A Phase 1b/2, Multicenter, Open-label Study of ACP-196 in Subjects With Recurrent Glioblastoma Multiforme (GBM)
Phase: PHASE1
Conditions: Glioblastoma Multiforme
Sponsor: Acerta Pharma BV

Product: ACP-196 (Acalabrutinib) 
Protocol: ACE-ST-209 
 
 
 
 
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PROTOCOL 
TITLE: 
A Phase 1b/2, Multicenter, Open-label Study of ACP-196 
in Subjects with Recurrent Glioblastoma Multiforme 
(GBM) 
PROTOCOL NUMBER: 
ACE-ST-209 
STUDY DRUG: 
Acalabrutinib (ACP-196) 
IND NUMBER: 
124612 
SPONSOR MEDICAL 
MONITOR: 
 
 
Phone: 
 
Email: 
 
SPONSOR: 
Acerta Pharma BV 
 
5349 AB Oss 
The Netherlands 
ORIGINAL PROTOCOL: 
Version 0.0 – 06 September 2015 
AMENDMENT 1 DATE: 
Version 1.0 – 21 January 2016 
AMENDMENT 2 DATE: 
Version 2.0 – 21 March 2017 
AMENDMENT 3 DATE: 
Version 3.0 – 18 March 2020 
 
 
Confidentiality Statement 
This document contains proprietary and confidential information of Acerta Pharma BV that 
must not be disclosed to anyone other than the recipient study staff and members of the 
institutional review board (IRB)/independent ethics committee (IEC). This information cannot 
be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Acerta Pharma BV. 
  
PPD
PPD
PPD
PPD
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PROTOCOL APPROVAL PAGE 
Version 3.0 
I have carefully read Protocol ACE-ST-209 entitled “A Phase 1b/2, Multicenter, 
Open-label Study of ACP-196 in Subjects with Recurrent Glioblastoma Multiforme 
(GBM)”.  I agree to conduct this study as outlined herein and in compliance with Good 
Clinical Practices (GCP) and all applicable regulatory requirements.  Furthermore, I 
understand that the sponsor, Acerta Pharma, and the IRB/IEC must approve any 
changes to the protocol in writing before implementation. 
I agree not to divulge to anyone, either during or after the termination of the study, any 
confidential information acquired regarding the investigational product and processes or 
methods of Acerta Pharma.  All data pertaining to this study will be provided to Acerta 
Pharma.  The policy of Acerta Pharma requires that any presentation or publication of 
study data by clinical investigators be reviewed by Acerta Pharma, before release, as 
specified in the protocol. 
 
Principal Investigator’s Signature 
Date 
 
 
Print Name 
 

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SUMMARY OF AMENDMENT 3 
This protocol is being amended to update the safety language to align with latest 
Acalabrutinib Investigator Brochure and to add rollover language and align with other 
Acerta protocols.  The medical monitor has also been updated to 
 
 
Clarifying edits and typographical changes have been made throughout the protocol.  In 
addition, the following substantive changes were made as part of this amendment.  New 
text is shown in italics. 
Description of Change 
Sections 
Updated/added language to align with latest 
Acalabrutinib Investigator Brochure and/or to 
align with other Acerta protocols 
Sections 1.3, 1.5, 3.0, 3.2, 3.5, 3.6, 3.8.2, 
3.9.1 (new section added), 3.9.2 (new 
section added), 3.9.3 (new section added), 
3.9.5 (new section added), 3.9.6, 3.9.7, 3.9.8, 
6.1.3 (new section added), 6.2.1, 6.2.3 (new 
section added), Appendix 3, and Appendix 7 
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TABLE OF CONTENTS 
1.0 
BACKGROUND INFORMATION ............................................................. 21 
1.1 
Glioblastoma Multiforme .......................................................................... 21 
1.2 
Bruton Tyrosine Kinase Inhibition in Cancer ............................................ 22 
1.3 
Acalabrutinib ............................................................................................ 22 
1.3.1 
Mechanism of Action .................................................................. 23 
1.3.2 
Safety Pharmacology ................................................................. 23 
1.3.3 
Drug-Drug Interaction Potential .................................................. 23 
1.3.4 
Acalabrutinib and the Blood-Brain Barrier .................................. 23 
1.4 
Clinical Experience – Acalabrutinib .......................................................... 24 
1.5 
Benefit/Risk .............................................................................................. 25 
2.0 
STUDY OBJECTIVES ............................................................................. 25 
2.1 
Primary Objectives: .................................................................................. 25 
2.2 
Secondary Objectives: ............................................................................. 25 
2.3 
Exploratory Objectives: ............................................................................ 25 
3.0 
STUDY DESIGN ...................................................................................... 26 
3.1 
Study Parameters .................................................................................... 30 
3.1.1 
Safety Parameters ...................................................................... 30 
3.1.2 
Pharmacodynamic, Pharmacokinetic, and Biomarker 
Parameters ................................................................................. 30 
3.1.3 
Efficacy Parameters ................................................................... 31 
3.2 
Rationale for Study Design and Dosing Regimen .................................... 31 
3.3 
Selection of Study Population .................................................................. 32 
3.3.1 
Inclusion Criteria ......................................................................... 32 
3.3.2 
Exclusion Criteria ....................................................................... 33 
3.3.3 
Replacement of Subjects ........................................................... 35 
3.3.4 
Enrollment Procedures ............................................................... 35 
3.4 
Study Drug ............................................................................................... 35 
3.4.1 
Premedications ........................................................................... 35 
3.4.2 
Formulation, Packaging, and Storage ........................................ 36 
3.4.3 
Administration of Study Drug ...................................................... 36 
3.4.4 
Assuring Subject Compliance..................................................... 37 
3.5 
Study Treatment Schedule ...................................................................... 37 
3.6 
Duration of Therapy ................................................................................. 37 
3.7 
Dosing Delays and Modifications ............................................................. 38 
3.8 
Concomitant Therapy............................................................................... 39 
3.8.1 
Permitted Concomitant Therapy ................................................. 39 
3.8.2 
Prohibited or Restricted Concomitant Therapy ........................... 39 

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3.9 
Precautions .............................................................................................. 40 
3.9.1 
Reference Safety Information ..................................................... 40 
3.9.2 
Risks Associated with Acalabrutinib ........................................... 40 
3.9.3 
Dietary Restrictions .................................................................... 42 
3.9.4 
Hepatitis B Virus Reactivation .................................................... 42 
3.9.5 
Progressive Multifocal Leukoencephalopathy ............................ 43 
3.9.6 
Drug-Drug Interactions ............................................................... 43 
3.9.7 
Surgery ....................................................................................... 44 
3.9.8 
Reproductive Toxicity ................................................................. 44 
3.9.9 
Overdose Instructions ................................................................ 46 
3.10 
Withdrawal of Subjects from Study Treatment ......................................... 46 
3.11 
Reasons for Study Exit ............................................................................ 47 
3.12 
Data and Safety Monitoring ..................................................................... 48 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS ............................................ 48 
4.1 
Description of Procedures ........................................................................ 49 
4.1.1 
Informed Consent ....................................................................... 49 
4.1.2 
Medical History ........................................................................... 49 
4.1.3 
Adverse Events .......................................................................... 49 
4.1.4 
Concomitant Medications and Therapy ...................................... 49 
4.1.5 
Confirmation of Eligibility ............................................................ 49 
4.1.6 
ECOG Performance Status ........................................................ 49 
4.1.7 
Physical Examination, Vital Signs, Height, and Weight .............. 49 
4.1.8 
Electrocardiogram ...................................................................... 50 
4.1.9 
Urine or Serum Pregnancy Test ................................................. 50 
4.1.10 Hematology ................................................................................ 50 
4.1.11 Serum Chemistry ........................................................................ 50 
4.1.12 Coagulation ................................................................................ 50 
4.1.13 Urinalysis .................................................................................... 51 
4.1.14 T/B/NK/Monocyte Cell Count ..................................................... 51 
4.1.15 Hepatitis B and C Testing ........................................................... 51 
4.1.16 Pharmacodynamics/Pharmacokinetics and Biomarker Studies . 51 
4.1.17 
 ................................................................... 53 
4.1.18 
 ............................................................. 53 
4.1.19 Patient-Reported Outcome ......................................................... 54 
4.1.20 Study Drug Accountability .......................................................... 55 
4.2 
Investigator’s Assessment of Response to Treatment ............................. 55 
4.3 
Treatment Termination and Safety Follow-up Visits ................................ 56 
4.4 
Follow-Up for Progression and Survival ................................................... 57 
4.4.1 
Post-Treatment Disease Follow-Up ............................................ 57 
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4.4.2 
Long-Term Follow-Up ................................................................. 57 
4.5 
Missed Evaluations .................................................................................. 57 
5.0 
STATISTICAL METHODS OF ANALYSIS ............................................... 57 
5.1 
General Considerations ........................................................................... 57 
5.2 
Definition of Analysis Sets ....................................................................... 58 
5.3 
Missing Data Handling ............................................................................. 58 
5.4 
Endpoint Data Analysis ............................................................................ 58 
5.4.1 
Safety Endpoint .......................................................................... 58 
5.4.2 
Demographics and Baseline Characteristics .............................. 59 
5.4.3 
Study Treatment Administration and Compliance ...................... 59 
5.4.4 
Analysis of Efficacy Parameters ................................................. 59 
5.4.5 
PK, PD, or Biomarker Analyses.................................................. 60 
6.0 
ASSESSMENT OF SAFETY ................................................................... 61 
6.1 
Definitions ................................................................................................ 61 
6.1.1 
Adverse Events .......................................................................... 61 
6.1.2 
Serious Adverse Event ............................................................... 62 
6.1.3 
Adverse Events of Special Interest ............................................. 63 
6.1.4 
Severity ...................................................................................... 63 
6.2 
Documenting and Reporting of Adverse and Serious Adverse Events .... 64 
6.2.1 
Adverse Event Reporting Period ................................................ 64 
6.2.2 
Assessment of Adverse Events .................................................. 64 
6.2.3 
Second Primary Malignancies .................................................... 65 
6.2.4 
Pregnancy .................................................................................. 65 
6.2.5 
Expedited Reporting Requirements for Serious Adverse Events 66 
6.2.6 
Type and Duration of Follow-up of Subjects after Adverse 
Events ........................................................................................ 67 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ........ 67 
7.1 
Institutional Review Board and Independent Ethics Committee ............... 68 
7.2 
Informed Consent and Protected Subject Health Information 
Authorization ............................................................................................ 68 
7.3 
Subject Screening Log ............................................................................. 69 
7.4 
Case Report Forms ................................................................................. 69 
7.5 
Study Monitoring Requirements ............................................................... 69 
7.6 
Investigational Study Drug Accountability ................................................ 69 
7.7 
Record Retention ..................................................................................... 70 
7.8 
Protocol Amendments.............................................................................. 70 
7.9 
Publication of Study Results .................................................................... 71 
7.10 
Clinical Trial Insurance............................................................................. 71 

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7.11 
General Investigator Responsibilities ....................................................... 71 
8.0 
REFERENCES ........................................................................................ 73 
APPENDICES .................................................................................................... 75 
 
 
IN-TEXT TABLES 
 
Table 1-1:  BTK Target Occupancy in Rat Brain Tissue .................................................24 
Table 3-1.  Drug Modification Actions for Acalabrutinib ..................................................38 
Table 4-1.  Criteria for Response Assessment ...............................................................55 
 
IN-TEXT FIGURES 
 
Figure 1-1:  Acalabrutinib Levels in Rat Brain Tissue and CSF ......................................24 
Figure 3-1.  Study Schema ............................................................................................29 
 
LIST OF APPENDICES 
Appendix 1.  Schedule of Assessments .........................................................................76 
Appendix 2.  RANO Criteria ...........................................................................................79 
Appendix 3.  Examples of Coadministered Drugs that Need Additional Consideration ..90 
Appendix 4.  Performance Status Scores ......................................................................92 
Appendix 5.  
 ...................................................................................................93 
Appendix 6.  Adverse Event Assessment of Causality ...................................................96 
Appendix 7.  Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ...........................................................................................97 
 
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ABBREVIATIONS 
Abbreviation 
Definition 
λz 
terminal elimination rate constant 
ACP-196 
Acalabrutinib (acalabrutinib = ACP-196) 
AE 
adverse event 
AKT 
protein kinase b 
ALC 
absolute lymphocyte count 
anti-HBc 
hepatitis B core antibody 
anti-HBs 
hepatitis B surface antibody 
BID 
twice per day (dosing) 
BMX 
bone marrow X-linked (nonreceptor tyrosine kinase) 
BTK 
Bruton tyrosine kinase 
CCNU 
lomustine 
CD 
cluster of differentiation (cell surface marker) 
cGMP 
current Good Manufacturing Practice 
CLL 
chronic lymphocytic leukemia 
CR 
complete response (remission) 
CSF 
cerebral spinal fluid 
CTCAE 
Common Terminology Criteria For Adverse Events 
CYP 
cytochrome p450 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capturing (system) 
EIAED 
enzyme-inducing antiepileptic drug 
 
 
FDA 
Food and Drug Administration 
GBM 
glioblastoma multiforme 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
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Abbreviation 
Definition 
IC50 
half-maximal inhibitory concentration 
ICF 
Informed Consent Form 
IEC 
independent ethics committee 
IRB 
institutional review board 
K-M 
Kaplan-Meier (curve) 
MDSC 
myeloid-derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NK 
natural killer (cells) 
NPT 
non-protocol antitumor therapy 
ORR 
overall response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PFS 
progression-free survival 
 
 
PFS-6 
6-month progression-free survival 
PD 
pharmacodynamic 
P-gp 
P-glycoprotein 1 (transporter) 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PO 
orally 
PRO 
patient-reported outcome 
QD 
once per day (dosing) 
QOL 
quality of life 
QTc 
corrected QT interval 
RANO 
Response Assessment in Neuro-Oncology (criteria) 
SAC 
Scientific Advisory Committee 
SAE 
serious adverse event 
SFU 
safety follow-up (visit) 
SUSAR 
suspected unexpected serious adverse reaction 
TT 
treatment termination (visit) 
ULN 
upper limit of normal 
WOCBP 
women of child bearing potential 
 
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STUDY SYNOPSIS 
Study Title: 
A Phase 1b/2, Multicenter, Open-label Study of ACP-196 in 
Subjects with Recurrent Glioblastoma Multiforme (GBM) 
Protocol Number: 
ACE-ST-209 
Study Drug: 
Acalabrutinib (ACP-196) 
 
Phase: 
1b/2 
Comparator: 
None 
Study Centers: 
Subjects will be enrolled in approximately 20 to 30 centers in 
the United States. 
Background and 
Rationale for Study 
Glioblastoma multiforme (GBM) is the most common form of 
malignant primary tumor of the nervous system, with an 
annual incidence of 3.19 per 100,000 people.  GBM has a 
poor prognosis, with only a third of patients surviving for 
1 year.  The grim prognosis is at least partly due to the 
failure to successfully deliver drugs across the blood-brain 
barrier.  The five-year survival rate is 5% for glioblastomas 
and the average median survival is approximately 14 to 
16 months.   
Second-line chemotherapy regimens include temozolomide; 
nitrosureas; combination procarbazine, CCNU (lomustine), 
and vincristine (PCV); cyclophosphamide; and 
platinum-based regimens.  The antiangiogenic agent, 
bevacizumab (Avastin), received accelerated approval in the 
United States in 2009 for recurrent glioblastoma based on 
modest improvements in overall response rate (ORR) and 
median duration of response (DOR) in an open-label, 
randomized, noncomparative, multicenter study of 
bevacizumab with or without irinotecan and in a single-arm, 
single institutional trial; ORRs were 25.9% (in the 
bevacizumab-containing arm) and 19.6%, respectively, and 
median DORs were 4.2 months and 3.9 months, 
respectively (AVASTIN prescribing information).  However, 
use of bevacizumab (Avastin) is associated with potential 
serious adverse events (SAEs), including hypertension, 
impaired wound healing, colonic perforation, and 
thromboembolism.  Hence, a large unmet need exists in the 
treatment of newly diagnosed and recurrent GBM. 
Acalabrutinib  is a covalent inhibitor of Bruton tyrosine 
kinase (BTK), a non-receptor enzyme in the Tec kinase 
family, which also includes bone marrow X-linked (BMX) 
nonreceptor tyrosine kinase.  

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BTK-dependent activation of mast cells, myeloid cells, and 
other immunocytes in peritumoral inflammatory stroma has 
been shown to sustain the complex microenvironment 
needed for lymphoid and solid tumor maintenance.  
Inhibition of BTK may impair the capacity of 
tumor-associated macrophages to promote tumor invasion 
and metastasis.  Several lines of evidence demonstrate that 
BTK inhibition interferes with cross-talk between malignant 
cells and their microenvironment.  BTK is also a signaling 
hub in myeloid-derived suppressor cells (MDSCs), which 
may play an important part in the suppression of antitumor 
immune responses, creating an immunosuppressive 
environment necessary for the growth of malignant cells.  
In addition, BTK and BMX have been shown to be 
expressed in gliomas.  Across a panel of various cancer 
types, gliomas show the highest levels of BTK expression, 
second only to lymphomas.  BMX is preferentially expressed 
in glioblastoma stem cells (GSCs) and activates STAT3 
signaling, playing an essential role in maintaining the stem 
cell phenotype and tumorigenic potential.  Taken together, 
these findings suggest that inhibition of BTK and BMX may 
offer an attractive strategy for targeting GBM. 
Study Objectives: 
Primary Objectives: 
 
To characterize the safety profile of acalabrutinib 
monotherapy in subjects with recurrent GBM 
 
To evaluate the efficacy of acalabrutinib 
monotherapy in subjects with recurrent GBM based 
on overall response rate (ORR) per the Response 
Assessment in Neuro-oncology (RANO) criteria 
Secondary Objectives: 
 
To evaluate the efficacy of acalabrutinib 
monotherapy based on duration of response (DOR) 
per RANO criteria 
 
To evaluate the efficacy of acalabrutinib 
monotherapy based on progression-free survival 
(PFS) per RANO criteria 
 
To evaluate the efficacy of acalabrutinib 
monotherapy based on 6-month PFS (PFS-6) rate 
per RANO criteria   
 
To evaluate the efficacy of acalabrutinib 
monotherapy based on overall survival (OS) 

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Exploratory Objectives: 
Study Design: 
This Phase 1b/2, multicenter, open-label study is designed 
to evaluate the efficacy and safety of acalabrutinib in 
subjects with recurrent GBM who have progressed after 1 or 
2 prior systemic treatment regimens.  Subjects meeting the 
eligibility criteria for the study will be assigned 1:1 to one of 
the following cohorts: 
Cohort 1:  Acalabrutinib 200 mg administered orally (PO) 
twice per day (BID) 
Cohort 2:  Acalabrutinib 400 mg PO once per day (QD) (see 
note below regarding the discontinuation of Cohort 2) 
An interim safety and efficacy analysis will occur 
approximately 8 weeks (2 cycles) after the 12th subject has 
been enrolled in each cohort in the Phase 1b portion of the 
study.  Enrollment in each cohort will be held after the 12th 
subject has been enrolled while the interim safety and 
efficacy results are reviewed by a Scientific Advisory 
Committee (SAC) in collaboration with the Safety Review 
Committee.  If acceptable safety and efficacy (e.g., 2 or 
more of the 12 subjects [≥16.7%] achieve a complete 
response ([remission] CR) or PR; additional criteria may be 
considered by the SAC) are observed in either cohort, the 
sponsor may choose to expand the study to a total of 
72 subjects.  The acalabrutinib dosage for the Phase 2 
portion of the study will be based on available safety and 
efficacy data from the Phase 1b cohorts.  Note:  depending 
on the Phase 1b results, the SAC and the Safety Review 
Committee may recommend continued evaluation of both 
regimens in the Phase 2 portion of the study.  The final 
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analysis will occur 24 weeks after the last subject is enrolled 
to the study (see note below). 
For the purpose of analyzing potential drug-drug 
interactions, each initial 12-subject cohort will be comprised 
of 8 subjects who do not require enzyme-inducing 
antiepileptic drugs (EIAEDs) that are strong cytochrome 
P450 (CYP) inducers (including carbamazepine, 
oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and 
primidone) and 4 subjects who do require such drugs (see 
note below). 
Subjects will be treated until disease progression, 
unacceptable drug-related toxicity, death, the start of new 
anticancer therapy for GBM, consent withdrawal, or are lost 
to follow-up.  All subjects will be evaluated for response 
using the RANO criteria.    
Treatment can continue until the end of trial, defined as 
52 weeks after the last subject is enrolled to the study, for 
subjects without disease progression and who are tolerating 
therapy.  Subjects who have confirmed progressive 
disease or who start new anticancer therapy for GBM will 
discontinue study treatment.   
Subjects who are still on treatment at the end of the study 
and deriving clinical benefit from acalabrutinib treatment 
may continue treatment.  At the time of the final data cutoff 
(DCO) and database closure, subjects who remain in this 
study may be transitioned to a separate rollover study or 
remain within this study for continued access to study drug.  
Once all active subjects are eligible to continue to receive 
acalabrutinib and after database closure, this study would 
be considered closed.  There will be no further data 
collection other than reporting of SAEs per protocol.  Access 
within this study will enable continued treatment with visit 
assessments per standard of care, whereas the separate 
rollover study will enable treatment continuation with visit 
assessments and data collection per the rollover study 
protocol. 
Refer to protocol for a comprehensive list of study 
assessments and their timing.  A study schema is provided 
protocol. 
Note:  Under Amendment 2 of the protocol, an interim 
analysis was scheduled after the 12th subject was enrolled in 
each arm (n=24).  However, due to the paucity of 
EIAED-treated subjects, an interim analysis was held after 
16 non-EIAED subjects and 1 subject on EIAED were 
enrolled in the study.  The first interim analysis did not raise 
any safety concerns and showed some response in the 
200-mg BID group, while no response in 400-mg QD group.  
Therefore, the SAC recommended discontinuing Cohort 2 

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(400 mg QD) and enrolling 7 additional non-EIAED subjects 
planned for Phase 1b of the study into Cohort 1 (200 mg 
BID).  A second interim analysis for safety and efficacy will 
be performed after enrolling an additional 7 subjects, once 
15 total subjects enrolled in the 200-mg BID cohort 
(8 subjects enrolled prior to first interim analysis, and an 
additional 7 subjects planned to complete Phase 1b).  An 
ORR rate of 3/15 (20%) will yield a lower bound of a 1-sided 
90% exact binomial CI of 7.1%, which is greater than 5% 
(ORR estimate for the standard of care CCNU).  Based on 
these criteria, the SAC and the Safety Review Committee 
will review data after the 2nd interim analysis and will make a 
recommendation if study should be continued into Phase 2.  
If continued, up to 28 additional subjects may be enrolled for 
a total of 43 subjects on the 200-mg BID dose (15 subjects 
from Phase 1b and 28 subjects from Phase 2) in order to 
complete Phase 2.  The final analysis will occur 24 weeks 
after the last subject is enrolled in the study.  Treatment will 
continue until the last enrolled subject experiences disease 
progression. 
Safety Parameters: 
The safety of acalabrutinib will be characterized by the type, 
frequency, severity, timing of onset, duration, and 
relationship to study drug of any treatment-emergent 
adverse events (AEs) or abnormalities of laboratory tests; 
SAEs; or AEs leading to discontinuation of study treatment. 
Pharmacodynamic, 
Pharmacokinetic and 
Biomarker 
Parameters: 
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Efficacy Parameters: 
 
ORR 
 
DOR 
 
PFS 
 
PFS-6 
 
OS 
Sample Size: 
Up to 52 subjects may be enrolled on this study (24 subjects 
in Phase 1b and up to 43 combined subjects in Phase 1b 
[15 subjects] and Phase 2 [28 subjects] on the same dose of 
acalabrutinib).  
Note: Under Amendment 2 of the protocol, 24 subjects will 
be enrolled in Phase 1b.  Based on the 2nd interim analysis 
up to 28 subjects may be enrolled for a total of 43 subjects 
on the 200-mg BID dose (15 subjects from Phase 1b and 
28 subjects from Phase 2) to complete Phase 2.  
Inclusion Criteria: 
1. Men and women ≥ 18 years of age. 
2. Histologically confirmed GBM at first or second 
recurrence after concurrent or adjuvant chemotherapy 
and radiotherapy (must have received temozolomide).  
Subjects with an initial diagnosis of a lower grade glioma 
may be eligible if transformed to GBM; however, the 
same prior treatment criteria for GBM applies. 
a) A pathology report is adequate for documentation 
of GBM histology for study entry. 
b) If previously treated with gamma knife or other 
focal high-dose radiotherapy, the subject must 
have subsequent histologic documentation of 
recurrence, unless the recurrence is a new lesion 
outside the irradiated field. 
c) Histology slides from the most recent surgery 
must be available. 
3. Radiographic demonstration of disease progression by 
magnetic resonance imaging (MRI) obtained ≥4 weeks 
after any salvage surgery after the first or second 
relapse, or radiographic progression demonstrated on 
2 consecutive, post-radiotherapy MRI scans while the 
subject is on a stable or decreasing dose of steroids.  
4. Measurable disease (bidimensional) as defined by the 
RANO criteria, with a minimum measurement of 1 cm in 
longest diameter on MRI performed within 21 days of 
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first dose of acalabrutinib; MRI must have been obtained 
≥4 weeks after any salvage surgery after first or second 
relapse. 
5. Stable or decreasing dose of corticosteroids ≥5 days 
before baseline MRI (at study entry). 
6. On a stable dose of any required therapy (such as 
anticonvulsant medication for subjects to be enrolled into 
the Phase 1b portion), for ≥3 weeks before the first dose 
of acalabrutinib.   
7. Eastern Cooperative Oncology Group (ECOG) 
performance status of ≤2. 
8. Life expectancy ≥12 weeks. 
9. Completion of all prior anticancer therapy including 
investigational therapy >2 weeks before the first dose of 
acalabrutinib.  Exceptions include: ≥6 weeks for 
nitrosoureas, ≥4 weeks for surgery, and ≥12 weeks for 
radiotherapy. 
10. Need to have recovered (i.e., Grade ≤1 or baseline) from 
AEs associated with prior cancer therapy.  Note:  
Subjects with Grade ≤2 neuropathy or Grade ≤2 
alopecia are an exception, and may qualify for the study. 
11. Women who are sexually active and can bear children 
must agree to use highly effective forms of contraception 
during the study and for 90 days after the last dose of 
acalabrutinib.  Highly effective forms of contraception are 
defined in protocol. 
12. Men who are sexually active and can beget children 
must agree to use highly effective forms of contraception 
during the study and for 90 days after the last dose of 
acalabrutinib.  Highly effective forms of contraception are 
defined in protocol. 
13. Men must agree to refrain from sperm donation during 
the study and for 90 days after the last dose of 
acalabrutinib. 
14. Note: This inclusion criterion no longer applies under 
Amendment 1 of the protocol. 
15. Willing and able to participate in all required evaluations 
and procedures in this study protocol, including 
swallowing capsules without difficulty. 
16. Ability to understand the purpose and risks of the study 
and provide signed and dated informed consent and 
authorization to use protected health information (in 
accordance with national and local patient privacy 
regulations).  Note:  If clinically indicated, an authorized 
legal representative may provide informed consent. 

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Exclusion Criteria: 
1. Three or more prior lines of systemic therapy for GBM 
(including chemotherapy, monoclonal antibody therapy, 
small molecule, systemic investigational therapy, and 
biodegradable carmustine [BCNU] wafers). 
2. Unable to undergo brain MRI scans with gadolinium.  
3. Prior therapy with any inhibitor of BTK, AKT, JAK, 
mTOR, PI3K, or SYK. 
4. Prior malignancy (other than GBM), except for 
adequately treated basal cell or squamous cell skin 
cancer, in situ cervical cancer, or other cancer from 
which the subject has been disease free for ≥2 years.  
Any cases of prior malignancy allowed on study are to 
be approved by the study medical monitor. 
5. Significant cardiovascular disease such as uncontrolled 
or symptomatic arrhythmias, congestive heart failure, or 
myocardial infarction within 6 months of screening, or 
any Class 3 or 4 cardiac disease as defined by the New 
York Heart Association Functional Classification, or 
corrected QT interval (QTc) >480 msec at screening or 
QTc >480 msec (calculated using Fridericia’s formula: 
QT/RR0.33) at screening.  Exception: Subjects with 
controlled, asymptomatic atrial fibrillation during 
screening are allowed to enroll in the study.   
6. Malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach, or 
extensive small bowel resection that is likely to affect 
absorption, symptomatic inflammatory bowel disease, 
partial or complete bowel obstruction, or gastric 
restrictions and bariatric surgery, such as gastric bypass. 
7. Evidence of bleeding diathesis or coagulopathy (in the 
absence of therapeutic anticoagulation).  
8. Presence of a gastrointestinal ulcer diagnosed by 
endoscopy within 3 months before screening. 
9. Requires urgent palliative intervention for primary 
disease (e.g., impending herniation). 
10. Requires treatment with a strong CYP3A inhibitor.  
11. Subjects requiring EIAEDs that are strong CYP inducers 
(including carbamazepine, oxcarbazepine, phenytoin, 
fosphenytoin, phenobarbital, and primidone) cannot be 
enrolled to this study.  Note: under Amendment 2 of the 
protocol, subjects requiring EIAEDs are excluded.  
12. Requires or receiving anticoagulation with warfarin or 
equivalent vitamin K antagonists (e.g., phenprocoumon) 
within 7 days of first dose of study drug. 
13. Requires treatment with proton-pump inhibitors (e.g., 
omeprazole, esomeprazole, lansoprazole, 
dexlansoprazole, rabeprazole, or pantoprazole).  
Subjects receiving proton-pump inhibitors who switch to 

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H2-receptor antagonists or antacids are eligible for 
enrollment to this study. 
14. History of clinically significant stroke within 6 months 
before the first dose of study drug. 
15. History of clinically significant intracranial hemorrhage 
within 6 months before the first dose of study drug.  
Cases of Grade 1 radiographic-only hemorrhage (e.g., 
old hemosiderin) may be allowed per the discretion of 
the study medical monitor. 
16. Major surgical procedure within 28 days of first dose of 
study drug.  Note:  If a subject had major surgery, they 
must have recovered adequately from any toxicity and/or 
complications from the intervention before the first dose 
of study drug.  If a subject had a recent surgery for 
recurrent or progressive tumor, then the surgery must 
have confirmed the recurrence.  For core or needle 
biopsy, a minimum of 7 days must have elapsed before 
enrollment, the craniotomy or intracranial biopsy site 
must be adequately healed and free of drainage or 
cellulitis, and the underlying cranioplasty must appear 
intact at the time of first dose. 
17. ANC <1.5 x 109/L or platelet count <100 x 109/L or 
hemoglobin <8.0 g/dL 
18. Total bilirubin >1.5 x upper limit of normal (ULN). 
19.  AST or ALT >3.0 x ULN. 
20. 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]. 
21. Breastfeeding or pregnant. 
22. Concurrent participation in another therapeutic clinical 
trial. 
23. Known history of HIV, serologic status reflecting active 
hepatitis B or C infection, or any uncontrolled active 
systemic infection     
a. Subjects who are hepatitis B core antibody 
(anti-HBc) positive and who are surface antigen 
negative will need to have a negative polymerase 
chain reaction (PCR) result before enrollment.  
Those who are AbsAg positive or hepatitis B PCR 
positive will be excluded.  
b. Subjects who are hepatitis C antibody positive will 
need to have a negative PCR result before 
enrollment.  Those who are hepatitis C PCR positive 
will be excluded. 
24. Subjects previously treated with bevacizamab (Avastin). 

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Dose Regimen/Route 
of Administration: 
Acalabrutinib is provided as hard gelatin capsules for oral 
administration. 
Concomitant 
Medications: 
Permitted Concomitant Therapy 
Corticosteroids and anti-emetics are permitted, if clinically 
indicated.  Standard supportive care medications are 
permitted as per institutional standards.   
Prohibited or Restricted Concomitant Therapy 
Subjects requiring EIAEDs that are strong CYP inducers 
(including carbamazepine, oxcarbazepine, phenytoin, 
fosphenytoin, phenobarbital, and primidone) cannot be 
enrolled to this study.  
For subjects who are taking EIAEDs (e.g., carbamazepine 
or phenytoin), plasma concentration monitoring of low 
therapeutic index anticonvulsant cotherapy will be 
undertaken at weekly intervals during Cycle 1, and then 
monthly thereafter, or after a dose change during the study, 
according to the Schedule of Assessments (see protocol).  
Note:  Under Amendment 2 of the protocol, subjects 
requiring EIAEDs are not eligible for this study. 
Any anti-cancer therapy including, experimental therapy, or 
radiotherapy for treating GBM is prohibited. 
Warfarin or equivalent vitamin K antagonists (e.g., 
phenprocoumon) are prohibited. 
The concomitant use of strong inhibitors of CYP3A with 
acalabrutinib should be avoided when possible (see 
protocol).  If a subject requires short-term treatment with a 
strong CYP3A inhibitor (such as anti-infectives for up to 
7 days), interrupt acalabrutinib treatment. 
Statistical Methods: 
Descriptive statistics will be used to summarize baseline 
demographic and disease characteristics, study drug 
administration, efficacy and safety outcomes, PK 
parameters, and pharmacodynamic (PD) markers.  
Descriptive summaries of discrete data will present the 
sample size and the incidence as a frequency and as a 
percentage.  Descriptive summaries of continuous data will 
present the sample size, group mean, standard deviation, 
median, and range CIs will be included as appropriate.  
There are 2 timepoints for analyses: (1) the interim analysis 
will occur approximately 8 weeks (2 cycles) after the 12th 
subject has been enrolled in each cohort in the Phase 1b 
portion of the study, and (2) the final analysis will occur 
24 weeks after the last subject is enrolled to the study.  
Note:  Under Amendment 2 of the protocol, the 2nd interim 
analysis will be performed approximately when 7 additional 

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non-EIAED subjects complete 16 weeks (4 cycles) of 
treatment.  
Statistical Basis for the Sample Size 
The sample size for this study included subjects enrolled in 
Phase 1b and Phase 2 treated with the same dose regimen.  
An ORR observed in standard of care for second-line 
therapies (CCNU) ranged around 5 to 10%.  While 
bevacizumab (Avastin) demonstrated an ORR >20%, 
considerable toxicities were reported.  To reject the null 
hypothesis of ORR ≤5% in favor of an alternative hypothesis 
that the ORR is ≥20%, 43 subjects will preserve 
approximately 88% power to detect the difference at a 
0.025 significance level by a 1-sided exact test. 
Note:  Under Amendment 2 of the protocol, the sample size 
for this study will include subjects enrolled in Phase 1b and 
Phase 2 and treated with the same dose regimen.  Subjects 
enrolled in Phase 1b but treated with a different dose 
regimen not chosen for investigation in Phase 2, will not be 
included in these sample size calculations. 
 

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1.0 
BACKGROUND INFORMATION 
1.1 
GLIOBLASTOMA MULTIFORME 
Glioblastoma multiforme (GBM) is a primary brain neoplasm consisting of a genetically 
and phenotypically diverse group of brain tumors.  Ninety percent of GBMs develop 
de novo from normal glial cells through a multistep process of tumorigenesis.  It is the 
most common form of malignant primary tumor of the nervous system, with an annual 
incidence of 3.19 per 100,000 people (Ostrom 2014).  Median age at diagnosis is 
59 years, and it is 1.6 times more common in men than women, with a higher incidence 
among whites (Ostrom 2014).  
GBM develops mainly in the brainstem, cerebellum, or in the hemispheres of the brain.  
It is characterized by an infiltrating growth making total resection of the tumor 
challenging.  The most common clinical signs of GBM include ataxia, headache, 
dizziness, blurred vision, diplopia, and syncope.  Morphologic diagnosis is based on 
World Health Organization (WHO) classification, and GBM is classified as Grade IV, 
denoting it as among the most malignant tumors.  Diagnosis and treatment response is 
dictated by magnetic resonance imaging (MRI).  Age and performance status play a 
major role in determining therapy (Kumthekar 2014).   
Currently, maximal surgical resection followed by fractionated radiotherapy combined 
with concurrent temozolomide and 6 to 12 cycles of adjuvant temozolomide is the 
mainstay of GBM treatment.  GBM has a poor prognosis, with only a third of patients 
surviving for 1 year (National Comprehensive Cancer Network [NCCN]  
Guidelines 2015).  The grim prognosis is at least partly due to the failure to successfully 
deliver drugs across the blood-brain barrier.  The 5-year survival rate is 5% for 
glioblastoma and the average median survival is approximately 14 to 16 months (Stupp 
2009, Ostrom 2014).   
Unfortunately, nearly all glioblastomas recur or progress within 7 months of initial 
diagnosis (Alifieris 2015).  Second-line chemotherapy regimens include temozolomide; 
nitrosureas; combination procarbazine, CCNU (lomustine), and vincristine (PCV); 
cyclophosphamide; and platinum-based regimens.  The antiangiogenic agent, 
bevacizumab (Avastin), received accelerated approval in the United States in 2009 for 
recurrent glioblastoma based on modest improvements in overall response rate (ORR) 
and median duration of response (DOR) in an open-label, randomized, noncomparative, 
multicenter study of bevacizumab with or without irinotecan and in a single-arm, single 

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institutional trial; ORRs were 25.9% (in the bevacizumab-containing arm) and 19.6%, 
respectively, and median DORs were 4.2 months and 3.9 months, respectively 
(AVASTIN prescribing information).  However, use of bevacizumab (Avastin) is 
associated with potential serious adverse events (SAEs), including hypertension, 
impaired wound healing, colonic perforation, and thromboembolism (NCCN 
Guidelines 2015).  Hence, a large unmet need exists in the treatment of newly 
diagnosed and recurrent GBM.  
1.2 
BRUTON TYROSINE KINASE INHIBITION IN CANCER 
Acalabrutinib  is a covalent inhibitor of Bruton tyrosine kinase (BTK), a non-receptor 
enzyme in the Tec kinase family, which also includes bone marrow X-linked (BMX) 
nonreceptor tyrosine kinase.   
BTK-dependent activation of mast cells, myeloid cells, and other immunocytes in 
peritumoral inflammatory stroma has been shown to sustain the complex 
microenvironment needed for lymphoid and solid tumor maintenance (Soucek 2011, 
de Rooij 2012, Ponader 2012).  Inhibition of BTK may impair the capacity of 
tumor-associated macrophages to promote tumor invasion and metastasis 
(Mouchemore 2013).  Several lines of evidence demonstrate that BTK inhibition 
interferes with cross-talk between malignant cells and their microenvironment 
(Ponader 2012, Herman 2013).  BTK is also a signaling hub in myeloid-derived 
suppressor cells (MDSCs), which may play an important part in the suppression of 
antitumor immune responses, creating an immunosuppressive environment necessary 
for the growth of malignant cells (Schmidt 2004, Wesolowski 2013, Condamine 2014).   
In addition, BTK and BMX have been shown to be expressed in gliomas.  Across a panel 
of various cancer types, gliomas show the highest levels of BTK expression, second only 
to lymphomas (Uhlén 2015).  BMX is preferentially expressed in glioblastoma stem cells 
(GSCs) and activates STAT3 signaling, playing an essential role in maintaining the stem 
cell phenotype and tumorigenic potential (Guryanova 2011).  Taken together, these 
findings suggest that inhibition of BTK and BMX may offer an attractive strategy for 
targeting GBM.   
1.3 
ACALABRUTINIB 
Acalabrutinib is an imidazopyrazine analogue with a molecular weight of 465.5 g/mol.  
The compound has 1 stereogenic center and acalabrutinib is the S-enantiomer.  
Acalabrutinib is orally administered in humans and is suitable for formulating in capsules.  

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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).   
1.3.1 
Mechanism of Action 
 
  Acalabrutinib was 
specifically designed to be a more potent and selective inhibitor of BTK to avoid 
off-target side effects seen with other BTK inhibitors.  
 
   
1.3.2 
Safety Pharmacology 
In vitro and in vivo safety pharmacology studies with acalabrutinib have demonstrated a 
favorable nonclinical safety profile; for detailed information on the safety pharmacology 
of acalabrutinib, refer to the Investigator Brochure. 
1.3.3 
Drug-Drug Interaction Potential 
For more detailed information on drug-drug interaction potential for acalabrutinib, refer to 
the Investigator Brochure.  Please refer to Section 3.9.6 for guidance on drugs that may 
cause drug-drug interactions. 
1.3.4 
Acalabrutinib and the Blood-Brain Barrier 
Acalabrutinib is a P-glycoprotein substrate, which may contribute to the relatively low 
brain exposure observed in nonclinical studies in rats.  In a biodistribution study in rats 
using radiolabeled acalabrutinib, low relative concentrations (3 to 4% of plasma 
concentrations) were observed in the brain.  Brain pharmacokinetic (PK) experiments 
were performed to evaluate the potential for acalabrutinib to cross the blood-brain 
barrier.  Four Sprague-Dawley rats per group were treated with acalabrutinib by oral 
gavage at 5 or 30 mg/kg/day and tissues were collected at 30 minutes after dosing on 
Days 1, 3, and 5.  Two vehicle-treated rats were also sacrificed on each sampling day 
for comparison.  Cerebral spinal fluid (CSF) was collected, and then the brains were 
flushed with heparinized saline prior to collection and snap-frozen for analysis of 
acalabrutinib levels.  Bioanalytical methods specific to CSF and brain tissue were used 
to measure acalabrutinib levels.   
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Figure 1-1:  Acalabrutinib Levels in Rat Brain Tissue and CSF 
 
ACP-196 = acalabrutinib; CSF = cerebral spinal fluid. 
The ratio of acalabrutinib in the flushed brains, compared with matched plasma 
concentrations, showed that brain extracts had approximately 3 to 4% of the observed 
plasma concentrations, consistent with the results from the radiolabeled biodistribution 
study.  The ratios observed in clean cerebral spinal fluid samples from rats treated with 
5 and 30 mg/kg/day were between 1 to 2% of the plasma levels.  BTK target occupancy 
results showed 71 to 88% in the brain samples (see Table 1-1). 
 
Table 1-1:  BTK Target Occupancy in Rat Brain Tissue 
Timepoint 
Dose Level 
5 mg/kg/day 
30 mg/kg/day 
Day 1 
23% 
54% 
Day 3 
62% 
82% 
Day 5 
71% 
88% 
 
1.4 
CLINICAL EXPERIENCE – ACALABRUTINIB 
Acalabrutinib has been studied in a broad range of clinical studies, including subjects 
with hematologic malignancies and solid tumors.  No new safety concerns were 
identified for acalabrutinib monotherapy based on safety data available to date.  The 
safety data of acalabrutinib monotherapy are consistent among studies.  For more 
detailed and updated information on the clinical experience for acalabrutinib, please 
refer to the Acalabrutinib Investigator Brochure. 

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1.5 
BENEFIT/RISK 
Acalabrutinib is a potent, orally administered small-molecule inhibitor of BTK.  In the 
Phase 1/2 study of acalabrutinib in subjects with CLL or Richter’s syndrome 
(ACE-CL-001; Section 1.4.2), no dose-limiting toxicities (DLTs) were identified at any 
evaluated dosages, which included dosages up to 400 mg once per day (QD) or 100 to 
200 mg twice per day (BID).  The ORR in the evaluable subjects for this study is 95% 
(Byrd 2016).   
Given the high unmet need in patients with glioblastoma, new therapies are needed.  
Acalabrutinib has been administered to subjects with hematologic malignancies, healthy 
volunteers, and subjects with mild or moderate hepatic impairment.  See the 
Acalabrutinb Investigator Brochure for further details.    
Acalabrutinib 200 mg BID and 400 mg QD have been well tolerated by subjects with CLL 
(ACE-CL-001).  See the Acalabrutinib Investigator Brochure for details.  The preclinical 
hypothesis of altering the tumor microenvironment as well as the potential direct on 
target inhibition of BTK in gliomas warrants further study into the activity of acalabrutinib 
in GBM. 
2.0 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVES: 
 
To characterize the safety profile of acalabrutinib monotherapy in subjects with 
recurrent GBM 
 
To evaluate the efficacy of acalabrutinib monotherapy in subjects with recurrent 
GBM based on ORR per the Response Assessment in Neuro-Oncology (RANO) 
criteria 
2.2 
SECONDARY OBJECTIVES: 
 
To evaluate the efficacy of acalabrutinib monotherapy based on DOR per RANO 
criteria 
 
To evaluate the efficacy of acalabrutinib monotherapy based on progression-free 
survival (PFS) per RANO criteria 
 
To evaluate the efficacy of acalabrutinib monotherapy based on PFS-6 rate per 
RANO criteria   
 
To evaluate the efficacy of acalabrutinib monotherapy based on OS 
2.3 
EXPLORATORY OBJECTIVES: 
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3.0 
STUDY DESIGN 
This Phase 1b/2, multicenter, open-label study is designed to evaluate the efficacy and 
safety of acalabrutinib in subjects with recurrent GBM who have progressed after 1 or 2 
prior systemic treatment regimens.  Subjects meeting the eligibility criteria for the study 
will be assigned 1:1 to one of the following cohorts: 
Cohort 1:  acalabrutinib 200 mg administered orally (PO) BID 
Cohort 2:  acalabrutinib 400 mg PO QD (see note below) 
An interim safety and efficacy analysis will occur approximately 8 weeks (2 cycles) after 
the 12th subject has been enrolled in each cohort in the Phase 1b portion of the study.  
Enrollment in each cohort will be held after the 12th subject has been enrolled while the 
interim safety and efficacy results are reviewed by a Scientific Advisory Committee 
(SAC) in collaboration with the Safety Review Committee.  If acceptable safety and 
efficacy (e.g., 2 or more of the 12 subjects [≥16.7%] achieve a complete response 
([remission] CR) or PR; additional criteria may be considered by the SAC) are observed 
in either cohort, the sponsor may choose to expand the study to a total of 72 subjects.  
The acalabrutinib dosage for the Phase 2 portion of the study will be based on available 
safety and efficacy data from the Phase 1b cohorts.  Note:  depending on the Phase 1b 
results, the SAC and the Safety Review Committee may recommend continued 
evaluation of both regimens in the Phase 2 portion of the study.  The final analysis will 
occur 24 weeks after the last subject is enrolled to the study (see note below). 
For the purpose of analyzing potential drug-drug interactions, each initial 12-subject 
cohort will be comprised of 8 subjects who do not require enzyme-inducing antiepileptic 
drugs (EIAEDs) that are strong cytochrome P450 (CYP) inducers (including 
carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone) 
and 4 subjects who do require such drugs (see note below). 
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Subjects will be treated until disease progression, unacceptable drug-related toxicity, 
death, the start of new anticancer therapy for GBM, consent withdrawal, or are lost to 
follow-up.  All subjects will be evaluated for response using the RANO criteria 
(Wen 2010; Appendix 2).   
Treatment can continue until the end of trial, defined as 52 weeks after the last subject is 
enrolled to the study, for subjects without disease progression and who are tolerating 
therapy.  Subjects who have confirmed progressive disease or who start new 
anticancer therapy for GBM will discontinue study treatment.   
Subjects who are still on treatment at the end of the study and deriving clinical benefit 
from acalabrutinib treatment may continue treatment.  At the time of the final data cutoff 
(DCO) and database closure, subjects who remain in this study may be transitioned to a 
separate rollover study or remain within this study for continued access to study drug.  
Once all active subjects are eligible to continue to receive acalabrutinib and after 
database closure, this study would be considered closed.  There will be no further data 
collection other than reporting of SAEs per Section 6.2.  Access within this study will 
enable continued treatment with visit assessments per standard of care, whereas the 
separate rollover study will enable treatment continuation with visit assessments and 
data collection per the rollover study protocol. 
Refer to Appendix 1 for a comprehensive list of study assessments and their timing.  The 
study schema is provided below (Figure 3-1). 
Note:  Under Amendment 2 of the protocol, an interim analysis was scheduled after the 
12th subject was enrolled in each arm (n=24).  However, due to the paucity of 
EIAED-treated subjects, an interim analysis was held after 16 non-EIAED subjects and 
1 subject on EIAED were enrolled in the study.  The first interim analysis did not raise 
any safety concerns and showed some response in the 200 mg-BID group, while no 
response in 400-mg QD group.  Therefore, the SAC recommended discontinuing 
Cohort 2 (400 mg QD) and enrolling 7 additional non-EIAED subjects planned for 
Phase 1b of the study into Cohort 1 (200 mg BID).  A second interim analysis for safety 
and efficacy will be performed after enrolling an additional 7 subjects, once 15 total 
subjects enrolled in the 200-mg BID cohort (8 subjects enrolled prior to first interim 
analysis, and an additional 7 subjects planned to complete Phase 1b).  An ORR rate of 
3/15 (20%) will yield a lower bound of a 1-sided 90% exact binomial CI of 7.1%, which is 
greater than 5% (ORR estimate for the standard of care CCNU).  Based on these 

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criteria, the SAC and the Safety Review Committee will review data after the 2nd interim 
analysis and will make a recommendation if study should be continued into Phase 2.  If 
continued, up to 28 additional subjects may be enrolled for a total of 43 subjects on the 
200-mg BID dose (15 subjects from Phase 1b and 28 subjects from Phase 2) in order to 
complete Phase 2.  The final analysis will occur 24 weeks after the last subject is 
enrolled in the study.  Treatment will continue until the last enrolled subject experiences 
disease progression. 
 

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Figure 3-1.  Study Schema 
 
BID = twice per day; CYP = cytochrome P450; EIAEDs = enzyme-inducing antiepileptic drugs; GBM = glioblastoma multiforme; ORR = overall 
response rate; QD = once per day.

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3.1 
STUDY PARAMETERS 
3.1.1 
Safety Parameters 
The safety of acalabrutinib will be characterized by the type, frequency, severity, timing 
of onset, duration, and relationship to study drug of any treatment-emergent adverse 
events (AEs) or abnormalities of laboratory tests; SAEs; or AEs leading to 
discontinuation of study treatment. 
For consistency of interpretation, AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), and the severity of AEs and laboratory abnormalities 
will be graded using the Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.03 or higher.  Standard definitions for seriousness will be applied (see 
Section 6.1). 
3.1.2 
Pharmacodynamic, Pharmacokinetic, and Biomarker 
Parameters 
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3.1.3 
Efficacy Parameters 
Efficacy will be evaluated based on assessments of tumor response and progression 
using RANO criteria (Wen 2010; Appendix 2). 
Efficacy endpoints will include: 
 
ORR 
 
DOR 
 
PFS 
 
PFS-6 
 
OS 
3.2 
RATIONALE FOR STUDY DESIGN AND DOSING REGIMEN 
This Phase 1b/2, multicenter, open-label study is designed to evaluate the efficacy and 
safety of acalabrutinib in subjects with recurrent GBM who have progressed after 1 or 2 
prior systemic treatment regimens.  Acalabrutinib has been safely used to treat subjects 
with hematologic disorders, and 12 subjects in each cohort should be sufficient to 
preliminarily assess both safety and efficacy in subjects with GBM.  The expansion 
phase (Phase 2 portion) should allow for further safety data and was designed to 
sufficiently power the study for determination of ORR (see Section 5.1).  
The 200-mg BID and 400-mg QD dosages of acalabrutinib was selected to maximize 
CNS concentrations of acalabrutinib, given that relatively low brain penetration is 
expected due to transport by P-gp.   
Additionally, as described in Section 1.4, acalabrutinib is currently being evaluated in a 
Phase 1/2 study in subjects with CLL, Richter’s syndrome, or prolymphocytic leukemia 
(ACE-CL-001).  In this study, subjects have received oral dosages of 100 to 400 mg QD 
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and 100 to 200 mg BID of acalabrutinib.  All tested dose levels have been well tolerated.  
No DLT has occurred at any dose level.  Acalabrutinib 200 mg BID and 400 mg QD have 
been well tolerated by subjects with CLL (ACE-CL-001).  See the Acalabrutinib 
Investigator Brochure for details.  This study is exploring QD and BID regimens as the 
BTK resynthesis rate in target cells for this indication is unknown.  Robust clinical 
responses have been observed.   
Note, according to the original study design, subjects meeting the eligibility criteria for 
the study were to be assigned 1:1 (12 subjects per cohort) to either Cohort 1 
(acalabrutinib 200 mg administered PO BID) or Cohort 2 (acalabrutinib 400 mg PO QD).  
Each cohort was to enroll 8 subjects who did not require EIAEDs) and 4 subjects who 
required these EIAEDs.  However, EIAEDs are no longer considered the standard of 
care for patients with glioblastoma (NCCN Guidelines 2016).  Therefore, these subjects 
have been difficult to enroll.  As a result, the requirement for subjects on EIAEDs has 
been eliminated.  Also, due to some response observed in the 200-mg BID group, and 
none observed in the 400-mg QD group, the SAC recommended the 400-mg QD cohort 
be discontinued.  One patient on EIAEDs was enrolled into the 400-mg QD arm, was 
treated per protocol, and has exited the study due to disease progression.  
3.3 
SELECTION OF STUDY POPULATION 
3.3.1 
Inclusion Criteria 
Eligible subjects will be considered for inclusion in this study if they meet all of the 
following criteria:  
1. Men and women ≥18 years of age. 
2. Histologically confirmed GBM at first or second recurrence after concurrent or 
adjuvant chemotherapy and radiotherapy (must have received temozolomide).  
Subjects with an initial diagnosis of a lower grade glioma may be eligible if 
transformed to GBM; however, the same prior treatment criteria for GBM applies. 
a) A pathology report is adequate for documentation of GBM histology for study 
entry. 
b) If previously treated with gamma knife or other focal high-dose radiotherapy, 
the subject must have subsequent histologic documentation of recurrence, 
unless the recurrence is a new lesion outside the irradiated field. 
c) Histology slides from the most recent surgery must be available. 
3. Radiographic demonstration of disease progression by MRI obtained ≥4 weeks after 
any salvage surgery after the first or second relapse, or radiographic progression 
demonstrated on 2 consecutive, post-radiotherapy MRI scans while the subject is on 
a stable or decreasing dose of steroids. 

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4. Measurable disease (bidimensional) as defined by the RANO criteria, with a 
minimum measurement of 1 cm in longest diameter on MRI performed within 
21 days of first dose of acalabrutinib; MRI must have been obtained ≥4 weeks after 
any salvage surgery after first or second relapse. 
5. Stable or decreasing dose of corticosteroids ≥5 days before baseline MRI (at study 
entry). 
6. On a stable dose of any required therapy (such as anticonvulsant medication for 
subjects to be enrolled into the Phase 1b portion), for ≥3 weeks before the first dose 
of acalabrutinib. 
7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. 
8. Life expectancy ≥12 weeks. 
9. Completion of all prior anticancer therapy including investigational therapy >2 weeks 
before the first dose of acalabrutinib.  Exceptions include: ≥6 weeks for nitrosoureas, 
≥4 weeks for surgery, and ≥12 weeks for radiotherapy. 
10. Need to have recovered (i.e., Grade ≤1 or baseline) from AEs associated with prior 
cancer therapy.  Note:  Subjects with Grade ≤2 neuropathy or Grade ≤2 alopecia are 
an exception, and may qualify for the study. 
11. Women who are sexually active and can bear children must agree to use highly 
effective forms of contraception during the study and for 90 days after the last dose 
of acalabrutinib.  Highly effective forms of contraception are defined in Section 3.9.8. 
12. Men who are sexually active and can beget children must agree to use highly 
effective forms of contraception during the study and for 90 days after the last dose 
of acalabrutinib.  Highly effective forms of contraception are defined in Section 3.9.8. 
13. Men must agree to refrain from sperm donation during the study and for 90 days 
after the last dose of acalabrutinib. 
14. Note: This inclusion criterion no longer applies under Amendment 1 of the protocol. 
15. Willing and able to participate in all required evaluations and procedures in this study 
protocol including swallowing capsules without difficulty. 
16. Ability to understand the purpose and risks of the study and provide signed and 
dated informed consent and authorization to use protected health information (in 
accordance with national and local patient privacy regulations).  Note:  If clinically 
indicated, an authorized legal representative may provide informed consent. 
  
3.3.2 
Exclusion Criteria 
Subjects will be ineligible for this study if they meet any of the following criteria: 
1. Three or more prior lines of systemic therapy for GBM (including chemotherapy, 
monoclonal antibody therapy, small molecule, systemic investigational therapy, and 
biodegradable carmustine [BCNU] wafers) 
2. Unable to undergo brain MRI scans with gadolinium  
3. Prior therapy with any inhibitor of BTK, protein kinase b (AKT), Janus kinase (JAK), 
mammalian target of rapamycin (mTOR), phosphatidylinositol-3 kinase (PI3K), or 
spleen tyrosine kinase (SYK) 

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4. Prior malignancy (other than GBM), except for adequately treated basal cell or 
squamous cell skin cancer, in situ cervical cancer, or other cancer from which the 
subject has been disease free for ≥2 years.  Any cases of prior malignancy allowed 
on study are to be approved by the study medical monitor. 
5. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
congestive heart failure, or myocardial infarction within 6 months of screening, or any 
Class 3 or 4 cardiac disease as defined by the New York Heart Association 
Functional Classification, or corrected QT interval (QTc) >480 msec at screening or 
QTc >480 msec (calculated using Fridericia’s formula: QT/RR0.33) at screening.  
Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening 
are allowed to enroll in the study. 
6. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or 
resection of the stomach, or extensive small bowel resection that is likely to affect 
absorption, symptomatic inflammatory bowel disease, partial or complete bowel 
obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass  
7. Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic 
anticoagulation) 
8. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before 
screening  
9. Requires urgent palliative intervention for primary disease (e.g., impending 
herniation) 
10. Requires treatment with a strong CYP3A inhibitor   
11. Subjects requiring EIAEDs that are strong CYP inducers (including carbamazepine, 
oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone) cannot be 
enrolled to this study.  Note: under Amendment 2 of the protocol, subjects requiring 
EIAEDs are excluded. 
12. Requires or receiving anticoagulation with warfarin or equivalent vitamin K 
antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug 
13. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).  Subjects receiving 
proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible 
for enrollment to this study. 
14. History of clinically significant stroke within 6 months before the first dose of study 
drug 
15. History of clinically significant intracranial hemorrhage within 6 months before the 
first dose of study drug.  Cases of Grade 1 radiographic-only hemorrhage (e.g., old 
hemosiderin) may be allowed per the discretion of the study medical monitor. 
16. Major surgical procedure within 28 days of first dose of study drug.  Note:  If a 
subject had major surgery, they must have recovered adequately from any toxicity 
and/or complications from the intervention before the first dose of study drug.  If a 
subject had a recent surgery for recurrent or progressive tumor, then the surgery 
must have confirmed the recurrence.  For core or needle biopsy, a minimum of 
7 days must have elapsed before enrollment, the craniotomy or intracranial biopsy 
site must be adequately healed and free of drainage or cellulitis, and the underlying 
cranioplasty must appear intact at the time of first dose. 
17. ANC <1.5 x 109/L or platelet count <100 x 109/L or hemoglobin <8.0 g/dL 

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18. Total bilirubin >1.5 x upper limit of normal (ULN)  
19. AST or ALT >3.0 x ULN 
20. 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] 
21. Breastfeeding or pregnant 
22. Concurrent participation in another therapeutic clinical trial 
23. Known history of HIV, serologic status reflecting active hepatitis B or C infection, or 
any uncontrolled active systemic infection   
a. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are 
surface antigen negative will need to have a negative polymerase chain reaction 
(PCR) result before enrollment.  Those who are AbsAg positive or hepatitis B 
PCR positive will be excluded.  
b. Subjects who are hepatitis C antibody positive will need to have a negative PCR 
result before enrollment.  Those who are hepatitis C PCR positive will be 
excluded. 
24. Subjects previously treated with bevacizumab (Avastin)  
3.3.3 
Replacement of Subjects 
Subjects in the Phase 1b portion of the study may be replaced at the discretion of the 
sponsor and investigator. 
3.3.4 
Enrollment Procedures 
 
Enrollment of a subject into the study will be performed according to the following 
procedure: The study center will notify the sponsor when a clinically eligible 
subject is identified and is ready to screen, to ensure enrollment availability on 
the study. 
 
After the subject has signed and dated the Informed Consent Form (ICF), all 
screening procedures have been completed, and eligibility has been confirmed, 
the subject can be officially enrolled into the study.  
 
To confirm eligibility the study center will fax/email a completed Enrollment 
Confirmation Form to the sponsor.  The enrollment date will be the date that the 
Sponsor confirms enrollment. 
 
The sponsor will aim to fax/email a completed Enrollment Confirmation Form to 
the study center within 24 hours.   
Treatment must begin within the screening window (Section 4.1).   
3.4 
STUDY DRUG 
3.4.1 
Premedications 
No specific premedications or supporting medications are required in conjunction with 
acalabrutinib administration. 

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3.4.2 
Formulation, Packaging, and Storage 
Acalabrutinib 
Acalabrutinib is manufactured according to cGMP regulations and will be provided to the 
investigational site by Acerta Pharma or designee.  Acalabrutinib should be stored 
according to the instructions on the label affixed to the package of the drug product.  
Acalabrutinib will be provided in white, high-density polyethylene bottles.   
If a drug shipment arrives damaged, or if there are any other drug complaints, a Product 
Complaint Form should be completed and emailed or faxed to the sponsor or the 
sponsor’s representative. 
Refer to the Acalabrutinib Investigator Brochure for additional information regarding the 
drug product to be used in this trial. 
3.4.3 
Administration of Study Drug  
Investigators are prohibited from supplying acalabrutinib to any subjects not properly 
enrolled in this study.  The investigator must ensure that subjects receive acalabrutinib 
only from personnel who fully understand the procedures for administering the drug. 
Acalabrutinib is intended to be administered orally twice daily for those in the 200-mg 
BID cohort and once daily for those in the 400-mg QD cohort, with 8 ounces 
(approximately 240 mL) of water.  For subjects receiving acalabrutinib 200 mg BID, 
doses should be administered 12 hours apart (a window of ±1 hour is allowed).  The 
capsules should be swallowed intact.  Subjects should not attempt to open capsules or 
dissolve them in water.  Note: Under Amendment 2 of the protocol, the SAC observed 
that the response and disease-control rate noted in the 200-mg BID cohort were 
numerically higher than in the 400-mg QD cohort.  Therefore, the 400-mg QD cohort was 
discontinued.  
If a dose is not taken within the allowed window, it can be taken up to 3 hours after the 
scheduled time with a return to the normal schedule the same or following day.  If it has 
been >3 hours, the dose should not be taken, and the subject should take the next dose 
at the next scheduled time.  The missed dose will not be made up and must be returned 
to the site at the next scheduled visit.  
Guidance on coadministration of acalabrutinib with agents that affect gastric pH is 
provided in Section 3.9.6. 

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3.4.4 
Assuring Subject Compliance 
For treatments that are taken in the clinic, subjects should take the dose from the drug 
dispensed for them for that particular time period.  All other acalabrutinib treatments will 
be taken at home.  Subjects will receive a drug diary to record the specific time each 
dose was taken and to record reasons for any missed doses.   
Subject compliance with acalabrutinib dosing will be assessed at every visit.  The 
subject will be instructed to bring the diary and any remaining capsules to the clinic at 
their next visit.  The study staff will review the diary and ask the subject if all of the 
capsules were administered.  Any remaining or returned capsules will be counted and 
recorded as described in Section 7.6.  Returned capsules must not be redispensed to 
another subject.  
3.5 
STUDY TREATMENT SCHEDULE 
Acalabrutinib 200 mg BID and 400 mg QD will be administered orally. 
For information on dosing and dose modifications of acalabrutinib, refer to Section 3.7.  
Note:  under Amendment 2 of the protocol, the SAC observed that the response and 
disease-control rate observed in the 200-mg BID cohort were numerically higher than in 
the 400-mg QD cohort.  Therefore, the 400-mg QD cohort was discontinued. 
For subjects considered at risk for TLS, administer appropriate hydration and allopurinol 
or rasburicase per institutional standards prior to initiating treatment. 
3.6 
DURATION OF THERAPY 
Treatment may continue until the end of trial, defined as 52 weeks after the last subject 
is enrolled to the study, for subjects without disease progression and who are tolerating 
therapy.  Subjects who have confirmed progressive disease or who start new anticancer 
therapy for GBM will discontinue study drug.   
Subjects who are still on treatment at the end of the study and deriving clinical benefit 
from acalabrutinib treatment may continue treatment.  At the time of the final DCO and 
database closure, subjects who remain in this study may be transitioned to a separate 
rollover study or remain within this study for continued access to study drug.  Once all 
active subjects are eligible to continue to receive acalabrutinib and after database 
closure, this study would be considered closed.  There will be no further data collection 
other than reporting of SAEs per Section 6.2.  Access within this study will enable 
continued treatment with visit assessments per standard of care, whereas the separate 

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rollover study will enable treatment continuation with visit assessments and data 
collection per the rollover study protocol. 
3.7 
DOSING DELAYS AND MODIFICATIONS 
Subjects should be followed closely for AEs or laboratory abnormalities that might 
indicate acalabrutinib-related toxicity.  If a subject experiences an intolerable AE during 
the course of therapy, then acalabrutinib should be withheld, as necessary, until the AE 
resolves or stabilizes to an acceptable degree.   
The actions in Table 3-1 should be followed for the following toxicities: 
 
Grade 4 neutropenia (ANC <500/μL) for >7 days (neutrophil growth factors are 
permitted per American Society of Clinical Oncology (ASCO) guidelines 
[Smith 2015] and use must be recorded on the electronic case report form 
[eCRF]) 
 
Grade 3 thrombocytopenia - in presence of significant bleeding 
 
Grade 4 thrombocytopenia 
 
Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal 
antiemetic and/or anti-diarrheal therapy 
 
Any other Grade 4 toxicity or unmanageable Grade 3 toxicity 
Table 3-1.  Drug Modification Actions for Acalabrutinib 
Occurrence 
Action 
1st  
Hold acalabrutinib until recovery to Grade ≤1 or baseline; may restart at original 
dose level (200 mg BID or 400 mg QD) 
2nd 
Hold acalabrutinib until recovery to Grade ≤1 or baseline; restart at one dose 
level lower (100 mg BID or 300 mg QD, respectively) 
3rd 
Hold acalabrutinib until recovery to Grade ≤1 or baseline; restart at one dose 
level lower (100 mg QD or 200 mg QD, respectively) 
4th 
Discontinue acalabrutinib 
BID=twice per day; QD=once per day. 
Note:  Under Amendment 2 of the protocol, the SAC observed that the response and 
disease-control rate observed in the 200-mg BID cohort were numerically higher than in the 
400-mg QD cohort.  Therefore, the 400-mg QD cohort was discontinued. 
As appropriate, certain laboratory abnormalities may warrant more frequent monitoring 
(e.g., once per week) until abnormalities have recovered to Grade ≤1.  If acalabrutinib is 
reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even 
if there is minimal or no toxicity with the reduced dose.  However, if the subject tolerates 
a reduced dose of acalabrutinib for ≥4 weeks, then the dose may be increased to the 

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next higher dose level, at the discretion of the investigator.  Such re-escalation may be 
particularly warranted if further evaluation reveals that the AE that led to the dose 
reduction was not treatment-related.  However, the maximum dose of acalabrutinib is 
200 mg BID or 400 mg QD for this protocol.  Note:  Under Amendment 2 of the protocol, 
the 400-mg QD cohort was discontinued. 
The following action should be taken for a Grade ≥2 intracranial hemorrhage:  If 
evidence of a Grade ≥2 intracranial hemorrhage is observed, then acalabrutinib should 
be withheld until the subject is clinically stable and the medical monitor must be notified. 
Treatment with acalabrutinib should be withheld for any unmanageable, potentially study 
drug-related toxicity that is Grade ≥3 in severity.  Any other clinically important events 
where dose delays may be considered appropriate by the investigator must be 
discussed with the medical monitor.  Study drug may be withheld for a maximum of 
28 consecutive days from expected dose due to toxicity.  Study treatment should be 
discontinued in the event of a toxicity lasting >28 days, unless reviewed and approved 
by the medical monitor. 
Note:  Temporary withholding of acalabrutinib for as little as 7 days can cause a 
transient worsening of disease and/or of constitutional symptoms in CLL, which may also 
be applicable to glioblastoma.  Refer to Section 3.10 for more information on assessing 
disease progression under these circumstances. 
3.8 
CONCOMITANT THERAPY 
3.8.1 
Permitted Concomitant Therapy 
Corticosteroids and anti-emetics are permitted, if clinically indicated.  Standard 
supportive care medications are permitted as per institutional standards.   
3.8.2 
Prohibited or Restricted Concomitant Therapy 
Subjects requiring EIAEDs that are strong CYP inducers (including carbamazepine, 
oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone) cannot be 
enrolled to this study. 
For subjects who are taking EIAEDs (e.g., carbamazepine or phenytoin), plasma 
concentration monitoring of low therapeutic index anticonvulsant cotherapy will be 
undertaken at weekly intervals during Cycle 1, and then monthly thereafter, or after a 
dose change during the study, according to the Schedule of Assessments (Appendix 1).  

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Note:  Under Amendment 2 of the protocol, subjects requiring EIAEDs are not eligible for 
this study. 
Any anticancer therapy including experimental therapy or radiotherapy for treating GBM 
is prohibited. 
Warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) are prohibited. 
The concomitant use of strong inhibitors of CYP3A (see Appendix 3) with acalabrutinib 
should be avoided when possible (Section 3.9.6).  If a subject requires short-term 
treatment with a strong CYP3A inhibitor (such as anti-infectives for up to 7 days), 
interrupt acalabrutinib treatment. 
Although acalabrutinib is not expected to increase exposure of coadministered 
therapeutics that are substrates for CYP isoforms, in vitro data revealed weak or 
metabolism-dependent inhibition of some CYP isoforms including CYP3A/5.  For 
additional information on drugs with potential drug-drug interactions, refer to 
Section 3.9.6. 
3.9 
PRECAUTIONS 
3.9.1 
Reference Safety Information 
For the purpose of reporting AEs and SAEs: 
 
The Investigator Brochure contains the Reference Safety Information (RSI) for 
acalabrutinib 
3.9.2 
Risks Associated with Acalabrutinib 
The following summarizes the experience with acalabrutinib in hematological cancer 
studies.  Full details regarding the clinical safety of acalabrutinib are presented in the 
Acalabrutinib Investigator Brochure. 
Contraindications 
No contraindications are known for acalabrutinib. 
Warnings and Precautions 
 
Hemorrhage 
Serious hemorrhagic events, including fatal events, have occurred in clinical trials 
with acalabrutinib.  

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The mechanism for hemorrhage is not well understood.  Subjects receiving 
antithrombotic agents may be at increased risk of hemorrhage.  Use caution with 
antithrombotic agents and consider additional monitoring for signs of bleeding 
when concomitant use is medically necessary.  Consider the benefit-risk of 
withholding acalabrutinib for at least 3 days pre- and post-surgery. 
Subjects with hemorrhage should be managed per institutional guidelines with 
supportive care and diagnostic evaluations as clinically indicated. 
 
Infections  
Serious infections (bacterial, viral, and fungal), including fatal events, have 
occurred in clinical studies with acalabrutinib.  The most frequently reported 
Grade ≥3 infection was pneumonia (preferred term).  Across the acalabrutinib 
clinical development program (including subjects treated with acalabrutinib in 
combination with other drugs), cases of hepatitis B virus (HBV) reactivation, 
aspergillosis, and progressive multifocal leukoencephalopathy (PML) have 
occurred.  Consider prophylaxis in subjects who are at increased risk for 
opportunistic infections.  Subjects should be monitored for signs and symptoms 
of infection and treated as medically appropriate.  Refer to Section 3.9.4 and 
Section 4.1.15 for additional information and monitoring guidance for viral 
hepatitis, and Section 3.9.5 for additional information and management guidance 
for signs and symptoms of PML. 
 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias, including neutropenia, anemia, 
and thrombocytopenia have occurred in clinical studies with acalabrutinib.  
Monitor blood counts as specified in the schedule of assessments and as 
medically appropriate.  Refer to Section 3.7 for study drug modification guidance.  
Subjects with cytopenias should be managed according to institutional guidelines 
or as clinically indicated.  
 
Second Primary Malignancies 
Second primary malignancies, including solid tumors and skin cancers, have 
been reported in patients treated with acalabrutinib.  The most frequent second 
primary malignancy was skin cancer (basal cell carcinoma).  Subjects should be 
monitored for signs and symptoms of malignancy.  Subjects who develop a 

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second primary malignancy should be managed according to institutional 
guidelines with diagnostic evaluations as clinically indicated, and it may be 
necessary for subjects to permanently discontinue study treatment.  Continuation 
of acalabrutinib treatment should be discussed with the medical monitor.  Please 
refer to Section 6.2.3 for second primary malignancy reporting guidance. 
 
Atrial Fibrillation 
Events of atrial fibrillation/flutter have occurred in clinical studies with 
acalabrutinib, particularly in subjects with cardiac risk factors hypertension, 
diabetes mellitus, acute infections, and a previous history of atrial fibrillation.  
Monitor for symptoms of atrial fibrillation and atrial flutter (e.g., palpitations, 
dizziness, syncope, chest pain, dyspnea), and obtain an ECG as appropriate.  
Subjects with atrial fibrillation should be managed per institutional guidelines or 
as clinically indicated. 
3.9.3 
Dietary Restrictions 
Acalabrutinib can be taken with or without food.  Because acalabrutinib is metabolized 
by CYP3A, subjects should be strongly cautioned against using herbal remedies or 
dietary supplements (in particular, St John’s wort, which is a potent CYP3A inducer). 
Otherwise subjects should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea, or vomiting. 
3.9.4 
Hepatitis B Virus Reactivation 
Serious or life-threatening reactivation of viral hepatitis may occur in subjects treated 
with BTK inhibitor (de Jésus Ngoma 2015).  Therefore, subjects who are anti-HBc 
positive, or have a known history of hepatitis B virus (HBV) infection, should be 
monitored every 3 months with a quantitative PCR test for HBV DNA.   Regular 
monitoring (every 3 months) should continue until 12 months after last dose of 
acalabrutinib.  Any subject with a rising viral load (above lower limit of detection) should 
discontinue acalabrutinib and have antiviral therapy instituted and a consultation with a 
physician with expertise in managing hepatitis B.  Insufficient data exist regarding the 
safety of resuming acalabrutinib in subjects who develop HBV reactivation. 

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3.9.5 
Progressive Multifocal Leukoencephalopathy 
Serious or life-threatening occurrence of PML may occur in subjects treated with 
acalabrutinib.  Increased risk of infections including PML may also occur in subjects 
treated with standard chemotherapy, including fludarabine and cyclophosphamide.   
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 study treatment (as applicable, based on risks in the 
Investigator Brochure or local prescribing information) until PML is excluded.  A 
diagnostic evaluation may include (but is not limited to): 
 
Neurologic consultation 
 
Brain MRI 
 
PCR analysis for John Cunningham or JC virus DNA in cerebrospinal fluid 
If PML is confirmed, permanently discontinue study treatment (as applicable, based on 
risks in the Investigator Brochure or local prescribing information). 
3.9.6 
Drug-Drug Interactions 
Based on in vitro metabolism studies, acalabrutinib is not a strong direct inhibitor of 
CYP450 isoforms.  Acalabrutinib directly inhibited CYP2C8, CYP2C9, and CYP3A/5 (for 
both midazolam 1´-hydroxylation and testosterone 6β-hydroxylation) with IC50 values of 
37 μM, 28 μM, 69 μM, and 57 μM, respectively.  There was little or no evidence of direct 
inhibition of CYP1A2, CYP2B6, 2C19, or CYP2D6 by acalabrutinib (IC50 >100 μM).  
Acalabrutinib is a weak metabolism-dependent inhibitor of CYP2C8, CYP2C9, and 
CYP3A/5, and inhibited CYP3A/5 in an irreversible manner.  Based on these data, 
acalabrutinib is not expected to increase systemic exposure of coadministered CYP 
substrates, nonetheless, plasma concentration monitoring of narrow therapeutic index 
anticonvulsants will be undertaken in the Phase 1b portion of the study.  
If a subject requires treatment with a moderate CYP3A inhibitor, decrease the 
acalabrutinib dose to 100 mg QD during concomitant administration with the moderate 
inhibitor. 
Avoid coadministration of strong CYP3A inducers.  If a subject requires treatment with a 
strong CYP3A inducer, increase the acalabrutinib dose to 200 mg BID during 

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concomitant administration with the strong inducer and return to recommended dose of 
100 mg BID after stopping the strong CYP3A inducer. 
Use of proton-pump inhibitors, H2 receptor antagonists, or antacids while taking 
acalabrutinib has the potential to decrease acalabrutinib exposure.  If treatment with a 
gastric-acid reducing agent is required, consider using a H2-receptor antagonist (2 hours 
after acalabrutinib) or antacid (2 hours before or 2 hours after acalabrutinib).  Avoid 
coadministration with proton-pump inhibitors. 
3.9.7 
Surgery 
Susceptibility to bleeding has been observed with the first generation BTK inhibitor, 
ibrutinib (IMBRUVICA prescribing information).  As a precaution, it is suggested that 
acalabrutinib be withheld for 3 days before and for 3 days after any major surgical 
procedure. 
3.9.8 
Reproductive Toxicity 
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 that 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.  Women of childbearing potential (WOCBP) 
subjects who are sexually active must use highly effective methods of contraception 
during treatment and for 2 days after the last dose of acalabrutinib.  For male subjects 
with a pregnant or non-pregnant WOCBP partner, no contraception measures are 
required.  WOCBP are women who are fertile following menarche and until becoming 
postmenopausal unless permanently sterile; permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
Women are considered to be of non-reproductive potential if they meet any of the below 
criteria:  
 
Postmenopausal, defined as at least 12 months with no menses without an 
alternative medical cause; in women <45 years of age.  A high follicle-stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy.  In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.  

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 
Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or 
bilateral tubal ligation/occlusion, at least 6 weeks before Screening 
 
Have a congenital or acquired condition that prevents childbearing 
Men are considered to be of non-reproductive potential if they are permanently sterile 
due to bilateral orchidectomy. 
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 
 
Progesterone-only hormonal contraceptives associated with inhibition of 
ovulation, which may be oral, injectable, or implantable 
 
Intrauterine devices (IUD) or intrauterine hormone-releasing system (IUS) 
 
Bilateral tubal occlusion 
 
Vasectomy of a female subject's partner (with medical assessment and 
confirmation of vasectomy surgical success) 
 
Sexual abstinence (only if refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments) 
Hormonal contraception may be susceptible to interaction with study or other drugs, 
which may reduce the efficacy of the contraception method. 
Abstinence (relative to heterosexual activity) can only be used as the sole method of 
contraception if it is consistently employed during the entire period of risk associated 
with the study treatments as the subject’s preferred and usual lifestyle. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhea method (LAM) are not acceptable methods of contraception.  Female 
condom and male condom should not be used together as an effective method of 
contraception. 
Subjects should be informed that taking the study drug may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  To participate in the 

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study, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study drug initiation (or 14 days prior to the initiation of 
study drug for oral contraception) throughout the study period up to 2 days after the last 
dose of acalabrutinib.  If there is any question that a subject of childbearing potential will 
not reliably comply with the requirements for contraception, that subject should not be 
entered into the study.  
Subjects should promptly notify the investigator if they become pregnant during this 
study or within 2 days after the last dose of acalabrutinib.  If a woman becomes pregnant 
during the treatment period, she must discontinue acalabrutinib immediately.  Pregnancy 
in a woman must be reported as outlined in Section 6.2.4.   
3.9.9 
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 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). 
For any subject experiencing an acalabrutinib overdose, observation for any 
symptomatic side effects should be instituted, and vital signs, biochemical, and 
hematologic parameters should be followed closely (consistent with the protocol or more 
frequently, as needed).  Appropriate supportive management to mitigate adverse effects 
should be initiated.  If the overdose ingestion of acalabrutinib is recent and substantial, 
and if there are no medical contraindications, use of gastric lavage or induction of 
emesis may be considered. 
3.10 WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT 
The investigator, in consultation with the medical monitor, may withdraw any subject 
from study treatment, if, in the investigator’s opinion, it is not in the subject’s best interest 
to continue. 

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Any subject has the right to withdraw from the study treatment at any time.  In addition, 
subjects may be withdrawn from study treatment for the following reasons: 
 
Progressive disease 
 
Start of alternative anticancer therapy 
 
Adverse event 
 
Pregnancy 
 
Investigator decision 
 
Subject’s withdrawal of consent from study 
 
Decision by sponsor to terminate the study 
 
Subject lost to follow-up 
 
Death 
 
Other 
Note:  If the effects of ACP-196 stimulate an immune response in the tumor, it is 
possible that there could be pseudoprogression.  If there is uncertainty regarding 
whether there is true cancer progression, the subject may continue study treatment and 
remain under close observation (e.g., evaluated at 4-week intervals) pending 
confirmation of progression.  In particular, transient worsening of disease early in 
therapy or during temporary interruption of study therapy (e.g., for drug-related toxicity, 
surgery, or intercurrent illness) may not indicate cancer progression.  In such 
circumstances, and if medically appropriate, subjects may resume therapy and relevant 
clinical, laboratory, and/or radiographic assessment can be attempted to document 
whether tumor control can be maintained or whether cancer progression has occurred. 
Subjects who discontinue study treatment will continue to be followed on study for 
follow-up of safety (Section 4.3), disease progression, and survival unless they withdraw 
consent for further follow-up.  Thus, all subjects receiving ≥1 dose of study drug will be 
followed during the immediate post-therapy and long-term follow-up assessments unless 
the subject withdraws consent for such follow-up to be conducted.  The date the subject 
is withdrawn from study treatment or from the study (including long-term follow-up) and 
the reason for discontinuation will be recorded and also should be described on the 
appropriate eCRF.   
3.11 REASONS FOR STUDY EXIT 
Reasons for study exit include: 

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 
Subject’s withdrawal of consent from study 
 
Decision by sponsor to terminate the study 
 
Subject lost to follow-up 
 
Death 
3.12 DATA AND SAFETY MONITORING 
A Safety Review Committee will be formed as an internal monitoring committee to 
provide review and oversight of the safety/benefit-risk profile for the study.  Additionally, 
a SAC will be formed with external advisors to provide guidance on protocol conduct and 
safety/benefit-risk profile for the study.  Detailed information regarding the composition of 
the Safety Review Committee and SAC and detailed Safety Review Committee/SAC 
procedures will be provided in a separate charter.  Adverse events and SAEs will be 
reviewed collaboratively by the Safety Review Committee and SAC after the first 
24 subjects in the Phase 1b portion of the study, and on an ongoing basis (at least every 
3 months), to identify safety concerns according to the charter.  In addition, quarterly 
conference calls with the investigators and applicable site staff will be conducted to 
discuss study progress, obtain investigator feedback and exchange, and discuss 
"significant safety events" (i.e., AEs leading to dose reductions, related SAEs, and 
deaths). 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS 
The schedule of events is provided in Appendix 1.  Descriptions of the scheduled 
evaluations are outlined below and complete information on study drug and dosing is 
provided in Section 3.4. 
Before study entry, throughout the study, and at the follow-up evaluation, various clinical 
and diagnostic laboratory evaluations are outlined.  The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments.  
Clinical evaluations and laboratory studies may be repeated more frequently, if clinically 
indicated.  This study will primarily use central laboratory testing for safety laboratory 
evaluations.  Samples from sites’ local laboratories will only be used if central laboratory 
testing is unavailable. 

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4.1 
DESCRIPTION OF PROCEDURES 
4.1.1 
Informed Consent 
The subject must read, understand and sign the ICF approved by the institutional review 
board or independent ethics committee (IRB/IEC), confirming his or her willingness to 
participate in this study before initiating any screening activity that is not considered 
standard of care by institutional standards.  Subjects must also grant permission to use 
protected health information, if required by local regulations. 
4.1.2 
Medical History 
Collect and record the subject’s complete history through review of medical records and 
by interview.  Concurrent medical signs and symptoms must be documented to establish 
baseline severities.  A disease history, including the date of initial diagnosis and a list of 
all prior anticancer treatments, and responses and DOR to these treatments, also will be 
recorded. 
4.1.3 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 6.1.  The AE 
reporting period is described in Section 6.2.1.  Important additional requirements for 
reporting SAEs are explained in Section 6.2. 
4.1.4 
Concomitant Medications and Therapy 
Document all concomitant medications and procedures that occur within 21 days before 
the start of study drug administration through 30 days after the last dose of study drug. 
4.1.5 
Confirmation of Eligibility 
Subject eligibility for enrollment will be assessed per Section 3.3.  All screening 
procedures, unless otherwise indicated, should be completed within 21 days of the first 
dose of study drug. 
4.1.6 
ECOG Performance Status 
The ECOG performance index is provided in Appendix 4. 
4.1.7 
Physical Examination, Vital Signs, Height, and Weight 
The screening physical examination will include, at a minimum, the general appearance 
of the subject, height (screening only) and weight, and examination of the skin, eyes, 

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ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous 
system, and lymphatic system. 
Symptom-directed physical exams will be done during the treatment period and at the 
treatment termination (TT) and safety follow-up (SFU) visits. 
Vital signs (blood pressure, heart rate, and body temperature) will be assessed after the 
subject has rested in the sitting position.   
4.1.8 
Electrocardiogram  
An ECG will be performed at screening.  Subjects should be in a supine position and 
resting for at least 10 minutes before the ECG. 
4.1.9 
Urine or Serum Pregnancy Test 
Pregnancy tests will be required only for women of childbearing potential.  Testing will be 
done by a local or central laboratory as listed on the investigator’s Form Food and Drug 
Administration (FDA) 1572. 
4.1.10 
Hematology 
Hematology studies must include CBC with differential including, but not limited to white 
blood cell count, hemoglobin, hematocrit, platelet count, ANC, and absolute lymphocyte 
count (ALC).  Cycle 1 Day 1 hematology does not need to be repeated if screening 
hematology was done within 10 days.  Testing will be done by a local or central 
laboratory as listed on the investigator’s Form FDA 1572. 
4.1.11 
Serum Chemistry 
Chemistry will include albumin, alkaline phosphatase, ALT, AST, bicarbonate, BUN, 
calcium, chloride, creatinine, glucose, LDH, magnesium, phosphate/phosphorus, 
potassium, sodium, total bilirubin, total protein, and uric acid.  Cycle 1 Day 1 serum 
chemistry does not need to be repeated if screening serum chemistry was within 
10 days.  If an unscheduled ECG is done at any time, then an electrolyte panel (i.e., 
calcium, magnesium, and potassium) must be done to coincide with the ECG testing.  
Testing will be done by a local or central laboratory as listed on the investigator’s Form 
FDA 1572. 
4.1.12 
Coagulation 
Coagulation studies must include PT and aPTT.  Testing will be done by a local or 
central laboratory as listed on the investigator’s Form FDA 1572. 

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4.1.13 
Urinalysis 
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.  
Testing will be done by a local or central laboratory as listed on the investigator’s Form 
FDA 1572. 
4.1.14 
T/B/NK/Monocyte Cell Count 
Flow cytometry testing will include cluster of differentiation (CD)3+, CD4+, CD8+, CD19+, 
CD14+ and CD16/56+ cells.  Testing will be done by a local or central laboratory as listed 
on the investigator’s Form FDA 1572. 
4.1.15 
Hepatitis B and C Testing 
Hepatitis serology testing must include hepatitis B surface antigen (HBsAg), hepatitis B 
surface antibody (anti-HBs), anti-HBc, and hepatitis C (HCV) antibody.  In addition, any 
subjects testing positive for any hepatitis serology, must have PCR testing during 
screening and on study (see Appendix 1 and exclusion criterion #23).  Testing will be 
done by local or central laboratory.   
Subjects who are anti-HBc positive should have quantitative PCR testing for HBV DNA 
performed during screening and every 3 months thereafter.  Regular monitoring (every 
3 months) should continue until 12 months after last dose of study drug.  Any subject 
with a rising viral load (above lower limit of detection) should discontinue study drug and 
have antiviral therapy instituted and a consultation with a physician with expertise in 
managing hepatitis B.  
Subjects with a known history of hepatitis C or who are hepatitis C antibody positive, 
should be tested for HCV RNA, performed during screening.   
Refer to Section 3.9.4 and Appendix 1 regarding monitoring of subjects who are 
anti-HBc positive or have a known history of HBV. 
4.1.16 
Pharmacodynamics/Pharmacokinetics and Biomarker Studies 
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For subjects who are receiving the EIAEDs carbamazepine or phenytoin, who are either 
enrolled in the Phase 1b portion or approved by the medical monitor to participate in this 
study:  therapeutic drug monitoring for carbamazepine and/or phenytoin levels will be 
done (0) predose and 1 hour postdose on Cycle 1 Day 1, anytime during the visit on 
Cycle 1 Day 8, predose and 1 hour postdose on Cycle 1 Day 15 and Cycle 1 Day 22, 
then monthly thereafter and should be repeated after any dose change until sufficient 
data are available to discern whether time-dependent inhibition of CYP enzymes are or 
are not a concern.  Therapeutic drug monitoring will be performed locally.  Note:  Under 
Amendment 2 of the protocol, subjects requiring EIAEDs are excluded. 
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4.1.17 
 
4.1.18 
 
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4.1.19 
Patient-Reported Outcome 
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4.1.20 
Study Drug Accountability 
See Section 7.6. 
4.2 
INVESTIGATOR’S ASSESSMENT OF RESPONSE TO TREATMENT 
Responses will be categorized as CR, PR, stable disease, or progressive disease.  The 
definitions of response per the RANO criteria (Wen 2010) are provided in Table 4-1. 
Table 4-1.  Criteria for Response Assessment 
Response 
Category 
Definition 
CR 
Requires all of the following:  
 
Complete disappearance of all enhancing measurable and nonmeasurable disease 
sustained for at least 4 weeks 
 
No new lesions 
 
Stable or improved nonenhancing (T2/FLAIR) lesions 
 
Patients must be off corticosteroids (or on physiologic replacement doses only) 
 
Stable or improved clinically 
Note:  Patients with nonmeasurable disease only cannot have a complete response; the best 
response possible is stable disease. 
PR 
Requires all of the following:  
 
≥50% decrease compared with baseline in the sum of products of perpendicular diameters 
of all measurable enhancing lesions sustained for at least 4 weeks  
 
No progression of nonmeasurable disease 
 
No new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower 
dose of corticosteroids compared with baseline scan 
 
The corticosteroid dose at the time of the scan evaluation should be no greater than the 
dose at time of baseline scan 
 
Stable or improved clinically 
Note:  Patients with nonmeasurable disease only cannot have a partial response; the best response 
possible is stable disease. 
SD 
Requires all of the following:  
 
Does not qualify for complete response, partial response, or progression 
 
Stable nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared with baseline scan.  
In the event that the corticosteroid dose was increased for new symptoms and signs 
without confirmation of disease progression on neuroimaging, and subsequent follow-up 
imaging shows that this increase in corticosteroids was required because of disease 
progression, the last scan considered to show stable disease will be the scan obtained 
when the corticosteroid dose was equivalent to the baseline dose. 
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Table 4-1.  Criteria for Response Assessment 
Response 
Category 
Definition 
PD 
Defined by any of the following:  
 
≥25% increase in sum of the products of perpendicular diameters of enhancing lesions 
compared with the smallest tumor measurement obtained either at baseline (if no 
decrease) or best response, on stable or increasing doses of corticosteroids* 
 
Significant increase in T2/FLAIR nonenhancing lesion on stable or increasing doses of 
corticosteroids compared with baseline scan or best response after initiation of therapy* 
not caused by comorbid events (e.g., radiation therapy, demyelination, ischemic injury, 
infection, seizures, postoperative changes, or other treatment effects) 
 
Any new lesion 
 
Clear clinical deterioration not attributable to other causes apart from the tumor (e.g., 
seizures, medication adverse effects, complications of therapy, cerebrovascular events, 
infection, and so on) or changes in corticosteroid dose 
 
Failure to return for evaluation as a result of death or deteriorating condition 
 
Clear progression of nonmeasurable disease 
MRI=magnetic resonance imaging; FLAIR=fluid-attenuated inversion recovery. 
NOTE:  All measurable and nonmeasurable lesions must be assessed using the same techniques as at baseline. 
*Stable doses of corticosteroids include patients not on corticosteroids. 
 
4.3 
TREATMENT TERMINATION AND SAFETY FOLLOW-UP VISITS 
A TT visit is required for safety assessments for any subjects who permanently 
discontinue study drug for any reason (except for death, lost to follow-up, or withdrawal 
of consent), including disease progression.  The TT visit should be scheduled within 
7 days of the last dose of study drug, if possible, and is not required for subjects who 
discontinue from the study treatment within 10 days of a scheduled study visit or if the 
TT visit would be performed within 14 days of the SFU visit. 
In addition to the TT visit, each subject should be followed until the SFU visit at 
30 (+7) days after his or her last dose of study drug to monitor for resolution or 
progression of AEs and to document the occurrence of any new events, regardless of 
whether the subject receives a new anticancer therapy or demonstrates disease 
progression within this timeframe.  Subjects who withdraw consent for study treatment 
should still be encouraged to complete the SFU assessments, but these assessments 
cannot be mandated if subject consent for further study participation is withdrawn.  If the 
TT visit and the SFU visit coincide, then these can be combined into 1 visit.  The 
Schedule of Assessments (Appendix 1) describes the procedures required for the TT 
and SFU visits.  

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4.4 
FOLLOW-UP FOR PROGRESSION AND SURVIVAL 
4.4.1 
Post-Treatment Disease Follow-Up 
Each subject should be followed until disease progression or the start of alternative 
anticancer therapy.  If neither of these has occurred at the time of the 30-day SFU visit, 
Post-Treatment Disease Follow-Up visits should occur approximately every 3 months 
(12 weeks) from the date of last dose until disease progression or next anticancer 
treatment.  During this period, subjects will be followed via MRIs per investigator 
discretion.  
4.4.2 
Long-Term Follow-Up 
Once subjects progress or start use of alternative anticancer therapy—for all subjects 
who have not withdrawn consent—they will be contacted approximately every 3 months 
(12 weeks) from the date of last dose by clinic visit or telephone, to assess survival and 
the use of alternative anticancer therapy until death or lost to follow-up. 
4.5 
MISSED EVALUATIONS 
Missed evaluations should be rescheduled and performed as close to the original 
scheduled date as possible.  An exception is made when rescheduling becomes, in the 
investigator’s opinion, medically unnecessary or unsafe because it is too close in time to 
the next scheduled evaluation.  In that case, the missed evaluation should be 
abandoned. 
5.0 
STATISTICAL METHODS OF ANALYSIS  
5.1 
GENERAL CONSIDERATIONS 
Descriptive statistics will be used to summarize baseline demographic and disease 
characteristics, study drug administration, efficacy, and safety outcomes, PK 
parameters, and PD markers.  Descriptive summaries of discrete data will present the 
sample size and the incidence as a frequency and as a percentage.  Descriptive 
summaries of continuous data will present the sample size, group mean, standard 
deviation, median, and range.  CIs will be included as appropriate.  There are 
2 timepoints for analyses: (1) the interim analysis will occur approximately 8 weeks 
(2 cycles) after the 12th subject has been enrolled in each cohort in the Phase 1b portion 
of the study, and (2) the final analysis will occur 24 weeks after the last subject is 
enrolled to the study.  

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Note:  Under Amendment 2 of the protocol, the 2nd interim analysis will be performed 
approximately when 7 additional non-EIAED subjects complete 16 weeks (4 cycles) of 
treatment.  
Statistical Basis for the Sample Size 
The sample size for this study included subjects enrolled in Phase 1b and Phase 2 
treated with the same dose regimen.  An ORR observed in standard of care for 
second-line therapies (CCNU) ranged around 5 to 10%.  While bevacizumab (Avastin) 
demonstrated an ORR >20%, considerable toxicities were reported.  To reject the null 
hypothesis of ORR ≤5% in favor of an alternative hypothesis that the ORR is ≥20%, 
43 subjects will preserve approximately 88% power to detect the difference at a 
0.025 significance level by a 1-sided exact test.   
Note:  Under Amendment 2 of the protocol, the sample size for this study will include 
subjects enrolled in Phase 1b and Phase 2 and treated with the same dose regimen.  
Subjects enrolled in Phase 1b but treated with a different dose regimen not chosen for 
investigation in Phase 2, will not be included in these sample size calculations. 
5.2 
DEFINITION OF ANALYSIS SETS 
All efficacy and safety analysis will be performed using the safety population, which 
consists of all subjects who receive any amount of study treatment.  The analysis of 
DOR will only include subjects who have achieved objective response. 
5.3 
MISSING DATA HANDLING 
No imputation of values for missing data will be performed except that missing or partial 
start and end dates for AEs and concomitant medication will be imputed according to 
prespecified, conservative imputation rules.  Subjects lost to follow-up (or drop out) will 
be included in statistical analyses to the point of their last evaluation. 
5.4 
ENDPOINT DATA ANALYSIS 
5.4.1 
Safety Endpoint 
Verbatim descriptions of AEs will be mapped according to the MedDRA thesaurus terms 
and graded according to the National Cancer Institute (NCI) CTCAE, v4.03 or higher.  
Extent of exposure to study drug, all AEs, SAEs, non-SAEs leading to study drug 
discontinuation, and study drug-related AEs will be summarized.  The frequency of AEs 
will be summarized by system organ class and preferred terms according to MedDRA, 

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as well as per severity per NCI CTCAE grade.  Only treatment-emergent AEs will be 
summarized.  For events with varying severity, the worst reported grade will be used.  
Laboratory abnormalities will be defined based on laboratory normal ranges (universal 
normal ranges if central laboratory) and will be summarized by visit.  Selected laboratory 
parameters may be analyzed with shift tables and summaries of changes from baseline 
to worst post-treatment value.  Figures of changes in laboratory parameters over time 
may be generated, as appropriate, for certain labs. 
Change from baseline in vital sign assessments will be tabulated and summarized. 
5.4.2 
Demographics and Baseline Characteristics 
Additional analyses will include summaries of subject demographics, baseline 
characteristics, compliance, and concurrent treatments.  Concomitant medications will 
be coded and tabulated according to the World Health Organization Drug Dictionary 
(WHODRUG). 
5.4.3 
Study Treatment Administration and Compliance 
Descriptive information will be provided regarding the number of acalabrutinib doses 
prescribed, the total number of doses taken, the number of days of treatment, and the 
number and timing of prescribed dose delay, interruptions, and reductions.  
For each subject, acalabrutinib compliance will be described in terms of the proportion of 
study drug actually taken. 
5.4.4 
Analysis of Efficacy Parameters 
Response Rate 
ORR is defined as the proportion of subjects who achieve a CR or partial response 
(remission) (see Section 4.2).  ORR will be calculated, and the corresponding 2-sided 
exact 95% CI will be derived. 
Duration of Response 
For subjects who achieve objective response, DOR is defined as the time from the first 
tumor assessment showing response to the time of confirmed disease progression or 
death due to any cause, whichever occurs first.  Subjects who are still alive and free 
from progression at the time of data cutoff date, are lost to follow-up, have discontinued 
from the study, or have initiated other non-protocol antitumor therapy (NPT) will be 

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censored at the last evaluable tumor assessment.  A Kaplan-Meier (K-M) curve will be 
presented for DOR and K-M median will be calculated with 2-sided 95% CI. 
Progression-Free Survival 
PFS is defined as the time from first dose to documented disease progression, or death 
from any cause, whichever occurs first.  Subjects who are still alive and free from 
progression at the time of data cutoff date, are lost to follow-up, have discontinued from 
the study, or have initiated NPT will have their PFS time censored at last evaluable 
assessment (or, if there is no post-baseline tumor assessment, at the time of first dose).  
A K-M curve will be presented, and K-M estimates as well as exact 2-sided 95% CIs will 
be calculated for event time quartiles, and event-free rates at the protocol-specified 
disease assessment times. 
6-month and 
 Progression-Free Survival Rates 
PFS-6 rate is defined as the K-M estimate of subjects alive and without documented 
disease progression at 6 months.  In this study, 1 month is defined as 30.4375 days.  
The K-M method will be used to estimate the PFS-6 rate and corresponding 95% CIs.   
 
Overall Survival 
Overall survival (OS) is defined as the time from first dose to death from any cause.  
Subjects who are still alive at the time of data cutoff date, are lost to follow-up, or have 
discontinued from the study will have their OS time censored at the last date known to 
be alive on or before the data cutoff date.  The analysis of OS will be conducted, where 
applicable, using the same analysis method described for PFS. 
The SAP will describe analyses of all other exploratory endpoints.   
5.4.5 
PK, PD, or Biomarker Analyses 
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6.0 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and recording AEs and SAEs; 
measurements of protocol-specified hematology, clinical chemistry, urinalysis, and other 
laboratory variables; measurement of protocol-specified vital signs; and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study 
drug(s). 
6.1 
DEFINITIONS 
6.1.1 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational (medicinal) product or other 
protocol-imposed intervention, regardless of attribution. 
This includes the following: 
 
AEs not previously observed in the subject that emerge during the 
protocol-specified AE reporting period, including signs or symptoms 
associated with GBM that were not present before the AE reporting period 
(see Section 6.2.1). 
 
Pre-existing medical conditions (other than the condition being studied) 
judged by the investigator to have worsened in severity or frequency or 
changed in character during the protocol-specified AE reporting period. 
 
Abnormal laboratory values considered clinically significant by the investigator 
should be reported as an AE.   
The following are NOT considered an AE: 
 
Pre-existing condition that has not worsened: A pre-existing condition 
(documented on the medical history eCRF) 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. 

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 
Diagnostic testing and procedures: Testing and procedures should not be 
reported as AEs or SAEs but rather the cause for the test or procedure should be 
reported.  If a test or procedure is done to rule out a diagnosis, the sign or 
symptom leading to the test/procedure should be the event term and the event 
term should only be updated to the diagnosis if/when the diagnosis is confirmed.  
Testing and procedures performed solely as screening measures (e.g., routine 
screening mammography or colonoscopy) should not be reported as AEs or 
SAEs.  
 
Abnormal laboratory results that the investigator considers to not be 
clinically significant: Abnormal laboratory results are not AEs unless they are 
clinically significant.  For example, a clinically significant laboratory result is one 
that requires treatment (e.g., a blood transfusion for low hemoglobin) or requires 
a change in study drug (e.g., lowering the dose or withholding study drug while 
the laboratory finding resolves or stabilizes). 
 
Progression of underlying malignancy: Progression of underlying malignancy 
will not be reported as an AE if it is clearly consistent with the suspected 
progression of the underlying cancer.  Hospitalization due solely to the 
progression of underlying malignancy should NOT be reported as an SAE.  
Clinical symptoms of progression may be reported as AEs if the symptoms 
cannot be determined as exclusively due to the progression of the underlying 
malignancy or if they do not fit the expected pattern of progression for the 
disease under study. 
Symptomatic deterioration may occur in some subjects.  Symptomatic 
deterioration is when progression is evident in the subject’s clinical symptoms 
and the investigator may elect not to perform further disease assessments. 
If there is any uncertainty about an AE being due only to the disease under 
study, it should be reported as an AE or SAE. 
6.1.2 
Serious Adverse Event 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to 
the grade of an AE (see below).  “Serious” is a regulatory definition and is based on 
subject or event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  Seriousness (not severity) serves as the guide 

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for defining regulatory reporting obligations from the sponsor to applicable regulatory 
authorities. 
An AE should be classified as an SAE if it meets any 1 of the following criteria: 
 
It results in death (i.e., the AE actually causes or leads to death) 
 
It is life-threatening (i.e., the AE, in the view of the investigator, places the 
subject at immediate risk of death.  It does not include an AE that, had it 
occurred in a more severe form, might have caused death). 
 
It requires or prolongs inpatient hospitalization 
 
It results in persistent or significant disability/incapacity (i.e., the AE results 
in substantial disruption of the subject’s ability to conduct normal life 
functions) 
 
It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the investigational product 
 
It is considered a significant medical event by the investigator based on 
medical judgment (e.g., may jeopardize the subject or may require 
medical/surgical intervention to prevent 1 of the outcomes listed above) 
6.1.3 
Adverse Events of Special Interest 
The following events are adverse events of special interest (AESIs) and must be 
reported to the sponsors expeditiously (see Section 6.2.5 for reporting instructions), 
irrespective of regulatory seriousness criteria or causality: 
 
Ventricular arrhythmias (e.g., ventricular extrasystoles, ventricular tachycardia, 
ventricular arrhythmia, ventricular fibrillation, etc.) 
6.1.4 
Severity 
Definitions found in the CTCAE version 4.03 or higher will be used for grading the 
severity (intensity) of AEs.  The CTCAE displays Grades 1 through 5 with unique clinical 
descriptions of severity for each referenced AE.  Should a subject experience any AE 
not listed in the CTCAE, the following grading system should be used to assess severity: 
 
Grade 1 (Mild AE) – experiences that are usually transient, requiring no 
special treatment, and not interfering with the subject’s daily activities 
 
Grade 2 (Moderate AE) – experiences that 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 that are unacceptable or intolerable, 
significantly interrupt the subject’s usual daily activity, and require systemic 
drug therapy or other treatment 

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 
Grade 4 (Life-threatening or disabling AE) – experiences that cause the 
subject to be in imminent danger of death 
 
Grade 5 (Death related to AE) – experiences that result in subject death 
6.2 
DOCUMENTING AND REPORTING OF ADVERSE AND SERIOUS 
ADVERSE EVENTS 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, as outlined in the prior sections, are recorded on the eCRF.  
All SAEs must be reported on the SAE form or clinical database. 
6.2.1 
Adverse Event Reporting Period 
After the signing of the ICF and prior to the first dose of study drug, all SAEs must be 
reported.  After the first dose of study drug, all AEs/SAEs, irrespective of attribution of 
causality, must be reported.  
All AEs will be reported until 30 days after the last dose of study drug or the start of new 
anticancer therapy (whichever comes first).  After this period, investigators should report 
SAEs or other AEs of concern that are believed to be related to prior treatment with 
study drug.   
All SAEs that occur during the reporting period should be followed to resolution or until 
the investigator assesses the subject as stable or until the subject is lost to follow-up or 
withdraws consent.  Resolution/stable means the subject has returned to baseline state 
of health or the investigator does not expect any further improvement or worsening of 
the event.   
6.2.2 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation 
timepoints during the study.  All AEs and SAEs whether volunteered by the subject, 
discovered by study personnel during questioning, or detected through physical 
examination, or other means, will be recorded in the subject’s medical record and on the 
AE eCRF.  
Disease progression itself is not considered an AE; however, signs and symptoms of 
disease progression may be recorded as AEs or SAEs.  For additional details regarding 
disease progression and AEs, see Section 6.1.1.  
Each recorded AE or SAE will be described by its diagnostic term, duration (e.g., start 
and end dates), severity, regulatory seriousness criteria, if applicable, suspected 

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relationship to the study drug (see following guidance), and any actions taken.  The 
causality of AEs to the study drug will be assessed by means of the question: ‘Is there a 
reasonable possibility that the event may have been caused by the study drug?’ per FDA 
guidance on safety reporting requirements (FDA Guidance for Industry and 
Investigators:  Safety Reporting Requirements for INDs and BA/BE Studies (December 
2012). 
See Appendix 6 for more detail on assessing causality. 
6.2.3 
Second Primary Malignancies 
AEs for malignant tumors reported during a study should generally be assessed as 
SAEs.  If no other seriousness criteria apply, the “Important Medical Event” criterion 
should be used.  In certain situations, however, medical judgment on an individual event 
basis should be applied to clarify that the malignant tumor event should be assessed 
and reported as a nonserious AE.  For example, if the tumor is included as medical 
history and progression occurs during the study but the progression does not change 
treatment and/or prognosis of the malignant tumor, the AE may not fulfill the attributes 
for being assessed as serious, although reporting of the progression of the malignant 
tumor as an AE is valid and should occur.  Also, some types of malignant tumors, which 
do not spread remotely after a routine treatment that does not require hospitalization, 
may be assessed as nonserious; examples in adults include Stage 1 basal cell 
carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 
The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (i.e., it is not the tumor for which entry into the study is a criterion and 
that is being treated by the investigational product under study and is not the 
development of new or progression of existing metastasis to the tumor under study).  
Malignant tumors that—as part of normal, if rare, progression—undergo transformation 
(e.g., Richter's transformation of B-cell chronic lymphocytic leukemia into diffuse large 
B-cell lymphoma) should not be considered a new malignant tumor. 
6.2.4 
Pregnancy 
The investigator should report all pregnancies of subjects within 24 hours using the 
Pregnancy Report Form.  This form should be faxed or emailed to Acerta Pharma Drug 
Safety.  Any pregnancy-associated SAE must be reported to Acerta Pharma, according 
to the usual timelines and directions for SAE reporting (Section 6.2.5). 

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Any uncomplicated pregnancy that occurs with the subject during this study will be 
reported.  All 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 
90 days after the last dose of study medication will be reported, followed to conclusion, 
and the outcome reported. 
A pregnancy itself is not regarded as an AE unless there is suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Likewise, elective abortions without complications are not 
considered AEs.  Any SAEs associated with pregnancy (e.g., congenital 
abnormalities/birth defects/spontaneous miscarriage or any other serious events) must 
additionally be reported as such using the SAE report form. 
Subjects should be instructed to immediately notify the investigator of any pregnancies.  
Any female subjects receiving study drug who become pregnant must immediately 
discontinue study drug.  The investigator should counsel the subject, discussing any 
risks of continuing the pregnancy and any possible effects on the fetus. 
Upon completion of the pregnancy, additional information on the mother, pregnancy, and 
baby will be collected and sent to 
 
6.2.5 
Expedited Reporting Requirements for Serious Adverse 
Events 
All SAEs must be reported within 24 hours of discovery.  Initial SAE reports and 
follow-up information will be reported using the protocol-specific electronic data 
capturing (EDC) system, according to the instructions provided in the investigator site 
file.  If electronic SAE reporting is not available, paper SAE/Product Complaint forms 
must be emailed or faxed to Acerta Pharma Drug Safety, or designee.  Email/fax is only 
to be used if the EDC is unavailable.  Acerta Pharma may request follow-up and other 
additional information from the investigator (e.g., hospital admission/discharge notes and 
laboratory results). 
Whenever possible, AEs/SAEs should be reported by diagnosis term not as a 
constellation of symptoms.  Death due to disease progression should be recorded on the 
appropriate form in the EDC 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 AE term, as 
PPD

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death is typically the outcome of the event, not the event itself.  The primary cause of 
death on the autopsy report should be the term reported.  Autopsy and postmortem 
reports must be forwarded to Acerta Pharma Drug Safety, or designee, as outlined 
above. 
If study drug is discontinued because of an SAE, this information must be included in the 
SAE report. 
An SAE may qualify for mandatory expedited reporting to regulatory authorities if the 
SAE is attributable to the investigational product (or if a causality assessment is not 
provided for the SAE, in which case a default of “related” may be used for expedited 
reporting purposes) and is not listed in the current Investigator Brochure (i.e., an 
unexpected event).  In this case, Acerta Pharma Drug Safety/Designee will forward a 
formal notification describing the suspected unexpected serious adverse reaction 
(SUSAR) to all investigators.  Each investigator must then notify his or her IRB/IEC of 
the SUSAR. 
Drug Safety Contact Information 
Fax: 
 (United States) or 
 (for outside the United States) 
Email: 
 
6.2.6 
Type and Duration of Follow-up of Subjects after Adverse 
Events 
All AEs and SAEs that are encountered during the protocol-specified AE reporting period 
should be followed to resolution, or until the investigator assesses the subject as stable, 
or the subject is lost to follow-up or withdraws consent. 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
Acerta Pharma retains the right to terminate the study and remove all study materials 
from a study site at any time.  Specific circumstances that may precipitate such 
termination are: 
 
Unsatisfactory subject enrollment with regard to quality or quantity 
 
Significant or numerous deviations from study protocol requirements, such as 
failures to perform required evaluations on subjects and maintain adequate study 
records 
 
Inaccurate, incomplete and/or late data recording on a recurrent basis 
 
The incidence and/or severity of AEs in this or other studies indicating a potential 
health hazard caused by the study treatment 
PPD
PPD
PPD

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7.1 
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE 
The investigator will submit this protocol, the informed consent, Investigator Brochure, 
and any other relevant supporting information (e.g., all advertising materials) to the 
appropriate IRB/IEC for review and approval before study initiation.  A signed protocol 
approval page; a letter confirming IRB/IEC approval of the protocol and informed 
consent; and a statement that the IRB/IEC is organized and operates according to GCP 
guidelines and the applicable laws and regulations; must be forwarded to Acerta 
Pharma before screening subjects for the study.  Additionally, sites must forward a 
signed Form FDA 1572 (Statement of Investigator) to Acerta Pharma before screening 
subjects for study enrollment.  Amendments to the protocol must also be approved by 
the IRB/IEC and local regulatory agency, as appropriate, before the implementation of 
changes in this study. 
7.2 
INFORMED CONSENT AND PROTECTED SUBJECT HEALTH 
INFORMATION AUTHORIZATION 
A copy of the IRB/IEC-approved informed consent must be forwarded to Acerta Pharma 
for regulatory purposes.  The investigator, or designee (designee must be listed on the 
Study Personnel Responsibility/Signature Log, see Section 7.11), must explain to each 
subject the purpose and nature of the study, the study procedures, the possible adverse 
effects, and all other elements of consent as defined in § 21 Code of Federal 
Regulations (CFR) Part 50, and other applicable national and local regulations governing 
informed consent form.  Each subject must provide a signed and dated informed consent 
before enrollment into this study.  If allowed by the protocol, a legal representative may 
sign the informed consent form for a subject incapable of giving consent.  Signed 
consent forms must remain in each subject’s study file and be available for verification 
by study monitors at any time. 
In accordance to individual local and national patient privacy regulations, the investigator 
or designee must explain to each subject that for the evaluation of study results, the 
subject’s protected health information obtained during the study may be shared with 
Acerta Pharma and its designees, regulatory agencies, and IRBs/IECs.  As the study 
sponsor, Acerta Pharma will not use the subject’s protected health information or 
disclose it to a third party without applicable subject authorization.  It is the investigator’s 
or designee’s responsibility to obtain written permission to use protected health 
information from each subject, or if appropriate, the subject’s legal guardian.  If a subject 

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or subject’s legal guardian withdraws permission to use protected health information, it is 
the investigator’s responsibility to obtain the withdrawal request in writing from the 
subject or subject’s legal guardian and to ensure that no further data will be collected 
from the subject.  Any data collected on the subject before withdrawal will be used in the 
analysis of study results. 
7.3 
SUBJECT SCREENING LOG 
The investigator must keep a record that lists all subjects considered for enrollment 
(including those who did not undergo screening) in the study.  For those subjects 
subsequently excluded from enrollment, record the reason(s) for exclusion. 
7.4 
CASE REPORT FORMS 
Authorized study site personnel (see Section 7.11) will complete eCRFs designed for 
this study according to the completion guidelines that will be provided within the clinical 
database.  The investigator will ensure that the eCRFs are accurate, complete, legible, 
and completed promptly.  Refer to Section 7.7 for record retention requirements. 
7.5 
STUDY MONITORING REQUIREMENTS 
Representatives of Acerta Pharma or its designee will monitor this study until 
completion.  The purpose of monitoring is to ensure compliance with the protocol and 
the quality and integrity of the data.  This study is also subject to reviews or audits. 
Every effort will be made to maintain the anonymity and confidentiality of all subjects 
during this clinical study.  However, because of the experimental nature of this 
treatment, the investigator agrees to allow the IRB/IEC, representatives of Acerta 
Pharma, its designated agents, and authorized employees of the appropriate regulatory 
agencies to inspect the facilities used in this study and, for purposes of verification, allow 
direct access to the hospital or clinic records of all subjects enrolled into this study.  This 
includes providing by fax, email, or regular mail de-identified copies of radiology, 
pathology, and/or laboratory results when requested by the sponsor.  A statement to this 
effect will be included in the informed consent and permission form authorizing the use 
of protected health information. 
7.6 
INVESTIGATIONAL STUDY DRUG ACCOUNTABILITY 
Acalabrutinib capsules must be kept in a locked limited access cabinet or space.  The 
study drug must not be used outside the context of the protocol.   

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Study drug accountability records must be maintained and readily available for 
inspection by representatives of Acerta Pharma and are open to inspections by 
regulatory authorities at any time.  
All study supplies and associated documentation will be regularly reviewed and verified 
by the monitor. 
7.7 
RECORD RETENTION 
The investigator and other appropriate study staff are responsible for maintaining all 
documentation relevant to the study.  Mandatory documentation includes copies of study 
protocols and amendments, each Form FDA 1572, IRB/IEC approval letters, signed 
ICFs, drug accountability records, SAE information transmitted to Acerta Pharma, 
subject files (source documentation) that substantiate entries in 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 returned to Acerta Pharma. 
Acerta Pharma must be notified in advance of, and Acerta Pharma must provide express 
written approval of, any change in the maintenance of the foregoing documents if the 
investigator wishes to move study records to another location or assign responsibility for 
record retention to another party.  If the investigator cannot guarantee the archiving 
requirements set forth herein at his or her study site for all such documents, special 
arrangements must be made between the investigator and Acerta Pharma to store such 
documents in sealed containers away from the study site so that they can be returned 
sealed to the investigator for audit purposes. 
7.8 
PROTOCOL AMENDMENTS 
Acerta Pharma will initiate any change to the protocol in a protocol amendment 
document.  The amendment will be submitted to the IRB/IEC together with, if applicable, 
a revised model ICF.  If the change in any way increases the risk to the subject or 

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

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12. All SAEs are reported to Acerta Pharma Drug Safety/Designee within 24 hours of 
knowledge via the clinical database and to the IRB/IEC per their requirements. 
 

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8.0 
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APPENDICES 
 
 
 

CCI
CCI

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Treatment Phasea 
TT Visit SFU Visitb 
Post-
Treat-
ment 
Disease 
Follow-
Upc 
LTFUd 
Cycles 
 
Cycle 1 
Cycle 2 
Cycles 3-4 
Cycles 5+ 
+7 days 
after 
last 
dose 
+30 days 
after last 
dose 
Q12W 
Q12W 
Study Days 
Screeninge 
1 
8 
15 
22 
1 
8 
15 
22 
1 
15 
1 
Study Window 
-21 days 
 
±3 days 
±3 days 
±3 days 
±3 days 
+7 days 
±10 
days 
±10 days 
Concomitant medicationsz 
Corticosteroids 
EIAEDs 
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 
 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
x 
anti-HBc=hepatitis B core antibody; anti-HBs=hepatitis B surface antibody; BID=twice per day; CR=complete remission; DFU=disease follow-up; ECOG=Eastern 
Cooperative Oncology Group; EIAEDs=enzyme-inducing anti-epileptic drugs; 
 HBsAg=hepatitis B surface 
antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; LTFU=long-term follow-up; MRI=magnetic resonance imaging; 
 PCR=polymerase chain 
reaction; 
 PE=physical examination; Q12W=every 12 weeks; Q3M=every 3 months; SAC=Scientific Advisory Committee; TT=treatment 
termination. 
 
Footnotes for ACE-ST-209 Schedule of Study Activities: 
a. 
Any subjects who are tolerating study drug and have not progressed at the end of trial, defined as 52 weeks after the last subject is enrolled to the study, may 
continue to receive their study treatment after discussion with the medical monitor.  They will continue to have scheduled visits as outlined for Cycles 5+ on the 
schedule of assessments. 
b. 
A 30-day (+7 days) safety follow-up visit is required when subjects discontinue study drug.  After the end of the protocol-defined adverse event reporting period 
(see Section 6.2.1), only serious adverse events considered related to study drug(s) or study procedures are required to be collected. 
c. 
Each subject should be followed until disease progression or the start of alternative anticancer therapy.  If neither of these has occurred at the time of the 30-day 
SFU visit, DFU visits should occur approximately every 3 months (12 weeks) from date of last dose until disease progression or next anticancer treatment.  During 
this period, subjects will be followed via MRIs. 
d. 
Once subjects progress or start use of alternative anticancer therapy—for all subjects who have not withdrawn consent—they will be contacted approximately 
every 3 months (12 weeks) from date of last dose by clinic visit or telephone, to assess survival and the use of alternative anticancer therapy until death or lost to 
follow-up. 
e. 
An MRI must be performed within 21 days before the administration of study drug; all other screening tests should be performed within 21 days before the first 
administration of study drug, unless otherwise indicated. 
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f. 
The screening physical examination will include, at a minimum, the general appearance of the subject, height (screening only) and weight, and examination of the 
skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system.  Symptom-directed physical 
examinations, including tumor assessments by palpation, are done thereafter.   
g. 
Vital signs (blood pressure, pulse, and temperature) will be assessed after the subject has rested in the sitting position.   
h. 
An ECG will be performed during screening.  Subjects should be in supine position and resting for ≥10 minutes before the ECG. 
i. 
Women of childbearing potential only. 
j. 
This urine or serum pregnancy test is to be performed on Cycle 1 Day 1 (-3 days).  
k. 
Hematology includes complete blood count with differential including, but not limited to white blood cell count, hemoglobin, hematocrit, platelet count, ANC, and 
ALC.  Cycle 1 Day 1 hematology does not need to be repeated if screening hematology was done within 10 days.   
l. 
Serum chemistry: albumin, alkaline phosphatase, ALT, AST, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, magnesium, phosphate/phosphorus, 
potassium, sodium, total bilirubin, total protein, and uric acid.  Cycle 1 Day 1 serum chemistry does not need to be repeated if screening serum chemistry was 
within 10 days.  If an unscheduled ECG is done at any time, then an electrolyte panel (i.e., calcium, magnesium, and potassium) must be done to coincide with the 
ECG testing. 
m. PT and aPTT. 
n. 
Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.   
q. 
For subjects who are receiving the EIAEDs carbamazepine or phenytoin, who are either enrolled in the Phase 1b portion or approved by the medical monitor to 
participate in this study: blood samples for therapeutic drug monitoring for carbamazepine and/or phenytoin levels will be drawn predose and 1 hour postdose on 
Cycle 1 Day 1, anytime during the visit on Cycle 1 Day 8, predose and 1 hour postdose on Cycle 1 Day 15 and Cycle 1 Day 22, and then monthly thereafter, and 
should be repeated after any dose change, until sufficient data are available to discern that time-dependent inhibition of CYP3A is or is not a concern.  The 
predose sample can be taken up to 30 minutes before dosing.  The window for other timepoints is ±5 minutes.  Therapeutic drug monitoring will be performed 
locally.  Refer to the protocol for more detailed information. Note:  Under Amendment 2 of the protocol, no additional subjects on EIAEDs will be enrolled. 
r. 
Hepatitis serology must include HBsAg, anti-HBs, anti-HBc, and HCV antibody.  In addition, any subjects testing positive for any hepatitis serology, must have 
PCR testing (see exclusion criterion #23). 
s. 
Subjects who are anti-HBc positive (or have a known history of HBV infection) should have a quantitative PCR test for HBV DNA performed during screening and 
every 3 months thereafter.  Regular monitoring (every 3 months) should continue until 12 months after last dose of acalabrutinib.  Any subject with a rising viral 
load (above lower limit of detection) should discontinue acalabrutinib and have antiviral therapy instituted and a consultation with a physician with expertise in 
managing hepatitis B.   
 
v. 
Under Amendment 2 of the protocol, the SAC observed that the response and disease-control rate observed in the 200-mg BID cohort were numerically higher 
than in the 400-mg QD cohort. Therefore, the 400-mg QD cohort was discontinued. 
w. An MRI of the CNS must be performed at screening, on Cycle 3 Day 1, Cycle 4 Day 1 (4 weeks after Cycle 3 Day 1 scan to evaluate for response stability), then 
on Day 1 of every other cycle (every 8 weeks) thereafter (e.g., Cycle 6 Day 1, Cycle 8 Day 1); if symptomatic, then MRIs may be performed more frequently at 
investigator discretion. 
z. 
Concomitant medications of interest that will be collected throughout the study include corticosteroids and EIAEDs. Note:  Under Amendment 2 of the protocol, no 
additional subjects on EIAEDs will be enrolled. 
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Appendix 2.  RANO Criteria 
 
 
 

Updated Response Assessment Criteria for High-Grade
Gliomas: Response Assessment in Neuro-Oncology
Working Group
Patrick Y. Wen, David R. Macdonald, David A. Reardon, Timothy F. Cloughesy, A. Gregory Sorensen,
Evanthia Galanis, John DeGroot, Wolfgang Wick, Mark R. Gilbert, Andrew B. Lassman, Christina Tsien,
Tom Mikkelsen, Eric T. Wong, Marc C. Chamberlain, Roger Stupp, Kathleen R. Lamborn,
Michael A. Vogelbaum, Martin J. van den Bent, and Susan M. Chang
From the Center for Neuro-Oncology,
Dana-Farber/Brigham and Women’s
Cancer Center; Division of Neurology,
Brigham and Women’s Hospital; Depart-
ment of Radiology, Massachusetts
General Hospital; Brain Tumor Center,
Department of Neurology, Beth Israel
Deaconess Medical Center, Boston, MA;
Preston Robert Tisch Brain Tumor
Center, Duke University Medical Center,
Durham, NC; Neuro-Oncology Program,
David Geffen School of Medicine at
University of California, Los Angeles, Los
Angeles; Division of Neuro-Oncology,
Department of Neurological Surgery,
University of California, San Francisco,
San Francisco, CA; Department of Medi-
cal Oncology, Mayo Clinic, Rochester,
MN; Department of Neuro-Oncology, The
University of Texas M.D. Anderson
Cancer Center, Houston, TX; Department
of Neurology and Brain Tumor Center,
Memorial Sloan-Kettering Cancer Center,
New York, NY; Department of Radiation
Oncology, University of Michigan Medical
Center, Ann Arbor; Department of Neuro-
Oncology, Henry Ford Hospital, Detroit,
MI; Fred Hutchinson Cancer Center,
Seattle, WA; Brain Tumor and Neuro-
Oncology Center, Department of Neuro-
surgery, Cleveland Clinic, Cleveland OH;
Department of Medical Oncology,
London Regional Cancer Program,
University of Western Ontario, London,
Ontario, Canada; Department of Neuro-
Oncology, University of Heidelberg,
Heidelberg, Germany; Centre Hospitalier
Universitaire Vaudois; University of
Lausanne, Lausanne, Switzerland; and
Neuro-Oncology Unit, Daniel den Hoed
Cancer Center/Erasmus University Hospi-
tal, Rotterdam, the Netherlands.
Submitted September 26, 2009;
accepted December 14, 2009;
published online ahead of print at
www.jco.org on March 15, 2010.
P.Y.W., D.R.M., M.A.V., M.J.v.d.B. and
S.M.C. contributed equally to this work.
Authors’ disclosures of potential con-
ﬂicts of interest and author contribu-
tions are found at the end of this
article.
Corresponding author: Patrick Y. Wen,
MD, Center for Neuro-Oncology, Dana
Farber/Brigham and Women’s Cancer
Center, SW430D, 44 Binney St,
Boston, MA 02115; e-mail: pwen@
partners.org.
© 2010 by American Society of Clinical
Oncology
0732-183X/10/2811-1963/$20.00
DOI: 10.1200/JCO.2009.26.3541
A
B
S
T
R
A
C
T
Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas
are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic
resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the
Macdonald Criteria). It is increasingly apparent that there are signiﬁcant limitations to these criteria,
which only address the contrast-enhancing component of the tumor. For example, chemoradio-
therapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement
(pseudoprogression) in 20% to 30% of patients, which is difﬁcult to differentiate from true tumor
progression. Antiangiogenic agents produce high radiographic response rates, as deﬁned by a
rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of
treatment and that is partly a result of reduced vascular permeability to contrast agents rather than
a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop
tumor recurrence characterized by an increase in the nonenhancing component depicted on
T2-weighted/ﬂuid-attenuated inversion recovery sequences. The recognition that contrast en-
hancement is nonspeciﬁc and may not always be a true surrogate of tumor response and the need
to account for the nonenhancing component of the tumor mandate that new criteria be developed
and validated to permit accurate assessment of the efﬁcacy of novel therapies. The Response
Assessment in Neuro-Oncology Working Group is an international effort to develop new
standardized response criteria for clinical trials in brain tumors. In this proposal, we present the
recommendations for updated response criteria for high-grade gliomas.
J Clin Oncol 28:1963-1972. © 2010 by American Society of Clinical Oncology
INTRODUCTION
Gliomas are the most common form of malignant
primary brain tumors in adults, with an annual in-
cidence of approximately four to ﬁve per 100,000
people.1,2 Theevaluationoftreatmentinhigh-grade
gliomas currently relies either on the duration of
patientsurvivalor,morecommonlyinpatientswith
recurrent disease, the radiographic response rate or
progression-free survival (PFS).3,4 In 1990, Mac-
donald et al5 published criteria for response assess-
ment in high-grade gliomas (Table 1). These criteria
provided an objective radiologic assessment of
tumor response and were based primarily on
contrast-enhanced computed tomography (CT)
and the two-dimensional WHO oncology response
criteria using enhancing tumor area (the product of
the maximal cross-sectional enhancing diameters)
as the primary tumor measure.6,7 These criteria also
considered the use of corticosteroids and changes in
the neurologic status of the patient. The Macdonald
Criteria enabled response rates to be compared be-
tween clinical trials and have been widely used in
high-grade glioma studies since their introduction.
Although the Macdonald Criteria were devel-
oped primarily for CT scans, they have been extrap-
olatedtomagneticresonanceimaging(MRI),which
is now the standard neuroimaging modality used to
assess treatment response in high-grade gliomas.
Like CT scans, areas of the tumor with abnormal
vascular architecture and disrupted integrity of the
blood-brain barrier are depicted as the contrast-
enhancing component on MRI.8
In systemic cancers, one-dimensional tumor
measurements have become the standard criteria to
determine response. The Response Evaluation Cri-
teria in Solid Tumors (RECIST) ﬁrst introduced the
use of one-dimensional measurements in 20009 and
were recently revised (RECIST version 1.1).10 Sev-
eralstudieshavecomparedtheRECISTcriteriawith
JOURNAL OF CLINICAL ONCOLOGY
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A R T I C L E
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10
2010
© 2010 by American Society of Clinical Oncology
1963

ROLE OF VOLUMETRIC AND ADVANCED MRI ASSESSMENT
Given the limitations of two-dimensional tumor measurements,
there is signiﬁcant interest in volumetric anatomic assessment. The
use of volumetric assessment would allow more accurate determina-
tion of the contrast-enhancing and nonenhancing volumes and over-
come the limitations of two-dimensional measurements of lesions
surrounding a surgical cavity.14-16 However, the RANO Working
Group and colleagues in neuroradiology do not believe that there is
sufﬁcient standardization and availability to recommend adoption of
volumetric assessment of tumor volume at present. Nonetheless, this
is an important area of research. Eventually, as volumetric imaging
becomes more standardized and widely available and as data validat-
ingthisapproachemerge,itmaybepossibletoincorporatevolumetric
measurements in the response assessment of high-grade gliomas.
Emerging data also suggest that advanced MRI techniques such
as perfusion imaging (dynamic susceptibility MRI), permeability im-
aging (dynamic contrast-enhanced MRI), diffusion imaging, mag-
netic resonance spectroscopy, and [18F]-ﬂuorothymidine and amino
acid positron emission tomography may predict tumor response or
allow the differentiation of nonenhancing tumor from other causes of
increasedFLAIRsignal.Thesetechniqueswillrequirerigorousclinical
validation studies before they can be incorporated into response crite-
ria used in clinical trials in high-grade gliomas.
OTHER METHODS OF DETERMINING EFFICACY
Growing data suggest that other end points such as neurocognitive
function,qualityoflife,andcorticosteroidusemaybeusedtomeasure
clinical beneﬁt. At present, these end points are not sufﬁciently vali-
dated to be incorporated into the current response criteria but could
be added in the future as further data emerge.
CONCLUSION
We propose updated response assessments for the evaluation of
therapies in high-grade gliomas incorporating MRI characteristics
to address the recognized and accepted limitations of the current
Macdonald Criteria. These recommendations were generated as part
of an international neuro-oncology effort with consensus building
and are an attempt to develop standardized assessment criteria. Im-
plementation into future clinical trials will be critical so we can
validate the criteria as a surrogate to end points such as survival
and, ultimately, improve the accuracy and efﬁciency of the early
evaluation of novel therapies.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) indicated a ﬁnancial or other interest that is relevant to the subject
matter under consideration in this article. Certain relationships marked
with a “U” are those for which no compensation was received; those
relationships marked with a “C” were compensated. For a detailed
description of the disclosure categories, or for more information about
ASCO’s conﬂict of interest policy, please refer to the Author Disclosure
Declaration and the Disclosures of Potential Conﬂicts of Interest section in
Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory
Role: Michael A. Vogelbaum, AstraZeneca (C), Schering-Plough (C)
Stock Ownership: None Honoraria: Michael A. Vogelbaum, BrainLAB,
BrainLAB, Genentech, Eisai Research Funding: None Expert
Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Patrick Y. Wen, David R. Macdonald, David A.
Reardon, Timothy F. Cloughesy, A. Gregory Sorensen, Evanthia Galanis,
John DeGroot, Wolfgang Wick, Mark R. Gilbert, Andrew B. Lassman,
Christina Tsien, Tom Mikkelsen, Eric T. Wong, Marc C. Chamberlain,
Roger Stupp, Kathleen R. Lamborn, Michael A. Vogelbaum, Martin J.
van den Bent, Susan M. Chang
Administrative support: Patrick Y. Wen
Provision of study materials or patients: Patrick Y. Wen, Susan M.
Chang, A. Gregory Sorensen
Collection and assembly of data: Patrick Y. Wen, David R.
Macdonald, David A. Reardon, Timothy F. Cloughesy, A. Gregory
Sorensen, Evanthia Galanis, John DeGroot, Wolfgang Wick,
Mark R. Gilbert, Andrew B. Lassman, Christina Tsien, Tom
Mikkelsen, Eric T. Wong, Marc C. Chamberlain, Roger Stupp,
Kathleen R. Lamborn, Michael A. Vogelbaum, Martin J. van den
Bent, Susan M. Chang
Data analysis and interpretation: Patrick Y. Wen, David R. Macdonald,
David A. Reardon, Timothy F. Cloughesy, A. Gregory Sorensen,
Evanthia Galanis, John DeGroot, Wolfgang Wick, Mark R. Gilbert,
Andrew B. Lassman, Christina Tsien, Tom Mikkelsen, Eric T. Wong,
Marc C. Chamberlain, Roger Stupp, Kathleen R. Lamborn, Michael A.
Vogelbaum, Martin J. van den Bent, Susan M. Chang
Manuscript writing: Patrick Y. Wen, David R. Macdonald, David A.
Reardon, Timothy F. Cloughesy, A. Gregory Sorensen, Evanthia Galanis,
John DeGroot, Wolfgang Wick, Mark R. Gilbert, Andrew B. Lassman,
Christina Tsien, Tom Mikkelsen, Eric T. Wong, Roger Stupp, Kathleen
R. Lamborn, Michael A. Vogelbaum, Martin J. van den Bent,
Susan M. Chang
Final approval of manuscript: Patrick Y. Wen, David R. Macdonald,
David A. Reardon, Timothy F. Cloughesy, A. Gregory Sorensen,
Evanthia Galanis, John DeGroot, Wolfgang Wick, Mark R. Gilbert,
Andrew B. Lassman, Christina Tsien, Tom Mikkelsen, Eric T. Wong,
Marc C. Chamberlain, Roger Stupp, Kathleen R. Lamborn, Michael A.
Vogelbaum, Martin J. van den Bent, Susan M. Chang
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52. Rubenstein J, Kim J, Ozawa T, et al: Anti-
VEGF antibody treatment of glioblastoma prolongs
survival but results in increased vascular cooption.
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53. Paez-Ribes M, Allen E, Hudock J, et al: Anti-
angiogenic therapy elicits malignant progression of
tumors to increased local invasion and distant me-
tastasis. Cancer Cell 15:220-231, 2009
54. Bergers G, Hanahan D: Modes of resistance
to anti-angiogenic therapy. Nat Rev Cancer 8:592-
603, 2008
55. Chawla S, Poptani H, Melhem ER: Ana-
tomic, physiologic and metabolic imaging in neuro-
oncology. Cancer Treat Res 143:3-42, 2008
56. Ullrich RT, Kracht LW, Jacobs AH: Neuroim-
aging in patients with gliomas. Semin Neurol 28:
484-494, 2008
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1972
© 2010 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY

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Appendix 3.  Examples of Coadministered Drugs that Need Additional 
Consideration 
 
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 
 
Note:  After discontinuation of the strong or moderate CYP3A inhibitor, wait 
3 days before resuming ACP-319 or acalabrutinib. 
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. 
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/DevelopmentResou
rces/DrugInteractionsLabeling/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/guidancecomplianceregulator
yinformation/lawsactsandrules/ucm428333.pdf 
 
 

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

CCI

CCI

CCI

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

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Appendix 7.  Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law 
INTRODUCTION 
This Appendix describes the process to be followed to identify and appropriately report 
potential Hy’s law (PHL) cases and Hy’s law (HL) cases.  It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.  
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a subject meets 
PHL criteria at any point during the study.  All sources of laboratory data are appropriate 
for the determination of PHL and HL events; this includes samples taken at scheduled 
study visits and other visits, including central and all local laboratory evaluations, even if 
collected outside of the study visits (e.g., PHL criteria could be met by an elevated ALT 
from a central laboratory and/or elevated total bilirubin from a local laboratory).  The 
investigator will also review adverse event (AE) data (e.g., for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events. 
The investigator participates with the sponsor in the review and assessment of cases 
meeting PHL criteria to agree whether HL criteria are met.  HL criteria are met if there is 
no alternative explanation for the elevations in liver biochemistry other than drug-induced 
liver injury (DILI) caused by the investigational medicinal product (IMP).  The investigator 
is responsible for recording data pertaining to PHL/HL cases and for reporting AEs and 
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 PHL 
case as an SAE of Potential Hy’s law: seriousness criteria “Important medical event” 
and causality assessment “yes/related” or in accordance with the clinical study 
protocol as appropriate. 
 
Request a repeat of the test (new blood draw) without delay 
 
Complete the appropriate unscheduled laboratory electronic Case Report Form 
(eCRF) module(s)  
 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the clinical study protocol, as applicable 
 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
The instructions in this section should be followed by the investigator for all cases where 
PHL criteria are met. 
As soon as possible after the biochemistry abnormality is initially detected, the study 
Medical Monitor and the Investigator will review available data, to agree whether there is 
an alternative explanation for meeting PHL criteria other than DILI caused by the IMP 
and to ensure that timely analysis and reporting to health authorities within 15 calendar 
days from the date PHL criteria were met.    
Where there is an agreed alternative explanation for the ALT or AST and total bilirubin 
elevations, a determination of whether the alternative explanation is an AE will be made 
and, subsequently, whether the AE meets the criteria for an SAE: 
 
If the alternative explanation is not an AE, record the alternative explanation on the 
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 
SAEreport following the clinical study protocol process, according to the outcome of 
the review. 
ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S LAW 
This section is applicable when a subject meets PHL criteria while receiving study 
treatment and has already met PHL criteria at a previous on-study treatment visit.  The 
requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous 
occurrence.   
The investigator should determine the cause for the previous occurrence of PHL and 
answer the following question: 
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)? 

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 
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 
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 

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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