.2 
Assessment of Adverse Events .................................................. 58 
6.2.3 
Second Primary Malignancies .................................................... 58 
6.2.4 
Pregnancy .................................................................................. 59 
6.2.5 
Expedited Reporting Requirements for Serious Adverse 
Events ........................................................................................ 60 
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6.2.6 
Type and Duration of Follow-up of Subjects after Adverse 
Events ........................................................................................ 61 
6.2.7 
Hy’s Law ..................................................................................... 61 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ........ 61 
7.1 
Institutional Review Board and Independent Ethics Committee ............... 62 
7.2 
Informed Consent and Protected Subject Health Information 
Authorization ............................................................................................ 62 
7.3 
Subject Screening Log ............................................................................. 63 
7.4 
Case Report Forms ................................................................................. 63 
7.5 
Study Monitoring Requirements ............................................................... 63 
7.6 
Investigational Study Drug Accountability ................................................ 64 
7.7 
Record Retention ..................................................................................... 64 
7.8 
Protocol Amendments.............................................................................. 65 
7.9 
Publication of Study Results .................................................................... 65 
7.10 
Clinical Trial Insurance............................................................................. 65 
7.11 
General Investigator Responsibilities ....................................................... 65 
8.0 
REFERENCES ........................................................................................ 67 
 
 
IN-TEXT TABLES 
 
Table 1  Drug Modification Actions for Acalabrutinib ......................................................34 
Table 2  95% Confidence Intervals for Various Observed Overall Response Rate 
Values....................................................................................................................51 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments ...................................................................69 
Appendix 2 
IWCLL Response Assessment Criteria (Modified from Hallek 2008) ...73 
Appendix 3 
Cumulative Illness Rating Scale-Geriatric (CIRS-G) Calculator ...........75 
Appendix 4 
Known Strong in Vivo Inhibitors or Inducers of CYP3A ........................76 
Appendix 5 
Performance Status Scores .................................................................77 
Appendix 6 
Adverse Event Assessment of Causality .............................................78 
Appendix 7 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ...........................................................................................79 
 

 
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ABBREVIATIONS 
Abbreviation 
Definition 
ACP-196 
acalabrutinib 
AE 
adverse event 
ALC 
absolute lymphocyte count 
ANC 
absolute neutrophil count 
anti-HBc 
hepatitis B core antibody 
anti-HBs 
hepatitis B surface antibody 
ASCO 
American Society of Clinical Oncology 
BID 
twice per day (dosing) 
BOR 
best overall response 
BTK 
Bruton tyrosine kinase 
BUN 
blood urea nitrogen 
CD 
cluster of differentiation (cell surface marker) 
cGMP 
current Good Manufacturing Practice 
CIRS-G 
Cumulative Illness Rating Scale-Geriatric 
CLL 
chronic lymphocytic leukemia 
CR 
complete response (remission) 
CrCL 
creatinine clearance 
CRF 
case report form 
CRi 
complete remission with incomplete bone marrow recovery 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome p450 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EE 
efficacy-evaluable (population) 
EGFR 
epidermal growth factor receptor 
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 

 
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Abbreviation 
Definition 
HCV 
hepatitis C virus 
HR 
hazard ratio 
ICF 
Informed Consent Form 
IEC 
independent ethics committee 
IFNγ 
interferon gamma 
Ig 
immunoglobulin 
IRB 
institutional review board 
ITK 
interleukin-2-inducible T-cell kinase 
IV 
intravenous 
IVIG 
intravenous immunoglobulins 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
K-M 
Kaplan-Meier 
LTFU 
long-term follow-up 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NK 
natural killer (cells) 
nPR 
nodular partial remission 
ORR 
overall response rate 
OS 
overall survival 
PFS 
progression-free survival 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial response (remission) 
QD 
once per day (dosing) 
QTc 
corrected QT interval 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan  
SD 
stable disease or standard deviation 
SFU 
safety follow-up (visit) 
SUSAR 
suspected unexpected serious adverse reaction 
TT 
treatment termination (visit) 
TTNT 
time-to-next treatment 
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Abbreviation 
Definition 
TXK 
tyrosine kinase 
ULN 
upper limit of normal 
WHODRUG 
World Health Organization Drug Dictionary 

 
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STUDY SYNOPSIS 
Study Title: 
A Phase 2 Study of the Efficacy and Safety of ACP-196 in 
Subjects with Relapsed/Refractory CLL and Intolerant of Ibrutinib 
Therapy 
Protocol Number: 
ACE-CL-208 
Study Drug: 
Acalabrutinib (also known as ACP-196) 
Phase: 
Phase 2 
Comparator: 
None 
Study Centers: 
Subjects were enrolled in approximately 50 centers globally. 
Background and 
Rationale for Study 
Chronic lymphocytic leukemia (CLL) is a malignancy of B cells 
that predominantly affects the older population.  
Chemoimmunotherapy, in particular the combination of purine 
analogs (e.g., fludarabine) with cyclophosphamide and rituximab, 
has become a standard for the treatment of young and/or fit 
individuals with CLL who require treatment.  However, elderly 
subjects and those with comorbidities are often unable to tolerate 
combination chemoimmunotherapy regimens or experience 
inferior clinical outcomes when treated with these regimens.  In 
addition, those subjects who have high-risk cytogenetics have 
inferior outcomes and may prove to be refractory to therapy 
and/or experience short remission durations and rapid 
progression of disease when treated with standard and currently 
available treatment regimens  
Bruton tyrosine kinase inhibition is an established therapeutic 
intervention for the treatment of CLL.  Ibrutinib (IMBRUVICA®), a 
first-generation Bruton tyrosine kinase (BTK) inhibitor, has 
demonstrated efficacy in patients with relapsed or refractory CLL 
based on data from single-arm Phase 2 studies (PCYC 
1102/1103) and the randomized Phase 3 study (RESONATE) 
(IMBRUVICA® [prescribing information]).  Important safety risks 
have been observed with ibrutinib (see protocol). 
Chemical optimization, pharmacologic characterization, and 
toxicologic evaluation have led to identification of acalabrutinib, 
an orally administered, new chemical entity that covalently inhibits 
BTK and shows encouraging activity and acceptable safety in 
clinical and nonclinical studies.  Within the class of BTK inhibitors, 
acalabrutinib is a more selective inhibitor of BTK than ibrutinib.  
An improved kinase selectivity profile for acalabrutinib may 
translate to pharmacologic benefits (see protocol) 

 
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Acalabrutinib was specifically designed to be a more potent and 
selective inhibitor of BTK to avoid off-target side effects seen with 
other BTK inhibitors.  When profiled against 395 human kinases, 
acalabrutinib was more selective than ibrutinib. 
In vitro and in vivo safety pharmacology studies with acalabrutinib 
have demonstrated a favorable nonclinical safety profile  
To date, no subjects have discontinued acalabrutinib due to 
reoccurrence of events that occurred with ibrutinib therapy.  A 
better tolerated BTK inhibitor with fewer adverse events (AEs) 
has important efficacy implications.  Recent studies have shown 
patients who require dose interruptions or discontinuation on 
ibrutinib therapy have poor outcomes, including increased 
progression events  
Recently emerging data report a median overall survival (OS) of 3 
to 8 months for patients with relapsed/refractory CLL after 
discontinuation of ibrutinib treatment, including discontinuation 
due to AEs.  In addition, patients with relapsed/refractory CLL 
who reduce their ibrutinib dosage (<420 mg daily) or miss 
≥8 consecutive days of dosing experience shorter PFS.  These 
results suggest a new unmet need has arisen to address 
therapeutic options for patients with relapsed/refractory CLL who 
are intolerant of ibrutinib, especially if they are not candidates for 
treatment or retreatment with purine analogue-based therapy. 
Thus an alternative BTK inhibitor—with a potentially distinct 
safety profile—may provide meaningful clinical benefit for 
relapsed/refractory patients with CLL who cannot, or can no 
longer, tolerate ibrutinib therapy, especially if purine 
analogue-based therapy is not an option. 
Study Objectives: 
Primary Objective: 
• 
Evaluate the efficacy of acalabrutinib in subjects with 
relapsed/refractory CLL who are intolerant of ibrutinib 
therapy  
Secondary Objective: 
• 
Evaluate the safety and tolerability of acalabrutinib in 
subjects with relapsed/refractory CLL who are intolerant of 
ibrutinib therapy 
Exploratory Objectives: 
 
 
 
 
 
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Study Design: 
This is a multicenter, open-label, Phase 2 study evaluating the 
efficacy and safety of acalabrutinib in subjects with 
relapsed/refractory CLL (N=60) who are intolerant of ibrutinib 
therapy.  For the purpose of this protocol, ibrutinib intolerant is 
defined as patients who cannot tolerate, or no longer can tolerate, 
ibrutinib therapy due to adverse reactions associated with 
treatment.  Such patients may benefit from treatment with an 
alternative BTK inhibitor with a different safety profile than 
ibrutinib.  
Each treatment cycle will consist of 28 days (4 weeks).  
Radiologic tumor assessment will be done at screening, at the 
end of Cycles 3, 6, 9, 12, 18, 24, and then every year thereafter, 
while receiving acalabrutinib treatment.  Confirmation of CR will 
require bone marrow analysis and radiologic tumor assessment.  
Safety evaluations will be done at every visit and will consist of 
assessment of AEs, physical examinations, and safety laboratory 
panels.  Visits will be every 2 weeks for the first 2 cycles, then 
monthly through the end of Cycle 6, then every 3 cycles 
thereafter.  Subjects who discontinue study drug for any reason 
other than disease progression will be followed for disease 
progression, regardless of whether the subject receives new 
anticancer treatment.  A treatment termination (TT) visit is 
required for safety assessments for any subjects who 
permanently discontinue study drug for any reason (except for 
death, loss to follow-up, or withdrawal of consent), including 
disease progression, and should be scheduled within 7 days of 
his or her last dose of study drug, if possible.  In addition to the 
TT visit, all subjects who discontinue study drug will have a safety 
follow-up (SFU) visit 30 (+7) days after the last dose of study 
drug.  
All endpoints in this study will be investigator assessed.  Clinical 
sites will be used to collect and store computed tomography (CT) 
scan images. 
The end of study is defined as the date of the last subject’s last 
visit.  
Subjects who are still on treatment at the time of the final study 
analysis and deriving clinical benefit from acalabrutinib treatment 
may continue treatment.  At the time of the final data cutoff (DCO) 
and database closure, subjects who remain in this study may be 
transitioned to a separate rollover study or remain within this 
study protocol for continued access to study drug.  All active 
subjects are eligible to continue to receive acalabrutinib after 
database closure.  There will be no further data collection other 
than reporting of SAEs per Section 6.2.5.  Access to study 
treatment within this study protocol will enable continued 
treatment with visit assessments per standard of care, whereas 
the separate rollover study will enable treatment continuation with 

 
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visit assessments and data collection per the rollover study 
protocol.  
Efficacy Endpoints: 
Efficacy will be evaluated based on the modified International 
Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 
criteria  
The primary efficacy endpoint is overall response rate (ORR) 
assessed by the investigators. 
The secondary efficacy endpoints are: 
• 
Duration of response (DOR)  
• 
Progression-free survival (PFS) 
• 
Time-to-next treatment (TTNT) 
• 
Overall survival (OS) 
Safety Endpoints: 
The safety of acalabrutinib will be characterized by laboratory 
assessments and the type, frequency, severity, and causal 
attribution of AEs, or AEs leading to discontinuation of study 
treatment. 
For consistency of interpretation, AEs and laboratory results will 
be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), and the severity of both hematologic and 
nonhematologic AEs will be graded using the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03 or 
higher.  Standard definitions for seriousness will be applied  
 
 
 
 
 
 
 
 
 
 
Sample Size: 
Approximately 60 subjects. 
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. Prior diagnosis of CLL that meets published diagnostic criteria 
as follows: 
a. Monoclonal B-cells (either kappa or lambda light chain 
restricted) that are clonally co-expressing ≥1 B-cell marker 
(CD19, CD20, or CD23) and CD5. 
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b. Prolymphocytes may comprise ≤55% of blood 
lymphocytes. 
c. No evidence of cyclin D1 rearrangement or BCL-1 
overexpression. 
d. Presence of ≥5 x 109 B lymphocytes/L (5000 µL) in the 
peripheral blood (at any point since diagnosis). 
3. Must have received ≥1 prior therapy for CLL and not be 
appropriate for treatment or retreatment with purine 
analogue-based therapy as defined by ≥1 of the following 
criteria: 
a. Failure to respond (stable disease [SD] or disease 
progression on treatment) or progression-free interval of 
<3 years from treatment with a purine analogue-based 
therapy and anti-CD20 antibody-containing 
chemoimmunotherapy regimen after ≥2 cycles. 
b. Age ≥70 years 
c. Age ≥65 years with the presence of 1 of the following 
comorbidities that might place the subject at an 
unacceptable risk for treatment-related toxicity with purine 
analogue-based therapy, provided they have received 
≥1 prior treatment including ≥2 cycles of an 
alkylating-agent based (or purine analogue-based) 
anti-CD20 antibody-containing chemoimmunotherapy 
regimen: 
i. 
Cumulative Illness Rating Scale-Geriatric (CIRS-G; 
see protocol) ≥6. 
ii. 
Creatinine clearance (CrCL) <70 mL/min. 
d. History of purine analogue-associated autoimmune 
anemia, neutropenia, or autoimmune thrombocytopenia. 
e. Fluorescent in situ hybridization (FISH) showing 17p 
deletion mutation or p53 mutation (by central laboratory). 
4. Intolerant of ibrutinib, defined as:  
a. The subject has discontinued ibrutinib therapy due to 
Grade 3 or 4 AEs that persisted in spite of optimal 
supportive care measures OR 
b. Subjects who had Grade 2 AEs related to ibrutinib 
therapy, in spite of optimal supportive care measures that 
persisted for ≥2 weeks or that recurred ≥2 times whether 
dose was reduced or discontinued.   
5. Measurable nodal disease by CT, defined as ≥1 lymph node 
>1.5 cm as measured in the longest diameter in a site that 
has not been previously irradiated.  An irradiated lesion may 
be assessed for measurable disease only if there has been 
documented progression in that lesion since radiotherapy has 
ended. 
6. Documented disease progression after stopping ibrutinib 
therapy as defined by the IWCLL 2008 criteria (see protocol). 

 
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7. Eastern Cooperative Oncology Group (ECOG) performance 
status of ≤2. 
8. Women who are sexually active and can bear children must 
agree to use highly effective forms of contraception during the 
study and for 2 days after the last dose of acalabrutinib.  
Highly effective forms of contraception are defined in the 
protocol. 
9. This criterion has been removed as of Protocol Amendment 3. 
10. This criterion has been removed as of Protocol Amendment 3. 
11. Willing and able to participate in all required evaluations and 
procedures in this study protocol including, swallowing 
capsules without difficulty. 
12. 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: 
Subjects will be ineligible for this study if they meet any of the 
following criteria: 
1. Ongoing Grade 3 or 4 AE attributed to ibrutinib therapy.  Note:  
Subjects may be eligible for enrollment once the 
ibrutinib-related AE improves to Grade ≤2. 
2. Treatment with systemic anticancer therapy for CLL is 
prohibited between discontinuation of ibrutinib and enrollment 
on this trial.  
3. Prior exposure to a BCL-2 inhibitor (e.g., 
venetoclax/ABT-199). 
4. Prior malignancy (other than CLL), except for adequately 
treated basal cell or squamous cell skin cancer, in situ cancer, 
or other cancer from which the subject has been disease free 
for ≥2 years.   
5. Significant cardiovascular disease such as uncontrolled or 
symptomatic untreated arrhythmias, congestive heart failure, 
or myocardial infarction within 6 months of screening, or any 
Class 3 or 4 cardiac disease as defined by the New York 
Heart Association Functional Classification, or corrected QT 
interval (QTc) >480 msec at screening.  Exception:  Subjects 
with controlled, asymptomatic atrial fibrillation during 
screening are allowed to enroll on study. 
6. Malabsorption syndrome, disease significantly affecting 
gastrointestinal function, resection of the stomach, extensive 
small bowel resection that is likely to affect absorption, 
symptomatic inflammatory bowel disease, partial or complete 
bowel obstruction, or gastric restrictions and bariatric surgery, 
such as gastric bypass. 
7. Evidence of active Richter's transformation or any evidence of 
disease progression on ibrutinib therapy or any BTK inhibitor. 

 
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8. CNS involvement by CLL or related Richter’s transformation. 
9. Known history of human immunodeficiency virus (HIV), 
serologic status reflecting active hepatitis B or C infection, or 
any uncontrolled active systemic infection.   
a) Subjects who are hepatitis B core antibody (anti-HBc) 
positive and who are surface antigen negative will 
need to have a negative polymerase chain reaction 
(PCR) result before enrollment.  Those who are 
hepatitis B surface antigen (HBsAg) positive or 
hepatitis B PCR positive will be excluded. 
b) Subjects who are hepatitis C antibody positive will 
need to have a negative PCR result before enrollment.  
Those who are hepatitis C PCR positive will be 
excluded. 
10. Uncontrolled autoimmune hemolytic anemia (AIHA) or 
idiopathic thrombocytopenic purpura (ITP) defined as 
declining hemoglobin or platelet count secondary to 
autoimmune destruction within the screening period or 
requirement for high doses of steroids (>20 mg daily of 
prednisone or equivalent for longer than 2 weeks). 
11. History of stroke or intracranial hemorrhage within 2 months 
before the first dose of study drug. 
12. History of bleeding diathesis (e.g., hemophilia or von 
Willebrand disease). 
13. Presence of a gastrointestinal ulcer diagnosed by endoscopy 
within 3 months before screening. 
14. Major surgical procedure within 28 days of first dose of study 
drug.  Note:  If a subject had major surgery, they must have 
recovered adequately from any toxicity and/or complications 
from the intervention before the first dose of study drug. 
15. Requires treatment with a strong CYP3A inhibitor 
16. Requires treatment with proton-pump inhibitors (e.g., 
omeprazole, esomeprazole, lansoprazole, dexlansoprazole, 
rabeprazole, or pantoprazole).  Subjects receiving 
proton-pump inhibitors who switch to H2-receptor antagonists 
or antacids are eligible for enrollment to this study. 
17. Requires or receiving anticoagulation with warfarin or 
equivalent vitamin K antagonists (e.g., phenprocoumon).  
18. Absolute neutrophil count (ANC) <0.75 x 109/L or platelet 
count <50 x 109/L, unless there is bone marrow involvement. 
19. Total bilirubin >1.5 x upper limit of normal (ULN); or AST or 
ALT >3.0 x ULN. 
20. Estimated CrCL of <30 mL/min, calculated using the formula 
of Cockcroft and Gault [(140-Age) • Mass (kg)/(72 • 
creatinine mg/dL) • multiply by 0.85 if female] 
21. Breastfeeding or pregnant.  

 
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22. Concurrent participation in another therapeutic clinical trial. 
Dose Regimen/Route 
of Administration: 
Acalabrutinib 100 mg is intended to be administered orally twice 
per day (BID) with 8 ounces (approximately 240 mL) of water.  
Doses should be administered 12 hours apart (a window of 
±1 hour is allowed).  The capsules should be swallowed intact.  
Subjects should not attempt to open capsules or dissolve them in 
water. 
Concomitant 
Medications: 
Permitted Concomitant Therapy 
Antiemetics are permitted if clinically indicated.  Standard 
supportive care medications are permitted as per institutional 
standards.  Use of hematopoietic growth factors is permitted per 
the American Society of Clinical Oncology (ASCO) guidelines. 
Prohibited or Restricted Concomitant Therapy 
Any chemotherapy, anticancer immunotherapy, experimental 
therapy, or radiotherapy for treating CLL are prohibited if being 
used to treat the disease initially under study.  High-dose 
corticosteroids used to treat underlying CLL are not allowed on 
study.  Localized, short courses of radiotherapy are allowed for 
the treatment of lesions unrelated to the disease under study, if 
approved by the medical monitor. 
Warfarin or equivalent vitamin K antagonists (e.g., 
phenprocoumon) are prohibited. 
The concomitant use of strong inhibitors/inducers of CYP3A (see 
protocol) should be avoided when possible (see protocol).  If a 
subject requires short-term treatment with a strong CYP3A 
inhibitor (i.e., anti-infectives for up to 7 days), interrupt 
acalabrutinib treatment.  
Avoid coadministration of strong CYP3A inducers.  If a subject 
requires treatment with a strong CYP3A inducer, increase the 
acalabrutinib dose to 200 mg BID during concomitant 
administration with the strong inducer and return to 
recommended dose of 100 mg BID after stopping the strong 
CYP3A inducer.  For additional information on drugs with 
potential drug-drug interactions, refer to protocol. 
Safety Plan 
This trial will be monitored in accordance with the sponsor’s 
pharmacovigilance procedures.  AEs and SAEs will be reviewed 
internally as part of ongoing safety surveillance.  Quarterly 
conference calls with the investigators and applicable site staff 
will be conducted to discuss study progress, obtain investigator 
feedback and exchange, and discuss "significant safety events" 
(i.e., AEs leading to dose reductions, related SAEs, and deaths). 
In addition, an independent data monitoring committee (DMC) will 
be formed to review data for subject safety.  Data review will be 

 
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focused on, but not limited to deaths, treatment discontinuations, 
SAEs, and Grade 3/4 AEs, as well as special events of interest.  
After review of data, the DMC will provide recommendations 
regarding stopping or continuing the study in accordance with the 
DMC charter.  The DMC will meet approximately when the first 
15 subjects have been treated through Week 8, 30 subjects have 
been treated through Week 8, and subsequently every year, as 
needed, until the final DCO and database closure for the study.  
Additional meetings may be scheduled at the request of the DMC 
or the sponsor. 
Statistical Methods: 
The statistical methods presented in this section provide a 
high-level summary of analysis to be performed for this study.  
Detailed analyses will be described in the Statistical Analysis Plan 
(SAP).  The SAP will be finalized before database lock.  Any 
changes to the methods described in the final SAP will be justified 
and described in the clinical study report.  
No interim analysis is planned for this study.  The primary 
analysis will be performed after all subjects have completed the 
study. 
Continuous variables will be summarized by number of 
observations, mean, standard deviation, median, minimum, and 
maximum.  Categorical variables will be summarized by the 
number of subjects and percentage in each category. 
 
Statistical Basis for the Sample Size 
The primary objective of this study is to determine the ORR as 
assessed by investigators according to modified IWCLL criteria.  
A target true ORR rate of 40% is believed to be clinically 
meaningful in this difficult-to-treat population with limited 
alternative treatment options.  With a total of 60 subjects, the 95% 
confidence interval for various observed ORR values are 
provided in the protocol.  This provides reasonable precision for 
estimating ORR in this target patient population.  Finally, the 
probability of observing one or more instances of an AE with a 
background rate of 1%, 2%, 5%, and 10% in 60 subjects is 
45.3%, 70.2%, 95.4%, and 99.8%, respectively.   
 

 
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1.0 
BACKGROUND INFORMATION 
1.1 
CHRONIC LYMPHOCYTIC LEUKEMIA 
Chronic lymphocytic leukemia (CLL) is a malignancy of B cells that predominantly affects 
the older population.  Chemoimmunotherapy, in particular the combination of purine 
analogs (e.g., fludarabine) with cyclophosphamide and rituximab, has become a 
standard for the treatment of young and/or fit individuals with CLL who require treatment.  
However, elderly subjects and those with comorbidities are often unable to tolerate 
combination chemoimmunotherapy regimens or experience inferior clinical outcomes 
when treated with these regimens.  In addition, those subjects who have high-risk 
cytogenetics have inferior outcomes and may prove to be refractory to therapy and/or 
experience short remission durations and rapid progression of disease when treated with 
standard and currently available treatment regimens (Hallek 2010, Hillmen 2007).   
1.2 
BRUTON TYROSINE KINASE INHIBITION IN CLL 
Bruton tyrosine kinase (BTK) inhibition is an established therapeutic intervention for the 
treatment of CLL.  Ibrutinib (IMBRUVICA®), a first-generation BTK inhibitor, has 
demonstrated efficacy in patients with relapsed or refractory CLL based on data from 
single-arm Phase 2 studies (PCYC 1102/1103) and the randomized Phase 3 study 
(RESONATE) (IMBRUVICA® [prescribing information]).  In the RESONATE study, which 
had a median follow-up of 9.4 months, ibrutinib demonstrated clinically and statistically 
significant improvement over ofatumumab in progression-free survival (PFS) (hazard 
ratio [HR]=0.22), overall survival (OS) (HR=0.43) and ORR (42.6% versus 4.1% by 
independent assessment and 69.7% versus 21.4% by investigator assessment).    
Important safety risks observed with ibrutinib include the following adverse reactions 
(IMBRUVICA® [prescribing information]): 
• 
Fatal bleeding events have occurred in patients treated with ibrutinib.  Major 
hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., 
intracranial hemorrhage [including subdural hematoma], gastrointestinal 
bleeding, hematuria, and post-procedural hemorrhage) have occurred in 4% of 
patients, with fatalities occurring in 0.4% of patients. 
 
• 
Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred 
with ibrutinib therapy.  Grade ≥3 infections have occurred in 24% of patients.  

 
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• 
Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), 
thrombocytopenia (8%), and anemia (3%) based on laboratory measurements 
occurred in patients with B-cell malignancies. 
• 
Fatal and serious cardiac arrhythmias have occurred with ibrutinib therapy. 
Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and 
Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of patients.   
• 
Hypertension of any grade occurred in 12% of patients treated with ibrutinib in 
clinical trials.  Grade 3 or greater hypertension occurred in 5% of patients. 
• 
Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 
patients treated with ibrutinib in clinical trials.  The most frequent second primary 
malignancy was non-melanoma skin cancer (6%). 
• 
Tumor lysis syndrome (TLS) has been infrequently reported with ibrutinib 
therapy. 
• 
Based on findings in animals, ibrutinib can cause fetal harm when administered 
to a pregnant woman.  Administration of ibrutinib to pregnant rats and rabbits 
during the period of organogenesis caused embryofetal toxicity including 
malformations at exposures that were 2 to 20 times higher than those reported in 
patients with hematologic malignancies. 
Chemical optimization, pharmacologic characterization, and toxicologic evaluation have 
led to identification of acalabrutinib, an orally administered, new chemical entity that 
covalently inhibits BTK and shows encouraging activity and acceptable safety in clinical 
and nonclinical studies.  Within the class of BTK inhibitors, acalabrutinib is a more 
selective inhibitor of BTK than ibrutinib.  An improved kinase selectivity profile for 
acalabrutinib may translate to pharmacologic benefits as outlined below: 
• 
Ibrutinib is a potent covalent inhibitor of epidermal growth factor receptor 
(EGFR); acalabrutinib is not (Covey 2015).   
• 
Ibrutinib is associated with clinically significant bleeding events in patients 
including intracranial hemorrhage.  The mechanism for the bleeding events is not 
well understood.  However, ibrutinib impairs thrombus formation in an in vivo 
model at physiologically relevant concentrations; acalabrutinib does not 
(Covey 2015).  
• 
Ibrutinib is a potent covalent inhibitor of interleukin-2-inducible T-cell kinase 
(ITK).  As such, ibrutinib interferes with natural killer (NK) cell-mediated function 
and antitumor activities of therapeutic CD20 antibodies (Da Roit 2015).  
Acalabrutinib does not inhibit ITK.  Consequently in vitro studies show no effect 
of acalabrutinib on NK cell function or antitumor activities of therapeutic CD20 
antibodies (Rajasekaran 2014). 

 
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• 
Ibrutinib is also a potent covalent inhibitor of tyrosine kinase (TXK).  ITK and TXK 
regulate the development of cytotoxic CD8+ T cells (Atherly 2006) and modulate 
interferon gamma (IFNγ) release (Takeba 2002).  Acalabrutinib is not a potent 
inhibitor of TXK.  In vivo tumor models show robust expansion of CD8+ T cells 
with acalabrutinib treatment compared with ibrutinib (Lannutti 2015).  In vitro 
T-cell studies show reduced CD8+ T-cell viability with ibrutinib treatment 
compared with acalabrutinib (Covey 2015).  Recently conducted in vitro CD8+ 
T-cell functional assays show ibrutinib negatively impacts T-cell function (i.e., 
cytotoxicity and IFNγ release), while acalabrutinib does not.  The differential 
potency of acalabrutinib versus ibrutinib on key modulators of T-cell function may 
lead to better clinical outcomes in patients, such as a reduced incidence of 
infections with acalabrutinib treatment.  
1.3 
ACALABRUTINIB 
  
  
Acalabrutinib is orally administered in humans and is suitable for formulating in capsules.  
For clinical testing, acalabrutinib has been manufactured and formulated according to 
current Good Manufacturing Practices (cGMP). 
Acalabrutinib is an investigational product.  Calquence® has been approved by United 
States and other markets for the treatment of adult patients with mantle cell lymphoma 
who have received at least one prior therapy, CLL, and small lymphocytic lymphoma 
(SLL). 
1.3.1 
Mechanism of Action 
Acalabrutinib was specifically designed to be a more potent and selective inhibitor of 
BTK to avoid off-target side effects seen with other BTK inhibitors.  When profiled 
against 395 human kinases, acalabrutinib was more selective than ibrutinib 
(Covey 2015).  For additional details, refer to the Acalabrutinib Investigator Brochure. 
1.3.2 
Safety Pharmacology 
In vitro and in vivo safety pharmacology studies with acalabrutinib have demonstrated a 
favorable nonclinical safety profile; for detailed information on the safety pharmacology 
of acalabrutinib, refer to the Acalabrutinib Investigator Brochure.   
CCI
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1.3.3 
Drug-Drug Interaction Potential 
For more detailed information on drug-drug interaction potential for acalabrutinib, refer to 
the Acalabrutinib Investigator Brochure. 
Please refer to Section 3.10.10 for guidance on drugs that may cause drug-drug 
interactions. 
1.4 
CLINICAL EXPERIENCE – ACALABRUTINIB 
For detailed information on the clinical experience for acalabrutinib, please refer to the 
Acalabrutinib Investigator Brochure.   
This section briefly summarizes data from ACE-CL-001 (NCT02029443), an ongoing 
non-randomized, sequential group, dose-escalation Phase 1/2 study in subjects with 
relapsed/refractory or previously untreated CLL, Richter’s syndrome, or prolymphocytic 
leukemia. 
Subjects with relapsed CLL have been evaluated for tumor response based on modified 
International Working Group response criteria (Hallek 2008) as recently updated 
(Cheson 2012) to include partial response (PR) with treatment-induced lymphocytosis.  
Few subjects have had disease progression and no Richter’s transformation has been 
observed in these subjects. 
To date, no subjects have discontinued acalabrutinib due to reoccurrence of events that 
occurred with ibrutinib therapy.  A better tolerated BTK inhibitor with fewer AEs has 
important efficacy implications.  Recent studies have shown patients who require dose 
interruptions or discontinuation on ibrutinib therapy have poor outcomes, including 
increased progression events (Barr 2015).  For more detailed, up-to-date information, 
refer to the Acalabrutinib Investigator Brochure. 
1.5 
BENEFIT/RISK 
Acalabrutinib is a potent, orally administered small-molecule inhibitor of BTK.  In the 
Phase 1/2 study of acalabrutinib in subjects with CLL, no dose-limiting toxicities (DLTs) 
have been identified at dosages of ≤400 mg once per day (QD) or 100 to 200 mg twice 
per day (BID).  The ORR in the evaluable subjects for this study is 94% with some 
subjects obtaining PRs after only 2 cycles of therapy.  In summary, the preliminary data 
suggest that acalabrutinib is well tolerated and has robust activity as a single agent in 
the treatment of subjects with relapsed or refractory CLL, including those with 17p del or 

 
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11q del.  In addition, pharmacodynamic (PD) results show the 100-mg BID regimen 
produces optimal target coverage over 24 hours (i.e., more complete coverage of de 
novo synthesis of BTK), which may provide greater clinical benefit than the QD regimen 
of ibrutinib.  
Recently emerging data report a median OS of 3 to 8 months for patients with 
relapsed/refractory CLL after discontinuation of ibrutinib treatment, including 
discontinuation due to adverse events (AEs) (Jain 2015, Maddocks 2015, Pinilla-
Ibarz 2015).  In addition, patients with relapsed/refractory CLL who reduce their ibrutinib 
dosage (<420 mg daily) or miss ≥8 consecutive days of dosing experience shorter PFS 
(Barr 2015).  These results suggest a new unmet need has arisen to address therapeutic 
options for patients with relapsed/refractory CLL who are intolerant of ibrutinib, 
especially if they are not candidates for treatment or retreatment with purine 
analogue-based therapy.  For this subset of patients, the recommended therapy is 
idelalisib plus rituximab per National Comprehensive Cancer Network (NCCN) 
guidelines (NCCN 2015).  However, little, if any, clinical data have been reported for 
patients who receive idelalisib therapy after ibrutinib discontinuation.  In fact, the 
idelalisib Phase 3 registration study excluded patients previously treated with ibrutinib.  
Thus, the quality and duration of objective responses in patients who receive idelalisib in 
the post-ibrutinib setting is unknown.  In addition, the reported Phase 2 and Phase 3 
PFS results for ibrutinib therapy (Byrd 2014a, Byrd 2014b) in patients with 
relapsed/refractory CLL are consistently suggestive of a longer median PFS than 
reported for idelalisib plus rituximab therapy (Sharman 2014).  Just as importantly, 
idelalisib therapy is also associated with serious risks of hepatotoxicity, colitis, 
pneumonitis, and intestinal perforation (ZYDELIG® prescribing information); none of 
which have been associated with either ibrutinib or acalabrutinib therapy.  Other 
treatment options for this subset of patients include anti-CD20 antibody monotherapy 
(NCCN 2015), though the Phase 3 studies for ibrutinib and idelalisib showed minimal 
clinical activity of single-agent ofatumumab or rituximab, respectively, in 
relapsed/refractory CLL (Byrd 2014b, Furman 2014).  Thus an alternative BTK 
inhibitor—with a potentially distinct safety profile—may provide meaningful clinical 
benefit for relapsed/refractory patients with CLL who cannot, or can no longer, tolerate 
ibrutinib therapy, especially if purine analogue-based therapy is not an option. 

 
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2.0 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE: 
• 
Evaluate the efficacy of acalabrutinib in subjects with relapsed/refractory CLL 
who are intolerant of ibrutinib therapy  
2.2 
SECONDARY OBJECTIVE: 
• 
Evaluate the safety and tolerability of acalabrutinib in subjects with 
relapsed/refractory CLL who are intolerant of ibrutinib therapy 
2.3 
EXPLORATORY OBJECTIVES: 
 
 
 
 
3.0 
STUDY DESIGN 
This is a multicenter, open-label, Phase 2 study evaluating the efficacy and safety of 
acalabrutinib in subjects with relapsed/refractory CLL (N=60) who are intolerant of 
ibrutinib therapy.  For the purpose of this protocol, ibrutinib intolerant is defined as 
patients who cannot tolerate, or no longer can tolerate, ibrutinib therapy due to adverse 
reactions associated with treatment.  Such patients may benefit from treatment with an 
alternative BTK inhibitor with a different safety profile than ibrutinib.  
Subjects will be considered ibrutinib intolerant (at any dose/or duration) if they have 
discontinued ibrutinib therapy due to Grade 3 or 4 AEs that persisted in spite of optimal 
supportive care measures (for example atrial fibrillation/flutter, cardiac arrhythmia, 
diarrhea, rash, ecchymosis, myalgia or arthralgia), or if subjects had Grade 2 AEs 
related to ibrutinib therapy, in spite of optimal supportive care measures, that persisted 
for ≥2 weeks or that recurred ≥2 times, whether dose was reduced or discontinued.  
Subjects will be treated with acalabrutinib 100 mg BID.  Treatment may be continued 
until disease progression or an unacceptable drug-related toxicity occurs.     
Each treatment cycle will consist of 28 days (4 weeks).  Radiologic tumor assessments 
will be done at screening, at the end of Cycles 3, 6, 9, 12, 18, 24, and then every year 
thereafter, while receiving acalabrutinib treatment.  Confirmation of complete response 
(CR) will require bone marrow analysis and radiologic tumor assessment.  Safety 
evaluations will be done at every visit and will consist of assessment of AEs, physical 
CCI

 
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examinations, and safety laboratory panels.  Visits will be every 2 weeks for the first 
2 cycles, then monthly through the end of Cycle 6, then every 3 cycles thereafter.  
Subjects who discontinue study drug for any reason other than disease progression will 
be followed for disease progression, regardless of whether the subject receives new 
anticancer treatment.  A treatment termination (TT) visit is required for safety 
assessments for any subjects who permanently discontinue study drug for any reason 
(except for death, loss to follow-up, or withdrawal of consent), including disease 
progression, and should be scheduled within 7 days of his or her last dose of study drug, 
if possible.  In addition to the TT visit, all subjects who discontinue study drug will have a 
safety follow-up (SFU) visit 30 (+7) days after the last dose of study drug.   
All endpoints in this study will be investigator assessed.  Clinical sites will be used to 
collect and store computed tomography (CT) scan images. 
Refer to Appendix 1 for a comprehensive list of study assessments and their timing.   
3.1 
END OF STUDY 
The final analysis will take place no earlier than the date the last subject has completed 
the end of Cycle 36 or has been withdrawn for any reason and completed the 30-day 
SFU visit (if applicable), whichever occurs first. 
The end of study is defined as the date of the last subject’s last visit.   
Subjects who are still on treatment at the time of the final study analysis and deriving 
clinical benefit from acalabrutinib treatment may continue treatment.  At the time of the 
final data cutoff (DCO) and database closure, subjects who remain in this study may be 
transitioned to a separate rollover study or remain within this study protocol for continued 
access to study drug.  All active subjects are eligible to continue to receive acalabrutinib 
after database closure.  There will be no further data collection other than reporting of 
serious adverse events (SAEs) per Section 6.2.5.  Access to study treatment within this 
study protocol will enable continued treatment with visit assessments per standard of 
care, whereas the separate rollover study will enable treatment continuation with visit 
assessments and data collection per the rollover study protocol.   

 
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3.2 
STUDY ENDPOINTS 
3.2.1 
Efficacy Endpoints 
Efficacy will be evaluated based on the modified International Workshop on Chronic 
Lymphocytic Leukemia (IWCLL) 2008 criteria (Appendix 2). 
The primary efficacy endpoint is ORR assessed by the investigators. 
The secondary efficacy endpoints are: 
• 
Duration of response (DOR) 
• 
PFS 
• 
Time-to-next treatment (TTNT) 
• 
OS 
3.2.2 
Safety Endpoints 
The safety of acalabrutinib will be characterized by laboratory assessments and the 
type, frequency, severity, and causal attribution of AEs, or AEs leading to discontinuation 
of study treatment. 
For consistency of interpretation, AEs and laboratory results will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA), and the severity of both 
hematologic and nonhematologic AEs will be graded using the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03 or higher.  Standard definitions for 
seriousness will be applied (see Section 6.1).   
3.2.3 
 
 
  
 
  
 
 
3.3 
RATIONALE FOR STUDY DESIGN AND DOSING REGIMEN 
3.3.1 
Dose Selection Rationale 
As described in Section 1.4, acalabrutinib is currently being evaluated in a Phase 1/2 
study in subjects with CLL, Richter’s syndrome, or prolymphocytic leukemia 
CCI
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(ACE-CL-001).  In this study, subjects have received oral dosages of 100 to 400 mg QD 
and 100 to 200 mg BID of acalabrutinib.  All tested dose levels have been well tolerated.  
No DLT has occurred at any dose level, and the MTD was not reached.  PD results from 
this study also show 100 and 200 mg BID have the highest BTK occupancy at 24 hours 
of all the regimens evaluated.  Robust clinical responses have been observed.  
Therefore, based on pharmacokinetic (PK)/PD and efficacy results of ACE-CL-001, 
acalabrutinib 100 mg BID will be evaluated in this study.  
3.3.2 
Selection of the Patient Population 
As discussed in Section 1.5, patients with relapsed/refractory CLL who discontinue 
ibrutinib due to AEs or who reduce their ibrutinib dosage or miss ≥8 consecutive days of 
dosing experience poor clinical outcomes (OS and PFS).  Treatment options are limited 
for these patients with relapsed/refractory CLL who are intolerant to ibrutinib and not 
considered appropriate candidates for purine analogue-based therapy.  Per NCCN 
guidelines (NCCN 2015), the preferred therapy for this subset of patients after ibrutinib is 
idelalisib plus rituximab.  However, as stated in Section 1.5, no significant data exist on 
ORR or PFS in patients treated with idelalisib after ibrutinib therapy because the 
Phase 3 idelalisib study excluded patients with previous exposure to ibrutinib. 
In addition, the reported Phase 2 and Phase 3 PFS results for ibrutinib therapy 
(Byrd 2014a, Byrd 2014b) in patients with relapsed/refractory CLL are consistently 
suggestive of a longer median PFS than reported for idelalisib + rituximab therapy 
(Sharman 2014).  Per NCCN guidelines (NCCN 2015), monotherapy with anti-CD20 
antibodies is listed as a potential treatment option for this population.  However, the 
recent results from the ibrutinib and idelalisib Phase 3 studies show monotherapy with 
anti-CD20 antibodies has minimal clinical activity in relapsed/refractory CLL 
(Byrd 2014b, Furman 2014).  In other words, this protocol is designed to assess the 
efficacy and safety of a second-generation BTK inhibitor in patients who cannot, or can 
no longer, tolerate ibrutinib therapy and have few alternative treatment options. 
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:  

 
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1. Men and women ≥18 years of age. 
2. Prior diagnosis of CLL that meets published diagnostic criteria (Hallek 2008) as 
follows: 
a. Monoclonal B cells (either kappa or lambda light chain restricted) that are clonally 
co-expressing ≥1 B-cell marker (CD19, CD20, or CD23) and CD5. 
b. Prolymphocytes may comprise ≤55% of blood lymphocytes. 
c. No evidence of cyclin D1 rearrangement or BCL-1 overexpression. 
d. Presence of ≥5 x 109 B lymphocytes/L (5000 µL) in the peripheral blood (at any 
point since diagnosis). 
3. Must have received ≥1 prior therapy for CLL and not be appropriate for treatment or 
retreatment with purine analogue-based therapy as defined by ≥1 of the following 
criteria: 
a. Failure to respond (stable disease [SD] or disease progression on treatment) or 
progression-free interval of <3 years from treatment with a purine 
analogue-based therapy and anti-CD20 antibody–containing 
chemoimmunotherapy regimen after ≥2 cycles. 
b. Age ≥70 years 
c. Age ≥65 years with the presence of 1 of the following comorbidities that might 
place the subject at an unacceptable risk for treatment-related toxicity with purine 
analogue-based therapy, provided they have received ≥1 prior treatment 
including ≥2 cycles of an alkylating-agent based (or purine analogue-based) 
anti-CD20 antibody-containing chemoimmunotherapy regimen: 
i. 
Cumulative Illness Rating Scale - Geriatric (CIRS-G) (Appendix 3) ≥6.  
ii. 
Creatine clearance (CrCL) <70 mL/min.   
d. History of purine analogue-associated autoimmune anemia, neutropenia, or 
autoimmune thrombocytopenia. 
e. Fluorescent in situ hybridization (FISH) showing 17p deletion mutation or p53 
mutation (by central laboratory). 
4. Intolerant of ibrutinib, defined as:  
a. The subject has discontinued ibrutinib therapy due to Grade 3 or 4 AEs that 
persisted in spite of optimal supportive care measures OR 
b. Subjects who had Grade 2 AEs related to ibrutinib therapy, in spite of optimal 
supportive care measures that persisted for ≥2 weeks or that recurred ≥2 times 
whether dose was reduced or discontinued.   
5. Measurable nodal disease by CT defined as ≥1 lymph node >1.5 cm as measured in 
the longest diameter in a site that has not been previously irradiated.  An irradiated 
lesion may be assessed for measurable disease only if there has been documented 
progression in that lesion since radiotherapy has ended. 
6. Documented disease progression after stopping ibrutinib therapy as defined by the 
IWCLL 2008 criteria (Appendix 2). 
7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. 

 
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8. Women who are sexually active and can bear children must agree to use highly 
effective forms of contraception during the study and for 2 days after the last dose of 
acalabrutinib.  Highly effective forms of contraception are defined in Section 3.10.11. 
9. This criterion has been removed as of Protocol Amendment 3. 
10. This criterion has been removed as of Protocol Amendment 3. 
11. Willing and able to participate in all required evaluations and procedures in this study 
protocol, including swallowing capsules without difficulty. 
12. 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. Ongoing Grade 3 or 4 AE attributed to ibrutinib therapy.  Note:  Subjects may be 
eligible for enrollment once the ibrutinib-related AE improves to Grade ≤2. 
2. Treatment with systemic anticancer therapy for CLL is prohibited between 
discontinuation of ibrutinib and enrollment on this trial. 
3. Prior exposure to a BCL-2 inhibitor (e.g., venetoclax/ABT-199).  
4. Prior malignancy (other than CLL), except for adequately treated basal cell or 
squamous cell skin cancer, in situ cancer, or other cancer from which the subject has 
been disease free for ≥2 years. 
5. Significant cardiovascular disease such as uncontrolled or symptomatic untreated 
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of 
screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart 
Association Functional Classification, or corrected QT interval (QTc) >480 msec at 
screening.  Exception:  Subjects with controlled, asymptomatic atrial fibrillation during 
screening are allowed to enroll on study. 
6. Malabsorption syndrome, disease significantly affecting gastrointestinal function, 
resection of the stomach, extensive small bowel resection that is likely to affect 
absorption, symptomatic inflammatory bowel disease, partial or complete bowel 
obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. 
7. Evidence of active Richter's transformation or any evidence of disease progression 
on ibrutinib therapy or any BTK inhibitor. 
8. CNS involvement by CLL or related Richter’s transformation. 
9. Known history of HIV, serologic status reflecting active hepatitis B or C infection, or 
any uncontrolled active systemic infection.   
a) Subjects who are anti-hepatitis B core antibody (anti-HBc) positive and who 
are surface antigen negative will need to have a negative polymerase chain 
reaction (PCR) result before enrollment.  Those who are hepatitis B surface 
antigen (HBsAg) positive or hepatitis B PCR positive will be excluded. 
b) Subjects who are hepatitis C antibody positive will need to have a negative 
PCR result before enrollment.  Those who are hepatitis C PCR positive will 
be excluded. 

 
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10. Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic 
purpura (ITP) defined as declining hemoglobin or platelet count secondary to 
autoimmune destruction within the screening period or requirement for high doses of 
steroids (>20 mg daily of prednisone or equivalent for longer than 2 weeks). 
11. History of stroke or intracranial hemorrhage within 2 months before the first dose of 
study drug. 
12. History of bleeding diathesis (e.g., hemophilia or von Willebrand disease). 
13. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before 
screening. 
14. Major surgical procedure within 28 days of first dose of study drug.  Note:  If a 
subject had major surgery, they must have recovered adequately from any toxicity 
and/or complications from the intervention before the first dose of study drug. 
15. Requires treatment with a strong CYP3A inhibitor.    
16. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).  Subjects receiving 
proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible 
for enrollment to this study. 
17. Requires or receiving anticoagulation with warfarin or equivalent vitamin K 
antagonists (e.g., phenprocoumon). 
18. Absolute neutrophil count (ANC) <0.75 x 109/L or platelet count <50 x 109/L, unless 
there is bone marrow involvement. 
19. Total bilirubin >1.5 x upper limit of normal (ULN); or AST or ALT >3.0 x ULN. 
20. Estimated CrCL of <30 mL/min, calculated using the formula of Cockcroft and Gault 
[(140-Age) • Mass (kg)/(72 • creatinine mg/dL) • multiply by 0.85 if female]. 
21. Breastfeeding or pregnant.  
22. Concurrent participation in another therapeutic clinical trial. 
3.4.3 
Replacement of Subjects 
Subjects who are withdrawn or removed from study treatment will not be replaced. 
3.4.4 
Enrollment Procedures 
Enrollment of a subject into the study will be performed according to the following 
procedure:  
• 
The study center will notify the sponsor when a clinically eligible subject is 
identified and is ready to screen, to ensure enrollment availability on the study. 
• 
After the subject has signed and dated the ICF, all screening procedures have 
been completed, and eligibility has been confirmed, the subject can be officially 
enrolled into the study.  
• 
To enroll a subject, the study center will fax/email a completed Enrollment 
Confirmation Form to the sponsor.  The enrollment date will be the date that the 
sponsor confirms enrollment. 

 
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• 
The sponsor will aim to fax/email a completed Enrollment Confirmation Form to 
the study center within 48 hours.   
Treatment must begin within the screening window (Section 4.1). 
A CT scan documenting progression while off ibrutinib treatment or other objective 
criteria (e.g., absolute lymphocyte count [ALC] increasing >50%) must be available for 
review by the sponsor. 
3.5 
STUDY DRUG 
3.5.1 
Premedications 
No specific premedications or supporting medications are required in conjunction with 
acalabrutinib administration. 
3.5.2 
Formulation, Packaging, and Storage 
Acalabrutinib 
Acalabrutinib is manufactured according to cGMP regulations and will be provided to the 
investigational site by Acerta Pharma or designee.  Acalabrutinib should be stored 
according to the instructions on the label affixed to the package of the drug product.  
Acalabrutinib will be provided in white, high-density polyethylene bottles.   
If a drug shipment arrives damaged, or if there are any other drug complaints, a Product 
Complaint Form should be completed and emailed or faxed to the sponsor or the 
sponsor’s representative.  Refer to the Acalabrutinib Investigator Brochure for additional 
information regarding the drug product to be used in this trial. 
3.5.3 
Administration of Study Drug  
Investigators are prohibited from supplying acalabrutinib to any subjects not properly 
enrolled in this study.  The investigator must ensure that subjects receive acalabrutinib 
only from personnel who fully understand the procedures for administering the drug. 
Acalabrutinib 100 mg is intended to be administered orally BID with 8 ounces 
(approximately 240 mL) of water.  Doses should be administered 12 hours apart (a 
window of ±1 hour is allowed).  The capsules should be swallowed intact.  Subjects 
should not attempt to open capsules or dissolve them in water.   
If a dose is not taken within the allowed window, it can be taken up to 3 hours after the 
scheduled time with a return to the normal schedule the same or following day.  If it has 

 
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been >3 hours, the dose should not be taken and the subject should take the next dose 
at the next scheduled time.  The missed dose will not be made up and must be returned 
to the site at the next scheduled visit. 
Guidance on coadministration of acalabrutinib with agents that affect gastric pH is 
provided in Section 3.10.10. 
For subjects considered at risk for TLS, administer appropriate hydration and allopurinol 
or rasburicase per institutional standards prior to initiating treatment. 
3.5.4 
Assuring Subject Compliance 
For treatments that are taken in the clinic, subjects should take the dose from the drug 
dispensed for them for that particular time period.  All other acalabrutinib treatments will 
be taken at home.  Subjects will receive a drug diary to record the specific time each 
dose was taken and to record reasons for any missed doses.   
Subject compliance with acalabrutinib dosing will be assessed at every visit.  The 
subject will be instructed to bring the diary and any remaining capsules to the clinic at 
their next visit.  The study staff will review the diary and ask the subject if all of the 
capsules were administered.  Any remaining or returned capsules will be counted and 
recorded as described in Section 7.6.  Returned capsules must not be redispensed to 
another subject.  
3.6 
STUDY TREATMENT SCHEDULE 
Acalabrutinib 100 mg BID will be administered orally. 
For information on dosing and dose modifications of acalabrutinib, refer to Section 3.8. 
3.7 
DURATION OF THERAPY 
Treatment can continue until the end of study for subjects without disease progression 
and who are tolerating therapy.  The end of study is defined as the date of the last 
subject’s last visit.  Refer to Section 3.11 for details on withdrawal of study treatment.   
3.8 
DOSING DELAYS AND MODIFICATIONS 
3.8.1 
Dose Delays and Modifications of Acalabrutinib 
Subjects should be followed closely for AEs or laboratory abnormalities that might 
indicate acalabrutinib–related toxicity.  If a subject experiences an intolerable AE during 

 
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the course of therapy, then acalabrutinib should be withheld, as necessary, until the AE 
resolves or stabilizes to an acceptable degree.  
The actions in Table 1 should be followed for the following treatment-emergent toxicities: 
• 
Grade 4 ANC (<500/μL) for >7 days (neutrophil growth factors are permitted per 
American Society of Clinical Oncology [ASCO] guidelines [Smith 2015] and use 
must be recorded on the case report form [CRF]). 
• 
Grade 3 platelet decreases in presence of significant bleeding. 
• 
Grade 4 platelet decreases.  
• 
Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal 
antiemetic and/or anti-diarrheal therapy. 
• 
Any other Grade 4 toxicity or unmanageable Grade 3 toxicity. 
Table 1  Drug Modification Actions for Acalabrutinib 
Occurrence 
Action 
1st – 2nd 
Hold acalabrutinib until recovery to Grade ≤1 or baseline; may restart at 
original dose level 
3rd 
Hold acalabrutinib until recovery to Grade ≤1 or baseline; restart at one 
dose level lower (100 mg QD) 
4th 
Discontinue acalabrutinib 
QD=once per day. 
 
As appropriate, certain laboratory abnormalities may warrant more frequent monitoring 
(e.g., once per week) until abnormalities have recovered to Grade ≤1.  If acalabrutinib is 
reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even 
if there is minimal or no toxicity with the reduced dose.  However, if the subject tolerates 
a reduced dose of acalabrutinib for ≥4 weeks then the dose may be increased to the 
next higher dose level, at the discretion of the investigator.  Such re-escalation may be 
particularly warranted if further evaluation reveals that the AE that led to the dose 
reduction was not treatment-related.  However, the maximum dose of acalabrutinib is 
100 mg BID for this protocol. 
Treatment with acalabrutinib should be withheld for any unmanageable, potentially study 
drug-related toxicity that is Grade ≥3 in severity.  Any other clinically important events 
where dose delays may be considered appropriate by the investigator must be 
discussed with the medical monitor.  Study drug may be withheld for a maximum of 

 
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28 consecutive days from expected dose due to toxicity.  Study treatment should be 
discontinued in the event of a toxicity lasting >28 days, unless reviewed and approved 
by the medical monitor.   
For full study treatment discontinuation criteria, refer to Section 3.11. 
Note: Temporary withholding of acalabrutinib (e.g., for drug-related toxicity, 
surgery, or intercurrent illness) for as little as 7 days can cause a transient 
worsening of disease and/or of constitutional symptoms.  In such circumstances, 
and if medically appropriate, subjects may resume therapy and relevant clinical, 
laboratory, and/or radiographic assessment can be attempted to document whether 
tumor control can be maintained or whether cancer progression has occurred. 
3.9 
CONCOMITANT THERAPY 
3.9.1 
Permitted Concomitant Therapy 
Antiemetics are permitted if clinically indicated.  Standard supportive care medications 
are permitted as per institutional standards.  Use of hematopoietic growth factors is 
permitted per the ASCO guidelines (Smith 2015). 
3.9.2 
Prohibited or Restricted Concomitant Therapy 
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy 
for treating CLL are prohibited if being used to treat the disease initially under study.  
High-dose corticosteroids used to treat underlying CLL are not allowed on study.  
Localized, short courses of radiotherapy are allowed for the treatment of lesions 
unrelated to the disease under study, if approved by the medical monitor. 
Warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) are prohibited. 
The concomitant use of strong inhibitors/inducers of CYP3A (see Appendix 4) should be 
avoided when possible (see Section 3.10.9 and Section 3.10.10).  If a subject requires 
short-term treatment with a strong CYP3A inhibitor (i.e., anti-infectives for up to 7 days), 
interrupt acalabrutinib treatment.  
Avoid coadministration of strong CYP3A inducers.  If a subject requires treatment with a 
strong CYP3A inducer, increase the acalabrutinib dose to 200 mg BID during 
concomitant administration with the strong inducer and return to recommended dose of 

 
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100 mg BID after stopping the strong CYP3A inducer.  For additional information on 
drugs with potential drug-drug interactions, refer to Section 3.10.10. 
3.10 RISKS ASSOCIATED WITH ACALABRUTINIB TREATMENT 
The following summarizes the experience with acalabrutinib in hematological cancer 
studies.  Full details regarding the clinical safety of acalabrutinib are presented in 
Sections 5 and 6 of the Acalabrutinib Investigator’s Brochure. 
3.10.1 
Hemorrhage 
Bleeding events, some fatal, including CNS, respiratory, and gastrointestinal 
hemorrhage, have been reported in subjects treated with acalabrutinib.  
Subjects receiving antithrombotic agents may be at increased risk of hemorrhage.  Use 
caution with antithrombotic agents and consider additional monitoring for signs of 
bleeding when concomitant use is medically necessary.  As a precaution, it is suggested 
that acalabrutinib be withheld for at least 3 days pre- and post-surgery.  
Subjects with hemorrhage should be managed per institutional guidelines with 
supportive care and diagnostic evaluations as clinically indicated. 
3.10.2 
Infections 
Serious infections, including fatal events, have occurred in clinical studies with 
acalabrutinib.  Subjects should be monitored for signs and symptoms of infection and 
treated as medically appropriate.   
Consider prophylaxis in subjects who are at increased risk for opportunistic infections.  
Subjects should be monitored for signs and symptoms of infection and treated as 
medically appropriate.  Refer to Sections 3.10.3 and 4.1.14 for additional information and 
monitoring guidance for viral hepatitis, and Section 3.10.4 for additional information and 
management guidance for signs and symptoms of progressive multiofocal 
leukoencophalopathy (PML). 
3.10.3 
Hepatitis B Virus Reactivation 
Cases of hepatitis B virus (HBV) reactivation have occurred in clinical studies with 
acalabrutinib.  Subjects who are anti-HBc positive, or have a known history of HBV 
infection, should be monitored every 3 months with a quantitative PCR test for HBV 
DNA.  Monitoring should continue every 3 months until 12 months after last dose of 

 
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acalabrutinib.  Any subject with a rising viral load (above lower limit of detection) should 
discontinue study drug and have antiviral therapy instituted and a consultation with a 
physician with expertise in managing hepatitis B.  Insufficient data exist regarding the 
safety of resuming acalabrutinib in subjects who develop HBV reactivation.   
3.10.4 
Progressive Multifocal Leukoencephalopathy 
Cases of PML have occurred in clinical studies with acalabrutinib.  Signs and symptoms 
of PML may include cognitive and behavioral changes, language disturbances, visual 
disturbances, sensory deficits, weakness, and coordination and gait difficulties. 
If PML is suspected, hold further treatment with acalabrutinib treatment until PML is 
excluded.  A diagnostic evaluation may include (but is not limited to): 
• 
Neurologic consultation 
• 
Brain magnetic resonance imaging (MRI) 
• 
PCR analysis for John Cunningham virus DNA in cerebrospinal fluid 
If PML is confirmed, permanently discontinue acalabrutinib. 
3.10.5 
Cytopenias 
Grade 3 or 4 events of cytopenias, including neutropenia, anemia, and 
thrombocytopenia have occurred in clinical studies with acalabrutinib.  Monitor blood 
counts as specified in the schedule of assessments and as medically appropriate.  
Please refer to Section 3.8 for study drug modification guidance.  Subjects with 
cytopenias should be managed according to institutional guidelines or as clinically 
indicated. 
3.10.6 
Second Primary Malignancies 
Second primary malignancies, including solid tumors and skin cancers, have been 
reported in patients treated with acalabrutinib.  The most frequent second primary 
malignancy was skin cancer(basal cell carcinoma).  Subjects should be monitored for 
signs and symptoms of malignancy.  Subjects who develop a second primary 
malignancy should be managed according to institutional guidelines with diagnostic 
evaluations as clinically indicated, and it may be necessary for subjects to permanently 
discontinue study treatment.  Continuation of acalabrutinib treatment should be 
discussed with the medical monitor.  Please refer to Section 6.2.3 for second primary 
malignancy reporting guidance. 

 
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3.10.7 
Atrial Fibrillation 
Events of atrial fibrillation/flutter have occurred in clinical studies with acalabrutinib, 
particularly in subjects with cardiac risk factors, hypertension, diabetes mellitus, acute 
infections, and a previous history of atrial fibrillation.  Monitor for symptoms of atrial 
fibrillation and atrial flutter (e.g., palpitations, dizziness, syncope, chest pain, dyspnea) 
and obtain an ECG as clinically indicated.  Subjects with atrial fibrillation should be 
managed per institutional guidelines with supportive care and diagnostic evaluations as 
appropriate. 
3.10.8 
Reference Safety Information 
For the purpose of reporting AEs and SAEs: 
The Acalabrutinib Investigator Brochure contains the Reference Safety 
Information (RSI) for acalabrutinib. 
3.10.9 
Dietary Restrictions 
Acalabrutinib can be taken with or without food.  St John’s wort is a potent CYP3A 
inducer and should be avoided in subjects treated with acalabrutinib, which is partially 
metabolized by CYP3A. 
Otherwise, subjects should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea, or vomiting. 
3.10.10 
Drug-Drug Interactions 
Acalabrutinib is not a strong direct inhibitor or inducer or CYP isoforms; thus, 
acalabrutinib, at the currently used clinical doses, is unlikely to be a perpetrator of a 
drug-drug interaction at the level of inhibition or induction of CYP isoforms.  Acalabrutinib 
is partially metabolized by CYP3A; its exposure is affected when coadministered with 
strong CYP3A inducers or inhibitors.  Consequently, the concomitant use of strong 
inhibitors/inducers of CYP3A (see Appendix 4) should be avoided when possible.  
Based on these considerations, subjects who require therapy with drugs listed in 
Appendix 4 should not be enrolled into the study.  If medically justified, subjects may be 
enrolled if such inhibitors or inducers can be discontinued or alternative drugs that do not 
affect these enzymes can be substituted within 7 days before first dose of study drug.  If 
a subject requires a strong or moderate CYP3A inhibitor while on study, the subject 
should be monitored closely for potential toxicities.   

 
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Avoid coadministration of strong CYP3A inducers.  If a subject requires treatment with a 
strong CYP3A inducer, increase the acalabrutinib dose to 200 mg BID during 
concomitant administration with the strong inducer and return to recommended dose of 
100 mg BID after stopping the strong CYP3A inducer. 
Use of proton-pump inhibitors, H2-receptor antagonists, or antacids while taking 
acalabrutinib has the potential to decrease acalabrutinib exposure.  If treatment with a 
gastric acid-reducing agent is required, consider using an H2-receptor antagonist 
(2 hours after acalabrutinib) or antacid (2 hours before or 2 hours after acalabrutinib).  
Avoid coadministration with proton-pump inhibitors. 
3.10.11 
Reproductive Toxicity 
Definition of women of non-reproductive potential:  
Women will be considered of non-reproductive potential if they are either:  
Postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women <45 years of age a high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy.  In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.);  
OR 
Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy 
or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR 
Have a congenital or acquired condition that prevents childbearing. 
Definition of contraception: 
Practice abstinence† from heterosexual activity;  
OR 
Use (or have their partner use) highly effective contraception during heterosexual 
activity. 
Highly effective methods of contraception are (to be used during heterosexual activity) 
defined as methods that can achieve a failure rate of <1% per year when used 
consistently and correctly.  Such methods include‡: 

 
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• 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation, which may be oral, intravaginal, or 
transdermal  
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation, 
which may be oral, injectable, or implantable  
• 
Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomy of a female subject’s male partner (with medical assessment and 
confirmation of vasectomy surgical success) 
• 
Sexual abstinence (only if refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments) 
Hormonal contraception may be susceptible to interaction with study or other drugs, 
which may reduce the efficacy of the contraception method. 
†Abstinence (relative to heterosexual activity) can only be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and independent ethics 
committees (IECs)/institutional review boards (IRBs).  Periodic abstinence (e.g., 
calendar, ovulation, sympto-thermal, and postovulation methods) and withdrawal are not 
acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for subjects participating at 
sites in this country/region. 
Female subjects with reproductive potential (see definition above) who are sexually 
active must use highly effective methods of contraception during the study and for 
2 days after the last dose of acalabrutinib.  If there is any question that a subject of 
childbearing potential will not reliably comply with the requirements for contraception, 
that subject should not be entered into the study.   
Developmental and reproductive toxicology studies in rats have not identified 
acalabrutinib-related toxicities for fertility, reproductive success, embryofetal 
development or embryofetal survival.  In rabbits, at dose levels which resulted in 
maternal toxicities skeletal variations were associated with reductions in fetal weights.  
Effects on parturition and post-natal development are pending.  For additional details, 
refer to the Acalabrutinib Investigator Brochure. 

 
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Subjects should promptly notify the investigator if they, or their partners, become 
pregnant during this study, or within 2 days after the last dose of acalabrutinib.  If a 
woman becomes pregnant during the treatment period, she must discontinue 
acalabrutinib immediately.  Pregnancy in a female subject or a male subject’s female 
partner must be reported as outlined in Section 6.2.4.   
3.10.12 
Overdose Instructions 
For any subject experiencing an acalabrutinib overdose (ingestion of more than the 
recommended dosage), observation for any symptomatic side effects should be 
instituted, and vital signs, 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 of acalabrutinib is recent and substantial, and if there are no medical 
contraindications, use of gastric lavage or induction of emesis may be considered. 
The medical monitor must be contacted if a study drug overdose occurs. 
3.11 WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT 
The investigator, in consultation with the medical monitor, may withdraw any subject 
from study treatment, if, in the investigator’s opinion, it is not in the subject’s best interest 
to continue.  
Any subject has the right to withdraw from the study at any time.  In addition, subjects 
may be withdrawn from study treatment for the following reasons: 
• 
Progressive disease 
• 
Adverse event 
• 
Start of alternative anticancer therapy 
• 
Pregnancy 
• 
Investigator decision 
• 
Subject’s withdrawal of consent from study 
• 
Decision by sponsor to terminate the study 
• 
Subject was lost to follow-up 
• 
Death 
• 
Other 

 
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Subjects who discontinue study therapy will continue to be followed on study for 
follow-up of safety (Section 4.2), and survival, unless they withdraw consent for further 
follow-up.  Thus, all subjects receiving ≥1 dose of study drug will be followed during the 
immediate post-therapy and long-term follow-up (LTFU) assessments unless the subject 
withdraws consent for such follow-up to be conducted (Section 4.3).  The date the 
subject is withdrawn from study treatment or from the study (including LTFU) and the 
reason for discontinuation will be recorded and also should be described on the 
appropriate CRF.   
Subjects who meet criteria of PD and are continuing to gain clinical benefit from therapy 
may be able to temporarily remain on acalabrutinib after discussion with the medical 
monitor.   
3.12 REASONS FOR STUDY EXIT 
Reasons for study exit include: 
• 
Subject’s withdrawal of consent from study 
• 
Decision by sponsor to terminate the study 
• 
Subject was lost to follow-up 
• 
Death 
3.13 DATA AND SAFETY MONITORING 
This trial will be monitored in accordance with the sponsor’s pharmacovigilance 
procedures.  AEs and SAEs will be reviewed internally as part of ongoing safety 
surveillance.  Quarterly conference calls with the investigators and applicable site staff 
will be conducted to discuss study progress, obtain investigator feedback and exchange, 
and discuss "significant safety events" (i.e., AEs leading to dose reductions, related 
SAEs, and deaths).  
In addition, an independent data monitoring committee (DMC) will be formed to review 
data for subject safety.  Data review will be focused on, but not limited to deaths, 
treatment discontinuations, SAEs, and Grade 3/4 AEs, as well as special events of 
interest.  After review of data, the DMC will provide recommendations regarding stopping 
or continuing the study in accordance with the DMC charter.  The DMC will meet 
approximately when the first 15 subjects have been treated through Week 8, 30 subjects 
have been treated through Week 8, and subsequently every year, as needed, until the 

 
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final DCO and database closure for the study.  Additional meetings may be scheduled at 
the request of the DMC or the sponsor. 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS 
The schedule of events is provided in Appendix 1.  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.  This study will primarily use central laboratory testing for laboratory 
evaluations.  Samples from sites' local laboratories will be used if central testing is 
unavailable.  
4.1 
DESCRIPTION OF PROCEDURES 
4.1.1 
Informed Consent 
The subject must read, understand, and sign the ICF approved by the IRB/IEC, 
confirming his or her willingness to participate in this study before initiating any 
screening activity that is not considered standard of care by institutional standards.  
Subjects must also grant permission to use protected health information, if required by 
local regulations. 
4.1.2 
Medical History 
Collect and record the subject’s complete history through review of medical records and 
by interview.  Concurrent medical signs and symptoms must be documented to establish 
baseline severities.  A disease history, including the date of initial diagnosis and list of all 
prior anticancer treatments, responses, and duration of response to these treatments, 
also will be recorded. 
4.1.3 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 6.1.  The AE 
reporting period is described in Section 6.2.1.  Important additional requirements for 
reporting SAEs are explained in Section 6.2. 

 
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4.1.4 
Concomitant Medications and Therapy 
Document all concomitant medications and procedures from within 21 days before the 
start of study drug administration through 30 days after the last dose of study drug. 
4.1.5 
Confirmation of Eligibility 
Subject eligibility for enrollment will be assessed per Section 3.4.  All screening 
procedures, unless otherwise indicated, should be completed within 30 days of the first 
dose of study drug. 
4.1.6 
ECOG Performance Status 
The ECOG performance index is provided in Appendix 5. 
4.1.7 
Physical Examination, Vital Signs, Height and Weight, and 
Disease-Related Symptoms 
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 examinations, including attention to neurologic signs and 
symptoms of PML, will be done during the treatment period and at the TT and SFU visits 
and during the post-treatment disease follow-up. 
Disease-related symptoms will be assessed and recorded in the subject records and are 
defined per Hallek 2008 as: 
a. Unintentional weight loss of 10% or more within the previous 6 months; 
b. Significant fatigue (i.e., ECOG performance status 2 or worse; inability to work or 
perform usual activities); 
c. Fevers higher than 100.5°F or 38°C for 2 or more weeks without other evidence 
of infection; or 
d. Night sweats for more than 1 month without evidence of infection 
Vital signs (blood pressure, heart rate, and body temperature) will be assessed after the 
subject has rested in the sitting position.   

 
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4.1.8 
Electrocardiogram 
Subjects should be supine and resting for ≥10 minutes before the baseline 
electrocardiogram (ECG).  
4.1.9 
Urine or Serum Pregnancy Test 
Pregnancy tests will be required only for women of childbearing potential.  Testing will be 
done locally by use of central laboratory provided kits.  Pregnancy testing may be done 
by local laboratories and can be done more frequently than the protocol-defined 
schedule, if required by local regulatory authorities. 
4.1.10 
Hematology 
Hematology studies must include CBC with differential including, but not limited to white 
blood cell count, hemoglobin, hematocrit, platelet count, ANC, and ALC.  Testing will be 
done by a local or central laboratory as listed on the investigator’s Form FDA 1572. 
4.1.11 
Serum Chemistry 
Chemistry will include albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood 
urea nitrogen (BUN), calcium, chloride, creatinine, glucose, lactate dehydrogenase 
(LDH), magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin, total 
protein, and uric acid.  If an unscheduled ECG is done at any time, then an electrolyte 
panel (i.e., calcium, magnesium, and potassium) must be done to coincide with the ECG 
testing.  Testing will be done by a local or central laboratory as listed on the 
investigator’s Form FDA 1572. 
4.1.12 
Urinalysis 
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.  
Testing will be done by a local or central laboratory as listed on the investigator’s Form 
FDA 1572. 
4.1.13 
 
 
 
 
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4.1.14 
Hepatitis B and C Testing 
Hepatitis serology testing must include HBsAg, hepatitis B surface antibody (anti-HBs), 
anti-HBc, and hepatitis C virus (HCV) antibody.  In addition, any subjects testing positive 
for any hepatitis serology must have PCR testing during screening and on study (see 
Appendix 1 and exclusion criterion #9).  Testing will be done by local or central 
laboratory.   
Subjects who are anti-HBc positive should have quantitative PCR testing for HBV DNA 
performed during screening and every 3 months thereafter.  Monitoring should continue 
every 3 months until 12 months after last dose of study drug(s).  Any subject with a rising 
viral load (above lower limit of detection) should discontinue study drug and have 
antiviral therapy instituted and a consultation with a physician with expertise in managing 
hepatitis B.  As intravenous immunoglobulins (IVIG) may cause false positive hepatitis 
serology, monthly PCR testing is not required in subjects who are currently receiving or 
received prophylactic IVIG within 3 months before study enrollment and have a 
documented negative anti-HBc test before the initiation of IVIG therapy.  PCR testing 
should be performed when clinically indicated (e.g., in the setting of rising transaminase 
levels). 
Subjects with a known history of hepatitis C or who are hepatitis C antibody positive 
should be tested for HCV RNA during screening and at Cycle 6.  No further testing 
beyond Cycle 6 is necessary if PCR results are negative. 
Refer to Section 3.10.3 and Appendix 1 regarding monitoring of subjects who are 
anti-HBc positive or hepatitis C antibody positive or who have a known history of HBV or 
HCV. 
4.1.15 
Serum Immunoglobulin 
Testing for immunoglobulin G (IgG), IgM, IgA, and total immunoglobulin (if available) will 
be done by a local or central laboratory as listed on the investigator’s Form FDA 1572. 
4.1.16 
 
 
 
  
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4.1.17 
 
 
 
 
 
 
4.1.18 
Bone Marrow Aspirate and Biopsy 
For Eligibility 
A unilateral bone marrow aspirate and biopsy will be done at screening or ≤3 months 
before enrollment.  Subjects who have a bone marrow aspirate and biopsy results may 
use these results in lieu of the baseline bone marrow aspirate/biopsy required for this 
study, provided the biopsy/aspirate was done within 3 months before enrollment. 
Response Evaluation 
If the subject’s physical examination findings, laboratory evaluations, and radiographic 
evaluations suggest that CR has been achieved in all response parameters, a bone 
marrow aspirate and biopsy and peripheral blood sample must be obtained to confirm 
the CR and to evaluate minimal residual disease by flow cytometry.  The bone marrow 
aspirate and biopsy and the peripheral blood sample must be done within 4 weeks of the 
CT scan that showed CR.  In cases where cytopenic progression is suspected, a bone 
marrow aspirate or biopsy should be performed to distinguish autoimmune and 
drug-related cytopenias. 
4.1.19 
CT Scans 
Pretreatment radiologic tumor assessment should be performed within 30 days before 
the first dose.  Radiologic tumor assessment will also be performed at the end of 
Cycles 3, 6, 9, 12, 18, 24 (-7 days), and then every year thereafter, while receiving 
acalabrutinib treatment.  Note:  Please refer to Section 3.8.1 regarding the potential for 
tumor flare during drug holds.  Therefore, we recommend not staging subjects (e.g., with 
CT scans) during drug holds. 
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Confirmation of CR will require bone marrow analysis and radiologic tumor assessment.  
Radiological imaging by CT with contrast is required and must include the pelvis, 
abdomen, chest, and neck (and any other disease area).  Subjects who are intolerant to 
intravenous (IV) CT contrast agents will have CT scans performed with oral contrast.  
When possible, all subjects should have radiographic tumor measurements done at the 
participating study center or at an acceptable alternate imaging facility using an identical 
imaging protocol and similar equipment.  The same imaging equipment should be used 
for all scans whenever possible.  The same radiologist should be assigned to read all the 
scans for a given subject throughout the study as much as possible.  MRI may be used 
to evaluate nontarget lesions that cannot be adequately imaged using CT (in cases 
where MRI is desirable, the MRI must be obtained at baseline and at all subsequent 
response evaluations).  If MRI is required for any other reason, this must be discussed 
with the study medical monitor first. 
Up to 6 measurable lymph nodes (only target lesions >1.5 cm in the longest diameter 
may be assessed), clearly measurable in 2 perpendicular dimensions, will be followed as 
target lesions for each subject.  Measurable sites of disease should be chosen such that 
they are representative of the subject’s disease.  In addition, selection of target lesions 
should be from as disparate regions of the body as possible when these areas are 
significantly involved.  If additional lesions are present but are not included in the target 
lesion assessment, they can be added as non-target lesions followed throughout the 
study.  The cranial-caudal measurement of the spleen and longest diameter of the liver 
will be assessed at screening and all subsequent response evaluations. 
CT scans will be performed until disease progression is confirmed, regardless of 
whether or not the subject remains on treatment.  In the event disease progression is 
suspected due to physical examination or laboratory test, a CT scan must be performed 
to confirm disease progression.  There must be radiographically measurable disease at 
screening (≥1 lymph node >1.5 cm in the longest diameter). 
A central imaging service will be used to provide independent radiologic assessments for 
the purposes of the primary endpoint.  These measurements will not be reported back to 
the site.   

 
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4.1.20 
Routine Clinical Assessments 
Routine clinical assessments include physical examinations, recording of symptoms, and 
hematologic evaluations to evaluate for both AEs and for disease progression at times 
when the CT scan is not obtained.  
4.1.21 
Overall Response Evaluations 
Overall response assessments will include evaluation of physical examinations, 
recording of symptoms, hematologic evaluations (Note: CBC with differential must be 
done within 7 days and bone marrow aspirate/biopsy [when applicable] must be done 
within 4 weeks of the contemporaneous radiographic evaluation), and radiographic 
evaluations per the schedule of assessments.  Subjects who have signs and symptoms 
of progression outside of the scheduled assessment should be evaluated by the 
investigator with a physical examination and a CBC with differential to determine if 
disease progression is present.  The blood samples for response or disease progression 
determination should be confirmed by a central laboratory (samples from local 
laboratories can be used if central testing is unavailable).  Any suspected case of 
disease progression should be confirmed with a CT scan if one was not obtained and 
should be reported to the sponsor or designee.  Subjects may continue study treatment 
until progression is confirmed by a serial examination at least 2 weeks later.  In addition, 
when clinically appropriate, based on investigator perceived risk-benefit assessment, a 
subject may continue treatment and remain under close observation until progression is 
confirmed.  New anticancer therapy should be withheld if clinically appropriate in the 
absence of confirmed progressive disease.   
4.2 
TREATMENT TERMINATION AND SAFETY FOLLOW-UP VISITS 
A TT visit is required for safety assessments for any subjects who permanently 
discontinue study drug for any reason (except for death, loss to follow-up, or withdrawal 
of consent), including disease progression.  The TT visit should be scheduled within 
7 days of the last dose of study drug, if possible, and is not required for subjects who 
discontinue from study treatment within 10 days of a scheduled study visit.   
In addition to the TT visit, each subject should be followed until the SFU visit at 
30 (+7) days after his or her last dose of study drug to monitor for resolution or 
progression of AEs and to document the occurrence of any new events, regardless of 
whether the subject receives a new anticancer therapy or demonstrates disease 

 
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progression within this timeframe.  Subjects who withdraw consent for study treatment 
should still be encouraged to complete the SFU assessments before withdrawing 
consent, but these assessments cannot be mandated if subject consent for further study 
participation is withdrawn.  If the TT visit and the SFU visit coincide, then these can be 
combined into 1 visit.  The Schedule of Assessments (Appendix 1) describes the 
procedures required for the TT and SFU visits.  
4.3 
FOLLOW-UP FOR PROGRESSION 
4.3.1 
Post-Treatment Disease Follow-Up 
Each subject should be followed until disease progression.  If disease progression has 
not occurred at the time of the 30-day SFU visit, post-treatment disease follow-up visits 
should occur approximately every 3 months (12 weeks) until disease progression, 
regardless of whether the subject receives new anticancer treatment.  During this period, 
subjects will be followed via CT scans, CBC with differential, physical examinations 
(including vital signs and weight), serum chemistry, and bone marrow biopsy and 
aspirate (as clinically indicated).  Refer to Appendix 1 for the full list of assessments 
required during this period.   
4.3.2 
Long-Term Follow-Up 
Once subjects progress—for all subjects who have not withdrawn consent—they will be 
contacted approximately every 3 months (12 weeks) by clinic visit or telephone, to 
assess survival and the use of alternative anticancer therapy until death or loss to 
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 
The statistical methods presented in this section provide a high-level summary of 
analysis to be performed for this study.  Detailed analyses will be described in the 
Statistical Analysis Plan (SAP).  The SAP will be finalized before database lock.  Any 
changes to the methods described in the final SAP will be justified and described in the 
clinical study report.  
No interim analysis is planned for this study.  The primary analysis will be performed 
after all subjects have completed the study. 
Continuous variables will be summarized by number of observations, mean, standard 
deviation, median, minimum, and maximum.  Categorical variables will be summarized 
by the number of subjects and percentage in each category. 
5.2 
RATIONALE FOR SAMPLE SIZE 
 
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5.3 
ANALYSIS POPULATIONS 
The analysis populations for statistical analyses and study summary are defined as 
follows:  
• 
All-treated population: All enrolled subjects who receive ≥1 dose of study drug 
• 
Efficacy-evaluable (EE) population: All subjects in the All-treated population 
who have ≥1 radiologic response assessment after the first dose of study drug. 
The All-treated population is the primary analysis population for efficacy and safety 
summaries.  The EE population will be used for sensitivity analyses. 
5.4 
MISSING DATA HANDLING 
Subjects not evaluable for ORR due to a lack of postbaseline response assessment will 
be counted as a non-responder in the primary analysis using the All-treated population.  
Alternatively, those non-evaluable subjects will be excluded from the ORR calculation 
using the EE population for a sensitivity analysis.  
5.5 
ENDPOINT DATA ANALYSIS 
5.5.1 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized using descriptive 
statistics.  Demographic summaries will include age, sex, race and/or ethnicity.  Baseline 
characteristics will include disease-related parameters of interest before dosing.    
5.5.2 
Study Treatment Administration and Compliance 
Descriptive statistics will be provided to summarize study treatment administration and 
compliance.  The total number of doses taken, the number of days of treatment, the 
number of missing doses, and relative dose intensity will be presented.   
5.5.3 
Analysis of Efficacy Endpoints 
5.5.3.1 
Primary Efficacy Endpoint 
Overall Response Rate (ORR) 
ORR is defined as the proportion of subjects achieving a best overall response (BOR) of 
either CR, complete remission with incomplete bone marrow recovery (CRi), nodular 
partial remission (nPR), or PR at or before initiation of subsequent anticancer therapy.  
ORR will be analyzed per investigator’s assessment.   

 
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ORR and the associated 95% exact (Clopper-Pearson) CI will be provided.  ORR will 
also be tested against the historical control of 21%, as assumed for the sample size 
calculation, using the exact binomial test. 
5.5.3.1 
Secondary Efficacy Endpoints 
Duration of Response (DOR) 
DOR is defined as the duration from time of initial response until documented disease 
progression.  Initial response includes CR, CRi, nPR, or PR.  
Progression-Free Survival (PFS) 
PFS is defined as the time from date of first dose to date of first documented disease 
progression by investigator or death due to any cause, whichever comes first.  
Time-to-Next Treatment (TTNT)  
TTNT is defined as the time from date of first dose to date of institution of subsequent 
anticancer therapy for CLL or death due to any cause, whichever comes first.  Subjects 
who do not start anticancer therapy or die before the data cutoff date will be censored at 
the date of last visit. 
Overall Survival (OS) 
OS is defined as the time from date of first dose to date of death due to any cause.   
Kaplan-Meier (K-M) methods will be used to estimate the distribution of DOR, PFS, 
TTNT, and OS.  K-M point estimates and corresponding 95% CIs will be calculated at 
25th percentile, median (50th percentile), 75th percentile, and selected landmark points.  
5.5.4 
Safety Endpoint 
All reported AEs will be mapped to MedDRA.  Prior and concomitant medications will be 
recorded and coded using World Health Organization Drug Dictionary (WHODRUG).  
The frequency (number and percentage) of treatment-emergent AEs will be tabulated by 
system organ class (SOC) and preferred term (PT).  Summaries will also be presented 
by the severity of the AE and by relationship to study drug.  Laboratory shift tables 
containing numbers and percentages will be presented by laboratory parameter.  
Figures of changes in laboratory parameters over time will be generated.  Prior and 
concomitant medications will be summarized by anatomical therapeutic chemical (ATC) 

 
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classification system and preferred term.  Vital signs and other safety endpoints may be 
tabulated as needed.  
5.5.5 
 
 
 
 
 
 
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, regardless of 
attribution. 
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the 
protocol-specified AE reporting period, including signs or symptoms 
associated with CLL that were not present before the AE reporting period 
(see Section 6.2.1). 
• 
Pre-existing medical conditions (other than the condition being studied) 
judged by the investigator to have worsened in severity or frequency or 
changed in character during the protocol-specified AE reporting period. 
• 
Abnormal laboratory values considered clinically significant by the investigator 
should be reported as an AE. 
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The following are NOT considered an AE: 
• 
Pre-existing condition that has not worsened: A pre-existing condition 
(documented on the medical history CRF) is not considered an AE unless the 
severity, frequency, or character of the event worsens during the study period. 
• 
Preplanned hospitalization: A hospitalization planned before signing the ICF is 
not considered an SAE but rather a therapeutic intervention.  However, if during 
the preplanned hospitalization an event occurs, which prolongs the 
hospitalization or meets any other SAE criteria, the event will be considered an 
SAE.  Surgeries or interventions that were under consideration but not performed 
before enrollment in the study will not be considered serious if they are 
performed after enrollment in the study for a condition that has not changed from 
its baseline level.  Elective hospitalizations for social reasons, solely for the 
administration of chemotherapy, or due to long travel distances are also not 
SAEs.  
• 
Diagnostic testing and procedures: Testing and procedures should not be 
reported as AEs or SAEs, but rather the cause for the test or procedure should 
be reported.  If a test or procedure is done to rule out a diagnosis, the sign or 
symptom leading to the test/procedure should be the event term, and the event 
term should only be updated to the diagnosis if/when the diagnosis is confirmed.  
Testing and procedures performed solely as screening measures (e.g., routine 
screening mammography or colonoscopy) should not be reported as AEs or 
SAEs. 
• 
Abnormal laboratory results that the investigator considers to not be clinically 
significant:  Abnormal laboratory results are not AEs unless they are clinically 
significant.  For example, a clinically significant laboratory result is one that 
requires treatment (e.g., a blood transfusion for low hemoglobin) or requires a 
change in study drug (e.g., lowering the dose or withholding study drug while the 
laboratory finding resolves or stabilizes). 
• 
Progression of underlying malignancy:  Progression of underlying malignancy will 
not be reported as an AE if it is clearly consistent with the suspected progression 
of the underlying cancer.  Hospitalization due solely to the progression of 
underlying malignancy should NOT be reported as an SAE.  Clinical symptoms of 

 
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progression may be reported as AEs if the symptoms cannot be determined as 
exclusively due to the progression of the underlying malignancy, or if they do not 
fit the expected pattern of progression for the disease under study.  
Symptomatic deterioration may occur in some subjects.  Symptomatic 
deterioration is when progression is evident in the subject’s clinical symptoms 
and the investigator may elect not to perform further disease assessments. 
If there is any uncertainty about an AE being due only to the disease under 
study, it should be reported as an AE or SAE. 
6.1.2 
Serious Adverse Event 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to 
the grade of an AE (see below).  “Serious” is a regulatory definition and is based on 
subject or event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  Seriousness (not severity) serves as the guide 
for defining regulatory reporting obligations from the sponsor to applicable regulatory 
authorities. 
An AE should be classified as an SAE if it meets any 1 of the following criteria: 
• 
It results in death (i.e., the AE actually causes or leads to death). 
• 
It is life-threatening (i.e., the AE, in the view of the investigator, places the 
subject at immediate risk of death.  It does not include an AE that, had it 
occurred in a more severe form, might have caused death). 
• 
It requires or prolongs inpatient hospitalization. 
• 
It results in persistent or significant disability/incapacity (i.e., the AE results 
in substantial disruption of the subject’s ability to conduct normal life 
functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the investigational product. 
• 
It is considered a significant medical event by the investigator based on 
medical judgment (e.g., may jeopardize the subject or may require 
medical/surgical intervention to prevent 1 of the outcomes listed above). 

 
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6.1.3 
Severity 
Definitions found in the CTCAE version 4.03 or higher will be used for grading the 
severity (intensity) of AEs.  The CTCAE displays Grades 1 through 5 with unique clinical 
descriptions of severity for each referenced AE.  Should a subject experience any AE 
not listed in the CTCAE, the following grading system should be used to assess severity: 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no 
special treatment, and not interfering with the subject’s daily activities 
• 
Grade 2 (Moderate AE) – experiences which introduce some level of 
inconvenience or concern to the subject, and which may interfere with daily 
activities, but are usually ameliorated by simple therapeutic measures 
• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, 
significantly interrupt the subject’s usual daily activity, and require systemic 
drug therapy or other treatment 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the 
subject to be in imminent danger of death 
• 
Grade 5 (Death related to AE) – experiences which result in subject death 
6.1.4 
Adverse Events of Special Interest 
The following events are adverse events of special interest (AESIs) and must be 
reported to the sponsors expeditiously (see Section 6.2.5 for reporting instructions), 
irrespective of regulatory seriousness criteria or causality: 
Ventricular arrhythmias (e.g., ventricular extrasystoles, ventricular tachycardia, 
ventricular arrhythmia, ventricular fibrillation) 
6.2 
DOCUMENTING AND REPORTING OF ADVERSE AND SERIOUS 
ADVERSE EVENTS 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, as outlined in the prior sections, are recorded on the CRF.  All 
SAEs must be reported on the SAE form or clinical database. 
6.2.1 
Adverse Event Reporting Period 
After the signing of the ICF and prior to the first dose of study drug, all SAEs must be 
reported.   

 
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After the first dose of study drug, all AEs/SAEs, irrespective of attribution of causality, 
must be reported.  
All AEs will be reported until 30 days after the last dose of study drug(s) or the start of 
new anticancer therapy (whichever comes first).  After this period, investigators should 
report SAEs or other AEs of concern that are believed to be related to prior treatment 
with study drug.  
All SAEs that occur during the reporting period should be followed to resolution or until 
the investigator assesses the subject as stable or the subject is lost to follow-up or 
withdraws consent.  Resolution/stable means the subject has returned to baseline state 
of health or the investigator does not expect any further improvement or worsening of 
the event.  
6.2.2 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation 
timepoints during the study.  All AEs and SAEs whether volunteered by the subject, 
discovered by study personnel during questioning, or detected through physical 
examination, or other means, will be recorded in the subject’s medical record and on the 
AE CRF.  
Each recorded AE or SAE will be described by its diagnostic term, duration (e.g., start 
and end dates), severity, regulatory seriousness criteria, if applicable, suspected 
relationship to the study drug (see following guidance), and any actions taken.  The 
causality of AEs to the study drug will be assessed by means of the question: ‘Is there a 
reasonable possibility that the event may have been caused by the study drug?’ per FDA 
guidance on safety reporting requirements (FDA Guidance 2012).  
See Appendix 6 for more detail on assessing causality. 
6.2.3 
Second Primary Malignancies 
AEs for malignant tumors reported during a study should generally be assessed as 
SAEs.  If no other seriousness criteria apply, the “Important Medical Event” criterion 
should be used.  In certain situations, however, medical judgment on an individual event 
basis should be applied to clarify that the malignant tumor event should be assessed 
and reported as a nonserious AE.  For example, if the tumor is included as medical 
history and progression occurs during the study but the progression does not change 

 
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treatment and/or prognosis of the malignant tumor, the AE may not fulfil the attributes for 
being assessed as serious, although reporting of the progression of the malignant tumor 
as an AE is valid and should occur.  Also, some types of malignant tumors, which do not 
spread remotely after a routine treatment that does not require hospitalization, may be 
assessed as nonserious; examples in adults include Stage 1 basal cell carcinoma and 
Stage 1A1 cervical cancer removed via cone biopsy. 
The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (i.e., it is not the tumor for which entry into the study is a criterion and 
that is being treated by the investigational product (IP) under study and is not the 
development of new or progression of existing metastasis to the tumor under study).  
Malignant tumors that—as part of normal, if rare, progression—undergo transformation 
(e.g., Richter's transformation of B-cell chronic lymphocytic leukemia into diffuse large 
B-cell lymphoma) should not be considered a new malignant tumor. 
6.2.4 
Pregnancy 
The investigator should report all pregnancies and pregnancies in the partners of 
subjects within 24 hours using the Pregnancy Report Form.  This form should be faxed 
or emailed to Acerta Pharma Drug Safety.  Any pregnancy-associated SAE must be 
reported to Acerta Pharma, according to the usual timelines and directions for SAE 
reporting (Section 6.2.5). 
Any uncomplicated pregnancy that occurs with the subject or with the partner of a 
treated subject during this study will be reported.  All pregnancies and partner 
pregnancies that are identified during or after this study, wherein the estimated date of 
conception is determined to have occurred from the time of consent to 2 days after the 
last dose of acalabrutinib will be reported, followed to conclusion, and the outcome 
reported, as long as the subject or partner has consented to participate in follow-up. 
A pregnancy itself is not regarded as an AE unless there is suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Likewise, elective abortions without complications are not 
considered AEs.  Any SAEs associated with pregnancy (e.g., congenital 
abnormalities/birth defects/spontaneous miscarriage or any other serious events) must 
additionally be reported as such using the SAE report form. 

 
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Subjects should be instructed to immediately notify the investigator of any pregnancies.  
Any female subjects receiving study drug who become pregnant must immediately 
discontinue study drug.  The investigator should counsel the subject, discussing any 
risks of continuing the pregnancy and any possible effects on the fetus. 
Upon completion of the pregnancy, additional information on the mother, pregnancy, and 
baby will be collected and sent to 
 
6.2.5 
Expedited Reporting Requirements for Serious Adverse 
Events 
All SAEs must be reported within 24 hours of discovery.  All initial SAE reports and 
follow-up information will be reported using the protocol-specific electronic data capture 
system.  If electronic SAE reporting is not available, paper SAE forms must be emailed 
or faxed to Acerta Pharma Drug Safety, or designee.  Acerta Pharma may request 
follow-up and other additional information from the investigator (e.g., hospital 
admission/discharge notes and laboratory results). 
Whenever possible, AEs/SAEs should be reported by diagnosis term, not as a 
constellation of symptoms.  Death due to disease progression should be recorded on the 
appropriate form in the electronic data capture system.  If the primary cause of death is 
disease progression, the death due to disease progression should not be reported as an 
SAE.  If the primary cause of death is something other than disease progression, then 
the death should be reported as an SAE with the primary cause of death as the event 
term, as death is typically the outcome of the event, not the event itself.  The primary 
cause of death on the autopsy report should be the term reported.  Autopsy and 
postmortem reports must be forwarded to Acerta Pharma Drug Safety, or designee, as 
outlined above. 
If study drug is discontinued because of an SAE, this information must be included in the 
SAE report. 
An SAE may qualify for mandatory expedited reporting to regulatory authorities if the 
SAE is attributable to the investigational product (or if a causality assessment is not 
provided for the SAE, in which case a default of ‘related’ may be used for expedited 
reporting purposes) and the SAE is not listed in the current Acalabrutinib Investigator 
Brochure (i.e., an unexpected event).  In this case, Acerta Pharma Drug 
Safety/Designee will forward a formal notification describing the suspected unexpected 
PPD

 
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serious adverse reaction (SUSAR) to all investigators.  Each investigator must then 
notify his or her IRB/IEC of the SUSAR. 
Drug Safety Contact Information 
Fax: 
(United States) 
(for outside the United States) 
Email: 
 
 
6.2.6 
Type and Duration of Follow-up of Subjects after Adverse 
Events 
All AEs and SAEs that are encountered during the protocol-specified AE reporting period 
should be followed to resolution, or until the investigator assesses the subject as stable, 
or the subject is lost to follow-up or withdraws consent. 
6.2.7 
Hy’s Law 
Cases where a subject shows elevations in liver biochemistry may require further 
evaluation, and occurrences of AST or ALT ≥3×ULN together with total bilirubin ≥2×ULN 
may need to be reported as SAEs.  Please refer to Appendix 7 for further instruction on 
cases of increases in liver biochemistry and evaluation of Hy’s Law. 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
Acerta Pharma retains the right to terminate the study and remove all study materials 
from a study site at any time.  Specific circumstances that may precipitate such 
termination are: 
• 
Unsatisfactory subject enrollment with regard to quality or quantity 
• 
Significant or numerous deviations from study protocol requirements, such as 
failures to perform required evaluations on subjects and maintain adequate study 
records 
• 
Inaccurate, incomplete and/or late data recording on a recurrent basis 
• 
The incidence and/or severity of AEs in this or other studies indicating a potential 
health hazard caused by the study treatment 
PPD
PPD

 
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7.1 
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE 
The investigator will submit this protocol, the informed consent, Investigator Brochure, 
and any other relevant supporting information (e.g., all advertising materials) to the 
appropriate IRB/IEC for review and approval before study initiation.  A signed protocol 
approval page; a letter confirming IRB/IEC approval of the protocol and informed 
consent; and a statement that the IRB/IEC is organized and operates according to GCP 
guidelines and the applicable laws and regulations; must be forwarded to Acerta 
Pharma before screening subjects for the study.  Additionally, sites must forward a 
signed Form FDA 1572 (Statement of Investigator) to Acerta Pharma before screening 
subjects for study enrollment.  Amendments to the protocol must also be approved by 
the IRB/IEC and local regulatory 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 § 21 Code of Federal 
Regulations (CFR) Part 50, and other applicable national and local regulations governing 
informed consent form.  Each subject must provide a signed and dated informed consent 
before enrollment into this study.  If allowed by the protocol, a legal representative may 
sign the informed consent form for a subject incapable of giving consent.  Signed 
consent forms must remain in each subject’s study file and be available for verification 
by study monitors at any time. 
In accordance to individual local and national patient privacy regulations, the investigator 
or designee must explain to each subject that for the evaluation of study results, the 
subject’s protected health information obtained during the study may be shared with 
Acerta Pharma and 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 

 
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information from each subject, or if appropriate, the subject’s legal guardian.  If a subject 
or subject’s legal guardian withdraws permission to use protected health information, it is 
the investigator’s responsibility to obtain the withdrawal request in writing from the 
subject or subject’s legal guardian and to ensure that no further data will be collected 
from the subject.  Any data collected on the subject before withdrawal will be used in the 
analysis of study results. 
7.3 
SUBJECT SCREENING LOG 
The investigator must keep a record that lists all subjects considered for enrollment 
(including those who did not undergo screening) in the study.  For those subjects 
subsequently excluded from enrollment, record the reason(s) for exclusion. 
7.4 
CASE REPORT FORMS 
Authorized study site personnel (see Section 7.11) will complete CRFs designed for this 
study according to the completion guidelines that will be provided within the clinical 
database.  The investigator will ensure that the CRFs are accurate, complete, legible, 
and completed promptly.  Refer to Section 7.7 for record retention requirements.  
7.5 
STUDY MONITORING REQUIREMENTS 
Representatives of Acerta Pharma or its designee will monitor this study until 
completion.  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 
Acalabrutinib capsules must be kept in a locked limited access cabinet or space.  The 
study drug must not be used outside the context of the protocol.  
Study drug accountability records must be maintained and readily available for 
inspection by representatives of Acerta Pharma and are open to inspections by 
regulatory authorities at any time.  
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 Form FDA 1572, IRB/IEC approval letters, signed 
ICFs, drug accountability records, SAE information transmitted to Acerta Pharma, 
subject files (source documentation) that substantiate entries in CRFs, all relevant 
correspondence and other documents pertaining to the conduct of the study. 
An investigator shall retain records for a period of at least 2 years after the date the last 
marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified.  The investigator must notify Acerta Pharma and obtain 
written approval from Acerta Pharma before destroying any clinical study records at any 
time.  Acerta Pharma will inform the investigator of the date that study records may be 
destroyed or returned to Acerta Pharma. 
Acerta Pharma must be notified in advance of, and Acerta Pharma must provide express 
written approval of, any change in the maintenance of the foregoing documents if the 
investigator wishes to move study records to another location or assign responsibility for 
record retention to another party.  If the investigator cannot guarantee the archiving 
requirements set forth herein at his or her study site for all such documents, special 
arrangements must be made between the investigator and Acerta Pharma to store such 
documents in sealed containers away from the study site so that they can be returned 
sealed to the investigator for audit purposes. 

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

 
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9. Any significant protocol deviations are reported to Acerta Pharma and the 
IRB/IEC according to the guidelines at each study site. 
10. CRF pages are completed promptly. 
11. All Investigational New Drug (IND) Safety Reports/ SUSAR Reports are 
submitted promptly to the IRB/IEC. 
12. All SAEs are reported to Acerta Pharma Drug Safety/Designee within 24 hours of 
knowledge via the clinical database and to the IRB/IEC per their requirements. 
 

 
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8.0 
REFERENCES 
Atherly LO, Lucas JA, Felices M, et al. The Tec family tyrosine kinases Itk and Rlk 
regulate the development of conventional CD8+ T cells. Immunity 2006;25:79–91. 
Barr PM, Brown JR, Hillmen P, et al. Dose adherence and baseline exposure analysis of 
the ibrutinib 420 mg dose administered to patients with previously treated chronic 
lymphocytic leukemia (CLL). J Clin Oncol 2015;33 (suppl; abstr 7012). 
Byrd JC, Brown JR, O'Brien S, et al. RESONATE Investigators. Ibrutinib versus 
ofatumumab in previously treated chronic lymphoid leukemia. NEJM 2014a;371:213–23. 
Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic 
lymphocytic leukemia. NEJM 2013;369:32-42. Erratum in: NEJM 2014b;370:786. 
Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic 
lymphocytic leukemia. NEJM 2016;374:323–32. 
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;30:2820–2. 
Covey T, Barf T, Gulrajani M, et al. ACP-196: a novel covalent Bruton’s tyrosine kinase 
(Btk) inhibitor with improved selectivity and in vivo target coverage in chronic 
lymphocytic leukemia (CLL) patients.  In: Proceedings of the 106th Annual Meeting of 
the American Association for Cancer Research; 2015 Apr 18–22; Philadelphia, PA. 
Philadelphia (PA): AACR; 2015. Abstract #2596. 
Da Roit F, Engelberts PJ, Taylor RP, et al. Ibrutinib interferes with the cell-mediated anti 
tumour activities of therapeutic CD20 antibodies: implications for combination therapy. 
Haematologica 2015;100:77–86. 
FDA Guidance 2012. Food and Drug Administration. Guidance for Industry and 
Investigators:  Safety Reporting Requirements for INDs and BA/BE Studies (December 
2012). Available at: http://www.fda.gov/downloads/Drugs/.../Guidances/UCM227351.pdf, 
accessed on: 24June2015. 
Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic 
lymphocytic leukemia.  NEJM 2014;370:997–1007. 
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.  Erratum in: Blood 2008;112(13):5259. 
Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and 
cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, 
open-label,phase 3 trial. Lancet. 2010;376:1164–74. 
Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as 
first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 2007;25:5616–23. 
ICMJE 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. 
Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic 
leukemia after discontinuing ibrutinib. Blood 2015;125:2062–7. 

 
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Lannutti BJ, Gulrajani M, Krantz F, et al. ACP-196, an orally bioavailable covalent 
selective inhibitor of Btk, modulates the innate tumor microenvironment, exhibits 
antitumor efficacy and enhances gemcitabine activity in pancreatic cancer. In: 
Proceedings of the 106th Annual Meeting of the American Association for Cancer 
Research; 2015 Apr 18–22; Philadelphia, PA. Philadelphia (PA): AACR; 2015. Abstract 
#408. 
Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy 
discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA 
Oncol 2015;1:80–7. 
NCCN 2015 Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphomas. 
Version 2. 2015. Available at: NCCN.org. 
Pinilla-Ibarz J, Chavez JC. Life after ibrutinib? A new unmet need in CLL. Blood 
2015;125:2013–4.  
Rajasekaran N, Sadaram M, Hebb J, et al. Three BTK-specific inhibitors, in contrast to 
ibrutinib, do not antagonize rituximab-dependent NK-cell mediated cytotoxicity. Blood 
2014 ASH Annual Meeting Abstract #3118. 
Sharman JP, Coutre SE, Furman RR, et al. Second interim analysis of a Phase 3 Study 
of idelalisib (ZYDELIG®) plus rituximab (R) for relapsed chronic lymphocytic leukemia 
(CLL): Efficacy analysis in patient subpopulations with del(17p) and other adverse 
prognostic factors. Blood 2014;124:330. 
Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the Use of WBC Growth 
Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin 
Oncol 2015;33(28):3199–212. 
Takeba Y, Nagafuchi H, Takeno M, et al. Txk, a member of nonreceptor tyrosine kinase 
of Tec family, acts as a Th1 cell-specific transcription factor and regulates IFN-gamma 
gene transcription. J Immunol 2002;168:2365–70. 
 

 
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Appendix 1 
Schedule of Assessments 
 
 
Treatment Phasea 
 
 
 
 
 
 
Screeningb 
Cycle 1 
Cycle 
2 
Cycle 3 Cycle 4 Cycle 5 Cycle 6 
Cycles 9, 
15, 21, 27, 
≥33 
Cycles 12, 
18, 24, 30, 
≥36 
Response 
Evaluation 
TT Visitc SFU Visitc 
Post-
treatment 
Disease 
Follow-upd LTFUe 
Days 
 
1 
15 
28 15 28 
28 
28 
28 
28 
28 
28 
 
+ 7 days 
after last 
dose 
30 days 
after last 
dose 
Q12W 
Q12W 
Study Windows 
-30 days 
 
± 2 
days 
± 2 days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 days 
± 2 days 
 
+ 7 days 
± 7 days 
± 7 
days 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PEf/Vital 
signsg/Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
Disease-related 
symptoms 
x 
 
 
 
 
 
x 
 
 
x 
Cycle 9 
Cycles 12, 
18 & 24 
x 
 
 
x 
 
ECOG status 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
 
ECGh 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lab assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Urine or serum 
pregnancy testi 
x 
xj 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
 
 Hematologyk 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ANC, ALC, 
PLT, Hgb 
(within 7 
days of  CT) 
x 
x 
x 
 
 Serum chemistryl 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
 Urinalysism 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Serum Igp 
 
xo 
 
x 
 
 
x 
 
 
x 
 
Cycle 12, 
then every 
6 cycles 
 
 
 
Q24W 
 
CCI

 
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Treatment Phasea 
 
 
 
 
 
 
Screeningb 
Cycle 1 
Cycle 
2 
Cycle 3 Cycle 4 Cycle 5 Cycle 6 
Cycles 9, 
15, 21, 27, 
≥33 
Cycles 12, 
18, 24, 30, 
≥36 
Response 
Evaluation 
TT Visitc SFU Visitc 
Post-
treatment 
Disease 
Follow-upd LTFUe 
Days 
 
1 
15 
28 15 28 
28 
28 
28 
28 
28 
28 
 
+ 7 days 
after last 
dose 
30 days 
after last 
dose 
Q12W 
Q12W 
Study Windows 
-30 days 
 
± 2 
days 
± 2 days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 days 
± 2 days 
 
+ 7 days 
± 7 days 
± 7 
days 
Hepatitis serologyq 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV PCRr 
x 
 
 
 
 
 
x 
 
 
x 
Q3M 
Q3M 
 
 
 
Q3M 
Q3M 
HCV PCRs 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Bone marrow 
(aspirate/biopsy)v 
x 
 
 
 
 
 
 
 
 
 
 
To 
confirm 
CR 
To confirm 
CR 
 
 
As 
clinically 
indicated 
 
Acalabrutinib  
100 mg BID 
 
Continuous twice daily dosing 
 
 
 
 
 
Study drug 
compliance 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
CT scansx 
xy 
 
 
 
 
 
xz 
 
 
xz 
Cycle 9z 
Cycles 12, 
18 & 24z 
xz 
 
 
x 
 
Overall response 
assessment 
 
 
 
 
 
 
x 
 
 
x 
Cycle 9 
Cycles 12, 
18 & 24 
x 
 
 
 
 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
AE=adverse event; ALC=absolute lymphocyte count; ANC=absolute neutrophil count; anti-HBc=hepatitis B core antibody; anti-HBs anti-HBs=hepatitis B surface antibody; 
BID=twice daily; 
 BUN=blood urea nitrogen; CLL=chronic lymphocytic leukemia; CR=complete response; CT=computed tomography; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
 Hgb=hemoglobin level; HBsAg=hepatitis B surface antigen; 
HBV=hepatitis B virus; HCV=hepatitis C virus; Ig=immunoglobulin; 
 IV=intravenous; IVIG=intravenous immunoglobulins; 
CCI
CCI
CCI
CCI
CCI

 
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LDH=lactate dehydrogenase; LTFU=long-term follow-up; 
 PE=physical examination; PCR=polymerase chain reaction; 
 
PLT=platelet count; PML=progressive multifocal leukoencephalopathyQ24W=every 24 weeks; Q3M=every 3 months; SFU=safety follow-up; TT=treatment termination. 
Footnotes for ACE-CL-208 Schedule of Study Activities: 
a. 
Subjects will have visits every 2 weeks for the first 2 cycles, then monthly through end of Cycle 6, then every 3 cycles thereafter.  The end of study is defined as the date of 
the last subject’s last visit.  Subjects who are still on treatment at the end of Cycle 36 and deriving clinical benefit from acalabrutinib treatment may continue treatment. 
b.  Screening tests should be completed within 30 days before the first administration of study drug, unless otherwise indicated. 
c. 
A TT visit is required for subjects who permanently discontinue study drug for any reason (except for death, loss to follow-up, or withdrawal of consent), including disease 
progression.  A 30-day (+7 days) SFU visit after the last dose of study drug is required when subjects discontinue study drug.  The TT visit should be scheduled within 
7 days of the last dose of study drug, if possible, and is not required for subjects who discontinue from study treatment within 10 days of a scheduled study visit.  In addition 
to the TT visit, each subject should be followed until the SFU visit at 30 (+7) days after his or her last dose of study drug to monitor for resolution or progression of AEs and 
to document the occurrence of any new events, regardless of whether the subject receives a new anticancer therapy or demonstrates disease progression within this 
timeframe.   
d.  Each subject should be followed until disease progression.  If disease progression has not occurred at the time of the 30-day SFU visit, post-treatment disease follow-up 
visits should occur approximately every 3 months (12 weeks) until disease progression, regardless of whether the subject receives new anticancer treatment.  During this 
period, subjects will be followed via CT scans, CBC with differential, physical examinations (including vital signs and weight), serum chemistry, and bone marrow biopsy and 
aspirate (as clinically indicated).    
e. 
Once subjects progress—for all subjects who have not withdrawn consent—they will be contacted approximately every 3 months (12 weeks) by clinic visit or telephone, to 
assess survival and the use of alternative anticancer therapy until death or loss to follow-up. 
f. 
The screening physical examination will include, at a minimum, the general appearance of the subject, height (screening only) and weight, and examination of the skin, 
eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system.  Symptom-directed physical examinations, 
including neurological examinations for signs and symptoms of PML, will be done during the treatment period and at the TT and SFU visits and during the post-treatment 
disease follow-up.   
g. 
Vital signs (blood pressure, heart rate, and body temperature) will be assessed after the subject has rested in the sitting position.   
h. 
Subjects should be in supine position and resting for ≥10 minutes before the baseline ECG.  
i. 
Women of childbearing potential only.  Testing will be done locally by use of central laboratory provided kits.  Pregnancy testing may be done by local laboratories and can 
be done more frequently than the protocol-defined schedule, if required by local regulatory authorities. 
j. 
This urine or serum pregnancy test is to be performed on Cycle 1 Day 1 (-3 days).   
k. 
Hematology must include CBC with differential including but not limited to white blood cell count, hemoglobin, hematocrit, platelet count, ANC, and ALC. 
l. 
Serum chemistry: albumin, alkaline phosphatase, ALT, AST, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, magnesium, phosphate/phosphorus, potassium, 
sodium, total bilirubin, total protein, and uric acid.  If an unscheduled ECG is done at any time, then an electrolyte panel (i.e., calcium, magnesium, and potassium) must be 
done to coincide with the ECG testing. 
m. Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.  
n. 
 
 
o. 
Samples at the indicated timepoints are to be collected predose. 
p.  Serum immunoglobulin: IgG, IgM, IgA, and total immunoglobulin (if available).  Testing will be performed on Cycle 1 Days 1 and 28, end of Cycles 3, 6, 12, then every 
6 cycles therafter. 
q. 
Hepatitis serology must include HBsAg, anti-HBs, anti-HBc, and HCV antibody.  In addition, any subjects testing positive for any hepatitis serology, must have PCR testing 
(see exclusion criterion #9). 
r. 
Subjects who are anti-HBc positive (or have a known history of HBV infection) should have a quantitative PCR test for HBV DNA performed during screening and every 
3 months thereafter.  Monitoring every 3 months should continue until 12 months after last dose of acalabrutinib.  Any subject with a rising viral load (above lower limit of 
detection) should discontinue acalabrutinib and have antiviral therapy instituted and a consultation with a physician with expertise in managing hepatitis B.  As IVIG may 
cause false positive hepatitis serology, monthly PCR testing is not required in subjects who are currently receiving or received prophylactic IVIG within 3 months before 
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study enrollment and have a documented negative anti-HBc test before the initiation of IVIG therapy.  PCR testing should be performed when clinically indicated (e.g., in the 
setting of rising transaminase levels). 
s. 
Subjects with a known history of hepatitis C or who are hepatitis C antibody positive should be tested for HCV RNA during screening and at Cycle 6.  No further testing 
beyond Cycle 6 is necessary if PCR results are negative. 
t. 
 
 
 
u. 
 
v. 
A bone marrow aspirate and biopsy will be done at screening or ≤3 months before enrollment, and to confirm CR. 
w.  
 
 
x. 
Radiological imaging by CT with contrast is required and must include the pelvis, abdomen, chest, and neck (and any other disease area).  Subjects who are intolerant to IV 
CT contrast agents will have CT scans performed with oral contrast. 
y. 
Pretreatment radiologic tumor assessment should be performed within 30 days before the first dose.   
z. 
Radiologic tumor assessments will be performed at the end of Cycles 3, 6, 9, 12, 18, 24, (-7 days) and then every year thereafter, while receiving acalabrutinib treatment.  
Otherwise, radiologic tumor assessments are done at investigator discretion.  Bone marrow and radiologic assessments are both required for confirmation of a CR.  Testing 
for minimal residual disease will be done on subjects with confirmed CRs.  Clinical sites will be used to collect and store CT scan images. 
 
 
 
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Appendix 2 
IWCLL Response Assessment Criteria (Modified from Hallek 2008) 
Response 
Lymphocytes 
Bone Marrow 
Physical Examinationa 
(Nodes, Liver, Spleen) 
Peripheral Blood 
CR* 
Lymphocytes <4 x 109/L 
Normocellular 
<30% lymphocytes 
No B-lymphoid nodules 
Normal (e.g., no lymph nodes 
>1.5 cm) 
ANC >1.5 x 109/Lb 
Platelets >100 x 109/Lb 
Hemoglobin >11.0 g/dL (untransfused)b 
CRi 
Lymphocytes <4 x 109/L 
Hypocellular 
<30% lymphocytes 
Normal (e.g., no lymph nodes 
>1.5 cm) 
Persistent anemia, thrombocytopenia, or neutropenia 
related to drug toxicity 
nPR 
CR with the presence of lymphoid nodules in the bone marrow which reflect residual disease. 
PR* 
Lymphocytes <5 x 109/L 
Or 
≥50% decrease from baseline 
Not assessed 
≥50% reduction in 
lymphadenopathyc and/or in 
spleen or liver enlargement 
ANC >1.5 x 109/L 
Or 
Platelets >100 x 109/L or 
50% improvement over baselineb 
Or 
Hemoglobin >11.0 g/dL or 50% improvement over 
baseline (untransfused)b 
PRL* 
Lymphocytes ≥5 x 109/L 
Not assessed 
≥50% reduction in 
lymphadenopathyc and/or in 
spleen or liver enlargement 
ANC >1.5 x 109/L 
Or 
Platelets >100 x 109/L or 
50% improvement over baselineb 
Or 
Hemoglobin >11.0 g/dL or 50% improvement over 
baseline (untransfused)b 

 
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Response 
Lymphocytes 
Bone Marrow 
Physical Examinationa 
(Nodes, Liver, Spleen) 
Peripheral Blood 
SD 
Absence of PD and failure to achieve at least a PR 
PD* 
Lymphocytes ≥50% increase 
over baseline, with ≥5000 
B lymphocytes/µL 
Not assessed  
(except to confirm PD as 
assessed by progressive 
cytopenias) 
Appearance of any new lesion 
or de novo appearance of 
hepatomegaly or splenomegaly 
Or 
Increase ≥50% in 
lymphadenopathy 
Or 
Increase ≥50% in hepatomegaly 
Or 
Increase ≥50% in  
splenomegaly 
Platelets decrease of ≥50% from baseline secondary 
to CLL 
Or 
Hemoglobin decrease of >2 g/dL from baseline 
secondary to CLL 
ANC=absolute neutrophil count; CLL=chronic lymphocytic leukemia; CR=complete remission (response); CRi=CR with incomplete bone marrow recovery; 
CT=computed tomography; IWCLL=International Workshop on Chronic Lymphocytic Leukemia; nPR=nodular partial remission; PD=progressive disease; 
PR=partial remission (response); PRL=partial remission (response) with lymphocytosis; SD=stable disease. 
*CR:  all of the above CR criteria have to be met, and patients have to lack disease-related constitutional symptoms;  PR: at least two of the above PR criteria for 
lymphadenopathy, splenomegaly, hepatomegaly, or lymphocytes plus one of the criteria for ANC, platelets, or hemoglobin have to be met; PRL: presence of 
lymphocytosis, plus ≥50% reduction in lymphadenopathy and/or in spleen or liver enlargement, plus one of the criteria for ANC, platelets or hemoglobin have to be met; 
PD: at least one of the above PD criteria has to be met, or transformation to a more aggressive histology (e.g., Richter syndrome).  For PD as assessed by progressive 
cytopenias, a bone marrow biopsy is required for confirmation.  Note:  Isolated elevation of treatment-related lymphocytosis by itself will not be considered PD unless 
patient becomes symptomatic from this per Cheson 2012. 
a 
CT scan of abdomen, pelvis, and thorax may be used if previously abnormal. 
b 
Without need for exogenous growth factors. 
c 
In the sum products of ≤6 lymph nodes or in the largest diameter of the enlarged lymph node(s) detected before therapy and no increase in any lymph node or new 
enlarged lymph nodes. 
 

 
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Appendix 3 
Cumulative Illness Rating Scale-Geriatric (CIRS-G) 
Calculator 
Web-based CIRS-G calculator link:  
 
http://eforms.moffitt.org/cirsgScore.aspx 
 
 

 
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Appendix 4 
Known Strong in Vivo Inhibitors or Inducers of CYP3A 
 
Strong Inhibitors of CYP3Aa 
Strong Inducers of CYP3Ae 
boceprevir 
carbamazepinef 
clarithromycinb 
phenytoinf 
conivaptinb 
rifampinf 
grapefruit juicec 
St John's wortf  
indinavir 
 
itraconazoleb 
 
ketoconazoleb 
 
lopinavir/ritonavirb (combination drug) 
 
mibefradild 
 
nefazodone 
 
nelfinavir 
 
posaconazole 
 
ritonavirb 
 
saquinavir 
 
telaprevir 
 
telithromycin 
 
voriconazole 
 
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. 
a. 
A strong inhibitor for CYP3A is defined as an inhibitor that increases the area under 
the concentration-time curve (AUC) of a substrate for CYP3A by ≥5-fold. 
b. 
In vivo inhibitor of P-glycoprotein. 
c. 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, 
and preparation-dependent.  Studies have shown that it can be classified as a “strong 
CYP3A inhibitor” when a certain preparation was used (e.g., high dose, double 
strength) or as a “moderate CYP3A inhibitor” when another preparation was used 
(e.g., low dose, single strength). 
d. 
Withdrawn from the United States market because of safety reasons. 
e. 
A strong inducer for CYP3A is defined as an inducer that results in ≥80% decrease in 
the AUC of a substrate for CYP3A. 
f. 
In vivo inducer of P-glycoprotein. 
Source:  FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors 
and Inducers. Web link Accessed 11 June 2015: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm#inVivo. 
 

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

 
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Appendix 6 
Adverse Event Assessment of Causality 
 
Is there a reasonable possibility that the event may have been caused by study drug?  
No___ Yes___ 
The descriptions provided below will help guide the principal investigator in making the 
decision to choose either “yes” or “no”: 
No = There is no reasonable possibility that the event may have been caused by study 
drug. 
The adverse event: 
• 
may be judged to be due to extraneous causes such as disease or environment 
or toxic factors 
• 
may be judged to be due to the subject’s clinical state or other therapy being 
administered 
• 
is not biologically plausible 
• 
does not reappear or worsen when study drug is re-administered 
• 
does not follow a temporal sequence from administration of study drug 
Yes = There is a reasonable possibility that the event may have been caused by study 
drug. 
The adverse event: 
• 
follows a temporal sequence from administration of study drug 
• 
is a known response to the study drug based on clinical or preclinical data 
• 
could not be explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other therapy administered to the subject 
• 
disappears or decreases upon cessation or reduction of dose of study drug 
• 
reappears or worsens when study drug is re-administered 
 

 
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Appendix 7 
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law 
INTRODUCTION 
This Appendix describes the process to be followed to identify and appropriately report 
potential Hy’s law (PHL) cases and Hy’s law (HL) cases.  It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.  
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a subject meets 
PHL criteria at any point during the study.  All sources of laboratory data are appropriate 
for the determination of PHL and HL events; this includes samples taken at scheduled 
study visits and other visits, including central and all local laboratory evaluations, even if 
collected outside of the study visits (e.g., PHL criteria could be met by an elevated ALT 
from a central laboratory and/or elevated total bilirubin from a local laboratory).  The 
investigator will also review adverse event (AE) data (e.g., for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events. 
The investigator participates with the sponsor in the review and assessment of cases 
meeting PHL criteria to agree whether HL criteria are met.  HL criteria are met if there is 
no alternative explanation for the elevations in liver biochemistry other than drug-induced 
liver injury (DILI) caused by the investigational medicinal product (IMP).  The investigator 
is responsible for recording data pertaining to PHL/HL cases and for reporting AEs and 
serious adverse events (SAEs) according to the outcome of the review and assessment 
in line with standard safety-reporting processes.   
DEFINITIONS 
Potential Hy’s Law  
AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN at any point during the study 
after the start of study drug, irrespective of an increase in alkaline phosphatase.  
Hy’s Law 
AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN, where no reason other than 
the IMP can be found to explain the combination of increases (e.g., elevated alkaline 
phosphatase indicating cholestasis, viral hepatitis, or another drug).   

 
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For PHL and HL, the elevation in transaminases must precede or be coincident with (i.e., 
on the same day) the elevation in total bilirubin, but there is no specified timeframe 
within which the elevations in transaminases and total bilirubin must occur. 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
Laboratory data must be comprehensively reviewed by the investigator for each subject 
to identify laboratory values meeting the following criteria: 
• 
ALT ≥3 x ULN 
• 
AST ≥3 x ULN 
• 
Total bilirubin ≥2 x ULN 
When the identification criteria are met from central or local laboratory results, the 
investigator will perform the following: 
• 
Notify the sponsor representative/Medical Monitor by telephone and report the case 
as an SAE of Potential Hy’s law; seriousness criteria “Important medical event” and 
causality assessment “yes/related” or in accordance with the clinical study protocol 
as appropriate. 
• 
Request a repeat of the test (new blood draw) without delay 
• 
Complete the appropriate unscheduled laboratory electronic Case Report Form 
(eCRF) module(s)  
• 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the clinical study protocol, as applicable 
 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
The instructions in this section should be followed by the investigator for all cases where 
PHL criteria are met. 
As soon as possible after the biochemistry abnormality is initially detected, the study 
Medical Monitor and the Investigator will review available data, to agree whether there is 
an alternative explanation for meeting PHL criteria other than DILI caused by the IMP 
and to ensure that timely analysis and reporting to health authorities within 15 calendar 
days from the date PHL criteria were met.    

 
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Where there is an agreed alternative explanation for the ALT or AST and total bilirubin 
elevations, a determination of whether the alternative explanation is an AE will be made 
and, subsequently, whether the AE meets the criteria for an SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF. 
• 
If the alternative explanation is an AE/SAE, update the previously submitted PHL 
SAE accordingly with the new information (reassessing event term, causality, and 
seriousness criteria) following the sponsor’s standard processes. 
If it is agreed that there is no explanation that would explain the ALT or AST and total 
bilirubin elevations other than the IMP, then: 
• 
Send updated SAE (report term “Hy’s law”) according to the sponsor’s standard 
processes:  
o The “Medically Important” serious criterion should be used if no other serious 
criteria apply. 
o Because there is no alternative explanation for the HL case, a causality 
assessment of “related” should be assigned. 
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until an informed decision can be made: 
• 
Provide any further update to the previously submitted SAE of PHL (report term now 
“Hy’s law case”), ensuring causality assessment is related to IMP and seriousness 
criteria are medically important, according to clinical study protocol process. 
• 
Continue follow-up and review according to the agreed plan.  After the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are still met.  Update the previously submitted PHL 
SAE report following the clinical study protocol process, according to the outcome of 
the review. 
ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S LAW 
This section is applicable when a subject meets PHL criteria while receiving study 
treatment and has already met PHL criteria at a previous on-study treatment visit.  The 

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

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