A Randomized, Multicenter, Open-Label, 3 Arm Phase 3 Study of Obinutuzumab in Combination With Chlorambucil, Acalabrutinib (ACP-196) in Combination With Obinutuzumab, and Acalabrutinib Monotherapy in Subjects With Previously Untreated CLL
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia
Sponsor: Acerta Pharma BV

Product: ACP-196 (acalabrutinib) 
Protocol: ACE-CL-007 
 
 
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PROTOCOL 
 
 
TITLE: 
A Randomized, Multicenter, Open-Label, 3 Arm Phase 3 Study of 
Obinutuzumab in Combination with Chlorambucil, ACP-196 in 
Combination with Obinutuzumab, and ACP-196 Monotherapy in 
Subjects with Previously Untreated Chronic Lymphocytic 
Leukemia 
PROTOCOL NUMBER: 
ACE-CL-007 
STUDY DRUG: 
Acalabrutinib (ACP-196) 
IND NUMBER: 
118717 
EUDRACT NUMBER: 
2014-005582-73 
SPONSOR MEDICAL 
MONITOR: 
Phone: 
 
Email:
SPONSOR: 
Acerta Pharma, BV  
5349 AB Oss 
The Netherlands  
ORIGINAL PROTOCOL: 
Version 0.0 – 11 March 2015 
AMENDMENTS: 
Version 1.0 – 01 April 2015 
 
Version 2.0 – 27 April 2015 
 
Version 3.0 – 16 March 2016 
 
Version 4.0 – 06 March 2017 
 
Version 5.0 – 04 December 2017 
 
Version 6.0 – 17 June 2020 
 
 
Confidentiality Statement 
This document contains proprietary and confidential information of Acerta Pharma BV that 
must not be disclosed to anyone other than the recipient study staff and members of the 
institutional review board (IRB)/independent ethics committee (IEC). This information cannot 
be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Acerta Pharma BV. 
 
PPD
PPD
PPD
PPD

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PROTOCOL APPROVAL 
Version 6.0 
I have carefully read Protocol ACE-CL-007 entitled “A Randomized, Multicenter, Open-Label, 
3 Arm Phase 3 Study of Obinutuzumab in Combination with Chlorambucil, ACP-196 in 
Combination with Obinutuzumab, and ACP-196 Monotherapy in Subjects with Previously 
Untreated Chronic Lymphocytic Leukemia”.  I agree to conduct this study as outlined herein and 
in compliance with Good Clinical Practice (GCP), all applicable regulatory requirements, and 
with the ethical principles laid down in the Declaration of Helsinki.  Furthermore, I understand 
that the Sponsor, Acerta Pharma, and the 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 BV 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 6.0 
This protocol is being amended to update clinical trial data and safety information, including 
Reference Safety Information, based on the current Acalabrutinib Investigator Brochure as well 
as to clarify hepatitis testing during crossover, to add Rollover and Safety Extension Study text, 
to add Hy’s law information, 
 will no longer be collected, 
investigator-assessed progressive disease (PD) after crossover will be confirmed by the study 
Medical Monitor, to clarify several study details, and to correct inconsistencies. 
Appendix N (Management of Study Procedures During Pandemic) has been added to 
consolidate guidance for subject safety and ongoing access to medical care and investigational 
product during the global COVID-19 pandemic. 
Clarifying edits and typographical changes have been made throughout the protocol.  In 
addition, the substantive changes that were made as part of this amendment are noted in the 
table below. 
Summary of Changes for Amendment 6.0 
Section(s) Impacted 
Rationale 
Headers and Footers 
Updated to align with Acerta protocol standards 
Updated heading numbers throughout 
protocol 
Updated heading numbers to align with new Acerta protocol 
template 
Title page 
Updated Medical Monitor and contact information  
Study Synopsis 
Updated the Synopsis to reflect changes in the protocol. 
1.3.1 Chemistry 
Updated this section with Calquence approval in CLL and SLL. 
1.4.2 Clinical Experience of Acalabrutinib in 
CLL 
Updated based on the current Acalabrutinib Investigator Brochure. 
3.4 Exploratory Objectives 
4.1 Treatment Arm A: Obinutuzumab in 
Combination with Chlorambucil 
Added text for Arm A crossover subjects:  “After the interim analysis 
and per Amendment 6.0, at investigator discretion, subjects 
randomized to Arm A, who have IRC-confirmed progressive disease 
(PD) (through Amendment 5.0) or investigator-assessed PD 
(Amendment 6.0) will be eligible to receive crossover treatment with 
single-agent acalabrutinib at 100 mg BID until disease progression 
or unacceptable toxicity.  However, the investigator-assessed PD 
must be confirmed by the study Medical Monitor.” 
The rationale for this change is that the IRC primary endpoint has 
been met.  Sponsor review is deemed sufficient. 
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4.4 Crossover 
Added text that screening for eligibility may occur concurrently with 
the study Medical Monitor as needed.  Added text that IRC 
assessments for confirmation of PD for crossover subjects was 
required through Amendment 5.0.  Added that any new systemic 
therapy or crossover treatment with acalabrutinib could not be 
started without investigator-assessed PD confirmed by the study 
Medical Monitor. 
The rationale for this change is that the IRC primary endpoint has 
been met.  Sponsor review is deemed sufficient. 
4.5 Screening, Treatment, and Follow-up 
Phases 
Added text for the Rollover or Safety Extension Study to ensure 
treatment continuation, with visit assessments per the rollover or 
extension protocol and alignment with other acalabrutinib protocols.  
Revised the following sentence “The Post-disease Progression 
Phase will begin after IRC-confirmed PD (through Amendment 5.0) 
or investigator-assessed PD (Amendment 6.0); 
investigator-assessed PD must be confirmed by the study Medical 
Monitor.” 
The rationale for this change is that the IRC primary endpoint has 
been met.  Sponsor review is deemed sufficient. 
6.3.3.1 Tumor Lysis Syndrome for 
acalabrutinib 
Added this section and text for subjects considered at risk for TLS 
on acalabrutinib 
6.4.1.1 Hemorrhage 
Updated based on the current Acalabrutinib Investigator Brochure. 
6.4.1.2 Infections 
Updated based on the current Acalabrutinib Investigator Brochure. 
6.4.1.5 Cytopenias 
Updated based on the current Acalabrutinib Investigator Brochure. 
6.4.1.6 Second Primary Malignancies 
Updated based on the current Acalabrutinib Investigator Brochure. 
6.4.1.7 Atrial Fibrillation 
Updated based on the current Acalabrutinib Investigator Brochure. 
6.4.1.8 Dietary Restrictions 
Updated based on the current Acalabrutinib Investigator Brochure. 
6.4.4 Reproductive Toxicity 
Updated based on the current Acalabrutinib Investigator Brochure. 
6.5.2 Guideline for Use of 
CYP-Inhibiting/Inducing Drugs 
Updated based on the current Acalabrutinib Investigator Brochure. 
6.5.3 Guideline for Use of Drugs that Affect 
Gastric pH 
Updated based on the current Acalabrutinib Investigator Brochure. 
6.5.4 Prohibited Concomitant Medications 
Updated based on the current Acalabrutinib Investigator Brochure. 
7.1.10 Hepatitis Serologies 
Clarified hepatitis testing during the randomized part of the study 
and the crossover part. 
7.1.12 Genetic and Molecular Prognostic 
Markers 
Revised the 
 section to specify that 
 endpoints would not 
be collected under Amendment 6.0. 
The rationale for this change is that the exploratory 
 endpoints 
were met for the study. 
7.1.26 Overall Response Evaluations 
Revised the sentence to state: “In addition, prior to crossover from 
Arm A to the crossover arm, a subject may continue treatment and 
remain under close observation until progression is confirmed by the 
IRC (through Amendment 5.0) or until progression is assessed by 
the investigator and confirmed by the study Medical Monitor 
(Amendment 6.0).” 
Added 1 new section within Section 7.2.1 
Definitions 
7.2.1.3 Adverse Events of Special Interest 
This section was added to provide consistency across Acerta’s 
acalabrutinib protocols. 
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7.2.2.1 Adverse Event Reporting Period 
This text has been updated to provide consistency across Acerta’s 
acalabrutinib protocols. 
7.2.2.3 Second Primary Malignancies 
This section and text have been added to provide safety information 
and consistency across Acerta’s acalabrutinib protocols. 
7.2.2.5 Expedited Reporting Requirements 
for Serious Adverse Events and AESIs 
This section was updated to include expedited reporting 
requirements for AESIs and to provide the source of Reference 
Safety Information, to provide consistency across Acerta’s 
acalabrutinib protocols.    
7.2.2.7 Hy’s Law 
This section and text have been added to provide safety information 
and consistency across Acerta’s acalabrutinib protocols. 
9.9.4 Exploratory Endpoints 
9.10.3 AESIs 
Revised this section to refer to Section 7.2.1.6 for the definitions of 
AESIs.   
12 Appendices A, B, and C 
Added footnote to the Schedule of Assessments tables to clarify that 
 endpoints will not be collected under Amendment 6.0 
12 Appendices 
Appendix H has been removed:  The obinutuzumab and 
chlorambucil label has been removed from the protocol (previously 
Appendix H) to ensure the most current labels are accessed by the 
investigators and sites.  The Appendices have been renumbered 
accordingly. 
Appendix F Examples of Coadministered 
Drugs That Need Additional Consideration 
This section was updated to provide safety information and 
consistency across Acerta’s acalabrutinib protocols. 
Appendix M Actions Required in Cases of 
Increases in Liver Biochemistry and 
Evaluation of Hy’s Law 
This Appendix has been added to provide detailed safety 
information, instruction, and consistency regarding Hy’s law across 
Acerta’s acalabrutinib protocols. 
Appendix N Management of Study 
Procedures During Pandemic 
Appendix N has been added to consolidate guidance for subject 
safety and ongoing access to medical care and investigational 
product during the global COVID-19 pandemic. 
Entire protocol 
Text has been updated throughout the protocol to cite the local 
prescribing information and SmPCs to ensure the most current 
labels are accessed by the investigators and sites. 
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STUDY SYNOPSIS 
Study Title: 
A Randomized, Multicenter, Open-Label, 3 Arm Phase 3 Study of 
Obinutuzumab in Combination with Chlorambucil, ACP-196 in 
Combination with Obinutuzumab, and ACP-196 Monotherapy in 
Subjects with Previously Untreated Chronic Lymphocytic 
Leukemia 
Protocol Number: 
ACE-CL-007 
Study Phase: 
3 
Study Duration: 
The study duration will be approximately 4.5 years including 
enrollment time. 
Investigational Product 
and Reference Therapy: 
The investigational product, acalabrutinib (also known as 
ACP-196), will be supplied as hard gelatin capsules for oral (PO) 
administration. 
Commercially available obinutuzumab (GAZYVA / GAZYVARO) 
and chlorambucil (LEUKERAN®) will be the reference therapy.  
Obinutuzumab is administered by intravenous (IV) infusion. 
Chlorambucil is administered orally. 
Objectives 
Primary Objective: 
• 
To evaluate the efficacy of obinutuzumab in combination 
with chlorambucil (Arm A) compared with acalabrutinib in 
combination with obinutuzumab (Arm B) based on 
Independent Review Committee (IRC) assessment of 
progression-free survival (PFS) per International 
Workshop on Chronic Lymphocytic Leukemia criteria 
(IWCLL, Hallek 2008) with incorporation of the clarification 
for treatment-related lymphocytosis (Cheson 2012)—
hereafter referred to as IWCLL 2008 criteria—in subjects 
with previously untreated chronic lymphocytic leukemia 
(CLL). 
Secondary Objectives: 
• 
To evaluate the efficacy of obinutuzumab in combination 
with chlorambucil (Arm A) versus acalabrutinib 
monotherapy (Arm C) based on IRC assessment of PFS 
per IWCLL 2008 criteria. 
• 
To compare obinutuzumab plus chlorambucil (Arm A) 
versus acalabrutinib plus obinutuzumab (Arm B) and 
obinutuzumab plus chlorambucil (Arm A) versus 
acalabrutinib monotherapy (Arm C) in terms of: 
• 
IRC-assessed objective response rate (ORR) per IWCLL 
2008 criteria. 
• 
Time to next treatment (TTNT) (defined as the time from 
randomization to institution of non-protocol specified 
treatment for CLL). 
• 
Overall survival (OS). 

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Safety Objective: 
• 
Incidence of adverse events (AEs) and serious adverse 
events (SAEs) and changes in laboratory measurements. 
Exploratory Objectives: 
Study Design: 
This randomized, global, multicenter, open-label, 3-arm Phase 3 
study will evaluate the efficacy and safety of Arm A, Arm B, and 
Arm C in subjects with previously untreated CLL. 
Approximately 510 eligible subjects will be randomized in a 
1:1:1 ratio into 3 arms (n=170) to receive either Arm A 
(obinutuzumab in combination with chlorambucil per the package 
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inserts), Arm B (acalabrutinib 100 mg twice per day [BID] in 
combination with obinutuzumab per the package insert), or 
Arm C (acalabrutinib 100 mg BID). 
This study will use an Interactive Web Response System (IWRS) 
for randomization.  Randomization will be used to minimize bias 
in the assignment of subjects to treatment groups, to increase the 
likelihood that known and unknown subject attributes (e.g., 
demographic and baseline characteristics) are evenly balanced, 
and to enhance the validity of statistical comparisons across 
treatment groups. 
Subjects will be randomized based on the following stratification 
factors: 
• 
Presence versus absence of 17p deletion mutation 
(17p del). 
• 
Eastern Cooperative Oncology Group (ECOG) 
Performance Status 0, 1 versus 2. 
• 
Geographic region (North America and Western Europe 
versus Other). 
Subject participation will include a Screening Phase, a Treatment 
Phase, Post-treatment Phase and a Post-disease Progression 
Phase.  The Screening Phase will last up to 28 days before the 
first dose of study drug, during which the subject’s eligibility and 
baseline characteristics will be determined.  The “Treatment 
Phase” will last from randomization until study drug(s) 
discontinuation.  Treatment with acalabrutinib may be continued 
until an unacceptable drug-related toxicity occurs or until disease 
progression.  Dose modification provisions are provided in the 
study protocol.  Note: temporary withholding of acalabrutinib for 
as little as 7 days can cause a transient worsening of disease 
and/or of constitutional symptoms.  Refer to Section 8.1 for more 
information on assessing disease progression under these 
circumstances.  Treatment with obinutuzumab or 
obinutuzumab/chlorambucil is up to 6 cycles per the 
obinutuzumab package insert. 
Assessment for tumor response and progression will be 
conducted in accordance with the IWCLL 2008 criteria until 
disease progression.  Disease assessments will be done every 
12 weeks (± 14 days) with the first on-treatment radiologic 
assessment occurring on Cycle 4 Day 1, the second 
on-treatment scan on Cycle 7 Day 1, and so on through 
Cycle 25, and then every 24 weeks (± 14 days) thereafter for all 
subjects (including subjects who discontinue from study 
treatment due to an AE or any reason) until confirmation of 
disease progression or death, consent withdrawal, or lost to 
follow up.  Subjects from Arm A who have IRC-confirmed disease 
progression may be eligible to receive single agent acalabrutinib 
at 100 mg PO BID at investigator discretion.  A pre-planned 
interim analysis was performed and met the primary objective.  

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After the interim analysis and per Amendment 6.0, subjects can 
crossover with either IRC-confirmation (through Amendment 5.0) 
or investigator-assessed (Amendment 6.0) progressive disease 
(PD); however, the investigator-assessed PD must be confirmed 
by the study Medical Monitor 
An early termination (ET) visit is required for safety assessments 
for any subjects who permanently discontinue study treatment for 
any reason (except for death, lost to follow-up or withdrawal of 
consent), including disease progression.  The ET visit should be 
performed within 7 days of the last dose of all study drugs, 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 ET visit would be performed within 14 days of the safety 
follow-up (SFU) visit.  If the SFU visit is within ± 7 days of a 
regularly scheduled visit during the Post-treatment Phase, these 
visits may be combined into a single visit.  In addition to the ET 
visit, a SFU visit should be conducted 30 (+7) days after his or 
her last dose of all study drugs 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 demonstrated disease progression within 
this time frame.  Per Amendment 6.0, the Post-disease 
Progression Phase will begin after IRC-confirmed (through 
Amendment 5.0) or investigator-assessed (Amendment 6.0) 
progressive disease, if confirmed by the study Medical Monitor.  
During this phase, subsequent anticancer therapy with start date 
of therapy, IWCLL indication for treatment initiation, additional 
malignancy occurrence, and survival status will be recorded.  The 
Post-disease Progression Phase will continue until death, lost to 
follow up, consent withdrawal, or study closure, whichever occurs 
first. 
Subjects who are still on treatment at the end of the study 
(ACE-CL-007) 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 will be considered closed.  
There will be no further data collection other than reporting of 
SAEs per Section 7.2.2.5.  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. 
Population: 
Subjects with previously untreated CLL 
Centers: 
Approximately 200 global centers in North America, Europe, 
Australia/New Zealand, and Latin America. 

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Inclusion Criteria: 
1. Men and women:  
a. ≥ 65 years of age, OR 
b. > 18 and < 65 years of age provided that they 
meet at least one of the following criteria: 
i. Creatinine clearance 30 to 69 mL/min 
using the Cockcroft-Gault equation. 
ii. A score higher than 6 on the Cumulative 
Illness Rating Scale-Geriatric (CIRS-G) 
(Appendix L). 
2. ECOG performance status of 0, 1, or 2. 
3. Diagnosis of CD20+ CLL that meets published diagnostic 
criteria (Hallek 2008): 
a. Monoclonal B cells (either kappa or lambda light 
chain restricted) that are clonally co-expressing 
≥ 1 B-cell marker (CD19, CD20, or CD23) and 
CD5. 
b. Prolymphocytes may comprise ≤ 55% of blood 
lymphocytes. 
c. Presence of ≥ 5 x 109 B lymphocytes/L (5000/µL) 
in the peripheral blood (at any point since 
diagnosis). 
4. Active disease meeting ≥ 1 of the following IWCLL 2008 
criteria for requiring treatment: 
a. Evidence of progressive marrow failure as 
manifested by the development of, or worsening 
of, anemia (hemoglobin < 10 g/dL) and/or 
thrombocytopenia (platelets < 100,000/μL). 
b. Massive (i.e., ≥ 6 cm below the left costal margin), 
progressive, or symptomatic splenomegaly. 
c. Massive nodes (i.e., ≥ 10 cm in the longest 
diameter), progressive, or symptomatic 
lymphadenopathy. 
d. Progressive lymphocytosis with an increase of 
> 50% over a 2-month period or a lymphocyte 
doubling time (LDT) of < 6 months.  LDT may be 
obtained by linear regression extrapolation of 
absolute lymphocyte counts (ALC) obtained at 
intervals of 2 weeks over an observation period of 
2 to 3 months.  In subjects with initial blood 
lymphocyte counts of < 30 x 109/L (30,000/μL), 
LDT should not be used as a single parameter to 
define indication for treatment.  In addition, factors 
contributing to lymphocytosis or lymphadenopathy 
other than CLL (e.g., infections) should be 
excluded. 
e. Autoimmune anemia and/or thrombocytopenia that 
is poorly responsive to standard therapy. 
f. Constitutional symptoms documented in the 
subject’s chart with supportive objective 

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measures, as appropriate, defined as ≥ 1 of the 
following disease -related symptoms or signs: 
i. Unintentional weight loss ≥ 10% within the 
previous 6 months before Screening. 
ii. Significant fatigue (i.e., ECOG 
performance status 2; inability to work or 
perform usual activities). 
iii. Fevers higher than 100.5°F or 38.0°C for 
2 or more weeks before Screening without 
evidence of infection. 
iv. Night sweats for > 1 month before 
Screening without evidence of infection. 
5. This criterion was removed as of Protocol Amendment 
3Meet the following laboratory parameters: 
a. Absolute neutrophil count (ANC) ≥ 750 cells/μL 
(0.75 x 109/L) or ≥ 500 cells/μL (0.50 x 109/L) in 
subjects with documented bone marrow 
involvement and independent of growth factor 
support 7 days before assessment. 
b. Platelet count ≥ 50,000 cells/μL (50 x 109/L), or 
≥ 30,000 cells/μL (30 x 109/L) in subjects with 
documented bone marrow involvement, and 
without transfusion support 7 days before 
assessment.  Subjects with transfusion-dependent 
thrombocytopenia are excluded. 
c. Serum aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT) ≤ 3.0 x upper limit 
of normal (ULN). 
d. Total bilirubin ≤ 1.5 x ULN. 
e. Estimated creatinine clearance (i.e., estimated 
glomerular filtration rate [eGFR] using 
Cockcroft-Gault) ≥ 30 mL/min. 
7. Able to receive all outpatient treatment, all laboratory 
monitoring, and all radiologic evaluations. 
8. Women who are sexually active and can bear children 
must agree to use highly effective forms of contraception 
while on the study and for 2 days after the last dose of 
acalabrutinib or 18 months after the last dose of 
obinutuzumab in combination with chlorambucil, 
whichever is longer.  Highly effective forms of 
contraception are defined in Section 6.4.4. 
9. 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 
obinutuzumab or chlorambucil, whichever is later.  Highly 
effective forms of contraception are defined in 
Section 6.4.4. 
10. Men must agree to refrain from sperm donation during the 
study and for 90 days after the last dose of obinutuzumab 
or chlorambucil, whichever is later. 

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11. Are willing and able to adhere to the study visit schedule, 
understand and comply with other protocol requirements, 
and provide written informed consent and authorization to 
use protected health information.  Note vulnerable 
subjects, as defined in International Conference on 
Harmonisation (ICH) GCP, are not allowed on this 
protocol (e.g., prisoners or institutionalized subjects). 
Exclusion Criteria: 
1. Any prior systemic treatment for CLL (note: Prior localized 
radiotherapy is allowed). 
2. Known central nervous system (CNS) lymphoma or 
leukemia. 
3. Known prolymphocytic leukemia or history of, or currently 
suspected, Richter’s syndrome. 
4. Missing or incomplete documentation of FISH results 
reflecting the presence or absence of 17p del and the 
percentage of cells with the deletion in subject records 
before randomization. 
5. Uncontrolled autoimmune hemolytic anemia (AIHA) or 
idiopathic thrombocytopenic purpura (ITP), defined as 
declining hemoglobin or platelet count secondary to 
autoimmune destruction within the screening period or 
requirement for high doses of steroids (> 20 mg daily of 
prednisone daily or equivalent). 
6. Corticosteroid use > 20 mg within 1 week before first dose 
of study drug, except as indicated for other medical 
conditions such as inhaled steroid for asthma, topical 
steroid use, or as premedication for administration of 
study drug or contrast.  For example, subjects requiring 
steroids at daily doses > 20 mg prednisone equivalent 
systemic exposure daily, or those who are administered 
steroids for leukemia control or white blood cell count 
(WBC) lowering are excluded. 
7. Major surgery within 4 weeks before first dose of study 
drug. 
8. History of prior malignancy except for the following: 
a. Malignancy treated with curative intent and with no 
evidence of active disease present for more than 
3 years before Screening and felt to be at low risk 
for recurrence by treating physician.   
b. Adequately treated lentigo maligna melanoma 
without current evidence of disease or adequately 
controlled non-melanomatous skin cancer. 
c. Adequately treated cervical carcinoma in situ 
without current evidence of disease. 
9. Significant cardiovascular disease such as uncontrolled or 
symptomatic arrhythmias, congestive heart failure, or 
myocardial infarction within 6 months of screening, or any 

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Class 3 or 4 cardiac disease as defined by the New York 
Heart Association Functional Classification, or QTc 
> 480 msec at screening. 
10. Unable to swallow capsules or malabsorption syndrome, 
disease significantly affecting gastrointestinal function, or 
resection of the stomach or small bowel or gastric bypass, 
symptomatic inflammatory bowel disease, or partial or 
complete bowel obstruction. 
11. Uncontrolled active systemic fungal, bacterial, viral, or 
other infection (defined as exhibiting ongoing 
signs/symptoms related to the infection and without 
improvement, despite appropriate antibiotics or other 
treatment) or ongoing intravenous anti-infective treatment. 
12. Known history of infection with human immunodeficiency 
virus (HIV). 
13. Vaccinated with live, attenuated vaccines within 4 weeks 
of first dose of study drug. 
14. Serologic status reflecting active hepatitis B or C infection. 
Subjects with hepatitis B core antibody positive who are 
surface antigen negative or who are hepatitis C antibody 
positive will need to have a negative polymerase chain 
reaction (PCR) result before randomization.  Those who 
are hepatitis B surface antigen positive or hepatitis B PCR 
positive and those who are hepatitis C PCR positive will 
be excluded.  
15. History of stroke or intracranial hemorrhage within 
6 months before randomization. 
16. History of a bleeding diathesis (e.g., hemophilia, von 
Willebrand disease). 
17. Requires or receiving anticoagulation with warfarin or 
equivalent vitamin K antagonists (e.g., phenprocoumon) 
within 7 days of first dose of study drug. 
18. Requires treatment with proton-pump inhibitors (e.g., 
omeprazole, esomeprazole, lansoprazole, 
dexlansoprazole, rabeprazole, or pantoprazole). 
19. Breast feeding or pregnant. 
20. Current life-threatening illness, medical condition, or 
organ system dysfunction which, in the Investigator’s 
opinion, could compromise the subject’s safety or put the 
study at risk. 
21. Concurrent participation in another therapeutic clinical 
trial. 
22. Requires treatment with a strong cytochrome P450 3A 
(CYP3A) inhibitor/inducer. 
23. Presence of a gastrointestinal ulcer diagnosed by 
endoscopy within 3 months before screening 

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Primary Endpoint: 
The primary endpoint of the study is PFS as assessed by IRC 
review per IWCLL 2008 criteria.  The primary analysis is a 
comparison of PFS between Arm A and Arm B. 
Secondary Endpoints: 
Efficacy: 
The first secondary endpoint is a comparison of IRC-assessed 
PFS between Arm A and Arm C. 
Other secondary endpoints are as follows and compare Arm A 
versus Arm B and Arm A versus Arm C in terms of: 
• 
ORR defined as complete remission (CR), complete 
remission with incomplete bone marrow recovery (CRi), 
nodular partial remission (nPR), or partial remission (PR) 
(per IWCLL 2008 criteria). 
• 
TTNT (defined as the time from randomization to 
institution of non-protocol specified treatment for CLL). 
• 
OS. 
Safety: 
• 
Frequency, severity, and relatedness of AEs.  
• 
Frequency of AEs requiring discontinuation of study drug 
or dose reductions. 
• 
Change in laboratory assessments. 
Exploratory Endpoints: CCI

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Study Treatment: 
Acalabrutinib: 
Acalabrutinib is provided as 100-mg hard gelatin capsules for PO 
administration.  Acalabrutinib 100 mg will be administered BID 
until disease progression or unacceptable toxicity.  For subjects 
randomized to Arm B (acalabrutinib in combination with 
obinutuzumab), acalabrutinib administration will begin 28 days 
before the first dose of obinutuzumab (i.e., acalabrutinib begins 
on Cycle 1 Day 1, obinutuzumab begins on Cycle 2 Day 1).   
Obinutuzumab: 
Commercially available obinutuzumab will be supplied as a liquid 
concentrate (25 mg/mL) for dilution for IV administration 
Obinutuzumab must be administered as an IV infusion and 
premedication is required.  Obinutuzumab will be administered 
for a maximum of 6 cycles.  Refer to the obinutuzumab local 
prescribing information for more details. 
Chlorambucil: 
Commercially available chlorambucil will be provided as 
film-coated tablets (2 mg) for PO administration.  In this study, 
chlorambucil will be administered for a maximum of 6 cycles in 
combination with obinutuzumab.  Refer to chlorambucil local 
prescribing information for more details. 
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Concomitant Therapy 
and Clinical Practice: 
Permitted Concomitant Therapy 
Standard supportive care medications are permitted; this 
includes premedication for obinutuzumab infusion as per the 
obinutuzumab package insert.  Use of hematopoietic growth 
factors is permitted per the American Society of Clinical Oncology 
(ASCO) guidelines. 
For subjects considered at risk for tumor lysis syndrome (TLS), 
administer appropriate hydration and allopurinol or rasburicase 
per institutional standards prior to initiating treatment with 
acalabrutinib. 
Subjects who are considered to be at risk of TLS (e.g., subjects 
with a high tumor burden and/or a high circulating lymphocyte 
count [> 25 x 109/L] and/or renal impairment [creatinine clearance 
<70 mL/min]) should receive prophylaxis.  Prophylaxis should 
consist of adequate hydration and administration of uricostatics 
(e.g., allopurinol) or a suitable alternative such as a urate oxidate 
(e.g., rasburicase), before the infusion of obinutuzumab.  All 
subjects considered at risk should be carefully monitored during 
the initial days of treatment with a special focus on renal function, 
potassium, and uric acid values.  Any additional guidelines 
according to standard practice should be followed.  For treatment 
of TLS, correct electrolyte abnormalities, monitor renal function 
and fluid balance, and administer supportive care, including 
dialysis as indicated.  Subjects should continue to receive 
repeated prophylaxis before each subsequent infusion, if deemed 
appropriate. 
Prohibited Concomitant Therapy 
Any chemotherapy, anticancer immunotherapy, experimental 
therapy, or radiotherapy for treating CLL are prohibited if being 
used to treat the disease initially under study.  Short course use 
of steroids (≤ 2 weeks) > 20 mg/day) is permitted for 
premedication use, or to manage infusion-related reactions or to 
manage other inflammatory reactions such as asthma 
exacerbations.  High dose corticosteroids used to treat 
underlying CLL are not allowed on study.  Warfarin or equivalent 
vitamin K antagonists (e.g., phenprocoumon) are prohibited. 
Acalabrutinib and Concomitant Therapy 
The effect of agents that reduce gastric acidity (e.g., antacids or 
proton-pump inhibitors) on acalabrutinib absorption was 
evaluated in a healthy volunteer study (ACE-HV-004).  Results 
from this study indicate that subjects should avoid the use of 
calcium carbonate containing drugs or supplements for a period 
of at least 2 hours before and at least 2 hours after taking 
acalabrutinib.  Use of omeprazole or esomeprazole or 
lansoprazole or any other proton-pump inhibitors while taking 
acalabrutinib is not recommended due to a potential decrease in 
study drug exposure (see Section 6.5.3 for more detailed 
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inhibitors during the study is at the investigator’s discretion, with 
an understanding of the potential benefit to the subject’s 
gastrointestinal condition and a potential risk of decreased 
exposure to acalabrutinib.  Although the effect of H2receptor 
antagonists (such as famotidine or ranitidine) on 
acalabrutinib- absorption has not been evaluated, if treatment 
with an H2-receptor antagonist is required, the H2-receptor 
antagonist should be taken approximately 2 hours after an 
acalabrutinib dose. 
Concomitant use of strong inhibitors/inducers of CYP3A should 
be avoided when possible (see Section 6.5.2 for more detailed 
information). 
Safety Plan: 
The safety of this study will be monitored by an independent Data 
Monitoring Committee (DMC).  The independent DMC will be 
chaired by a physician with expertise in CLL. 
An early safety analysis will be performed by the DMC after 
60 subjects have been treated for approximately 8 weeks.  This 
analysis will focus on deaths, treatment discontinuations, SAEs, 
and Grade 3/4 AEs as well as special events of interest.   
The DMC will review data and provide recommendations 
regarding stopping or continuing the trial in accordance with the 
DMC charter. 
Statistical Methods and 
Data Analysis: 
All efficacy analyses will be performed using the intent-to-treat 
(ITT) population. 
Primary Efficacy Analysis: 
Analysis of the PFS endpoint is event-driven and will be 
conducted when enrollment is completed and approximately 
167 events have occurred in Arms A and B.  PFS will be 
assessed between Arm A versus Arm B using a stratified 2-sided 
log-rank with the strata used for randomization (17p del: present 
or absent; ECOG performance status: 0, 1 or 2, and geographic 
region: North America and Western Europe or Other).  The 
hazard ratio (HR) and its 95% confidence interval (CI) will be 
computed from a stratified Cox regression model. 
Secondary Endpoints and Analysis:  
Arms A and C will be compared for PFS in a manner similar to 
the method described for the primary analysis. 
The following 2 secondary outcomes will be assessed by 
comparing the proportions in Arms A and B and Arms A and C 
using a Cochran-Mantel-Haenszel test stratified by the 
randomization strata: 
• 
ORR defined as achieving CR, CRi, nPR, or PR per 
IWCLL 2008 criteria. 
The following 2 secondary outcomes will be assessed for Arms A 
vs B and Arms A vs C in a manner similar to the method used for 
PFS: 

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• 
TTNT (defined as the time from randomization to 
institution of non-protocol-specified treatment for CLL). 
• 
OS 
The Statistical Analysis Plan (SAP) will describe the methodology 
to be used to maintain Type I error rate control. 
Safety Analysis: 
Detailed tabulations of safety data (AEs and clinical laboratory 
tests) will be provided for all subjects receiving the study drug.  
The number and percent of subjects with treatment-emergent 
adverse events (TEAEs) will be summarized.  Summary of other 
safety parameters by treatment group will be provided where 
appropriate. 
Interim Analysis: 
An interim analysis will be conducted to assess superiority futility 
of Arm A when compared with Arm B with respect to the primary 
efficacy endpoint, PFS.  The analysis will occur when 
approximately two-thirds (e.g., 111 total PFS events across Arms 
A and B) of the outcomes in Arms A and B have occurred.  
 
 
 
Sample Size: 
The study is expected to enroll approximately 510 subjects.  
Subjects will be randomized in a 1:1:1 ratio so that 170 subjects 
enter each of Arms A, B, and C.  The study is sized to achieve 
approximately 90% power to detect a hazard ratio of 0.60 in PFS 
which, under the model assumptions, 
 
 at the 2-sided 
significance level of 0.05. 
This sample size calculation was performed assuming 
 
 in Arm A (Goede 2014). 
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TABLE OF CONTENTS 
PROTOCOL APPROVAL ........................................................................................................... 2 
STUDY SYNOPSIS ................................................................................................................... 6 
TABLE OF CONTENTS ............................................................................................................19 
LIST OF TABLES ......................................................................................................................22 
LIST OF FIGURES ...................................................................................................................22 
LIST OF APPENDICES ............................................................................................................23 
ABBREVIATIONS AND DEFINITIONS .....................................................................................24 
1 
BACKGROUND INFORMATION .......................................................................................28 
1.1 
Front Line Treatment for Elderly Patients with CLL ...............................................28 
1.2 
BTK inhibition in CLL ............................................................................................29 
1.3 
Preclinical Studies ................................................................................................31 
1.3.1 
Chemistry ..............................................................................................31 
1.3.2 
Mechanism of Action of Acalabrutinib ...................................................31 
1.3.3 
Dog Lymphoma Study ...........................................................................31 
1.3.4 
Acalabrutinib and Antibody-dependent Cell-mediated Cytotoxicity ........32 
1.3.5 
Acalabrutinib and Thrombus Formation ................................................33 
1.3.6 
Safety Pharmacology ............................................................................34 
1.3.7 
Drug-drug Interaction Potential .............................................................35 
1.3.8 
In Vivo General Toxicology ...................................................................35 
1.4 
Clinical Studies .....................................................................................................36 
1.4.1 
 and Pharmacodynamics of Acalabrutinib in 
Healthy Volunteers ................................................................................36 
1.4.2 
Clinical Experience of Acalabrutinib in CLL ...........................................37 
1.5 
Summary and Conclusions ...................................................................................38 
2 
STUDY RATIONALE .........................................................................................................38 
2.1 
Dose Selection Rationale for Acalabrutinib ...........................................................39 
2.2 
Selection of Obinutuzumab in Combination with Chlorambucil as Comparator .....39 
2.3 
Combination Therapy with a BTK Inhibitor Plus CD20+ Monoclonal Antibody .......40 
2.4 
Justification for a Trial Combining Acalabrutinib with Obinutuzumab ....................40 
2.5 
Benefit/Risk ..........................................................................................................40 
3 
STUDY OBJECTIVES .......................................................................................................41 
3.1 
Primary Objective .................................................................................................41 
3.2 
Secondary Objectives ...........................................................................................41 
3.3 
Safety Objective ...................................................................................................41 
3.4 
Exploratory Objectives ..........................................................................................41 
4 
STUDY DESIGN ...............................................................................................................42 
4.1 
Treatment Arm A: Obinutuzumab in Combination with Chlorambucil ....................43 
4.2 
Treatment Arm B: Acalabrutinib BID in Combination with Obinutuzumab .............43 
4.3 
Treatment Arm C: Acalabrutinib BID Monotherapy ...............................................43 
4.4 
Crossover .............................................................................................................44 
4.5 
Screening, Treatment, and Follow-up Phases ......................................................44 
5 
SELECTION OF SUBJECTS .............................................................................................46 
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5.1 
Inclusion Criteria ...................................................................................................46 
5.2 
Exclusion Criteria ..................................................................................................47 
6 
DOSAGE AND ADMINISTRATION ...................................................................................49 
6.1 
Identification of Investigational Product .................................................................49 
6.1.1 
Acalabrutinib .........................................................................................49 
6.1.2 
Obinutuzumab.......................................................................................49 
6.1.3 
Chlorambucil .........................................................................................50 
6.2 
Drug Preparation and Administration ....................................................................50 
6.2.1 
Acalabrutinib in Combination with Obinutuzumab Administration 
(Arm B) .................................................................................................50 
6.2.2 
Obinutuzumab and Chlorambucil Administration (Arm A) ......................51 
6.2.3 
Acalabrutinib Monotherapy Administration (Arm C) ...............................51 
6.3 
Dose Modifications and Delays .............................................................................51 
6.3.1 
Assessment of Toxicity .........................................................................51 
6.3.2 
Dose Delays for Acalabrutinib ...............................................................52 
6.3.3 
Dose Modification and Discontinuation for Acalabrutinib .......................52 
6.3.4 
Dose Modification and Discontinuation for Obinutuzumab and 
Chlorambucil .........................................................................................53 
6.3.5 
Premedication Requirements (Obinutuzumab) ......................................55 
6.3.6 
Tumor Lysis Syndrome (Obinutuzumab) ...............................................55 
6.4 
Precautions...........................................................................................................56 
6.4.1 
Risks Associated with Acalabrutinib ......................................................56 
6.4.2 
Obinutuzumab and Chlorambucil ..........................................................59 
6.4.3 
Hepatitis B Virus Reactivation ...............................................................61 
6.4.4 
Reproductive Toxicity ............................................................................62 
6.5 
Concomitant Medications ......................................................................................64 
6.5.1 
Allowed Concomitant Medications.........................................................64 
6.5.2 
Guideline for Use of CYP-Inhibiting/Inducing Drugs ..............................65 
6.5.3 
Guideline for Use of Drugs that Affect Gastric pH .................................65 
6.5.4 
Prohibited Concomitant Medications .....................................................65 
6.6 
Treatment Compliance .........................................................................................66 
7 
EFFICACY AND SAFETY PROCEDURES .......................................................................66 
7.1 
Description of Procedures .....................................................................................66 
7.1.1 
Informed Consent .................................................................................66 
7.1.2 
Confirmation of Eligibility .......................................................................66 
7.1.3 
Medical History .....................................................................................67 
7.1.4 
Physical Examination ............................................................................67 
7.1.5 
Disease-related Symptoms ...................................................................67 
7.1.6 
Cumulative Illness Rating Scale-Geriatric (CIRS-G) ..............................68 
7.1.7 
Vital Signs .............................................................................................68 
7.1.8 
Electrocardiogram .................................................................................68 
7.1.9 
ECOG Performance Status ...................................................................68 
7.1.10 
Hepatitis Serologies ..............................................................................68 
7.1.11 
 ...............................................................69 
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7.1.12 
Genetic and Molecular Prognostic Markers ...........................................69 
7.1.13 
Pregnancy Test .....................................................................................70 
7.1.14 
Hematology ...........................................................................................70 
7.1.15 
Determination of T/B/NK Cell Counts ....................................................71 
7.1.16 
Serum Chemistry ..................................................................................71 
7.1.17 
Serum Immunoglobulins and β2-microglobulin ......................................71 
7.1.18 
 ............................................71 
7.1.19 
...........................................................................72 
7.1.20 
Bone Marrow Aspirate and Biopsy ........................................................72 
7.1.21 
CT/MRI Scans.......................................................................................74 
7.1.22 
Medical Resources Utilization ...............................................................75 
7.1.23 
Adverse Events .....................................................................................75 
7.1.24 
Prior and Concomitant Medications .......................................................75 
7.1.25 
Routine Clinical Assessments ...............................................................75 
7.1.26 
Overall Response Evaluations ..............................................................75 
7.1.27 
Early Termination (ET) Visit/Safety Follow-up (SFU) Visit .....................76 
7.1.28 
Survival .................................................................................................76 
7.1.29 
Subsequent Anticancer Therapies ........................................................77 
7.2 
Assessment of Safety ...........................................................................................77 
7.2.1 
Definitions .............................................................................................77 
7.2.2 
Documenting and Reporting of Adverse and Serious Adverse Events 
by Investigators .....................................................................................81 
8 
WITHDRAWAL OF SUBJECT FROMTREATMENT OR ASSESSMENT ...........................85 
8.1 
Withdrawal of Subjects from Study Treatment ......................................................85 
8.2 
Reasons for Study Exit .........................................................................................86 
9 
STATISTICAL METHODS .................................................................................................86 
9.1 
General Considerations ........................................................................................86 
9.1.1 
Independent Review Committee ...........................................................86 
9.1.2 
Data Monitoring Committee...................................................................86 
9.2 
Randomization ......................................................................................................87 
9.3 
Determination of Sample Size ..............................................................................87 
9.4 
Interim Analysis ....................................................................................................88 
9.5 
Final Analysis .......................................................................................................89 
9.6 
Analysis Populations .............................................................................................89 
9.6.1 
Intent-to-Treat (ITT) Population .............................................................89 
9.6.2 
Safety Population ..................................................................................89 
9.7 
Handling of Missing Values/Censoring/Discontinuations .......................................89 
9.8 
Control for Bias .....................................................................................................89 
9.9 
Efficacy Analyses..................................................................................................90 
9.9.1 
Primary Endpoint and Methods .............................................................90 
9.9.2 
Secondary Endpoints and Methods .......................................................90 
9.9.3 
Other Secondary Endpoints ..................................................................91 
9.9.4 
Exploratory Endpoints ...........................................................................91 
9.10 
Safety Analyses ....................................................................................................93 
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9.10.1 
Adverse Events .....................................................................................93 
9.10.2 
Treatment-emergent Adverse Events ....................................................93 
9.10.3 
AESIs ....................................................................................................94 
9.10.4 
Clinical Laboratory Tests .......................................................................94 
9.10.5 
ECOG Performance Status ...................................................................95 
9.10.6 
Vital Signs and Weight ..........................................................................95 
10 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ..................................95 
10.1 
Regulatory and Ethical Compliance ......................................................................95 
10.2 
Institutional Review Board (IRB) and Independent Ethics Committee (IEC) 
Approval ...............................................................................................................95 
10.3 
Informed Consent and Protected Subject Health Information Authorization ..........96 
10.4 
Quality Control and Quality Assurance .................................................................96 
10.5 
Study Files and Record Retention ........................................................................97 
10.6 
Case Report Forms and Record Maintenance ......................................................97 
10.7 
Investigational Study Drug Accountability .............................................................98 
10.8 
Study Monitoring/Audit Requirements ...................................................................98 
10.9 
Investigator Responsibilities .................................................................................98 
10.10 Clinical Trial Insurance .........................................................................................99 
10.11 Protocol Amendments ..........................................................................................99 
10.12 Publication of Study Results .................................................................................99 
11 
REFERENCE LIST .......................................................................................................... 100 
12 
APPENDICES ................................................................................................................. 104 
LIST OF TABLES 
Table 6-1.  Drug Discontinuation Actions for Acalabrutinib .................................................. 53 
Table 6-2.  Hematologic Dose Modifications for Obinutuzumab and Chlorambucil .............. 54 
Table 9-1. Summary of α Levels for Interim and Final Analysis ........................................... 88 
 
LIST OF FIGURES 
Figure 1-1.  NK Cell Natural Cytotoxicity ............................................................................. 33 
Figure 1-2.  In Vivo Thrombus Formation ............................................................................ 34 
Figure 4-1.  Study Schema.................................................................................................. 42 
 

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LIST OF APPENDICES 
Appendix A:  Schedule of Assessments – Treatment Arm A ............................................. 105 
Appendix B:  Schedule of Assessments – Treatment Arm B ............................................. 108 
Appendix C:  Schedule of Assessments – Treatment Arm C ............................................. 112 
Appendix D:  Schedule of Assessments – Crossover ........................................................ 115 
Appendix E:  Performance Status Scores ......................................................................... 118 
Appendix F:  Examples of Coadministered Drugs that Need Additional Consideration ...... 119 
Appendix G:  Response Assessment Criteria (modified from Hallek 2008) ....................... 121 
Appendix H:  Adverse Event Assessment of Causality ...................................................... 123 
Appendix I: 
...................................................................................... 124 
Appendix J:
...................................................................................... 126 
Appendix K:
...................................................................................... 129 
Appendix L:  Cumulative Illness Rating Scale-Geriatric (CIRS-G) Calculator .................... 130 
Appendix M:  Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ................................................................................ 131 
Appendix N:  Management of Study Procedures During Pandemic ................................... 135 
 
 
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ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
11q del 
chromosome deletion 11 q 
13q del 
chromosome deletion 13 q 
17p del 
chromosome deletion 17p13.1 
ACP-196 
Acalabrutinib 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE(s) 
adverse event(s) 
AESI 
adverse event of special interest 
AIHA 
autoimmune hemolytic anemia  
ALC 
absolute lymphocyte count 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
hepatitis B core antibody 
Anti-HBs 
hepatitis B surface antibody 
ASCO 
American Society of Clinical Oncology  
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-12 
area under the plasma concentration-time curve from time 0 to the 12-hour 
time point 
AUC0-24 
area under the plasma concentration-time curve from time 0 to the 24-hour 
time point 
AUC0-inf 
area under the plasma concentration-time curve from time 0 to infinity 
AUC0-last 
area under the plasma concentration-time curve from time 0 to time t, 
where t is the last measurable concentration 
BCR 
B-cell receptor 
BID 
twice per day 
BTK 
Bruton tyrosine kinase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
CI 
confidence interval 
CIRS-G 
Cumulative Illness Rating Score-Geriatric 
CL/F 
oral clearance 

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Abbreviation 
Definition 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed drug concentration 
CNS 
central nervous system 
CR 
complete remission (response) 
CRF 
case report form 
CRi 
CR with incomplete bone marrow recovery  
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DCO 
data cutoff 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capturing  
eGFR 
estimated glomerular filtration rate 
EGFR 
epidermal growth factor receptor 
 
ET 
early termination 
 
FcR 
Fc receptor 
FDA 
Food and Drug Administration 
 
FSH 
follicle-stimulating hormone 
GCLLSG 
German CLL study group 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
hERG 
human ether-à-go-go-related gene 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
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Abbreviation 
Definition 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
IC50 
half maximal inhibitory concentration  
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IGHV 
immunoglobulin heavy-chain variable 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRR 
Infusion-related reaction 
ITP 
idiopathic thrombocytopenic purpura 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IV 
Intravenous 
IVIG 
intravenous immunoglobulins 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IWRS 
Interactive Web Response System 
LDH 
lactate dehydrogenase 
LDT 
lymphocyte doubling time 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
MRI 
magnetic resonance imaging 
 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NDA 
New Drug Application 
NHL 
non-Hodgkin lymphoma 
NK 
natural killer (cells) 
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Abbreviation 
Definition 
NOAEL 
no observable adverse effect level 
nPR 
nodular partial remission 
ORR 
objective response rate or overall response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PFS 
progression free survival 
 
 
PLL 
prolymphocytic leukemia 
PML 
progressive multifocal leukoencephalopathy 
PO 
per os (by mouth, orally) 
PR 
partial remission (response) 
PRL 
partial remission (response) with lymphocytosis 
 
 
QD 
once per day 
QM 
every month 
QTc 
corrected QT interval 
R/R 
relapsed/refractory 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SD 
stable disease 
SFU 
safety follow up 
SmPC 
Summary of Product Characteristics 
SUSAR 
suspected unexpected serious adverse reaction  
TEAE(s) 
treatment-emergent adverse events 
TLS 
tumor lysis syndrome 
Tmax 
time to maximum drug concentration 
TTNT 
time to next treatment 
ULN 
upper limit of normal 
US 
United States 
Vz/F 
volume of distribution 
WBC 
white blood cell (count) 
 
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1 
BACKGROUND INFORMATION 
1.1 
Front Line Treatment for Elderly Patients with CLL 
Chronic lymphocytic leukemia (CLL) is a malignancy of B cells that predominantly affects the 
older population.  CLL has a variable clinical course, where many patients do not require 
treatment for years and have survival equal to age matched controls.  Other patients, however, 
exhibit aggressive disease and have a poor prognosis despite appropriate therapy (Byrd 2004).  
While patients with early disease have not been shown to have a survival advantage with early 
treatment, most patients will eventually require therapy for their disease with the onset of 
symptoms or cytopenias.  Despite the relatively long life expectancy for early stage disease, 
CLL remains an incurable disease. 
The treatment of CLL has progressed significantly over the previous decades.  While alkylator 
therapy was used in the past (O'Brien 1995), randomized trials have demonstrated a higher 
response rate and longer PFS with fludarabine and subsequently with fludarabine- and 
cyclophosphamide-based combinations in young, fit patients with CLL (Johnson 1996, Rai 
2000, Leporrier 2001, Eichhorst 2006, Catovsky 2007, Flinn 2007).  At the same time, the 
chimeric anti-CD20+ monoclonal antibody, rituximab was introduced for the treatment of CLL 
(Byrd 2001, O'Brien 2001).  The efficacy of rituximab has been improved by combining it with 
traditional cytotoxic agents such as fludarabine (Byrd 2003, Byrd 2005) or fludarabine plus 
cyclophosphamide (Wierda 2005), which have produced high CR rates and extended PFS 
compared with historical controls.  A large randomized clinical trial, reported by the German CLL 
study group (GCLLSG), has shown the benefit of the addition of rituximab to fludarabine and 
cyclophosphamide in PFS and OS in patients with previously untreated CLL (Hallek 2010). 
While fludarabine-based chemoimmunotherapy is standard for treatment-naive younger/fitter 
patients with CLL, the therapy for older patients or patients with co-morbidities is less well 
defined.  In the large Phase 2 and 3 trials outlined previously, median ages were typically in the 
early-60s, while the average age of patients diagnosed with CLL is 72 years, which calls into 
question whether these results are generalizable to the entire CLL population.  In fact, a 
randomized Phase 3 trial investigating primary CLL therapy (fludarabine vs chlorambucil) 
demonstrated that in patients ≥ 65 years of age, fludarabine was not superior to chlorambucil 
(Eichhorst 2009).  This finding was corroborated by a large retrospective study of front-line trials 
performed by the Alliance for Clinical Trials in Oncology, which confirmed that fludarabine is not 
superior to chlorambucil in older patients and also showed that the addition of rituximab to 
chemotherapy was beneficial regardless of age (Woyach 2013). 

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Recently, the type II glycoengineered CD20+ monoclonal antibody, obinutuzumab, was 
introduced.  In a Phase 1 trial in patients with previously treated CLL, obinutuzumab had a 62% 
response rate including a 
 negative CR, suggesting that obinutuzumab may be more active 
in CLL than rituximab (Morschhauser 2009).  The GCLLSG recently completed a Phase 3 trial 
of rituximab + chlorambucil or obinutuzumab + chlorambucil vs chlorambucil alone in patients 
with previously untreated CLL and significant comorbidities.  In this population, obinutuzumab + 
chlorambucil (but not rituximab + chlorambucil) improved OS over chlorambucil alone (HR 0.41, 
p=0.002), and obinutuzumab + chlorambucil improved PFS over rituximab + chlorambucil 
 vs 15.2 months, p<0.001) (Goede 2014).  On the basis of these 
favorable data, the combination of obinutuzumab + chlorambucil has received regulatory 
approval as frontline therapy for CLL patients. 
1.2 
BTK inhibition in CLL 
In February 2014, ibrutinib (IMBRUVICA®) monotherapy, the first Bruton tyrosine kinase (BTK) 
inhibitor developed for clinical use, was awarded marketing approval in the United States for the 
treatment of patients with CLL who have had ≥ 1 prior therapy or 17p del.  Approval in Europe 
was in October 2014 with an indication for the treatment of patients with CLL who have received 
≥ 1 prior therapy or as first-line therapy in the presence of 17p deletion or TP53 mutation in 
patients unsuitable for chemoimmunotherapy.  These approvals for ibrutinib were based on data 
from single-arm Phase 2 studies (PCYC 1102/1103) and the randomized Phase 3 study 
(RESONATE) (IMBRUVICA® package insert).  In the RESONATE study, which had a median 
follow up of 9.4 months, ibrutinib demonstrated improvement in PFS (HR=0.22), OS (HR=0.43) 
and ORR (42.6% vs 4.1%) compared with an active comparator, ofatumumab as adjudicated by 
the IRC.  The progression and survival benefits seen with ibrutinib treatment were demonstrated 
in all subgroup analyses including patients aged ≥ 65 years (Byrd 2014).  Longer follow up on 
the PCYC 1102/1103 study shows the median PFS has not been reached with 30 months of 
ibrutinib treatment as assessed by investigators (Brown 2014). 
In March 2016, ibrutinib monotherapy was also approved in the United States as a first-line 
treatment for patients with CLL (IMBRUVICA® package insert). 
Important safety risks observed with ibrutinib can be found in the package insert and include the 
following adverse reactions (IMBRUVICA® package insert): 
• 
Fatal and non-fatal infections  
• 
Atrial fibrillation and atrial flutter  
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• 
Other malignancies  
• 
Fatal bleeding events  
• 
Cytopenias (including anemia, neutropenia, and thrombocytopenia) 
• 
Hypertension 
• 
Tumor lysis syndrome 
• 
Embryo-fetal toxicity  
Chemical optimization, pharmacologic characterization, and toxicologic evaluation have led to 
identification of acalabrutinib (also known as ACP-196), an orally administered, new chemical 
entity that covalently inhibits BTK and shows encouraging activity and acceptable safety in 
nonclinical studies.  Within the class of BTK inhibitors, acalabrutinib is a more selective inhibitor 
of BTK than ibrutinib.  An improved kinase selectivity profile for acalabrutinib may translate to 
pharmacologic benefits as outlined below: 
• 
Ibrutinib is a potent covalent inhibitor of epidermal growth factor receptor (EGFR); 
acalabrutinib is not (Section 1.3.2). 
• 
Ibrutinib is a potent covalent inhibitor of ITK kinase.  As such, ibrutinib interferes with 
natural killer (NK) cell-mediated function and anti-tumor activities of therapeutic CD20+ 
antibodies (Da Roit 2015).  Acalabrutinib does not inhibit ITK.  Consequently in vitro 
studies show no effect of acalabrutinib on NK cell function (Section 1.3.4) or antitumor 
activities of therapeutic CD20+ antibodies (Rajasekaran 2014). 
• 
Ibrutinib is also a potent covalent inhibitor of TXK kinase.  ITK and TXK kinases regulate 
the development of cytotoxic CD8+ T cells (Atherly 2006) and modulate interferon 
gamma release (Takeba 2002).  Acalabrutinib is not a potent inhibitor of TXK.  In vivo 
tumor models show robust expansion of CD8+ T cells with acalabrutinib treatment 
compared with ibrutinib and in vitro T-cell studies show reduced CD8+ T cell viability with 
ibrutinib treatment compared with acalabrutinib (Acerta data on file).  The differential 
potency of acalabrutinib vs ibrutinib on key modulators of T-cell function may lead to 
better clinical outcomes in patients, such as a reduced incidence of infections with 
acalabrutinib treatment. 
• 
Ibrutinib is associated with bleeding events in patients.  The mechanism for the bleeding 
events is not well understood.  However, ibrutinib impairs thrombus formation in an in 
vivo model at physiologically relevant concentrations; acalabrutinib does not 
(Section 1.3.5). 
The nonclinical and toxicology results of acalabrutinib suggest it may have an improved 
therapeutic window relative to ibrutinib; it may be more readily combined with other agents for 
the treatment of cancer. 
This Phase 3 study (ACE-CL-007) will investigate whether acalabrutinib in combination with 
obinutuzumab (Arm B) is superior, based on centrally determined, independently reviewed PFS, 
to obinutuzumab in combination with chlorambucil (Arm A) and whether acalabrutinib 

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monotherapy (Arm C) is superior, based on centrally determined, independently reviewed PFS, 
to obinutuzumab in combination with chlorambucil (Arm A) in subjects with previously untreated 
CLL.  In addition, the study aims to evaluate safety and tolerability of Arms A versus B and Arms 
A versus C. 
1.3 
Preclinical Studies 
Summaries of preclinical studies are provided below.  For more detailed information please refer 
to the Acalabrutinib Investigator Brochure. 
1.3.1 
 
 
 
 
 
 
 
 
 
   
1.3.2 
Mechanism of Action of Acalabrutinib 
Acalabrutinib was specifically designed to be a more potent and selective inhibitor of BTK to 
avoid off-target side effects seen with other BTK inhibitors.  When profiled against 395 human 
kinases, acalabrutinib was more selective than ibrutinib (Covey 2015).  For additional details, 
refer to the Acalabrutinib Investigator Brochure. 
1.3.3 
Dog Lymphoma Study 
Spontaneous canine B-cell lymphoma shares many characteristics with human non-Hodgkin 
lymphoma (NHL), including diagnostic classifications and response to BTK inhibition (Honigberg 
2010).  The life expectancy in untreated animals with aggressive disease is approximately 6 
weeks, thus enabling rapid assessment of drug efficacy (Vail 2004).  Acalabrutinib was 
evaluated in an ongoing study in canine spontaneous B-cell lymphoma (Harrington 2016).  
Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 
20mg/kg every 12 or 24 hours.  Acalabrutinib was generally well tolerated, with adverse events 
consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy.  Per 
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Veterinary Cooperative Oncology Group criteria for assessment of response in peripheral nodal 
lymphoma (Vail 2010), ORR was 25% (5/20) with a median progression free survival (PFS) of 
22.5 days. Clinical benefit was observed in 30% (6/20) of dogs.  These findings suggest that 
acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the 
use of canine lymphoma as a relevant model for human NHL.  These findings are similar to the 
clinical responses observed with ibrutinib in dogs with spontaneous B-cell lymphoma 
(Honigberg 2010). 
1.3.4 
Acalabrutinib and Antibody-dependent Cell-mediated Cytotoxicity 
As acalabrutinib is not an inhibitor of ITK kinase, it is expected to have less activity against 
non-malignant cells that require ITK for development and functional activation, such as T and 
NK cells.  ITK kinase is required for Fc receptor (FcR)-stimulated NK cell function including 
calcium mobilization, granule release (Khurana 2007), and overall antibody-dependent 
cell-mediated cytotoxicity (ADCC).  Anti-CD20+ antibodies are standard of care drugs, often as 
part of combination regimens, for the treatment of CD20+ B-cell malignancies; obinutuzumab 
has been specifically designed to increase Fc interactions and promote ADCC and 
phagocytosis of malignant CD20+ cells.  Ibrutinib has been evaluated for effects on NK activity, 
including ADCC, using in vitro assays of cytokine release, lytic granule release, and cellular 
cytotoxicity (Kohrt 2014).  In contrast to more specific BTK inhibitors, ibrutinib inhibited all these 
NK cell functions, and impaired NK activity against rituximab-coated autologous CLL cells and in 
mouse tumor models requiring Fc-mediated effector functions (Kohrt 2014).  Acalabrutinib was 
tested in ADCC and natural cytotoxicity assays, using cells from healthy donors.  In these in 
vitro tests, NK cell function was preserved with acalabrutinib treatment, whereas ibrutinib 
inhibited functional activity, including natural cytotoxicity against K562 cells. 

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Figure 1-1.  NK Cell Natural Cytotoxicity 
 
Peripheral blood mononuclear cells were cultured with 51Cr labelled K562 targets at an E:T ratio of 100:1 
for 4 hours.  Cytotoxicity was evaluated by scintillation counting of supernatants.  Treatment, dose and 
interaction effect were significant in 2-way ANOVA (n = 5 healthy donors; ibrutinib v. acalabrutinib p < 
0.0001; all ibrutinib doses p < 0.0001 compared with control; p = 0.0117 for control vs. acalabrutinib 1µM, 
other acalabrutinib doses not statistically different from control condition). 
 
1.3.5 
Acalabrutinib and Thrombus Formation 
Ibrutinib is associated with an increased risk of bleeding (Kamel 2015).  Hence, the effects of 
acalabrutinib and ibrutinib were evaluated on human platelet-mediated thrombus formation by 
using the in vivo human thrombus formation in VWFHA1 murine model, which has been 
previously described (Chen 2008).  The in vivo function of platelets isolated from blood of 
healthy volunteers (n = 5), CLL patients treated with 420 mg QD ibrutinib (n = 5) or CLL patients 
treated with 100 mg BID acalabrutinib (n = 3) was evaluated in the VWFHA1 model.  Results from 
this study showed a reduction in platelet-vessel wall interactions of platelets from 
ibrutinib-treated CLL patients, but not of those from CLL patients treated with acalabrutinib (Byrd 
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Figure 1-2.  In Vivo Thrombus Formation 
 
Platelets from patients treated with ibrutinib 420 mg once per day (QD) (n = 5) or acalabrutinib 100 mg 
twice per day (BID) (n=3) were evaluated for their ability to support thrombus formation in laser injured 
arterioles of VWFHA1 mice.  Freshly isolated platelets from healthy volunteers (n=5) were used as 
non-drug treated controls.  A minimum of 4 arterioles per mouse was used to assess thrombus formation 
for each patient/volunteer sample.  Median fluorescence intensity as a function of time is provided in the 
figure (shading denotes standard error of the median). 
 
1.3.6 
Safety Pharmacology 
In vitro and in vivo safety pharmacology studies with acalabrutinib have demonstrated a 
favorable nonclinical safety profile. 
When screened at 10 μM in binding assays evaluating interactions with 80 known 
pharmacologic targets such as G-protein-coupled receptors, nuclear receptors, proteases, and 
ion channels, acalabrutinib shows significant activity only against the A3 adenosine receptor; 
follow-up dose-response experiments indicated a half-maximal inhibitory concentration (IC50) of 
4.5 µM, suggesting a low clinical risk of off-target effects. 
The in vitro effect of acalabrutinib on human ether-à-go-go-related gene (hERG) channel activity 
was investigated in vitro in human embryonic kidney cells stably transfected with hERG.  
Acalabrutinib inhibited hERG channel activity by 25% at 10 μM, suggesting a low clinical risk 
that acalabrutinib would induce clinical QT prolongation as predicted by this assay. 
Acalabrutinib was well tolerated in standard in vivo Good Laboratory Practice (GLP) studies of 
pharmacologic safety.  A functional observation battery in rats at doses through 300 mg/kg (the 

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highest dose level) revealed no adverse effects on neurobehavioral effects or body temperature 
at any dose level.  A study of respiratory function in rats also indicated no treatment-related 
adverse effects at doses through 300 mg/kg (the highest dose level).  In a cardiovascular 
function study in awake telemetered male beagle dogs, single doses of acalabrutinib at dose 
levels through 30 mg/kg (the highest dose level) induced no meaningful changes in body 
temperature, cardiovascular, or electrocardiographic (including QT interval) parameters.  The 
results suggest that acalabrutinib is unlikely to cause serious off-target effects or adverse effects 
on critical organ systems. 
1.3.7 
Drug-drug Interaction Potential 
For more detailed information on drug-drug interaction potential for acalabrutinib, refer to the 
Investigator Brochure. 
Please refer to Section 6.5 for guidance on drugs that may cause drug-drug interactions. 
1.3.8 
In Vivo General Toxicology 
The systemic toxicity of acalabrutinib has been fully investigated in repeat-dose sub-chronic 
studies in mice, rats, and dogs, reproductive toxicity studies in rats and rabbits, and ongoing 
chronic studies in the rats and dogs.  The pivotal GLP studies were 28- and 91-day repeat dose 
studies in rats and dogs, each with recovery periods to assess the reversibility of observed 
changes. 
In rats, 100 mg/kg/day was selected initially to represent the highest non-severely toxic dose; 
however, in subsequent studies the 100 mg/kg/day dose level was determined to be a no 
observable adverse effect level (NOAEL).  In rats, the target organs of toxicity were the kidney, 
liver and heart. 
The NOAEL in the dog was 30 mg/kg/day; dose levels higher than 30 mg/kg/day were not 
tolerated.  In dogs, the target organs of toxicity, observed only at doses exceeding the MTD, 
were the kidney and liver.  Heart findings were also observed in 2 dogs with kidney toxicity, 
which were interpreted as possibly secondary to uremia, as has been reported for this species. 
In rats and dogs, no adverse ECG or histopathologic cardiovascular effects were noted at the 
planned conclusion of the sub-chronic dog studies or in histopathologic endpoints of rats that 
survived treatment phase in sub-chronic rat toxicity studies.  However, in 5 of 6 rats from the 
4-week study that died early, slight to moderate necrosis of the myocardium and/or white blood 

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cell infiltration/inflammation of the myocardium were noted on microscopic examination of the 
hearts. 
1.4 
Clinical Studies 
1.4.1 
 and Pharmacodynamics of Acalabrutinib in Healthy 
Volunteers 
ACE-HV-001 was a 
pharmacodynamic, dose-ranging, food-effect, and drug-drug interaction 
study evaluating BID and QD dosing for 1 or 2 days in healthy volunteers.  This study evaluated 
the 
pharmacodynamics of acalabrutinib at various dose levels and regimens.  The starting 
dose for acalabrutinib was 2.5 mg BID.  This study has been completed and no adverse 
laboratory, vital signs, or electrocardiogram (ECG) findings were observed (2.5 to 50 mg BID; 
50 to 100 mg QD).  Three AEs related to study drug were reported.  Each AE was Grade 1 and 
resolved without treatment.  The AEs were constipation (2.5 mg BID), feeling cold (75 mg QD), 
and somnolence (75 mg QD). 
In Part 1, 
 properties of acalabrutinib were evaluated after oral administration of 2 daily 
divided doses of 2.5 to 50 mg and a single dose of 100 mg.  Of the 30 subjects evaluated, all 
observed systemic concentrations of acalabrutinib.  Acalabrutinib plasma time to maximum drug 
concentration (Tmax) values were between 0.5 and 1.0 hour for all dose cohorts and were 
independent of dose level.  The increase in mean maximum observed drug concentration (Cmax) 
values was greater than dose proportional based on the increases of Cmax from the first dose 
administered.  When evaluating area under the plasma concentration-time curve from time 0 to 
the 12-hour time point (AUC0-12), area under the plasma concentration-time curve from time 0 to 
the 24-hour time point (AUC0-24) or area under the plasma concentration-time curve from time 0 
to infinity (AUC0-inf), the mean values increased in a dose proportional manner based on the 
increases of the total dose administered.  Mean half-life values ranged from 0.97 to 2.1 hours 
and appeared to decrease as the dose increased.  The mean calculated oral clearance (CL/F: 
165 to 219 L/h) and volume of distribution values (Vz/F: 233 to 612 L) appeared to be 
independent of the dose administered. 
Acalabrutinib was not detected in the urine of subjects receiving the 2.5- or 5.0-mg BID doses of 
acalabrutinib.  Acalabrutinib was detected in urine of other subjects (0.4% to 0.6% of dose) and 
amounts increased in a dose-dependent manner. 
In Part 2, the effect of food on the 
 of acalabrutinib (75 mg) after a single oral administration 
was evaluated in 6 men and 6 women.  Median acalabrutinib plasma Tmax values were 
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increased in the fed state (2.5 hours) relative to the fasted state (0.5 hour).  The mean plasma 
acalabrutinib Cmax fed values decreased to 27.3% of the Cmax values observed in the fasted 
state.  In contrast, the relative AUC exposure of acalabrutinib remained mostly unchanged in 
both states.  This decrease in exposure in not clinically significant.  Therefore, acalabrutinib can 
be taken without regard to meals. 
In Part 3, the effect of itraconazole on the 
 of acalabrutinib (50 mg) after a single oral 
administration was evaluated in 17 subjects.  No difference in acalabrutinib Tmax values was 
observed in the presence or absence of itraconazole. 
Mean acalabrutinib exposures (as assessed by Cmax, AUC0-last, AUC0-24, and AUC0-inf) increased 
in the presence of itraconazole.  The mean plasma acalabrutinib Cmax values increased 3.7-fold 
in the presence of itraconazole.  The mean plasma AUC0-last, AUC0-24, and AUC0-inf values also 
increased between 4.9- to 5.1-fold in the presence of itraconazole.  Mean CL/F and Vz/F values 
decreased in the presence of itraconazole (CL/F: 217 vs 44 L/h; Vz/F: 1190 vs 184L).  No 
differences in half-life values were observed (3.3 vs 2.5 hours). 
The pharmacodynamics of acalabrutinib was evaluated using a BTK occupancy assay and 
correlated with a functional assay that determines the level of BTK inhibition by measuring 
expression of CD69+ and CD86+ on B cells.  A dose-dependent increase in BTK occupancy and 
corresponding decrease in CD69+/86+ expression was observed in this study.  Full BTK 
occupancy (≥ 90%) and complete CD86+ and CD69+ inhibition (≥ 90%) occurred at the 75- and 
100-mg single dosed cohorts 1 to 3 hours after administration.  However, only the 100-mg 
cohort maintained high BTK occupancy (91.5%) and high B-cell receptor (BCR) functional 
inhibition (CD86+: 86 ± 3% and CD69+: 78 ± 8%) at 24 hours.  For subjects receiving a second 
dose of acalabrutinib 12 hours after the first administration, full BTK target occupancy was 
observed 3 hours after the second dose for the 50-mg dosed cohort (BTK occupancy 97 ± 4%). 
1.4.2 
Clinical Experience of Acalabrutinib in CLL 
Acalabrutinib has been studied in a broad range of clinical studies, including subjects with 
hematologic malignancies and solid tumors.  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. 
This section briefly summarizes data from ACE-CL-001 (NCT02029443), an ongoing 
non-randomized, sequential group, dose-escalation Phase 1/2 study in subjects with 
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relapsed/refractory (R/R) or previously untreated CLL, Richter’s syndrome, or prolymphocytic 
leukemia (PLL).  Subjects received up to 400 mg of acalabrutinib daily. 
Preliminary efficacy data for ACE-CL-001 based on subjects with R/R CLL (N=134 as of 
01 December 2017), treatment-naive subjects (N=99 as of 04 September 2018), 
ibrutinib-intolerant subjects (N=33 as of 03 April 2018), and subjects with Richter’s syndrome or 
PLL transformation (N=29 as of 01 December 2017) have been evaluated for tumor response 
based on International Working Group response criteria (Hallek 2008) as updated (Cheson 
2012) to include partial response (PR) with treatment-induced lymphocytosis (PRL).  Median 
time on study for the R/R, treatment-naive, ibrutinib-intolerant, and Richter’s syndrome 
populations were 31.8, 41.6, 19.0, and 2.8 months, respectively.  Overall response rate (ORR) 
for the 4 populations were 96.2%, 99.0%, 80.6%, and 40.7%, respectively.  Progressive disease 
was experienced by 14.9%, 2.0%, 12.1%, and 65.5% of subjects in the R/R, treatment-naive, 
ibrutinib-intolerant, and Richter’s syndrome populations, respectively.  Preliminary safety data 
indicate the regimen is well tolerated (refer to the Acalabrutinib Investigator Brochure).  
1.5 
Summary and Conclusions 
This study (ACE-CL-007) will evaluate the safety and activity of the potent, small-molecule BTK 
inhibitor, acalabrutinib alone or in combination with obinutuzumab, versus obinutuzumab in 
combination with chlorambucil in subjects with previously untreated CLL.  The design and 
conduct of this study is supported by an understanding of the natural history and current 
therapies for subjects with CLL; knowledge of the activity and safety of the first-generation BCR 
inhibitor (i.e., ibrutinib) in subjects with B-cell malignancies; and the available nonclinical and 
clinical information regarding acalabrutinib.  Clinical studies have shown that acalabrutinib is an 
orally administered BTK inhibitor with fast absorption and rapid clearance that maintains optimal 
target coverage over 24 hours with a dosage of 100 mg BID.  Acalabrutinib has been well 
tolerated in healthy volunteers and subjects with CLL or Richter’s syndrome.  Despite poor 
prognostic characteristics in the CLL study population, acalabrutinib has induced sustained 
decreases in lymphadenopathy and provides rapid reduction and/or resolution of lymphocytosis. 
2 
STUDY RATIONALE 
This randomized controlled Phase 3 study in previously untreated subjects with CLL is designed 
to determine whether treatment with acalabrutinib in combination with obinutuzumab (Arm B) 
results in a clinically significant improvement in PFS as compared with treatment with 
obinutuzumab in combination with chlorambucil (Arm A), and whether treatment with 

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acalabrutinib monotherapy (Arm C) results in a clinically significant improvement in PFS as 
compared with treatment with Arm A. 
2.1 
Dose Selection Rationale for Acalabrutinib 
Preliminary 
 data from ACE-CL-001 as described in Section 1.4.2 suggests a plateauing of 
exposure after 250 mg QD.  Pharmacodynamic results from this study also suggest BTK 
resynthesis occurs in malignant B cells within 24 hours.  While all dosages evaluated show full 
BTK occupancy 4 hours after dosing, the 100-mg BID cohort shows full target coverage over 
24 hours (≥ 97% BTK occupancy at 4 and 24 hours).  Therefore, based on 
 
pharmacodynamic and efficacy results of the Phase 1/2 study, acalabrutinib 100 mg BID will be 
evaluated in this Phase 3 study.  This regimen is expected to provide optimal target coverage 
with lower exposure levels (Cmax) of acalabrutinib to avoid any potential off-target effects from 
acalabrutinib. 
2.2 
Selection of Obinutuzumab in Combination with Chlorambucil as 
Comparator 
Obinutuzumab is a type II humanized CD20+ monoclonal antibody.  In preclinical studies, 
obinutuzumab, as compared with rituximab, has shown superior efficacy by inducing direct cell 
death and enhanced ADCC (with less complement-dependent toxicity) (Goede 2014).  
Moreover, a recent Phase 3 clinical trial by the GCLLSG (CLL 11) was completed comparing 
obinutuzumab in combination with chlorambucil to rituximab in combination with chlorambucil in 
terms of PFS and ORR in patients with CLL and comorbidities (Cumulative Illness Rating Scale 
> 6 or a creatinine clearance of 30 to 69 mL per minute).  
 as confirmed by the 
IRC, was 
 in the obinutuzumab plus chlorambucil arm as compared with 
14.9 months with rituximab in combination with chlorambucil HR=0.42 (95%CI: 0.33-0.54), 
p<0.0001 (GAZYVARO® Summary of Product Characteristics).  Importantly, the combination of 
obinutuzumab and chlorambucil achieved a statistically significant improvement in the 
negative rate in the bone marrow of 19.5% of subjects whereas only 2.6% of the subjects 
in the rituximab plus chlorambucil arm achieved 
negative status in the marrow (p<0.001) 
(Goede 2014).  This Phase 3 study has established the combination of obinutuzumab with 
chlorambucil as an acceptable standard of care in patients for whom fludarabine-based 
chemoimmunotherapy is not an acceptable option (National Comprehensive Cancer Network 
[NCCN] Guidelines Version 1.2016).  The most frequent Grade 3 or higher AEs with 
obinutuzumab in combination with chlorambucil are: neutropenia 35%, infusion related reaction 
21%, thrombocytopenia 11%, and infections 2%. 
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2.3 
Combination Therapy with a BTK Inhibitor Plus CD20+ Monoclonal 
Antibody 
The combination of ibrutinib and the CD20+ monoclonal antibodies ofatumumab or rituximab are 
currently being evaluated in patients with relapsed CLL in 3 separate trials of which 2 have 
published results as follows: 
• 
A Phase 1b/2 study of ibrutinib (420 mg) and ofatumumab in patients with CLL, small 
lymphocytic leukemia, prolymphocytic leukemia, or Richter’s syndrome has enrolled 
3 time-sequential cohorts (Jaglowski 2014).  In the first cohort of 27 patients, ibrutinib 
began on Day 1, Week 1 while ofatumumab began with 300 mg on Week 5, 
2000 mg/week for Weeks 6 to 12 and then monthly for 4 months.  All 27 subjects 
completed the first month of therapy without a dose-limiting toxicity (DLT).  Of the 
24 subjects with CLL, all attained a PR (100%) with 23 subjects remaining on treatment 
and 1 proceeding to a non-myeloablative stem cell transplant.  Infusion toxicities with 
ofatumumab were more modest than expected.  Cohorts administering ofatumumab 
either concurrently or before ibrutinib have also been completed.  However, either early 
toxicity (concurrent schedule) or early progression (ofatumumab-first arm) have resulted 
in choosing the run-in arm with ibrutinib for 1 month followed by addition of ofatumumab 
for a future study. 
• 
Another Phase 2 trial has evaluated rituximab and ibrutinib in patients with high-risk CLL.  
Rituximab and ibrutinib were administered concurrently beginning in Cycle 1, with 
4 doses of weekly rituximab and then monthly administration for a total of 6 cycles.  In 
this trial, toxicities were modest, and responses were seen at an earlier time point than 
expected from single-agent therapy (Burger 2012). 
2.4 
Justification for a Trial Combining Acalabrutinib with Obinutuzumab 
Bruton tyrosine kinase inhibition is currently transforming the treatment of CLL.  While patients 
appear to be having durable responses, very few responses are CRs, which suggests that drug 
discontinuation will not be an option.  The combination of BTK inhibition with CD20+ antibody 
therapy is appealing to expedite and potentially deepen remissions.  Of the CD20+ antibodies 
available, obinutuzumab appears to be the most effective, and has shown the potential to 
induce complete and even 
negative responses.  While ibrutinib is a BTK inhibitor with 
robust efficacy and safety data, the negative effect of ibrutinib on NK function (Section 1.3.4) 
has important implications for combining ibrutinib with anti-CD20+ monoclonal antibodies.  This 
justifies exploration of more selective BTK inhibitors, such as acalabrutinib, to optimize the 
addition of CD20+ monoclonal antibodies to BTK inhibitor therapy. 
2.5 
Benefit/Risk 
Acalabrutinib is a potent, orally available 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 DLTs were identified at any evaluated dosages, which included dosages up to 400 mg QD or 
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100 to 200 mg BID.  The ORR in the evaluable subjects for this study is 95% (Byrd 2016).  In 
summary, the preliminary data suggest that acalabrutinib is well tolerated and has robust activity 
as a single agent in the treatment of subjects with CLL.  In addition, 
pharmacodynamic 
results show the 100-mg BID regimen produces optimal target coverage over 24 hours (i.e., 
more complete coverage of de novo synthesis of BTK), which may provide greater clinical 
benefit than the QD regimen of ibrutinib. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective  
• 
To evaluate the efficacy of obinutuzumab in combination with chlorambucil (Arm A) 
compared with acalabrutinib in combination with obinutuzumab (Arm B), based on IRC 
assessment of PFS per 
 criteria, in subjects with previously untreated CLL. 
3.2 
Secondary Objectives 
• 
To evaluate the efficacy of obinutuzumab in combination with chlorambucil (Arm A) 
versus acalabrutinib monotherapy (Arm C) based on IRC assessment of PFS per 
 
 
• 
To compare obinutuzumab plus chlorambucil (Arm A) versus acalabrutinib plus 
obinutuzumab (Arm B), and obinutuzumab plus chlorambucil (Arm A) versus 
acalabrutinib monotherapy (Arm C) in terms of:  
o IRC-assessed objective response rate (ORR) per 
 
o TTNT (defined as the time from randomization to institution of non-protocol specified 
treatment for CLL); and 
o OS. 
3.3 
Safety Objective 
Incidence of AEs and SAEs and changes in laboratory measurements. 
3.4 
Exploratory Objectives 
CCI
CCI
CCI
CCI
CCI

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4 
STUDY DESIGN 
This randomized, multicenter (i.e., approximately 200 global centers), open-label, 3-arm 
Phase 3 study is designed to evaluate the safety and efficacy of Arm A, Arm B, and Arm C in 
subjects with previously untreated CLL. 
Approximately 510 eligible subjects will be randomized in a 1:1:1 ratio into 3 arms (n=170 each) 
to receive either Arm A (obinutuzumab in combination with chlorambucil per the package 
inserts), Arm B (acalabrutinib 100 mg BID in combination with obinutuzumab per the package 
insert), or Arm C (acalabrutinib 100 mg BID). 
Figure 4-1.  Study Schema 
 
Abbreviations: BID = twice per day, ECOG = Eastern Cooperative Oncology Group; IRC = Independent 
Review Committee; NA = North America; PO = oral; PS = performance status; WEU = Western Europe. 
CCI

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This study will use IWRS for randomization.  Randomization will be used to minimize bias in the 
assignment of subjects to treatment groups, to increase the likelihood that known and unknown 
subject attributes (e.g., demographic and baseline characteristics) are evenly balanced, and to 
enhance the validity of statistical comparisons across treatment groups.  Eligible subjects will be 
stratified with regard to: 
• 
The presence or absence of 17p del by central laboratory; 
• 
ECOG PS 0, 1 versus 2; and 
• 
Geographic region (North America and Western Europe vs Other). 
4.1 
Treatment Arm A: Obinutuzumab in Combination with Chlorambucil 
Obinutuzumab IV infusions will be administered over a total of 6 treatment cycles.  On Cycle 1 
Day 1, subjects will receive obinutuzumab 100 mg.  On Cycle 1 Day 2, subjects will receive 
900 mg.  On Cycle 1 Days 8 and 15, subjects will receive 1000 mg.  On Day 1 of Cycles 2 to 6, 
subjects will receive 1000 mg. 
Chlorambucil will be orally administered at a dose of 0.5 mg/kg on Days 1 and 15 of Cycles 1 
through 6. 
Note:  A pre-planned interim analysis was performed and met the primary objective.  After the 
interim analysis and per Amendment 6.0, at investigator discretion, subjects randomized to 
Arm A, who have IRC-confirmed progressive disease (PD) (through Amendment 5.0) or 
investigator-assessed PD (Amendment 6.0) will be eligible to receive crossover treatment with 
single-agent acalabrutinib at 100 mg BID until disease progression or unacceptable toxicity.  
However, the investigator-assessed PD must be confirmed by the study Medical Monitor 
(Amendment 6.0). 
4.2 
Treatment Arm B: Acalabrutinib BID in Combination with Obinutuzumab 
Acalabrutinib will be orally administered at 100 mg BID starting on Cycle 1 Day 1.  Daily 
administration of acalabrutinib will continue until disease progression or unacceptable toxicity. 
Obinutuzumab will be administered as described above for Arm A, starting on Cycle 2 Day 1 for 
a maximum of 6 cycles. 
4.3 
Treatment Arm C: Acalabrutinib BID Monotherapy 
Acalabrutinib will be orally administered at 100 mg BID starting on Cycle 1 Day 1, and will 
continue until disease progression or unacceptable toxicity. 

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4.4 
Crossover 
Subjects eligible to cross over to acalabrutinib monotherapy will receive acalabrutinib treatment 
if they meet eligibility for crossover.  Eligibility for crossover includes meeting the criteria for 
ECOG performance status and the laboratory parameters as outlined in the inclusion criteria.  
Screening for eligibility for crossover, and trial assessments during crossover, are described in 
Appendix D and may occur concurrently with the study Medical Monitor (Amendment 6.0) and 
could have occurred concurrently with IRC assessment (through Amendment 5.0) for disease 
progression.  Subjects may not receive any new systemic therapy after IRC confirmation of 
disease progression (through Amendment 5.0) or investigator-assessed PD confirmed by the 
study Medical Monitor (Amendment 6.0) along with the initiation of crossover therapy with 
acalabrutinib.  The following de-identified documentation will be reviewed before enrollment to 
the crossover arm: 
• 
Radiology reports from computed tomography (CT)/magnetic resonance imaging (MRI) 
documenting measurable nodal disease; CT/MRI from disease progression can be used 
if within 60 days of crossover dosing Cycle 1 Day 1; and 
• 
4.5 
Screening, Treatment, and Follow-up Phases 
The subject’s eligibility and baseline characteristics will be determined during the Screening 
Phase.  For Arms A, B, and C, the Screening Phase will be up to 28 days before the first dose 
of study drug and for the crossover arm (Arm D), the Screening Phase will be up to 42 days 
before the first dose of study drug.  The Treatment Phase will extend from the start of 
randomization until study drug discontinuation.  The Post-disease Progression Phase will begin 
after IRC-confirmed PD (through Amendment 5.0) or investigator-assessed (Amendment 6.0) 
PD; investigator-assessed PD must be confirmed by the study Medical Monitor.  During this 
phase, subsequent anticancer therapy with start date of therapy, IWCLL indication for treatment 
initiation, additional malignancy occurrence, and survival status will be recorded.  The 
Post-disease Progression Phase will continue until death, lost to follow up, consent withdrawal, 
or study closure, whichever occurs first. 
Assessment of response and progression will be conducted in accordance with the IWCLL 2008 
criteria, with the modification that treatment-related lymphocytosis in the absence of other signs 
or symptoms of disease progression will not be considered progressive disease.  The 
investigator will evaluate sites of disease by radiological imaging (primary), physical 
examination or other procedures as necessary, review of hematology results, and 
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disease-related symptoms.  The same methods of assessment used to assess disease at 
baseline should be used throughout the study.  A central laboratory will perform all hematology 
testing for the primary endpoint analysis. 
Disease assessments will be done every 12 weeks (± 14 days) with the first on-treatment 
radiologic assessment occurring on Cycle 4 Day 1, the second on treatment scan on Cycle 7 
Day 1, and so on through Cycle 25, and then every 24 weeks (± 14 days) thereafter for all 
subjects (including subjects who discontinue from the study treatment due to an AE or any 
reason) until confirmation of disease progression or death, consent withdrawal, or lost to 
follow-up. 
The primary efficacy analysis will be based on assessment from an IRC.  As part of the IRC 
review, radiographic evaluations assessed by independent central radiologists and hematology 
results from a central laboratory will be provided.  Detailed procedures will be described in a 
separate charter. 
An independent DMC will be formed and constituted according to regulatory agency guidelines.  
Detailed information regarding the composition of the DMC and detailed DMC procedures will 
be provided in a separate charter.  The DMC will review the safety data periodically and the 
interim analysis results and provide recommendations according to the charter. 
One interim analysis using Lan-DeMets alpha spending function based on an O’Brien-Fleming 
boundary for superiority and futility (non-binding) is planned for the study (see Section 9.4). 
The end of trial is defined as the point when the last subject on the study has documented 
disease progression or death, or has been lost of follow up, whichever occurs first.  The 
anticipated study duration is 4.5 years including enrollment time. 
Subjects who are still on treatment at the end of the study (ACE-CL-007) 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 will be considered closed.  There will be no further data collection other than reporting of 
SAEs per Section 7.2.2.5.  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. 

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5 
SELECTION OF SUBJECTS 
5.1 
Inclusion Criteria 
Eligible subjects will be considered for inclusion in this study if they meet all of the following 
criteria: 
1. Men and women: 
a. ≥ 65 years of age OR 
b. > 18 and < 65 years of age, provided that they meet at least one of the following 
criteria: 
i. Creatinine clearance 30 to 69 mL/min using the Cockcroft-Gault equation 
ii. A score higher than 6 on the CIRS-G (Appendix L). 
2. ECOG performance status of 0, 1, or 2. 
3. Diagnosis of CD20+ CLL that meets published diagnostic criteria (Hallek 2008): 
a. Monoclonal B cells (either kappa or lambda light chain restricted) that are clonally 
co-expressing ≥ 1 B-cell marker (CD19, CD20, or CD23) and CD5. 
b. Prolymphocytes may comprise ≤ 55% of blood lymphocytes. 
c. Presence of ≥ 5 x 109 B lymphocytes/L (5000 µL) in the peripheral blood (at any 
point since diagnosis) 
4. Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment: 
a. Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelets 
< 100,000/μL). 
b. Massive (i.e., ≥ 6 cm below the left costal margin), progressive, or symptomatic 
splenomegaly. 
c. Massive nodes (i.e., ≥ 10 cm in the longest diameter), progressive, or 
symptomatic lymphadenopathy. 
d. Progressive lymphocytosis with an increase of > 50% over a 2-month period or a 
LDT of < 6 months.  LDT may be obtained by linear regression extrapolation of 
ALC obtained at intervals of 2 weeks over an observation period of 2 to 
3 months.  In subjects with initial blood lymphocyte counts of < 30 x 109/L 
(30,000/μL), LDT should not be used as a single parameter to define indication 
for treatment.  In addition, factors contributing to lymphocytosis or 
lymphadenopathy other than CLL (e.g., infections) should be excluded. 
e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to 
standard therapy. 
f. Constitutional symptoms documented in the subject’s chart with supportive 
objective measures, as appropriate, defined as ≥ 1 of the following 
disease-related symptoms or signs: 
i. Unintentional weight loss ≥ 10% within the previous 6 months before 
Screening. 

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ii. Significant fatigue (i.e., ECOG performance status 2; inability to work or 
perform usual activities). 
iii. Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before 
Screening without evidence of infection. 
iv. Night sweats for > 1 month before Screening without evidence of 
infection. 
5. This criterion was deleted as of Protocol Amendment 3. 
6. Meet the following laboratory parameters: 
a. ANC ≥ 750 cells/μL (0.75 x 109/L), or ≥ 500 cells/μL (0.50 x 109/L) in subjects 
with documented bone marrow involvement, and independent of growth factor 
support 7 days before assessment. 
b. Platelet count ≥ 50,000 cells/μL (50 x 109/L), or ≥ 30,000 cells/μL (30 x 109/L) in 
subjects with documented bone marrow involvement, and without transfusion 
support 7 days before assessment.  Subjects with transfusion-dependent 
thrombocytopenia are excluded. 
c. Serum AST and ALT/SGPT ≤ 3.0 x ULN. 
d. Total bilirubin ≤ 1.5 x ULN. 
e. Estimated creatinine clearance (i.e., eGFR using Cockcroft-Gault) ≥ 30 mL/min  
7. Able to receive all outpatient treatment, all laboratory monitoring, and all radiologic 
evaluations. 
8. Women who are sexually active and can bear children must agree to use highly effective 
forms of contraception while on the study and for 2 days after the last dose of 
acalabrutinib or 18 months after the last dose of obinutuzumab in combination with 
chlorambucil, whichever is longer.  Highly effective forms of contraception are defined in 
Section 6.4.4. 
9. 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 
obinutuzumab or chlorambucil, whichever is later.  Highly effective forms of 
contraception are defined in Section 6.4.4. 
10. Men must agree to refrain from sperm donation during the study and for 90 days after 
the last dose of obinutuzumab or chlorambucil, whichever is later. 
11. Must be willing and able to adhere to the study visit schedule, understand and comply 
with other protocol requirements, and provide written informed consent and authorization 
to use protected health information (in accordance with national and local subject privacy 
regulations).  Note vulnerable subjects, as defined in International Conference on 
Harmonisation (ICH) GCP, are not allowed on this protocol (e.g., prisoners or 
institutionalized subjects). 
5.2 
Exclusion Criteria 
Subjects will be ineligible for this study if they meet any of the following criteria: 
1. Any prior systemic treatment for CLL (note: Prior localized radiotherapy is allowed). 
2. Known CNS lymphoma or leukemia. 

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3. Known prolymphocytic leukemia or history of, or currently suspected, Richter’s 
syndrome. 
4. Missing or incomplete documentation of FISH results reflecting the presence or absence 
of 17p del and the percentage of cells with the deletion in subject records before 
randomization. 
5. Uncontrolled AIHA or ITP defined as declining hemoglobin or platelet count secondary to 
autoimmune destruction within the screening period or requirement for high doses of 
steroids (> 20 mg daily of prednisone daily or equivalent). 
6. Corticosteroid use > 20 mg within 1 week before first dose of study drug, except as 
indicated for other medical conditions such as inhaled steroid for asthma, topical steroid 
use, or as premedication for administration of study drug or contrast.  For example, 
subjects requiring steroids at daily doses > 20 mg prednisone equivalent systemic 
exposure daily, or those who are administered steroids for leukemia control or WBC 
count lowering are excluded. 
7. Major surgery within 4 weeks before first dose of study drug. 
8. History of prior malignancy except for the following: 
a. Malignancy treated with curative intent and with no evidence of active disease 
present for more than 3 years before Screening and felt to be at low risk for 
recurrence by treating physician. 
b. Adequately treated lentigo maligna melanoma without current evidence of disease or 
adequately controlled non-melanomatous skin cancer. 
c. Adequately treated cervical carcinoma in situ without current evidence of disease. 
9. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
congestive heart failure, or myocardial infarction within 6 months of screening, or any 
Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional 
Classification, or QTc > 480 msec at screening. 
10. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or small bowel or gastric bypass, 
symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. 
11. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as 
exhibiting ongoing signs/symptoms related to the infection and without improvement, 
despite appropriate antibiotics or other treatment) or ongoing intravenous anti-infective 
treatment. 
12. Known history of infection with HIV. 
13. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. 
14. Serologic status reflecting active hepatitis B or C infection.  Subjects with hepatitis B 
core antibody positive who are surface antigen negative or who are hepatitis C antibody 
positive will need to have a negative PCR result before randomization.  Those who are 
hepatitis B surface antigen positive or hepatitis B PCR positive and those who are 
hepatitis C PCR positive will be excluded. 
15. History of stroke or intracranial hemorrhage within 6 months before randomization. 
16. Known history of a bleeding diathesis (e.g., hemophilia, von Willebrand disease). 

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17. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists 
(e.g., phenprocoumon) within 7 days of first dose of study drug. 
18. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). 
19. Breast feeding or pregnant. 
20. Current life-threatening illness, medical condition, or organ system dysfunction which, in 
the Investigator’s opinion, could compromise the subject’s safety or put the study at risk. 
21. Concurrent participation in another therapeutic clinical trial. 
22. Requires treatment with a strong CYP3A inhibitor/inducer. 
23. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before 
screening. 
6 
DOSAGE AND ADMINISTRATION 
6.1 
Identification of Investigational Product 
6.1.1 Acalabrutinib 
Acalabrutinib is provided as hard gelatin capsules for oral administration.  The capsules are 
packaged in opaque high-density polyethylene (HDPE) plastic bottles with labels bearing the 
appropriate label text as required by governing regulatory agencies.  The drug product is 
manufactured for Acerta Pharma by a contract manufacturer.  All formulation excipients are 
compendial and are commonly used in oral formulations. 
Refer to the Acalabrutinib Investigator Brochure for additional information regarding the drug 
product to be used in this study. 
6.1.2 Obinutuzumab 
This study will use commercially available obinutuzumab.  The Sponsor will either directly 
supply sites with obinutuzumab or the sites will be reimbursed to prescribe obinutuzumab; this 
will be detailed separately in each site’s clinical trial agreement. 
Commercially available obinutuzumab will be supplied as a liquid concentrate (25 mg/mL) for 
dilution for IV administration.  Refer to the local prescribing information for obinutuzumab for 
further details. 

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6.1.3 Chlorambucil 
This study will use commercially available chlorambucil.  The Sponsor will either directly supply 
sites with chlorambucil or the sites will be reimbursed to prescribe chlorambucil; this will be 
detailed separately in each site’s clinical trial agreement. 
Commercially available chlorambucil will be supplied as 2-mg film-coated tablets for PO 
administration.  Refer to the local prescribing information for chlorambucil for further details. 
6.2 
Drug Preparation and Administration 
6.2.1 Acalabrutinib in Combination with Obinutuzumab Administration (Arm B) 
Acalabrutinib is intended to be administered orally twice daily with 8 ounces (approximately 
240 mL) of water.  Acalabrutinib may be taken with or without food.  The capsules should be 
swallowed intact and subjects should not attempt to open capsules or dissolve them in liquid. 
It is recommended that acalabrutinib be taken as close to the scheduled time as possible.  If a 
dose is missed, it can be taken up to 3 hours after the scheduled time with a return to the 
normal schedule with the following dose.  If it has been longer than 3 hours, the dose should not 
be taken and the subject should take the next dose at the next scheduled time.  The missed 
dose will not be made up and must be returned to the site at the next scheduled time. 
Below is the recommended infusion schedule for this study; however, locally approved labelling 
may be considered for administration of obinutuzumab.  Obinutuzumab should be administered 
as an IV infusion through a dedicated line and under the close supervision of an experienced 
physician.  Obinutuzumab infusions should not be administered as an IV push or bolus. 
Dose of obinutuzumab to be administered during 6 treatment cycles each of 28 days duration: 

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Day of Treatment Cycle 
Dose of 
Obinutuzumab 
Rate of Infusion  
(In the absence of infusion reactions/ 
hypersensitivity during previous 
infusions) 
First Cycle 
(loading 
doses) 
Day 1 
100 mg 
Administer at 25 mg/hr over 4 hours.  
Do not increase the infusion rate. 
Day 2 
900 mg 
Administer at 50 mg/hr.  
The rate of the infusion can be escalated 
in increments of 50 mg/hr every 30 
minutes to a maximum rate of 400 mg/hr. 
Day 8 
1000 mg 
Infusions can be started at a rate of 
100 mg/hr and increased by 100 mg/hr 
increments every 30 minutes to a 
maximum of 400 mg/hr. 
Day 15 
1000 mg 
Subsequent 
Cycles 
Day 1 
1000 mg 
 
On days when acalabrutinib and obinutuzumab are both administered, the order of study 
treatment administration will be acalabrutinib followed at least 1 hour later by obinutuzumab. 
6.2.2 Obinutuzumab and Chlorambucil Administration (Arm A) 
Obinutuzumab will be administered as described above (Section 6.2.1), but starting on Cycle 1 
Day 1.  Locally approved labelling may be considered for administration of chlorambucil. 
Chlorambucil will be orally administered at a dose of 0.5 mg/kg of body weight on Days 1 and 
15 of Cycles 1 through 6.  Chlorambucil should not be dosed sooner than 14 days from the last 
dose of chlorambucil.  On days when chlorambucil and obinutuzumab are both administered, 
the order of study treatment administration will be chlorambucil followed by obinutuzumab. 
6.2.3 Acalabrutinib Monotherapy Administration (Arm C) 
Acalabrutinib monotherapy will be administered as described above (Section 6.2.1). 
6.3 
Dose Modifications and Delays 
6.3.1 Assessment of Toxicity 
The evaluation of potential treatment-induced toxicity in subjects with advanced CLL may be 
quite difficult requiring careful consideration of the manifestations of the underlying disease, as 
well as adverse reactions to the therapy under study.  Dose modification decisions for 
hematologic toxicity will be based on the grading scale in the Common Terminology Criteria for 
Adverse Events (CTCAE) v4.03 or higher. 

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For dose modifications or discontinuation guidance of acalabrutinib in Arm B, Arm C, and Arm D 
(crossover) see Section 6.3.3.  For dose modifications or discontinuation guidance of 
obinutuzumab or chlorambucil in Arm A and/or Arm B, see Section 6.3.4. 
6.3.2 Dose Delays for Acalabrutinib 
Treatment with acalabrutinib should be held for any unmanageable, potentially study 
drug-related toxicity that is Grade ≥ 3 in severity.  Any other clinically important events where 
dose delays may be considered appropriate by the Investigator must be discussed with the 
Medical Monitor.  Study drug may be held for a maximum of 28 consecutive days from expected 
dose due to toxicity.  Study treatment should be discontinued in the event of a toxicity lasting 
>28 days, unless reviewed and approved by the Medical Monitor. 
Note: temporary withholding of study drug (e.g., for drug-related toxicity, surgery, or intercurrent 
illness) for as little as 7 days can cause a transient worsening of disease and/or of constitutional 
symptoms.  In such circumstances, and if medically appropriate, subjects may resume therapy 
and relevant clinical, laboratory, and/or radiologic assessments should be done to document 
whether tumor control can be maintained or whether actual disease progression has occurred. 
6.3.3 Dose Modification and Discontinuation for Acalabrutinib 
The actions in Table 6-1 should be followed for the following toxicities: 
• 
Grade 4 ANC (< 500/μL) for > 7 days (neutrophil growth factors are permitted per ASCO 
guidelines [Smith 2015] and use must be recorded on the case report form [CRF]). 
• 
Grade 3 platelet decreases in presence of significant bleeding. 
• 
Grade 4 platelet decreases. 
• 
Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal antiemetic 
and/or anti-diarrheal therapy. 
• 
Any other Grade 4 toxicity or unmanageable Grade 3 toxicity. 
For subjects on Arm B: If acalabrutinib or obinutuzumab is discontinued, then the other study 
drug (obinutuzumab or acalabrutinib, respectively) can be continued at the discretion of the 
investigator (up to a total of 6 cycles of obinutuzumab). 

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Table 6-1.  Drug Discontinuation Actions for Acalabrutinib 
Occurrence 
Action 
1st – 2nd 
Hold acalabrutinib until recovery to Grade 1 or baseline; may restart at original 
dose level 
3rd 
Hold acalabrutinib until recovery to Grade 1 or baseline; restart at one dose 
level lower (100 mg QD) 
4th 
Discontinue acalabrutinib 
Abbreviation: QD = once per day. 
If acalabrutinib is reduced for apparent treatment-related toxicity, the dose need not be 
re-escalated, even if there is minimal or no toxicity with the reduced dose.  However, if the 
subject tolerates a reduced dose of acalabrutinib for ≥4 weeks then the dose may be increased 
to the next higher dose level, at the discretion of the investigator.  Such re-escalation may be 
particularly warranted if further evaluation reveals that the AE that led to the dose reduction was 
not treatment-related.  However, the maximum dose of acalabrutinib is 100 mg BID for this 
protocol. 
Any changes to the dosing regimen must be recorded in the Dosage Administration CRF. 
6.3.3.1 Tumor Lysis Syndrome for acalabrutinib 
For subjects considered at risk for tumor lysis syndrome (TLS), administer appropriate hydration 
and allopurinol or rasburicase per institutional standards prior to initiating treatment with 
acalabrutinib. 
6.3.4 Dose Modification and Discontinuation for Obinutuzumab and 
Chlorambucil 
No reduction in the dose of obinutuzumab is allowed.  Recommendations for chlorambucil dose 
reductions are described below.  A dose delay of up to 4 weeks is permitted for obinutuzumab 
or chlorambucil to allow recovery of hematologic toxicities to ≤Grade 2 or non-hematologic 
toxicities to Grade 1 or baseline level.  If the treatment is delayed for more than 4 weeks, 
chlorambucil should be discontinued; obinutuzumab may continue at the discretion of the 
investigator. 
For subjects on Arm A: if obinutuzumab or chlorambucil is discontinued, then the other study 
drug (chlorambucil or obinutuzumab) can be continued at the discretion of the investigator (up to 
a total of 6 cycles of obinutuzumab or chlorambucil). 
Obinutuzumab plus chlorambucil administration on Day 1 of the following cycle will be given if 
the cytopenia has resolved to Grade ≤2.  If the cytopenia persists, obinutuzumab plus 

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chlorambucil administration will be delayed until the cytopenia has improved to Grade ≤2.  If a 
subject experiences Grade 3 or 4 cytopenia, the guidelines for dose delay and dose reduction 
are outlined in Table 6-2.  Below are the recommended hematologic dose modifications for 
chlorambucil and obinutuzumab; investigators may also elect to follow appropriate dose 
modification guidelines in locally approved labeling for these drugs. 
Table 6-2.  Hematologic Dose Modifications for Obinutuzumab and Chlorambucil 
 
Chlorambucil 
Obinutuzumab 
Grade 3 or 4 cytopenia* 
Delay dosing for a maximum 
of 4 weeks. 
Administer granulocyte 
colony-stimulating factor 
(G-CSF) for neutropenia or 
platelets or red blood cells as 
required. 
First episode: If improvement 
to Grade ≤2 (or baseline), 
decrease chlorambucil dose to 
75% of initial dose for 
subsequent cycles 
Second episode: If 
improvement to Grade ≤2 (or 
baseline), decrease 
chlorambucil dose to 50% of 
initial dose for subsequent 
cycles 
Third episode: Discontinue 
chlorambucil 
Delay dose for a maximum of 4 
weeks. 
 
If improvement to maximum of 
Grade ≤2 (or baseline), 
administer full dose. 
 
If chlorambucil is discontinued, 
obinutuzumab may continue at 
the 
Investigator’s discretion.  
Grade 1 or 2 cytopenia* 
No dose reduction or delay 
No dose reduction or delay 
 
Chlorambucil has been reported to exacerbate or precipitate AIHA and subjects should be 
monitored carefully for this condition.  If a rapid decrease of hemoglobin occurs during therapy, 
the possibility of chlorambucil- or autoantibody induced hemolysis should be considered and 
appropriate diagnostic tests (lactate dehydrogenase [LDH], bilirubin, haptoglobin, reticulocytes, 
Coombs-test) be performed.  If hemolysis is suspected a Coomb’s test should be performed.  If, 
in the judgment of the treating physician, there is evidence of clinically significant hemolytic 
anemia secondary to chlorambucil, study treatment should be promptly discontinued.  Full 
details of the hemolytic anemia should be recorded on the AE pages of the CRF. 
A subject must discontinue obinutuzumab/chlorambucil if any of the following 
occur: 
• 
Acute life-threatening respiratory symptoms 
• 
Grade 4 infusion-related symptom – subject must be withdrawn immediately 

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• 
Grade 3 infusion-related symptom at rechallenge 
• 
Grade 3 or 4 cytopenia (if not present at baseline) that has not resolved to Grade ≤2 and 
delays treatment by ≥ 4 weeks 
• 
Grade ≥2 non-cytopenia toxicity that does not resolve to ≤Grade 1/baseline and delays 
treatment by ≥4 weeks 
Refer to the local Summary of Product Characteristics (SmPC) or the local prescribing 
information for guidance on obinutuzumab/chlorambucil discontinuations. 
6.3.5 Premedication Requirements (Obinutuzumab) 
6.3.5.1 Infusion-related Reactions 
Since some subjects may develop infusion-related reactions to obinutuzumab, premedications 
must be administered before any obinutuzumab infusions.  Complete details on recommended 
premedications are provided in the obinutuzumab local prescribing information and briefly 
outlined below: 
Obinutuzumab 
cycles 
Subjects requiring 
premedication 
Premedication 
Administration 
First Cycle: 
Day 1,  
Day 2 
All subjects 
Intravenous glucocorticoid: 
20 mg dexamethasone or 
80 mg methylprednisolone* 
Completed at least 
1 hour prior to 
obinutuzumab infusion.  
650–1000 mg acetaminophen 
At least 30 minutes 
before obinutuzumab 
infusion. 
Antihistamine (e.g., 50 mg 
diphenhydramine)  
First Cycle: 
Day 8, 
Day 15 
 
Subsequent 
Cycles (total 
of 6 
maximum): 
Day 1 
All subjects 
650–1000 mg acetaminophen 
At least 30 minutes 
before obinutuzumab 
infusion. 
Subjects with an IRR 
(Grade ≥1) with the 
previous infusion 
Antihistamine (e.g., 50 mg 
diphenhydramine)  
At least 30 minutes 
before obinutuzumab 
infusion. 
Subjects with a 
Grade 3 IRR with the 
previous infusion OR 
with a lymphocyte 
count >25 x 109/L 
prior to next 
treatment 
Intravenous glucocorticoid: 
20 mg dexamethasone or 
80 mg methylprednisolone* 
Completed at least 
1 hour prior to 
obinutuzumab infusion. 
Abbreviations: IRR = infusion-related reaction 
*Hydrocortisone is not recommended as it has not been effective in reducing the rate of infusion reactions 
6.3.5.2 
Tumor Lysis Syndrome (Obinutuzumab) 
Subjects who are considered to be at risk of TLS (e.g., subjects with a high tumour burden 
and/or a high circulating lymphocyte count [> 25 x 109/L] and/or renal impairment [creatinine 
clearance < 70 mL/min]) should receive prophylaxis.  Prophylaxis should consist of adequate 

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hydration and administration of uricostatics (e.g., allopurinol) or a suitable alternative such as a 
urate oxidate (e.g., rasburicase), before the infusion of obinutuzumab.  All subjects considered 
at risk should be carefully monitored during the initial days of treatment with a special focus on 
renal function, potassium, and uric acid values.  Any additional guidelines according to standard 
practice should be followed.  For treatment of TLS, correct electrolyte abnormalities, monitor 
renal function and fluid balance, and administer supportive care, including dialysis as indicated. 
Subjects should continue to receive repeated prophylaxis before each subsequent infusion, if 
deemed appropriate. 
6.4 
Precautions 
6.4.1 Risks Associated with Acalabrutinib 
The following summarizes the experience with acalabrutinib in hematological cancer studies.  
Full details regarding the clinical safety of acalabrutinib are presented in Sections 5 and 6 of the 
Acalabrutinib Investigator’s Brochure. 
6.4.1.1 Hemorrhage 
Serious hemorrhagic events, including fatal events, have occurred in clinical trials with 
acalabrutinib. 
The mechanism for hemorrhage is not well understood.  Subjects receiving antithrombic 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. 
6.4.1.2 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 reactivation, 
aspergillosis, and PML have occurred. 

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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. 
Subjects with infection events should be managed according to institutional guidelines with 
maximal supportive care and diagnostic evaluations as clinically indicated. 
6.4.1.3 Hepatitis B Reactivation 
Cases of hepatitis B virus (HBV) reactivation have been reported in patients treated with 
acalabrutinib, with 1 case resulting in liver failure and death.  Please refer to Section 6.4.3 for 
monitoring of HBV and management of patients with HBV reactivation. 
6.4.1.4 Progressive Multifocal Leukoencephalopathy 
Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients 
treated with acalabrutinib.  Signs and symptoms of PML may include cognitive and behavioral 
changes, language disturbances, visual disturbances, sensory deficits, weakness, and 
coordination and gait difficulties. 
If PML is suspected, hold further treatment with acalabrutinib until PML is excluded.  A 
diagnostic evaluation may include (but is not limited to): 
• 
Neurologic consultation 
• 
Brain magnetic resonance imaging (MRI) 
• 
Polymerase chain reaction (PCR) analysis for John Cunningham virus DNA in 
cerebrospinal fluid 
If PML is confirmed, permanently discontinue acalabrutinib. 
6.4.1.5 Cytopenias  
Grade 3 or 4 cytopenias, including neutropenia, anemia, and thrombocytopenia, have occurred 
in clinical studies with acalabrutinib.  Monitor blood counts as medically appropriate. 
Subjects with cytopenias should be managed according to institutional guidelines with maximal 
supportive care and diagnostic evaluations as clinically indicated.  Subjects should be closely 
monitored as appropriate. 
6.4.1.6 Second Primary Malignancies 
Second primary malignancies, including solid tumors and skin cancers, have been reported in 
patients treated with acalabrutinib.  The most frequent second primary malignancy was skin 

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cancer (basal cell carcinoma).  Subjects should be monitored for signs and symptoms of 
malignancy. 
Subjects who develop a second primary malignancy should be managed according to 
institutional guidelines, with diagnostic evaluations as clinically indicated, and it may be 
necessary for subjects to permanently discontinue study treatment.  Continuation of 
acalabrutinib treatment should be discussed with the Medical Monitor.  Please refer to 
Section 7.2.2.3 for second primary malignancy reporting guidance. 
6.4.1.7 Atrial Fibrillation 
Events of atrial fibrillation/flutter have occurred in clinical studies with acalabrutinib, particularly 
in subjects with cardiac risk factors, hypertension, diabetes mellitus, acute infections, and a 
previous history of atrial fibrillation. 
Monitor for symptoms of atrial fibrillation and atrial flutter (e.g., palpitations, dizziness, syncope, 
chest pain, dyspnea) and obtain an electrocardiogram (ECG) as clinically indicated.  Subjects 
with atrial fibrillation should be managed per institutional guidelines with supportive care and 
diagnostic evaluations as clinically indicated. 
6.4.1.8 Dietary Restrictions 
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). 
Acalabrutinib should be taken with water and may be taken with or without food. 
6.4.1.9 Treatment-related Lymphocytosis 
Treatment-related lymphocytosis is defined as an ALC > 5000 cells per microliter and an 
increase above baseline and is associated with agents known to inhibit BCR (Hallek 2008, 
National Comprehensive Cancer Network [NCCN] Version 1.2016, Cheson 2012).  Given the 
known mechanism of action of BCR-inhibiting agents including ibrutinib, treatment-related 
lymphocytosis is an expected and frequent phenomenon observed with initiation (or re-initiation) 
of BTK inhibitors.  Specifically, the IMBRUVICA® approved label states an increase in 
lymphocyte counts (i.e., ≥ 50% increase from baseline and above ALC of 5,000/μL) occurred in 
77% of subjects (N=195) in the pivotal Phase 3 CLL study treated with ibrutinib monotherapy.  
The onset of lymphocytosis occurred during the first month of ibrutinib therapy and resolved by 
a median of 23 weeks (range 1 to 104+ weeks).  Asymptomatic treatment-related lymphocytosis 

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should not be considered an AE and subjects should remain on study treatment.  A high number 
of circulating malignant cells (≥ 400,000/μL) may confer increased risk; these subjects should be 
closely monitored.  Administer supportive care such as hydration and/or leukophoresis as 
indicated. Acalabrutinib may be temporarily held and the Medical Monitor should be contacted. 
Note: for complete information on precautions for acalabrutinib refer to the Acalabrutinib 
Investigator Brochure. 
6.4.1.10 
Overdose Instructions 
For any subject experiencing an acalabrutinib overdose (ingestion of more than the 
recommended dosage), observation for any symptomatic side effects should be instituted, and 
vital signs, biochemical and hematologic parameters should be followed closely (consistent with 
the protocol or more frequently, as needed).  Appropriate supportive management to mitigate 
adverse effects should be initiated.  If the overdose ingestion of acalabrutinib is recent and 
substantial, and if there are no medical contraindications, use of gastric lavage or induction of 
emesis may be considered. 
The Medical Monitor must be contacted if a study drug overdose occurs. 
6.4.2 Obinutuzumab and Chlorambucil 
For complete information on warnings and precautions, refer to the local prescribing information 
for obinutuzumab and chlorambucil.  A brief summary of warnings and precautions for 
obinutuzumab is provided below. 
6.4.2.1 Progressive Multifocal Leukoencephalopathy 
John Cunningham (JC) virus infection resulting in PML, which can be fatal, was observed in 
patients treated with obinutuzumab.  Consider the diagnosis of PML in any subject presenting 
with new onset or changes to preexisting neurologic manifestations.  Evaluation of PML 
includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture.  
Discontinue obinutuzumab therapy and consider discontinuation or reduction of any 
concomitant chemotherapy or immunosuppressive therapy in subjects who develop PML. 
6.4.2.2 Infusion Reactions 
Obinutuzumab can cause severe and life-threatening infusion reactions.  Two-thirds of patients 
experienced a reaction to the first 1000 mg infusion of obinutuzumab.  Infusion reactions can 
also occur with subsequent infusions.  Symptoms may include hypotension, tachycardia, 

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dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, 
laryngeal edema).  Other common symptoms include nausea, vomiting, diarrhea, hypertension, 
flushing, headache, pyrexia, and chills.  Refer to Section 6.3.5 for premedication requirements 
to reduce risk of infusion reactions. 
For subjects with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute 
life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the 
obinutuzumab infusion.  Permanently discontinue obinutuzumab therapy. 
For subjects with Grade 1, 2, or 3 infusion reactions: Interrupt obinutuzumab for Grade 3 
reactions until resolution of symptoms.  Interrupt or reduce the rate of the infusion for Grade 1 or 
2 reactions and manage symptoms. 
For subjects with pre-existing cardiac or pulmonary conditions, monitor more frequently 
throughout the infusion and the postinfusion period since they may be at greater risk of 
experiencing more severe reactions.  Hypotension may occur as part of the obinutuzumab 
infusion reaction.  Consider withholding antihypertensive treatments for 12 hours prior to, during 
each obinutuzumab infusion, and for the first hour after administration until blood pressure is 
stable.  For patients at increased risk of hypertensive crisis, consider the benefits versus the 
risks of withholding their antihypertensive medication as is suggested here. 
6.4.2.3 Tumor Lysis Syndrome 
Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia 
from TLS can occur within 12 to 24 hours after the first infusion.  Refer to Section 6.3.5 for 
premedication requirements to reduce risk of TLS. 
6.4.2.4 Infections 
Serious bacterial, fungal, and new or reactivated viral infections can occur during and after 
obinutuzumab therapy.  Fatal infections have been reported with obinutuzumab.  Do not 
administer obinutuzumab to subjects with an active infection.  Subjects with a history of 
recurring or chronic infections may be at increased risk of infection. 
6.4.2.5 Neutropenia 
Obinutuzumab in combination with chlorambucil caused Grade 3 or 4 neutropenia in 33% of 
patients in the Phase 3 trial.  Subjects with Grade 3 to 4 neutropenia should be monitored 
frequently with regular laboratory tests until resolution.  Anticipate, evaluate, and treat any 
symptoms or signs of developing infection.  Neutropenia can also be of late onset (occurring 

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more than 28 days after completion of treatment) and/or prolonged (lasting longer than 
28 days).  Subjects with neutropenia are strongly recommended to receive antimicrobial 
prophylaxis throughout the treatment period.  Antiviral and antifungal prophylaxis should be 
considered. 
6.4.2.6 Thrombocytopenia 
Obinutuzumab in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 
10% of patients in the Phase 3 trial.  In 4% of patients, obinutuzumab caused acute 
thrombocytopenia occurring within 24 hours after the obinutuzumab infusion.  Fatal hemorrhagic 
events during Cycle 1 have also been reported in patients treated with obinutuzumab. 
Monitor all subjects frequently for thrombocytopenia and hemorrhagic events, especially during 
the first cycle.  In subjects with Grade 3 or 4 thrombocytopenia, monitor platelet counts more 
frequently until resolution and consider subsequent dose delays of obinutuzumab and 
chlorambucil or dose reductions of chlorambucil.  Transfusion of blood products (i.e., platelet 
transfusion) may be necessary.  Consider withholding concomitant medications which may 
increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle. 
6.4.2.7 Immunization 
The safety and efficacy of immunization with live or attenuated viral vaccines during or after 
obinutuzumab therapy has not been studied.  Immunization with live virus vaccines is not 
recommended during treatment and until B-cell recovery. 
6.4.2.8 Risk of Gastrointestinal Perforation 
The sponsor has been notified of the important identified risk of GI perforation with 
obinutuzumab treatment in patients with NHL by the manufacturer of obinutuzumab (Genentech 
Inc.).  Monitoring of subjects with GI involvement for GI perforation is recommended. 
6.4.3 Hepatitis B Virus Reactivation 
Serious or life-threatening reactivation of viral hepatitis may occur in subjects treated with a BTK 
inhibitor (de Jésus Ngoma 2015, FDA Drug Safety Communication 2013).  Cases of HBV 
reactivation have been reported in patients treated with acalabrutinib with 1 case resulting in 
liver failure and death.  HBV reactivation can also occur with anti-CD20+ antibody therapy.  
Therefore, subjects who are hepatitis B core antibody (anti-HBc) positive, or have a known 
history of HBV infection, should be monitored every month with a quantitative PCR test for HBV 
DNA.  Monitoring should continue until 12 months after last dose of study drug(s).  Any subject 

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with a rising viral load (above lower limit of detection) should discontinue study drug and have 
antiviral therapy instituted and a consultation with a physician with expertise in managing 
hepatitis B.  Insufficient data exist regarding the safety of resuming acalabrutinib in subjects who 
develop HBV reactivation. 
In subjects who develop reactivation of HBV while receiving obinutuzumab, immediately 
discontinue obinutuzumab and any concomitant chemotherapy and institute appropriate 
treatment.  Insufficient data exist regarding the safety of resuming obinutuzumab in subjects 
who develop HBV reactivation. 
6.4.4 Reproductive Toxicity 
Men are considered to be of non-reproductive potential if they are permanently sterile due to 
bilateral orchidectomy. 
Definition of women of non-reproductive potential: 
Women will be considered of non-reproductive potential if they are either: 
• 
Postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle-stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy.  In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
• 
Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
• 
Have a congenital or acquired condition that prevents childbearing. 
Definition of contraception: 
• 
 Sexual abstinence† (only if refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments); 
OR 
• 
Use (or have their partner use) highly effective contraception during heterosexual 
activity. 
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‡: 

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Combination method (requires use of a male condom in combination with 1 of the following): 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation, which may be oral, intravaginal, or transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation, which 
may be oral, injectable, or implantable 
• 
Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomy of a female subject’s male partner (with medical assessment and 
confirmation of vasectomy surgical success) 
Hormonal contraception may be susceptible to interaction with study or other drugs, which may 
reduce the efficacy of the contraception method.  Women using hormonal contraceptives should 
add a barrier 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 and if considered acceptable by 
local regulatory agencies and IECs/IRBs.  Periodic abstinence (e.g., calendar, ovulation, 
sympto-thermal, and post-ovulation methods) and withdrawal (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. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does 
not qualify as an acceptable method of contraception for subjects participating at sites in this 
country/region. 
Pilot reproductive toxicity studies have been performed that evaluate the effects of acalabrutinib 
on embryofetal development.  At acalabrutinib exposures comparable to the clinical exposures 
at the intended therapeutic dosage, no acalabrutinib-related adverse effects of target organ 
toxicity, reproductive toxicity, or embryofetal development were identified in the nonclinical 
safety assessment (see the Acalabrutinib Investigator Brochure). 
There are no data from the use of obinutuzumab in pregnant women.  Chlorambucil is 
considered a probable genotoxicant and can cause fetal harm when administered to pregnant 
women. 

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Women who are sexually active and can bear children (see definition above) must agree to use 
highly effective forms of contraception during the study and 2 days after the last dose of 
acalabrutinib or 18 months after the last dose of obinutuzumab and chlorambucil, whichever is 
longer.  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 obinutuzumab or 
chlorambucil, whichever is later.  Men must also refrain from donating sperm during the study 
and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later.  In 
addition, since chlorambucil is probably mutagenic and teratogenic in humans (LEUKERAN® 
package insert), condom (barrier) use is also required for all male subjects treated with 
chlorambucil (including vasectomized male subjects) during and up to 90 days after the last 
dose of chlorambucil to prevent possible direct exposure to a developing fetus (in case of a 
pregnant female partner). 
Female subjects should be informed that taking the study medication may involve unknown 
risks to the fetus (unborn baby) if pregnancy were to occur during the study.  To participate in 
the study, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation of 
study medication for oral contraception) throughout the study period up to 2 days after the last 
dose of acalabrutinib or 18 months after the last dose of obinutuzumab or chlorambucil, 
whichever is longer.  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 in clinical studies should promptly notify the investigator if they, or their partners, 
become pregnant during this period.  If a woman becomes pregnant during the treatment 
period, she must discontinue study drug immediately.  Pregnancy in a female subject or a male 
subject’s partner must be reported as outlined in Section 7.2.2. 
6.5 
Concomitant Medications 
6.5.1 Allowed Concomitant Medications 
Antiemetics are permitted if clinically indicated.  Standard supportive care medications are 
permitted.  Use of hematopoietic growth factors is permitted per the ASCO guidelines 
(Smith 2015). 

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6.5.2 Guideline for Use of CYP-Inhibiting/Inducing Drugs 
At the systemic exposure levels expected in this study, acalabrutinib inhibition of CYP 
metabolism is not anticipated.  However, as discussed in Section 1.4.1, concomitant 
administration of acalabrutinib with a strong CYP3A inhibitor increased exposure by 
approximately 5-fold.  Consequently, the concomitant use of strong inhibitors/inducers of 
CYP3A (Appendix F) should be avoided when possible.  Avoid coadministration of strong 
CYP3A inducers.  If a subject requires treatment with a strong CYP3A inducer, increase the 
acalabrutinib dose to 200 mg BID during concomitant administration with the strong inducer and 
return to recommended dose of 100 mg BID after stopping the strong CYP3A inducer. 
If the subject requires treatment with a moderate CYP3A inhibitor, the acalabrutinib dose should 
be reduced to 100 mg QD.  
6.5.3 Guideline for Use of Drugs that Affect Gastric pH 
Use of proton-pump inhibitors, H2 receptor antagonists, or antacids while taking acalabrutinib 
has the potential to decrease acalabrutinib exposure.  If treatment with a gastric acid reducing 
agent is required, consider using an H2-receptor antagonist (2 hours after acalabrutinib) or 
antacid (2 hours before or 2 hours after acalabrutinib).  Avoid coadministration with proton-pump 
inhibitors.  
6.5.4 Prohibited Concomitant Medications 
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy for 
treating CLL are prohibited if being used to treat the disease initially under study.  Short course 
use of steroids (≤ 2 weeks) > 20 mg/day is permitted for premedication use, or to manage 
infusion-related reactions or to manage other inflammatory reactions, such as asthma 
exacerbations.  High-dose corticosteroids used to treat the underlying CLL are not allowed on 
study.  Localized, short courses of radiotherapy are allowed for the treatment of lesions 
unrelated to the disease under study, if approved by the Medical Monitor.  Should a subject 
develop a second primary malignancy while on trial, continuation on trial medication after 
curative treatment of the second primary malignancy may be considered after discussion with 
the Medical Monitor. 
Steroids used to premedicate or manage obinutuzumab infusion-related reactions are permitted. 
Warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) are prohibited. 

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For additional information on potential drug-drug interactions, refer to the Acalabrutinib 
Investigator Brochure. 
6.6 
Treatment Compliance 
Subject compliance with acalabrutinib will be assessed at each study visit.  Compliance will be 
assessed by the Investigator and/or study personnel at each visit using direct questioning, 
examination of subject diaries, or pill counts. 
7 
EFFICACY AND SAFETY PROCEDURES 
The Schedule of Assessments are provided in Appendix A, Appendix B, Appendix C, and 
Appendix D.  Descriptions of the scheduled evaluations are outlined below. 
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 efficacy assessments.  Clinical evaluations and 
laboratory studies may be repeated more frequently if clinically indicated.  Such assessments 
will be captured in the protocol-specific electronic database as appropriate.  This study will 
primarily use central laboratory testing for laboratory evaluations.  Samples from sites' local 
laboratories will be used if central testing is unavailable.  
Some study centers may choose to provide subjects with clinical trial cards, which include 
information about the study and emergency contact details. 
7.1 
Description of Procedures 
7.1.1 Informed Consent 
The subject must read, understand, and sign the IRB/IEC-approved informed consent form 
(ICF) confirming his or her willingness to participate in this study before initiating any screening 
activity that is not considered standard of care by institutional standards.  Subjects must also 
grant permission to use protected health information if required by local regulations.  In addition, 
subjects must sign all approved ICF amendments per the site IRB/IEC’s guidelines during the 
course of the study. 
7.1.2 Confirmation of Eligibility 
Perform all necessary procedures and evaluations to document that the subject meets each 
eligibility criterion (Section 5).  Blood samples for hematology and serum chemistry collected at 
Screening will be evaluated by a central laboratory to confirm eligibility.  With the exception of 

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 if central laboratory results submitted during the screening period are unavailable, the 
Medical Monitor may review local laboratory results and approve the subject for randomization 
based on these laboratory values on a case-by-case basis provided another sample is redrawn 
and submitted before treatment.  The following de-identified documentation will be reviewed 
before enrollment: 
 
 
 
 
Please refer to the study manual for a more detailed description of the randomization 
procedures.  Treatment with study drug should begin within 7 days of randomization. 
7.1.3 Medical History 
Collect and record the subject’s complete history including concurrent medical signs and 
symptoms, alcohol use and, if a smoker, cigarette use. Disease history, including the date of 
initial diagnosis, Rai or Binet staging within 28 days of first dose with study drug, and history of 
autoimmune CLL complications and their treatment will also be recorded based upon available 
documents and subject history. 
7.1.4 Physical Examination 
The physical examination includes height (Screening only) and weight, and examination of the 
skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal, nervous, 
and lymphatic system and general appearance.  The lymphatic system examination will include 
bidimensional measurements of palpable lymph nodes and measurement of spleen and liver 
sizes by centimeters below the costal margin on the respective side.  Only physicians, physician 
assistant, or oncology nurse practitioners should perform the lymphatic system examination.  As 
much as possible, the same person should perform all the lymphatic exams for a given subject. 
7.1.5 Disease-related Symptoms 
Disease-related symptoms will be assessed and recorded in the subject records and are 
defined per Hallek 2008 as: 
a. Unintentional weight loss of 10% of more within the previous 6 months; 
b. Significant fatigue (i.e., ECOG performance status 2 or worse; inability to work or 
perform usual activities); 
CCI
CCI

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c. Fevers higher than 100.5°F or 38°C for 2 or more weeks without other evidence of 
infection; or 
d. Night sweats for more than 1 month without evidence of infection 
7.1.6 Cumulative Illness Rating Scale-Geriatric (CIRS-G) 
CIRS-G (Appendix L) is an indicator of illness severity and comorbidity in older subjects 
(Extermann 1998).  CIRS-G scoring is to be performed by a licensed provider (e.g., physician, 
physician assistant, or nurse) for subjects > 18 and < 65 years of age. 
Rating Strategy 
Please see specific scoring guidelines below for each organ system. 
0: No Problem. 
1: Current mild problem or past significant problem. 
2: Moderate disability or morbidity/requires “first line” therapy. 
3: Severe/constant significant disability/”uncontrollable” chronic problems. 
4: Extremely severe/immediate treatment required/end organ failure/severe impairment 
of function. 
7.1.7 Vital Signs 
Vital signs will include blood pressure, heart rate, respiratory rate, and body temperature. 
7.1.8 Electrocardiogram 
Subjects should be in supine position and resting for at least 10 minutes before the Screening 
ECG. 
7.1.9 ECOG Performance Status 
The ECOG performance status index is provided in Appendix E. 
7.1.10 Hepatitis Serologies 
Hepatitis serology testing must include HBsAg, anti-HBs, anti-HBc, and hepatitis C (HCV) 
antibody.  In addition, any subjects testing positive for anti-HBc , must have PCR testing during 
screening and on study (see Appendix A, Appendix B, Appendix C, Appendix D, and exclusion 
criterion #14).  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 month thereafter during the randomized part of the study, 

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at screening for crossover, and during crossover.  Monthly monitoring should continue until 
12 months after last dose of study drug(s).  Any subject with a rising viral load (above lower limit 
of detection) should discontinue study treatment and have antiviral therapy instituted and a 
consultation with a physician with expertise in managing hepatitis B.  As IVIG may cause false 
positive hepatitis serology, monthly PCR testing is not required in subjects who are currently 
receiving or received prophylactic IVIG within 3 months before study enrollment and have a 
documented negative anti-HBc test before the initiation of IVIG therapy.  PCR testing should be 
performed when clinically indicated (e.g., in the setting of rising transaminase levels). 
Subjects with a known history of hepatitis C or who are hepatitis C antibody positive should be 
tested for HCV RNA performed during screening.  Refer to Section 6.4 and Appendix A, 
Appendix B, Appendix C, and Appendix D regarding monitoring of subjects who are anti-HBc 
positive. 
7.1.11 
 
7.1.12 Genetic and Molecular Prognostic Markers 
A blood sample will be collected and analyzed centrally to study the pretreatment prognostic 
factors.  These prognostic factors have previously been associated with disease outcome in 
CLL subjects. 
One sample will be collected for immunoglobulin heavy-chain variable (IGHV and p53 
mutational status. 
One sample will be collected to study the leukemia cell expression of CD38+ and ZAP-70. 
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7.1.13 Pregnancy Test 
Serum pregnancy tests are required only for women with childbearing potential and may be 
done by local laboratories.  Pregnancy tests will be performed at Screening, on Cycle 1 Day 1, 
and at the safety-follow-up visit, and may be performed more frequently if required by local 
regulatory authorities. 
7.1.14 Hematology 
Hematology will be evaluated by a central laboratory and will include a complete blood count 
(CBC) with WBC differential.  Any missing central laboratory blood samples should be redrawn 
as soon as possible.  In the event that the missing central laboratory sample is unrecoverable, 
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local laboratory results will be collected, if available, and entered in the clinical database for 
response or progression confirmation. 
7.1.15 Determination of T/B/NK Cell Counts 
Whole blood samples will be analyzed for absolute T/B/NK counts (CD3+, CD19+, CD4+, CD8+, 
CD16+/56+) using a standard cell marker panel.  This assay will be performed at the central 
laboratory on the same blood sample collected for standard hematology. 
7.1.16 Serum Chemistry 
Serum chemistry will be evaluated by a central laboratory and will include albumin, alkaline 
phosphatase, ALT, AST, blood urea nitrogen (BUN), calcium, creatinine, glucose, LDH, 
phosphate/phosphorus, potassium, sodium, total bilirubin, and uric acid.  Any missing central 
laboratory blood samples should be redrawn as soon as possible. 
7.1.17 Serum Immunoglobulins and β2-microglobulin 
Sample(s) will be sent to a central laboratory for quantitative immunoglobulin (IgG, IgM, IgA) 
levels and serum β2-microglobulin. 
7.1.18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.1.19 
 
 
 
 
 
 
 
  
 
 
 
 
 
7.1.20 Bone Marrow Aspirate and Biopsy 
7.1.20.1 
For Eligibility 
A unilateral bone marrow aspirate and biopsy will be done at Screening or ≤3 months before 
randomization.  The Screening sample must be sent to the central laboratory for analysis. 
Subjects who have a bone marrow biopsy done within 3 months of randomization may use 
these results in lieu of the Screening sample required for this study.  If slides (both bone marrow 
and aspirate) are available, these should be sent to the central laboratory for analysis. 
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7.1.20.2 
/Response Evaluation (more details 
provided in Appendix G) 
If the subject’s physical examination findings, laboratory evaluations, and radiographic 
evaluations suggest that CR has been achieved in all response parameters, a bone marrow 
aspirate and biopsy and peripheral blood sample must be obtained and sent to the central 
laboratory for analysis to confirm the CR and 
  In cases where cytopenic 
progression is suspected, a bone marrow aspirate or biopsy should be performed to distinguish 
autoimmune and drug-related cytopenias. 
Arm A:  Obinutuzumab + Chlorambucil: 
For subjects on treatment with obinutuzumab plus chlorambucil, if the subject’s physical 
examination findings, laboratory evaluations, and radiographic evaluations suggest that CR has 
been achieved, a confirmatory bone marrow biopsy/aspirate and peripheral blood sample 
 
 
  For subjects who completed treatment, if the 
subject’s physical examination findings, laboratory evaluations, and radiographic evaluations 
suggest that CR has been achieved, a confirmatory bone marrow biopsy/aspirate and peripheral 
blood sample 
 
 
Arm B:  Obinutuzumab + Acalabrutinib: 
For subjects on obinutuzumab plus acalabrutinib, if the subject’s physical examination findings, 
laboratory evaluations, and radiographic evaluations suggest that CR has been achieved, a 
confirmatory bone marrow biopsy/aspirate and peripheral blood sample 
 
  For subjects on 
acalabrutinib monotherapy, if the subject’s physical examination findings, laboratory 
evaluations, and radiographic evaluations suggest that CR has been achieved, a confirmatory 
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bone marrow biopsy/aspirate and peripheral blood sample 
 
 
Arm C or Crossover Acalabrutinib Monotherapy Arm: 
For subjects on acalabrutinib monotherapy, if the subject’s physical examination findings, 
laboratory evaluations, and radiographic evaluations suggest that CR has been achieved, a 
confirmatory bone marrow biopsy/aspirate and peripheral blood sample t
 
 
At the discretion of the investigator, a repeat bone marrow biopsy/aspirate and peripheral blood 
testing 
 
7.1.21 CT/MRI Scans 
Radiological imaging by CT with contrast is required and must include the pelvis, abdomen, 
chest, and neck.  Subjects who are intolerant to IV CT contrast agents will have CT scans 
performed with oral contrast.  When possible, all subjects should have radiographic tumor 
measurements done at the participating study center or at an acceptable alternate imaging 
facility using an identical imaging protocol and similar equipment.  The same imaging equipment 
should be used for all scans whenever possible.  The same radiologist should be assigned to 
read all the scans for a given subject throughout the study as much as possible.  MRI may be 
used for imaging assessments if a contrast CT scan is contraindicated or unobtainable (in cases 
where MRI is desirable, the MRI must be obtained at baseline and at all subsequent response 
evaluations). 
Up to 6 measurable lymph nodes (only target lesions > 1.5 cm in the longest diameter may be 
assessed), clearly measurable in 2 perpendicular dimensions, will be followed as target lesions 
for each subject.  Measurable sites of disease should be chosen such that they are 
representative of the subject’s disease.  In addition, selection of target lesions should be from as 
disparate regions of the body as possible when these areas are significantly involved.  If at any 
time (screening and postdose) the liver or spleen are abnormal in size, the cranial-caudal 
measurement of the spleen and longest diameter of the liver should be assessed by CT/MRI at 
response evaluations. 
In the event disease progression is suspected due to physical examination or laboratory test 
results, a CT scan must be performed to confirm disease progression.  A central imaging 
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service will be used to provide independent radiologic assessments for the purposes of the 
primary endpoint.  These measurements will not be reported back to the site. 
7.1.22 Medical Resources Utilization 
Hospitalizations, emergency department visits, blood product transfusions, and hematopoietic 
growth factor use will be collected for each treatment arm. 
7.1.23 Adverse Events 
The accepted regulatory definition for an AE is provided in Section 7.2.1.  The AE reporting 
period is described in Section  7.2.2.1.  Important additional requirements for reporting SAEs 
are explained in Section  7.2.2.6. 
7.1.24 Prior and Concomitant Medications 
Document all concomitant medications and procedures from 14 days before the start of study 
drug administration through 30 days after the last dose of all study drugs, or at documented 
disease progression, whichever is longer. 
After a subject discontinues study treatment, receipt of all subsequent anticancer therapies will 
be collected. 
7.1.25 Routine Clinical Assessments 
Routine clinical assessments include physical exams, recording of symptoms, and hematologic 
evaluations to evaluate for both AEs and for disease progression at times when the CT scan is 
not obtained. 
7.1.26 Overall Response Evaluations 
Response evaluations will be done every 12 weeks (± 14 days) with the first on-treatment 
radiologic assessment occurring on Cycle 4 Day 1, the second on-treatment scan on Cycle 7 
Day 1, and so on through Cycle 25, and then every 24 weeks (± 14 days) thereafter.  Response 
evaluations should be completed during the Treatment Phase and the Post-Treatment Phase, 
until the subject has progressive disease. 
Overall response assessments will include evaluation of physical exams, recording of 
symptoms, hematologic evaluations (Note: CBC with differential must be done within 7 days), 
and radiographic evaluations per the schedule of assessments.  Subjects who have signs and 
symptoms of progression outside of the scheduled assessment should be evaluated by the 
Investigator with a physical exam and a CBC with differential to determine if disease 

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progression is present.  The blood samples for response or disease progression determination 
are to be confirmed by a central laboratory (samples from local laboratories can be used if 
central testing is unavailable).  Any suspected case of disease progression should be confirmed 
with a CT scan if one was not obtained and should be reported to the Sponsor or designee.  
Subjects may continue study treatment until progression is confirmed by a serial exam at least 2 
weeks later.  In addition, prior to crossover from Arm A to the crossover arm, a subject may 
continue treatment and remain under close observation until progression is confirmed by the 
IRC (through Amendment 5.0) or until disease progression is assessed by the investigator and 
confirmed by the study Medical Monitor (Amendment 6.0). 
7.1.27 Early Termination (ET) Visit/Safety Follow-up (SFU) Visit 
An ET visit is required for safety assessments for any subjects who permanently discontinue 
study treatment for any reason (except for death, lost to follow-up, or withdrawal of consent), 
including disease progression.  The ET visit should be performed within 7 days of the last dose 
of all study drugs, 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 ET visit would be performed within 
14 days of the SFU visit.  If the SFU visit is within ± 7 days of a regularly scheduled visit during 
the Post-treatment Phase, the visits may be combined into a single visit. 
In addition to the ET visit, a SFU visit should be conducted at 30 (+ 7) days after his or her last 
dose of all study drugs 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 time frame.  Refer to Appendix A, 
Appendix B, Appendix C, and Appendix D for the assessments required for the ET and SFU 
visits. 
7.1.28 Survival 
After progression, subjects will be contacted to assess survival status approximately every 
12 weeks until death, withdrawal by subject, lost to follow-up, or study terminated by Sponsor, 
whichever comes first.  At the time of the interim analysis and at study closure, a survival sweep 
will be conducted.  All subjects who are on study and not known to have died before the survival 
sweep will be contacted at that time. 

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7.1.29 Subsequent Anticancer Therapies 
After study drug treatment is complete, the following information on subsequent anticancer 
therapies will be collected approximately every 12 weeks until death, withdrawal by subject, lost 
to follow-up, or study terminated by Sponsor, whichever comes first: 
• 
Receipt of all subsequent anticancer therapies. 
• 
IWCLL indication for initiation of subsequent anticancer therapy. 
• 
Response to all subsequent anticancer therapies. 
7.2 
Assessment of Safety  
The safety of this study will be assessed by an independent DMC.  All randomized subjects will 
be evaluated clinically and using standard laboratory testing during their participation in this 
study.  Safety assessments will consist of monitoring and recording AEs and SAEs; 
measurements of protocol-specified hematology, clinical chemistry, 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). 
7.2.1 Definitions 
7.2.1.1 Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporarily associated 
with the use of an investigational (medicinal) product, regardless of attribution.  This includes 
the following: 
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with CLL that were not present 
before the AE reporting period (see Section 7.2.2). 
• 
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 CRF) is not considered an AE unless the severity, frequency, or 
character of the event worsens during the study period. 
• 
Preplanned hospitalization: A hospitalization planned before signing the ICF is not 
considered an SAE, but rather a therapeutic intervention.  However, if during the 

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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 randomization in the study, will 
not be considered serious if they are performed after randomization in the study for a 
condition that has not changed from its baseline level.  Elective hospitalizations for social 
reasons, solely for the administration of chemotherapy, or due to long travel distances 
are also not SAEs. 
• 
Diagnostic testing and procedures: Testing and procedures should not be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported.  If a test 
or procedure is done to rule out a diagnosis, the sign or symptom leading to the 
test/procedure should be the event term, and the event term should only be updated to 
the diagnosis if/when the diagnosis is confirmed.  Testing and procedures performed 
solely as screening measures (e.g., routine screening mammography or colonoscopy) 
should not be reported as AEs or SAEs. 
• 
Abnormal laboratory results:  Abnormal laboratory results are not AEs unless they are 
clinically significant.  For example, a clinically significant laboratory result is one that 
requires treatment (for example a blood transfusion for low hemoglobin) or requires a 
change in study drug (e.g., lowering the dose or withholding study drug while the 
laboratory finding resolves or stabilizes). 
• 
Progression of underlying malignancy:  Progression of underlying malignancy will not 
be reported as an AE if it is clearly consistent with the suspected progression of the 
underlying cancer.  Hospitalization due solely to the progression of underlying 
malignancy should NOT be reported as an SAE.  Clinical symptoms of progression may 
be reported as AEs if the symptoms cannot be determined as exclusively due to the 
progression of the underlying malignancy, or if they do not fit the expected pattern of 
progression for the disease under study. 
Symptomatic deterioration may occur in some subjects.  Symptomatic deterioration is 
when progression is evident in the subject’s clinical symptoms and the investigator may 
elect not to perform further disease assessments. 
If there is any uncertainty about an AE being due only to the disease under study, it 
should be reported as an AE or SAE. 
7.2.1.2 Serious Adverse Event 
Note: 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. 
A serious adverse event (experience) (SAE) or reaction is any untoward medical occurrence 
that at any dose: 
• 
Results in death (i.e., the AE actually causes or leads to death). 
• 
Is life-threatening (with regards to determining if an AE is serious, “life-threatening” is 
defined as an AE in which the subject was at risk of death at the time of the event.  It 
does not refer to an event which hypothetically might have caused death if it were more 
severe.  If either the Investigator or the Sponsor believes that an AE meets the definition 
of life-threatening, it will be considered life-threatening.). 

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• 
Requires in-subject hospitalization >24 hours or prolongation of existing hospitalization. 
• 
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). 
• 
Is a congenital anomaly/birth defect. 
• 
Is an important medical event that may not result in death, be immediately 
life-threatening or require hospitalization, but may be considered a serious adverse 
experience when, based upon appropriate medical judgment, the event may jeopardize 
the subject or subject may require intervention to prevent one of the other outcomes 
listed in this definition.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsion 
that do not result in hospitalization; or development of drug dependency or drug abuse. 
Given that the investigator’s perspective may be informed by having actually observed the 
event, and the Sponsor is likely to have broader knowledge of the drug and its effects to inform 
its evaluation of the significance of the event, if either the Sponsor or the Investigator believes 
that the event is serious, the event will be considered serious. 
7.2.1.3 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 7.2.2.5 for reporting instructions), irrespective of regulatory 
seriousness criteria or causality: 
• 
Ventricular arrhythmias (e.g., ventricular extrasystoles, ventricular tachycardia, 
ventricular arrhythmia, ventricular fibrillation, etc.) 
For study treatment containing biologic products: 
• 
Suspected transmission of an infectious agent by the study drug whereby any organism, 
virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform 
encephalopathy), pathogenic or non-pathogenic is considered an infectious agent.  A 
transmission of an infectious agent may be suspected from clinical symptoms or 
laboratory findings indicating an infection in a subject exposed to a medicinal product.  
This term ONLY applies when a contamination of the study drug is suspected, NOT for 
infections supported by the mode of action, e.g., immunosuppression. 
7.2.1.4 Suspected Adverse Reaction 
The Food and Drug Administration (FDA) has published a guidance on the reporting of SAEs.  
This document directs Sponsors to consider more carefully the AEs that are reported in an 
expedited (urgent) fashion to the FDA.  Key elements of this guidance are outlined below: 

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The guidance defines any AE for which there is a “reasonable possibility” that the drug caused 
the AE as a Suspected Adverse Reaction. 
“Reasonable Possibility”, for the purposes of safety reporting, means there is evidence to 
suggest a causal relationship between the drug and the AE.  Examples of evidence that would 
suggest a causal relationship between the drug and the AE are: 
• 
A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (e.g., angioedema, blood dyscrasias, rhabdomyolysis, hepatic injury, 
anaphylaxis, and Stevens-Johnson Syndrome). 
• 
One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., 
include tendon rupture or heart valve lesions in young adults, or intussusception in 
healthy infants).  If the event occurs in association with other factors strongly suggesting 
causation (e.g., strong temporal association, event recurs on rechallenge), a single case 
may be sufficiently persuasive; but often, more than one occurrence (from one or 
multiple studies) would be needed before the Sponsor could make a determination of 
whether the drug caused the event. 
• 
An aggregate analysis of specific events that can be anticipated to occur in the study 
population independent of drug exposure.  Such events include known consequences of 
the underlying disease or condition under investigation (e.g., symptoms or disease 
progression), or events unlikely to be related to the underlying disease or condition 
under investigation, but commonly occur in the study population independent of drug 
therapy (e.g., cardiovascular events in an elderly population).  An aggregate analysis 
(across studies) will identify those events that occur more frequently in the drug 
treatment group than in a concurrent or historical control group. 
This definition of “suspected adverse reaction” and the application of the “reasonable possibility” 
causality standard is considered to be consistent with the concepts and discussion about 
causality in the ICH E2A guidance. 
7.2.1.5 Severity 
Definitions found in the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 or 
higher will be used for grading the severity (intensity) of nonhematologic and hematologic AEs.  
The CTCAE v4.03 displays Grades 1 through 5 with unique clinical descriptions of severity for 
each referenced AE.  Should a subject experience any AE not listed in the CTCAE v4.03 or 
higher, the following grading system should be used to assess severity: 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities. 
• 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures. 

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• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment. 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be 
in imminent danger of death. 
• 
Grade 5 (Death related to AE) – experiences which result in subject death. 
7.2.1.6 Causality 
The causality of AEs to the study drug will be assessed by means of the question: ‘Is there a 
reasonable possibility that the event may have been caused by the study drug?’ per FDA 
guidance on safety reporting requirements (FDA Guidance 2012). 
See Appendix H for more detail on assessing causality. 
7.2.1.7 Unexpected Adverse Events 
An “unexpected” AE is an AE that is not listed in the Reference Safety Information for the study 
drug or is not listed at the specificity or severity that has been observed.  The Reference Safety 
Information for acalabrutinib is the Investigator Brochure.  The Reference Safety Information for 
the comparator drugs is the respective SmPCs.  For example, hepatic necrosis would be 
“unexpected” (by virtue of greater severity) if the Investigator Brochure referred only to elevated 
hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism and cerebral vasculitis 
would be “unexpected” (by virtue of greater specificity) if the Investigator Brochure/package 
insert listed only cerebral vascular accidents.  “Unexpected” also refers to AEs that are 
mentioned in the Investigator Brochure as occurring with a class of drugs or as anticipated from 
the pharmacologic properties of the drug, but are not specifically mentioned as occurring with 
the study drug under investigation. 
7.2.2 Documenting and Reporting of Adverse and Serious Adverse Events by 
Investigators 
The Investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, as outlined in the prior sections, are recorded on the CRF.  All SAEs also must 
be reported using the SAE report form (see “Expedited Reporting Requirements for Serious 
Adverse Events” later in this section). 

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7.2.2.1 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. 
7.2.2.2 Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation timepoints 
during the study.  All AEs and SAEs whether volunteered by the subject, discovered by study 
personnel during questioning, or detected through physical examination, or other means will be 
recorded in the subject’s medical record and on the AE CRF. 
Each recorded AE or SAE will be described by its diagnostic term, duration (i.e., start and end 
dates), severity, regulatory seriousness criteria (if applicable), suspected relationship to study 
drug, and any actions taken.  Whenever possible, AEs/SAEs should be reported by diagnosis 
term not as a constellation of symptoms. 
7.2.2.3 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. 

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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. 
7.2.2.4 Pregnancy 
The Investigator should report all pregnancies and pregnancies of the partners of subjects 
within 24 hours of notification using the Pregnancy Report Form.  This form should be faxed or 
emailed to Acerta Pharma Drug Safety.  Any pregnancy-associated SAE must be reported using 
the SAE report form, according to the usual timeline and direction for SAE reporting as 
described below. 
Any uncomplicated pregnancy that occurs with the subject or with the partner of a treated 
subject during this study will be reported for tracking purposes only, if agreed to by the subject 
or the partner of the subject in this study.  All pregnancies and partner pregnancies that are 
identified during or after this study will be reported.  All pregnancies and partner pregnancies 
that are identified during or after this study, wherein the estimated date of conception is 
determined to have occurred from the time of consent to 2 days after the last dose of 
acalabrutinib or 18 months after last dose of obinutuzumab in combination with chlorambucil 
(whichever is longer) must be reported, followed to conclusion, and the outcome reported, as 
long as the subject or partner has consented to participate in follow-up. 
Pregnancy itself is not regarded as an AE unless there is suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication.  
Likewise, elective abortions without complications are not considered AEs.  Any SAEs 
associated with pregnancy (e.g., congenital abnormalities/birth defects/spontaneous 
miscarriage or any other serious events) must additionally be reported as such using the SAE 
report form. 
Subject should be instructed to immediately notify the Investigator of any pregnancies.  Any 
female subjects receiving acalabrutinib who become pregnant must immediately discontinue 
study drug.  The Investigator should counsel the subject, discussing any risks of continuing the 
pregnancy and any possible effects on the fetus. 

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Upon completion of the pregnancy, additional information on the mother, pregnancy, and baby 
will be collected and sent to 
 
7.2.2.5 Expedited Reporting Requirements for Serious Adverse Events and AESIs 
All SAEs and AESIs must be reported within 24 hours of discovery.  All initial SAE and AESI 
reports and follow-up information will be reported using the protocol-specific electronic data 
capture (EDC) system, according to the instructions provided in the investigator site file.  If 
electronic SAE/AESI reporting is not available, paper SAE/AESI report forms must be emailed 
or faxed to Acerta Pharma Drug Safety, or designee.  Acerta Pharma may request follow-up and 
other additional information from the Investigator (e.g., hospital admission/discharge notes and 
laboratory results). 
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 death is typically the outcome of the event, not the event 
itself.  The primary cause of death on the autopsy report should be the term reported.  Autopsy 
and postmortem reports must be forwarded to Acerta Pharma Drug Safety, or designee, as 
outlined above. 
If study drug is discontinued because of an SAE, this information must be included in the SAE 
report. 
An SAE may qualify for mandatory expedited reporting to regulatory authorities if the SAE is 
attributable to the investigational product (or if a causality assessment is not provided for the 
SAE, in which case a default of “related” may be used for expedited reporting purposes) and the 
SAE is not listed in the Acalabrutinib Investigator Brochure (i.e., an unexpected event).  In this 
case, Acerta Pharma Drug Safety/Designee will forward a formal notification describing the 
suspected unexpected 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 United States) 
Email: 
 
 
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Reference Safety Information 
For the purpose of reporting AEs and SAEs: 
• 
The Investigator Brochure contains the Reference Safety Information (RSI) for 
acalabrutinib 
• 
The respective SmPC contains the RSI for obinutuzumab and chlorambucil 
7.2.2.6 Reporting of Serious Adverse Events by Sponsor 
Regulatory Authorities, IRBs/IECs, and Investigators will be notified of SAEs in accordance with 
applicable requirements (e.g., GCP, ICH guidelines, national regulations, and local 
requirements).  For the purpose of this protocol, Acerta Pharma considers acalabrutinib, 
obinutuzumab, and chlorambucil as investigational agents and will follow applicable guidelines 
for reporting SAEs for all drugs. 
7.2.2.7 Hy’s Law 
During the course of the study (ACE-CL-007), the investigator will remain vigilant for increases 
in liver biochemistry.  The investigator is responsible for determining whether a subject meets 
potential Hy’s law criteria at any point during the study.  All sources of laboratory data are 
appropriate for the determination of potential Hy’s law and Hy’s law events; see Appendix M for 
details. 
8 
WITHDRAWAL OF SUBJECT FROMTREATMENT OR ASSESSMENT 
8.1 
Withdrawal of Subjects from Study Treatment 
Subjects may be withdrawn from study treatment for the following reasons: 
• 
Progressive disease 
• 
Completed treatment 
• 
Start of alternative anticancer therapy 
• 
Adverse event 
• 
Pregnancy 
• 
Investigator decision 
• 
Subject’s withdrawal of consent from the study 
• 
Decision by sponsor to terminate the study 
• 
Subject lost to follow-up 
• 
Death 
• 
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8.2 
Reasons for Study Exit 
Reasons for study exit include: 
• 
Subject’s withdrawal of consent from study 
• 
Decision by sponsor to terminate the study. 
• 
Subject lost to follow-up 
• 
Death 
In case a subject is lost to follow-up, every possible effort must be made by the study site 
personnel to contact the subject and determine the reason for discontinuation.  The measures 
taken to follow-up must be documented. 
When a subject withdraws before completing the study, the reason for withdrawal must be 
documented in the CRF and in the source documents.  Subjects who withdraw consent should 
still be encouraged to complete the safety follow-up assessments before withdrawing consent, 
but these assessments cannot be mandated once consent is withdrawn. 
Subjects who are withdrawn or removed from study treatment will not be replaced. 
9 
STATISTICAL METHODS 
9.1 
General Considerations 
The statistical and analytical plans presented below summarize the more complete plans to be 
detailed in the SAP.  A change to the data analysis methods described in the protocol will 
require a protocol amendment only if it alters a principal feature of the protocol. 
The SAP will be finalized before database lock.  Any changes to the methods described in the 
final SAP will be described and justified in the clinical study report. 
9.1.1 Independent Review Committee 
A physician with expertise in CLL will chair the IRC.  The IRC will conduct response evaluations 
in accordance with its charter. 
9.1.2 Data Monitoring Committee 
The interim efficacy and overall safety of this study will be monitored by an independent DMC.  
The independent DMC will be chaired by a physician with expertise in CLL. 
An early safety analysis will be performed after approximately 60 subjects have been treated for 
approximately 8 weeks.  This analysis will focus on deaths, treatment discontinuations, SAEs, 

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and Grade 3/4 AEs as well as special events of interest.  This information will be reviewed by 
the Medical Monitor on an ongoing basis until this early safety analysis is conducted. 
The DMC will meet and review data approximately every 6 months (24 weeks) and provide 
recommendations regarding stopping or continuing the trial in accordance with the DMC charter. 
9.2 
Randomization 
This study will use an IWRS for randomization.  Approximately 510 eligible subjects will be 
randomized in a 1:1:1 ratio into 3 arms (n=170 each) to receive either obinutuzumab in 
combination with chlorambucil per the package inserts (Arm A), acalabrutinib 100 mg BID in 
combination with obinutuzumab per the package insert (Arm B), or acalabrutinib 100 mg BID 
(Arm C). 
Subjects will be randomized based on the following stratification factors: 
• 
Presence versus absence of 17p del by central laboratory 
• 
ECOG performance status 0, 1 versus 2. 
• 
Geographic region (North America and Western Europe versus Other). 
9.3 
Determination of Sample Size 
The study is expected to enroll approximately 510 subjects.  Subjects will be randomized in a 
1:1:1 ratio.  Thus, approximately 170 subjects will be in each arm. 
The study is sized to achieve approximately 90% power to detect a hazard ratio (Arm B/Arm A) 
of 0.60 for PFS which, under the model assumptions, 
 
 in median PFS time: 
 
  Given the study assumptions, the 
minimum detectable treatment difference at the final analysis of PFS corresponds to a 
 
 
 
 
 
One final analysis and one interim analysis for PFS are planned.  The final analysis of PFS is 
planned to occur when a total of 167 PFS events have been observed, which is anticipated to 
occur at 
 after the first subject randomized.  The interim analysis of PFS will be 
conducted when approximately two-thirds of the final analysis PFS event goal (i.e., 111 events 
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across Arms A and B) have been observed, which is expected to occur approximately 
 after the first subjects has been randomized. 
EAST6 (Version 6.3.1) was employed to conduct the sample size calculations. 
9.4 
Interim Analysis 
An interim analysis will be conducted to assess superiority and futility of Arm A vs Arm B with 
respect to the primary efficacy endpoint, PFS, as assessed by IRC.  An event-based interim 
analysis will occur when approximately two-thirds (e.g., 111 total PFS events across Arms A 
and B) of the required PFS events for final analysis have occurred.  
 
 
  The nominal alpha 
levels for the interim and final analyses will be determined based on the actual number of PFS 
events observed at the time of the analyses. 
All tests for interim and final analyses will be performed at 2-sided significance level.  The 
Lan-DeMets alpha spending function based on the O’Brien-Fleming boundary for superiority 
and futility (non-binding) will be used.  
 
 
 
Table 9-1. 
 
 
The nominal α1 and α2 levels will be determined based on the actual information fraction at the 
time of the interim analysis. 
If the criteria for early efficacy or futility are met at the time of the interim analysis, the DMC may 
recommend stopping the study.  An independent statistician will conduct the interim analysis for 
review by the DMC.  The DMC will make its recommendation to the Sponsor in accordance with 
the terms of the DMC charter. 
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If the interim analysis of the primary endpoint, PFS as assessed by IRC between Arms A and B, 
meets the significance level, then Arms A and C will be also compared for PFS as assessed by 
IRC, in a manner that will preserve the overall Type I error rate at a 0.05 level.  The SAP will 
describe the methodology for multiplicity adjustment. 
9.5 
Final Analysis 
The final analysis for PFS as assessed by IRC will be conducted after approximately 167 events 
across Arms A and B are confirmed by the IRC.  The median duration of PFS and the 
associated 95% CI for each treatment arm will be estimated using the Kaplan-Meier method.  
The HR and the 2-sided 95% of HR will be estimated using a Cox proportional-hazard model 
stratified by the randomization strata. 
If the primary endpoint is significant, Arms A and C will be tested for PFS as assessed by IRC in 
a way that maintains the overall 2-sided Type I error rate at a 0.05 level.  The SAP will describe 
the methodology for multiplicity adjustment. 
9.6 
Analysis Populations 
9.6.1 Intent-to-Treat (ITT) Population 
The ITT population will be defined as all randomized subjects.  All efficacy analysis will be 
performed in the ITT population and will be analyzed as randomized.  In addition, the ITT 
population will be used to summarize demographics, as well as baseline and disease 
characteristics. 
9.6.2 Safety Population 
The safety population includes all subjects who received ≥ 1 dose of study drug.  The safety 
population will be used for the safety analyses.  Subjects will be analyzed as treated. 
9.7 
Handling of Missing Values/Censoring/Discontinuations 
Missing or partial start and end dates for AEs and concomitant medications will be imputed 
according to prespecified, conservative imputation rules.  The SAP will describe approaches for 
other missing data. 
9.8 
Control for Bias 
The following study design components will facilitate the control for bias: 
• 
Large (approximately 510 subjects). 

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• 
Multicenter. 
• 
Randomized. 
The treatment assignment for any individual study subject will not be known to study and site 
personnel or the subject before subject randomization into the study. 
9.9 
Efficacy Analyses 
9.9.1 Primary Endpoint and Methods 
The primary efficacy endpoint is PFS, which is defined as the time from the date of 
randomization until disease progression (assessed by the IRC per IWCLL 2008 criteria) or 
death from any cause, whichever occurs first.  Subjects who withdraw from the study or are 
considered lost to follow-up without prior documentation of disease progression will be censored 
on the date of the last adequate disease assessment.  Subjects who start new anticancer 
therapy before documentation of disease progression will be censored on the date of the last 
adequate disease assessment that is on or before the start date of the new anticancer therapy.  
For subjects without an adequate post-baseline disease assessment, PFS will be censored on 
the date of randomization.  The primary efficacy analysis will be performed in the ITT population 
to compare PFS as assessed by the IRC between Arms A and B treatment arms using a 
stratified 2-sided log rank test.  The distribution of PFS will be summarized for each treatment 
arm using median and its corresponding 95% CI based on Kaplan-Meier estimates.  The 
estimate of the hazard ratio and its corresponding 95% CI will be computed using a Cox 
Proportional Hazards model stratified by the randomization strata. 
The SAP will describe the sensitivity analyses to be performed. 
9.9.2 Secondary Endpoints and Methods 
9.9.2.1 PFS 
The first secondary endpoint of the study is PFS compared between Arms A and C, where PFS 
is assessed by IRC review per IWCLL 2008 criteria.  The analysis will be performed in the ITT 
population to compare PFS between Arms A and C using a 2-sided log rank test.  The 
distribution of PFS will be summarized for each treatment arm using median and its 
corresponding 95% CI based on Kaplan-Meier estimates.  The estimate of the hazard ratio and 
its corresponding 95% CI will be computed using a Cox Proportional Hazards model. 

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9.9.3 Other Secondary Endpoints 
The SAP will describe Type I error control for the secondary outcomes. 
The following secondary endpoints will be compared first between Arms A and B and between 
Arms A and C. 
9.9.3.1 Objective Response Rate 
ORR is defined as achieving CR, CRi, nPR, or PR per the investigator or IRC assessment per 
IWCLL 2008 criteria at or before initiation of subsequent anticancer therapy. 
ORR will be compared between treatment arms (A vs B and A vs C) using the 
Cochran-Mantel-Haenszel chi-square test, adjusted for randomization stratification factors. 
9.9.3.2 Time to Next Treatment 
TTNT (defined as the time from randomization to institution of non-protocol specified treatment 
for CLL) will be compared between the treatment arms using a 2-sided log rank test.  
Distribution of PFS will be summarized for each treatment arm using the median and its 
corresponding 95% CI based on Kaplan-Meier estimates.  The estimated HR and its 
corresponding 95% CI will be computed from a Cox Proportional Hazards model. 
9.9.3.3 Overall Survival 
The OS analysis will be performed in the ITT population comparing Arms A and B using a 
2-sided log rank test.  The distribution of OS will be summarized for each treatment arm using 
the median and its corresponding 95% CI based on Kaplan-Meier estimates.  The estimated HR 
and its corresponding 95% CI will be computed using a Cox Proportional Hazards model 
stratified by the randomization strata. 
9.9.4 
Exploratory Endpoints 
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9.10 
Safety Analyses 
Safety data will be summarized for the safety population.  The baseline value for the safety 
analysis is defined as the value collected at the time closest to and before the start of study drug 
administration. 
9.10.1 Adverse Events 
Adverse events will be graded by the Investigator according the National Cancer Institute 
(NCI)-CTCAE v4.03 or higher for hematologic and nonhematologic AEs.  Each AE verbatim 
term will be coded to a system organ class and a preferred term using the Medical Dictionary for 
Regulatory Activities (MedDRA). 
9.10.2 Treatment-emergent Adverse Events 
All TEAEs will be summarized by treatment arm as treated.  In addition, AE incidence rates will 
also be summarized by severity and relationship to study drug.  In addition, TEAE with onset 
during the first 6 months (i.e., 24 weeks or 198 days) of study treatment will be similarly 
summarized since the treatment for Arm A is 12 IV doses over 24 weeks or until disease 
progression. 
Grade 3 or Grade 4 TEAEs; TEAEs leading to permanent study drug treatment discontinuation; 
TEAEs leading to dose reduction; serious TEAEs; and TEAEs resulting in death will be 
summarized by treatment arm as treated. 
For subjects who received cross-over acalabrutinib therapy, all TEAEs collected in the treatment 
emergent period of cross-over acalabrutinib therapy will be summarized. 
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9.10.3 AESIs 
AESIs are defined in Section 7.2.1.6.  These events of interest will be summarized similarly to 
TEAEs by treatment arms. 
9.10.4 Clinical Laboratory Tests 
9.10.4.1 
Data Summary Methods 
For gradable parameters, a summary of worst postbaseline toxicity grade will be provided in the 
treatment-emergent period and during the first 6 months (6 cycles) of treatment by treatment 
arm and worst toxicity grade (any Grade and Grade 3/4).  The difference in percentages will be 
displayed.  Only subjects whose grades got worsened are counted in the numerator of 
percentage calculation while the denominator is all subjects in each treatment arm. 
9.10.4.2 
Analysis of Lymphocytosis 
For all subjects with baseline and any post-baseline ALC measurements, ALC at peak summary 
will be provided by treatment arm. 
Lymphocytosis is defined as an ALC > 5000 cells per microliter and an increase above baseline.  
The number of subjects with at least one occurrence of lymphocytosis will be summarized.  For 
subjects with lymphocytosis, resolution of lymphocytosis is defined as 1) a decrease of ALC 
value to the baseline level or lower, or 2) an achievement of ALC value that is below 5,000/μL, 
whichever occurs first.  The following analyses will be conducted for subjects with lymphocytosis 
by treatment arm: ALC at peak and time to peak ALC for subjects who have lymphocytosis will 
be summarized with descriptive statistics. 
Duration of lymphocytosis is defined as the duration of time from the earliest date on which the 
ALC value met the lymphocytosis criteria at a post-baseline assessment to the earliest date on 
which a subsequent ALC value met the resolution criteria. 
9.10.4.3 
Analysis of Serum Immunoglobulins 
Serum immunoglobulins (IgA, IgG and IgM) are collected as scheduled in Appendix A, 
Appendix B, Appendix C, and Appendix D.  For each variable, descriptive statistics will be 
presented at each scheduled post-baseline assessment by treatment arm.  Subjects who 
received IV immunoglobulin on the study will be excluded from the summary for IgG. 

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9.10.5 ECOG Performance Status 
The ECOG performance status will be collected as scheduled in Appendices A-D.  The ECOG 
performance status grade ranges from 0 to 5.  Descriptive statistics and change from baseline 
will be provided for each visit over time. 
9.10.6 Vital Signs and Weight 
Body temperature, heart rate (beats/min), respiratory rate (breaths/min), systolic blood pressure 
(mmHg), diastolic blood pressure (mm Hg), and weight will be collected for this study.  Those 
parameters will be collected as scheduled in Appendices A-D.  For each parameter, descriptive 
statistics and change from baseline will be provided over time. 
10 
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. 
10.1 Regulatory and Ethical Compliance  
This clinical study was designed and will be implemented in accordance with the protocol, the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local 
regulations (including US Code of Federal Regulations Title 21 and European Directive 
2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki (October 
2008). 
10.2 Institutional Review Board (IRB) and Independent Ethics Committee (IEC) 
Approval 
The Investigator will submit this protocol, the informed consent, Investigator Brochure, and any 
other relevant supporting information (e.g., all advertising materials) to the appropriate IRB/IEC 
for review and approval before study initiation.  A signed protocol approval page; a letter 
confirming IRB/IEC approval of the protocol and informed consent; and a statement that the 
IRB/IEC is organized and operates according to GCP and the applicable laws and regulations; 
must be forwarded to Acerta Pharma before screening subjects for the study.  Additionally, 

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sites must forward a signed FDA 1572 form (Investigator Obligation Form) or local equivalent 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. 
10.3 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), 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.  Each subject must provide a signed 
and dated informed consent before randomization into this study.  In the case of a subject who 
is incapable of providing informed consent, the Investigator (or designee) must obtain a signed 
and dated ICF from the subject’s legal guardian.  Signed consent forms must remain in each 
subject’s study file and be available for verification by study monitors at any time. 
In accordance to individual local and national patient privacy regulations, the Investigator or 
designee must explain to each subject that for the evaluation of study results, the subject’s 
protected health information obtained during the study may be shared with Acerta Pharma and 
its designees, regulatory agencies, and IRBs/IECs.  As the study Sponsor, Acerta Pharma will 
not use the subject’s protected health information or disclose it to a third party without applicable 
subject authorization.  It is the Investigator’s or designee’s responsibility to obtain written 
permission to use protected health information from each subject, or if appropriate, the subject’s 
legal guardian.  If a subject or subject’s legal guardian withdraws permission to use protected 
health information, it is the Investigator’s responsibility to obtain the withdrawal request in writing 
from the subject or subject’s legal guardian and to ensure that no further data will be collected 
from the subject.  Any data collected on the subject before withdrawal will be used in the 
analysis of study results. 
10.4 Quality Control and Quality Assurance 
Sponsor shall implement and maintain quality control and quality assurance procedures to 
ensure that the study is conducted and data are generated, documented and reported in 
compliance with the protocol, GCP, and applicable regulatory requirements.  This study shall be 
conducted in accordance with the provisions of the Declaration of Helsinki (October 2008) and 

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all revisions thereof, and in accordance with FDA regulations (21 CFR Parts 11, 50, 54, 56, and 
312, Subpart D – Responsibilities of Sponsors and Investigators) and with the ICH guidelines on 
GCP (ICH E6). 
10.5 Study Files and Record Retention 
The Investigator and other appropriate study staff are responsible for maintaining all 
documentation relevant to the study.  Mandatory documentation includes copies of study 
protocols and amendments, each FDA Form 1572, IRB/IEC approval letters, signed ICFs, drug 
accountability records, SAE forms transmitted to Acerta Pharma, subject files (source 
documentation) that substantiate entries in CRFs, all relevant correspondence, and other 
documents pertaining to the conduct of the study. 
An Investigator shall retain records for a period of at least 2 years after the date the last 
marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and regulatory authorities have 
been notified.  Local regulations may require a longer period for record retention; said local 
regulations will supersede this protocol.  The Investigator must notify Acerta Pharma and obtain 
written approval from Acerta Pharma before destroying any clinical study records at any time. 
Acerta Pharma will inform the Investigator of the date that study records may be destroyed or 
return to Acerta Pharma. 
Acerta Pharma must be notified in advance of, and Acerta Pharma must provide express written 
approval of, any change in the maintenance of the foregoing documents if the Investigator 
wishes to move study records to another location or assign responsibility for record retention to 
another party.  If the Investigator cannot guarantee the archiving requirements set forth herein 
at his or her study site for all such documents, special arrangements must be made between the 
Investigator and Acerta Pharma to store such documents in sealed containers away from the 
study site so that they can be returned sealed to the Investigator for audit purposes. 
10.6 Case Report Forms and Record Maintenance 
Authorized study site personnel (see Section 10.9) will complete CRFs designed for this study 
according to the completion guidelines that will be provided as part of the clinical database.  The 
investigator will ensure that the CRFs are accurate, complete, legible, and completed promptly.  
Refer to Section 10.5 for record retention requirements. 

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10.7 Investigational Study Drug Accountability 
All study drugs must be kept in a locked limited access cabinet or space.  The study drug must 
not be used outside the context of the protocol. 
Study drug accountability records must be maintained and readily available for inspection by 
representatives of Acerta Pharma and are open to inspections by regulatory authorities at any 
time. 
All study supplies and associated documentation will be regularly reviewed and verified by the 
monitor. 
10.8 Study Monitoring/Audit Requirements 
Representatives of Acerta Pharma or its designee will monitor this study until completion.  
Monitoring will be conducted through personal visits with the Investigator and site staff as well 
as any appropriate communications by mail, fax, email, or telephone.  The purpose of 
monitoring is to ensure compliance with the protocol and the quality and integrity of the data.  
This study is also subject to reviews or audits. 
Every effort will be made to maintain the anonymity and confidentiality of all subjects during this 
clinical study.  However, because of the experimental nature of this treatment, the Investigator 
agrees to allow the IRB/IEC, representatives of Acerta Pharma, its designated agents, and 
authorized employees of the appropriate regulatory agencies to inspect the facilities used in this 
study and, for purposes of verification, allow direct access to the hospital or clinic records of all 
subjects randomized 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. 
10.9 Investigator Responsibilities 
A complete list of Investigator responsibilities is outlined in the clinical trial research agreement 
and the Statement of Investigator FDA Form 1572, both of which are signed by the Investigator 
before commencement of the study.  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. 

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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 Investigational New Drug (IND) Safety Reports/SUSAR Reports are submitted 
promptly to the IRB/IEC. 
12. 
All SAEs are reported to Acerta Pharma Drug Safety/Designee within 24 hours of 
knowledge and to the IRB/IEC per their requirements. 
10.10 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. 
10.11 Protocol Amendments 
Acerta Pharma will initiate any change to the protocol in a protocol amendment document. The 
amendment will be submitted to the IRB/IEC together with, if applicable, a revised model ICF.  If 
the change in any way increases the risk to the subject or changes the scope of the study, then 
written documentation of IRB/IEC approval must be received by Acerta Pharma before the 
amendment may take effect.  Additionally, under this circumstance, information on the 
increased risk and/or change in scope must be provided to subjects already actively 
participating in the study, and they must read, understand, and sign any revised ICF confirming 
willingness to remain in the trial. 
10.12 Publication of Study Results 
Authorship, in general, will follow the recommendations of the International Committee of 
Medical Journal Editors (International Committee of Medical Journal Editors 2014). 

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11 
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Brown JR, Hillmen P, O’Brien S, et al. Updated efficacy including genetic and clinical subgroup 
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previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma. Blood 2014 Nov 
15; 24 (21): Abstract 3331. 
Burger JA, Keating MJ, Wierda WG, et al. The Btk Inhibitor Ibrutinib (PCI-32765) in Combination 
with Rituximab Is Well Tolerated and Displays Profound Activity in High-Risk Chronic 
Lymphocytic Leukemia (CLL) Patients. ASH Annual Meeting Abstracts. 2012;120:187. 
Byrd JC, Harrington B, O’Brien S, et al.  Acalabrutinib (ACP-196) in relapsed chronic 
lymphocytic leukemia. NEJM 2016;374:323-332. 
Byrd JC, Brown JR, O’Brien S, et al.  Ibrutinib versus ofatumumab in previously treated chronic 
lymphoid leukemia.  NEJM 2014 Jul 17;371(3):213-23. 
Byrd JC, Rai K, Peterson BL, et al. Addition of rituximab to fludarabine may prolong 
progression-free survival and overall survival in patients with previously untreated chronic 
lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and 
CALGB 9011. Blood 2005 Jan 1;105(1):49-53. 
Byrd JC, Stilgenbauer S, Flinn IW. Chronic lymphocytic leukemia. Am Soc Hematol Educ 
Program. 2004:163-183. 
Byrd JC, Peterson BL, Morrison VA, et al. Randomized phase 2 study of fludarabine with 
concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with 
B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 
9712). Blood 2003 Jan 1;101(1):6-14. 
Byrd JC, Murphy T, Howard RS, et al. Rituximab using a thrice weekly dosing schedule in B-cell 
chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity 
and acceptable toxicity. J Clin Oncol 2001 Apr 15;9(8):2153-2164. 
Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for 
patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. 
Lancet 2007 Jul 21;370(9583):230-239. 
Cella D, Lai JS, Chang CH, Peterman A, Slavin M.  Fatigue in cancer patients compared with 
fatigue in the general United States population. Cancer 2002;94:528-538. 
Chen J, Tan K, Zhou H, et al. Modifying murine von Willebrand factor A1 domain for in vivo 
assessment of human platelet therapies. Nat Biotechnol 2008 Jan;26(1):114-119. 
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end 
points in chronic lymphocytic leukemia. J Clin Oncol 2012;30:2820-2822. 
Covey T, Barf T, Gulrajani M, et al.  ACP-196: a novel covalent Bruton’s tyrosine kinase (Btk) 
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#2596. 
de Jésus Ngoma P, Kabamba B, Dahlgvist G, et al. Occult HBV reactivation induced by ibrutinib 
treatment: a case report. Acea Gastroenterol Belg. 2015;78:424-426. 

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Da Roit F, Engelberts PJ, Taylor RP, et al.  Ibrutinib interferes with the cell-mediated 
anti-tumour activities of therapeutic CD20 antibodies: implications for combination therapy.  
Haematologica 2015 Jan;100(1):77-86. 
Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with 
chlorambucil does not result in a major benefit for elderly patients with advanced chronic 
lymphocytic leukemia. Blood 2009 Oct 15;114(16):3382-3391. 
Eichhorst BF, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide versus 
fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. 
Blood 2006 Feb 1;107(3):885-891. 
EuroQol Group.  EuroQol—a new facility for the measurement of health-related quality of life.  
Health Policy 1990;16:199-208. 
Extermann M, Overcash J, Lyman GH, et al. Comorbidity and functional status are independent 
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FDA guidance for industry.  ICH E2A Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting.  1995 Mar.  Available at: 
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ucm065004.htm. 
Food and Drug Administration. FDA Drug Safety Communication 2013: Boxed warning and new 
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anti-cancer drugs Arzerra (ofatumumab) and Rituxan (rituximab) (25 September 2013). 
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FDA Guidance 2012.  Food and Drug Administration. Guidance for Industry and 
Investigators:  Safety Reporting Requirements for INDs and BA/BE Studies (December 2012). 
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28 January 2016. 
Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of fludarabine plus cyclophosphamide 
compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: 
US Intergroup Trial E2997. J Clin Oncol 2007 Mar 1;5(7):793-798. 
GAZYVA® [package insert].  South San Francisco, CA: Genentech, Inc; 2016 
GAZYVARO [Annex 1: Summary of Product Characteristics], 2014 
Goede V, Fischer K, et al. Obinutuzumab plus Chlorambucil in Patients with CLL and Coexisting 
Conditions. NEJM 2014;370:1101-1110.  
Hallek M, Cheson BD, Catovsky D, et al.  Guidelines for the diagnosis and treatment of chronic 
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Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and 
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IMBRUVICA® [package insert].  Horsham, PA: Janssen Biotech, Inc; 2015. 
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of the BTK inhibitor ibrutinib in combination with ofatumumab in patients with chronic 
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12 
APPENDICES 
 
 

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Appendix A:  Schedule of Assessments – Treatment Arm A 
Appendix A: Schedule of Assessments – Treatment Arm A 
 
Screening 
Treatment Phase 
Post-treatment Phasem 
Treatment and 
Post-Treatment 
Phase 
Response 
Evaluation 
ET/SFU 
visita 
Post-disease 
Progression 
Phase 
Days 
 
Cycle 1 
(28-day cycle) 
Cycle 2 
(28-day cycle) 
Cycles 3-6 
(28-day cycles) 
Cycle 7 
(28-day cycle) q12 wks starting at 
Cycle 10 (e.g., 
Cycles 10, 13, 16) 
Assessed 
q12/q24 wksb 
 
q12 wks 
1 
2 
8 
15 
22 
1 
8 
15 
1 
15 
1 
Study Windows 
-28 days 
 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 14 days 
± 7 days 
± 7 days 
Study Drug Administration 
 
 
 
 
 
 
 
 
 
ARM A 
Obinutuzumab 
100-1000 mg IV  
 
x 
x 
x 
x 
 
x 
 
 
x 
 
 
 
 
 
 
Chlorambucil 
0.5 mg/kg PO 
 
x 
 
 
x 
 
x 
 
x 
x 
x 
 
 
 
 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility & 
randomize 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam  
x 
x 
 
 
 
 
x 
 
 
x 
 
x 
x 
x 
x 
 
ECOG PS 
x 
x 
 
 
 
 
x 
 
 
x 
 
x 
x 
 
x 
 
Weight 
x 
x 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
 
x 
 
Cumulative Illness Rating 
Scale 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease-related Symptoms 
x 
 
 
 
 
 
x 
 
 
x 
 
x 
x 
x 
 
 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x  
x 
x 
 
x 
 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
x 
x 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
 
x 
 
Adverse eventsk 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SAE only 
Pregnancy testd 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Hepatitis serologye 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix A: Schedule of Assessments – Treatment Arm A 
 
Screening 
Treatment Phase 
Post-treatment Phasem 
Treatment and 
Post-Treatment 
Phase 
Response 
Evaluation 
ET/SFU 
visita 
Post-disease 
Progression 
Phase 
Days 
 
Cycle 1 
(28-day cycle) 
Cycle 2 
(28-day cycle) 
Cycles 3-6 
(28-day cycles) 
Cycle 7 
(28-day cycle) 
q12 wks starting at 
Cycle 10 (e.g., 
Cycles 10, 13, 16) 
Assessed 
q12/q24 wksb 
 
q12 wks 
1 
2 
8 
15 
22 
1 
8 
15 
1 
15 
1 
Study Windows 
-28 days 
 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 14 days 
± 7 days 
± 7 days 
HBV PCRi 
x 
 
 
 
 
 
x 
 
 
QM 
 
x 
QM 
 
 
QM 
Hematology 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
ANC, ALC, PLT, 
Hgb (within 7 days 
of CT) 
x 
 
Serum chemistry 
x 
x 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
x 
 
Serum immunoglobulins, 
β2-microglobulin, T/B/NK 
counts 
x 
 
 
 
 
 
 
 
 
 
 
x 
Every 24 weeks from 
Cycle 7 (e.g., Cycles 
13, 19)c 
x 
 
 
Cytogenetics and genetic 
molecular prognostic 
markers 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scansh 
xj 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Overall response 
assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Bone marrow biopsy and 
aspirate 
x 
 
 
 
 
 
 
 
 
 
 
 
 
To confirm CRl 
 
 
Survival status and new 
anticancer therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Abbreviations: ALC = absolute lymphocyte count; ANC = absolute neutrophil count; anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis B surface antibody; 
CR = complete remission (response); CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; 
ET = early termination; 
  HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; 
Hgb = hemoglobin level; IV = intravenous;IVIG = intravenous immunoglobulins; 
 PCR = polymerase chain reaction; PLT = platelet 
count; 
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PO = oral;
 QM = every month; SFU = safety follow up; wks = weeks. 
a. 
An early termination visit will be done for subjects who permanently discontinue study drug early for any reason (except for death, lost to follow-up, or 
withdrawal of consent).  A safety follow-up visit is conducted 30 (+ 7) days after the last dose of study drug, regardless of whether the subject receives a new 
anticancer therapy or demonstrates disease progression within this timeframe.  If the safety follow-up visit is within ± 7 days of a regularly scheduled visit 
during the Post-treatment Phase, the visits may be combined into a single visit. 
b. 
Response evaluations will be done every 12 weeks (± 14 days) with the first on-treatment radiologic assessment occurring on Cycle 4 Day 1, the second 
on-treatment scan on Cycle 7 Day 1, and so on through Cycle 25, and then every 24 weeks (± 14 days) thereafter.  Hematology results must be done within 7 
days of CT scans.  For additional details on the confirmatory bone marrow biopsy for subjects in Arm A, see Minimal Residual Disease/Response Evaluation 
in Section 7.1. 
c. 
After Cycle 7 Day 1, 
 (through Amendment 5.0), Serum immunoglobulins, β2-microglobulin, T/B/NK counts, and 
 
 should be collected every 24 weeks starting at Cycle 13. 
d. 
Serum pregnancy tests are required for women with childbearing potential only. 
e. 
Hepatitis serology must include hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), and 
hepatitis C (HCV) antibody.  In addition, any subjects testing positive for anti-HBc must have polymerase chain reaction (PCR) testing during screening and on 
study (see exclusion criterion #14). 
f. 
If these samples are damaged during collection or shipment, they should be redrawn at any subsequent visit. 
g. 
 
 
 
h. 
CT scan can be performed up to 7 days before response evaluation. 
i. 
Subjects who are anti-HBc positive should have a quantitative PCR test for HBV DNA performed during screening and every month thereafter.  Monthly 
monitoring should continue until 12 months after last dose of study drug(s).  Any subject with a rising viral load (above lower limit of detection) should 
discontinue study drug and have antiviral therapy instituted and a consultation with a physician with expertise in managing hepatitis B.  As intravenous 
immunoglobulins (IVIG) may cause false positive hepatitis serology, monthly PCR testing is not required in subjects who are currently receiving or received 
prophylactic IVIG within 3 months before study enrollment and have a documented negative anti-HBc test before the initiation of IVIG therapy.  PCR testing 
should be performed when clinically indicated (e.g., in the setting of rising transaminase levels). 
j. 
Subjects who have standard of care CT/MRI results may use these results in lieu of the Screening CT/MRI required for this study, provided the CT/MRI was 
done within 28 days of first dose and was acquired in accordance with the guidelines outlined in Section 7.1 CT Scans. 
k. 
After the end of the protocol-defined adverse event reporting period (Section 7.2.2), only serious adverse events considered related to study drug(s) or study 
procedures are required to be collected. 
l. 
If the subject’s physical examination findings, laboratory evaluations, and radiographic evaluations suggest that CR has been achieved, a confirmatory bone 
marrow aspirate/biopsy and peripheral blood sample must be obtained to confirm the CR and 
 
  For subjects with bone marrow-confirmed CR, peripheral blood testing to follow 
 until disease 
progression or death, consent withdrawal, or lost to follow-up. 
m. Subjects who stop both drugs early because of an adverse event will then enter an early Post-treatment Phase. 
n. 
 
 
 
o. 
Through Amendment 5.0 
 endpoints were collected and analyzed; with the adaptation of Amendment 6.0, the 
 endpoints will not be collected. 
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Appendix B:  Schedule of Assessments – Treatment Arm B 
Appendix B: Schedule of Assessments – Treatment Arm B 
 
Screening 
Treatment Phasea 
Treatment and Post-treatment 
Phasep 
ET/SFU 
visitb 
Post-disease 
Progression 
Phase 
Days 
 
Cycle 1 
(28-day cycle) 
Cycle 2 
(28-day cycle) 
Cycles 3-7 
(28-day 
cycles) 
q12 wks starting at 
Cycle 10 (e.g., Cycles 
10, 13, 16) 
Response 
Evaluation 
Assessed 
q12/q24 wksc 
 
q12 wks 
1 
8 
15 
22 
1 
2 
8 
15 
1 
Study Windows 
-28 days 
± 3 days 
± 3 days 
 
± 3 days 
± 3 days 
± 3 days 
± 14 days 
± 7 days 
± 7 days 
Study Drug Administration 
 
 
 
 
 
 
 
 
ARM B 
Acalabrutinib 
100 mg BID (± 1 hour) 
PO  
 
Continuous Twice Daily Dosingd 
 
 
 
Obinutuzumab 
100-1000 mg IV  
 
 
 
 
 
x 
x 
x 
x 
x 
 
 
 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility & randomize 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
x 
x 
 
 
 
x 
 
 
 
x 
x 
x 
x 
 
ECOG PS 
x 
x 
 
 
 
x 
 
 
 
x 
x 
 
x 
 
Weight 
x 
x 
 
 
 
x 
 
 
 
x 
x 
 
x 
 
Cumulative Illness Rating Scale 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease-related Symptoms 
x 
 
 
 
 
x 
 
 
 
x 
x 
x 
 
 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
x 
x 
 
x 
 
x 
 
 
x 
x 
x 
 
x 
 
Adverse eventsn 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SAE only 
Pregnancy testf 
x 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
Hepatitis serologyg 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix B: Schedule of Assessments – Treatment Arm B 
 
Screening 
Treatment Phasea 
Treatment and Post-treatment 
Phasep 
ET/SFU 
visitb 
Post-disease 
Progression 
Phase 
Days 
 
Cycle 1 
(28-day cycle) 
Cycle 2 
(28-day cycle) 
Cycles 3-7 
(28-day 
cycles) 
q12 wks starting at 
Cycle 10 (e.g., Cycles 
10, 13, 16) 
Response 
Evaluation 
Assessed 
q12/q24 wksc 
 
q12 wks 
1 
8 
15 
22 
1 
2 
8 
15 
1 
Study Windows 
-28 days 
± 3 days 
± 3 days 
 
± 3 days 
± 3 days 
± 3 days 
± 14 days 
± 7 days 
± 7 days 
HBV PCRl 
x 
 
 
 
 
x 
 
 
 
QM 
QM 
 
 
QM 
Hematology 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
ANC, ALC, 
PLT, Hgb 
(within 7 days 
of CT) 
x 
 
Serum chemistry 
x 
x 
 
x 
 
x 
x 
 
x 
x 
x 
 
x 
 
Serum immunoglobulins, 
β2-microglobulin, T/B/NK 
counts 
x 
 
 
 
 
 
 
 
 
Cycle 7 only 
Every 24 weeks (e.g., 
Cycles 13, 19)e 
x 
 
 
 
 
 
 
 
 
 
 
 
Cytogenetics and genetic 
molecular prognostic markers 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scansk 
xm 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Overall response assessment 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Bone marrow biopsy and aspirate 
x 
 
 
 
 
 
 
 
 
 
 
To confirm CRo 
 
 
Survival status and new 
anticancer therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Abbreviations: ALC = absolute lymphocyte count; ANC = absolute neutrophil count; anti-HBc = hepatitis B core antibody; BID = twice daily; CR = complete remission 
(response); CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; ET = early termination; 
 anti-HBs = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C 
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virus; Hgb = hemoglobin level; IV = intravenous; IVIG = intravenous immunoglobulins; 
 PCR = polymerase chain reaction; 
 PLT = platelet count; PO = oral; 
 QM = every month; SFU = safety follow up; wks = weeks. 
a. 
There is no restriction on maximum treatment allowed with acalabrutinib. 
b. 
An early termination visit will be done for subjects who permanently discontinue study drug early for any reason (except for death, lost to follow-up, or 
withdrawal of consent).  A safety follow-up visit is conducted 30 (+ 7) days after the last acalabrutinib dose, regardless of whether the subject receives a new 
anticancer therapy or demonstrates disease progression within this timeframe.  If the safety follow-up visit is within ± 7 days of a regularly scheduled visit 
during the Post-treatment Phase, the visits may be combined into a single visit. 
c. 
Response evaluations will be done every 12 weeks (± 14 days) with the first on-treatment radiologic assessment occurring on Cycle 4 Day 1, the second 
on-treatment scan on Cycle 7 Day 1, and so on through Cycle 25, and then every 24 weeks (± 14 days) thereafter.  Hematology results must be done within 7 
days of CT scans.  For additional details on the confirmatory bone marrow biopsy for subjects in Arm B, see 
Response Evaluation 
in Section 7.1. 
d. 
Subjects in Arm B will receive 28 days of acalabrutinib monotherapy before beginning obinutuzumab. 
e. 
After Cycle 7 Day 1, 
 (through Amendment 5.0), Serum immunoglobulins, β2-microglobulin, T/B/NK counts, and 
 
 should be collected every 24 weeks starting at Cycle 13. 
f. 
Serum pregnancy tests are required for women with childbearing potential only. 
g. 
Hepatitis serology must include hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), and 
hepatitis C (HCV) antibody.  In addition, any subjects testing positive for anti-HBc must have polymerase chain reaction (PCR) testing during screening and on 
study (see exclusion criterion #14). 
h. 
If these samples are damaged during collection or shipment, they should be redrawn at any subsequent visit. 
i. 
 
 
 
j. 
 
 
 
 
k. 
CT scan can be performed up to 7 days before response evaluation. 
l. 
Subjects who are anti-HBc positive should have a quantitative PCR test for HBV DNA performed during screening and every month thereafter.  Monthly 
monitoring should continue until 12 months after last dose of study drug(s).  Any subject with a rising viral load (above lower limit of detection) should 
discontinue study drug and have antiviral therapy instituted and a consultation with a physician with expertise in managing hepatitis B.  As intravenous 
immunoglobulins (IVIG) may cause false positive hepatitis serology, monthly PCR testing is not required in subjects who are currently receiving or received 
prophylactic IVIG within 3 months before study enrollment and have a documented negative anti-HBc test before the initiation of IVIG therapy.  PCR testing 
should be performed when clinically indicated (e.g., in the setting of rising transaminase levels). 
m. Subjects who have standard of care CT/MRI results may use these results in lieu of the Screening CT/MRI required for this study, provided the CT/MRI was 
done within 28 days of first dose and was acquired in accordance with the guidelines outlined in Section 7.1 CT Scans. 
n. 
After the end of the protocol-defined adverse event reporting period (Section 7.2.2), only serious adverse events considered related to study drug(s) or study 
procedures are required to be collected. 
o. 
 
 
 
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p. 
For subjects who discontinue both study drugs. 
q. 
 
 
 
r. 
Through Amendment 5.0 
 endpoints were collected and analyzed; with the adaptation of Amendment 6.0, the PRO endpoints will not be collected. 
 
 
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Appendix C:  Schedule of Assessments – Treatment Arm C 
Appendix C: Schedule of Assessments – Treatment Arm C 
Screening 
Treatment Phasea 
Treatment and Post-treatment Phaseo 
ET/SFU 
visitb 
Post-disease 
Progression 
Phase 
Days 
 
Cycle 1 
(28-day cycle) 
Cycle 2 
(28-day cycle) 
Cycles 3-7 
(28-day cycles) 
q12 wks starting at 
Cycle 10 (e.g., Cycles 
10, 13, 16) 
Response Evaluation 
Assessed 
q12/24 wksc 
 
q12 wks 
1 
8 
15 
22 
1 
8 
15 
1 
Study Windows 
-28 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 14 days 
± 7 days 
± 7 days 
Study Drug Administration 
 
 
 
 
 
 
 
 
ARM C 
Acalabrutinib 
100 mg BID (± 1 hour) 
PO  
 
Continuous Twice Daily Dosing 
 
 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility & randomize 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam   
x 
x 
 
 
 
x 
 
 
x 
x 
x 
x 
 
ECOG PS 
x 
x 
 
 
 
x 
 
 
x 
x 
 
x 
 
Weight 
x 
x 
 
 
 
x 
 
 
x 
x 
 
x 
 
Cumulative Illness Rating Scale 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Disease-related Symptoms 
x 
 
 
 
 
x 
 
 
x 
x 
x 
 
 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
x 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
 
Adverse eventsm 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SAE only 
Pregnancy teste 
x 
x 
 
 
 
 
 
 
 
 
 
x 
 
Hepatitis serologyj 
x 
 
 
 
 
 
 
 
 
 
 
 
 
HBV PCRk 
x 
 
 
 
 
x 
 
 
QM 
QM 
 
 
QM 
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Appendix C: Schedule of Assessments – Treatment Arm C 
Screening 
Treatment Phasea 
Treatment and Post-treatment Phaseo 
ET/SFU 
visitb 
Post-disease 
Progression 
Phase 
Days 
 
Cycle 1 
(28-day cycle) 
Cycle 2 
(28-day cycle) 
Cycles 3-7 
(28-day cycles) 
q12 wks starting at 
Cycle 10 (e.g., Cycles 
10, 13, 16) 
Response Evaluation 
Assessed 
q12/24 wksc 
 
q12 wks 
1 
8 
15 
22 
1 
8 
15 
1 
Study Windows 
-28 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 14 days 
± 7 days 
± 7 days 
Hematology 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ANC, ALC, PLT, Hgb 
(within 7 days of CT) 
x 
 
Serum chemistry 
x 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
 
Serum immunoglobulins, 
β2-microglobulin, T/B/NK 
counts 
x 
 
 
 
 
 
 
 
Cycle 7 only 
Every 24 weeks (e.g., 
Cycles 13, 19)d 
x 
 
 
 
 
 
 
 
 
 
 
Cytogenetics and genetic 
molecular prognostic markers 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scansi 
xl 
 
 
 
 
 
 
 
 
 
x 
 
 
Overall response assessment 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Bone marrow biopsy and 
aspirate 
x 
 
 
 
 
 
 
 
 
 
To confirm CRn 
 
 
Survival status and new 
anticancer therapy 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Abbreviations: ALC = absolute lymphocyte count; ANC = absolute neutrophil count; anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis B surface antibody; 
BID = twice daily; CR = complete remission (response); CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group 
performance status; ET = early termination; 
  HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C 
virus; Hgb = hemoglobin level; IVIG = intravenous immunoglobulins; 
 PCR = polymerase chain reaction; 
 
PLT = platelet count; PO = oral; 
 QM = every month; SFU = safety follow up; wks = weeks. 
a. 
There is no restriction on maximum treatment allowed with acalabrutinib. 
b. 
An early termination visit will be done for subjects who permanently discontinue study drug early for any reason (except for death, lost to follow-up, or withdrawal 
of consent).  A safety follow-up visit is conducted 30 (+ 7) days after the last acalabrutinib dose, regardless of whether the subject receives a new anticancer 
therapy or demonstrates disease progression within this timeframe.  If the safety follow-up visit is within ± 7 days of a regularly scheduled visit during the 
Post-treatment Phase, the visits may be combined into a single visit. 
c. 
Response evaluations will be done every 12 weeks (± 14 days) with the first on-treatment radiologic assessment occurring on Cycle 4 Day 1, the second 
on-treatment scan on Cycle 7 Day 1, and so on through Cycle 25, and then every 24 weeks (± 14 days) thereafter.  Hematology results must be done within 7 days of 
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CT scans.  For additional details on the confirmatory bone marrow biopsy for subjects in Arm C, see 
Response Evaluation in Section 7.1. 
d. 
After Cycle 7 Day 1, 
 (through Amendment 5.0), Serum immunoglobulins, β2-microglobulin, T/B/NK counts, and 
 
should be collected every 24 weeks starting at Cycle 13. 
e. 
Serum pregnancy tests are required for women with childbearing potential only. 
f. 
If these samples are damaged during collection or shipment, they should be redrawn at any subsequent visit. 
g. 
 
 
 
h. 
 
 
 
 
i. 
CT scan can be performed up to 7 days before response evaluation. 
j. 
Hepatitis serology must include hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), and hepatitis C 
(HCV) antibody.  In addition, any subjects testing positive for anti-HBc must have polymerase chain reaction (PCR) testing during screening and on study (see 
exclusion criterion #14). 
k. 
Subjects who are anti-HBc positive should have a quantitative PCR test for HBV DNA performed during screening and every month thereafter.  Monthly 
monitoring should continue until 12 months after last dose of study drug(s).  Any subject with a rising viral load (above lower limit of detection) should discontinue 
study drug and have antiviral therapy instituted and a consultation with a physician with expertise in managing hepatitis B.  As intravenous immunoglobulins (IVIG) 
may cause false positive hepatitis serology, monthly PCR testing is not required in subjects who are currently receiving or received prophylactic IVIG within 
3 months before study enrollment and have a documented negative anti-HBc test before the initiation of IVIG therapy.  PCR testing should be performed when 
clinically indicated (e.g., in the setting of rising transaminase levels). 
l. 
Subjects who have standard of care CT/MRI results may use these results in lieu of the Screening CT/MRI required for this study, provided the CT/MRI was done 
within 28 days of first dose and was acquired in accordance with the guidelines outlined in Section 7.1 CT Scans. 
m. After the end of the protocol-defined adverse event reporting period (Section 7.2.2), only serious adverse events considered related to study drug(s) or study 
procedures are required to be collected. 
n. 
If the subject’s physical examination findings, laboratory evaluations, and radiographic evaluations suggest that CR has been achieved, a confirmatory bone 
marrow aspirate/biopsy and peripheral blood sample must be obtained to confirm the CR and to evaluate minimal residual disease by flow cytometric and 
DNA based methods.  For subjects with bone marrow-confirmed CR, peripheral blood testing to follow 
 until disease 
progression or death, consent withdrawal, or lost to follow-up. 
o. For subjects who discontinue study drug. 
p. 
 
 
 
q. 
 
 
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Appendix D:  Schedule of Assessments – Crossover 
Appendix D: Schedule of Assessments – Crossover 
Screening 
Treatment Phasea 
Treatment and Post-treatment Phasei 
ET/SFU 
visitb 
Post-disease 
Progression 
Phase 
Days 
 
Cycle 1 
(28-day cycle) 
Cycle 2 
(28-day cycle) 
Cycles 3-7 
(28-day cycles) 
q12 wks starting 
at Cycle 10 (e.g., 
Cycles 10, 13, 16) 
Response 
Evaluation 
Assessed 
q12/q24 wksc 
 
q12 wks 
1 
8 
15 
22 
1 
8 
15 
1 
Study Windows 
-42 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 14 days 
± 7 days 
± 7 days 
Study Drug Administration 
 
 
 
 
 
 
 
 
CROSSOVER 
Acalabrutinib 
100 mg BID PO 
 
Continuous Twice Daily Dosing 
 
 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam  
x 
x 
 
 
 
x 
 
 
x 
x 
x 
x 
 
ECOG PS 
x 
x 
 
 
 
x 
 
 
x 
x 
 
x 
 
Weight 
x 
x 
 
 
 
x 
 
 
x 
x 
 
x 
 
Disease-related Symptoms 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
x 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
 
Adverse eventsg 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SAE only 
Pregnancy testd 
x 
x 
 
 
 
 
 
 
 
 
 
x 
 
HBV PCRe 
x 
 
 
 
 
x 
 
 
QM 
QM 
 
QM 
 
Hematology 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ANC, ALC, PLT, Hgb 
(within 7 days of CT) 
x 
 
Serum chemistry 
x 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
 
Serum immunoglobulins, 
β2-microglobulin, T/B/NK 
counts 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Cytogenetics and genetic 
molecular prognostic markers 
x 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix D: Schedule of Assessments – Crossover 
Screening 
Treatment Phasea 
Treatment and Post-treatment Phasei 
ET/SFU 
visitb 
Post-disease 
Progression 
Phase 
Days 
 
Cycle 1 
(28-day cycle) 
Cycle 2 
(28-day cycle) 
Cycles 3-7 
(28-day cycles) 
q12 wks starting 
at Cycle 10 (e.g., 
Cycles 10, 13, 16) 
Response 
Evaluation 
Assessed 
q12/q24 wksc 
 
q12 wks 
1 
8 
15 
22 
1 
8 
15 
1 
Study Windows 
-42 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 14 days 
± 7 days 
± 7 days 
CT scansf 
xf 
 
 
 
 
 
 
 
 
 
xf 
 
 
Overall response assessment 
 
 
 
 
 
 
 
 
 
 
x 
   
 
Bone marrow biopsy and 
aspirate 
 
 
 
 
 
 
 
 
 
 
To confirm CRh 
 
 
Survival status and new 
anticancer therapy 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Abbreviations: ALC = absolute lymphocyte count; ANC = absolute neutrophil count; anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis B surface antibody; 
BID = twice daily; CR = complete remission (response); CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group 
performance status; ET = early termination; 
  HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis 
C virus; Hgb = hemoglobin level; IVIG = intravenous immunoglobulins; 
 PCR = polymerase chain reaction; 
 
PLT = platelet count; PO = oral; 
 QM = every month; SFU = safety follow up; wks = weeks. 
a. 
There is no restriction on maximum treatment allowed with acalabrutinib. 
b. 
An early termination visit will be done for subjects who permanently discontinue study drug early for any reason (except for death, lost to follow-up, or withdrawal 
of consent).  A safety follow-up visit is conducted 30 (+ 7) days after the last acalabrutinib dose, regardless of whether the subject receives a new anticancer 
therapy or demonstrates disease progression within this timeframe.  If the safety follow-up visit is within ± 7 days of a regularly scheduled visit during the 
Post-treatment Phase, the visits may be combined into a single visit. 
c. 
Response evaluations will be done every 12 weeks (± 14 days) with the first on-treatment radiologic assessment occurring on Cycle 4 Day 1, the second 
on-treatment scan on Cycle 7 Day 1, and so on through Cycle 25, and then every 24 weeks (± 14 days) thereafter.  Hematology results must be done within 
7 days of CT scans.  For additional details on the confirmatory bone marrow biopsy for subjects in Arm D, see 
Response Evaluation in 
Section 7.1. 
d. 
Serum pregnancy tests are required for women with childbearing potential only. 
e. 
Subjects who are anti-HBc positive should have a quantitative PCR test for HBV DNA performed during screening and every month thereafter.  Monthly 
monitoring should continue until 12 months after last dose of study drug(s).  Any subject with a rising viral load (above lower limit of detection) should discontinue 
study drug and have antiviral therapy instituted and a consultation with a physician with expertise in managing hepatitis B.  As intravenous immunoglobulins (IVIG) 
may cause false positive hepatitis serology, monthly PCR testing is not required in subjects who are currently receiving or received prophylactic IVIG within 
3 months before study enrollment and have a documented negative anti-HBc test before the initiation of IVIG therapy.  PCR testing should be performed when 
clinically indicated (e.g., in the setting of rising transaminase levels). 
f. 
CT scans that showed disease progression from Arm A can be used for the crossover screening CT scan, if within 60 days of crossover dosing Cycle 1 Day 1.  
CT scan can be performed up to 7 days before response evaluation. 
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g. 
After the end of the protocol-defined adverse event reporting period (Section 7.2.2), only serious adverse events considered related to study drug(s) or study 
procedures are required to be collected. 
h. If the subject’s physical examination findings, laboratory evaluations, and radiographic evaluations suggest that CR has been achieved, a confirmatory bone 
marrow aspirate/biopsy and peripheral blood sample must be obtained to confirm the CR and to evaluate minimal residual disease by flow cytometric and 
DNA-based assay.  For subjects with bone marrow-confirmed CR, peripheral blood testing to follow 
 until disease 
progression or death, consent withdrawal, or lost to follow-up. 
i. 
The Post-treatment Phase begins when the subject stops acalabrutinib. 
j. 
 
 
 
 
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Appendix E:  Performance Status Scores 
Status 
Eastern Cooperative Oncology Group (ECOG) Performance Status* 
0 
Fully active, able to carry on all predisease 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 housework, 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. 
* Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. J Clin 
Oncol. 1982;5:649-655. 
Available at: http://www.ecog.org/general/perf_stat.html.  Accessed March 2015. 
 

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Appendix F:  Examples of Coadministered Drugs that Need Additional 
Consideration 
The lists of drugs in these tables are not exhaustive.  Any questions about drugs not on this list 
should be addressed to the Medical Monitor of this study. 
Strong Inhibitors of CYP3A 
Moderate inhibitors of CYP3A 
Boceprevir 
aprepitant 
clarithromycina 
cimetidine 
cobicistata 
ciprofloxacin 
conivaptana 
clotrimazole 
danoprevir and ritonavirb 
crizotinib 
diltiazema 
cyclosporine 
elvitegravir and ritonavirb 
dronedaronea 
grapefruit juice 
erythromycin 
Idelalisib 
fluconazole 
indinavir and ritonavirb 
fluvoxamine 
itraconazolea 
imatinib 
Ketoconazole 
tofisopam 
lopinavir and ritonavira,b 
verapamila 
Nefazodone 
 
nelfinavira 
 
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir)b 
 
Posaconazole 
 
ritonavira, b 
 
saquinavir and ritonavira, b 
 
telaprevira 
 
tipranavir and ritonavira, b 
 
Troleandomycin 
 
Voriconazole 
 
a. 
Inhibitor of P-glycoprotein. 
b.  
Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. Caution 
should be used when extrapolating the observed effect of ritonavir alone to the effect of combination 
regimens on CYP3A activities. 
c.  
After discontinuation of the strong or moderate CYP3A inhibitor, wait 3 days before resuming ventoclax or 
acalabrutinib. 
 
 
Strong Inducers of CYP3A 
Moderate Inducers of CYP3A 
Carbamazepine 
bosentan 
Enzalutamide 
efavirenz 
Mitotane 
etravirine 
Phenytoin 
modafinil 
Rifampin 
 
St. John’s worta 
 
a. The effect of St. John’s wort varies widely and is preparation-dependent. 
 

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P-gp Inhibitors 
BCRP Inhibitors 
Narrow Therapeutic Index 
P-gp Substrates 
Amiodarone 
curcumin 
digoxin 
Carvedilol 
cyclosporine A 
everolimus 
Clarithromycin 
eltrombopag 
sirolimus 
Dronedarone 
 
 
Itraconazole 
 
 
Lapatinib 
 
 
lopinavir and ritonavir 
 
 
Propafenone 
 
 
Quinidine 
 
 
Ranolazine 
 
 
Ritonavir 
 
 
saquinavir and ritonavir 
 
 
Telaprevir 
 
 
tipranavir and ritonavir 
 
 
Verapamil 
 
 
Source:  FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 
Web link Accessed 18 July 2018: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLab
eling/ucm093664.htm#inVivo 
 

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Appendix G:  Response Assessment Criteria (modified from Hallek 2008) 
Response 
Lymphocytes 
Bone Marrow 
Physical Exama (Nodes, 
Liver, Spleen) 
Peripheral Blood 
CR* 
Lymphocytes 
< 4 x 109/L 
Normocellular 
< 30% lymphocytes 
No B-lymphoid nodules 
Normal (e.g., no lymph 
nodes > 1.5 cm) 
ANC > 1.5 x 109/Lb 
Platelets > 100 x 109/Lb 
Hemoglobin > 11.0 g/dL 
(untransfused)b 
CRi 
Lymphocytes 
< 4 x 109/L 
Hypocellular 
< 30% lymphocytes 
No B-lymphoid nodules 
Normal (e.g., no lymph 
nodes > 1.5 cm) 
Persistent anemia, 
thrombocytopenia, or neutropenia 
related to drug toxicity 
nPR 
CR with the presence of B-lymphoid nodules in the bone marrow which reflect residual disease 
PR* 
Lymphocytes 
< 5 x 109/L  
Or 
≥ 50% decrease 
from baseline 
Not assessed 
≥ 50% reduction in 
lymphadenopathyc and/or 
in spleen or liver 
enlargement 
ANC > 1.5 x 109/L 
Or 
Platelets > 100 x 109/L or 
 ≥ 50% improvement over baselineb 
Or 
Hemoglobin > 11.0 g/dL or ≥ 50% 
improvement over baseline 
(untransfused)b 
PRL* 
Lymphocytes ≥ 5 
x 109/L 
AND 
<50% decrease 
from baseline 
Not assessed 
≥ 50% reduction in 
lymphadenopathyc and/or 
in spleen or liver 
enlargement 
ANC > 1.5 x 109/L 
Or 
Platelets > 100 x 109/L or 
≥ 50% improvement over baselineb 
Or 
Hemoglobin > 11.0 g/dL or ≥ 50% 
improvement over baseline 
(untransfused)b 
SD 
Absence of PD and failure to achieve at least a PR 
PD* 
Lymphocytes ≥ 
50% increase 
over baseline, 
with ≥ 5000 
B lymphocytes/µL 
Not assessed 
(except to confirm PD 
as assessed by 
progressive cytopenias) 
Appearance of any new 
lesion or de novo 
appearance of 
hepatomegaly or 
splenomegaly 
Or  
Increase ≥ 50% in 
lymphadenopathy 
Or 
Increase ≥ 50% in 
hepatomegaly 
Or  
Increase ≥ 50% in 
splenomegaly 
Platelets decrease of ≥ 50% from 
baseline secondary to CLL or < 
100,000/uL and worsening bone 
marrow due to CLL 
Or 
Hemoglobin decrease of > 2 g/dL 
from baseline secondary to CLL or 
decrease to < 100 g/L and 
worsening bone marrow due to CLL 
Abbreviations: ANC = absolute neutrophil count; CLL= chronic lymphocytic leukemia; CR = complete remission 
(response); CRi = CR with incomplete bone marrow recovery; nPR = nodular partial remission; PD = progressive 
disease; PR = partial remission (response); PRL = partial remission (response) with lymphocytosis; SD = stable disease. 
* 
CR: all of the above CR criteria have to be met, and patients have to lack disease-related constitutional symptoms; 
PR: at least two of the above PR criteria for lymphadenopathy, splenomegaly, hepatomegaly, or lymphocytes plus 
one of the criteria for ANC, platelets or hemoglobin have to be met; PRL: presence of lymphocytosis, plus ≥ 50% 
reduction in lymphadenopathy and/or in spleen or liver enlargement, plus one of the criteria for ANC, platelets or 
hemoglobin have to be met; PD: at least one of the above PD criteria has to be met, or transformation to a more 
aggressive histology (e.g., Richter’s syndrome).  For PD as assessed by progressive cytopenias, a bone marrow 
biopsy is required for confirmation.  Note: Isolated elevation of treatment-related lymphocytosis by itself will not be 
considered PD unless patient becomes symptomatic from this per Cheson 2012. 
a. 
Computed tomography (CT) scan of abdomen, pelvis, and thorax may be used if previously abnormal 
b. 
Without need for exogenous growth factors 

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c. 
In the sum products of ≤ 6 lymph nodes or in the largest diameter of the enlarged lymph node(s) detected before 
therapy and no increase in any lymph node or new enlarged lymph nodes 
 

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Appendix H:  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 I:  
 
(through Amendment 5.0) 
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Appendix J:  
 
(through Amendment 5.0) 
 
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Appendix K:  
 
(through Amendment 5.0) 
 
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Appendix L:  Cumulative Illness Rating Scale-Geriatric (CIRS-G) Calculator 
Web-based CIRS-G calculator link: 
http://eforms.moffitt.org/cirsgScore.aspx 
 
 

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

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IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
Laboratory data must be comprehensively reviewed by the investigator for each subject to identify 
laboratory values meeting the following criteria: 
• 
ALT ≥3 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 was initially detected, the study Medical Monitor 
and 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 
• 
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 

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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: 
• 
The “Medically Important” serious criterion should be used if no other serious criteria apply. 
• 
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”), 
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 agreed plan.  After the necessary supplementary 
information is obtained, repeat the review and assessment to determine whether HL criteria are 
still met.  Update the previously submitted PHL SAE report following the clinical study protocol 
process, according to the outcome of the review. 
ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S LAW 
This section is applicable when a subject meets PHL criteria while receiving study treatment and has 
already met PHL criteria at a previous on-study treatment visit.  The requirement to conduct follow-up, 
review, and assessment of a repeat occurrence(s) of PHL is based on the nature of the alternative cause 
identified for the previous occurrence.   
The investigator should determine the cause for the previous occurrence of PHL and answer the following 
question: 
Was the alternative cause for the previous occurrence of PHL determined to be the disease 
under study (e.g., chronic or progressing malignant disease, severe infection, or liver 
disease)? 
• 
If the answer is No:  
Follow the process described in “Potential Hy’s Law Criteria Met” in this Appendix for reporting 
PHL as an SAE. 
• 
If the answer is Yes: 
Determine if there has been a significant change in the subject’s condition compared with the 
previous occurrence of PHL.  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. 

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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 
Ferritin 
Transferrin 
Transferrin saturation 
 
REFERENCES 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical evaluation’ 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM17409
0.pdf  
 

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Appendix N:  Management of Study Procedures During Pandemic 
This appendix consolidates guidance for subject safety and ongoing access to medical care and 
investigational product during the global COVID-19 pandemic.  The measures detailed below 
will be implemented across Acerta Pharma studies on a temporary basis until the pandemic is 
considered resolved by governmental and public health organizations, as applicable.  
Regardless of the guidance below, please consider public health advice in your local market 
and individual risk/benefit in treatment decisions for patients at your study site during the 
pandemic.  Please also consider logistical requirements such as the ability of patients to travel 
to the study site, accessibility of public transport, etc. 
If the subject is unable or unwilling to visit the study site due to COVID-19 related reasons, 
investigators may ask enrolled subjects to use healthcare facilities local to the subject to ensure 
safety and efficacy measures are done per protocol. If a study assessment is not done at either 
the site or a facility local to the subject, then its absence should be documented as a protocol 
deviation.  Any protocol deviations resulting from the COVID-19 situation should be recorded 
and prefixed with COVID-19. 
Study Subject Participation 
Conduct of Telephone Visits 
Due to the current pandemic, it is conceivable that not all subject visit commitments may be able 
to be fulfilled.  If a subject is unable or unwilling to attend a study visit, adaptation of the onsite 
visit to a telephone visit is recommended to ensure continuity of study care (as an interim 
measure; e.g., telephone contacts instead of visits, shipping study medication to the subject).  
Priority should be given to maintaining ongoing safety follow-up (even if this is conducted by 
telephone contacts).  Study sites should speak with their site monitor before performing a 
telephone visit so he or she may provide guidance regarding logistics that may need 
consideration.  Also, study sites should speak with the site monitor if the subject cannot attend 
more than one onsite visit in succession, because multiple incomplete visits may have the 
potential to impact evaluation of study endpoints. 
Acalabrutinib Dose Modification Recommendation for COVID-19 
The sponsor recognizes that coronavirus 2019-nCoV (COVID-19) presents an increased risk for 
all patients.  Due to the potential impact of COVID-19 on multiple organ systems, the sponsor 

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recommends the following dose modification and management plan for patients with confirmed 
or suspected COVID-19 while receiving treatment with acalabrutinib.  
First and foremost, the following safety reporting guidelines are required:  
All confirmed or suspected COVID-19-related adverse events (AEs) must be recorded in the 
eCRF. All dose modifications should be based on the worst Common Terminology Criteria for 
Adverse Events (CTCAE) grade.  All interruptions or modifications must be recorded on the AE 
and drug administration eCRFs.  The CTCAE general grading criteria should be used to 
evaluate COVID-19.  
If an event is suspected to be COVID -19 infection, the sponsor recommends interrupting 
acalabrutinib and testing for COVID-19 per local guidance.  
• 
If COVID-19 is ruled out, standard clinical practice and the study protocol procedures 
should be followed regarding any dose modifications required for management of severe 
infections.  
• 
If COVID-19 is confirmed or diagnosis is suspected after evaluation, COVID-19 infection 
should be managed per local guidance until the subject achieves full recovery, defined 
as no signs or symptoms.  
In case of COVID-19 positivity, the investigator must determine the risk and benefit of 
interruption versus continuation of acalabrutinib and whether to resume it at full or modified 
doses or discontinue treatment.  
Please contact the study medical monitor for further discussion.  
Comparator Drugs or Drugs used in Combination with Acalabrutinib 
• 
Please refer to guidance from the manufacturer.  
Drug-drug interactions (DDI) may occur with some of the drugs being used as best supportive 
care (e.g., drugs that are strong inducers or inhibitors of cytochrome P450 [CYP]3A). Guidance 
is provided below:  
Drug-Drug Interaction Guidance for Investigators with Subjects Enrolled in an 
Acalabrutinib Clinical Study Who Are COVID-19 Positive  
• 
The potential combination with chloroquine or 8-8-OH-chloroquine (8-OH-CHQ) and 
azithromycin are not predicted to have a pharmacokinetic DDI with acalabrutinib.  
However, both agents are known to cause cardiovascular risk of QT prolongation.  

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Therefore, the risk/benefit of initiating 8-OH-CHQ + azithromycin should be discussed 
with the medical monitor.  
• 
Many antivirals and antibiotics are considered strong CYP3A4 inhibitors or inducers and 
are therefore likely to cause complex DDIs with acalabrutinib.  The risk benefit balance 
of acalabrutinib use in the setting of COVID-19 treatment should be discussed between 
the investigator and the medical monitor.  
• 
Remdesivir is rapidly metabolized to a pharmacologically active metabolite, GS-443902.  
Based on published and publicly available data, remdesivir does not appear to inhibit 
CYP isoforms and will likely not interact in a meaningful way with drug transport 
systems.  Remdesivir does not prolong QTc interval.  
• 
Systemic steroids and acalabrutinib may impair the ability of the body to fight infection; it 
is best to avoid high-dose systemic steroids while taking acalabrutinib.  
• 
The study protocol and investigator brochure should be referenced for other DDI 
information.  
COVID-19 Specific Data Entry Instructions for Investigational Sites 
Adverse Event Recording 
Currently no changes to normal data capture procedures are required for COVID-19 data in the 
eCRF.  For subjects who have confirmed or who are suspected of having coronavirus infection, 
the infection should be documented as an AE or serious adverse event (SAE), in line with 
instructions for safety reporting documented in the clinical study protocol.  Either 
“COVID-19 Confirmed” or “COVID-19 Suspected” should be used when reporting the event as 
follows: 
• 
If test is positive, “COVID-19 confirmed” should be recorded in the AE field. 
• 
If test is negative, AE/SAE signs and symptoms and/or other diagnosis should be 
recorded in the AE field(s). 
• 
If test is not available and signs and symptoms, as judged by the investigator, are highly 
suspicious of COVID-19 infection, record “COVID-19 suspected” in the AE field. 
Details of any testing or procedure to determine the status of COVID-19 infection should be 
documented on the Concomitant Procedure Form if available or on the appropriate eCRF page 
in the study. 

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For fatal SAEs, the Death Information Form, End of Study Treatment Form, and Study Exit 
Form should be completed.  
Study Treatment Recording 
If an AE or SAE is associated with COVID-19, the investigator should determine whether the 
subject’s treatment with investigational product should continue, be interrupted, or be 
discontinued in accordance with the clinical study protocol. 
For dosing interruptions, where applicable, the following guidelines should be used: 
• 
Related to AE:  
o On the Dose Administration Forms(s), dose change/missed should be indicated 
with AE as the reason. The dosing stop date must correlate to the AE/SAE 
start/stop dates. 
• 
Related to Logistics:  
o For subjects who have missed a study treatment due to an inability to travel to 
the clinic or for some other logistical reason, on the Dose Administration Form(s) 
dose change/missed should be indicated with Other as the reason, and “Logistic” 
as Other, Specify. 
If these options are not available in the eCRF, then either dose discontinuation should be 
recorded (if permanently stopped) or a protocol deviation should be recorded, prefixed 
COVID19. 
For dosing discontinuations, where applicable, the dosing discontinuation guidelines should 
be followed, and the End of Treatment Form(s) completed. 
Capturing Telephone Contacts with Subjects 
If a telephone visit is substituted for an onsite study visit, the following are guidelines for data 
capture: 
1. If the visit is specified as a phone visit as per protocol, no additional action is required.  
2. If the visit is listed as on-site but the subject will be contacted by phone, data should be 
completed as per a normal visit (i.e., using the relevant eCRF pages to capture a phone 
Visit Date), and any possible assessment that can be obtained remotely should be 
captured, such as AEs, study drug administration and/or concomitant medications, and 
any additional safety information.  All assessments that cannot be performed should be 

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marked as not done or eCRF inactivated/marked Blank.  A protocol deviation should be 
recorded in the clinic notes prefixed COVID19 detailing the use of a phone visit in place 
of an onsite visit.   
3. If the visit requires procedures which cannot be performed via telephone contact (e.g., 
MRI or CT scan), this should be discussed with the site monitor because this procedure 
may impact primary efficacy or safety analyses. 
Acalabrutinib Site-to-Subject Drug Shipment Instructions During Pandemic 
Containment or in Case of Force Majeure 
If a subject is definitively unable to physically go to the study site or unable to be represented by 
a third person because of pandemic containment or other force majeure, the study site's 
pharmacy may ship the study drug to the home of the subject following approval by the sponsor.  
For such a shipment, the following conditions must be met: 
• 
The sponsor is responsible for delivery of the study drug to the study site.  Any 
shipments made from the site to the subject will be the responsibility of the study site. 
• 
The subject is informed about the shipment method, confirms the address for receipt of 
the drug, and agrees that his or her personal information (i.e., name and address) may 
be given to a professional carrier. 
• 
The pharmacy securely packages the drug for shipment.  
• 
A professional carrier is used by the pharmacy to ship the drug securely and maintain 
chain of custody, with evidence provided.  Acalabrutinib must be stored and shipped at 
room temperature (15°C to 30°C).  The professional carrier must ensure that 
temperature monitoring is conducted for all shipments. 
• 
To respect patient confidentiality, the carrier should only be given the name and address 
of the subject.  The sponsor should not receive any personal information about the 
subject. 
• 
A procedure is defined with the carrier to confirm the receipt of the drug by the subject 
and that it is received in good condition. 
• 
The site contacts the subject to confirm the receipt and integrity of the drug and gives 
instructions about the drug administration. 

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• 
The pharmacy completes its accountability with each shipment made directly to a 
subject.