A Phase 1/2, Multicenter, Open-label, and Dose-escalation Study of ACP-196 in Subjects With Chronic Lymphocytic Leukemia, Richter's Syndrome or Prolymphocytic Leukemia
Phase: PHASE1
Conditions: Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Richter's Syndrome, Prolymphocytic Leukemia
Sponsor: Acerta Pharma BV

Product: ACP-196 (acalabrutinib) 
Protocol: ACE-CL-001 
 
 
 
Acerta Pharma 
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Page 1 
A Phase 1/2, Multicenter, Open-label, and Dose-escalation Study 
of ACP-196 in Subjects with Chronic Lymphocytic Leukemia, Richter’s Syndrome 
or Prolymphocytic Leukemia 
Protocol Number: 
ACE-CL-001 
IND Number: 
118717 
EUDRACT NUMBER 
2014-000440-15 
Drug Product: 
ACP-196 (acalabrutinib) 
Medical Monitor: 
Sponsor: 
Acerta Pharma BV (A Member of the 
AstraZeneca Group) 
 
The Netherlands 
Protocol Date: 
Version 0.0 - 01 October 2013 
Amendment 1 Date: 
Version 1.0 - 18 December 2013 
Amendment 2 Date: 
Version 2.0 - 06 May 2014 
Amendment 3 Date: 
Version 3.0 - 03 July 2014 
Amendment 4 Date: 
Version 4.0 - 22 September 2014 
Amendment 5 Date: 
Version 5.0 - 14 February 2015 
Amendment 6 Date: 
Version 6.0 - 01 May 2015 
Amendment 7 Date: 
Version 7.0 – 14 December 2015 
Amendment 8 Date: 
Version 8.0 – 08 January 2016 
Amendment 9 Date: 
Version 9.0 – 30 March 2017 
Amendment 10 Date: 
Version 10.0 – 22 February 2018 
Amendment 11 Date: 
Version 11.0 – 17 January 2020 
Amendment 12 Date:  
Version 12.0 – 15 January 2021 
Amendment 13 Date: 
Version 13.0 – 25 August 2021 
 
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 independent 
ethics committee.  This information cannot be used for any purpose other than the evaluation or 
conduct of the clinical investigation without the prior written consent of Acerta Pharma BV.  
PPD
PPD

Product: ACP-196 (acalabrutinib) 
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INVESTIGATOR’S AGREEMENT:  AMENDMENT 13 
I have carefully read Protocol ACE-CL-001 entitled “A Phase 1/2, Multicenter, 
Open-label, and Dose-escalation Study of ACP-196 in Subjects with Chronic 
Lymphocytic Leukemia, Richter’s Syndrome or Prolymphocytic Leukemia”  
I agree to conduct this study as outlined herein and in compliance with Good Clinical 
Practices (GCP), all applicable regulatory requirements, and with the ethical principles 
laid down in the Declaration of Helsinki.  Furthermore, I understand that the Sponsor, 
Acerta Pharma, and the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) must approve any changes to the protocol in writing before implementation.  
I agree not to divulge to anyone, either during or after the termination of the study, any 
confidential information acquired regarding the investigational product and processes or 
methods of Acerta Pharma.  All data pertaining to this study will be provided to Acerta 
Pharma.  The policy of Acerta Pharma requires that any presentation or publication of 
study data by clinical investigators be reviewed by Acerta Pharma, before release, as 
specified in the protocol. 
 
 
 
Signature 
 
 
Print Name of Principal investigator 
 
Date (DD Month YYYY) 
 

Product: ACP-196 (acalabrutinib) 
Protocol: ACE-CL-001 
 
 
 
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SUMMARY OF AMENDMENT 13 
This protocol is being amended to describe the continued treatment after data cutoff  
with acalabrutinib when commercially available or not commercially available in a 
particular country.  
The substantive changes that were made as part of this amendment are as follows: 
Change 
Rationale 
Section 3.1.3 End of Study 
Added language regarding continued treatment 
with acalabrutinib after data cutoff (associated with 
final database lock) whether acalabrutinib is 
commercially available or not.  
To implement commercial drug 
transition language.  
 
 

Product: ACP-196 (acalabrutinib) 
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PROTOCOL SYNOPSIS 
Protocol Number: 
ACE-CL-001 
Study Drug: 
ACP-196 (acalabrutinib) 
Protocol Title: 
A Phase 1/2, Multicenter, Open-label, and Dose-escalation Study 
of ACP-196 in Subjects with Chronic Lymphocytic Leukemia, 
Richter’s Syndrome or Prolymphocytic leukemia 
Phase: 
Phase 1/2 
Study period: 
Approximately 7 years, until final data cutoff (DCO); approximately 
>5 years, until last subject last visit (LSLV) (total of >12 years) 
Comparator: 
None 
Background and 
Rationale for Study 
Clinical studies have shown that targeting the B-cell receptor 
(BCR) signaling pathway by inhibiting Bruton tyrosine kinase (BTK) 
produces significant clinical benefit in patients with non-Hodgkin 
lymphoma (NHL). 
Acerta Pharma BV (Acerta Pharma) has developed a potent, 
highly selective, orally bioavailable BTK inhibitor, acalabrutinib 
(also known as ACP-196 and Calquence®).  
The purpose of this study is to evaluate the safety and efficacy of 
acalabrutinib in the treatment of subjects with chronic lymphocytic 
leukemia (CLL)/small lymphocytic lymphoma (SLL), Richter’s 
syndrome, or prolymphocytic leukemia transformation. 
Study Design: 
This study is a multicenter (approximately 15 global centers), 
open-label, nonrandomized, sequential group, dose-escalation 
study.  In the Phase 1 portion of the study, the following dose 
cohorts will be evaluated: 
 Dosing Cohorts 
Cohort 1: 
 
Cohort 2a: 
 
Cohort 3: 
 
Cohort 4a: 
 
 Dosing Cohorts 
Cohort 2b: 
 
Cohort 4b: 
 
Dose-limiting toxicity (DLT) reviews have occurred for all cohorts 
and no DLTs were observed.  Consequently, no maximum 
tolerated dose (MTD) has been reached.  The Phase 2 portion of 
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the study expands Cohort 2b to approximately 65 subjects and 
adds Cohort 2c at a dosage of 
 for up to 30 subjects.  
Both cohorts are for subjects with relapsed or refractory CLL.  
The Phase 2 portion of this study also includes 4 treatment 
subgroups to evaluate additional subpopulations with up to 
30 subjects per cohort (except for Cohorts 10 and 11, which will 
have up to 6 and 60 subjects, respectively): 
• 
Treatment Naive Group:  
o Cohort 7: 
 (N = 11 to 30) 
o Cohort 11: 
 (N = 11 to 60) 
• 
Ibrutinib Intolerant Group: Cohort 8: 
 
(N = 11 to 35) 
• 
Richter’s Syndrome/ Prolymphocytic leukemia 
Transformation Group: Cohort 9: 
 
(N = 11 to 30) 
• 
Ibrutinib R/R Group: Cohort 10: 
 (N = 6) 
Note: Under Amendment 6 of this protocol, all subjects will be 
switched to 
 except for subjects in the Richter’s 
Syndrome/Prolymphocytic Leukemia and Ibrutinib R/R groups 
(Cohort 9 and Cohort 10, respectively).  Subjects in Cohort 4b will 
be switched from 
  Any 
subjects not switched to 
 will need to be reviewed with 
the medical monitor.   
Treatment with acalabrutinib may be continued for 
 until 
disease progression or an unacceptable drug-related toxicity 
occurs.  Subjects who meet criteria of disease progression and are 
continuing to gain clinical benefit from therapy may be able to 
temporarily remain on acalabrutinib after discussion with the 
medical monitor.  All subjects who discontinue study drug will have 
a safety follow-up visit 30 (+ 7) days after the last dose of study 
drug, regardless of whether the subject receives a new anticancer 
therapy or demonstrates disease progression within this 
timeframe.   
For all cohorts except Cohort 9, radiologic tumor assessment will 
be done at screening and at the end of Cycle 2, Cycle 4, and 
Cycle 6, then every 6 cycles until Cycle 36, and then every 
12 cycles thereafter.  For subjects in Cohort 9, radiologic tumor 
assessment will be done at screening and at the end of Cycle 2, 
Cycle 4, Cycle 6, Cycle 9, Cycle 12, Cycle 15, Cycle 18, Cycle 21, 
Cycle 24, and every 6 cycles thereafter.  Otherwise, radiologic 
tumor assessments are done at investigator discretion.  
Confirmation of complete response (CR) will require bone marrow 
analysis and radiologic tumor assessment (as applicable for 
subjects in Cohort 9).  For subjects who remain on study for 
> 11 months, a mandatory bone marrow aspirate and biopsy is 
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required in Cycle 12 concurrent with the radiologic tumor 
assessment.   
Note: Under amendment 9 of this protocol, subjects in all cohorts 
will synchronize their clinic visits and laboratory assessments 
(excluding the HBV testing that will be every 3 cycles regardless of 
the imaging/clinic frequency) with the new imaging scheduled 
visits. 
All subjects will have standard hematology, chemistry, and 
urinalysis safety panels done at screening.  This study also 
includes pancreatic function assessment (serum amylase and 
serum lipase) through Cycle 6 due to the pancreatic findings in the 
28-day Good Laboratory Practice (GLP) rat toxicity study.  This 
study also includes cardiac troponin testing through Cycle 6 and 
echocardiograms at screening and at end of Cycle 6.  Once dosing 
commences, all subjects will be evaluated for safety once weekly 
for the first 4 weeks, every other week for Cycle 2, and monthly 
thereafter.  Blood samples will be collected in Cycle 1 for 
pharmacokinetics (PK)/
 assessments.  
Electrocardiograms (ECGs) will be done at screening, and on 
Day 1-2, 8, 15, 22, 28 of Cycle 1, Day 15 and 28 of Cycle 2, and 
monthly thereafter through Cycle 6 for a subset of subjects in the 
dose escalation cohorts (i.e., Cohorts 1, 2a, 2b, 3, 4a, and 4b).  
ECGs are done in triplicate for screening only.  Thereafter, single 
ECGs are done unless a repeat ECG is required.  Note:  The 
Phase 1 portion of the study has been closed, therefore the 
intensive ECG schedule for the subjects in the dose-escalation 
cohorts has been completed. 
A study schema is provided at the end of this synopsis. 
Definition of 
Dose-limiting Toxicity 
The DLT review portion of the study is now over.  However, during 
dose escalation a DLT was defined as any of the following events 
unless the adverse event (AE) is clearly related to disease 
progression or the subject’s current medical history and associated 
comorbidities: 
1. Any Grade 3 or greater nonhematologic toxicity with the 
exception of alopecia and Grade 3 nausea, vomiting and 
diarrhea that respond to supportive therapy.  
2. The following hematologic toxicities should be considered 
as DLTs: 
a. Grade 4 neutropenia lasting more than 5 days.  
b. Grade 4 thrombocytopenia, or Grade 3 
thrombocytopenia with bleeding, or any requirement 
for platelets transfusion.  
c. Grade 3 or greater febrile neutropenia (temperature 
≥ 38.5 °C).  
d. Grade 4 anemia, unexplained by underlying 
disease.  
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3. Dosing delay due to toxicity for > 7 consecutive days 

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Study Objectives: 
Primary Objectives: 
• 
Establish the safety and the MTD of orally administered 
acalabrutinib in subjects with CLL/SLL 
• 
Determine the PK of orally administered acalabrutinib and 
identification of its major metabolite 
Secondary Objective: 
• 
Evaluate tumor response by overall response rate (ORR), 
duration of response (DOR), and progression-free survival 
(PFS) 
Exploratory Objective: 
• 
 
 
  
Efficacy Parameters: 
• 
ORR by investigator assessment 
• 
DOR by investigator assessment 
• 
PFS by investigator assessment 
Safety Parameters: 
• 
DLTs and MTD 
• 
Frequency, severity, and attribution of AEs based on the 
Common Terminology Criteria for Adverse Events (CTCAE 
v4.03 or higher) for hematologic and nonhematologic AEs  
Pharmacokinetic 
Parameters: 
The plasma PK of acalabrutinib and a metabolite will be 
characterized using noncompartmental analysis  The following PK 
parameters will be calculated, whenever possible, from plasma 
concentrations of acalabrutinib: 
• 
AUC0-last:  Area under the plasma concentration-time curve 
calculated using linear trapezoidal summation from time 0 
to time last, where “last” is the time of the last measurable 
concentration. 
• 
AUC0-12: Area under the plasma concentration-time curve 
from 0 to 12 hours, calculated using linear trapezoidal 
summation. 
• 
AUC0-24:  Area under the plasma concentration-time curve 
from 0 to 24 hours, calculated using linear trapezoidal 
summation. 
• 
AUC0-inf:  Area under the plasma concentration-time curve 
from 0 to infinity, calculated using the formula: AUC0-inf = 
AUC0-last + Clast / λz, where λz is the apparent terminal 
elimination rate constant. 
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• 
AUC0-24calc:  Area under the concentration-time curve, from 
time 0 to 24 hour timepoint, calculated by doubling the 
value for AUC0-12 
• 
Cmax:  Maximum observed plasma concentration 
• 
Tmax:  Time of the maximum plasma concentration 
(obtained without interpolation) 
• 
t½:  Terminal elimination half-life (whenever possible) 
• 
λz: Terminal elimination rate constant (whenever possible) 
• 
CL/F:  Oral clearance 
• 
Vz/F: Oral volume of distribution 
Sample Size: 
Approximately 286 subjects 
Inclusion Criteria: 
1. Men and women ≥ 18 years of age with a confirmed 
diagnosis of CLL/SLL, which has relapsed after, or been 
refractory to, ≥ 2 previous treatments for CLL/SLL.  
2. Must have measurable CLL/SLL defined as ≥ 1 lymph node 
≥ 2 cm as measured in the longest diameter. 
3. Active disease meeting ≥ 1 of the following IWCLL 2008 
criteria for requiring treatment: 
a. Evidence of progressive marrow failure as 
manifested by the development of, or worsening of, 
anemia (hemoglobin < 10 g/dL) and/or 
thrombocytopenia (platelets < 100,000/μL). 
b. Massive (i.e., ≥ 6 cm below the left costal margin), 
progressive, or symptomatic splenomegaly. 
c. Massive nodes (i.e., ≥ 10 cm in the longest 
diameter), progressive, or symptomatic 
lymphadenopathy. 
d. Progressive lymphocytosis with an increase of 
> 50% over a 2-month period or a lymphocyte 
doubling time (LDT) of < 6 months.  LDT may be 
obtained by linear regression extrapolation of 
absolute lymphocyte counts (ALC) obtained at 
intervals of 2 weeks over an observation period of 
2 to 3 months.  In subjects with initial blood 
lymphocyte counts of < 30 X 109/L (30,000/μL), LDT 
should not be used as a single parameter to define 
indication for treatment.  In addition, factors 
contributing to lymphocytosis or lymphadenopathy 
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other than CLL (e.g., infections) should be 
excluded. 
e. Autoimmune anemia and/or thrombocytopenia that 
is poorly responsive to standard therapy. 
f. Constitutional symptoms documented in the 
subject’s chart with supportive objective measures, 
as appropriate, defined as ≥ 1 of the following 
disease-related symptoms or signs: 
i. Unintentional weight loss ≥ 10% within the 
previous 6 months before Screening. 
ii. Fevers higher than 100.5°F or 38.0°C for 
2 or more weeks before Screening without 
evidence of infection. 
iii. Night sweats for > 1 month before Screening 
without evidence of infection. 
4. Eastern Cooperative Oncology Group (ECOG) 
performance status of ≤ 2. 
5. Agreement to use highly effective methods of contraception 
during the study and for 2 days after the last dose of study 
drug if sexually active and able to bear or beget children 
(see Section 3.7.9 for list of highly effective methods of 
contraception). 
6. Willing and able to participate in all required evaluations 
and procedures in this study protocol including swallowing 
capsules without difficulty. 
7. Ability to understand the purpose and risks of the study and 
provide signed and dated informed consent and 
authorization to use protected health information (in 
accordance with national and local subject privacy 
regulations). 
8. Removed at Amendment 11. 
Inclusion Criteria for 
Treatment Subgroups 
1. Treatment Naive only: Men and women ≥ 18 years of age 
with confirmed diagnosis of CLL/SLL, who require 
treatment per National Cancer Institute (NCI) or 
International Working Group guidelines and a) do not want 
to receive chemoimmunotherapy or b) have comorbidities 
that would preclude chemoimmunotherapy. 
2. Ibrutinib Intolerant only: Men and women ≥ 18 years of age 
with confirmed diagnosis of CLL/SLL who are not tolerating 
ibrutinib due to ibrutinib-related AEs. 
3. Richter’s Syndrome/Prolymphocytic Leukemia 
Transformation only: Men and women ≥ 18 years of age 
and biopsy proven diffuse large B cell lymphoma (DLBCL) 
Richter's transformation or prolymphocytic leukemia 
transformation. 

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4. Ibrutinib R/R only: Men and women ≥ 18 years of age with 
confirmed diagnosis of CLL/SLL whose best response after 
2 cycles of ibrutinib therapy was SD or nonresponse or who 
initially responded to ibrutinib therapy and now have signs 
of clinical progression. 
Exclusion Criteria: 
1. Prior malignancy, except for adequately treated basal cell, 
squamous cell skin cancer or in situ cervical cancer.  
Subjects with other prior malignancies from which the 
subject has been disease free for ≥ 2 years may be 
included if approved by the medical monitor. 
2. A life-threatening illness, medical condition or organ system 
dysfunction which, in the investigator’s opinion, could 
compromise the subject’s safety, interfere with the 
absorption or metabolism of acalabrutinib, or put the study 
outcomes at undue risk. 
3. Significant cardiovascular disease such as uncontrolled or 
symptomatic arrhythmias, congestive heart failure, or 
myocardial infarction within 6 months of screening, or any 
Class 3 or 4 cardiac disease as defined by the New York 
Heart Association Functional Classification, or left 
ventricular ejection fraction (LVEF) ≤ 40%. 
4. Malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or 
small bowel, symptomatic inflammatory bowel disease, 
partial or complete bowel obstruction, or gastric restrictions 
and bariatric surgery, such as gastric bypass. 
5. Any immunotherapy within 4 weeks of first dose of study 
drug. 
6. For subjects with recent chemotherapy or experimental 
therapy the first dose of study drug must occur after 5 times 
the half-life of the agent(s). 
7. Relapsed after, or refractory to, prior BTK inhibitor therapy 
(Note:  Does not apply to Ibrutinib R/R or Richter’s 
Syndrome Group). 
8. Any history of Richter's transformation (Note: Does not 
apply to Richter’s Syndrome Group). 
10. Central nervous system (CNS) involvement by lymphoma. 
11. Grade ≥ 2 toxicity (other than alopecia) continuing from 
prior anticancer therapy including radiation. 
12. Known history of human immunodeficiency virus (HIV) or 
serologic status indicating active hepatitis C virus (HCV) or 
hepatitis B virus (HBV) infection or any uncontrolled active 
systemic infection.  Subjects with hepatitis B core antibody 
positive who are surface antigen negative or who are 
hepatitis C antibody positive will need to have a negative 

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polymerase chain reaction (PCR) result before enrollment.  
Those who are hepatitis B surface antigen positive or 
hepatitis B PCR positive and those who are hepatitis C 
PCR positive will be excluded. 
13. Uncontrolled AIHA or 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 daily or equivalent). 
14. History of stroke or intracranial hemorrhage within 
6 months prior to the first dose of study drug. 
15. Requires treatment with proton-pump inhibitors (e.g., 
omeprazole, esomeprazole, lansoprazole, dexlansoprazole, 
rabeprazole, or pantoprazole). 
16. Requires anticoagulation with warfarin or equivalent 
vitamin K antagonists (e.g., phenprocoumon) within 7 days 
of first dose of study drug. 
17. Major surgery within 4 weeks before first dose of study 
drug. 
18. 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 ULN (total bilirubin ≤ 2.5 x ULN 
allowed in subjects with autoimmune hemolytic anemia that 
is otherwise controlled); and aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) > 3.0 x ULN 
unless disease related. 
20. Serum amylase > 1.5 x ULN or serum lipase > 1.5 x ULN. 
21. Significant screening ECG abnormalities including, 2nd 
degree AV block type II, 3rd degree block, Grade 2 or higher 
bradycardia, or QTc ≥ 480 ms. 
22. Cardiac troponin I levels above the limit of normal as 
specified by the manufacturer. 
23. Breast feeding or pregnant. 
24. History of bleeding diathesis (e.g., hemophilia, von 
Willebrand disease). 
25. Concurrent participation in another therapeutic clinical trial. 
26. Estimated creatinine clearance of < 30 mL/min, calculated 
using the formula of Cockcroft and Gault [(140-Age) • Mass 
(kg)/(72 • creatinine mg/dL); multiply by 0.85 if female]. 
27. Presence of a gastrointestinal ulcer diagnosed by 
endoscopy within 3 months before screening. 
Dosage Form: 
Acalabrutinib is provided as hard gelatin capsules prepared using 
standard pharmaceutical grade excipients.  

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Dose Regimen/Route 
of Administration: 
Acalabrutinib is an orally administered product. 
Statistics: 
No formal statistical tests of hypotheses will be performed.  
Descriptive statistics (including means, standard deviations, and 
medians for continuous variables and proportions for discrete 
variables) will be used to summarize data as appropriate. 
The Phase 1 trial design (dose-escalation) is specified because of 
its practical simplicity, use of a biomarker, and not because of 
power considerations.  The MTD is defined as the largest daily 
dose for which fewer than 33% of the subjects experience a DLT 
during Cycle 1 during the dose-escalation phase of the protocol.  
The MTD was not reached on this protocol. 
The Phase 2 (expansion portion) of the study will test the null 
hypothesis that the ORR is ≤ 10% against the alternative 
hypothesis that it is ≥ 35%.  Using Simon’s optimal 2-stage design 
(Simon 1989), a total sample size of 30 subjects per cohort has 
power = 0.90 to achieve a 1-sided significance level of ≤ 0.025.  In 
Stage 1, 11 subjects will be enrolled per cohort; if ≥ 2 subjects 
(18%) achieve an objective response of a PR/PRL or better within 
the first 4 cycles of treatment, then that cohort will continue to full 
enrollment (Stage 2).  Under the Simon design, an ORR of ≥ 23% 
(i.e., ≥ 7 subjects responding of 30 subjects evaluated) will achieve 
a significance level of ≤ 0.025.  Using an exact binomial confidence 
interval (CI), an ORR of 23% (i.e., 7 subjects responding of 
30 subjects evaluated) will achieve a 2-sided 90% lower bound of 
11.5%.   
 
 
 

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STUDY SCHEMA FOR DOSE-ESCALATION COHORTS 
 
Note: No DLTs occurred during dose escalation and the MTD was not reached.  Under Amendment 5 
of the protocol, subjects in Cohort 1, Cohort 2a, and Cohort 4a will be switched to 
  Under 
Amendment 6 of the protocol, subjects in Cohort 2c and in Cohort 4b 
 
will be switched to 
   
Abbreviations:  BID = twice daily; DLT = dose-limiting toxicity; MTD = maximum tolerated dose; 
QD = once daily 
 
 
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STUDY SCHEMA FOR TREATMENT SUBGROUPS 
 
 
Note: Under Amendment 6 of the protocol, subjects in Cohort 7 will be switched to 
    
Abbreviations:  BID = twice daily; QD = once daily 
 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
λz 
terminal elimination rate constant 
ACP-196 
Acalabrutinib 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE(s) 
adverse event(s) 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
hepatitis B core antibody 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BCR 
B-cell receptor 
BCRP 
breast cancer-related protein 
BID 
twice daily 
BTK 
Bruton tyrosine kinase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
CL/F 
oral clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CR 
complete remission (response) 
CRi 
CR with incomplete blood count recovery 
CSSF 
Clinical Supplies Shipping Receipt Form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DCO 
data cutoff 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
Electrocardiogram 

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Abbreviation 
Definition 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
FcR 
Fc receptor 
FDA 
Food and Drug Administration 
FDG 
[18F]fluorodeoxyglucose 
FISH 
fluorescence in situ hybridization 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
HNSTD 
highest non-severely toxic dose 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
Ig 
Immunoglobulin 
IGHV 
immunoglobulin heavy-chain variable 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITK 
Interleukin-2-inducible tyrosine kinase 
IVIG 
intravenous immunoglobulin 
LDH 
lactate dehydrogenase 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mos 
Months 
MRD 
minimal residual disease 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin lymphoma 

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Abbreviation 
Definition 
NK 
natural killer (cells) 
NOAEL 
no observable adverse effect level 
ORR 
overall response rate 
PBMCs 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PD 
Pharmacodynamics 
PE 
physical examination 
PET 
positron-emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetics 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial remission (response) 
PRL 
partial remission (response) with lymphocytosis 
QD 
once daily 
QM 
every month 
QTc 
corrected QT interval 
R/R 
relapsed/refractory 
SAE(s) 
serious adverse event(s) 
SD 
stable disease 
SLL 
small lymphocytic lymphoma 
SPD 
sum of the product of the diameters 
t1/2 
half life 
Tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
Vz/F 
oral volume of distribution 
WHO 
World Health Organization 
XLA 
X-linked agammaglobulinemia 
 
 
 

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TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT:  AMENDMENT 13 ..................................................... 2 
SUMMARY OF AMENDMENT 13 ................................................................................... 3 
PROTOCOL SYNOPSIS ................................................................................................. 4 
STUDY SCHEMA FOR DOSE-ESCALATION COHORTS ............................................ 14 
STUDY SCHEMA FOR TREATMENT SUBGROUPS ................................................... 15 
LIST OF ABBREVIATIONS ........................................................................................... 16 
TABLE OF CONTENTS ................................................................................................ 19 
LIST OF TABLES .......................................................................................................... 23 
LIST OF FIGURES ........................................................................................................ 24 
LIST OF APPENDICES ................................................................................................. 25 
1. 
INTRODUCTION .................................................................................................. 26 
1.1. Role of BTK in Lymphoid Cancers .............................................................. 26 
1.2. Preclinical Studies ....................................................................................... 27 
1.2.1. 
Chemistry ..................................................................................... 27 
1.2.2. 
Mechanism of Action of Acalabrutinib ........................................... 28 
1.2.3. 
Dog Lymphoma Study .................................................................. 28 
1.2.4. 
Acalabrutinib and Antibody-dependent Cell-mediated 
Cytotoxicity ................................................................................... 28 
1.2.5. 
Acalabrutinib and Thrombus Formation ........................................ 29 
1.2.6. 
Safety Pharmacology ................................................................... 30 
1.2.7. 
Drug-drug Interaction Potential ..................................................... 31 
1.2.8. 
General Toxicity Studies .............................................................. 32 
1.3. Clinical Experience ..................................................................................... 32 
1.3.1. 
Pharmacokinetics and Pharmacodynamics of Acalabrutinib 
in Healthy Volunteers ................................................................... 32 
1.3.2. 
Clinical Experience of Acalabrutinib in CLL .................................. 34 
1.4. Risks/Benefits ............................................................................................. 34 
1.5. Summary and Conclusions ......................................................................... 35 
2. 
STUDY OBJECTIVES .......................................................................................... 35 
2.1. Primary Objectives ...................................................................................... 35 
2.2. Secondary Objective ................................................................................... 35 
2.3. Exploratory Objective .................................................................................. 35 
3. 
INVESTIGATIONAL PLAN ................................................................................... 35 
3.1. Overall Study Design .................................................................................. 36 
3.1.1. 
Escalation Portion – Phase 1 ....................................................... 36 
3.1.2. 
Expansion Cohorts – Phase 2 ...................................................... 36 
3.1.3. 
End of Study................................................................................. 39 

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3.2. Study Parameters ....................................................................................... 40 
3.2.1. 
Efficacy Parameters ..................................................................... 40 
3.2.2. 
Safety Parameters........................................................................ 40 
3.2.3. 
Pharmacokinetic and 
 Parameters .................. 41 
3.3. Rationale for Study Design and Dosing Regimen ........................................ 41 
3.4. Selection of Study Population ..................................................................... 41 
3.4.1. 
Inclusion Criteria .......................................................................... 41 
3.4.2. 
Inclusion Criteria for Treatment Subgroups .................................. 43 
3.4.3. 
Exclusion Criteria ......................................................................... 43 
3.4.4. 
Replacement of Subjects.............................................................. 44 
3.4.5. 
Enrollment Procedures ................................................................. 45 
3.5. Study Drug: Acalabrutinib Hard Gelatin Capsule ......................................... 45 
3.5.1. 
Premedications ............................................................................ 45 
3.5.2. 
Formulation, Packaging, and Storage .......................................... 45 
3.5.3. 
Administration of Acalabrutinib ..................................................... 46 
3.5.4. 
Assuring Subject Compliance ....................................................... 46 
3.5.5. 
Study Treatment Schedule ........................................................... 46 
3.6. Concomitant Therapy .................................................................................. 47 
3.6.1. 
Permitted Concomitant Therapy ................................................... 47 
3.6.2. 
Prohibited Concomitant Therapy .................................................. 47 
3.7. Risks Associated with Acalabrutinib Treatment ........................................... 47 
3.7.1. 
Hemorrhage ................................................................................. 47 
3.7.2. 
Infections ...................................................................................... 48 
3.7.3. 
Cytopenias ................................................................................... 49 
3.7.4. 
Second Primary Malignancies ...................................................... 49 
3.7.5. 
Atrial Fibrillation ............................................................................ 49 
3.7.6. 
Reference Safety Information ....................................................... 49 
3.7.7. 
Dietary Restrictions ...................................................................... 49 
3.7.8. 
Drug-drug Interactions .................................................................. 50 
3.7.9. 
Reproductive Toxicity ................................................................... 51 
3.7.10. 
Overdose Instructions .................................................................. 52 
3.8. Assessment of Dose Limiting Toxicity ......................................................... 53 
3.9. Assessment of QTc Interval Prolongation by Central ECG Testing ............. 53 
3.10. Stopping Rules............................................................................................ 54 
3.11. Dosing Delays and Modifications ................................................................ 55 
3.12. Data and Safety Monitoring ......................................................................... 55 
4. 
STUDY ACTIVITIES AND ASSESSMENTS ......................................................... 55 
4.1. Description of Procedures ........................................................................... 60 
4.2. Investigator’s Assessment of Response to Treatment ................................. 66 
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4.3. Safety Follow-up Visit .................................................................................. 70 
4.4. Missed Evaluations ..................................................................................... 70 
5. 
ASSESSMENT OF SAFETY ................................................................................ 70 
5.1. Definitions ................................................................................................... 71 
5.1.1. 
Adverse Events ............................................................................ 71 
5.1.2. 
Serious Adverse Event ................................................................. 72 
5.1.3. 
Severity ........................................................................................ 73 
5.1.4. 
Adverse Events of Special Interest ............................................... 74 
5.2. Documenting and Reporting of Adverse and Serious Adverse 
Events ............................................................................................... 74 
5.3. Adverse Event Reporting Period ................................................................. 74 
5.4. Assessment of Adverse Events ................................................................... 74 
5.5. Second Primary Malignancies ..................................................................... 75 
5.6. Pregnancy ................................................................................................... 76 
5.7. Expedited Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .................................................... 76 
5.8. Type and Duration of Follow-up of Subjects After Adverse Events .............. 77 
5.9. Hy’s Law ..................................................................................................... 77 
6. 
STATISTICAL METHODS OF ANALYSIS ............................................................ 78 
6.1. General Considerations and Determination of Sample Size ........................ 78 
6.2. Definition of Analysis Populations ............................................................... 79 
6.3. Missing Data Handling ................................................................................ 79 
6.4. Endpoint Data Analysis ............................................................................... 79 
6.4.1. 
Safety Endpoint ............................................................................ 79 
6.4.2. 
Demographics and Baseline Characteristics ................................ 80 
6.4.3. 
Analysis of Efficacy Parameters ................................................... 80 
6.4.4. 
Analysis of Pharmacokinetic / 
 
Parameters .................................................................................. 80 
7. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ..................... 81 
7.1. Regulatory and Ethical Compliance ............................................................ 82 
7.2. Institutional Review Board and Independent Ethics Committee ................... 82 
7.3. Informed Consent and Protected Subject Health Information 
Authorization ...................................................................................... 82 
7.4. Subject Screening Log ................................................................................ 83 
7.5. Case Report Forms ..................................................................................... 83 
7.6. Study Monitoring Requirements .................................................................. 83 
7.7. Investigational Study Drug Accountability .................................................... 84 
7.8. Record Retention ........................................................................................ 85 
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7.9. Protocol Amendments ................................................................................. 86 
7.10. Publication of Study Results........................................................................ 86 
7.11. Clinical Trial Insurance ................................................................................ 86 
7.12. General Investigator Responsibilities .......................................................... 86 
8. 
REFERENCES ..................................................................................................... 88 
 

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LIST OF TABLES 
Table 3-1.  QTc Toxicity Grading Defined by CTCAE .................................................... 54 
Table 4-1.  Schedule of Assessments............................................................................ 57 
Table 4-2.  ECG Acquisition Times ................................................................................ 62 
Table 4-3.  Pharmacokinetic Sample Schedule ............................................................. 65 
Table 4-4.  Response Assessment Criteria for CLL/SLL (modified from 
Hallek 2008) ................................................................................................ 67 
Table 4-5.  Response Assessment Criteria for Richter’s Syndrome 
(Cheson 2014) ............................................................................................ 69 
Table 6-1.  Two-Sided Exact 90% CIs for ORR in Expansion 
Cohorts (N = 30) ......................................................................................... 78 

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LIST OF FIGURES 
Figure 1-1.  NK Cell Natural Cytotoxicity ........................................................................ 29 
Figure 1-2.  In Vivo Thrombus Formation ...................................................................... 30 

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LIST OF APPENDICES 
Appendix 1  Examples of Coadministered Drugs That Need Additional 
Consideration .............................................................................................. 90 
Appendix 2  ECOG Performance Status ........................................................................ 92 
Appendix 3  Adverse Event Assessment of Causality .................................................... 93 
Appendix 4  Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law ......................................................................... 94 
Appendix 5  Management of Study Procedures During Pandemic ................................. 99 
 

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1. 
INTRODUCTION 
1.1. 
Role of BTK in Lymphoid Cancers 
Bruton tyrosine kinase (BTK) is a non-receptor enzyme of the Tec kinase family that is 
expressed among cells of hematopoietic origin, including B cells, myeloid cells, mast 
cells and platelets, where it regulates multiple cellular processes including proliferation, 
differentiation, apoptosis, and cell migration (Mohamed 2009, Bradshaw 2010).  
Functional null mutations of BTK in humans cause the inherited disease, X-linked 
agammaglobulinemia (XLA), which is characterized by a lack of mature peripheral B 
cells (Vihinen 2000).  Conversely, BTK activation is implicated in the pathogenesis of 
several B-cell malignancies (Buggy 2012).  Taken together, these findings have 
suggested that inhibition of BTK may offer an attractive strategy for treating B-cell 
neoplasms. 
Ibrutinib (PCI-32765) (IMBRUVICA®), an oral, small-molecule BTK inhibitor has been 
developed clinically for the treatment for B-cell malignancies and received marketing 
approval in the United States in November 2013 and in the European Union in 
October 2014.  The nonclinical and early clinical findings with ibrutinib have created the 
foundation on which agents, such as acalabrutinib (also known as ACP-196 and 
Calquence®), will be developed.  
In Phase 1/2 clinical testing as a monotherapy in subjects with hematologic malignancies 
(Advani 2013, Byrd 2013, Wang 2013), ibrutinib was generally well tolerated at dose 
levels through 840 mg (the highest dose tested).  No maximum tolerated dose (MTD) 
was apparent within the tested dose range.  Furthermore, subjects typically found the 
drug tolerable over periods extending to > 2 years.  No overt pattern of 
myelosuppression was associated with ibrutinib treatment.  No drug-related reductions in 
circulating CD4+ cells or serum immunoglobulins were noted.  Adverse events (AEs) with 
an apparent relationship to study drug included diarrhea, rash, severe hemorrhage and 
atrial fibrillation. 
While highly potent in inhibiting BTK, ibrutinib has also shown in vitro activity against 
other kinases with a cysteine in the same position as Cys481 in BTK to which the drug 
covalently binds.  The inhibition of epidermal growth factor receptor (EGFR) is also 
observed in cellular assays and may be the cause of ibrutinib-related AEs of diarrhea 
and rash (IMBRUVICA® prescribing information).  In addition, ibrutinib is a substrate for 
CYP3A; inhibition of CYP3A causes a 29-fold increase in maximum concentration (Cmax) 
and 24-fold increase in area under the curve (AUC) for ibrutinib (IMBRUVICA® 

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prescribing information).  This increases the possibility of drug-drug interactions in 
combination therapies with drugs currently used in management of subjects with cancer.  
These liabilities support the development of alternative BTK inhibitors for use in the 
therapy of B-cell malignancies. 
Chemical optimization, pharmacologic characterization, and toxicologic evaluation have 
led to identification of acalabrutinib, an orally administered, new chemical entity that 
covalently inhibits BTK and shows encouraging activity and acceptable safety in 
nonclinical studies.  Acalabrutinib is a potent, highly selective covalent inhibitor of BTK, 
which shows greater kinase selectivity for BTK than ibrutinib in laboratory studies.  Key 
nonclinical differentiators of acalabrutinib versus ibrutinib are: 
Acalabrutinib has been evaluated against ibrutinib in EGFR expressing cell lines.  
Ibrutinib is a potent covalent inhibitor of EGFR (EC50 = 5.3 nM).  Acalabrutinib did not 
inhibit EGFR even at the highest concentration tested (10 μM). 
• 
Acalabrutinib and ibrutinib have been evaluated in natural killer (NK) cell 
functional assays.  While ibrutinib inhibits NK cell functions including 
antibody-dependent cellular cytotoxicity (ADCC), lytic granule release and 
cytokine production (Kohrt 2014), the in vitro functional activity of 
acalabrutinib-treated NK cells was preserved.  
• 
Acalabrutinib has been evaluated against ibrutinib in an in vivo thrombus 
formation model.  Platelets from CLL patients treated with acalabrutinib had 
similar thrombus formation dynamics as platelets from healthy volunteers, while 
platelets from ibrutinib-treated CLL patients had impaired thrombus formation 
(Byrd 2016).  
The nonclinical and toxicology results of acalabrutinib suggest it may have an improved 
therapeutic window relative to ibrutinib; it may be more readily combined with other 
agents for the treatment of cancer.   
1.2. 
Preclinical Studies 
Summaries of preclinical studies are provided below.  For more detailed information 
please refer to the Investigator Brochure. 
1.2.1. 
Chemistry 
  
  
Acalabrutinib is orally bioavailable in animals and human subjects, and is suitable for 
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formulating in capsules.  For clinical testing, acalabrutinib has been manufactured and 
formulated according to current Good Manufacturing Practices (cGMP). 
Calquence® has been approved in the United States and other markets for the treatment 
of adult patients with mantle cell lymphoma (MCL) who have received at least one prior 
therapy, chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL).  
1.2.2. 
Mechanism of Action of Acalabrutinib 
Acalabrutinib was specifically designed to be a more potent and selective inhibitor of 
BTK to avoid off-target side effects as seen with ibrutinib.  When profiled against 
395 human kinases, acalabrutinib is more selective than ibrutinib (Byrd 2016).  For more 
detailed information please refer to the Investigator Brochure. 
1.2.3. 
Dog Lymphoma Study 
Spontaneous canine B-cell lymphoma shares many characteristics with human NHL, 
including diagnostic classifications and response to BTK inhibition (Honigberg 2010).  
The life expectancy in untreated animals with aggressive disease is ~6 weeks, thus 
enabling rapid assessment of drug efficacy (Vail 2004).  Acalabrutinib was evaluated in a 
dose-escalation study in canine spontaneous B-cell lymphoma (Harrington 2016).  
Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib dosages of 
2.5 to 20 mg/kg every 12 or 24 hours.  Acalabrutinib was generally well tolerated, with 
adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, 
diarrhea and lethargy.  Per Veterinary Cooperative Oncology Group criteria for 
assessment of response in peripheral nodal lymphoma (Vail 2010), the overall response 
rate (ORR) was 25% (5/20) with a median progression free survival (PFS) of 22.5 days.  
Clinical benefit was observed in 30% (6/20) of dogs.  These findings suggest that 
acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support 
the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma 
(NHL).  These findings are similar to the clinical responses (i.e., 1 dog with PR out of 
5 dogs treated with suspected or confirmed DLBCL) observed with ibrutinib in dogs with 
spontaneous B-cell lymphoma (Honigberg 2010). 
1.2.4. 
Acalabrutinib and Antibody-dependent Cell-mediated Cytotoxicity 
As acalabrutinib is not an inhibitor of inducible tyrosine kinase (ITK), it is expected to 
have less activity against non-malignant cells that require ITK for development and 
functional activation, such as T and NK cells.  ITK kinase is required for FcR-stimulated 
NK cell function including calcium mobilization, granule release, and overall 
antibody-dependent cell-mediated cytotoxicity (ADCC).  Anti-CD20 antibodies are 

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standard of care drugs, often as part of combination regimens, for the treatment of 
CD20+ B-cell malignancies; obinutuzumab has been specifically designed to increase Fc 
interactions and promote ADCC and phagocytosis of malignant CD20+ cells.  Ibrutinib 
has been evaluated for effects on NK activity, including ADCC, using in vitro assays of 
cytokine release, lytic granule release, and cellular cytotoxicity (Kohrt 2014).  In contrast 
to more specific BTK inhibitors, ibrutinib inhibited all these NK cell functions, and 
impaired NK activity against rituximab-coated autologous CLL cells and in mouse tumor 
models requiring Fc mediated effector functions (Kohrt 2014).  Acalabrutinib was tested 
in ADCC and natural cytotoxicity assays, using cells from healthy donors.  In these in 
vitro tests, NK cell function was preserved with acalabrutinib treatment, whereas ibrutinib 
inhibited functional activity, including natural cytotoxicity against K562 cells. 
Figure 1-1.  NK Cell Natural Cytotoxicity 
 
Peripheral blood mononuclear cells were cultured with 51Cr labelled K562 targets at an E:T ratio of 100:1 for 
4 hours.  Cytotoxicity was evaluated by scintillation counting of supernatants.  Treatment, dose and 
interaction effect were significant in 2-way ANOVA (n=5 healthy donors; ibrutinib vs acalabrutinib 
p < 0.0001; all ibrutinib doses p < 0.0001 compared with control; p = 0.0117 for control vs acalabrutinib 1µM, 
other acalabrutinib doses not statistically different from control condition).   
 
1.2.5. 
Acalabrutinib and Thrombus Formation 
Ibrutinib is associated with an increased risk of bleeding (Kamel 2014).  Hence, the 
effects of acalabrutinib and ibrutinib were evaluated on human platelet-mediated 
thrombus formation by using the in vivo human thrombus formation in VWFHA1 murine 
C o n tr o l 0 .2 5  u M
0 .5  u M
1  u M
0
5 0
1 0 0
K 5 6 2  C y to to x ic ity  (%  L y s is )
A c a la b ru tin ib
Ib ru tin ib

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model, which has been previously described (Chen 2008).  The in vivo function of 
platelets isolated from blood of healthy volunteers (n=5), CLL subjects treated with 
420 mg QD ibrutinib (n=5) or CLL subjects treated with 100 mg BID acalabrutinib (n=3) 
was evaluated in the VWFHA1 model.  Results from this study showed a reduction in 
platelet-vessel wall interactions of platelets from ibrutinib-treated CLL subjects, but not of 
those from CLL subjects treated with acalabrutinib (Byrd 2016). 
Figure 1-2.  In Vivo Thrombus Formation 
 
Platelets from subjects treated with ibrutinib 420 mg once per day (QD) (n=5) or acalabrutinib 100 mg twice 
per day (BID) (n=3) were evaluated for their ability to support thrombus formation in laser injured arterioles 
of VWFHA1 mice.  Freshly isolated platelets from healthy volunteers (n=5) were used as non-drug treated 
controls.  A minimum of 4 arterioles per mouse was used to assess thrombus formation for each 
patient/volunteer sample.  Median fluorescence intensity as a function of time is provided in the figure 
(shading denotes standard error of the median). 
 
1.2.6. 
Safety Pharmacology 
In vitro and in vivo safety pharmacology studies with acalabrutinib have demonstrated a 
favorable nonclinical safety profile.  
When screened at 10 μM in binding assays evaluating interactions with 80 known 
pharmacologic targets such as G-protein-coupled receptors, nuclear receptors, 
proteases, and ion channels, acalabrutinib shows significant activity only against the A3 
adenosine receptor; follow-up dose-response experiments indicated a IC50 of 1.5 µM, 
suggesting a low clinical risk of off-target effects.  Acalabrutinib at 10 μM showed no 
inhibition of in vitro EGFR phosphorylation in an A431 human epidermoid cancer cell line 
whereas ibrutinib had an IC50 of 66 nM.  

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The in vitro effect of acalabrutinib on human ether-à-go-go-related gene (hERG) channel 
activity was investigated in vitro in human embryonic kidney cells stably transfected with 
hERG.  Acalabrutinib inhibited hERG channel activity by 25% at 10 μM, suggesting a low 
clinical risk that acalabrutinib would induce clinical QT prolongation as predicted by this 
assay. 
Acalabrutinib was well tolerated in standard in vivo Good Laboratory Practices (GLP) 
studies of pharmacologic safety.  A functional observation battery in rats at doses of 
through 300 mg/kg (the highest dose level) revealed no adverse effects on 
neurobehavioral effects or body temperature at any dose level.  A study of respiratory 
function in rats also indicated no treatment-related adverse effects at doses through 
300 mg/kg (the highest dose level).  In a cardiovascular function study in awake 
telemeterized male beagle dogs, single doses of acalabrutinib at dose levels through 
30 mg/kg (the highest dose level) induced no meaningful changes in body temperature, 
cardiovascular, or electrocardiographic (ECG) (including QT interval) parameters.  The 
results suggest that acalabrutinib is unlikely to cause serious off-target effects or 
adverse effects on critical organ systems. 
1.2.7. 
Drug-drug Interaction Potential 
Based on available nonclinical and clinical data, acalabrutinib is metabolized by CYP3A, 
GSTM1/M2 and amide hydrolysis.  CYP3A -mediated oxidation appears to be the major 
route of metabolism in humans.  In a healthy volunteer study (ACE-HV-001), the effect of 
coadministration of a strong CYP3A and P-glycoprotein inhibitor, itraconazole, on the 
plasma levels of acalabrutinib was evaluated.  The mean plasma acalabrutinib Cmax and 
AUC0-inf values increased 3.7- and 5.1-fold, respectively, in the presence of itraconazole 
relative to no pretreatment. 
Based on results from study ACE-HV-112, consumption of grapefruit juice, which can 
result in CYP3A inhibition, will not result in substantially increased exposure to 
acalabrutinib.  Therefore, restrictions on grapefruit juice or Seville orange consumption 
are not necessary. 
In a healthy volunteer study (ACE-HV-004), rifampin, a strong CYP3A inducer, dosed at 
 decreased AUC to 23% of values obtained with acalabrutinib 
dosed alone.  PBPK modeling predicted the magnitude of changes due to a variety of 
moderate CYP3A inducers and inhibitors.  
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Results from studies in healthy subjects, ACE-HV-004 and ACE-HV-112, showed that 
drugs that reduce gastric acidity can lower acalabrutinib exposure.  
Acalabrutinib is unlikely to be a perpetrator of a drug-drug interaction at the level of 
inhibition or induction of CYP isoforms.  
Acalabrutinib co-administration may increase exposure to breast cancer-related protein 
(BCRP) substrates by inhibition of intestinal BCRP. 
For more detailed information, please refer to the Investigator Brochure. 
1.2.8. 
General Toxicity Studies 
The systemic toxicity of acalabrutinib has been fully evaluated in repeat-dose 
sub-chronic studies in mice, rats and dogs, reproductive toxicity studies in rats and 
rabbits, and ongoing chronic studies in rats and dogs.  The pivotal GLP studies were 
28- and 91-day repeat dose studies in rats and dogs, each with recovery periods to 
assess the reversibility of observed changes.  Refer to the Acalabrutinib Investigator 
Brochure for a detailed review of the nonclinical toxicology program. 
In rats, 100 mg/kg/day was selected initially to represent the highest non-severely toxic 
dose; however, in subsequent studies the 100 mg/kg/day dose level was determined to 
be a no observable adverse effect level (NOAEL).  In rats, the target organs of toxicity 
were the kidney, liver and heart.   
The NOAEL in the dog was 30 mg/kg/day; dose levels higher than 30 mg/kg/day were 
not tolerated.  In dogs, the target organs of toxicity, observed only at doses exceeding 
the MTD, were the kidney and liver.  Heart findings were also observed in 2 dogs with 
kidney toxicity, which were interpreted as possibly secondary to uremia, as has been 
reported for this species. 
In rats and dogs, no adverse ECG or histopathologic cardiovascular effects were noted 
at the planned conclusion of the sub-chronic studies or in the rat chronic toxicity study.  
However, in 5 of 6 rats from the 4-week study that died early at 300 mg/kg/day, slight to 
moderate necrosis of the myocardium and/or white blood cell infiltration/inflammation of 
the myocardium were noted on microscopic examination of the hearts.   
1.3. 
Clinical Experience 
1.3.1. 
Pharmacokinetics and Pharmacodynamics of Acalabrutinib in Healthy 
Volunteers 
ACE-HV-001 was a PK/pharmacodynamic (PD), dose-ranging, food-effect, and 
drug-drug interaction study evaluating 
 in healthy 
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volunteers.  This study evaluated the PK/PD of acalabrutinib at various dose levels and 
regimens.  The starting dose for acalabrutinib was 
  This study has been 
completed and no adverse laboratory, vital signs, or ECG findings were observed 
 
  Three adverse events (AEs) related to study drug were 
reported.  Each AE was Grade 1 and resolved without treatment.  The AEs were 
constipation 
 feeling cold 
 and somnolence 
 
In Part 1, PK properties of acalabrutinib were evaluated after oral administration of 
  Of the 30 subjects 
evaluated, all had observed systemic concentrations of acalabrutinib.  Acalabrutinib 
plasma time to maximum concentration (Tmax) values were between 0.5 and 1.0 hour for 
all dose cohorts and were independent of dose level.  The increase in mean Cmax values 
was greater than dose proportional based on the increases of Cmax from the first dose 
administered.  When evaluating AUC0-12, AUC0-24 or AUC0-inf, the mean values increased 
in a dose-proportional manner based on the increases of the total dose administered.  
Mean half-life (t1/2) values ranged from 0.97 to 2.1 hours, and appeared to decrease as 
the dose increased.  The mean calculated oral clearance (CL/F: 165 to 219 L/h) and 
volume of distribution values (Vz/F: 233 to 612 L) appeared to be independent of the 
dose administered. 
Acalabrutinib was not detected in the urine of subjects receiving the 
 
doses of acalabrutinib.  Acalabrutinib was detected in urine of other subjects (0.4% to 
0.6% of dose) and amounts increased in a dose dependent manner. 
In Part 2, the effect of food on the PK of acalabrutinib 
 after a single oral 
administration was evaluated in 6 men and 6 women.  Median time to maximum plasma 
acalabrutinib (Tmax) values were increased in the fed state (2.5 hours) relative to the 
fasted state (0.5 hour).  The mean plasma acalabrutinib Cmax fed values decreased to 
27.3% of the Cmax values observed in the fasted state.  In contrast, the relative AUC 
exposure of acalabrutinib remained mostly unchanged in both states.  This decrease in 
exposure is not clinically significant; therefore, acalabrutinib can be taken without regard 
to meals. 
In Part 3, the effect of itraconazole on the PK of acalabrutinib 
 after a single oral 
administration was evaluated in 17 subjects.  No difference in acalabrutinib Tmax values 
was observed in the presence or absence of itraconazole. 
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Mean acalabrutinib exposures (as assessed by Cmax, AUC0-last, AUC0-24, and AUC0-inf) 
increased in the presence of itraconazole.  The mean plasma acalabrutinib Cmax values 
increased 3.7-fold in the presence of itraconazole.  The mean plasma AUC0-last, AUC0-24, 
and AUC0-inf values also increased between 4.9- to 5.1-fold in the presence of 
itraconazole.  Mean CL/F and Vz/F values decreased in the presence of itraconazole 
(CL/F: 217 vs 44 L/h; Vz/F: 1190 vs 184 L).  No differences in half-life values were 
observed (3.3 vs 2.5 hours). 
The PD of acalabrutinib was evaluated using a BTK occupancy assay and correlated 
with a functional assay that determines the level of BTK inhibition by measuring 
expression of CD69 and CD86 on B cells.  A dose-dependent increase in BTK 
occupancy and corresponding decrease in CD69 and CD86 expression was observed in 
this study.  Full BTK occupancy (≥ 90%) and complete CD86 and CD69 inhibition 
(≥ 90%) occurred at the 
 cohorts 1 to 3 hours after 
administration.  However, only the 
 maintained high BTK occupancy 
(91.5%) and high BCR functional inhibition (CD86: 86 ± 3% and CD69: 78 ± 8%) at 
24 hours.  For subjects receiving a 
 of acalabrutinib 
 
 full BTK target occupancy was observed 
 
 cohort (BTK occupancy 97 ± 4%). 
For more detailed information, please refer to the Investigator Brochure. 
1.3.2. 
Clinical Experience of Acalabrutinib in CLL 
No new safety concerns were identified for acalabrutinib monotherapy based on safety 
data available to date.  The safety data of acalabrutinib monotherapy are consistent 
among studies.  For detailed information on the clinical experience for acalabrutinib, 
refer to the Investigator Brochure.  
1.4. 
Risks/Benefits 
Acalabrutinib is a potent, orally bioavailable small-molecule inhibitor of BTK.  A PK/PD 
study has been completed with acalabrutinib in healthy volunteers (ACE-HV-001; 
Section 1.3).  The safety results showed no safety risk was identified in healthy subjects 
receiving 
 of ACP 196 
  In the dose escalation portion of CLL study 
ACE-CL-001, no DLTs have been identified at dosages of 
 
  The response rate in the evaluable subjects for this study is currently 
an ORR of 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 
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activity as a single agent in the treatment of subjects with relapsed or refractory CLL/SLL 
including those with 17p del.  Based on these results, addition of expansion cohorts of 
various treatment subgroups is warranted to further evaluate the efficacy and safety of 
acalabrutinib.  The Phase 2 portion of this study also increases the number of subjects 
with previously treated or untreated CLL at the planned Phase 3 dosage of 
 
1.5. 
Summary and Conclusions 
This study comprises evaluation of the safety and activity of a potent, highly selective, 
BTK inhibitor, acalabrutinib, in subjects with previously treated or untreated CLL/SLL or 
Richter’s syndrome.  The design and conduct of this study is supported by an 
understanding of the natural history and current therapies for subjects with CLL/SLL; 
knowledge of the activity and safety of the first-generation BCR inhibitor (i.e., ibrutinib) in 
subjects with B-cell malignancies; and the available nonclinical and clinical information 
regarding acalabrutinib.  Clinical studies have shown that acalabrutinib is an orally 
bioavailable BTK inhibitor with fast absorption and rapid clearance that maintains optimal 
target coverage over 24 hours with a dosage of 
  Acalabrutinib has been 
well tolerated in healthy volunteers and subjects with CLL or Richter’s syndrome.  
Despite poor prognostic characteristics in the CLL study population, acalabrutinib has 
induced sustained decreases in lymphadenopathy and provides more rapid reduction 
and/or resolution of lymphocytosis than ibrutinib.  No specific drug-related toxicity has 
been identified to date for acalabrutinib. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
• 
Establish the safety and the MTD of orally administered acalabrutinib in subjects 
with CLL/SLL.  
• 
Determine pharmacokinetics (PK) of orally administered acalabrutinib and 
identification of its major metabolite 
2.2. 
Secondary Objective 
• 
Evaluate tumor response by ORR, DOR, and PFS 
2.3. 
Exploratory Objective 
• 
 
3. 
INVESTIGATIONAL PLAN 
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3.1. 
Overall Study Design 
3.1.1. 
Escalation Portion – Phase 1 
This study is a multicenter (approximately 15 global centers), open-label, 
nonrandomized, sequential group, dose-escalation study.  The following dose cohorts 
will be evaluated as part of the dose-escalation portion of the study: 
 Dosing Cohorts 
Cohort 1: 
 
Cohort 2a: 
 
Cohort 3: 
 
Cohort 4a: 
 
 Dosing Cohorts 
Cohort 2b: 
 
Cohort 4b: 
 
DLT reviews have occurred for all cohorts and no DLTs were observed.  Consequently, 
no maximum tolerated dose (MTD) has been reached.  Expansion of Cohort 2b is 
described below in the Phase 2 portion of the study.  Under Amendment 6 of the 
protocol, subjects in Cohort 4b 
 will be transitioned to 
 (i.e., the dosage of acalabrutinib for Phase 3 studies).  Subjects in Cohort 3 
had been transitioned to 
 under Amendment 4 of the protocol, and subjects 
in Cohorts 1, 2a, and 4a had been transitioned to 
 under Amendment 5 of 
the protocol.  Any subjects not switched to 
 will need to be reviewed with the 
medical monitor. 
3.1.2. 
Expansion Cohorts – Phase 2 
Due to the promising safety and efficacy data observed to date on the study, an 
expansion cohort of 
 (Cohort 2c) was added under Amendment 4 of the 
protocol.  In support of the planned Phase 3 program for acalabrutinib, Cohort 2b 
 is being expanded from 30 to approximately 65 subjects to further assess 
the safety and efficacy of this regimen in subjects with relapsed/refractory CLL/SLL.  
Therefore, the dosing regimens being evaluated in the Phase 2 portion of this protocol 
for subjects with previously treated CLL are as follows: 
• 
Cohort 2b is 
 (N = 65, approximately); this dose level is the planned 
dosage for Phase 3 studies with acalabrutinib in subjects with CLL. 
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• 
Cohort 2c is 
 (N = 30); under Amendment 6 of the protocol, subjects 
in Cohort 2c will be transitioned to 
 
This protocol also includes the following patient subgroups: 
Treatment Naive Group: Under Amendment 5, these subjects have been expanded 
from 60 to 90.  This group consists of 90 subjects who are treatment-naive and require 
treatment for CLL and a) do not want to receive chemoimmunotherapy or b) have 
comorbidities that would preclude chemoimmunotherapy.  The planned dosages for this 
group are: 
• 
Cohort 7 is 
 (N = 11 to 30); under Amendment 6 of the protocol, 
subjects in Cohort 7 were transitioned to 
 
• 
Cohort 11 is 
 (N = 11 to 60) 
Ibrutinib Intolerant (Cohort 8): A group of up to 35 subjects who experienced an 
ibrutinib-related adverse event (AE) and are not tolerating ibrutinib because of the AE.  
Examples of ibrutinib-related AEs include, but are not limited to, diarrhea, fatigue, 
arthralgia, rash, peripheral edema, bleeding events, atrial fibrillation, and blurry vision 
(Byrd 2013, Byrd 2014).  These AEs are likely related to off-target effects of ibrutinib 
including inhibition of epidermal growth factor receptor (EGFR).  As described in 
Section 1.2, acalabrutinib was designed to be a more selective molecule than ibrutinib 
and as such acalabrutinib has a better preclinical and, to date, clinical safety profile than 
ibrutinib.  Therefore, subjects who did not tolerate ibrutinib may fare better on 
acalabrutinib.  The planned dosage for this group is 
 based on the safety and 
PK/PD observed with acalabrutinib 
 (Section 1.3).  This dose regimen has a 
lower Cmax of acalabrutinib while providing full BTK occupancy for 24 hours. 
Richter’s Syndrome/Prolymphocytic Leukemia Transformation Group (Cohort 9):  
A group of up to 30 subjects with Richter’s syndrome or prolymphocytic leukemia 
transformation.  Richter’s syndrome is a transformation from CLL to DLBCL, which 
occurs in 5% to 10% of patients.  The median survival is 4 to 5 months for patients 
diagnosed with Richter’s syndrome (Jandl 1996).  Prolymphocytic leukemia 
transformation is manifested by the presence of > 50% of B-cell prolymphocytes in the 
peripheral blood and is a more aggressive disease state (Absi 2005).  The planned 
dosage for this group is 
 based on the safety observed with acalabrutinib 
  The 
 is supported by preliminary results from an ongoing study 
of acalabrutinib in spontaneous canine lymphoma, which is similar to human DLBCL.  
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Preliminary results from the canine study showed that BID dosing reversed progression 
in dogs receiving QD dosing and also produced more durable responses 
(Gardner 2014).  In addition, preliminary results assessing BTK occupancy using a 
biotin-tagged analogue of acalabrutinib show near complete BTK occupancy over 
24 hours with 
 compared with 
 (Section 1.3.2).  Therefore, 
 
 may ensure BTK inhibition for the entire 24 hours including inhibition of any newly 
synthesized BTK; this may be beneficial in terms of increased efficacy and/or decreased 
development of resistance to acalabrutinib in aggressive tumors. 
Ibrutinib R/R Group (Cohort 10):  A group of up to 6 subjects with CLL refractory to or 
relapsed after ibrutinib therapy when administered per the ibrutinib prescribing 
information (i.e., 
  Refractory subjects will be defined as subjects whose 
best response to ibrutinib was SD after 
 of therapy or did not respond to therapy.  
Relapsed subjects will be defined as subjects who initially responded to ibrutinib therapy 
but then developed signs of clinical progression.  The planned dosage for this group is 
 based on the safety observed with 
  As described above, BID 
dosing may ensure BTK inhibition for the entire 24 hours including inhibition of any newly 
synthesized BTK; this may be beneficial in terms of increased efficacy with acalabrutinib 
in comparison with ibrutinib QD. 
Treatment with acalabrutinib may be continued for 
 until disease progression 
or an unacceptable drug-related toxicity occurs.  Subjects who meet criteria of disease 
progression and are continuing to gain clinical benefit from therapy may be able to 
temporarily remain on acalabrutinib after discussion with the medical monitor.  All 
subjects who discontinue study drug will have a safety follow-up visit 30 (+ 7) days after 
the 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.  
For all cohorts except Cohort 9, radiologic tumor assessment will be done at screening 
and at the end of Cycle 2, Cycle 4, and Cycle 6, then every 6 cycles until Cycle 36, and 
then every 12 cycles thereafter.  For subjects in Cohort 9, radiologic tumor assessment 
will be done at screening and at the end of Cycle 2, Cycle 4, Cycle 6, Cycle 9, Cycle 12, 
Cycle 15, Cycle 18, Cycle 21, Cycle 24, and every 6 cycles thereafter.  Otherwise, 
radiologic tumor assessments are done at investigator discretion.  Confirmation of 
complete response (CR) will require bone marrow analysis and radiologic tumor 
assessment (as applicable for subjects in Cohort 9).  For subjects who remain on study 
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for > 11 months, a mandatory bone marrow aspirate and biopsy is required in Cycle 12 
concurrent with the radiologic tumor assessment.   
Note: Under amendment 9 of this protocol, subjects in all cohorts will synchronize their 
clinic visits and laboratory assessments (excluding the HBV testing that will be every 3 
cycles regardless of the imaging/clinic frequency) with the new imaging scheduled visits. 
In the event disease progression is suspected due to physical examination or laboratory 
test, a CT scan must be performed to confirm disease progression.  If the sole lesion lies 
within the field of prior radiotherapy, there must be evidence of disease progression in 
that lesion. 
All subjects will have standard hematology, chemistry, and urinalysis safety panels done 
at screening.  This study also includes pancreatic function assessment (serum amylase 
and serum lipase) through Cycle 6 due to the pancreatic findings in the 28-day GLP rat 
toxicity study.  This study also includes cardiac troponin testing through Cycle 6 and 
echocardiograms at screening and at end of Cycle 6.  Once dosing commences, all 
subjects will be evaluated for safety once weekly for the first 4 weeks, every other week 
for Cycle 2, and monthly thereafter.  Blood samples will be collected for PK/PD 
assessments in Cycle 1.  ECGs will be done at screening, and on Day 1-2, 8, 15, 22, 28 
of Cycle 1, Day 15 and 28 of Cycle 2, and monthly thereafter through Cycle 6 for a 
subset of subjects from the dose escalation portion of the study only.  ECGs are done in 
triplicate for screening only.  Thereafter, single ECGs are done unless a repeat ECG is 
required (see Section 4.1 for a more detailed description of ECG assessments).  
Note:  The Phase 1 portion of the study has been closed, therefore the intensive ECG 
schedule for the subjects in the dose-escalation cohorts has been completed.   
 
  
 
Refer to Table 4-1 for a comprehensive list of study assessments and their timing.   
3.1.3. 
End of Study 
The study duration is approximately 7 years, until final data cutoff (DCO); approximately 
>5 years, until last subject last visit (LSLV) (total of >12 years). 
The final data cutoff (DCO) in support of final database lock will occur approximately 
63 cycles after the last subject was administered the first dose of investigational product.  
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Final data analysis will be performed and a CSR will be written based on the final 
database lock.   
The end of study is defined as the date of the last visit of the last subject in the study.   
After the final DCO, the following applies to subjects who are still on treatment and, in 
the Investigator’s opinion, deriving clinical benefit: 
• 
Where acalabrutinib is commercially available and reasonably accessible, 
subjects will be transitioned off study, and treatment will continue outside of the 
study protocol, per local laws and regulations.  
• 
Where acalabrutinib is not commercially available or not reasonably accessible, 
subjects may be re-consented to continue within this study to receive 
acalabrutinib in line with standards of care through a continued treatment period 
(managed by the sponsor's Post Analysis and Reporting Team [PART] program) 
as long as, in the Investigator's opinion, the subject is deriving clinical benefit and 
has not fulfilled any discontinuation criteria. 
After the DCO, all subjects’ medical procedures and assessments will continue to 
be documented in the subject’s medical records, but only SAEs will be reported 
using a paper form. Of the data collected at the study site after the final DCO, 
only SAEs will be reported.  
Investigational product dispensation and reconciliation will be handled by the study site 
at each subject’s visit.  The investigational product accountability information must still 
be collected until all subjects have completed treatment.   
3.2. 
Study Parameters 
3.2.1. 
Efficacy Parameters 
• 
ORR by investigator assessment 
• 
DOR by investigator assessment 
• 
PFS by investigator assessment 
3.2.2. 
Safety Parameters 
• 
DLTs and MTD 
• 
Frequency, severity, and attribution of AEs 

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3.2.3. 
Pharmacokinetic and 
 Parameters 
A description of the pharmacokinetic parameters for acalabrutinib and its major 
metabolite in plasma are provided in Section 6.4.4. 
 
 
  
3.3. 
Rationale for Study Design and Dosing Regimen 
The starting acalabrutinib dose of 
 was selected based on the United States 
Food and Drug Administration (FDA) Guidance:  Estimating the Maximum Safe Starting 
Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (MSSD), and 
Nonclinical Evaluation for Anticancer Pharmaceuticals (ICH S9) (FDA 2005, FDA 2010).  
Standard GLP 28-day nonclinical systemic toxicity studies in rats and dogs were 
conducted in support of this trial.  The no observable adverse effect level in the dog was 
30 mg/kg/day, which was the highest dose evaluated.  In rats, 30 mg/kg/day resulted in 
minimal inflammation of the pancreas in some animals, with reversal, indicating the rat to 
be the more sensitive preclinical species.  The pancreatic effects were minimally 
increased at 100 mg/kg/day in the rat though there was no clinical evidence of toxicity.  
Hence, the 100 mg/kg/day was selected to conservatively represent the highest 
non-severely toxic dose (HNSTD).  Following the S9 guidance and using conversion 
factors from Table 1 in the MSSD guidance, the conversion factor for mg/kg to mg/m2 for 
rodents is 6, which converts to 600 mg/m2 in rats.  The starting human dose for oncology 
would be one-tenth the HNSTD, 60 mg/m2, 
 
  
The Phase 1, dose-escalation portion of the study in subjects with relapsed/refractory 
CLL was completed.  As no DLTs occurred during Phase 1 and escalation beyond 
 was not warranted based on PK results, the Phase 2 expansion portion of 
the protocol was initiated, as described in Section 3.1.2.  To date, all dose regimens 
evaluated have been well tolerated.  No drug-related toxicity had been identified.   
3.4. 
Selection of Study Population 
3.4.1. 
Inclusion Criteria  
To be eligible to participate in this study, a subject must meet the following criteria: 
1. Men and women ≥ 18 years of age with a confirmed diagnosis of CLL/SLL, which 
has relapsed after, or been refractory to, ≥ 2 previous treatments for CLL/SLL. 
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2. Must have measurable CLL/SLL defined as ≥ 1 lymph node ≥ 2 cm as measured 
in the longest diameter. 
3. Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring 
treatment: 
a. 
Evidence of progressive marrow failure as manifested by the 
development of, or worsening of, anemia (hemoglobin < 10 g/dL) and/or 
thrombocytopenia (platelets < 100,000/μL). 
b. 
Massive (i.e., ≥ 6 cm below the left costal margin), progressive, or 
symptomatic splenomegaly. 
c. 
Massive nodes (i.e., ≥ 10 cm in the longest diameter), progressive, or 
symptomatic lymphadenopathy. 
d. 
Progressive lymphocytosis with an increase of > 50% over a 2-month 
period or a lymphocyte doubling time (LDT) of < 6 months.  LDT may be 
obtained by linear regression extrapolation of absolute lymphocyte counts 
(ALC) obtained at intervals of 2 weeks over an observation period of 2 to 
3 months.  In subjects with initial blood lymphocyte counts of < 30 x 109/L 
(30,000/μL), LDT should not be used as a single parameter to define 
indication for treatment.  In addition, factors contributing to lymphocytosis 
or lymphadenopathy other than CLL (e.g., infections) should be excluded. 
e. 
Autoimmune anemia and/or thrombocytopenia that is poorly responsive to 
standard therapy. 
f. 
Constitutional symptoms documented in the subject’s chart with 
supportive objective measures, as appropriate, defined as ≥ 1 of the 
following disease-related symptoms or signs: 
i. 
Unintentional weight loss ≥ 10% within the previous 6 months 
before Screening 
ii. 
Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before 
Screening without evidence of infection 
iii. 
Night sweats for > 1 month before screening without evidence of 
infection 
4. ECOG performance status of ≤ 2. 
5. Agreement to use highly effective methods of contraception during the study and 
for 2 days after the last dose of study drug if sexually active and able to bear or 
beget children (see Section 3.7.9 for list of highly effective methods of 
contraception).   
6. Willing and able to participate in all required evaluations and procedures in this 
study protocol including swallowing capsules without difficulty. 
7. Ability to understand the purpose and risks of the study and provide signed and 
dated informed consent and authorization to use protected health information (in 
accordance with national and local subject privacy regulations). 
8. Removed at Amendment 11. 
 

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3.4.2. 
Inclusion Criteria for Treatment Subgroups 
Subjects meeting the following criteria will be eligible for the indicated Treatment 
Subgroups.  In addition, Inclusion Criteria 2 to 8 from Section 3.4.1 apply to the 
Treatment Subgroups as well. 
1. Treatment Naive only: Men and women ≥ 18 years of age with confirmed 
diagnosis of CLL/SLL, who require treatment per National Cancer Institute or 
International Working Group guidelines and a) do not want to receive 
chemoimmunotherapy or b) have comorbidities that would preclude 
chemoimmunotherapy. 
2. Ibrutinib Intolerant only: Men and women ≥ 18 years of age with confirmed 
diagnosis of CLL/SLL who are not tolerating ibrutinib due to ibrutinib-related AEs. 
3. Richter’s Syndrome and Prolymphocytic Leukemia Transformation only: 
Men and women ≥ 18 years of age with biopsy proven DLBCL Richter's 
transformation or prolymphocytic leukemia transformation. 
4. Ibrutinib R/R only: Men and women ≥ 18 years of age with confirmed diagnosis 
of CLL/SLL whose best response after 2 cycles of ibrutinib therapy was SD or 
nonresponse or who initially responded to ibrutinib therapy and now have signs 
of clinical progression. 
3.4.3. 
Exclusion Criteria 
A subject meeting any of the following criteria will be excluded from this study: 
1. Prior malignancy, except for adequately treated basal cell, squamous cell skin 
cancer or in situ cervical cancer.  Subjects with other prior malignancies from 
which the subject has been disease free for ≥ 2 years may be included if 
approved by the medical monitor. 
2. A life-threatening illness, medical condition or organ system dysfunction which, in 
the investigator’s opinion, could compromise the subject’s safety, interfere with 
the absorption or metabolism of acalabrutinib, or put the study outcomes at 
undue risk. 
3. Significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of 
screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart 
Association Functional Classification, or left ventricular ejection fraction (LVEF) 
≤ 40%. 
4. Malabsorption syndrome, disease significantly affecting gastrointestinal function, 
or resection of the stomach or small bowel, symptomatic inflammatory bowel 
disease, partial or complete bowel obstruction, or gastric restrictions and bariatric 
surgery, such as gastric bypass. 
5. Any immunotherapy within 4 weeks of first dose of study drug. 
6. For subjects with recent chemotherapy or experimental therapy the first dose of 
study drug must occur after 5 times the half-life of the agent(s). 
7. Relapsed after, or refractory to, prior BTK inhibitor therapy (Note:  Does not apply 
to Ibrutinib R/R or Richter’s Syndrome Group). 

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8. Any history of Richter's transformation (Note:  Does not apply to Richter’s 
Syndrome Group). 
10. Central nervous system (CNS) involvement by lymphoma. 
11. Grade ≥ 2 toxicity (other than alopecia) continuing from prior anticancer therapy 
including radiation. 
12. Known history of human immunodeficiency virus (HIV) or serologic status 
indicating active hepatitis C virus (HCV) or hepatitis B virus (HBV) infection or 
any uncontrolled active systemic infection.  Subjects with hepatitis B core 
antibody positive who are surface antigen negative or who are hepatitis C 
antibody positive will need to have a negative PCR result before enrollment.  
Those who are hepatitis B surface antigen positive or hepatitis B PCR positive 
and those who are hepatitis C PCR positive will be excluded. 
13. Uncontrolled AIHA or 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 daily or equivalent). 
14. History of stroke or intracranial hemorrhage within 6 months prior to the first dose 
of study drug. 
15. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). 
16. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., 
phenprocoumon) within 7 days of first dose of study drug. 
17. Major surgery within 4 weeks before first dose of study drug. 
18. 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 ULN (total bilirubin ≤ 2.5 x ULN allowed in subjects with 
autoimmune hemolytic anemia that is otherwise controlled); AST or ALT > 3.0 x 
ULN unless disease related. 
20. Serum amylase > 1.5 x ULN or serum lipase > 1.5 x ULN.  
21. Significant screening ECG abnormalities including 2nd degree AV block type II, 
3rd degree block, Grade 2 or higher bradycardia, or QTc ≥ 480 ms. 
22. Cardiac troponin I levels above the limit of normal as specified by the 
manufacturer. 
23. Breast feeding or pregnant. 
24. History of bleeding diathesis (e.g., hemophilia, von Willebrand disease). 
25. Concurrent participation in another therapeutic clinical trial. 
26. Estimated creatinine clearance of < 30 mL/min, calculated using the formula of 
Cockcroft and Gault [(140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 
0.85 if female]. 
27. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months 
before screening. 
3.4.4. 
Replacement of Subjects 
Subjects who meet any of the following criteria will be replaced: 

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• 
Did not receive at least 21 of 28 doses in Cycle 1, unless due to DLT or 
another safety-related issue 
• 
Did not undergo a DLT assessment at the start of Cycle 2 
• 
Discontinued treatment during Cycle 1 for reasons other than DLT 
It is not necessary to replace subjects if ≥ 4 subjects in a cohort have completed Cycle 1 
without a DLT. 
3.4.5. 
Enrollment Procedures 
Enrollment of a subject into the study will be performed according to the following 
procedure:  
• 
Notify the sponsor when a clinically eligible subject is identified to receive current 
dose level information and ensure availability on study. 
• 
After the subject has signed and dated the Informed Consent Form (ICF), 
eligibility has been confirmed, and all screening procedures have been 
completed, and if deemed eligible for entry, the subject can be officially enrolled 
in the study.  
• 
To enroll a subject, the study center will fax/email a completed Enrollment Form 
to the sponsor.  The enrollment date will be the date that the form is 
faxed/emailed to the sponsor. 
• 
An Enrollment Confirmation Form will be completed and faxed/emailed to the 
study center by the sponsor within 24 hours. 
Treatment must begin within 10 days after the enrollment form is faxed or emailed to the 
sponsor. 
3.5. 
Study Drug: Acalabrutinib Hard Gelatin Capsule 
3.5.1. 
Premedications 
No premedications are required for administration of acalabrutinib.   
3.5.2. 
Formulation, Packaging, and Storage 
Acalabrutinib drug substance and drug product are manufactured according to cGMP 
and will be provided to the investigational site by Acerta Pharma or a designee.  
Acalabrutinib should be stored according to the instructions on the label that is affixed to 
the package of the drug product.  Acalabrutinib will be provided in white, high-density 
polyethylene bottles.  
If a drug shipment arrives damaged, or if there are any other drug complaints, a Product 
Complaint Form should be completed and e-mailed or faxed to the sponsor or the 
sponsor’s representative.  Refer to the Investigator Brochure for additional information 
regarding the drug product to be used in this trial. 

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3.5.3. 
Administration of Acalabrutinib  
Investigators are prohibited from supplying acalabrutinib to any subjects not properly 
enrolled in this study.  The investigator must ensure that subjects receive acalabrutinib 
only from personnel who fully understand the procedures for administering the drug. 
Acalabrutinib is intended to be administered orally once or twice daily with 8 ounces 
(approximately 240 mL) of water.  The capsules should be swallowed intact and subjects 
should not attempt to open capsules or dissolve them in water.  Acalabrutinib can be 
taken with or without meals. 
It is recommended that acalabrutinib be taken as close to the scheduled time as possible 
(preferably within ± 1 hour).  However, if a dose is missed, it can be taken up to 3 hours 
after the scheduled time with a return to the normal scheduled time the following day.  If 
it has been greater than 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. 
3.5.4. 
Assuring Subject Compliance 
Refer to Table 4-1 and Section 4.1 for doses that must be administered in the clinic to 
comply with predose and postdose PK/PD measurements and /or ECG assessments.  
For treatments that are taken in the clinic, subjects should take the dose from the drug 
dispensed for them for that particular time period.  All other treatments will be taken at 
home.  Subjects will receive a diary to record the specific time each dose was taken and 
to record reasons for any missed doses.   
Subject compliance will be assessed at every visit.  The subject will be instructed to 
bring the diary and any remaining capsules to the clinic at their next visit.  The 
administrator will review the diary and ask the subject if all of the capsules were 
administered.  Any remaining or returned capsules will be counted and recorded as 
described in Section 7.7.  Returned capsules must not be redispensed to the same 
subject or to another subject.  The study staff will resupply the subject with the correct 
number of capsules needed for use until the next visit. 
3.5.5. 
Study Treatment Schedule 
Subjects will receive study treatment as detailed in Section 3.5.3 and assessments will 
be performed as outlined in the Schedule of Assessments (Table 4-1).  Subjects with 
stable disease or tumor response may continue on therapy until disease progression 

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(radiologic or clinical) or until the investigator considers the study treatment to be no 
longer tolerable or in the subject’s best interest. 
Intrapatient dose escalation from 
 may be allowed on this protocol 
with discussion and approval from the medical monitor. 
3.6. 
Concomitant Therapy 
3.6.1. 
Permitted Concomitant Therapy 
Antiemetics are permitted if clinically indicated.  Standard supportive care medications 
are permitted as per institutional standards.  Use of hematopoietic growth factors is 
permitted per the American Society of Clinical Oncology (ASCO) guidelines 
(Smith 2015).   
For subjects considered at risk for tumor lysis syndrome: Administer appropriate 
hydration and allopurinol or rasburicase per institutional standards prior to initiating 
treatment. 
3.6.2. 
Prohibited Concomitant Therapy 
Any chemotherapy (e.g., bendamustine, cyclophosphamide, pentostatin, or fludarabine), 
immunotherapy (e.g., rituximab, GA101, alemtuzumab, or ofatumumab), kinase 
inhibitors (e.g., ibrutinib and idelalisib), bone marrow transplant, experimental therapy, 
and radiotherapy are prohibited if being used to treat the disease initially under 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.  Likewise, 
other anticancer therapy may be allowed following discussion with the medical monitor.  
However, high-dose corticosteroids used to treat underlying CLL are not allowed on 
study. 
3.7. 
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 Brochure. 
3.7.1. 
Hemorrhage 
Serious hemorrhagic events, including fatal events, have occurred in clinical trials 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 
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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. 
3.7.2. 
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. 
Refer to Section 3.7.2.1and Table 4-1 for additional information and monitoring guidance 
for viral hepatitis and Section 3.7.2.2 for additional information and management 
guidance for signs and symptoms of PML. 
3.7.2.1. 
Hepatitis B Virus Reactivation 
Cases of hepatitis B virus (HBV) reactivation have occurred in clinical studies with 
acalabrutinib.  Therefore, subjects with a history of HBV infection should be monitored 
every 3 months with a quantitative PCR test for HBV DNA.  Monitoring every 3 months 
should continue until 12 months after the last dose of acalabrutinib.  Any subject with a 
rising viral load (above the 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.  
3.7.2.2. Progressive Multifocal Leukoencephalopathy 
Cases of progressive multifocal leukoencephalopathy (PML) have occurred in clinical 
studies with acalabrutinib.  Signs and symptoms of PML may include cognitive and 
behavioral changes, language disturbances, visual disturbances, sensory deficits, 
weakness, and coordination and gait difficulties. 
If PML is suspected, hold further treatment with acalabrutinib treatment until PML is 
excluded.  A diagnostic evaluation may include (but is not limited to): 
• 
Neurologic consultation 
• 
Brain magnetic resonance imaging (MRI) 
• 
Polymerase chain reaction (PCR) analysis for John Cunningham virus DNA 
in cerebrospinal fluid 
If PML is confirmed, permanently discontinue acalabrutinib. 

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3.7.3. 
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 3.11 for study drug modification guidance.  Subjects with 
cytopenias should be managed according to institutional guidelines or as clinically 
indicated. 
3.7.4. 
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.  Refer to Section 5.5 for second primary malignancy 
reporting guidance. 
3.7.5. 
Atrial Fibrillation  
Atrial fibrillation or flutter has occurred in clinical studies with acalabrutinib, particularly in 
subjects with cardiac risk factors, hypertension, diabetes mellitus, acute infections, or a 
previous history of atrial fibrillation.  Monitor for symptoms of atrial fibrillation and atrial 
flutter (e.g., palpitations, dizziness, syncope, chest pain, dyspnea) and obtain an ECG as 
appropriate.  Subjects with atrial fibrillation should be managed per institutional 
guidelines with supportive care and diagnostic evaluation as clinically indicated. 
3.7.6. 
Reference Safety Information 
For the purpose of reporting AEs and serious adverse events (SAEs): 
The Investigator Brochure contains the Reference Safety Information (RSI) for 
acalabrutinib. 
3.7.7. 
Dietary Restrictions 
Because acalabrutinib is metabolized by CYP3A (see Section 3.7.8), subjects should be 
strongly cautioned against using herbal remedies or dietary supplements (in particular, 
St John’s Wort, which is a potent CYP3A inducer). 
Acalabrutinib can be taken without regard to meals. 

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3.7.8. 
Drug-drug Interactions 
At the systemic exposure levels expected in this study, acalabrutinib inhibition of CYP 
metabolism is not anticipated. 
However, acalabrutinib is metabolized by CYP3A.  Concomitant administration of 
acalabrutinib with a strong CYP3A and P-glycoprotein (P-gp) inhibitor, itraconazole 
increased exposure by approximately 5-fold.  Conversely, concomitant administration of 
acalabrutinib with a strong CYP3A inducer, rifampin, decreases acalabrutinib exposure 
and could reduce efficacy.  Consequently, the concomitant use of strong 
inhibitors/inducers of CYP3A (see Appendix 1) should be avoided when possible.  
If a subject requires short-term treatment with a strong CYP3A inhibitor (such as 
anti-infectives for up to 7 days), interrupt acalabrutinib treatment.  If a subject requires 
short-term treatment with a moderate CYP3A inhibitor (see Appendix 1), decrease 
acalabrutinib dose to 
  
Avoid co-administration of strong CYP3A inducers.  If a subject requires treatment with a 
strong CYP3A inducer, increase the acalabrutinib dose to 
 during 
concomitant administration with the strong inducer and return to recommended dose of 
 after stopping the strong CYP3A inducer.  
The effect of agents that reduce gastric acidity (antacids or proton-pump inhibitors) on 
acalabrutinib absorption was evaluated in a healthy volunteer study (ACE-HV-004).  
Results from this study indicate that subjects should avoid the use of calcium 
carbonate-containing drugs or supplements for a period of 2 hours before and at least 
2 hours after taking acalabrutinib.  Use of omeprazole, esomeprazole, lansoprazole or 
any other proton-pump inhibitors while taking acalabrutinib is not recommended due to a 
potential decrease in study drug exposure.  However, the decision to treat with 
proton-pump inhibitors during the study is at the investigator’s discretion, with an 
understanding of the potential benefit to the subject’s gastrointestinal condition and a 
potential risk of decreased exposure to acalabrutinib. 
Although the effect of H2-receptor antagonists (such as famotidine or ranitidine) on 
acalabrutinib absorption has not been evaluated, if treatment with an H2-receptor 
antagonist is required, the H2-receptor antagonist should be taken approximately 
2 hours after an acalabrutinib dose.  
CCI
CCI
CCI

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3.7.9. 
Reproductive Toxicity 
Definition of women of non-reproductive potential 
Women will be considered of non-reproductive potential if they are either:  
1) Postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women <45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy.  In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
2) Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
3) Have a congenital or acquired condition that prevents childbearing. 
Highly Effective Methods of Contraception‡  
Highly effective methods of contraception (to be used during heterosexual activity) are 
defined as methods that can achieve a failure rate of <1% per year when used 
consistently and correctly.  Such methods include:  
• 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation, which may be oral, intravaginal, or 
transdermal  
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation, 
which may be oral, injectable, or implantable  
• 
Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)  
• 
Bilateral tubal occlusion  
• 
Vasectomy of a female subject’s male partner (with medical assessment and 
confirmation of vasectomy surgical success)  
• 
Sexual abstinence (only if refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments)  
 
Hormonal contraception may be susceptible to interaction with study or other drugs, 
which may reduce the efficacy of the contraception method.  
Periodic abstinence† (e.g., calendar, ovulation, sympto-thermal, and post-ovulation 
methods) and withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhea method (LAM) are not acceptable methods of contraception.  Female 

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condom and male condom should not be used together as an effective method of 
contraception.  
†Abstinence (relative to heterosexual activity) can only be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and IECs/IRBs.  Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, and post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for subjects participating at 
sites in this country/region. 
Developmental and reproductive toxicology studies in rats have not identified 
acalabrutinib-related toxicities for fertility, reproductive success, embryofetal 
development or embryofetal survival.  In rabbits, at dose levels which resulted in 
maternal toxicities, skeletal variations were associated with reductions in fetal weights.  
Effects on parturition and post-natal development are pending.  For additional details, 
refer to the acalabrutinib Investigator Brochure. 
Subjects should promptly notify the investigator if they, or their partners, become 
pregnant during this period.  Female subjects must also notify the investigator if they 
become pregnant within 2 days after the last dose of acalabrutinib.  If a female subject 
becomes pregnant during the treatment period, she must discontinue acalabrutinib 
immediately.  Pregnancy in a female subject or a male subject’s partner must be 
reported as described in Section 5.6. 
3.7.10. 
Overdose Instructions 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or incorrect administration of study drug is not 
an adverse event unless it results in untoward medical effects.    
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration electronic case report form (eCRF).   
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
serious criteria, the event should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event). 

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For any subject experiencing an acalabrutinib overdose (ingestion of more than the dose 
being tested in the cohort), observation for any symptomatic side effects should be 
instituted, and vital signs, biochemical and hematologic parameters, and ECGs should 
be followed closely (consistent with the protocol or more frequently, as needed).  
Appropriate supportive management to mitigate adverse effects should be initiated.  If 
the overdose ingestion is recent and substantial, and if there are no medical 
contraindications, use of gastric lavage or induction of emesis may be considered.  
3.8. 
Assessment of Dose Limiting Toxicity 
The DLT review period for dose-escalation is over.  However, during the dose-escalation 
portion of the study a DLT was defined as any of the following events unless the adverse 
event is clearly related to disease progression or the subject’s current medical history 
and associated comorbidities: 
1. 
Any Grade 3 or greater nonhematologic toxicity with the exceptions of alopecia 
and Grade 3 nausea, vomiting and diarrhea that respond to supportive therapy.  
2. 
The following hematologic toxicities should be considered as DLTs: 
a. 
Grade 4 neutropenia lasting more than 5 days.  
b. 
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding, 
or any requirement for platelets transfusion.  
c. 
Grade 3 or greater febrile neutropenia (temperature ≥ 38.5°C).  
d. 
Grade 4 anemia, unexplained by underlying disease. 
3. 
Dosing delay due to toxicity for > 7 consecutive days. 
3.9. 
Assessment of QTc Interval Prolongation by Central ECG Testing  
Central ECG testing will be used for a subset of subjects from the dose-escalation 
portion of the study only. 
The potential of acalabrutinib to delay cardiac repolarization will be evaluated using 
ECGs for the measurement of the QTc interval.  The study will be carried out in 
collaboration with a centralized cardiac safety monitoring laboratory that specializes in 
cardiac monitoring who will provide centralized ECG functions.  
Toxicity grading of QTc interval prolongation is defined by the Common Terminology 
Criteria for Adverse Events (CTCAE) and provided in Table 3-1. 

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Table 3-1.  QTc Toxicity Grading Defined by CTCAE 
Grade 
Definition 
1 
QTc 450 to 480 ms 
2 
QTc 481 to 500 ms 
3 
QTc ≥ 501 ms on at least 2 separate ECGs 
4 
QTc ≥ 501 ms or > 60 ms change from baseline and Torsades de 
pointes or polymorphic ventricular tachycardia or signs/symptoms of 
serious arrhythmia 
5 
Death 
 
Refer to Section 4.1 for instructions on ECG evaluation. 
3.10. 
Stopping Rules 
Subjects with stable disease or tumor response may continue on therapy until disease 
progression (radiologic or clinical) or until the investigator considers the study treatment 
to be no longer tolerable or in the subject’s best interest, whichever occurs first.  
Subjects who meet criteria of disease progression and are continuing to gain clinical 
benefit from therapy may be able to temporarily remain on acalabrutinib after discussion 
with the medical monitor. 
Treatment of subjects with study drug is terminated if: 
• 
Any subject who has objective evidence of disease progression while receiving 
protocol required study drug should be withdrawn from the study treatment.  If 
there is uncertainty regarding whether there is disease progression, the subject 
may continue study treatment and remain under close observation (e.g., 
evaluated at 2- to 4-week intervals) pending confirmation of disease progression.  
In particular, transient worsening of disease during temporary interruption of 
study therapy (e.g., for drug-related toxicity, surgery, or intercurrent illness) may 
not indicate disease progression.  In such circumstances, and if medically 
appropriate, subjects may resume therapy and relevant clinical, laboratory, 
and/or radiographic assessments should be done to document whether tumor 
control can be maintained or whether actual disease progression has occurred. 
• 
Toxicity as defined in dose discontinuation portions of the protocol. 
• 
Any subject whose medical condition substantially changes after entering the 
study should be carefully evaluated by the investigator in consultation with the 

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medical monitor.  Such subjects should be withdrawn from study treatment if 
continuing would place them at risk.  
• 
Withdrawal from treatment by subject including withdrawal of informed consent. 
• 
Pregnancy in a subject. 
• 
Investigator decision. 
• 
Requires prohibited treatment. 
• 
Study terminated by Sponsor. 
3.11. 
Dosing Delays and Modifications 
Clinical judgment should be used to determine appropriate management of the subject 
during any AE.  Temporary interruption or permanent discontinuation of the study drug 
should be considered if clinically indicated. 
Subjects who experience a non-DLT AE resulting in interruption of treatment for 
≤ 7 missed days, may restart treatment at the original dose if the abnormality returns to 
baseline or Grade 1.  
Note:  Temporary withholding of acalabrutinib for as little as 7 days can cause a 
transient worsening of disease and/or of constitutional symptoms.  Refer to Section 3.10 
for more information on assessing disease progression under these circumstances. 
3.12. 
Data and Safety Monitoring 
This trial will be monitored in accordance with the sponsor’s pharmacovigilance 
procedures.  Adverse events and serious adverse events (SAEs) will be reviewed 
internally on an ongoing basis to identify safety concerns.  Conference calls with the 
investigators will be conducted, as needed, 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, mandatory safety 
calls will occur before enrollment of subjects into the next dose escalation cohort level. 
4. 
STUDY ACTIVITIES AND ASSESSMENTS 
The schedules of events are shown in Schedule of Assessments.  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 

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detailed measurements is to ensure adequate safety and tolerability assessments.  
Clinical evaluations and laboratory studies may be repeated more frequently if clinically 
indicated.  This study will primarily use central laboratory testing for safety laboratory 
evaluation except hematology, urinalysis and pregnancy testing will be done using the 
site’s local laboratories. 
 

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Table 4-1.  Schedule of Assessments 
 
Screeninga 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 4 Cycle 5 Cycle 6
Cycles ≥9b 
(Cohort 9) 
Cycles ≥12b 
(Non-cohort 9) 
Follow Upc Continued 
Access to 
Study 
Drug* 
 
 
Days (± 2) 
Day(s) 
(± 2) 
Day(s) 
(± 2) 
Day(s) 
(± 2) 
Day(s) 
(± 2) 
Day(s) 
(± 2) 
Day(s) (± 2) 
Day(s) (± 2) 
30 days 
after last 
dose 
 
1 
8  
15  
22 
28 
15 
28 
28 
28 
28 
28 
28 
28 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PEd/Vital signse/Weight/ 
B symptomsd 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECOG status 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECGf (dose escalation 
only) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
ECGf (expansion 
cohorts) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogramt 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
Laboratory 
assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
testg 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Hematologyh 
x 
 
x 
x  
x  
x 
x  
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Serum chemistryi 
x 
 
x 
x  
x  
x 
x  
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Cardiac troponin It 
x 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
 
Amylase & Lipase 
x 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
 
Hepatitis serologyu 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV PCRv 
 
 
 
 
 
 
 
 
x 
 
 
xx 
Q3 cycles 
Q3 cycles 
x 
 
 
Urinalysisj 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T/B/NK/monocyte 
 
cell countk 
 
x 
 
 
 
 
 
x 
 
 
 
 
x 
xy 
 
 
 
Serum Igl 
 
x 
 
 
 
 
 
x 
 
 
 
 
x 
x 
 
x** 
 
Bone marrow 
 
(aspirate and 
biopsy) 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 12 
only & to 
confirm CR  
Cycle 12 only 
& to confirm 
CR 
 
 

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Screeninga 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 4 Cycle 5 Cycle 6
Cycles ≥9b 
(Cohort 9) 
Cycles ≥12b 
(Non-cohort 9) 
Follow Upc Continued 
Access to 
Study 
Drug* 
 
 
Days (± 2) 
Day(s) 
(± 2) 
Day(s) 
(± 2) 
Day(s) 
(± 2) 
Day(s) 
(± 2) 
Day(s) 
(± 2) 
Day(s) (± 2) 
Day(s) (± 2) 
30 days 
after last 
dose 
 
1 
8  
15  
22 
28 
15 
28 
28 
28 
28 
28 
28 
28 
 
 
(if 
applicablez) 
 
 
 
xm 
xm 
 
 
xn 
 
 
 
 
 
xn 
 
 
x 
 
 
Pharmacokineticso 
 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Molecular markersp 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acalabrutinib dispensedq 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
Study drug compliance 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
Tumor assessment 
xr 
 
 
 
 
 
 
xs 
 
xs 
 
xs 
xs 
xs 
 
 
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 
x 
Abbreviations: ECG = electrocardiogram, ECOG = Eastern Cooperative Oncology Group, HBV = hepatitis B virus; Ig = immunoglobulin; IGHV = immunoglobulin 
heavy-chain variable; mos = months; PCR = polymerase chain reaction; PE = physical examination; QM = every month 
Footnotes for ACE-CL-001 Schedule of Study Activities: 
a.  Screening tests should be performed within 10 days before the first administration of study drug, unless otherwise indicated. 
b. 
For subjects in Cohort 9, these study visits (including radiographic assessments) will occur every 3 cycles until cycle 24, then every 6 cycles thereafter.  For the other 
cohorts, the study visits and assessments beyond Cycle 6 will occur every 6 cycles, except for CT scans which will occur every 6 cycles until Cycle 36, and then every 
12 cycles thereafter.  Under amendment 9 of this protocol, subjects in all cohorts will synchronize their clinic visits and laboratory assessments (excluding the HBV testing 
that will be every 3 cycles regardless of the imaging/clinic frequency) with the new imaging scheduled visits.  Any subjects who have not progressed while receiving study 
drug treatment and are tolerating study drug may continue beyond Cycle 36 and will keep the same scheduled visits. 
c. 
A 30-day (+7 days) safety follow-up visit is required when subjects discontinue study drug. 
d. 
The screening physical examination will include, at a minimum, the general appearance of the subject, height (screening only) and weight, and examination of the skin, 
eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system.  Symptom-directed physical examinations are 
done thereafter.  B symptoms will be assessed at Cycle 1, Day 1, Cycle 2, Day 15, then at all visits thereafter (excluding the ET visit), and at the safety follow-up visit. 
e. 
Vital signs (blood pressure, pulse, respiratory rate, and temperature) will be assessed after the subject has rested in the sitting position.   
f. 
12-lead electrocardiogram (ECG) will be done in triplicate (≥ 1 minute apart) at screening for all subjects.  The intensive ECG schedule, which follows, is only for the 
subjects in the dose escalation portion of the study.  The calculated QTc average of the 3 ECGs must be < 480 ms for eligibility.  ECGs will be done on Cycle 1 Day 1 and 
Cycle 1 Day 8, single ECGs are done predose and at 1, 2, 4, and 6 h postdose.  The single ECG on Cycle 1 Day 2 is done predose.  On Cycle 1 Day 15, Day 22, and Day 
28, a single ECG is done 1 h postdose.  Starting with Cycle 2 and ending with Cycle 6, a single ECG is done per visit.  Subjects should be in supine position and resting for 
at least 10 minutes before study-related ECGs.  Two consecutive machine-read QTc > 500 ms or > 60 ms above baseline require central ECG review. 
g. 
Women of childbearing potential only.  
h. 
Hematology includes complete blood count with differential and platelet counts sent to a local laboratory. 
CCI

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i. 
Serum chemistry: 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. 
j. 
Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose. 
k. 
T/B/NK/monocyte cell count (i.e., CD3, CD4, CD8, CD14, CD19, CD16/56).  Testing will be performed on Cycle 1 Day 1; end of Cycles 2/9/15 then every 6 cycles until 
Cycle 36, and then every 12 cycles thereafter. 
l.  
Serum immunoglobulin: IgG, IgM, IgA, and total immunoglobulin (if available).  Testing will be performed on Cycle 1 Day 1, end of Cycle 2, then every 6 cycles until 
Cycle 36, and then every 12 cycles thereafter. 
m. 
 samples are drawn predose and 4 hours (± 10 minutes) postdose on the days indicated. 
n. 
 samples are drawn predose on the day indicated. 
o. 
Pharmacokinetic samples for Cycle 1 Day 1 are drawn predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6 and 24 h (before dose on Day 2) postdose.  Samples for Cycle 1 Day 8 are 
drawn predose and at 0.25, 0.5, 0.75, 1, 2, 4, and 6 h postdose.  On Cycle 1 Day 15, 22, and 28, a PK sample is drawn predose and the second PK sample must be drawn 
before (up to 10 minutes before) the ECG acquisition (if applicable), which is 1 h postdose.  PK sampling will be done at select centers and on up to 10 subjects per cohort. 
p. 
Includes, but is not limited to, interphase cytogenetics, stimulated karyotype, CLL FISH panel, IGHV mutational status, Zap-70 methylation, and beta-2 microglobulin levels. 
q. 
Acalabrutinib:  
 study drug is administered at the site.  Therefore, only dispense enough study drug for the days between 
visits.  Thereafter, starting with the end of Cycle 1, dispense enough bottles for 1 complete cycle for every cycle to Cycle 6, and thereafter as per study required visit 
interval.   
r. 
Pretreatment radiologic tumor assessment should be performed within 30 days before the first dose.  A computed tomography (CT) scan (with contrast unless 
contraindicated) is required of the chest, abdomen, and pelvis. 
s. 
For all cohorts except Cohort 9, radiologic tumor assessments are mandatory at the end of Cycle 2 (-7 days), Cycle 4 (-7 days), Cycle 6 (-7 days), then every 6 cycles until 
Cycle 36, and then every 12 cycles thereafter.  For subjects in Cohort 9, radiologic tumor assessment will be done at screening and at the end of Cycle 2, Cycle 4, Cycle 6, 
Cycle 9, Cycle 12, Cycle 15, Cycle 18, Cycle 21, Cycle 24, and every 6 cycles thereafter.  Otherwise, radiologic tumor assessments are done at investigator discretion.  A 
CT (with contrast unless contraindicated) scan of the chest, abdomen, and pelvis (and any other relevant diseased area such as the neck) is required.  Bone marrow biopsy 
(at 8 to 12 weeks after the response assessment scan) and radiologic assessments are both required for confirmation of a complete response (CR) (as applicable for 
subjects in Cohort 9).  Testing for minimal residual disease will be done on subjects with confirmed CRs.  Response assessment for subjects with Richter’s syndrome will 
require either CT scan with contrast (unless contraindicated) or PET-CT (preferred) of the chest, abdomen, and pelvis and any other disease areas.  For subjects with 
Richter’s syndrome, confirmation of CR will require PET/CT or CT with bone marrow biopsy, as outlined in Table 4-5.  Clinical assessments of tumor response should be 
done at every visit.  
t. 
An echocardiogram is required at screening and at the end of Cycle 6 OR with any Grade 3 increase in cardiac troponin I levels. 
u. 
Hepatitis serology must include hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (anti-HBc), and hepatitis C (HCV) 
antibody.  Subjects who are receiving prophylactic intravenous immunoglobulins (IVIG) and have positive HBsAg or anti-HBc must have negative hepatitis B DNA to be 
eligible.  In addition, any subjects testing positive for any hepatitis serology, must have PCR testing (see exclusion criterion #12). 
v. 
Subjects who are anti-HBc positive (or have a known history of HBV infection) should be monitored every 3 cycles with a quantitative PCR test for HBV DNA and this testing 
is recommended to continue until 12 months after last dose of study drug.  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. 
x. 
For the subjects who require HBV monitoring (see footnote v), HBV PCR testing at Cycle 9 also for all cohorts. 
y. 
T/B/NK/monocyte cell count testing at Cycle 9 also for all cohorts (see footnote k).  
z. 
This is not applicable for subjects in Cohort 9 if being followed by PET-CT for response. 
 
* “Continued access to study drug” phase is for subjects who are deriving clinical benefit from acalabrutinib and will continue acalabrutinib treatment per investigator assessment.  
This phase begins at the data cutoff (DCO) date defined in Section 3.1.3.  All monitoring of subjects will be recorded in the subject’s medical record per standard clinical 
practice.  Only SAEs will be reported to the sponsor using a paper form.  
** Serum immunoglobulin will include IgM and will be done at the discretion of the investigator.
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4.1. 
Description of Procedures 
Informed Consent 
Screening 
The subject must read, understand, and sign the Institutional Review Board 
(IRB)-approved ICF confirming his or her willingness to participate in this study before 
initiating any screening activity that is not considered standard of care.  Subjects must 
also grant permission to use protected health information if required by local regulations.   
Medical History 
Screening 
Collect and record the subject’s complete history through review of medical records and 
by interview.  Concurrent medical signs and symptoms must be documented to establish 
baseline severities.  A disease history, including the date of initial diagnosis and list of all 
prior anticancer treatments, and responses and duration of response to these 
treatments, also will be recorded.  
Adverse Events 
At all visits 
The accepted regulatory definition for an AE is provided in Section 5.1.  All medical 
occurrences from the time of first dose that meet this definition must be recorded.  
Important additional requirements for reporting SAEs are explained in Section 5.7. 
Concomitant Medications and Therapy  
At all visits 
Document all concomitant medications and procedures from within 14 days before the 
start of acalabrutinib administration through 30 days (+7 days) after the last dose of 
acalabrutinib. 
Confirmation of Eligibility 
Screening 
Perform all necessary procedures and evaluations to document that the subject meets 
each eligibility criterion.  Screening evaluations must be completed within 10 days before 
the subject’s first dose of acalabrutinib. 
Physical Examination & Vital Signs & Weight & B Symptoms 
Per Table 4-1 
The screening physical examination will include, at a minimum, the general appearance 
of the subject, height (screening only) and weight, and examination of the skin, eyes, 

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ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous 
system, and lymphatic system. 
Symptom-directed physical examinations will be done during the treatment period and at 
the safety follow-up visits.  B symptoms will be assessed at Cycle 1, Day 1, Cycle 2, Day 
15, then at all visits thereafter (excluding the ET visit), and at the safety follow-up visit. 
Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) will be 
assessed after the subject has rested in the sitting position.  Vital signs and weight will 
be measured at every visit.  
ECOG Performance Status 
At all visits 
The ECOG performance index is provided in Appendix 2. 
Electrocardiogram – Dose Escalation Portion Only 
Per Table 4-2 
A centralized cardiac safety monitoring laboratory will be used in this study.  The service 
provider will provide the ECG equipment (12-lead surface), instructions, and training 
(when requested).  At screening, results from the central ECG reader (i.e., 3 ECGs) will 
be averaged to determine eligibility and must meet the eligibility criteria of 
QTc < 480 ms.  Thereafter single ECGs are done at each timepoint.  However, if a 
machine read ECG registers a QTc (either Bazett’s or Fredericia’s) of ≥ 501 ms or 
> 60 ms above baseline then a second ECG must be done after 5 minutes.  If at any 
point, a subject experiences a Grade 3 QTc prolongation (i.e., 2 consecutive ECGs 
taken at least 5 minutes apart with QTc that are both ≥ 501 ms and/or > 60 ms change 
from baseline), per the machine on site, the dose must be held pending the QTc results 
from the centralized review.  If centralized review confirms both ECG QTc readings are 
≥ 501 ms or > 60 ms change from baseline then the subject must be withdrawn from the 
study.  Conversely, if the centralized review shows that both ECG QTc readings are 
≤ 500 ms and ≤ 60 ms change from baseline, dosing may be restarted at the same dose 
level, but missed doses will not be made up.  
Also, if a Grade 3 increase in cardiac troponin I occurs in a subject, ECG testing must be 
done and the ECGs (triplicates taken at least 1 minute apart) must be sent for central 
review. 

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Note:  The Phase 1 portion of the study has been closed, therefore the intensive ECG 
schedule for the subjects in the dose-escalation cohorts has been completed. 
Table 4-2.  ECG Acquisition Times 
Study Segment 
Day 
ECG Acquisition Times 
Screening 
-- 
Triplicate at least 1 min apart 
Cycle 1 
1-2 
Single ECG predose, and 1, 
2, 4, 6, and 24 h (before Day 
2 dose) after 1st dose; 
window for ECGs at 1, 2, 4, 
6 h is ±10 min.  The 24-h 
ECG must be predose on 
Day 2. 
Cycle 1 
8 
Single ECG predose, and 1, 
2, 4, and 6 h after 8th dose; 
window for ECGs at 1, 2, 4, 
6 h is ±10 min 
Cycle 1 
15, 22, 28 
Single ECG 1 h (±10 min) 
postdose 
Cycle 2 
15, 28 
Single ECG anytime during 
the visit 
Cycles 3 to 6 
28 
Single ECG anytime during 
the visit 
 
Electrocardiogram – Expansion Cohorts 
Screening  
Central ECG testing is not required for subjects in the expansion cohorts.  Sites can use 
their own 12-lead ECG machines for the screening ECGs. 
Echocardiogram 
Screening, end of Cycle 6 
An echocardiogram is required at screening.  LVEF must be > 40% for inclusion in the 
study.  Follow-up echocardiograms are required at the end of Cycle 6 or with a Grade 3 
increase in cardiac troponin I levels and at the safety follow-up visit. 
Urine Pregnancy Test 
Screening and safety follow-up visit 
Pregnancy tests are required only for women with childbearing potential.  

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Hematology 
Screening, then all visits starting with Cycle 1 Day 8 
Hematology studies must include complete blood count (CBC) with differential and 
platelet counts.  Hematology samples done at response assessment timepoints must be 
done within 7 days of the CT scan.  Testing will be performed at the study center’s local 
laboratory listed on the investigator’s form FDA 1572.   
Chemistry 
Screening, then all visits starting with Cycle 1 Day 8 
Chemistry must 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 performed at the study center’s local laboratory or central clinical 
laboratory listed on the investigator’s form FDA 1572.   
Amylase and Lipase 
Screening, Cycle 1 Day 1 then Day 28 visits on all cycles starting with Cycle 2 through 
end of Cycle 6 and as needed 
Serum amylase and serum lipase testing will be performed at the study center’s local 
laboratory or central clinical laboratory listed on the investigator’s form FDA 1572.   
Cardiac Troponin I  
Screening, Cycle 1 Day 1 then Day 28 visits on all cycles starting with Cycle 2 through 
end of Cycle 6 
Cardiac troponin testing will be performed at the study center’s local laboratory or central 
clinical laboratory listed on the investigator’s form FDA 1572.  If a subject experiences a 
Grade 3 increase in cardiac troponin I, study drug must be held and an echocardiogram 
AND ECG testing must be done.  Per CTCAE criteria, a Grade 3 increase in cardiac 
troponin I is defined as levels consistent with myocardial infarction as defined by the 
manufacturer. 
Hepatitis B and C Testing 
Screening 
Hepatitis serology testing must include hepatitis B surface antigen (HBsAg), hepatitis B 
surface antibody (HBsAb), anti-HBc, and HCV antibody.  Since intravenous 
immunoglobulins (IVIG) may cause false positive hepatitis serology, subjects who are 
receiving prophylactic IVIG and have positive HBsAg or anti-HBc must have negative 

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hepatitis B DNA to be eligible.  In addition, any subjects testing positive for any hepatitis 
serology, must have PCR testing (see Table 4-1 and exclusion criterion #12).  Testing 
will be done by local or central laboratory.   
Refer to Section 3.7.2.1 and Table 4-1 regarding monitoring of subjects who are 
anti-HBc positive or have a known history of HBV. 
Urinalysis 
Screening 
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.  
Testing will be performed at the study center’s local laboratory or central clinical 
laboratory listed on the investigator’s form FDA 1572.   
T/B/NK/Monocyte Cell Count 
Per Table 4-1 
Flow cytometry testing for CD3+, CD4+, CD8+, CD14+, CD19+, CD16/56+ cells.  Testing 
will be performed at the study center’s local laboratory or central clinical laboratory listed 
on the investigator’s form FDA 1572.   
Serum Immunoglobulin 
Per Table 4-1 
Testing for IgG, IgM, IgA and total immunoglobulin (if available) levels.  Testing will be 
performed at the study center’s local laboratory or central clinical laboratory listed on the 
investigator’s form FDA 1572. 
Pharmacokinetics 
Per Table 4-3 
Refer to the laboratory binder for instructions on collecting and processing these 
samples.  Testing will be performed at a central clinical laboratory.  PK testing will only 
be done at select centers and on a subset of subjects for each cohort 
(≤ 10 subjects/cohort). 
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Table 4-3.  Pharmacokinetic Sample Schedule 
 
Hours Postdose 
Cycle 
Day 
Predose 
0.25 
(± 1 
min) 
0.5 
(± 5 
min) 
0.75 
(± 5 
min) 
1 
(± 10 
min) 
2 
(± 10 
min) 
4 
(± 10 
min) 
6 
(± 10 
min) 
24 
(± 30 min) 
1 
1 
X 
X 
X 
X 
X 
X 
X 
X 
X*before 
Day 2 
dose 
 
8 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
15, 22, 28 
Predose and 1 hour (± 10 minutes) 
 
Molecular Testing 
Screening  
Blood will be drawn for molecular testing including, but not limited to, interphase 
cytogenetics, stimulated karyotype, CLL fluorescence in situ hybridization (FISH) panel, 
immunoglobulin heavy-chain variable (IGHV) mutational status, ZAP-70, and beta-2 
microglobulin levels.  Refer to the laboratory binder for instructions on collecting and 
processing these samples.  Testing will be performed at central clinical laboratories. 
Bone Marrow 
Cycle 12 and to confirm CR 
Bone marrow aspirate and biopsy are required to confirm a CR and must be done 8 to 
12 weeks following the CT scan (as applicable for subjects in Cohort 9).  A repeat bone 
marrow biopsy in 6 months may be performed to confirm CR in subjects with clinical, 
laboratory, and radiologic findings supportive of CR but with prior bone marrow 
biopsy/aspirate showing CLL disease involvement.  A mandatory bone marrow aspirate 
and biopsy are required at the end of Cycle 12 concurrent with the radiologic tumor 
assessment as outlined below.  Testing will be performed at the study center’s local 
laboratory listed on the investigator’s form FDA 1572. 
Tumor Assessment 
Per Table 4-1  
Pretreatment tumor assessment should be performed within 30 days (+7 days) before 
the first dose.  A computed tomography (CT) scan with contrast (unless contraindicated) 
is required of the chest, abdomen, and pelvis and any other diseased area (e.g., the 
neck) for the pretreatment tumor assessment for subjects.  Bone marrow and radiologic 
assessments are both required for confirmation of a CR, with the exception of subjects 

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with Richter’s syndrome.  In addition, 4-color flow cytometry will be used to determine 
the presence or absence of minimal residual disease (MRD) in subjects who achieve a 
CR per the response criteria outlined in Section 4.2.  Response assessment for subjects 
with Richter’s syndrome will require either CT scan with contrast (unless contraindicated) 
or PET-CT (preferred) of the chest, abdomen, and pelvis and any other disease areas.  
For subjects with Richter’s syndrome, confirmation of CR will require PET/CT or CT with 
bone marrow biopsy, as outlined in Table 4-5.  The overall efficacy response will assess 
the response of the underlying malignant transformation.   
Study Drug Accountability 
Cycle 1 Day 1, 2, 8, 15, 22, and 28, and at every visit 
See Section 7.7. 
4.2. 
Investigator’s Assessment of Response to Treatment  
The investigator must rate the subject’s response to treatment based on recent 
guidelines for CLL and SLL (Table 4-4) with incorporation of the clarification for 
treatment-related lymphocytosis (Cheson 2012).  For the Richter’s Syndrome, the 
guidelines for assessing response are provided in Table 4-5; the response assessment 
for Richter’s syndrome will be using PET/CT (preferred) or CT.  For all response 
assessments, hematology samples must be drawn within 7 days of the scan.  Bone 
marrow biopsy done to confirm a complete response must be done at 8 to 12 weeks 
after the response assessment scan. 
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 via the electronic 
data capture (EDC) system within 24 hours of discovery.  Subjects may continue study 
treatment until progression is confirmed by a serial exam at least 2 weeks later.  
Subjects who meet criteria of disease progression and are continuing to gain clinical 
benefit from therapy may be able to temporarily remain on acalabrutinib after discussion 
with the medical monitor. 

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Table 4-4.  Response Assessment Criteria for CLL/SLL (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 
No B-lymphoid nodules 
Normal (e.g., no lymph nodes 
> 1.5 cm) 
Persistent anemia, thrombocytopenia, or 
neutropenia related to drug toxicity 
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 
AND 
<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 
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 less than 100,000/µL 
and worsening bone marrow 
Or 
Hemoglobin decrease of > 2 g/dL from 
baseline secondary to CLL or decrease to 
less than 100g/L and worsening bone 
marrow 
Footnotes are on the next page. 
 

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Footnotes to Table 4-4 
ANC = absolute neutrophil count; CR = complete remission; CRi = CR with incomplete bone marrow recovery; 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 subjects have to lack disease-related constitutional symptoms; PR: at least two of the above PR 
criteria for lymphadenopathy, splenomegaly, hepatomegaly, or lymphocytes plus one of the criteria for ANC, platelets or hemoglobin have to be met; 
PRL: presence of lymphocytosis, plus ≥ 50% reduction in lymphadenopathy and/or in spleen or liver enlargement, plus one of the criteria for ANC, 
platelets or hemoglobin have to be met; PD: at least one of the above PD criteria has to be met, or transformation to a more aggressive histology (e.g., 
Richter’s syndrome).  For PD as assessed by progressive cytopenias, a bone marrow biopsy is required for confirmation.  Note:  Isolated elevation of 
treatment-related lymphocytosis by itself will not be considered PD unless patient becomes symptomatic from this per Cheson 2012. 
 
a 
Computed tomography (CT) scan of abdomen, pelvis, and thorax may be used if previously abnormal. 
b 
Without need for exogenous growth factors. 
c 
If the sum products of ≤ 6 lymph nodes or in the largest diameter of the enlarged lymph node(s) detected before therapy and no increase in any 
lymph node or new enlarged lymph nodes. 
 

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Table 4-5.  Response Assessment Criteria for Richter’s Syndrome (Cheson 2014) 
 
Abbreviations: CR = complete remission, CT = computed tomography, FDG = [18F]fluorodeoxyglucose, PET = positron-
emission tomography, PR = partial remission, SD = stable disease, SPD = sum of the product of the diameters 
 
 
 

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Table 4-5.  Response Assessment Criteria for Richter’s Syndrome (Cheson 2014) 
(continued) 
 
 
4.3. 
Safety Follow-up Visit 
The safety follow-up visit is conducted 30 (+ 7) days after the last acalabrutinib dose to 
monitor for resolution or progression of AEs and to document the occurrence of any new 
events or SAEs related to study drug if the AE reporting period ended prior to the safety 
follow-up visit with the start of new anticancer therapy.  Refer to Table 4-1 for the 
assessments done at these visits.  Subjects who withdraw consent should still be 
encouraged to complete the safety follow-up assessments, but these assessments 
cannot be mandated once consent is withdrawn.  The Schedule of Assessments 
(Table 4-1) describes the procedures required for the safety follow-up visit. 
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. 
5. 
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 

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protocol-specified tests that are deemed critical to the safety evaluation of the study 
drug(s). 
5.1. 
Definitions 
5.1.1. 
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/SLL that were 
not present before the AE reporting period (see Section 5.3). 
• 
Pre-existing medical conditions (other than the condition being studied) judged by 
the investigator to have worsened in severity or frequency or changed in character 
during the protocol-specified AE reporting period. 
• 
Abnormal laboratory values considered clinically significant by the investigator 
should be reported as AEs. 
The following are NOT considered an AE: 
• 
Pre-existing condition that has not worsened: A pre-existing condition 
(documented on the medical history CRF) is not considered an AE unless the 
severity, frequency, or character of the event worsens during the study period. 
• 
Preplanned hospitalization: A hospitalization planned before signing the ICF is not 
considered an SAE, but rather a therapeutic intervention.  However, if during the 
preplanned hospitalization an event occurs, which prolongs the hospitalization or 
meets any other SAE criteria, the event will be considered an SAE.  Surgeries or 
interventions that were under consideration, but not performed before signing the 
ICF, will not be considered serious if they are performed after signing the ICF for a 
condition that has not changed from its baseline level.  Elective hospitalizations for 
social reasons, solely for the administration of chemotherapy, or due to long travel 
distances are also not SAEs. 
• 
Diagnostic testing and procedures: Testing and procedures should not be 
reported as AEs or SAEs, but rather the cause for the test or procedure should be 

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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 (for example a blood transfusion for low hemoglobin) or requires a change 
in study drug (e.g., lowering the dose or withholding study drug while the laboratory 
finding resolves or stabilizes). 
• 
Progression of underlying malignancy:  Progression of underlying malignancy will 
not be reported as an AE if it is clearly consistent with the suspected progression of 
the underlying cancer.  Hospitalization due solely to the progression of underlying 
malignancy should NOT be reported as an SAE.  Clinical symptoms of progression 
may be reported as AEs if the symptoms cannot be determined as exclusively due to 
the progression of the underlying malignancy, or if they do not fit the expected 
pattern of progression for the disease under study. 
Symptomatic deterioration may occur in some subjects.  Symptomatic deterioration 
is when progression is evident in the subject’s clinical symptoms and the investigator 
may elect not to perform further disease assessments. 
If there is any uncertainty about an AE being due only to the disease under study, it 
should be reported as an AE or SAE. 
5.1.2. 
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: 

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• 
It results in death (i.e., the AE actually causes or leads to death). 
• 
It is life-threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death.  It does not include an AE that, had it occurred in a more 
severe form, might have caused death). 
• 
It requires or prolongs in-patient hospitalization. 
• 
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 study drug. 
• 
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). 
5.1.3. 
Severity 
Definitions found in the CTCAE version 4.03 (CTCAE v4.03) or higher will be used for 
grading the severity (intensity) of nonhematologic and hematologic AEs.  The CTCAE 
v4.03 displays Grades 1 through 5 with unique clinical descriptions of severity for each 
referenced AE.  Should a subject experience any nonhematologic AE not listed in the 
CTCAE v4.03, the following grading system should be used to assess severity: 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities 
• 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience 
or concern to the subject, and which may interfere with daily activities, but are 
usually ameliorated by simple therapeutic measures 
• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, 
significantly interrupt the subject’s usual daily activity, and require systemic drug 
therapy or other treatment 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to 
be in imminent danger of death 
• 
Grade 5 (Death related to AE) – experiences which result in subject death 

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5.1.4. 
Adverse Events of Special Interest 
The following events are adverse events of special interest (AESIs) and must be 
reported to the sponsor expeditiously (see Section 5.3 for reporting instructions), 
irrespective of regulatory seriousness criteria or causality: 
• 
Ventricular arrhythmias (e.g., ventricular extrasystoles, ventricular tachycardia, 
ventricular arrhythmia, ventricular fibrillation) 
5.2. 
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 up to the DCO (see Section 3.1.3), as outlined in the prior 
sections, are recorded on the electronic CRF (eCRF).  After the DCO, only SAEs, 
overdoses, and pregnancies must be reported; AEs will be recorded in the subject’s 
medical record.  All SAEs also must be reported on the SAE paper form (see 
Section 5.7). 
5.3. 
Adverse Event Reporting Period 
After the signing of the ICF and prior to the first dose of study drug, all SAEs must be 
reported. 
After the first dose of study drug, all AEs/SAEs, irrespective of attribution of causality, 
must be reported.   
All AEs will be reported until 30 days (+7 days) after the last dose of study drug or the 
start of new anticancer therapy (whichever comes first).  After this period, investigators 
should report SAEs or other AEs of concern that are believed to be related to prior 
treatment with study drug.  
All SAEs which 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. 
5.4. 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation time 
points during the study.  All AEs and SAEs whether volunteered by the subject, 
discovered by study personnel during questioning, or detected through physical 

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examination, or other means will be recorded in the subject’s medical record and on the 
AE eCRF. 
Disease progression itself is not considered an adverse event; however, signs and 
symptoms of disease progression may be recorded as AEs or SAEs. 
Each recorded AE or SAE will be described by its duration (i.e., start and end dates), 
severity, regulatory seriousness criteria, if applicable, suspected causality 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).  Answer Yes or No.  
See Appendix 3 for more detail on assessing causality. 
5.5. 
Second Primary Malignancies 
Adverse events (AEs) for malignant tumors reported during a study should generally be 
assessed as serious AEs (SAEs).  If no other seriousness criteria apply, the “Important 
Medical Event” criterion should be used.  In certain situations, however, medical 
judgment on an individual event basis should be applied to clarify that the malignant 
tumor event should be assessed and reported as a nonserious AE.  For example, if the 
tumor is included as medical history and progression occurs during the study but the 
progression does not change treatment and/or prognosis of the malignant tumor, the AE 
may not fulfill the attributes for being assessed as serious, although reporting of the 
progression of the malignant tumor as an AE is valid and should occur.  Also, some 
types of malignant tumors, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as nonserious; examples in adults 
include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone 
biopsy. 
The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (i.e., it is not the tumor for which entry into the study is a criterion and 
that is being treated by the 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.   

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5.6. 
Pregnancy 
The investigator should report all pregnancies and pregnancies of the partners of 
subjects within 24 hours using the Pregnancy Report Form.  This form should be sent to 
the Sponsor Representative.  Any pregnancy-associated SAE must be reported using 
the SAE report form, according to the usual timeline and direction for SAE reporting 
(Section 5.7). 
Any uncomplicated pregnancy that occurs with the subject or with the partner of a 
treated subject during this study will be reported for tracking purposes only, if agreed to 
by the subject or the partner of the subject in this study.  All pregnancies and partner 
pregnancies that are identified during or after this study, wherein the estimated date of 
conception is determined to have occurred from the time of consent to 2 days after the 
last dose of study medication with be reported, followed to conclusion, and the outcome 
reported, as long as the subject or partner has consented to participate in follow up. 
The pregnancy itself is not regarded as an AE unless there is suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Likewise, elective abortions without complications are not 
considered AEs.  Any SAEs associated with pregnancy (e.g., congenital 
abnormalities/birth defects/spontaneous miscarriage or any other serious events) must 
additionally be reported as such using the SAE report form. 
Subjects should be instructed to immediately notify the investigator of any pregnancies.  
Any female subjects receiving acalabrutinib who become pregnant must immediately 
discontinue study drug.  The investigator should counsel the subject, discussing any 
risks of continuing the pregnancy and any possible effects on the fetus. 
Upon completion of the pregnancy, additional information on the mother, pregnancy, and 
baby will be collected and sent to the Sponsor Representative. 
5.7. 
Expedited Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
All SAEs and AESIs must be reported within 24 hours of discovery.  Initial SAE/AESI 
reports and follow-up information will be reported using the protocol-specific electronic 
data capture system, according to the instructions provided by the sponsor.  If electronic 
SAE/AESI reporting is not available, paper SAE/AESI forms may be sent to the Sponsor 
Representative.  The Sponsor Representative may request follow-up and other 

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additional information from the investigator (e.g., hospital admission/discharge notes and 
laboratory results). After final DCO, SAEs will be reported using a paper form.  
Whenever possible, AEs/SAEs should be reported by diagnosis term, not as a 
constellation of symptoms.  Death due to disease progression should be recorded on the 
appropriate form in the electronic data capture system.  If the primary cause of death is 
disease progression, the death due to disease progression should not be reported as an 
SAE.  If the primary cause of death is something other than disease progression, then 
the death should be reported as an SAE with the primary cause of death as the event 
term, as death is typically the outcome of the event, not the event itself.  The primary 
cause of death on the autopsy report should be the term reported.  Autopsy and 
postmortem reports must be forwarded to the Sponsor Representative, as outlined 
above. 
If study drug is discontinued because of an SAE, this information must be included in the 
SAE report. 
An SAE may qualify for mandatory expedited reporting to regulatory authorities if the 
SAE is attributable to the study drug (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 Investigator Brochure (i.e., an unexpected event).  
In this case, Acerta Pharma will forward a formal notification describing the suspected 
unexpected serious adverse reaction (SUSAR) to all investigators.  Each investigator 
must then notify his or her IRB/IEC of the SUSAR. 
5.8. 
Type and Duration of Follow-up of Subjects After Adverse Events 
All AEs and SAEs that are encountered during the protocol-specified AE reporting period 
should be followed to resolution, or until the investigator assesses the subject as stable, 
a new anticancer therapy is initiated, or the subject is lost to follow-up or withdraws 
consent. 
5.9. 
Hy’s Law 
Cases where a subject shows elevations in liver biochemistry may require further 
evaluation, and occurrences of AST or ALT ≥3×ULN together with total bilirubin ≥2×ULN 
may need to be reported as SAEs.  Refer to Appendix 4 for further instruction on cases 
of increases in liver biochemistry and evaluation of Hy’s law. 

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6. 
STATISTICAL METHODS OF ANALYSIS 
6.1. 
General Considerations and Determination of Sample Size 
No formal statistical tests of hypotheses will be performed.  Descriptive statistics 
(including means, standard deviations, and medians for continuous variables and 
proportions for discrete variables) will be used to summarize data as appropriate. 
The design of the Phase 1 (i.e., dose-escalation portion) of the study is specified 
because of its practical simplicity, use of a biomarker, and not because of power 
considerations.  The MTD is defined as the largest daily dose for which < 33% of the 
subjects experience a DLT during Cycle 1.  The MTD was not reached in this study as 
PK data suggested a plateau in exposure between 250 and 400 mg. 
The Phase 2 (expansion portion) of the study will test the null hypothesis that the ORR is 
≤ 10% against the alternative hypothesis that it is ≥ 35%.  Using Simon’s optimal 2-stage 
design (Simon 1989), a total sample size of 30 subjects per cohort has power = 0.90 to 
achieve a 1-sided significance level of ≤ 0.025.  In Stage 1, 11 subjects will be enrolled 
per cohort; if ≥ 2 subjects (18%) achieve an objective response of a PR/PRL or better 
within the first 4 cycles of treatment, then that cohort will continue to full enrollment.  
Under the Simon design, an ORR of ≥ 23% (i.e., ≥ 7 subjects responding of 30 subjects 
evaluated) will achieve a significance level of ≤ 0.025.  Using an exact binomial 
confidence interval (CI), an ORR of 23% (i.e., 7 subjects responding of 30 subjects 
evaluated) will achieve a 2-sided 90% lower bound of 11.5%.   
Considering the planned expansion cohort size of 30 subjects, Table 6-1 shows the 
2-sided exact 90% binomial CIs on the true response rate for the range of possible 
values for the observed response rate.   
Table 6-1.  Two-Sided Exact 90% CIs for ORR in Expansion Cohorts (N = 30) 
Responses, n 
Response Rate, % 
90%CI 
Lower Bound 
Upper Bound 
0 
0% 
0.0% 
9.5% 
1 
3.3% 
0.2% 
14.8% 
2 
6.7% 
1.2% 
19.6% 
3 
10.0% 
2.8% 
23.9% 
4 
13.3% 
4.7% 
27.9% 
5 
16.7% 
6.8% 
31.9% 
6 
20.0% 
9.1% 
35.7% 
7 
23.3% 
11.5% 
39.4% 
8 
26.7% 
14.0% 
43.0% 
Abbreviation: CI=confidence interval, ORR = overall response rate 
 

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In addition, the Phase 2 portion of this protocol increases sample size of the 
 
cohorts (R/R CLL N = 65 approximately; treatment-naive CLL, N = 60) to provide safety 
and efficacy data in support of the Phase 3 program of acalabrutinib in CLL.  Therefore, 
depending on the number of subjects enrolled in each expansion cohort approximately 
286 evaluable subjects will be enrolled in this study. 
6.2. 
Definition of Analysis Populations 
• 
Enrolled population: All subjects who complete the enrollment procedures as 
specified in the Enrollment Procedures section (Section 3.4.5) of the protocol. 
• 
All-treated population: All enrolled subjects who receive ≥ 1 dose of study drug. 
• 
Efficacy-evaluable population: All subjects in the All-treated population who 
have ≥ 1 response assessment after the first dose of study drug.  
The safety analyses will be performed on the All-treated population.  Primary efficacy 
analyses for ORR and DOR will be based on the efficacy-evaluable population and will 
be assessed by investigators.  PFS analysis will be based on the all-treated population 
and will be assessed by investigators. 
6.3. 
Missing Data Handling 
No imputation of values for missing data will be performed except for missing or partial 
start and end dates for adverse events and concomitant medication will be imputed 
according to prespecified, conservative imputation rules.  Subjects lost to follow-up (or 
drop out) will be included in statistical analyses to the point of their last evaluation.  
6.4. 
Endpoint Data Analysis 
6.4.1. 
Safety Endpoint 
Safety summaries will include summaries in the form of tables and listings.  The 
frequency (number and percentage) of treatment emergent adverse events will be 
reported in each treatment group by Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class and Preferred Term.  Summaries will also be presented 
by the severity of the adverse event and by relationship to study drug. 
Laboratory shift tables containing counts and percentages will be prepared by treatment 
assignment, laboratory parameter, and time.  Summary tables will be prepared for each 
laboratory parameter.  Figures of changes in laboratory parameters over time will be 
generated. 
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Vital signs, ECGs, and physical examinations will be tabulated and summarized.   
6.4.2. 
Demographics and Baseline Characteristics 
Additional analyses will include summaries of subject demographics, baseline 
characteristics, compliance, and concurrent treatments.  Concomitant medications will 
be coded according to the World Health Organization (WHO) Drug Dictionary and 
tabulated. 
6.4.3. 
Analysis of Efficacy Parameters 
The following methods will be applied to the investigator assessments: 
Overall Response Rate 
The point estimate of the ORR will be calculated.  The corresponding 95% confidence 
interval also will be derived.  
Duration of Response 
The duration of response is measured from the time measurement criteria are met for 
CR, PR, or PRL (whichever is first recorded) until death or progressive disease is 
objectively documented.  Kaplan-Meier methodology will be used to estimate event-free 
curves and corresponding quantiles (including the median). 
Progression-free Survival  
PFS is measured from the time of first study drug administration until death or 
progressive disease is objectively documented.  Kaplan-Meier methodology will be used 
to estimate the event-free curves and corresponding quartiles (including the median). 
 
 
 
6.4.4. 
Analysis of Pharmacokinetic / 
 Parameters 
The plasma PK of acalabrutinib and a metabolite will be characterized using 
noncompartmental analysis.  The following PK parameters will be calculated, whenever 
possible, from plasma concentrations of acalabrutinib: 
• 
AUC0-last 
Area under the plasma concentration-time curve calculated 
using linear trapezoidal summation from time 0 to time last, 
where “last” is the time of the last measurable concentration. 
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• 
AUC0-12 
Area under the plasma concentration-time curve from 0 to 
12 hours, calculated using linear trapezoidal summation. 
• 
AUC0-24 
Area under the plasma concentration-time curve from 0 to 
24 hours, calculated using linear trapezoidal summation. 
• 
AUC0-24calc 
area under the concentration-time curve, from time 0 to 24 hour 
timepoint, calculated by doubling the value for AUC0-12 
• 
AUC0-inf 
Area under the plasma concentration-time curve from 0 to 
infinity, calculated using the formula: AUC0-inf = AUC0-last + Clast / 
λz, where λz is the apparent terminal elimination rate constant. 
• 
Cmax 
Maximum observed plasma concentration 
• 
Tmax 
Time of the maximum plasma concentration (obtained without 
interpolation) 
• 
t½ 
Terminal elimination half-life (whenever possible)  
• 
λz 
Terminal elimination rate constant (whenever possible) 
• 
CL/F 
Oral clearance 
• 
Vz/F 
Oral volume of distribution 
Missing dates or times may be imputed for PK and 
 samples if the missing values can 
be established with an acceptable level of accuracy based on other information obtained 
during the visit in question.  If PK and 
 sampling for a given subject is not performed 
according to protocol instructions that subject may be excluded from the PK and 
 
analyses. 
The PK parameters will be tabulated and summarized using descriptive statistics.  
 
 
7. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
Acerta Pharma retains the right to terminate the study and remove all study materials 
from a study site at any time.  Specific circumstances that may precipitate such 
termination are: 
• 
Unsatisfactory subject enrollment with regard to quality or quantity 
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• 
Significant or numerous deviations from study protocol requirements, such as failures 
to perform required evaluations on subjects and maintain adequate study records 
• 
Inaccurate, incomplete and/or late data recording on a recurrent basis 
• 
The incidence and/or severity of AEs in this or other studies indicating a potential 
health hazard caused by the study treatment 
 
7.1. 
Regulatory and Ethical Compliance 
This clinical study was designed and will be implemented in accordance with the 
protocol, the ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with 
applicable local regulations (including US Code of Federal Regulations Title 21 and 
European Directive 2001/20/EC), and with the ethical principles laid down in the 
Declaration of Helsinki. 
7.2. 
Institutional Review Board and Independent Ethics Committee 
The investigator will submit this protocol, the informed consent, Investigator Brochure, 
and any other relevant supporting information (e.g., all advertising materials) to the 
appropriate IRB for review and approval before study initiation.  A signed protocol 
approval page; a letter confirming IRB approval of the protocol and informed consent; 
and a statement that the IRB is organized and operates according to Good Clinical 
Practice (GCP) and the applicable laws and regulations; must be forwarded to Acerta 
Pharma before screening subjects for the study.  Additionally, sites must forward a 
signed FDA 1572 form (Statement of Investigator) to Acerta Pharma before screening 
subjects for study enrollment.  Amendments to the protocol must also be approved by 
the IRB and local regulatory agency, as appropriate, before the implementation of 
changes in this study. 
7.3. 
Informed Consent and Protected Subject Health Information 
Authorization 
A copy of the IRB-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 7.12), must explain to each 
subject the purpose and nature of the study, the study procedures, the possible adverse 
effects, and all other elements of consent as defined in §21CFR Part 50, and other 
applicable national and local regulations governing informed consent.  Each subject 
must provide a signed and dated informed consent before enrollment into this study.  In 
the case of a subject who is incapable of providing informed consent, the investigator (or 

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designee) must obtain a signed and dated informed consent form from the subject’s 
legal guardian.  Signed consent forms must remain in each subject’s study file and be 
available for verification by study monitors at any time. 
In accordance to individual local and national subject privacy regulations, the 
investigator or designee must explain to each subject that for the evaluation of study 
results, the subject’s protected health information obtained during the study may be 
shared with Acerta Pharma and its designees, regulatory agencies, and IRBs.  As the 
study sponsor, Acerta Pharma will not use the subject’s protected health information or 
disclose it to a third party without applicable subject authorization.  It is the investigator’s 
or designee’s responsibility to obtain written permission to use protected health 
information from each subject, or if appropriate, the subject’s legal guardian.  If a subject 
or subject’s legal guardian withdraws permission to use protected health information, it is 
the investigator’s responsibility to obtain the withdrawal request in writing from the 
subject or subject’s legal guardian and to ensure that no further data will be collected 
from the subject.  Any data collected on the subject before withdrawal will be used in the 
analysis of study results. 
7.4. 
Subject Screening Log 
The investigator must keep a record that lists all subjects considered for enrollment in 
the study.  For those subjects subsequently excluded from enrollment, record the 
reason(s) for exclusion. 
7.5. 
Case Report Forms 
Authorized study site personnel (see Section 7.12) will complete eCRFs designed for 
this study according to the completion guidelines that will be provided.  The investigator 
will ensure that the eCRFs are accurate, complete, legible, and completed promptly.  
The investigator will ensure that source documents that are required to verify the validity 
and completeness of data transcribed on the eCRFs are never obliterated or destroyed. 
7.6. 
Study Monitoring Requirements 
Representatives of Acerta Pharma or its designee will monitor this study until 
completion.  Monitoring will be conducted through personal visits with the investigator 
and site staff as well as any appropriate communications by mail, fax, email, or 
telephone.  The purpose of monitoring is to ensure compliance with the protocol and the 
quality and integrity of the data.  This study is also subject to reviews or audits. 

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Every effort will be made to maintain the anonymity and confidentiality of all subjects 
during this clinical study.  However, because of the experimental nature of this 
treatment, the investigator agrees to allow the IRB, representatives of Acerta Pharma, its 
designated agents, and authorized employees of the appropriate regulatory agencies to 
inspect the facilities used in this study and, for purposes of verification, allow direct 
access to the hospital or clinic records of all subjects enrolled into this study.  This 
includes providing by fax, email, or regular mail de-identified copies of radiology, 
pathology, and/or laboratory results when requested by the sponsor.  A statement to this 
effect will be included in the informed consent and permission form authorizing the use 
of protected health information. 
7.7. 
Investigational Study Drug Accountability 
Acalabrutinib must be kept in a locked limited access cabinet or space.  The study drug 
must not be used outside the context of the protocol.  
Acalabrutinib accountability records must be maintained and readily available for 
inspection by representatives of Acerta Pharma and are open to inspections by 
regulatory authorities at any time.  
Each shipment of acalabrutinib will contain a Clinical Supplies Shipping Receipt Form 
(CSSF).  Contents of each shipment must be visually inspected to verify the quantity and 
document the condition of acalabrutinib.  The person receiving the shipment and 
inspecting it must respond to the Drug Depot’s e-mail.  A copy of the signed and dated 
CSSF must be emailed to Acerta Pharma at the email address listed on the form; this 
completed form should be filed in the pharmacy binder. 
Additionally, a Drug Re-order Form for requesting more acalabrutinib is provided in the 
pharmacy binder.  If it is used, then the Drug Re-order Form must also be filed with the 
site’s drug accountability records.   
A Study Drug Accountability Log must be used for drug accountability.  For accurate 
accountability, the following information must be noted when drug supplies are used 
during the study: 
1. 
study identification number (ACE-CL-001) 
2. 
subject identification number 
3. 
lot number(s) of acalabrutinib dispensed for that subject 
4. 
date and quantity of drug dispensed 

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5. 
any unused drug returned by the subject 
At study initiation, the monitor will evaluate and approve the site’s procedure for study 
drug disposal/destruction to ensure that it complies with Acerta Pharma’s requirements.  
If the site cannot meet Acerta Pharma’s requirements for disposal/destruction, 
arrangements will be made between the site and Acerta Pharma or its representative, for 
return of unused study drug.  Before disposal/destruction, final drug accountability and 
reconciliation must be performed by the monitor. 
All study supplies and associated documentation will be regularly reviewed and verified 
by the monitor. 
7.8. 
Record Retention 
The investigator and other appropriate study staff are responsible for maintaining all 
documentation relevant to the study.  Mandatory documentation includes copies of study 
protocols and amendments, each FDA Form 1572, IRB approval letters, signed ICFs, 
drug accountability records, SAE forms transmitted to Acerta Pharma, subject files 
(source documentation) that substantiate entries in eCRFs, all relevant correspondence 
and other documents pertaining to the conduct of the study. 
An investigator shall retain records for a period of at least 2 years after the date the last 
marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified.  The investigator must notify Acerta Pharma and obtain 
written approval from Acerta Pharma before destroying any clinical study records at any 
time.  Acerta Pharma will inform the investigator of the date that study records may be 
destroyed or return to Acerta Pharma. 
Acerta Pharma must be notified in advance of, and Acerta Pharma must provide express 
written approval of, any change in the maintenance of the foregoing documents if the 
investigator wishes to move study records to another location or assign responsibility for 
record retention to another party.  If the investigator cannot guarantee the archiving 
requirements set forth herein at his or her study site for all such documents, special 
arrangements must be made between the investigator and Acerta Pharma to store such 
documents in sealed containers away from the study site so that they can be returned 
sealed to the investigator for audit purposes. 

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7.9. 
Protocol Amendments 
Acerta Pharma coordinate any change to the protocol in a protocol amendment 
document.  The amendment will be submitted to the IRB 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 approval must be received by 
Acerta Pharma before the amendment may take effect.  Additionally, under this 
circumstance, information on the increased risk and/or change in scope must be 
provided to subjects already actively participating in the study, and they must read, 
understand, and sign any revised ICF confirming willingness to remain in the trial. 
7.10. 
Publication of Study Results 
Authorship, in general, will follow the recommendations of the International Committee of 
Medical Journal Editors (ICMJE 2014).   
7.11. 
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. 
7.12. 
General Investigator Responsibilities 
The principal investigator must ensure that: 
1. 
He or she will personally conduct or supervise the study. 
2. 
His or her staff and all persons who assist in the conduct of the study clearly 
understand their responsibilities and have their names included in the Study 
Personnel Responsibility/Signature Log. 
3. 
The study is conducted according to the protocol and all applicable regulations. 
4. 
The protection of each subject’s rights and welfare is maintained. 
5. 
Signed and dated informed consent and 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 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. 
9. 
Any significant protocol deviations are reported to Acerta Pharma and the IRB 
according to the guidelines at each study site. 

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10. 
eCRF pages are completed promptly. 
11. 
All Safety Reports are submitted promptly to the IRB. 
12. 
All SAEs are reported to the Sponsor Representative within 24 hours of 
knowledge and to the IRB per their requirements. 
 

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8. 
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Absi A, His E, Kalaycio M. Prolymphocytic leukemia. Curr Treat Options Oncol 
2005;6:197-208. 
Advani RH, Buggy JJ, Sharman JP, et al.  Bruton tyrosine kinase inhibitor ibrutinib 
(PCI-32765) has significant activity in patients with relapsed/refractory B-cell 
malignancies.  JCO 2013;31:88-94. 
Bradshaw JM. The Src, Syk, and Tec family kinases: distinct types of molecular 
switches. Cell Signal 2010;22:1175-84.  
Buggy JJ, Elias L. Bruton tyrosine kinase (Btk) and its role in B-cell malignancy. Int Rev 
Immunol 2012;31:119-32. Erratum in: Int Rev Immunol 2012;31:428. 
Byrd JC, Furman RR, Coutre SE, Flinn IW, et al. Targeting Btk with ibrutinib in relapsed 
chronic lymphocytic leukemia. NEJM 2013;369:32-42. 
Byrd JC, Brown JR, O'Brien S, et al.  Ibrutinib versus ofatumumab in previously treated 
chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17;371(3):213-23. 
Byrd JC, Harrington B, O'Brien S, et al.  Acalabrutinib (ACP-196) in Relapsed Chronic 
Lymphocytic Leukemia. NEJM 2016;374:323-332. 
Chen J, Tan K, Zhou H, Lo HF, Roux DT, Liddington RC, Diacovo TG. Modifying murine 
von Willebrand factor A1 domain for in vivo assessment of human platelet therapies. Nat 
Biotechnol. 2008 Jan; 26(1):114-9. 
Cheson BD, Fisher RI, Barrington SF, et al.  Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification.  J Clin Oncol 2014 Sep 20;32(27):3059-3068. 
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical 
end points in chronic lymphocytic leukemia. J Clin Oncol 2012 30:2820-2822. 
FDA 2005 Guidance for industry. Estimating the maximum safe starting dose in initial 
clinical trials for therapeutics in adult healthy volunteers. 2005 Jul. Available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/ucm078932.pdf. 
FDA 2010 Guidance for industry. S9 nonclinical evaluation for anticancer 
pharmaceuticals. 2010 Mar. Available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/ucm085389. 
Gardner HL, Harrington BK, Izumi R, et al.  ACP-196: A second generation Btk inhibitor 
demonstrates biologic activity in a canine model of B-cell non-Hodgkin lymphoma.  
AACR 2014 Annual Meeting Abstract #1744. 
Hallek M, Cheson BD, Catovsky D, et al.  Guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia: a report from the International Workshop on Chronic 
Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 
guidelines. Blood 2008;111:5446-5456.  
Harrington BK, Gardner HL, Izumi R, et al. Preclinical evaluation of the novel BTK 
inhibitor acalabrutinib in canine models of B-cell Non-Hodgkin Lymphoma. PLoS One 
2016 Jul 19;11(7):e0159607. doi: 10.1371/journal.pone.0159607. eCollection 2016. 

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Honigberg LA, Smith AM, Sirisawad M, et al.  The Bruton tyrosine kinase inhibitor PCI-
32765 blocks B-cell activation and is efficacious in models of autoimmune disease and 
B-cell malignancy. PNAS 2010;107:13075-13080. 
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals. 2014 Dec.  
Available from: http://www.ICMJE.org.  Accessed 04 February 2015. 
Jandl JH. Chronic lymphatic leukemia. In: Blood: Textbook of Hematology.  Boston, 
Mass: Little Brown; 1996:991–1018. 
Kamel S, Horton L, Ysebaert L, et al.  Ibrutinib inhibits collagen-mediated but not 
ADP-mediated platelet aggregation.  Leukemia 2014 Aug 20 [epub]. 
Kohrt HE, Sagiv-Barfi I, Rafiq S, et al. Ibrutinib antagonizes rituximab-dependent NK cell 
mediated cytotoxicity. Blood 2014 Mar 20;123(12):1957-1960. 
Mohamed AJ, Yu L, Bäckesjö CM, et al. Bruton tyrosine kinase (Btk): function, 
regulation, and transformation with special emphasis on the PH domain. Immunol Rev 
2009;228:58-73. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 
1989;10:1-10. 
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. 
Vail DM, Michels GM, Khanna C, Selting KA, London CA; Veterinary Cooperative 
Oncology Group. Response evaluation criteria for peripheral nodal lymphoma in dogs 
(v1.0)—a Veterinary Cooperative Oncology Group (VCOG) consensus document. Vet 
Comp Oncol 2010;8:28-37. 
Vail DM, Thamm DH. Spontaneously occurring tumors in companion animals as models 
for drug development. In: Teicher BA, Anders PA, eds. Anticancer Drug Development 
Guide: Preclinical Screening, Clinical Trials, and Approval. 2nd Ed. Totowa, NJ: Human 
Press; 2004:259-284. 
Vihinen M, Mattsson PT, Smith CI. Bruton tyrosine kinase (Btk) in X-linked 
agammaglobulinemia (XLA). Front Biosci 2000;5:D917-D928. 
Wang ML, Rule S, Martin P, et al. Targeting Btk with ibrutinib in relapsed or refractory 
mantle-cell lymphoma.  NEJM 2013;369:507-516. 
 

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Appendix 1  Examples of Coadministered Drugs That Need Additional 
Consideration 
The lists of drugs in these tables are not exhaustive.  Any questions about drugs not on 
this list should be addressed to the medical monitor of this study. 
Strong Inhibitors of CYP3A 
Moderate inhibitors of CYP3A 
boceprevir 
aprepitant 
clarithromycina 
cimetidine 
cobicistata 
ciprofloxacin 
conivaptana 
clotrimazole 
danoprevir and ritonavirb 
crizotinib, 
diltiazema 
cyclosporine 
elvitegravir and ritonavirb 
dronedaronea 
grapefruit juice 
erythromycin 
idelalisib 
fluconazole 
indinavir and ritonavirb 
fluvoxamine 
itraconazolea 
imatinib 
ketoconazole, 
tofisopam 
lopinavir and ritonavira,b 
verapamila 
nefazodone 
 
nelfinavira 
 
paritaprevir and ritonavir and (ombitasvir 
and/or dasabuvir)b 
 
posaconazole 
 
ritonavira, b 
 
saquinavir and ritonavira, b 
 
telaprevira 
 
tipranavir and ritonavira, b 
 
troleandomycin 
 
voriconazole 
 
a. Inhibitor of P-glycoprotein. 
b.  Ritonavir is usually given in combination with other anti-HIV or anti-HCV 
drugs in clinical practice.  Caution should be used when extrapolating the 
observed effect of ritonavir alone to the effect of combination regimens on 
CYP3A activities. 
c.  After discontinuation of the strong CYP3A inhibitor, wait 3 days before 
resuming acalabrutinib.  
 
Strong Inducers of CYP3A 
Moderate inducers of 
CYP3A 
carbamazepine 
bosentan 
enzalutamide 
efavirenz 
mitotane 
etravirine 
phenytoin 
modafinil 
rifampin 
 
St. John’s worta 
 
a.  The effect of St. John’s wort varies widely and is preparation dependent. 
 
 

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P-gp Inhibitors 
BCRP Inhibitors 
Narrow Therapeutic 
Index P-gp Substrates 
amiodarone 
curcumin 
digoxin 
carvedilol 
cyclosporine A 
everolimus 
clarithromycin 
eltrombopag 
sirolimus 
dronedarone 
 
 
itraconazole 
 
 
lapatinib 
 
 
lopinavir and ritonavir 
 
 
propafenone 
 
 
quinidine 
 
 
ranolazine 
 
 
ritonavir 
 
 
saquinavir and ritonavir 
 
 
telaprevir 
 
 
tipranavir and ritonavir 
 
 
verapamil 
 
 
Source:  FDA Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers. Web link Accessed 18 July 2018: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dru
gInteractionsLabeling/ucm093664.htm#inVivo        
 
Bile Acid Sequestrants 
Proton Pump Inhibitors 
H2-Receptor Antagonists 
cholestyramine 
dexlansoprazole 
cimetidine 
colestipol 
esomeprazole 
famotidine 
colesevelam 
lansoprazole 
nizatidine 
 
omeprazole 
ranitidine 
 
rabeprazole 
 
 
pantoprazole 
 
Source: FDA Established Pharmacologic Class Text Phrase. Web link accessed 18 July 
2018:  
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/lawsactsan
drules/ucm428333.pdf 
 
 

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Appendix 2  ECOG Performance Status 
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, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin 
Oncol 5:649-655, 1982. 
Credit: Eastern Cooperative Oncology Group Chair: Robert Comis, MD 
Available at: http://www.ecog.org/general/perf_stat.html.  Accessed 23 August 2013. 

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Appendix 3  Adverse Event Assessment of Causality 
Is there a reasonable possibility that the event may have been caused by study drug?  
No___ Yes___ 
The descriptions provided below will help guide the principal investigator in making the 
decision to choose either “yes” or “no”: 
No = There is no reasonable possibility that the event may have been caused by study 
drug. 
The adverse event: 
• 
may be judged to be due to extraneous causes such as disease or environment 
or toxic factors 
• 
may be judged to be due to the subject’s clinical state or other therapy being 
administered 
• 
is not biologically plausible 
• 
does not reappear or worsen when study drug is re-administered 
• 
does not follow a temporal sequence from administration of study drug 
Yes = There is a reasonable possibility that the event may have been caused by study 
drug. 
The adverse event: 
• 
follows a temporal sequence from administration of study drug 
• 
is a known response to the study drug based on clinical or preclinical data 
• 
could not be explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other therapy administered to the subject 
• 
disappears or decreases upon cessation or reduction of dose of study drug 
• 
reappears or worsens when study drug is re-administered 

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Appendix 4  Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law 
 
INTRODUCTION 
This Appendix describes the process to be followed to identify and appropriately report 
potential Hy’s law (PHL) cases and Hy’s law (HL) cases.  It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.  
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a subject meets 
PHL criteria at any point during the study.  All sources of laboratory data are appropriate 
for the determination of PHL and HL events; this includes samples taken at scheduled 
study visits and other visits, including central and all local laboratory evaluations, even if 
collected outside of the study visits (e.g., PHL criteria could be met by an elevated ALT 
from a central laboratory and/or elevated total bilirubin from a local laboratory).  The 
investigator will also review adverse event (AE) data (e.g., for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events. 
The investigator participates with the sponsor in the review and assessment of cases 
meeting PHL criteria to agree whether HL criteria are met.  HL criteria are met if there is 
no alternative explanation for the elevations in liver biochemistry other than drug-induced 
liver injury (DILI) caused by the investigational medicinal product (IMP).  The investigator 
is responsible for recording data pertaining to PHL/HL cases and for reporting AEs and 
serious adverse events (SAEs) according to the outcome of the review and assessment 
in line with standard safety-reporting processes.  
DEFINITIONS 
Potential Hy’s Law  
AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN at any point during the study 
after the start of study drug, irrespective of an increase in alkaline phosphatase.  
Hy’s Law 
AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN, where no reason other than 
the IMP can be found to explain the combination of increases (e.g., elevated alkaline 
phosphatase indicating cholestasis, viral hepatitis, or another drug).   
For PHL and HL, the elevation in transaminases must precede or be coincident with 
(i.e., on the same day) the elevation in total bilirubin, but there is no specified timeframe 
within which the elevations in transaminases and total bilirubin must occur. 

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

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

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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. 
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 

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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 
 

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Appendix 5  Management of Study Procedures During Pandemic 
This appendix consolidates guidance for subject safety and ongoing access to medical 
care and investigational product during the global COVID-19 pandemic.  The measures 
detailed below will be implemented across Acerta Pharma studies on a temporary basis 
until the pandemic is considered resolved by governmental and public health 
organizations, as applicable.  
Regardless of the guidance below, please consider public health advice in your local 
market and individual risk/benefit in treatment decisions for patients at your study site 
during the pandemic.  Please also consider logistical requirements such as the ability of 
patients to travel to the study site, accessibility of public transport, etc. 
If the subject is unable or unwilling to visit the study site due to COVID-19 related 
reasons, investigators may ask enrolled subjects to use healthcare facilities local to the 
subject to ensure safety and efficacy measures are done per protocol. If a study 
assessment is not done at either the site or a facility local to the subject, then its 
absence should be documented as a protocol deviation.  Any protocol deviations 
resulting from the COVID-19 situation should be recorded and prefixed with COVID19. 
STUDY SUBJECT PARTICIPATION 
Conduct of Telephone Visits 
Due to the current pandemic, it is conceivable that not all subject visit commitments may 
be able to be fulfilled.  If a subject is unable or unwilling to attend a study visit, 
adaptation of the onsite visit to a telephone visit is recommended to ensure continuity of 
study care (as an interim measure; e.g., telephone contacts instead of visits, shipping 
study medication to the subject).  Priority should be given to maintaining ongoing safety 
follow-up (even if this is conducted by telephone contacts).  Study sites should speak 
with their site monitor before performing a telephone visit so he or she may provide 
guidance regarding logistics that may need consideration.  Also, study sites should 
speak with the site monitor if the subject cannot attend more than one onsite visit in 
succession, because multiple incomplete visits may have the potential to impact 
evaluation of study endpoints. 
Acalabrutinib Dose Modification Recommendation for COVID-19 
The sponsor recognizes that coronavirus 2019-nCoV (COVID-19) presents an increased 
risk for all patients.  Due to the potential impact of COVID-19 on multiple organ systems, 
the sponsor recommends the following dose modification and management plan for 
patients with confirmed or suspected COVID-19 while receiving treatment with 
acalabrutinib.  
First and foremost, the following safety reporting guidelines are required:  
All confirmed or suspected COVID-19-related adverse events (AEs) must be recorded in 
the eCRF. All dose modifications should be based on the worst Common Terminology 
Criteria for Adverse Events (CTCAE) grade.  All interruptions or modifications must be 
recorded on the AE and drug administration eCRFs.  The CTCAE general grading 
criteria should be used to evaluate COVID-19.  
If an event is suspected to be COVID -19 infection, the sponsor recommends 
interrupting acalabrutinib and testing for COVID-19 per local guidance.  
• 
If COVID-19 is ruled out, standard clinical practice and the study protocol 
procedures should be followed regarding any dose modifications required for 
management of severe infections.  

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• 
If COVID-19 is confirmed or diagnosis is suspected after evaluation, COVID-19 
infection should be managed per local guidance until the subject achieves full 
recovery, defined as no signs or symptoms.  
In case of COVID-19 positivity, the investigator must determine the risk and benefit of 
interruption versus continuation of acalabrutinib and whether to resume it at full or 
modified doses or discontinue treatment.  
Please contact the study medical monitor for further discussion.  
Comparator Drugs or Drugs used in Combination with Acalabrutinib 
• 
Please refer to guidance from the manufacturer.  
Drug-drug interactions (DDI) may occur with some of the drugs being used as best 
supportive care (e.g., drugs that are strong inducers or inhibitors of cytochrome P450 
[CYP]3A). Guidance is provided below:  
Drug-Drug Interaction Guidance for Investigators with Subjects Enrolled in an 
Acalabrutinib Clinical Study Who Are COVID-19 Positive  
• 
The potential combination with chloroquine or 8-8-OH-chloroquine (8-OH-CHQ) 
and azithromycin are not predicted to have a pharmacokinetic DDI with 
acalabrutinib.  However, both agents are known to cause cardiovascular risk of 
QT prolongation.  Therefore, the risk/benefit of initiating 8-OH-CHQ + 
azithromycin should be discussed with the medical monitor.  
• 
Many antivirals and antibiotics are considered strong CYP3A4 inhibitors or 
inducers and are therefore likely to cause complex DDIs with acalabrutinib.  The 
risk benefit balance of acalabrutinib use in the setting of COVID-19 treatment 
should be discussed between the investigator and the medical monitor.  
• 
Remdesivir is rapidly metabolized to a pharmacologically active metabolite, GS-
443902.  Based on published and publicly available data, remdesivir does not 
appear to inhibit CYP isoforms and will likely not interact in a meaningful way 
with drug transport systems.  Remdesivir does not prolong QTc interval.  
• 
Systemic steroids and acalabrutinib may impair the ability of the body to fight 
infection; it is best to avoid high-dose systemic steroids while taking 
acalabrutinib.  
• 
The study protocol and investigator brochure should be referenced for other DDI 
information.  
COVID-19 SPECIFIC DATA ENTRY INSTRUCTIONS FOR INVESTIGATIONAL SITES 
Adverse Event Recording 
Currently no changes to normal data capture procedures are required for COVID-19 
data in the eCRF.  For subjects who have confirmed or who are suspected of having 
coronavirus infection, the infection should be documented as an AE or serious adverse 
event (SAE), in line with instructions for safety reporting documented in the clinical study 
protocol.  Either “COVID 19 Confirmed” or “COVID-19 Suspected” should be used 
when reporting the event as follows: 
• 
If test is positive, “COVID-19 confirmed” should be recorded in the AE field. 
• 
If test is negative, AE/SAE signs and symptoms and/or other diagnosis should be 
recorded in the AE field(s). 

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• 
If test is not available and signs and symptoms, as judged by the investigator, are 
highly suspicious of COVID-19 infection, record “COVID-19 suspected” in the AE 
field. 
Details of any testing or procedure to determine the status of COVID-19 infection should 
be documented on the Concomitant Procedure Form if available or on the appropriate 
eCRF page in the study. 
For fatal SAEs, the Death Information Form, End of Study Treatment Form, and Study 
Exit Form should be completed.  
Study Treatment Recording 
If an AE or SAE is associated with COVID-19, the investigator should determine whether 
the subject’s treatment with investigational product should continue, be interrupted, or be 
discontinued in accordance with the clinical study protocol. 
For dosing interruptions, where applicable, the following guidelines should be used: 
• 
Related to AE:  
o On the Dose Administration Forms(s), dose change/missed should be 
indicated with AE as the reason. The dosing stop date must correlate to 
the AE/SAE start/stop dates. 
• 
Related to Logistics:  
o For subjects who have missed a study treatment due to an inability to 
travel to the clinic or for some other logistical reason, on the Dose 
Administration Form(s) dose change/missed should be indicated with 
Other as the reason, and “Logistic” as Other, Specify. 
If these options are not available in the eCRF, then either dose discontinuation should 
be recorded (if permanently stopped) or a protocol deviation should be recorded, 
prefixed COVID19. 
For dosing discontinuations, where applicable, the dosing discontinuation guidelines 
should be followed, and the End of Treatment Form(s) completed. 
Capturing Telephone Contacts with Subjects 
If a telephone visit is substituted for an onsite study visit, the following are guidelines for 
data capture: 
1. 
If the visit is specified as a phone visit as per protocol, no additional action is 
required.  
2. 
If the visit is listed as on-site but the subject will be contacted by phone, data 
should be completed as per a normal visit (i.e., using the relevant eCRF pages to 
capture a phone Visit Date), and any possible assessment that can be obtained remotely 
should be captured, such as AEs, study drug administration and/or concomitant 
medications, and any additional safety information.  All assessments that cannot be 
performed should be marked as not done or eCRF inactivated/marked Blank.  A protocol 
deviation should be recorded in the clinic notes prefixed COVID19 detailing the use of a 
phone visit in place of an onsite visit.   
3. 
If the visit requires procedures that cannot be performed via telephone contact 
(e.g., MRI or CT scan), this should be discussed with the site monitor because this 
procedure may impact primary efficacy or safety analyses. 

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ACALABRUTINIB SITE-TO-SUBJECT DRUG SHIPMENT INSTRUCTIONS DURING 
PANDEMIC CONTAINMENT OR IN CASE OF FORCE MAJEURE 
If a subject is definitively unable to physically go to the study site or unable to be 
represented by a third person because of pandemic containment or other force majeure, 
the study site's pharmacy may ship the study drug to the home of the subject following 
approval by the sponsor.  
For such a shipment, the following conditions must be met: 
• 
The sponsor is responsible for delivery of the study drug to the study site.  Any 
shipments made from the site to the subject will be the responsibility of the study 
site. 
• 
The subject is informed about the shipment method, confirms the address for 
receipt of the drug, and agrees that his or her personal information (i.e., name 
and address) may be given to a professional carrier. 
• 
The pharmacy securely packages the drug for shipment.  
• 
A professional carrier is used by the pharmacy to ship the drug securely and 
maintain chain of custody, with evidence provided.  Acalabrutinib must be stored 
and shipped at room temperature (15°C to 30°C).  The professional carrier must 
ensure that temperature monitoring is conducted for all shipments. 
• 
To respect patient confidentiality, the carrier should only be given the name and 
address of the subject.  The sponsor should not receive any personal information 
about the subject. 
• 
A procedure is defined with the carrier to confirm the receipt of the drug by the 
subject and that it is received in good condition. 
• 
The site contacts the subject to confirm the receipt and integrity of the drug and 
gives instructions about the drug administration. 
• 
The pharmacy completes its accountability with each shipment made directly to a 
subject.