A Phase 1b Study of ACP-196 in Combination With Obinutuzumab for Patients With Relapsed / Refractory or Untreated CLL/SLL/PLL
Phase: PHASE1
Conditions: Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Prolymphocytic Leukemia
Sponsor: Acerta Pharma BV

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A Phase 1b Study of ACP-196 in Combination with Obinutuzumab for Patients with 
Relapsed/Refractory or Untreated CLL/SLL/PLL 
Sponsor Protocol Number 
ACE-CL-003 
IND Number 
118717 
SPONSOR MEDICAL 
MONITOR 
 
 
Phone: 
 
 
SPONSOR 
Acerta Pharma, BV 
 
5349 AB Oss 
The Netherlands 
Protocol Date 
20 May 2014 
Amendment 1 
28 July 2014 
Amendment 2 
24 March 2015 
Amendment 3 
22 July 2015 
Amendment 4 
27 April 2016 
Amendment 5 
03 August 2017 
Amendment 5.1 
06 November 2017 
Amendment 6 
27 June 2018 
Amendment 7 
03 April 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/independent ethics committee. This information cannot be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Acerta Pharma, BV. 
PPD
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PROTOCOL APPROVAL PAGE 
 
Version – Protocol Amendment 7 
 
I have carefully read Protocol ACE-CL-003 entitled “A Phase 1b Study of ACP-196 in 
Combination with Obinutuzumab for Patients with Relapsed/Refractory or Untreated 
CLL/SLL/PLL.” I agree to conduct this study as outlined herein and in compliance with Good 
Clinical Practices and all applicable regulatory requirements. Furthermore, I understand that the 
sponsor, Acerta Pharma, BV, and the institutional review board/independent ethics committee 
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, BV. All data pertaining to this study will be provided to Acerta Pharma, BV. 
The policy of Acerta Pharma, BV, requires that any presentation or publication of study data by 
clinical investigators be reviewed by Acerta Pharma, BV, before release, as specified in the 
protocol. 
 
 
 
Principal Investigator’s Signature 
Date 
 
 
 
 
 
Print Name 

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SUMMARY OF AMENDMENT 7 
Acerta Pharma, BV, amended this protocol (Protocol Amendment 7) to update text to be 
consistent with the updated Investigator Brochure, including adding rollover study language, 
updating reproductive toxicity language, updating risks and contraindications of each study drug, 
updating drug interaction language, and others. The amendment also clarified the 
discontinuation of acalabrutinib is based on minimal residual disease and clinical response and 
removed the restart of treatment for subjects in treatment-free follow-up. The protocol was also 
updated to add PK analysis (predose and 2 hours postdose) in Cohorts 3 and 4 in subjects who 
had not previously participated in PK analysis. 
The substantive changes that were made as part of Protocol Amendment 7 are as follows: 
 
Change 
Rationale 
Protocol Title Page 
Updated medical monitor. 
Change in medical monitor. 
Study Schema 
Updated criteria for acalabrutinib discontinuation for all 
cohorts. Removed restart of acalabrutinib for subjects on 
treatment-free follow-up. 
To clarify criteria regarding discontinuation and 
restart of acalabrutinib. 
Section 2.2.4 Clinical Trial Experience with Acalabrutinib 
and Dose Justification 
Updated Calquence® approval language. Added statement 
that Calquence® has been approved in the US and other 
markets for the treatment of adult patients with MCL who 
have received at least 1 prior therapy, CLL, and SLL. 
To align with updated Calquence® approval 
language. 
Section 2.2.4 Clinical Trial Experience with Acalabrutinib 
and Dose Justification 
Removed clinical trial data and referred the reader to the 
IB. 
To refer the reader to the most recent information. 
Section 3.1 Inclusion Criteria 
Updated guidelines for males for contraception and 
duration of contraception after the study. 
To align with the current IB. 
Section 5.1 Acalabrutinib Formulation, Packaging, and 
Storage 
Updated recommended storage conditions for 
acalabrutinib capsules. 
To align with the current IB. 
Section 5.2.1 Acalabrutinib Administration 
Added instructions for subjects at risk for TLS. 
Updated safety to satisfy French Authority feedback 
on IB Version 8.1. 
Section 6.1.1 Acalabrutinib Plus Obinutuzumab 
Added “In Cohorts 1 and 2, subjects who achieve a bone 
marrow MRD-negative CR have the option to discontinue 
acalabrutinib.” Removed the restart of acalabrutinib. 
Updated based on investigator feedback. 
Section 6.1.2.1 Cohort 3 – Relapsed or Refractory CLL 
Updated based on investigator feedback. 

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Change 
Rationale 
Section 6.1.2.2 Cohort 4 – Treatment-naive CLL 
Updated criteria for subjects who received at least 24 
cycles of treatment. Removed restart of acalabrutinib. 
Section 6.3 Concomitant Medications 
Updated language with regards to antacids, H2-receptor 
antagonists, proton pump inhibitors, and CYP3A 
inhibitors and inducers. 
To align with current IB. 
Section 6.4.1 Risks Associated with Acalabrutinib 
Updated risks. 
To align with current IB. 
Section 6.4.2 Contraindications, Warnings, and 
Precautions 
For obinutuzumab and venetoclax: Updated to include 
contraindications, updated warnings and precautions. 
To align with current prescribing information. 
Section 6.4.2.5 Dietary Restrictions 
Removed restriction of grapefruit, grapefruit juice, Seville 
oranges, or Seville orange juice. 
To align with current IB. 
Section 6.4.3 Reproductive Toxicity 
Updated definitions of highly effective contraception. 
To align with current IB. 
Section 6.4.5 Hepatitis B Virus Reactivation 
Section 6.4.6 Progressive Multifocal 
Leukoencephalopathy 
Moved these sections from risks (Section 6.4.1) and 
updated the recommendations. 
To align with current IB. 
Section 6.4.7 Elevated Liver Function Tests 
Added section and referred to new appendix (Appendix 3). 
To align with AstraZeneca SOPs. 
Section 6.7 Duration of Therapy 
Updated discontinuation of therapy rules. 
To align with other sections of the protocol. 
Section 6.7 Duration of Therapy 
Added rollover study language. 
To allow continued access to study drug. 
Section 7.1.1 Obinutuzumab 
Removed information and referred to the GAZYVARO 
prescribing information. 
To refer to the most recent prescribing information. 
Section 8 Table 11 Schedule of Assessments: Cohorts 1 
and 2 
Section 8 Table 12 Schedule of Assessments: Cohorts 3 
and 4 
Updated ECG footnote to allow ECGs to be obtained as 
clinically indicated. 
To allow for additional monitoring as clinically 
indicated. 

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Change 
Rationale 
Section 8 Table 11 Schedule of Assessments: Cohorts 1 
and 2 
Updated MRD evaluations from bone marrow to 
peripheral blood. Clarified that peripheral blood samples 
will be used to evaluate for MRD every 3 cycles (or at the 
discretion of the PI), in line with scheduled response 
assessments, per protocol. 
To clarify the MRD evaluations. 
Section 8 Table 12 Schedule of Assessments: Cohorts 3 
and 4 
Updated footnote “A” regarding acalabrutinib 
discontinuation. 
To align with protocol updates. 
Section 10.1 Reference Safety Information 
Added this section. 
To refer to the current IB. 
Section 10.2 Monitoring of Adverse Events 
Updated AE reporting language. 
To align with updated reporting language. 
Section 10.5.1 Second Primary Malignancies 
Added section to include guidance for reporting second 
primary malignancies. 
Added to include reporting guidance of second 
primary malignancies. 
Section 10.5.2 Adverse Events of Special Interest 
Added section to include reporting guidance for adverse 
events of special interest (ventricular arrhythmias) and 
guidance for treatment containing biologic products 
regarding suspected transmission of infectious agent. 
Added to include adverse events of special interest 
“ventricular arrhythmias.” 
Section 13.3 Pharmacokinetics 
Added PK analysis in Cohorts 3 and 4 for subjects who 
had not previously participated in PK analysis at predose 
and 2 hours postdose, relative to acalabrutinib 
administration. 
For collection of additional PK data. 
Appendix 1 Known Strong In Vivo Inhibitors and 
Inducers of CYP3A 
Updated to current guidelines. 
Updated to current guidelines. 
Appendix 3 Actions Required in Cases of Increased in 
Liver Biochemistry and Evaluation of Hy’s Law 
Added section for process to identify and report potential 
Hy’s law and Hy’s law cases. 
For guidance to the investigator. 

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Acalabrutinib 
 
 
Obinutuzumab IV 
 
 
COHORT 1: 
• Relapsed or refractory 
disease* 
COHORT 2: 
• No previous treatment 
• 65 years or older OR refuse 
or are ineligible for approved 
chemotherapy and/or 
immunotherapy options 
ACALABRUTINIB 
 
Obinutuzumab 
 
 
 
STUDY SCHEMA 
PHASE 1B DOSE ESCALATION PORTION: OBINUTUZUMAB 
• At least 6 subjects with relapsed/refractory chronic lymphocytic leukemia (CLL), then at 
least 6 subjects with treatment-naive CLL 
 
PHASE 1B EXPANSION PORTION: COHORTS 1 AND 2 
TWO PARALLEL COHORTS WILL BE TREATED IDENTICALLY 
 
 
*Samples for pharmacokinetic analysis will be obtained from the first 8 subjects enrolled in the 
Phase 1b expansion of Cohort 1. 
# Subjects who achieve bone marrow minimal residual disease (MRD)-negative complete 
response (CR) have the option to discontinue acalabrutinib. 
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COHORT 3: 
• 
• 
Relapsed or refractory 
Rdiesleaapssee*d or refractory 
disease* 
COHORT 4: 
• No previous treatment* 
• 
ACALABRUTINIB 
 
Rituximab 
Rituximab 
ACALABRUTINIB 
Obinutuzumab 
Obinutuzumab 
Venetoclax 
STUDY SCHEMA (CONTINUED) 
PHASE 1B: COHORTS 3 AND 4 
Twelve subjects with relapsed/refractory CLL and 12 subjects with treatment-naive CLL 
 
 
TWO PARALLEL COHORTS WILL BE TREATED 
 
 
 
 
* Samples for pharmacokinetic analysis will be obtained from the first 8 subjects enrolled in 
each of Cohorts 3 and 4. 
# Discontinuation of acalabrutinib after 
 is possible by investigator decision based on 
minimal residual disease (MRD) and clinical response (refer to the Schedule of Assessments). 
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Table of Contents 
Summary of Amendment 7 ..................................................................................................... 3 
Study Schema ........................................................................................................................... 6 
Table of Contents ..................................................................................................................... 8 
List of Tables .......................................................................................................................... 12 
List of Figures ......................................................................................................................... 13 
Abbreviations and Definitions .............................................................................................. 14 
1 
Study Objectives......................................................................................................... 18 
1.1 
Primary Objectives ....................................................................................................... 18 
1.2 
Secondary Objectives ................................................................................................... 18 
1.3 
Exploratory Objectives ................................................................................................ 18 
2 
Background and Rationale........................................................................................ 19 
2.1 
Chronic Lymphocytic Leukemia Background ............................................................. 19 
2.2 
Acalabrutinib................................................................................................................ 22 
2.2.1 
Preclinical Data and Pharmacology .......................................................................... 22 
2.2.2 
Safety Pharmacology ................................................................................................ 22 
2.2.3 
In Vivo Toxicology ................................................................................................... 22 
2.2.4 
Clinical Trial Experience with Acalabrutinib and Dose Justification ....................... 23 
2.3 
Obinutuzumab .............................................................................................................. 23 
2.4 
Rituximab ..................................................................................................................... 24 
2.5 
Venetoclax ................................................................................................................... 25 
2.6 
Combination Therapy with a BTK Inhibitor Plus CD20 Monoclonal Antibody ......... 25 
2.7 
Combination Treatment with a BTK Inhibitor Plus BCL-2 Inhibitor ......................... 26 
2.8 
Justification for a Trial Combining Acalabrutinib with Obinutuzumab/Rituximab 
with Venetoclax ........................................................................................................... 27 
3 
Patient Eligibility Criteria ......................................................................................... 27 
3.1 
Inclusion Criteria ......................................................................................................... 27 
3.2 
Exclusion Criteria ........................................................................................................ 29 
4 
Registration of Patients ............................................................................................. 31 
4.1 
Informed Consent ......................................................................................................... 31 
4.2 
Registration Procedure ................................................................................................. 31 

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5 
Study Drugs and Administration Guidelines .......................................................... 31 
5.1 
Acalabrutinib Formulation, Packaging, and Storage ................................................... 31 
5.2 
Drug Preparation and Administration .......................................................................... 32 
5.2.1 
Acalabrutinib Administration ................................................................................... 32 
5.3 
Dose Delays ................................................................................................................. 33 
5.3.1 
Obinutuzumab Administration .................................................................................. 33 
5.3.2 
Venetoclax Administration ....................................................................................... 34 
5.3.3 
Rituximab Administration ........................................................................................ 35 
5.3.4 
Drug Supply Records ................................................................................................ 35 
6 
Treatment Plan........................................................................................................... 35 
6.1 
Overview ...................................................................................................................... 35 
6.1.1 
Acalabrutinib Plus Obinutuzumab ............................................................................ 35 
6.1.2 
Acalabrutinib Plus Venetoclax plus Rituximab or Obinutuzumab ........................... 36 
6.1.2.1 
Cohort 3 – Relapsed or Refractory CLL ................................................................. 36 
6.1.2.2 
Cohort 4 – Treatment-naive CLL ............................................................................ 37 
6.2 
Premedications ............................................................................................................. 38 
6.2.1 
Premedication for Acalabrutinib ............................................................................... 38 
6.2.2 
Premedication for Obinutuzumab ............................................................................. 38 
6.2.3 
Premedication for Venetoclax ................................................................................... 38 
6.2.4 
Premedication for Rituximab .................................................................................... 39 
6.3 
Concomitant Medications ............................................................................................ 39 
6.4 
Risks Associated with Study Treatment ...................................................................... 41 
6.4.1 
Risks Associated with Acalabrutinib Treatment ....................................................... 41 
6.4.1.1 
Hemorrhage ............................................................................................................. 41 
6.4.1.2 
Infections ................................................................................................................. 41 
6.4.1.3 
Cytopenias ............................................................................................................... 42 
6.4.1.4 
Second Primary Malignancies ................................................................................. 42 
6.4.1.5 
Atrial Fibrillation ..................................................................................................... 42 
6.4.2 
Contraindications, Warnings, and Precautions ......................................................... 42 
6.4.2.1 
Obinutuzumab ......................................................................................................... 43 
6.4.2.2 
Venetoclax ............................................................................................................... 44 
6.4.2.3 
Rituximab ................................................................................................................ 45 

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6.4.2.4 
Immunizations ......................................................................................................... 46 
6.4.2.5 
Dietary Restrictions ................................................................................................. 46 
6.4.3 
Reproductive Toxicity .............................................................................................. 46 
6.4.4 
Overdose Instructions ............................................................................................... 48 
6.4.5 
Hepatitis B Virus Reactivation ................................................................................. 49 
6.4.6 
Progressive Multifocal Leukoencephalopathy .......................................................... 49 
6.4.7 
Elevated Liver Function Tests .................................................................................. 50 
6.5 
Phase 1b Dose Escalation Portion ................................................................................ 50 
6.6 
Phase 1b Expansion Portion for Cohorts 1 and 2 ........................................................ 52 
6.7 
Duration of Therapy ..................................................................................................... 52 
7 
Dose Adjustments and Modifications. ......................................................................53 
7.1 
Subject Monitoring and Dose Modifications ............................................................... 53 
7.1.1 
Obinutuzumab ........................................................................................................... 53 
7.1.1.1 
Obinutuzumab Dose Modification and Discontinuation ......................................... 53 
7.1.2 
Venetoclax ................................................................................................................ 53 
7.1.3 
Rituximab .................................................................................................................. 53 
7.1.3.1 
Subject Monitoring During Infusion ....................................................................... 53 
7.1.3.2 
Management of Infusion Reactions with Rituximab ............................................... 53 
7.1.3.3 
Rituximab Dose Modification and Discontinuation ................................................ 53 
7.2 
Dose Adjustment and Management of Toxicity for Phase 1b After 
 and 
Phase 1b Expansion Phase, and Phase 1b Venetoclax Cohorts ................................... 54 
7.2.1 
Dose Adjustments for Hematologic Toxicity ........................................................... 54 
7.2.1.1 
Cohorts 1 and 2 ........................................................................................................ 54 
7.2.1.2 
Cohorts 3 and 4 ........................................................................................................ 55 
7.2.2 
Dose Adjustments for Specific Nonhematologic Toxicities ..................................... 56 
7.2.2.1 
Infusion Reactions with Obinutuzumab or Rituximab ............................................ 56 
7.2.2.2 
Progressive Multifocal Leukoencephalopathy or Hepatitis B Reactivation ............ 56 
7.2.3 
Dose Adjustments for All Other Nonhematologic Toxicities ................................... 56 
7.2.3.1 
Cohorts 1 and 2 ........................................................................................................ 57 
7.2.3.2 
Cohorts 3 and 4 ........................................................................................................ 57 
8 
Schedule of Activities ................................................................................................. 59 
8.1 
Pre-Treatment (Screening) Evaluation ........................................................................ 70 
8.2 
Study Evaluations ........................................................................................................ 70 
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8.3 
Safety Follow-up .......................................................................................................... 71 
8.4 
Discontinuation Follow-up .......................................................................................... 71 
8.5 
Long-Term Follow-up ................................................................................................. 71 
9 
Criteria for Response, Progression, and Relapse .................................................... 71 
10 
Patient Safety and Adverse Event Reporting .......................................................... 75 
10.1 
Reference Safety Information ...................................................................................... 75 
10.2 
Monitoring of Adverse Events ..................................................................................... 76 
10.3 
Definitions of Adverse Events and Causality .............................................................. 76 
10.4 
Definition of Serious Adverse Events .......................................................................... 78 
10.5 
Reporting of Adverse Events ....................................................................................... 78 
10.5.1 
Second Primary Malignancies .................................................................................. 79 
10.5.2 
Adverse Events of Special Interest ........................................................................... 80 
10.6 
Data Safety Monitoring Plan ........................................................................................ 80 
11 
Withdrawal of Subject from Treatment or Assessment ......................................... 81 
11.1 
Withdrawal of Subjects from Study Treatment ........................................................... 81 
11.2 
Reasons for Study Exit ................................................................................................. 81 
12 
Forms to Be Kept ....................................................................................................... 82 
13 
Correlative Studies ..................................................................................................... 82 
13.1 
Outline of Correlative Laboratory Studies ................................................................... 82 
13.2 
Correlative Sample Requirements (Exclusive of Pharmacokinetic Samples) ............. 84 
13.2.1 
Cohorts 1 and 2 ......................................................................................................... 84 
13.2.2 
Cohorts 3 and 4 ......................................................................................................... 86 
13.3 
Pharmacokinetics ......................................................................................................... 88 
13.4 
Health Related Quality of Life and Emotional Distress Assessment ........................... 90 
14 
Statistical Considerations .......................................................................................... 90 
14.1 
Study Overview............................................................................................................ 90 
14.2 
Sample Size .................................................................................................................. 91 
14.3 
Accrual Time and Study Duration ............................................................................... 91 
14.4 
Statistical Design ......................................................................................................... 92 
14.5 
Analysis Populations .................................................................................................... 92 
14.6 
Analysis Plan ............................................................................................................... 93 
14.6.1 
Primary Endpoints .................................................................................................... 93 

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14.6.2 
Secondary Endpoints ................................................................................................ 93 
15 
Ethical and Regulatory Considerations ................................................................... 94 
15.1 
Ethical Principles ......................................................................................................... 94 
15.2 
Institutional Review Board Approval .......................................................................... 94 
15.3 
Protocol Amendments .................................................................................................. 94 
15.4 
Confidentiality ............................................................................................................. 94 
15.5 
Case Report Forms and Record Retention ................................................................... 95 
15.5.1 
Record Retention ...................................................................................................... 95 
15.6 
Study Monitoring Requirements .................................................................................. 96 
15.7 
Investigational Study Drug Accountability .................................................................. 96 
16 
References ................................................................................................................... 97 
Appendix 1. Known Strong In Vivo Inhibitors and Inducers of CYP3A ...................... 103 
Appendix 2. Health-Related Quality of Life and Emotional Distress Survey ............... 106 
Appendix 3. Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ........................................................................................... 109 
 
 
 
List of Tables 
Table 1: 
Dose of Obinutuzumab to be Administered During 
 , 
Each of 
 Duration ........................................................................................... 34 
Table 2: 
Dosing Schedule for 
 Phase of Venetoclax Dosing .................................... 35 
Table 3: 
Recommended Tumor Lysis Syndrome Prophylaxis for Venetoclax Based 
on Tumor Burden from Clinical Trial Data ................................................................ 39 
Table 4: 
Dose Levels for Phase 1b Dose Escalation Portion for Cohorts 1 and 2 .................... 52 
Table 5: 
IWCLL 2008 Grading for Hematologic Toxicity ....................................................... 54 
Table 6: 
Dose Adjustments During 
 
 
 Phase 1b Expansion Subjects Only During 
 All Subjects 
During 
 ....................................................................................... 55 
Table 7: 
Acalabrutinib Dose Adjustments for All Other Nonhematologic Toxicities 
(All Cohorts) ............................................................................................................... 57 
Table 8: 
Obinutuzumab Dose Adjustments for All Other Nonhematologic Toxicities 
(All Cohorts) ............................................................................................................... 57 
Table 9: 
Dose Modification for Toxicity During Venetoclax Treatment (Cohorts 3 
and 4) .......................................................................................................................... 58 
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Table 10: Dose Adjustments for All Other Nonhematologic Toxicities for Which 
Individual Study Drug Attribution is Not Possible (All Cohorts) .............................. 58 
Table 11. Schedule of Activities:  Cohorts 1 and 2 .................................................................... 59 
Table 12: Schedule of Assessments – Cohort 3 .......................................................................... 62 
Table 13: Schedule of Assessments – Cohort 4 .......................................................................... 66 
Table 14: IWCLL Response Assessment Criteria ...................................................................... 74 
Table 15: Chronic Lymphocytic Leukemia Health-Related Quality of Life and 
Emotional Distress Assessment ................................................................................ 114 
 
 
 
List of Figures 
Figure 1: 
Phase 1b Dose Escalation Schema for Cohorts 1 and 2 ............................................. 50 
Figure 2: 
 ........................................ 84 
Figure 3: 
 ....................................................... 84 
Figure 4: 
Trial Design ................................................................................................................ 91 
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Abbreviations and Definitions 
 
Abbreviations and definitions of terms 
ACD 
acid citrate dextrose 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE 
adverse event 
AESI 
adverse event of special interest 
AIHA 
autoimmune hemolytic anemia 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
hepatitis B core antibody 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BCL 
B-cell lymphoma 
B-PLL 
B-cell prolymphocytic leukemia 
BCR 
B-cell receptor 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BR 
bendamustine plus rituximab 
BTK 
Bruton tyrosine kinase 
CBC 
complete blood count 
cGMP 
current Good Manufacturing Practices 
CI 
confidence interval 
CIRS 
Cumulative Illness Rating Score 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed drug concentration 
CR 
complete response 
CrCl 
creatinine clearance 
CRi 
CR with incomplete bone marrow recovery 
CT 
computed tomography 
CYP 
cytochrome P450 
DCO 
data cutoff 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DSMC 
Data Safety Monitoring Committee 

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Abbreviations and definitions of terms 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediamine tetra-acetic acid 
EGFR 
epidermal growth factor receptor 
EMA 
European Medicines Agency 
EORTC QLQ- 
C30 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FSH 
follicle-stimulating hormone 
GCLLSG 
German CLL Study Group 
G-CSF 
granulocyte colony-stimulating factor 
GI 
gastrointestinal 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HL 
Hy’s law 
HR 
hazard ratio 
HR-QOL 
health-related quality of life 
IBM 
ideal body mass 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IGHV 
immunoglobulin heavy-chain variable 
IHC 
immunohistochemistry 
IMP 
investigational medical product 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRR 
infusion-related reaction 
ITK 
inducible T-cell kinase 
IUD 
intrauterine device 

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Abbreviations and definitions of terms 
IV 
Intravenous 
IVIG 
intravenous immunoglobulins 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
LAM 
lactational amenorrhea method 
LDH 
lactate dehydrogenase 
MCL 
mantle cell lymphoma 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NCI-WG 
National Cancer Institute-sponsored Working Group 
NHL 
non-Hodgkin lymphoma 
NK 
natural killer (cells) 
nPR 
nodular partial remission 
ORR 
overall response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PFS 
progression-free survival 
PHL 
potential Hy’s law 
PK 
pharmacokinetic 
PLCG2 
phospholipase C gamma 2 
PLL 
prolymphocytic leukemia 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial response 
PRL 
partial remission (response) with lymphocytosis 
QD 
once daily 
QTc 
corrected QT interval 
RSI 
Reference Safety Information 
SAE 
serious adverse event 
SD 
stable disease 
SFU 
safety follow-up 
SLL 
small lymphocytic lymphoma 
SUSAR 
suspected unexpected serious adverse reaction 
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Abbreviations and definitions of terms 
TLS 
tumor lysis syndrome 
TTNT 
time-to-next treatment 
ULN 
upper limit of normal 
US 
United States 

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1 
Study Objectives 
 
1.1 
Primary Objectives 
Cohorts 1 and 2: 
• To determine the overall response rate (ORR) at 12 months with the combination of 
acalabrutinib plus obinutuzumab in subjects with relapsed or refractory chronic lymphocytic 
leukemia (CLL) 
• To determine the ORR at 12 months with the combination of acalabrutinib plus 
obinutuzumab in subjects with treatment-naive CLL 
• To establish the safety and feasibility of the combination of acalabrutinib plus obinutuzumab 
Cohorts 3 and 4: 
• To establish the safety of the combination of acalabrutinib plus rituximab plus venetoclax in 
subjects with relapsed or refractory CLL (Cohort 3) 
• To establish the safety of the combination of acalabrutinib plus obinutuzumab plus 
venetoclax in subjects with treatment-naive CLL (Cohort 4) 
 
1.2 
Secondary Objectives 
• To determine the complete response (CR) rate and minimal residual disease (MRD)-negative 
CR rate in subjects with previously untreated and relapsed and refractory CLL with these 
regimens (all cohorts) 
• To evaluate the ORR of the combination therapy of acalabrutinib plus venetoclax plus an 
anti-CD20 antibody at Cycle 16 (Cohorts 3 and 4) 
• To determine the time to response, duration of response (DOR), progression-free survival 
(PFS), time to CR, time-to-next treatment (TTNT), and overall survival (OS) with these 
regimens (all cohorts) 
• To assess for serial development of resistance by baseline and longitudinal assessment of 
mutations of Bruton tyrosine kinase (BTK) and phospholipase C gamma 2 (PLCG2) at 
regular follow-up intervals and by examining diagnosis to relapse samples by whole exome 
sequencing (all cohorts) 
• To determine trajectory of psychological and behavioral responses to acalabrutinib and 
covariation with response to therapy (all cohorts) 
• To determine the pharmacokinetics (PK) of orally administered acalabrutinib (all cohorts) 
and venetoclax (Cohorts 3 and 4) 
 
1.3 
Exploratory Objectives 
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2 
Background and Rationale 
 
2.1 
Chronic Lymphocytic Leukemia Background 
Chronic lymphocytic leukemia is the most prevalent form of adult leukemia. This disease 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 et al. 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, and despite 
the relatively long-life expectancy for early stage disease, CLL remains an incurable disease. 
Patients diagnosed with or progressing to advanced disease have a mean survival of 18 months to 
3 years. Unfortunately, these patients with advanced disease are also more refractory to 
conventional therapy. 
The treatment of CLL has progressed significantly over the previous decades. While alkylator 
therapy was used in the past (O'Brien et al. 1995), randomized trials have demonstrated a higher 
response rate and longer PFS with fludarabine (Rai et al. 2000, Johnson et al. 1996, Leporrier et 
al. 2001) and subsequently with fludarabine- and cyclophosphamide-based combinations 
(Catovsky et al. 2007, Eichhorst et al. 2006, Flinn et al. 2007). At the same time, the chimeric 
anti-CD20 monoclonal antibody rituximab was introduced for the treatment of CLL. At high 
doses (O'Brien et al. 2001) or with dose-intensive treatment (Byrd et al. 2001), single-agent 
rituximab has shown efficacy; however, CRs and extended remissions are very rare. The 
efficacy of rituximab has been improved by combining it with traditional cytotoxic agents such 
as fludarabine (Byrd et al. 2003), or fludarabine and cyclophosphamide (Wierda et al. 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 
a benefit of the addition of antibody therapy with rituximab to fludarabine and 
cyclophosphamide in the prolongation of PFS and OS in patients with untreated CLL (Hallek et 
al. 2010, Byrd et al. 2005). This encouraging progress in therapy and our understanding of the 
disease has resulted in significantly improved response rates and PFS. However, significant 
improvements in OS and ultimately cure, remain elusive goals. 
While fludarabine-based chemoimmunotherapy is standard for younger patients, the therapy for 
older patients 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, 
which calls into question whether these results are generalizable to the entire CLL population. In 
fact, the 1 randomized Phase 3 trial investigating primary CLL therapy in older patients 
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(Eichhorst et al. 2009) demonstrated that in patients ≥65 years old, fludarabine is not superior to 
chlorambucil. This finding was corroborated by a large retrospective study of front-line trials 
performed by the Alliance for Clinical Trials in Oncology, which not only demonstrated again 
that fludarabine is not superior to chlorambucil in older patients, but also showed that the 
addition of rituximab to chemotherapy was beneficial regardless of age (Woyach et al. 2013). 
Two studies have evaluated the combination of rituximab with chlorambucil, showing that this 
combination is safe and moderately effective (Foa et al. 2010, Hillmen et al. 2010). 
The Type II glycoengineered CD20 monoclonal antibody obinutuzumab was introduced. In a 
Phase 1 trial of previously treated CLL as monotherapy, this antibody has a 62% response rate 
including 1 MRD-negative CR, suggesting that alone this antibody may be more active in CLL 
than rituximab (Morschhauser et al. 2009). The GCLLSG recently completed a Phase 3 trial of 
rituximab plus chlorambucil or obinutuzumab plus chlorambucil versus chlorambucil alone in 
patients with untreated CLL and significant comorbidities. In this population, obinutuzumab 
plus chlorambucil (but not rituximab plus chlorambucil) improved OS over chlorambucil alone 
(hazard ratio [HR]: 0.41, p=0.002), and obinutuzumab plus chlorambucil improved PFS over 
rituximab plus chlorambucil (median PFS: 26.7 months vs 14.9 months, p<0.001) (Goede et al. 
2014). Based on these favorable data, the combination of obinutuzumab plus chlorambucil is 
Food and Drug Administration (FDA)-approved as frontline therapy for CLL patients. 
Many older patients are also treated with the combination of bendamustine plus rituximab (BR). 
Although BR has not been compared directly with chlorambucil plus rituximab, results of a 
recent Phase 2 trial show an ORR of 88% with a median event-free survival of 33.9 months and 
90.5% OS at 27 months. These results held for patients ≥70 years old and compare favorably 
with results published for chlorambucil plus rituximab (Fischer et al. 2012). While results with 
this regimen appear to be improved over historical controls, outcomes are not as good as those 
observed in younger patients with chemoimmunotherapy. Therefore, the optimal therapy for 
older patients remains an unmet need in clinical trials. 
Additionally, most patients eventually relapse and are frequently refractory to existing agents. 
Patients who relapse after combined chemoimmunotherapy have a poor outcome with 
subsequent standard therapies. While options for these patients include alemtuzumab, 
bendamustine, high-dose corticosteroids, ofatumumab, and combination-based approaches, none 
of these therapies produces durable remissions that exceed that observed with first-line 
chemoimmunotherapy. Several of these therapies, including alemtuzumab and high-dose 
steroids, are also associated with significant toxicities and sustained immunosuppression 
(Bergmann et al. 2005, Bowen et al. 2007, Castro et al. 2008, Coiffier et al. 2008, Keating et al. 
2002, Lozanski et al. 2004, Osuji et al. 2005, Thornton et al. 2003, Thornton et al. 1999, 
Tsimberidou et al. 2008). 
A breakthrough in CLL treatment occurred with the approval of ibrutinib, an inhibitor of BTK, 
which is a key signaling pathway of the B-cell receptor (BCR). In an ongoing Phase 1b/2 study, 

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ibrutinib has shown extraordinary activity in patients with relapsed or refractory CLL. In 
patients with relapsed or refractory CLL and measurable lymphadenopathy, the rate of lymph 
node shrinkage >50% is 89%. With a median follow-up of 4 months, ORR was 48% due to 
asymptomatic lymphocytosis (Byrd et al. 2011), and with longer follow-up of 26 months in 
patients receiving the 420-mg dose, has improved to 71%, with an additional 20% of patients 
achieving a partial remission (response) with lymphocytosis (PRL) (Byrd et al. 2013). 
Lymphocytosis with ibrutinib is observed within 1 to 2 weeks of starting therapy, reaches a 
plateau within the first 2 to 3 cycles, and resolves over time; the duration does not appear to be 
related to the depth of response or response duration (Woyach et al. 2014). Response to ibrutinib 
occurs independently of high-risk genomic features including immunoglobulin heavy-chain 
variable (IGHV) mutational status and del(17p13.1). Responses to this drug have been durable 
as well, with an estimated 26-month PFS of 76% and OS of 83% for these relapsed and 
refractory patients (Byrd et al. 2013). This study also included a cohort of 31 previously 
untreated patients. With 16.6 months of follow-up, ORR is 71%, with an additional 10% of 
patients having persistent lymphocytosis; estimated 22-month PFS is 96% (Byrd et al. 2012). 
The randomized, open-label, Phase 3 RESONATE-2 trial evaluated the use of ibrutinib versus 
chlorambucil in 269 treatment-naive subjects with CLL or small lymphocytic lymphoma (SLL) 
age 65 years or older. The ORR was 82.4% versus 35.3% p<0.0001 ibrutinib versus 
chlorambucil. Ibrutinib significantly prolonged PFS as determined by an Independent Review 
Committee (IRC) reducing the risk of disease progression or death by 84% versus chlorambucil 
(HR: 0.161 [95% confidence interval [CI]: 0.091, 0.283]; median PFS not reached for ibrutinib 
versus 18.9 months [95% CI: 14.1, 22.0] for chlorambucil (Burger et al. 2015). These studies 
have led to the approval of this agent in both treatment-naive disease and for the treatment of 
relapsed CLL. These data with ibrutinib support the potential benefits of selective BTK 
inhibition in CLL. 
While highly potent in inhibiting BTK, ibrutinib has also shown in vitro activity against other 
kinases (e.g., epidermal growth factor receptor [EGFR]) (Honigberg et al. 2010), which may be 
the cause of ibrutinib-related diarrhea and rash. In addition, it is a substrate for both cytochrome 
P450 (CYP) enzymes 3A4/5, which increases the possibility of drug-drug interactions. Finally, 
the inhibition of interleukin-2-inducible-T-cell-kinase (ITK) that is seen with ibrutinib has the 
potential to abrogate natural killer (NK) cell antibody-dependent cellular cytotoxicity (ADCC) 
(Kohrt et al. 2014), which makes combination with monoclonal antibodies less effective. These 
liabilities support the development of alternative BTK inhibitors for use in the therapy of 
lymphoid cancers. 
Venetoclax, a B-cell lymphoma -2 (BCL-2) inhibitor, received accelerated approved in 2016 for 
the treatment of patients with CLL with 17p deletion who have received at least 1 prior therapy. 
The efficacy of venetoclax was established in an open-label, single-arm, multicenter clinical trial 
of 106 patients with CLL with 17p deletion who had received at least 1 prior therapy. In the 

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study, 17p deletion was confirmed in peripheral blood specimens from patients using Vysis 
fluorescence in situ hybridization (FISH) Probe Kit, which is FDA approved for selection of 
patients for venetoclax treatment. Patients received venetoclax via a 
 schedule 
starting at 
 
Patients continued to receive 
 of venetoclax orally 
 
 The efficacy of venetoclax was evaluated by ORR as assessed by an IRC 
using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) updated 
National Cancer Institute-sponsored Working Group (NCI-WG) guidelines (Hallek et al. 2008). 
The median time on treatment at time of evaluation was 12.1 months (range: 0 to 21.5 months). 
Importantly, the efficacy results revealed an ORR of 80.2%, with a CR/CR with incomplete 
marrow recovery (Cri) rate of 7.5% (Stilgenbauer et al. 2015). 
 
2.2 
Acalabrutinib 
 
2.2.1 
Preclinical Data and Pharmacology 
 
 
For clinical testing, acalabrutinib has 
been manufactured and formulated according to current Good Manufacturing Practices (cGMP). 
 
 
 
 For additional details, refer to the 
acalabrutinib Investigator Brochure. 
 
2.2.2 
Safety Pharmacology 
 
for detailed information on the safety pharmacology of 
acalabrutinib, refer to the acalabrutinib Investigator Brochure. 
 
2.2.3 
In Vivo Toxicology 
In vitro and in vivo safety toxicology studies with acalabrutinib have demonstrated a favorable 
toxicology profile; for detailed information on the in vivo toxicology of acalabrutinib, refer to 
the acalabrutinib Investigator Brochure. 
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2.2.4 
Clinical Trial Experience with Acalabrutinib and Dose Justification 
Calquence® has been approved in the United States (US) and other markets for the treatment of 
adult patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy, 
CLL, and SLL. 
For more detailed information on the clinical experience for acalabrutinib, please refer to the 
Investigator Brochure. 
 
 
 
 Therefore, based on PK/PD, safety, and efficacy results of 
the Phase 1/2 study, acalabrutinib 
 will be evaluated in this study. This regimen is 
expected to provide optimal target coverage with lower exposure levels (i.e., maximum observed 
drug concentration [Cmax]) of acalabrutinib to avoid any potential off-target effects from 
acalabrutinib. 
 
2.3 
Obinutuzumab 
Obinutuzumab is a humanized monoclonal antibody that has been glycoengineered to produce 
high affinity type II binding to CD20, which leads to increased ADCC relative to other CD20 
antibodies as well as improved direct killing (Mossner et al. 2010). Obinutuzumab is currently 
FDA approved in combination with chlorambucil as initial therapy in CLL. In single-agent 
clinical trials with this agent, infusion reactions (mostly Grades 1 and 2) have been the most 
commonly observed adverse events (AEs). These reactions tend to occur only with the first 
infusion, and occasionally are associated with signs of tumor lysis syndrome (TLS). In 
combination with chlorambucil, Grades 3 and 4 thrombocytopenia and neutropenia have also 
been observed (in 12% and 34% of patients, respectively), and there have been documented 
cases of hepatitis B reactivation and progressive multifocal leukoencephalopathy (PML) 
associated with this agent. 
In combination with chemotherapy (fludarabine/chlorambucil or bendamustine), administration 
of obinutuzumab appears to be tolerable, and does not appear to induce added toxicity over that 
of chemotherapy itself (Brown et al. 2013). 
As described in Section 2.1, a 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 Score [CIRS] >6 or a creatinine clearance [CrCl] of 30 to 69 mL/minute). The 
median PFS, as confirmed by the IRC, was 26.7 months in the obinutuzumab plus chlorambucil 
arm as compared with 14.9 months with rituximab in combination with chlorambucil (HR=0.42; 
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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 MRD-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 
MRD-negative status in the bone marrow (p<0.001) (Goede et al. 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 Guidelines version 2.2015). 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%. 
 
2.4 
Rituximab 
Rituximab has been shown to be an effective treatment for CD20-positive B-cell malignancies 
and is commonly used both as a single agent and in combination with cytotoxic chemotherapy. 
Rituximab binds to CD20, a hydrophobic, transmembrane protein that is present on pre–B cells 
and mature B cells and in ≥90% of B-cell non-Hodgkin lymphomas (NHLs). Rituximab exerts 
its cytotoxic effects via complement-mediated B-cell lysis, ADCC, and induction of apoptosis 
(Cartron et al. 2004). 
In the US, rituximab has been approved by the FDA for the treatment of CLL. The European 
Medicines Agency (EMA) granted an approval for the use of rituximab in combination with 
chemotherapy for previously untreated CLL. The FDA approved the use of rituximab in 
combination with fludarabine and cyclophosphamide for patients with previously untreated and 
previously treated CD20-positive CLL. 
Rituximab is also being investigated in combination with venetoclax. The Murano Study 
(NCT02005471) is an open-label, multicenter, randomized, Phase 3 study to investigate the 
efficacy and safety of venetoclax in combination with rituximab compared with bendamustine in 
combination with rituximab in participants with relapsed or refractory CLL. The rationale for 
the combination of venetoclax with rituximab is partially based on the possible improved 
tolerability of rituximab in a generally older population (Eichhorst et al. 2016). 
Results from the Phase 1b M13-365 study showed combining venetoclax with rituximab led to 
objective responses in 86% of patients with relapsed/refractory CLL. The most frequently 
reported grade 3/4 AEs were neutropenia (53%), thrombocytopenia (16%), anemia (14%), febrile 
neutropenia (12%), and leukopenia (12%). Nonhematologic toxicities were common but 
generally mild, the most common being gastrointestinal (GI) toxicity. 

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2.5 
Venetoclax 
Venetoclax is a BCL-2 inhibitor indicated for the treatment of patients with CLL with 17p 
deletion, as detected by an FDA-approved test, who have received at least 1 prior therapy. 
Venetoclax is currently FDA approved for use as a single-agent therapy. 
The safety of single agent venetoclax at the 
 recommended 
 following a dose 
ramp-up schedule is based on pooled data of 240 patients with previously treated CLL from 
2 Phase 2 trials and 1 Phase 1 trial. The most common adverse reactions (≥20%) of any grade 
were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, 
and fatigue. Serious adverse reactions were reported in 43.8% of patients. The most frequent 
serious adverse reactions (≥2%) were pneumonia, febrile neutropenia, pyrexia, autoimmune 
hemolytic anemia (AIHA), anemia, and TLS. 
 
2.6 
Combination Therapy with a BTK Inhibitor Plus CD20 Monoclonal Antibody 
The combination of a BTK inhibitor with a CD20 monoclonal antibody is appealing because the 
rapid clearing of peripheral lymphocytosis that is seen with antibodies is expected to increase the 
rapidity of response with BTK inhibitors. Additionally, in the laboratory BTK inhibition 
antagonizes the tumor microenvironment (Herman et al. 2011), which may increase the bone 
marrow clearance, which is limited with rituximab. 
The combination of ibrutinib and the CD20 monoclonal antibodies ofatumumab or rituximab are 
currently being evaluated in relapsed CLL in 3 separate trials, of which 2 have published results 
as follows. 
One, a Phase 1b/2 study of ibrutinib 
 administered continuously until time of relapse 
and ofatumumab has enrolled 3 time-sequential cohorts. In the first cohort of 27 patients, 
ibrutinib begins on 
 and continues until disease progression, while ofatumumab begins at 
 
 All 27 patients completed the first month of therapy without a dose- 
limiting toxicity (DLT). Of the 24 patients with CLL, all attained a partial response (PR) (100%) 
with 23 remaining on treatment and 1 proceeding to a nonmyeloablative stem cell transplant. 
Infusion toxicities with ofatumumab were more modest than expected. Cohorts administering 
ofatumumab either concurrently or prior to ibrutinib have also been completed where feasibility 
was confirmed, but either early toxicity (concurrent schedule) or early progression (ofatumumab 
first arm) has resulted in choosing the run-in arm with ibrutinib for 
 followed by addition 
of ofatumumab for future study. 
In another Phase 2 trial performed at MD Anderson Cancer Center, which enrolled only patients 
with high-risk disease, rituximab and ibrutinib were administered concurrently beginning in 
 with 
 rituximab and then 
 administration for a total of 
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 In this trial, toxicities were modest, and responses were again seen at an earlier time 
point than expected from single-agent therapy (Burger et al. 2012). 
A third study, a Phase 3 trial of BR versus ibrutinib versus ibrutinib plus rituximab is currently 
accruing patients (A041202). Overall, experience with different administration sequences 
suggests that a run-in with BTK inhibitor for the 
 followed by initiation of antibody 
beginning 
 may be better tolerated, and in vivo pharmacodynamic studies support target 
modulation that would enhance tumor apoptosis. 
While combinations of ibrutinib with CD20 monoclonal antibodies are currently being pursued, 
laboratory data suggests that ibrutinib may not be the best BTK inhibitor for this. Our group has 
determined that besides inhibition of BTK, the homology between BTK and ITK leads to this 
drug functioning as an irreversible ITK inhibitor in vitro and in vivo in patients receiving this 
therapy (Dubovsky et al. 2013). While inhibiting ITK in T-cells may have benefit to diminish 
Th2 immune suppression, it has been shown in vitro to negatively impact NK-cell ADCC, 
thereby reducing the benefit of adding antibodies (Kluter et al. 2010). In addition, loss of ITK 
has been associated with fatal Epstein-Barr Virus (EBV) lymphoproliferative disorders, which 
have rarely been observed in patients receiving ibrutinib (Huck et al. 2009, Linka et al. 2012, 
Mansouri et al. 2012). 
 
2.7 
Combination Treatment with a BTK Inhibitor Plus BCL-2 Inhibitor 
Ibrutinib induces remissions in the majority of treated patients, but CR is uncommon even after 
prolonged administration. Early genetic studies have demonstrated that BCL-2 over-expression 
rescues BTK deficient XID murine B-cells from spontaneous apoptosis (Woodland et al. 1996). 
As such, combination therapy is being investigated clinically to determine whether the responses 
can be deepened. 
A Phase 2 trial (NCT02756897) of venetoclax and ibrutinib in patients with relapsed/refractory 
CLL is underway at MD Anderson Cancer Center assessing the rate of CR or PR; or CRi. 
Treatment-naive patients with high-risk disease (e.g., 17p deletion, mutated TP53) are also 
eligible. 
A Phase 1b/2 study (NCT02427451) of obinutuzumab, ibrutinib, and venetoclax in 
relapsed/refractory CLL is also underway at The Ohio State University. Obinutuzumab, 
ibrutinib, and venetoclax were started 
 Responses 
were assessed according to IWCLL 2008 criteria, including bone marrow biopsy with 4-color 
immunophenotyping of marrow and peripheral blood for MRD, after Cycles 8 and 14. The 
Phase 1b portion of the study established venetoclax 
 as the recommended Phase 2 
dose in this combination with no observed DLTs. Accrual to Phase 2 relapsed/refractory (n=25) 
and treatment-naive (n=25) CLL cohorts continues (Jones et al. 2016). A prospective, 
open-label, multicenter Phase 2 trial (NCT02758665) of ibrutinib plus venetoclax plus 
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obinutuzumab in physically fit (CIRS ≤6 and normal CrCl) and unfit (CIRS >6 and CrCl 
≥50 mL/min) patients with previously untreated CLL with TP53 deletion (17p-) and/or mutation 
is also underway (ClinicalTrials.gov, U.S. National Institutes of Health 2017). 
 
2.8 
Justification for a Trial Combining Acalabrutinib with Obinutuzumab/Rituximab 
with Venetoclax 
BTK inhibition is currently transforming the treatment of CLL. While patients appear to be 
having durable responses, very few responses are CR, which suggests that drug discontinuation 
will not be an option. The combination of BTK inhibition with CD20 antibody therapy is 
appealing to both expedite and potentially deepen these remissions. Of the CD20 antibodies 
available, obinutuzumab in combination with chemotherapy may be the most effective in the 
treatment of CLL and has shown the potential to induce complete and even MRD-negative 
responses (Goede et al. 2014). Rituximab has been shown to be better tolerated in older patients 
than obinutuzumab and has likewise demonstrated the potential for complete and MRD-negative 
responses in combination with venetoclax (Eichhorst et al. 2016). While ibrutinib is a BTK 
inhibitor with robust efficacy and safety data, the effect of ibrutinib on ITK has important 
implications for combining ibrutinib with CD20 antibodies, and justifies exploration of more 
selective BTK inhibitors, such as acalabrutinib, to optimize the addition of CD20 monoclonal 
antibodies to BTK inhibitor therapy. This Phase 1b trial therefore seeks to optimize the clinical 
efficacy and rates of MRD negativity of BTK inhibitor plus CD20 antibody therapy and 
venetoclax by exploring these combination therapies. With the approval of venetoclax and its 
possible synergistic effect with BTK inhibition and an anti-CD20 antibody, this study will 
further assess the safety of the combination with acalabrutinib, rituximab, and venetoclax in 
relapsed/refractory CLL subjects and acalabrutinib, obinutuzumab, and venetoclax in 
treatment-naive CLL subjects. 
 
3 
Patient Eligibility Criteria 
 
3.1 
Inclusion Criteria 
1. Subjects with a diagnosis of intermediate or high risk CLL (or variant 
immunophenotype), SLL, or B-cell prolymphocytic leukemia (B-PLL) by IWCLL 2008 
criteria (Hallek et al. 2008) who have: 
- Cohorts 1 and 3: Previously received at least 1 therapy for their disease (Cohort 3 
enrollment limited to CLL). 
- Cohort 2: Previously untreated disease and ≥65 years old OR under 65 years old and 
refuse or are ineligible for chemoimmunotherapy. 
- Cohort 4: Previously untreated disease; Cohort 4 enrollment limited to CLL. 

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2. Subjects in Cohorts 1 and 3 may have received previous ibrutinib (or another BTK 
inhibitor) as long as discontinuation was for a reason other than on-treatment disease 
progression. 
3. All subjects must satisfy one of the following criteria for active disease requiring therapy: 
- Evidence of marrow failure as manifested by the development or worsening of 
anemia or thrombocytopenia (not attributable to AIHA or thrombocytopenia) 
- Massive (≥6 cm below the costal margin), progressive or symptomatic splenomegaly 
- Massive nodes (≥10 cm) or progressive or symptomatic lymphadenopathy 
- Constitutional symptoms, which include any of the following: 
• Unintentional weight loss of 10% or more within 6 months 
• Significant fatigue limiting activity 
• Fevers ≥100.5°F for 2 weeks or more without evidence of infection 
• Night sweats >1 month without evidence of infection 
4. This criterion was removed with Amendment 5. 
5. Subjects with a history of Richter’s syndrome are eligible if they now have evidence of 
CLL only, with <10% large cells in the bone marrow. 
6. Subjects must have adequate organ function, defined as creatinine ≤2.5 times the upper 
limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤3.0 x ULN, and bilirubin ≤2.5 x ULN. For Cohorts 3 and 4, subjects must have 
creatinine clearance ≥50 mL/min using modified Cockcroft-Gault equation (using Ideal 
Body Mass [IBM] instead of mass): 
7. IBM (kg) = [(height cm – 154) ● 0.9] + (50 if male, 45.5 if female). 
8. Platelets >50 x 109/L. In subjects with CLL involvement of the marrow, >30 x 109/L for 
Cohorts 1 and 2.  For Cohorts 3 and 4, subjects must have hemoglobin >9 g/dL. 
9. Absolute neutrophil count (ANC) ≥750/mm3. In subjects with CLL involvement of the 
marrow, ANC ≥500/mm3.  For Cohorts 3 and 4, subjects must have ANC ≥1000/mm3. 
10. Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status 
≤2. 
11. Subject must not have secondary cancers that result in a life expectancy of <2 years or 
that would confound assessment of toxicity in this study. 
12. Subjects must be ≥18 years of age. 
13. Subject must provide written informed consent. A signed copy of the consent form will 
be retained in the subject’s chart. 

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14. Subject must be able to receive outpatient treatment and follow-up at the treating 
institution. 
15. Subject must have completed all CLL therapies ≥4 weeks prior to first study dose. 
Palliative steroids are allowed but must be at a dose equivalent of ≤20 mg prednisone 
daily for at least 1 week prior to treatment initiation. 
16. 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, 30 days after the last dose of venetoclax, 12 months the last dose of 
rituximab, or 18 months after the last dose of obinutuzumab, whichever is the longest 
period following the subject’s study drug discontinuation. Men who are sexually active 
and able to have children must agree to use highly effective methods of contraception 
during the study and use a barrier method (condom; even if the subject had a vasectomy) 
for 2 days after the last dose of acalabrutinib, 18 months after the last dose of 
obinutuzumab, or 12 months after the last dose of rituximab, or 30 days after the last dose 
of venetoclax, whichever is longer. Highly effective forms of contraception are defined 
in Section 6.4.3. Additionally, men must agree to refrain from sperm donation during the 
study and for 18 months after the last dose of obinutuzumab, or 12 months after the last 
dose of rituximab, or 30 days after the last dose of venetoclax, whichever is longer. 
17. Subjects must be able to swallow whole capsules. 
18. Inclusion of women and minorities: Subjects of both genders and all racial/ethnic groups 
are eligible for the study if they meet eligibility criteria outlined. To date, there is no 
information that suggests that differences in drug metabolism or disease response would 
be expected in one group compared with another. The small number of subjects in a 
Phase 1b trial precludes any analysis of data to compare subject subgroups based on 
gender or race/ethnicity. 
 
3.2 
Exclusion Criteria 
1. For Cohorts 2 and 4, received previous therapy for CLL. Treatment of autoimmune 
complications of CLL with steroids or rituximab is allowed, however, CD20 must have 
returned on 10% of the CLL cells if rituximab was recently administered. Palliative 
steroids are acceptable at doses ≤20 mg prednisone equivalent daily. 
2. Any life-threatening illness, medical condition, or organ dysfunction, which in the 
investigator’s opinion, could compromise the subjects’ safety, interfere with the 
absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk. 
3. Female subjects who are pregnant or breastfeeding. 
4. Subjects with active cardiovascular disease not medically controlled or those who have 
had myocardial infarction in the past 6 months, or corrected QT interval (QTc) ≥480 ms. 
5. Malabsorption syndrome, disease significantly affecting GI function, or resection of the 
stomach or small bowel or gastric bypass, ulcerative colitis, symptomatic inflammatory 
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6. Grade ≥2 toxicity (other than alopecia) continuing from prior anticancer therapy 
including radiation. 
7. Major surgery within 4 weeks before first dose of study drug. 
8. History of a bleeding diathesis (e.g., hemophilia, Von Willebrand disease). 
9. Uncontrolled AIHA or idiopathic thrombocytopenia purpura. 
10. History of stroke or intracranial hemorrhage within 6 months before the first dose of 
study drug. 
11. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists 
(e.g., phenprocoumon) within 28 days of first dose of study drug. 
12. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). 
13. Subjects with active infections requiring intravenous (IV) antibiotic/antiviral therapy are 
not eligible for entry onto the study until resolution of the infection. Subjects on 
prophylactic antibiotics or antivirals are acceptable. 
14. Subjects with history of or ongoing drug-induced pneumonitis. 
15. Subjects with human immunodeficiency virus (HIV) or active infection with hepatitis C 
virus (HCV) or hepatitis B virus (HBV) or any uncontrolled active systemic infection. 
16. Serologic status reflecting active hepatitis B or C infection. 
a. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis 
B surface antigen (HBsAg) negative will need to have a negative hepatitis B DNA 
result by polymerase chain reaction (PCR) before randomization. Those who are 
HBsAg-positive and/or hepatitis B PCR positive will be excluded. 
b. Subjects receiving prophylactic intravenous immunoglobulin (IVIG) may have 
positive hepatitis serologies. Subjects who are on IVIG who have positive hepatitis 
serologies must have a negative hepatitis B DNA to be eligible. 
c. Subjects with a history of HBV infection but negative HBV serologies at screening 
must also have a negative HBV PCR to be eligible. 
d. Subjects with a known history of hepatitis C or who are hepatitis C antibody positive 
should be tested for HCV RNA during screening. Subjects who are hepatitis C 
antibody positive will need to have a negative PCR result before randomization. 
Those who are hepatitis C PCR positive will be excluded. No further testing beyond 
screening is necessary if PCR results are negative. However, in the setting of rising 
transaminase and/or bilirubin levels, HCV PCR testing should be performed when 
clinically indicated. 
17. Subjects with substance abuse or other medical or psychiatric conditions that, in the 
opinion of the investigator, would confound study interpretation or affect the subject’s 
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18. Subjects cannot concurrently participate in another therapeutic clinical trial. 
19. Subject who have received a live virus vaccination within 1 month of starting study drug. 
 
4 
Registration of Patients 
 
4.1 
Informed Consent 
The subject must be aware of the neoplastic nature of his/her disease and willingly consent after 
being informed of the procedure to be followed, the experimental nature of the therapy, 
alternatives, potential benefits, side effects, risks, and discomforts. Human protection committee 
approval of this protocol and a consent form are required. Written informed consent will be 
obtained by a co-investigator or a specific designee previously approved by The Ohio State 
University Institutional Review Board (IRB), using forms approved by the IRB. 
 
4.2 
Registration Procedure 
The study will be conducted at 1 site in the US. The principal investigator/scientific protocol 
chairman will serve as the liaison with Acerta and will coordinate protocol management. 
Subjects will undergo an initial assessment to determine eligibility and to determine baseline 
disease status prior to study enrollment. Subjects will be registered through the database of The 
Ohio State University Clinical Trials Office and provide written informed consent. All subjects 
for whom questions arise relative to eligibility for the study should be discussed with the medical 
monitor prior to entry onto the study. 
To ensure timely communication of treatment tolerance, the progress of each subject will be 
discussed with the principal investigator on a monthly basis, or as needed, with any AEs being 
promptly communicated to the principal investigator by the treating physician or designee to 
ensure safe treatment of other subjects in the study. 
 
5 
Study Drugs and Administration Guidelines 
 
5.1 
Acalabrutinib Formulation, Packaging, and Storage 
Acalabrutinib drug substance and drug product are manufactured according to cGMP and will be 
provided to the investigational site by Acerta Pharma, BV, or a designee in hard gelatin capsules 
intended for oral administration. Each capsule contains 
 
Acalabrutinib will be provided in white, high-density polyethylene bottles. 
 
Labels for study drug bottles will meet all applicable requirements of the US FDA, Annex 13 of 
cGMP (Manufacture of Investigational Medicinal Products, July 2003), and/or other local 
regulations, as applicable. Each bottle is closed with a white, continuous-thread, child-resistant, 
polypropylene screw cap. 
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Bottles containing acalabrutinib will be shipped and stored at room temperature (approximately 
15°C to 30°C). The recommended storage condition for acalabrutinib capsules is below 30°C. 
If a drug shipment arrives damaged, or if there are any other drug complaints, a Product 
Complaint Form should be completed and faxed to the sponsor or the sponsor’s representative. 
Refer to the acalabrutinib Investigator Brochure for additional information regarding the drug 
product to be used in this trial. 
 
5.2 
Drug Preparation and Administration 
 
5.2.1 
Acalabrutinib Administration 
Acalabrutinib is intended to be administered orally 
 
 The capsules should be swallowed intact and subjects should not attempt to open capsules 
or dissolve them in water. Acalabrutinib can be taken with or without food. For Cohorts 3 and 
4, venetoclax should be given first, followed at least 30 minutes later by acalabrutinib. 
Anti-CD20 antibody (i.e., rituximab or obinutuzumab) should be administered last, at least 
1 hour after acalabrutinib. 
In this study, acalabrutinib is to be administered 
 
 Note: Any subjects enrolled on the prior versions of the protocol were switched from 
acalabrutinib 
 as of Protocol Amendment 4. 
It is recommended that acalabrutinib be taken as close to the scheduled time as possible 
(preferably within ±1 hour). However, if a dose is missed, it can be taken up to 3 hours after the 
scheduled time with a return to the normal schedule with the following dose. If it has been 
greater than 3 hours, the dose should not be taken, and the subject should take the next dose at 
the next scheduled time. 
Subjects will receive a diary to record the specific time each dose was taken and to record 
reasons for any missed doses. Compliance will be assessed at every visit. Subjects will be 
instructed to bring the diary and any remaining capsules to the clinic at their next visit. The 
administrator will review the diary and ask the subject if all of the capsules were administered. 
Any remaining or returned capsules will be counted and recorded as described in Section 15.7. 
Returned capsules must not be redispensed to the same subject or to another subject. The study 
staff will resupply the subject with the correct number of capsules needed for use until the next 
visit. 
For subjects considered at risk for TLS, administer appropriate hydration and allopurinol or 
rasburicase per institutional standards prior to initiating treatment. 
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5.3 
Dose Delays 
Any clinically important events where dose delays may be considered appropriate by the 
investigator must be discussed with the medical monitor. 
• 
Note: Temporary withholding of study drug for as little as 7 days can cause a 
transient worsening of disease and/or of constitutional symptoms. 
Transient worsening of disease during temporary interruption of study therapy (e.g., for 
intercurrent illness, drug-related toxicity, or surgery) may also not indicate definitive disease 
progression. In these instances, relevant clinical, laboratory, and/or radiographic assessment 
should be attempted to document whether definitive disease progression has occurred. If 
subsequent evaluations suggest that the subject has experienced persistent definitive disease 
progression, then the date of progression will be the time point at which progression was first 
objectively documented. 
Study treatment should be discontinued in the event of a toxicity lasting >28 days, unless 
reviewed and approved by the medical monitor. For full study treatment discontinuation criteria, 
refer to Section 11. 
 
5.3.1 
Obinutuzumab Administration 
Obinutuzumab will be obtained commercially as a standard therapy for CLL. Complete details 
on recommended premedications are provided in the prescribing information. 
Obinutuzumab will be administered by IV infusion as an absolute (flat) dose. Obinutuzumab 
will be administered in a single day, with the exception of the first administration when subjects 
will receive their first dose of obinutuzumab over 
 
 For subjects treated at 
 
obinutuzumab), 
 will be given on 
 and 
 on 
 
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Table 1: Dose of Obinutuzumab to be Administered During 
 , Each of 
 Duration 
 
Day of Treatment Cycle 
Dose of 
Obinutuzumab 
Rate of Infusion 
(in the absence of infusion reactions/ 
hypersensitivity during previous infusions) 
 
On days when both acalabrutinib and obinutuzumab are given, the order of study treatment 
administration could be acalabrutinib followed at least 1 hour later by obinutuzumab. 
Obinutuzumab should be administered via IV infusion through a dedicated line. Do not 
administer as an IV push or bolus. Administration of obinutuzumab should occur at least 1 hour 
after the acalabrutinib dose on days of concomitant dosing. 
 
5.3.2 
Venetoclax Administration 
Venetoclax will either be obtained commercially, if available, or be supplied by Acerta. 
Preparation and administration are per prescribing information. 
Assess subject-specific factors for level of risk of TLS and provide prophylactic hydration and 
antihyperuricemics to subjects prior to first dose of venetoclax to reduce risk of TLS (see Dosage 
and Administration and Warnings and Precautions in the venetoclax prescribing information). 
Administer the venetoclax dose according to a 
 to the 
recommended 
 as shown in Table 2. The 
 dosing schedule 
is designed to gradually reduce tumor burden (debulk) and decrease the risk of TLS. Venetoclax 
should be given first, followed at least 30 minutes later by acalabrutinib. 
Instruct subjects to take venetoclax tablets with a meal and water at approximately the same time 
each day. Venetoclax tablets should be swallowed whole and not chewed, crushed, or broken 
prior to swallowing. 
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Table 2: Dosing Schedule for 
 Phase of Venetoclax Dosing 
 
Week 
Venetoclax 
 Dose 
 
5.3.3 
Rituximab Administration 
Rituximab will be obtained commercially as a standard therapy for CLL. Preparation and 
administration are per prescribing information. Complete details on recommended 
premedications are provided in the prescribing information. 
The rituximab regimen will be
 
 Administration of 
rituximab should occur 
 the acalabrutinib dose on days of concomitant 
dosing. 
 
5.3.4 
Drug Supply Records 
Accurate accounting of all study medication must be maintained. Drug disposition records must 
be kept in compliance with applicable guidelines and regulations. 
 
6 
Treatment Plan 
 
6.1 
Overview 
 
6.1.1 
Acalabrutinib Plus Obinutuzumab 
In the Phase 1b dose-escalation portion of the study, 2 cohorts (Cohort 1, relapsed/refractory and 
Cohort 2, treatment-naive) will be evaluated with slightly staggered enrollment. First, 6 subjects 
with relapsed/refractory CLL will be enrolled into Cohort 1. Once the safety has been evaluated, 
the relapsed/refractory cohort will be expanded to 26 subjects and enrollment of 
6 treatment-naive subjects can begin in Cohort 2. Once safety is established for Cohort 2, then 
the cohort will be expanded to 19 subjects (Phase 1b expansion portion). 
Each cycle will be 
 
 
Acalabrutinib will be administered starting 
 and will be administered 
 
 until disease progression. 
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Obinutuzumab will be given in the standard dosing fashion starting on 
 
 On 
 subjects will receive 
 IV. On 
 subjects 
will receive 
 On 
 subjects will receive 
 IV. On 
 
 subjects will receive 
 of each cycle. For subjects treated at 
 
 will be given on 
 and 
 on 
 On 
 
subjects will receive 
 IV and during 
 subjects will receive 
 on 
 
of each cycle. 
It is acceptable for cycles to begin 
 
 of a new cycle. For example, if the treatment due date is a 
 
New cycles can be started up to 
 the protocol-defined date for 
major life events (e.g., serious illness in a family member, major holiday, vacation that cannot be 
rescheduled). Documentation to justify a delay or advance of a cycle should be provided. 
In Cohorts 1 and 2, subjects who achieve a bone marrow MRD-negative CR have the option to 
discontinue acalabrutinib. 
 
6.1.2 
Acalabrutinib Plus Venetoclax plus Rituximab or Obinutuzumab 
In the acalabrutinib plus venetoclax plus rituximab or obinutuzumab Phase 1b portion of the 
study, 12 subjects with relapsed/refractory CLL and 12 subjects with treatment-naive CLL will 
be enrolled into Cohorts 3 and 4, respectively. Subjects in Cohort 3 will be treated with 
acalabrutinib, rituximab, and venetoclax. Subjects in Cohort 4 will be treated with acalabrutinib, 
obinutuzumab, and venetoclax. Based on the safety observed with the combination of ibrutinib, 
venetoclax, and obinutuzumab in an ongoing study (Jones et al. 2016), safety will be reviewed 
for the first 3 subjects who complete Cycle 3 in each cohort. The review will be repeated for 
additional subjects if needed. Unless a safety concern is identified (e.g., dose delays 
 
 enrollment in Cohorts 3 and 4 will continue during the safety review until the desired 
number of subjects is reached. There are no DLTs defined for this portion of the study. See 
Section 5 for study drugs and administration guidelines. 
 
6.1.2.1 
Cohort 3 – Relapsed or Refractory CLL 
Acalabrutinib will be administered starting 
 until disease 
progression. Subjects who received at least 
 of treatment and achieved CR, CRi, and/or 
MRD negativity may have therapy discontinued at investigator discretion. 
Rituximab will be given at a starting dose of 
 followed by 
 
 
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Venetoclax will be given in the standard dosing fashion starting on 
 On 
 
 subjects will receive 
 orally 
 for 
 On 
 subjects will 
receive 
 orally 
 for 
 On 
 subjects will receive 
 orally 
 for 
  On 
 subjects will receive 
 orally 
 for 
 
Beginning with 
 subjects will receive 
 orally 
 until the completion of 
 (Table 2). 
Each cycle will be 
 
 
It is acceptable for cycles to begin 
 
 of a new cycle. For example, if the treatment due date is a 
 
 New cycles can be started up to 
 the protocol-defined date for 
major life events (e.g., serious illness in a family member, major holiday, vacation that cannot be 
rescheduled). Documentation to justify a delay or advance of a cycle should be provided. 
 
6.1.2.2 
Cohort 4 – Treatment-naive CLL 
Acalabrutinib will be administered starting 
 until disease 
progression. Subjects who received at least 
 of treatment and achieved CR, CRi, and/or 
MRD negativity may have therapy discontinued at investigator discretion. 
Obinutuzumab will be given in the standard dosing fashion starting on 
 On 
 subjects will receive 
 IV. On 
 subjects will receive 
 On 
 subjects will receive 
 IV. On 
 
subjects will receive 
 of each cycle. There will be a total of  obinutuzumab 
infusions through the end of 
 For subjects treated at 
 will be given 
on 
 and 
 on 
 On 
 subjects will receive 
 IV and during 
 subjects will receive 
 on 
 of each cycle. 
Venetoclax will be given in the standard dosing fashion starting on 
 On 
 
 subjects will receive 
 orally 
 for 
 On 
 subjects will 
receive 
 orally 
 for 
 On 
 subjects will receive 
 orally 
 for 
  On 
 subjects will receive 
 orally 
 for 
 
Beginning with 
 subjects will receive 
 orally 
 until the completion of 
 (see Table 2). 
Each cycle will be 
 
 
It is acceptable for cycles to begin 
 
 of a new cycle. For example, if the treatment due date is a 
 
New cycles can be started up to 
 the protocol-defined date for 
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major life events (e.g., serious illness in a family member, major holiday, vacation that cannot be 
rescheduled). Documentation to justify a delay or advance of a cycle should be provided. 
 
6.2 
Premedications 
 
6.2.1 
Premedication for Acalabrutinib 
No premedication is required for acalabrutinib administration. 
 
6.2.2 
Premedication for Obinutuzumab 
Thirty to 60 minutes prior to the first dose of obinutuzumab, subjects may receive: 
• Acetaminophen 650 mg orally 
• Diphenhydramine 50 mg IV; this may be reduced or discontinued by the treating physician if 
it is not tolerated due to side effects. 
• Dexamethasone 20 mg IV 
Premedication may continue for all subsequent doses of obinutuzumab at the discretion of the 
investigator, but diphenhydramine and dexamethasone may be discontinued in subjects who do 
not experience an infusion reaction after 2 doses.  Refer to the prescribing information. 
 
6.2.3 
Premedication for Venetoclax 
Venetoclax can cause rapid reduction in tumors and thus poses a risk for TLS in the initial 
 phase. Changes in blood chemistries consistent with TLS requiring prompt 
management can occur as early as 6 to 8 hours following the first dose of venetoclax and at each 
dose increase. 
The risk of TLS is a continuum based on multiple factors, including tumor burden and 
comorbidities. Perform tumor burden assessments, including radiographic evaluation (e.g., 
computed tomography [CT] scan), assess blood chemistry (potassium, uric acid, phosphorus, 
calcium, and creatinine) in all subjects and correct pre-existing abnormalities prior to initiation of 
treatment with venetoclax. A repeat CT scan may be performed at Cycle 2, Day 21 (±3 days) in 
subjects at high risk of TLS, at investigator’s discretion. Reduced renal function (CrCl 
<80 mL/min) further increases the risk. The risk may decrease as tumor burden decreases [see 
VENCLEXTA™ prescribing information: Warnings and Precautions (5.1) and Use in Specific 
Populations (8.6)]. 
Table 3 below describes the recommended TLS prophylaxis and monitoring during venetoclax 
treatment based on tumor burden determination from clinical trial data. All subject 
co-morbidities should be considered before final determination of prophylaxis and monitoring 
schedule. 
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Table 3: Recommended Tumor Lysis Syndrome Prophylaxis for Venetoclax Based on 
Tumor Burden from Clinical Trial Data 
 
Tumor Burden 
Prophylaxis 
Blood Chemistry Monitoringc,d 
Hydrationa 
Antihyperuricemics 
Setting and Frequency of 
Assessments 
Low 
All LN <5 cm 
AND 
ALC <25 x 109/L 
Oral (1.5 to 2 L) 
Allopurinolb 
Outpatient 
• Predose, 6 to 8 hours, 24 hours 
at first dose of 
 and 
 
• Predose at subsequent ramp-up 
doses 
Medium 
Any LN 5 cm to 
<10 cm 
OR 
ALC ≥25 x 109/L 
Oral (1.5 to 2 L) 
and consider 
additional 
intravenous 
Allopurinol 
Outpatient 
• Predose, 6 to 8 hours, 24 hours 
at first dose of 
 and 
 
• Predose at subsequent ramp-up 
doses 
• Consider hospitalization for 
subjects with CrCl 
<80 mL/min at first dose of 
 and 
 see below 
for monitoring in hospital 
High 
Any LN ≥10 cm 
OR 
ALC ≥25 x 109/L 
AND 
any LN ≥5 cm 
Oral (1.5 to 2 L) 
and intravenous 
(150 to 
200 mL/hr as 
tolerated) 
Allopurinol; 
consider rasburicase 
if baseline uric acid 
is elevated 
In hospital at first dose of 
 
and 
 
• Predose, 4, 8,12 and 24 hours 
Outpatient at subsequent ramp- 
up doses 
• Predose, 6 to 8 hours, 24 hours 
ALC = absolute lymphocyte count; CrCl = creatinine clearance; LN = lymph node; TLS = tumor lysis syndrome 
a Administer intravenous hydration for any subject who cannot tolerate oral hydration. 
b Start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of venetoclax. 
c Evaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine), review in real time. 
d For subjects at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each subsequent 
ramp-up dose. 
 
 
6.2.4 
Premedication for Rituximab 
Premedicate before each rituximab infusion with acetaminophen and an antihistamine in 
accordance with prescribing information or institutional standards. 
 
6.3 
Concomitant Medications 
All concomitant medications (including over-the-counter medications and herbal preparations) 
must be recorded in the subject’s chart. There are no required concomitant medications on this 
study. 
Avoid co-administration of strong CYP3A inhibitors with acalabrutinib. Alternatively, if the 
inhibitor will be used short term, interrupt acalabrutinib. When acalabrutinib is administered 
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with moderate CYP3A inhibitors, reduce acalabrutinib dose to 
 Avoid co- 
administration of strong CYP3A inducers with acalabrutinib. If a strong CYP3A inducer cannot 
be avoided, increase the acalabrutinib dose to 
 A list of inhibitors/inducers of 
CYP3A can be found in Appendix 1. 
Separate dosing of acalabrutinib with antacids by at least 2 hours. Acalabrutinib should be taken 
2 hours before an H2-receptor antagonist. Avoid co-administration with proton pump inhibitors. 
Concomitant use of venetoclax with strong CYP3A inhibitors at initiation and during ramp-up 
phase is contraindicated. Concomitant use of venetoclax with strong CYP3A inhibitors increases 
venetoclax exposure (i.e., Cmax and area under the plasma concentration-time curve [AUC]) and 
may increase the risk for TLS at initiation and during ramp-up phase [see VENCLEXTA 
prescribing information, Contraindications (4)]. For subjects who have completed the ramp-up 
phase and are on a steady daily dose of venetoclax, reduce the venetoclax dose by at least 75% 
when strong CYP3A inhibitors must be used concomitantly. 
Avoid concomitant use of venetoclax with moderate CYP3A inhibitors or P-gp inhibitors. 
Consider alternative treatments. If a moderate CYP3A inhibitor or a P-gp inhibitor must be 
used, reduce the venetoclax dose by at least 50%. Monitor these subjects more closely for signs 
of toxicities [see prescribing information, Dosage and Administration (2.4)]. Resume the 
venetoclax dose that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2 to 
3 days after discontinuation of the inhibitor [see VENCLEXTA prescribing information, Dosage 
and Administration (2.4) and Drug Interactions (7.1)]. 
At the systemic exposure levels expected in this study, venetoclax inhibition of CYP metabolism 
is not anticipated. 
The following is a list of permitted and prohibited medications: 
 
Permitted 
• Allopurinol at a dose of up to 300 mg daily is recommended for subjects at high risk TLS and 
should begin at least 3 days prior to the start of protocol therapy. 
• Rasburicase is permitted at the discretion of the investigator if clinical suspicion for TLS is 
very high, or if TLS occurs. 
• IVIG at standard doses for prophylaxis of recurrent infections 
• Anti-emetics, antidiarrheals, anticholinergics, antispasmodics, antipyretics, antihistamines, 
analgesics, antibiotics, and other medications intended to treat symptoms. 
• Prophylactic antivirals are permitted at the discretion of the treating physician. 
• Prophylactic filgrastim or pegfilgrastim is not permitted before the first dose of medications 
but may be administered in subjects who experience Grade 3 or 4 neutropenia per American 
Society of Clinical Oncology (ASCO) guidelines. 
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• Transfusions of packed red blood cells or platelets are permitted at the discretion of the 
investigator. All transfusions should be leukopore filtered and irradiated. 
Prohibited 
• 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. 
• Warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) are prohibited. 
• For subjects in Cohorts 3 and 4, use of strong or moderate CYP3A inhibitors or inducers 
within 7 days of the first dose of venetoclax is prohibited. Concomitant use of strong 
inhibitors of CYP3A during venetoclax ramp-up phase is contraindicated. 
 
6.4 
Risks Associated with Study Treatment 
 
6.4.1 
Risks Associated with Acalabrutinib Treatment 
The following summarizes the experience with acalabrutinib in hematological cancer studies. 
Full details regarding the clinical safety of acalabrutinib are presented in Sections 5 and 6 of the 
acalabrutinib Investigator Brochure. 
 
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. Patients receiving antithrombotic agents 
may be at increased risk of hemorrhage. Use caution with antithrombotic agents and consider 
additional monitoring for signs of bleeding when concomitant use is medically necessary. 
Consider the benefit-risk of withholding acalabrutinib for at least 3 days presurgery and 
postsurgery. Subjects with hemorrhage should be managed per institutional guidelines with 
supportive care and diagnostic evaluations as clinically necessary. 
 
6.4.1.2 
Infections 
Serious infections (bacterial, viral, and fungal), including fatal events, have occurred in clinical 
studies with acalabrutinib. The most frequent reported Grade ≥3 infection was pneumonia 
(preferred term). 

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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. 
Refer to Section 6.4.5 and Section 7.2.2.2 for additional information and monitoring guidance for 
viral hepatitis and Section 6.4.6 and Section 7.2.2.2 for additional information and management 
guidance for signs and symptoms of PML. 
6.4.1.3 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias, including neutropenia, anemia, and 
thrombocytopenia have occurred in clinical studies with acalabrutinib. Monitor blood counts as 
specified in the Schedule of Assessments and as medically appropriate. Please refer to Section 7 
for study drug modification guidance. 
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. 
 
6.4.1.4 
Second Primary Malignancies 
Second primary malignancies, including solid tumors and skin cancers, have been reported in 
patients treated with acalabrutinib. The most frequent second primary malignancy was skin 
cancer (basal cell carcinoma). 
Subjects should be monitored for signs and symptoms of malignancy. Subjects who develop a 
second primary malignancy should be managed according to institutional guidelines with 
diagnostic evaluations as clinically indicated, and it may be necessary for subjects to 
permanently discontinue study treatment. Continuation of acalabrutinib treatment should be 
discussed with the medical monitor. Please refer to Section 10.5.1 for second primary 
malignancy reporting guidance. 
 
6.4.1.5 
Atrial Fibrillation 
Events of atrial fibrillation or 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. 
 
6.4.2 
Contraindications, Warnings, and Precautions 
For study drugs other than acalabrutinib, please refer to the respective US prescribing 
information. 

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6.4.2.1 
Obinutuzumab 
Contraindications 
Obinutuzumab is contraindicated in subjects with known hypersensitivity reactions (e.g., 
anaphylaxis) to obinutuzumab or to any of the excipients, or serum sickness with prior 
obinutuzumab use. 
 
Warnings and Precautions 
• Infusion-related Reactions:  IRR were the most frequently observed adverse drug reactions in 
subjects receiving obinutuzumab and occurred predominantly during infusion of the first 
 IRR may be related to cytokine release syndrome, which has also been reported in 
obinutuzumab-treated subjects. In the majority of subjects, IRRs were mild to moderate and 
could be managed by slowing or temporary halting of the first infusion, but severe and 
life-threatening IRRs have also been reported. Mitigation measures to reduce IRRs should be 
followed (see local prescribing information and Section 7.2.2). 
Patients must not receive further obinutuzumab infusions if they experience: 
• Acute life-threatening respiratory symptoms, 
• Grade 4 (i.e., life-threatening) IRR or, 
• Second occurrence of a Grade 3 (prolonged/recurrent) IRR (after resuming the first infusion 
or during a subsequent infusion). 
Subjects who have pre-existing cardiac or pulmonary conditions should be monitored carefully 
throughout the infusion and post-infusion period.  Since hypotension may occur, withholding of 
antihypertensive treatments should be considered for 12 hours before and throughout each 
obinutuzumab infusion and for the first hour after administration. 
• Hypersensitivity Reactions: Hypersensitivity reactions with immediate (e.g., anaphylaxis) 
and delayed onset (e.g., serum sickness) have been reported in subjects treated with 
obinutuzumab and may be difficult to clinically distinguish from IRRs. However, 
hypersensitivity very rarely occurs with the first infusion and, when observed, often occurs 
after previous exposure. If a hypersensitivity reaction is suspected during or after an 
infusion, the infusion must be stopped, and treatment permanently discontinued. Subjects 
with known hypersensitivity to obinutuzumab are not eligible for enrollment in this study. 
• Tumor Lysis Syndrome: TLS has been reported with obinutuzumab. 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 [CrCl <70 mL/min]) 
should receive prophylaxis as described in the obinutuzumab prescribing information. 
Mitigation measures to reduce risk of TLS should be followed (see local prescribing 
information and Section 7.1.1). 
• Neutropenia: Severe and life-threatening neutropenia, including febrile neutropenia, has 
been reported during treatment with obinutuzumab. Refer to Section 7.1.1 and local 
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prescribing information for dose modification and discontinuation guidance. Supportive 
measures for any signs of infection should be considered. Subjects with renal impairment 
(CrCl <50 mL/min) are more at risk of neutropenia. 
• Thrombocytopenia: Severe and life-threatening thrombocytopenia, including acute 
thrombocytopenia (occurring within 24 hours after the infusion), has been observed during 
treatment with obinutuzumab. Fatal hemorrhagic events have also been reported in Cycle 1 
in subjects treated with obinutuzumab. A clear relationship between thrombocytopenia and 
hemorrhagic events has not been established. 
• Worsening of Pre-existing Cardiac Conditions: Worsening of pre-existing cardiac conditions 
has been reported with obinutuzumab. In subjects with underlying cardiac disease, 
arrhythmias (such as atrial fibrillation and tachyarrhythmia), angina pectoris, acute coronary 
syndrome, myocardial infarction, and heart failure have occurred when treated with 
obinutuzumab. These events may occur as part of an IRR and can be fatal. Therefore, 
subjects with a history of cardiac disease should be monitored closely. 
• Infections, Including HBV and PML: Obinutuzumab should not be administered in the 
presence of an active infection, and caution should be exercised when considering the use of 
obinutuzumab in subjects with a history of recurring or chronic infections. Fatal infections 
have been reported. 
HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can 
occur in subjects treated with anti-CD20 antibodies including obinutuzumab. Refer to 
Section 6.4.5 for additional information and monitoring guidance for viral hepatitis. 
 
PML has been reported in subjects treated with obinutuzumab. Refer to Section 6.4.6 for 
additional information and management guidance for signs and symptoms of PML. 
Obinutuzumab should be withheld during the investigation of potential PML and permanently 
discontinued in case of confirmed PML. 
• Immunizations: The safety of immunization with live or attenuated viral vaccines following 
obinutuzumab therapy has not been studied and vaccination with live virus vaccines is not 
recommended during treatment and until B-cell recovery. 
 
6.4.2.2 
Venetoclax 
Contraindications 
Concomitant use of venetoclax with strong CYP3A inhibitors at initiation and during the ramp-up 
phase is contraindicated. 
Warnings and Precautions 
• TLS: TLS, including fatal events and renal-failure requiring dialysis, has occurred in 
previously treated patients with CLL and high tumor burden when treated with 
venetoclax. Mitigation measures to reduce risk of TLS should be followed (see 
venetoclax prescribing information and Section 5.3.2). 

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• 
Drug interactions, including CYP3A: Although the risk of TLS is a continuum based on 
multiple factors, concomitant use of venetoclax with strong or moderate CYP3A 
inhibitors increases venetoclax exposure and may increase the risk for TLS at initiation 
and at the dose titration phase. Inhibitors of P-gp or breast cancer resistance protein 
(BCRP) may also increase venetoclax exposure. Additional information on venetoclax 
drug interactions is provided in Section 6.3, and dose modification information is 
provided in Section 7.1.2. 
• Neutropenia: Grade 3 or 4 neutropenia has been reported in subjects treated with 
venetoclax. Refer to Section 7.1.2 for local prescribing information for dose 
modification and discontinuation guidance. Supportive measures for any signs of 
infection should be considered. 
• Immunization: Do not administer live attenuated vaccines prior to, during, or after 
venetoclax treatment until B-cell recovery occurs. The safety and efficacy of 
immunization with live attenuated vaccines during or following venetoclax therapy have 
not been studied. 
• Embryofetal toxicity: Based on its mechanism of action and findings in animals, 
venetoclax may cause embryofetal harm when administered to a pregnant woman. Refer 
to Section 6.4.3 for additional reproductive toxicity information and contraception 
guidance. 
 
6.4.2.3 
Rituximab 
• TLS: Administer aggressive IV hydration, antihyperuricemic agents, and monitor renal 
function. 
• Infections: Withhold rituximab and institute appropriate anti-infective therapy. 
• Cardiac arrhythmias and angina: Discontinue infusions in case of serious or 
life-threatening events. 
• Bowel obstruction and perforation: Consider and evaluate for abdominal pain, vomiting, 
or related symptoms. 
• Live virus vaccines: Do not administer live virus vaccines prior to or during rituximab. 
• Cytopenias: Monitor blood counts at regular intervals. 
• Infusion reactions: Rituximab administration can result in serious, including fatal 
infusion reactions. Deaths within 24 hours of rituximab infusion have occurred. 
Approximately 80% of fatal infusion reactions occurred in association with the first 
infusion. Monitor patients closely. Discontinue rituximab infusion for severe reactions 
and provide medical treatment for Grade 3 or 4 infusion reactions. 
• Severe mucocutaneous reactions: Severe, including fatal, mucocutaneous reactions can 
occur in patients receiving rituximab. 
• HBV reactivation: HBV reactivation can occur in patients treated with rituximab, in 
some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients 

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for HBV infection before treatment initiation and monitor patients during and after 
treatment with rituximab. Discontinue rituximab and concomitant medications in the 
event of HBV reactivation. Any subject with a rising viral load (above lower limit of 
detection) should discontinue study drug, have antiviral therapy instituted, and have a 
consultation with a physician with expertise in managing hepatitis B. Patients who are 
anti-HBc positive may receive prophylactic antiviral agents while undergoing CLL 
therapy, per institutional guidelines. 
• PML, including fatal PML, can occur in patients receiving rituximab. 
6.4.2.4 
Immunizations 
Do not administer live attenuated vaccines prior to, during, or after treatment with venetoclax, 
obinutuzumab, or rituximab until B-cell recovery occurs. The safety and efficacy of 
immunization with live attenuated vaccines during or following venetoclax therapy have not 
been studied.  Advise subjects that vaccinations may be less effective. 
Based on nonclinical data, no changes are recommended to standard of care practices with regard 
to vaccinations in subjects treated with acalabrutinib. As appropriate, vaccines consistent with 
standard practices for specific subject populations (e.g., patients with CLL) should be used. 
 
6.4.2.5 
Dietary Restrictions 
As 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). These restrictions also apply to venetoclax. 
 
6.4.3 
Reproductive Toxicity 
Definition of women of nonreproductive potential: 
 
Women will be considered of non-reproductive potential if they are either: 
(1) 
Postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women <45 years of age a high follicle-stimulating hormone [FSH] 
level in the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.). 
OR 
(2) 
Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening. 
OR 
(3) 
Have a congenital or acquired condition that prevents childbearing. 

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Highly effective methods of contraception (to be used during heterosexual activity) are defined 
as methods that can achieve a failure rate of <1% per year when used consistently and correctly. 
Such methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation, which may be oral, intravaginal, or transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation, which 
may be oral, injectable, or implantable 
• Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomy of a female subject’s male partner (with medical assessment and confirmation 
of vasectomy surgical success) 
• Sexual abstinence (only if refraining from heterosexual intercourse during entire period 
of risk associated with the study treatments) 
Hormonal contraception may be susceptible to interaction with study or other drugs, which 
may reduce the efficacy of the contraception method. 
Abstinence (relative to heterosexual activity) can only be used as the sole method of 
contraception if it is consistently employed during the entire period of risk associated with 
the study treatment as the subject’s preferred and usual lifestyle. 
Period abstinence (e.g., calendar, ovulation, symptom-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. 
Please refer to the acalabrutinib Investigator Brochure for information on reproductive toxicity 
studies. 
Obinutuzumab is likely to cause fetal B cell depletion, although there are no data from the use of 
obinutuzumab in pregnant women to inform a drug-associated risk. 
There are no adequate and well-controlled studies of rituximab in pregnant women. Women of 
childbearing potential should use effective contraception while receiving rituximab and for 
12 months following treatment. Rituximab is a pregnancy class C drug. 
 
There are no available human data on the use of venetoclax in pregnant women. Based on 
toxicity observed in mice, venetoclax may cause fetal harm when administered to pregnant 
women. In mice, venetoclax was fetotoxic at exposures 1.2 times the human clinical exposure 

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based on AUC at the recommended human dose of 
 If venetoclax is used during 
pregnancy or if the patient becomes pregnant while taking venetoclax, the subject should be 
apprised of the potential risk to a fetus. 
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 30 days after the last dose of 
venetoclax, 2 days after the last dose of acalabrutinib, 12 months after the last dose of rituximab, 
or 18 months after the last dose of obinutuzumab, whichever is the longest period following the 
subject’s study drug discontinuation. Men who are sexually active and are able to have children 
must agree to use highly effective forms of contraception and use a barrier method (condom, 
even if the subject had a vasectomy) during the study and for 18 months after the last dose of 
obinutuzumab, or 12 months after the last dose of rituximab, or 30 days after the last dose of 
venetoclax, whichever is longer. Men must also refrain from donating sperm during the study 
and for 18 months after the last dose of obinutuzumab, or 12 months after the last dose of 
rituximab, or 30 days after the last dose of venetoclax, whichever is longer. 
 
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, 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 should 
promptly notify the investigator if they, or their partner, become pregnant during this period. If a 
female subject becomes pregnant during the treatment period, she must discontinue acalabrutinib 
immediately. Pregnancy in a female subject or a male subject’s partner must be reported in the 
same manner as any serious adverse event (SAE). 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 the last dose of obinutuzumab (whichever is longer) will be reported, followed to 
conclusion, and the outcome reported, as long as the subject or partner is willing to participate in 
follow-up. 
6.4.4 
Overdose Instructions 
Study drug overdose is the accidental or intentional use of the drug in an amount higher than the 
dose being studied. An overdose or incorrect administration of study drug is not an AE unless it 
results in untoward medical effects. 
Any study drug overdose or incorrect administration of study drug should be noted on the Study 
Drug Administration electronic case report form (eCRF). 
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All AEs associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF. If the associated AE fulfills serious criteria, the event 
should be reported to the sponsor immediately (i.e., no more than 24 hours after learning of the 
event). 
For any subject experiencing an acalabrutinib overdose, observation for any symptomatic side 
effects should be instituted, and vital signs and biochemical and hematologic parameters should 
be followed closely (consistent with the protocol or more frequently, as needed). Appropriate 
supportive management to mitigate adverse effects should be initiated. If the overdose ingestion 
is recent and substantial, and if there are no medical contraindications, use of gastric lavage or 
induction of emesis may be considered. 
Subjects who experience an overdose of venetoclax should be closely monitored and provided 
appropriate supportive treatment. During the ramp-up phase, interrupt venetoclax and monitor 
carefully for signs and symptoms of TLS along with other toxicities. Based on venetoclax large 
volume of distribution and extensive protein binding, dialysis is unlikely to result in significant 
removal of venetoclax. 
6.4.5 
Hepatitis B Virus Reactivation 
Cases of HBV reactivation have been reported in patients treated with acalabrutinib with one 
case resulting in liver failure and death. Any subject with a rising viral load (above lower limit 
of detection: approximately 10 IU/mL) should discontinue study treatment, have antiviral 
therapy instituted, and have a consultation with a physician with expertise in managing hepatitis 
B. Patients who are anti-HBc positive may receive prophylactic antiviral agents while 
undergoing CLL therapy, per institutional guidelines. 
 
Refer to the Schedule of Activities for frequency and duration of HBV monitoring. 
 
6.4.6 
Progressive Multifocal Leukoencephalopathy 
Cases of 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 treatment until PML is excluded. 
A diagnostic evaluation may include (but is not limited to): 
• Neurologic consultation 
• Brain magnetic resonance imaging (MRI) 
• PCR analysis for John Cunningham virus DNA in cerebrospinal fluid 
If PML is confirmed, permanently discontinue acalabrutinib. 

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Step 2: 
Step 1: 
Enroll 6 
patients in 
Cohort 1 
Enroll 6 
patients in 
Cohort 2 
Go back 
to Step 1 
at 1 DL 
lower 
Go back 
to Step 2 
at 1 DL 
lower 
2+ 
DLT 
2+ 
DLT 
0-1 
DLT 
0-1 
DLT 
6.4.7 
Elevated Liver Function Tests 
Subjects should be monitored for increases in liver biochemistry indicating potential Hy’s law 
(PHL) or Hy’s law (HL). The investigator is responsible for determining whether a subject 
meets PHL criteria at any point during the study. The process to be followed in identifying and 
reporting cases of PHL and HL is summarized in Appendix 3. 
 
6.5 
Phase 1b Dose Escalation Portion 
Figure 1 depicts the dose escalation schema Cohorts 1 and 2 of this study. 
 
Figure 1: Phase 1b Dose Escalation Schema for Cohorts 1 and 2 
 
 
 
 
As this combination has not previously been evaluated in a clinical trial, a toxicity assessment 
will occur after the first 6 subjects with relapsed/refractory CLL have been accrued to dose 
level 1. At this time, accrual will be held until all subjects are followed for 8 weeks (2 cycles). 
Toxicities will then be reviewed by the principal investigator. If, during this time, there is 
≤1 DLT (outlined below), Phase 1b expansion will begin for Cohort 1. If more toxicity than 
expected is observed and there are 2 or more DLTs in this group, the next 3 to 6 subjects will be 
Open 
Cohort 1 
to full 
Open 
Cohort 2 
to full 
accrual 

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accrued at 
 and this group will be monitored until all have completed 
 of 
therapy. If there are 2 or more DLTs in this group, 3 to 6 subjects will be accrued at 
 
 The highest dose level at which less than 2/6 subjects experience DLT will be the 
recommended Phase 1b expansion dose. Once the Phase 1b dose-escalation portion is complete 
for Cohort 1 and dose level is established, this cohort will open to full accrual and Cohort 2 will 
open enrollment for 6 subjects at the recommended Phase 1b expansion dose for Cohort 1. A 
safety analysis for Cohort 2 will be performed after the first 6 subjects are followed for at least 
8 weeks (2 cycles).  The Acerta Review Committee will discuss the data in conjunction with the 
principal investigator and, once safety is established in this cohort, Cohort 2 will open for full 
Phase 1b expansion. 
Dose-limiting toxicity will be defined as the following toxicities related to protocol therapy 
during the first 
 of therapy: 
• ≥ Grade 3 nonhematologic toxicity lasting for ≥7 days 
• ≥ Grade 3 prolongation of the QTc interval 
• Grade 4 neutropenia (ANC <500/µL) lasting ≥7 days after discontinuation of therapy without 
growth factors or lasting ≥5 days after discontinuation of therapy while on growth factors in 
subjects with pre-treatment ANC ≥1 x 109/L 
• ≥ Grade 3 febrile neutropenia 
• Grade 4 thrombocytopenia (platelet count <20,000/µL) lasting ≥7 days after discontinuation 
of therapy or requiring transfusion in subjects with pretreatment platelet count >50,000/µL. 
• Dose delay due to toxicity for >14 consecutive days 
Prior to amending dosing from 
 the 6 subjects in the 
relapsed/refractory disease cohort had been enrolled. Since the new dose is the same daily dose 
of acalabrutinib, the previously accrued safety cohort can still be used to evaluate toxicity of the 
combination. 
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Table 4: Dose Levels for Phase 1b Dose Escalation Portion for Cohorts 1 and 2 
 
Dose level 
Acalabrutinib 
Obinutuzumab 
 
 
6.6 
Phase 1b Expansion Portion for Cohorts 1 and 2 
For both Cohort 1 and Cohort 2, after 6 subjects have been treated in the Phase 1b 
dose-escalation portion and followed for 8 weeks (2 cycles) with ≤1 DLT in Cohort 1 and 
satisfactory safety observed in Cohort 2, this dose level will be considered the recommended 
Phase 1b expansion dose and that cohort of the study will open to full accrual. 
 
6.7 
Duration of Therapy 
For Cohorts 1 and 2, acalabrutinib treatment can continue until the end of study for subjects 
without disease progression and who are tolerating therapy. The end of study is defined as 
36 cycles after the last subject is enrolled to allow for long term follow-up beyond 36 cycles. 
For Cohorts 3 and 4, protocol therapy with obinutuzumab or rituximab will continue for up to 
 (until the end of 
 in responding subjects. Subjects will discontinue venetoclax 
at the end of 
 Treatment with acalabrutinib is continued until evidence of disease 
progression, toxicity, or end of study, whichever occurs first. Acalabrutinib; however, can be 
discontinued by investigator decision after 
 in subjects with CR/CRi and/or negative 
MRD. 
 
In Cohorts 1 and 2, subjects who achieve a bone marrow 
MRD-negative CR have the option to discontinue acalabrutinib. 
 
Subjects who are still on treatment at the end of study and deriving clinical benefit from 
acalabrutinib monotherapy may continue treatment. At the time of the final data cutoff (DCO) 
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and database closure, subjects who remain in the 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 10.5. 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. 
See Section 7 for dose modifications and Section 11 for criteria for removal from the study. 
 
7 
Dose Adjustments and Modifications 
 
7.1 
Subject Monitoring and Dose Modifications 
 
7.1.1 
Obinutuzumab 
Please refer to the GAZYVARO prescribing information for subject monitoring during infusion 
and management of infusion reactions. 
 
7.1.1.1 
Obinutuzumab Dose Modification and Discontinuation 
Refer to Section 7.2 for dose adjustments for toxicities relating to obinutuzumab. 
 
7.1.2 
Venetoclax 
Venetoclax Dose Modifications Based on Toxicities 
Please refer to the VENCLEXTA® prescribing information for recommendations regarding dose 
modifications for toxicity and Section 7.1.2 and Section 7.2. 
 
7.1.3 
Rituximab 
 
7.1.3.1 
Subject Monitoring During Infusion 
Refer to RITUXAN® prescribing information. 
7.1.3.2 
Management of Infusion Reactions with Rituximab 
Management of infusion reactions are per RITUXAN® prescribing information and 
Section 7.2.2.1. 
 
7.1.3.3 
Rituximab Dose Modification and Discontinuation 
Dose modification of rituximab is not recommended; please refer to the RITUXAN® prescribing 
information and Section 7.1.2 and Section 7.2 for details. If rituximab is discontinued, subjects 
can continue acalabrutinib and venetoclax as outlined in the protocol. If acalabrutinib or 
venetoclax is discontinued, a subject may continue to receive rituximab up to the maximum 
number of infusions as outlined in the protocol. 

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The US Prescribing Information for rituximab will serve as Reference Safety Information (RSI) 
for this study to facilitate determination of expectedness or unexpectedness of AEs possibly 
associated with rituximab. 
7.2 
Dose Adjustment and Management of Toxicity for Phase 1b After 
 and 
Phase 1b Expansion Phase, and Phase 1b Venetoclax Cohorts 
This section describes management of hematologic and nonhematologic toxicities for subjects in 
the Phase 1b dose-escalation portion after 
 subjects in Cohorts 1 and 2 in the Phase 1b 
expansion portion. This section also describes management of hematologic and nonhematologic 
toxicities in the Phase 1b portion wherein venetoclax is added during 
 (Cohorts 3 and 4). 
 
7.2.1 
Dose Adjustments for Hematologic Toxicity 
 
7.2.1.1 
Cohorts 1 and 2 
Hematologic toxicity will be graded according to the IWCLL 2008 guidelines (Hallek et al. 
2008). 
 
Table 5: IWCLL 2008 Grading for Hematologic Toxicity 
 
Grade 
Decrease in Plateletsa or HGBb 
from Pretreatment Value 
Absolute Neutrophil Count (µL)c 
1 
11% to 24% 
≥1500 and <2000 
2 
25% to 49% 
≥1000 and <1500 
3 
50% to 75% 
≥500 and <1000 
4 
≥75% 
<500 
a Platelet counts must be below normal levels for any grade toxicity to be recorded. If platelet count is <20 x 1012/L, 
this will be considered Grade 4 toxicity. 
b Hgb levels must be below normal levels for any grade toxicity to be recorded. 
c If ANC is <1000 prior to study, the patient is not evaluable for toxicity assessment based on ANC. 
 
During Cycle 1, laboratory parameters will be monitored according to the Schedule of 
Assessments and will be used in the evaluation of hematologic toxicities. Beginning Cycle 8, 
laboratory parameters will be monitored monthly and used in the evaluation of hematologic 
toxicities. If subjects experience Grade ≥3 hematologic toxicity, febrile neutropenia, or 
significant bleeding attributable to study drug, acalabrutinib should be held until toxicity resolves 
to ≤ Grade 1 or to baseline. For the first occurrence, acalabrutinib may be restarted at the same 
dose level 
 however, for the second occurrence acalabrutinib should be restarted at 
 
Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating 
factor (GM-CSF) may not be used prophylactically but may be used at the treating physician’s 
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discretion in subjects with neutropenia related to obinutuzumab or acalabrutinib who are 
otherwise tolerating therapy and responding well. 
 
Table 6: Dose Adjustments During 
 
 
Phase 1b Expansion Subjects Only During 
 All Subjects During 
 
 
 
Dose Level 
Acalabrutinib Dose 
Obinutuzumab Dose 
 
 
For any Grade ≥3 hematologic toxicity, febrile neutropenia, or clinically significant bleeding 
attributable to study drug, obinutuzumab and acalabrutinib should be held and complete blood 
count (CBC) monitored weekly. When toxicity resolves to ≤ Grade 1 or to baseline, study drugs 
should be resumed with 1 dose level reduction (obinutuzumab to restart at the next cycle). If 
subjects are stable at a reduced dose level for 
 dose escalation can occur by 1 dose level. 
 
7.2.1.2 
Cohorts 3 and 4 
During Cycle 1, laboratory parameters will be monitored weekly and will be used in the 
evaluation of hematologic toxicities. Beginning Cycle 4, laboratory parameters will be 
monitored on Day 1 of each cycle, while on Cycle 7 results will be monitored Day 1 every 
3 cycles.  Results will be used in the evaluation of hematologic toxicities. 
If subjects experience Grade ≥3 hematologic toxicity, febrile neutropenia, or significant bleeding 
attributable to study treatment within Cycles 1 and 2, acalabrutinib should be held until toxicity 
resolves to ≤ Grade 1 or to baseline. For the first occurrence, acalabrutinib may be restarted at 
the same dose level 
 however, for the second occurrence acalabrutinib should be 
restarted at 
 
After start of venetoclax in 
 for any Grade ≥3 hematologic toxicity, febrile neutropenia, 
or clinically significant bleeding attributable to study treatment, recommendations regarding 
dose interruptions or modifications should be applied to venetoclax first. Recommendations are 
provided in the current prescribing information for venetoclax (please refer to Table 9 for 
venetoclax dose reduction guidelines). Consider discontinuing venetoclax for subjects who 
require dose reductions to less than 
 for more than 
 
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If subjects continue to experience Grade ≥3 hematologic toxicity, febrile neutropenia, or 
significant bleeding, please follow the recommendations for acalabrutinib as noted for 
 
 
G-CSF and GM-CSF may not be used prophylactically but may be used at the treating 
physician’s discretion in subjects with neutropenia related to obinutuzumab, rituximab, 
venetoclax, or acalabrutinib who are otherwise tolerating therapy and responding well. 
Missed doses of either drug should not be made up. 
 
7.2.2 
Dose Adjustments for Specific Nonhematologic Toxicities 
 
7.2.2.1 
Infusion Reactions with Obinutuzumab or Rituximab 
Manage as in Section 7.1.1. Subjects with Grade 3 infusion reaction upon re-challenge or 
Grade 4 infusion reactions should not receive further doses of obinutuzumab but can continue 
acalabrutinib. For rituximab, please refer to the product information for guidance. 
 
7.2.2.2 
Progressive Multifocal Leukoencephalopathy or Hepatitis B Reactivation 
Permanently discontinue all study drugs. 
 
7.2.3 
Dose Adjustments for All Other Nonhematologic Toxicities 
Table 7 and Table 8, respectively, display the acalabrutinib and obinutuzumab dose adjustments 
for all other nonhematologic toxicities (dose reductions are not recommended for rituximab). 
Table 9 displays dose modification for toxicity during venetoclax treatment, and Table 10 
displays dose adjustments for all other nonhematologic toxicities for which individual study drug 
attribution is not possible. 
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Table 7: Acalabrutinib Dose Adjustments for All Other Nonhematologic Toxicities (All 
Cohorts) 
 
Dose Level 
Acalabrutinib Dose 
 
Table 8: Obinutuzumab Dose Adjustments for All Other Nonhematologic Toxicities (All 
Cohorts) 
 
Dose Level 
Obinutuzumab Dose 
 
 
7.2.3.1 
Cohorts 1 and 2 
For ≥ Grade 3 nonhematologic toxicity attributable to acalabrutinib, acalabrutinib should be held 
until toxicity resolves to ≤ Grade 1, and then restarted at the same dose 
 with the 
first occurrence; however, for the second occurrence, acalabrutinib should be restarted at 
 
 Missed doses should not be made up. Subjects who are stable at a lower dose level for 
 may be dose-escalated by 1 dose level. 
 
For ≥ Grade 3 nonhematologic toxicity attributable to obinutuzumab, obinutuzumab should be 
held until toxicity resolves to ≤ Grade 1, and then restarted at 1 dose level lower 
 for 
each occurrence. Missed doses should not be made up. Subjects who are stable at a lower dose 
level for 
 may be dose-escalated by 1 dose level. 
For ≥ Grade 3 nonhematologic toxicity for which individual study drug attribution is not 
possible, subjects should have all drugs held until toxicity resolves to ≤ Grade 1, and then 
subjects should be restarted at 1 dose level lower using Table 10. Subjects who are stable at a 
lower dose level for 
 may be dose-escalated by 1 dose level. 
 
7.2.3.2 
Cohorts 3 and 4 
After start of 
 for ≥ Grade 3 nonhematologic toxicity attributable to study drugs, apply 
dose medication guidelines to venetoclax first. Per current prescribing information, venetoclax 
should be held until toxicity resolves to ≤ Grade 1, and then restarted at the same dose with the 
first occurrence; however, for the second occurrence, venetoclax should be restarted following 
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the reduction guidelines in Table 9. Missed doses should not be made up. Subjects who are 
stable at a lower dose for 
 may be dose-escalated by 1 dose level. 
For Grade ≥3 nonhematologic toxicity in Cycles 1 and 2 or despite following recommendations 
for venetoclax, please follow the guidelines noted in Section 7.2.2 for acalabrutinib and/or 
obinutuzumab. 
For ≥ Grade 3 nonhematologic toxicity for which individual study drug attribution is not 
possible, subjects should have all drugs held until toxicity resolves to ≤ Grade 1, and then 
subjects should be restarted at 1 dose level lower again using Table 10. Subjects who are stable 
at a lower dose level for 
 may be dose-escalated by 1 dose level. 
 
Table 9: Dose Modification for Toxicity During Venetoclax Treatment 
(Cohorts 3 and 4) 
 
Dose at Interruption, mg 
Restart Dose, mga 
a During the 
 continue the reduced dose for 
 before increasing the dose. 
 
 
Table 10: Dose Adjustments for All Other Nonhematologic Toxicities for Which Individual 
Study Drug Attribution is Not Possible (All Cohorts) 
 
Dose Level 
Acalabrutinib 
Dose 
Rituximab Dose 
Obinutuzumab 
Dose 
Venetoclaxa 
a During the 
 continue the reduced dose for 
 before increasing the dose. 
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8 
Schedule of Activities 
 
Table 11. Schedule of Activities: Cohorts 1 and 2 
 
Tests & Observations 
(all labs listed here are 
standard of care except those 
labeled correlative studies 
and PK) 
Screening 
Day 1, 8, 
15 of 
Cycle 1 
Day 2 of 
Cycle 1 
Day 1 of 
Cycles 2-12 
Day 1 of 
Cycles 15, 18, 
21, 24H 
Relapse/ 
Disease 
progression 
Safety 
Follow-upI 
Discontinua 
-tion 
Follow-upJ 
Long-term 
Follow-upK 
ACP-196 
 PO 
administration 
Obinutuzumab administration 
History & physical 
examination with tumor 
measurements1 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
2 buccal swabs 
X 
ECG2 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
FISH/stimulated karyotype3 
X 
X 
Zap-70 methylation4 
X 
IGHV mutational status4 
X 
Complete blood count (CBC) 
X 
X 
X 
X 
X 
X 
Chem 10 
X 
X 
X 
X 
X 
Liver function panel 
X 
X 
X 
X 
X 
LDH, uric acid 
X 
X 
X 
X 
X 
Beta-2-microglobulin 
X 
Direct antiglobulin test 
(Coomb’s test) 
X 
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Table 11. Schedule of Activities: Cohorts 1 and 2 
 
Tests & Observations 
(all labs listed here are 
standard of care except those 
labeled correlative studies 
and PK) 
Screening 
Day 1, 8, 
15 of 
Cycle 1 
Day 2 of 
Cycle 1 
Day 1 of 
Cycles 2-12 
Day 1 of 
Cycles 15, 18, 
21, 24H 
Relapse/ 
Disease 
progression 
Safety 
Follow-upI 
Discontinua 
-tion 
Follow-upJ 
Long-term 
Follow-upK 
Serum or urine HCG5 
X 
HBsAg, HBsAb, HCV, 
anti-HBc 
X 
HBV PCR6,7 
X 
QM 
See footnote 6 
Peripheral blood flow 
cytometry 
X 
A 
X 
X 
X 
Serum immunoglobulins 
X 
A 
X 
X 
CT scan (chest, neck, 
abdomen, and pelvis) 
X 
B 
B 
X 
X 
Bone marrow aspirate and 
biopsy 
X 
C 
C 
X 
Peripheral blood for 
correlative studies 
D 
D 
D 
D 
D 
D 
D 
Peripheral blood for PK8 
E 
Bone marrow for correlative 
studies 
X 
C 
C 
X 
Lymph node sample for 
correlative studies 
F 
Quality of life assessment 
G 
G 
G 
G 
G 
G 
Survival status 
X 
Footnotes are on the next page. 
Abbreviations: anti-HBc = hepatitis B core antibody; 
 CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology 
Group performance status; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCG = human HCV = hepatitis C virus; 
LDH = lactate dehydrogenase; PCR = polymerase chain reaction; PK = pharmacokinetics; PO = orally; Q = every; wks = weeks. 
 
Footnotes for Table 11: 
1. During the physical examination, palpable lymph nodes will be measured, and data will be collected on a separate case report form. 
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2. ECGs may be obtained at unscheduled time points as clinically indicated. 
3. Does not need to be repeated at screening if performed within 60 days of registration 
4. Does not need to be repeated if previously performed 
5. For women of child-bearing potential only 
6. Hepatitis B DNA must be performed in any patient positive for HBsAg or HB core 
7. Subjects who are anti-HBc positive should have a quantitative PCR test for HBV DNA performed during screening. Subjects who receive combination 
therapy with an anti-CD20 monoclonal antibody (i.e., obinutuzumab) should have a quantitative PCR test monthly during treatment and until 12 months 
after the last dose of anti-CD20 therapy. After that, HBV PCR monitoring should continue quarterly (e.g., every 3 months) until at least 12 months after the 
last dose of acalabrutinib. 
8. As outlined in Section 13.3 
A. Cycles 4 and 7 only 
B. Response evaluations will be done every 12 weeks from randomization for the first 24 months (with the 4th evaluation shifted to Cycle 12 Day 1 rather than 
Cycle 13 Day 1, to align with study visits), and then every 24 weeks thereafter. Hematology results must be done within 7 days of CT scans. Bone marrow 
biopsies/aspirates to confirm a CR must be done within 4 weeks of the CT scan, which showed CR. 
C. PB samples will be used to evaluate for MRD every 3 cycles (at the discretion of the investigator, in line with scheduled response assessments, per protocol. 
D. Specific times and tube types for correlative samples are outlined in Section 13.2. 
E. PK analysis will be performed on the first 8 expansion group patients of Cohort 1. Schedule can be found in Section 13.3. 
F. If performed as part of relapse analysis 
G. As outlined in Section 13.4 
H. Visits to continue every 6 cycles thereafter (± 7 days). 
I. 
A safety follow-up (SFU) visit is required for all subjects 30 days (+7) from the last dose of study drug. 
J. 
After discontinuation of study treatment for any reason, each subject should be followed until disease progression or the start of alternative anticancer 
therapy. If disease progression has not occurred at the time of the 30-day SFU visit, discontinuation follow-up (DFU) visits should occur approximately 
every 12 weeks until disease progression. During this period, subjects will be followed via CT scans every 24 weeks; after 2 years in DFU, CT scans will be 
yearly. AE and concomitant medication reporting, irrespective of seriousness, ends 30 days after the last dose of study drug(s). 
K. After disease progression or the start of alternative anticancer therapy, all subjects (unless they have withdrawn consent) will be contacted approximately 
every 12 weeks by telephone, to assess survival until death or lost to follow up. 

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Table 12: Schedule of Assessments – Cohort 3 
 
Treatment Phase & Response Evaluation 
SFU 
Discontinuation 
follow-upI 
Relapse/ 
Disease 
Progression 
Long-term 
follow-up 
Day 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles 4 
-7 
Cycles 10, 
13, 16, 19, 
22 
Cycle 
24 
Cycle 24 
q6 cycles 
1 
15 
1 
8 
15 
22 
1 
8 
15 
22 
1 
1 
1 
1 
Study Windows (days) 
-28 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
+7 
±7 
±7 
Study Drug Administration1 
Acalabrutinib 
Rituximab 
Venetoclax 
Procedures 
History & physical 
examination with tumor 
measurements2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease-related symptoms 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG3 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test4 
X 
X 
Buccal swabs (2) 
X 
Hepatitis serologies5 
X 
HBV PCR5,6 
X 
QM 
QM 
QM6 
See 
Footnote 6 
Q3M 
Direct antiglobulin test 
(Coomb’s test) 
X 
CBC with differential7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chem 107 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Function Panel7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LDH, uric acid7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Calculated CrCl 
X 
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Table 12: Schedule of Assessments – Cohort 3 
 
Treatment Phase & Response Evaluation 
SFU 
Discontinuation 
follow-upI 
Relapse/ 
Disease 
Progression 
Long-term 
follow-up 
Day 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles 4 
-7 
Cycles 10, 
13, 16, 19, 
22 
Cycle 
24 
Cycle 24 
q6 cycles 
1 
15 
1 
8 
15 
22 
1 
8 
15 
22 
1 
1 
1 
1 
Study Windows (days) 
-28 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
+7 
±7 
±7 
Beta-2-microglobulin 
X 
Serum immunoglobulins 
X 
C4, C7 
X 
X 
X 
FISH/stimulated karyotype8 
X 
X 
Zap-70 methylation, IGHV 
mutational status9 
X 
Peripheral blood flow 
cytometry for B/T/NK cells 
X 
C4, C7 
C16, C19, 
C22 
X 
X 
X 
X 
Peripheral blood for 
correlative studies 
X 
C 
C 
C 
C 
C 
PK sample collection 
D 
D 
D 
CT scan (chest, neck, 
abdomen, & pelvis)10 
X 
E 
C4, C7 
X 
X 
X; q12 cycles 
after C36 
XJ 
X 
Overall response assessment11 
C4, C7 
X 
X 
X 
X 
X 
X 
Bone marrow biopsy/aspirateF 
X 
X 
MRD assessmentG 
X 
C10, C16 
X 
q6 
month 
s 
X 
Lymph node sample for 
correlative studies12 
X 
X 
Cell death proteinsC 
X 
X 
X 
X 
X 
X 
ImmunophenotypingC 
X 
X 
X 
X 
X 
X 
QoL assessments13 
X 
X 
X 
X 
C13, C19 
X 
X 
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Table 12: Schedule of Assessments – Cohort 3 
 
Treatment Phase & Response Evaluation 
SFU 
Discontinuation 
follow-upI 
Relapse/ 
Disease 
Progression 
Long-term 
follow-up 
Day 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles 4 
-7 
Cycles 10, 
13, 16, 19, 
22 
Cycle 
24 
Cycle 24 
q6 cycles 
1 
15 
1 
8 
15 
22 
1 
8 
15 
22 
1 
1 
1 
1 
Study Windows (days) 
-28 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
+7 
±7 
±7 
Survival status 
H 
Note: All labs listed here are standard-of-care except those labeled correlative studies and PK. 
Abbreviations: 
 C = cycle; CBC = complete blood count; CrCl = creatinine clearance; CT = computed tomography; ECG = electrocardiogram; ECOG 
PS = Eastern Cooperative Oncology Group performance status; HBV = hepatitis B virus; IGHV = immunoglobulin heavy-chain variable; LDH = lactate dehydrogenase; 
MRD = minimal residual disease; PCR = polymerase chain reaction; PK = pharmacokinetics; PO = orally; Q = every; QoL = quality of life; SFU = safety follow-up; wks = weeks. 
Additional footnotes are on the next page. 
 
Footnotes to Table 12: 
1. Subjects will receive 
 of acalabrutinib 
 before beginning rituximab, starting 
 Venetoclax will commence 
 with standard 
 dosing for 
 prior to full-dose therapy starting 
 Starting 
 venetoclax should be given first, followed at least 30 minutes later 
by acalabrutinib. Rituximab should be administered last on days of concomitant dosing. 
2. During the physical examination, palpable lymph nodes will be measured, and data will be collected on a separate case report form. 
3. Screening laboratory tests and ECG must be done within 14 days prior to initiating treatment. ECGs may be obtained at unscheduled time points as clinically 
indicated. 
4. Serum or urine HCG for women of child-bearing potential only. 
5. Hepatitis serologies 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 any hepatitis serology must have PCR testing (see exclusion criterion #16). 
6. Subjects who are anti-HBc positive should have a quantitative PCR test for HBV DNA performed during screening. Subjects who receive combination 
therapy with an anti-CD20 monoclonal antibody (i.e., rituximab) should have a quantitative PCR test monthly during treatment and until 12 months after the 
last dose of anti-CD20 therapy. After that, HBV PCR monitoring should continue quarterly (e.g., every 3 months) until at least 12 months after the last dose 
of acalabrutinib. 
7. Laboratory evaluations must be performed on the date specified, ± 3 days. 
8. Does not need to be repeated at Screening if performed within 60 days of registration. 
9. Does not need to be repeated if previously performed. 
10. CT scans and bone marrow biopsies may be performed within 7 days of the specified dates. Screening CT scans may be used if obtained as standard-of-care 
within 42 days prior to initiating treatment provided no prior therapy has been given. Screening bone marrow biopsies may, likewise, be used if obtained as 
standard of care within 90 days prior to initiating treatment provided no prior therapy has been given. 
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11. Overall response evaluations will be done every 12 weeks from randomization for the first 24 months, and then every 24 weeks. After Cycle 36, CT scan is 
yearly. Hematology results must be done within 7 days of CT scans. Bone marrow aspirates/biopsies to confirm complete response (CR) must be done within 
4 weeks of the CT scan, which showed CR. 
12. LN sample should also be sent for correlative studies at time of progressive disease/relapse, if performed as part of disease analysis. 
13. EORTC QLQ-C30 will be assessed. See Appendix 2. 
 
A. At investigator decision subjects who are in CR or CR with incomplete bone marrow recovery (CRi) and/or MRD negativity may discontinue acalabrutinib 
after Cycle 24. 
B. 
 
 
C. Specific times and tube types of correlative samples are outlined in Section 13.2. 
D. As outlined in Section 13.3. Drug and metabolite concentrations in plasma will be done by a bioanalytical contract research organization (CRO). 
 
 Refer to the laboratory manual for instructions on 
collection and shipment of PK samples. 
E. On Day 21, if indicated based on TLS risk. 
F. To confirm CR, bone marrow aspirate/biopsy may be performed at any time. At time of bone marrow (BM) biopsy for CR confirmation, bone marrow 
should also be sent for correlative studies. 
G. To confirm CR, draw PB for flow cytometry MRD at any time point if (i) PE/Lab/CT suggestive of CR OR (ii) there is lone residual splenomegaly and/or 
probable lone reactive lymphadenopathy in absence of other peripheral signs of residual CLL disease. If PB MRD is negative, in 2 to 3 months check BM 
biopsy/aspirate with BM MRD. If PB MRD is positive, PB MRD may be repeated q3 months until negative and then proceed to BM 3 months after negative 
PB MRD. Post-CR/CRi, PB MRD is completed every 6 cycles until PD (per Hallek et al 2008). Site may synchronize this activity with any protocol 
scheduled PB MRD if the blood draws are ±2 months apart. 
H. After disease progression, subjects will be contacted to assess survival status approximately every 12 weeks until death, withdrawal of consent by subject, 
lost to follow-up, or study terminated by sponsor, whichever comes first. 
I. 
If disease progression has not occurred at the time of the 30-day SFU, discontinuation follow-up visits should occur approximately every 12 weeks until 
disease progression. AE and concomitant medication reporting, irrespective of seriousness, ends 30 days after the last dose of study drug(s). 
J. 
CT scans should be performed every 24 weeks. After 2 years in discontinuation follow-up, CT scans will be performed annually. 
 
K. 
 
 
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Table 13: Schedule of Assessments – Cohort 4 
 
Treatment Phase & Response Evaluation 
SFU 
Discontinuation 
follow-upI 
Relapse/ 
Disease 
Progression 
Long-term 
follow-up 
Day 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles 4 
-7 
Cycles 10, 
13, 16, 19, 
22 
Cycle 
24 
> Cycle 24 
q6 cycles 
1 
15 
1 
2 
8 
15 
1 
8 
15 
22 
1 
1 
1 
1 
Study Windows (days) 
-28 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
+7 
±7 
±7 
Study Drug Administration1 
Acalabrutinib 
Obinutuzumab 
Venetoclax 
Procedures 
History & physical 
examination with tumor 
measurements2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease-related symptoms 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG3 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test4 
X 
X 
Buccal swabs (2) 
X 
Hepatitis serologies5 
X 
HBV PCR5,6 
X 
QM 
QM 
QM 
See footnote 
6 
X 
Q3M 
Direct antiglobulin test 
(Coomb’s test) 
X 
CBC with differential7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chem 107 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver function panel7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LDH, uric acid7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Calculated CrCl 
X 
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Table 13: Schedule of Assessments – Cohort 4 
 
Treatment Phase & Response Evaluation 
SFU 
Discontinuation 
follow-upI 
Relapse/ 
Disease 
Progression 
Long-term 
follow-up 
Day 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles 4 
-7 
Cycles 10, 
13, 16, 19, 
22 
Cycle 
24 
> Cycle 24 
q6 cycles 
1 
15 
1 
2 
8 
15 
1 
8 
15 
22 
1 
1 
1 
1 
Study Windows (days) 
-28 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
+7 
±7 
±7 
Beta-2-microglobulin 
X 
Serum immunoglobulins 
X 
C4, C7 
X 
X 
X 
FISH/stimulated karyotype8 
X 
X 
Zap-70 methylation, IGHV 
mutational status9 
X 
Peripheral blood flow 
cytometry for B/T/NK cells 
X 
C4, C7 
C16, C19, 
C22 
X 
X 
X 
X 
Peripheral blood for 
correlative studies 
X 
C 
C 
C 
C 
C 
PK sample collection 
D 
D 
D 
CT scan (chest, neck, 
abdomen, & pelvis)10 
X 
E 
C4, C7 
X 
X 
X; 
q12 cycles 
after C36 
XJ 
X 
Overall response assessment11 
C4, C7 
X 
X 
X 
X 
X 
X 
Bone marrow biopsy/aspirateF 
X 
X 
MRD assessmentG 
X 
C10, C16 
X 
q6 
months 
X 
Lymph node sample for 
correlative studies12 
X 
X 
Cell death proteinsC 
X 
X 
X 
X 
X 
X 
ImmunophenotypingC 
X 
X 
X 
X 
X 
X 
QoL assessments13 
X 
X 
X 
X 
C13, C19 
X 
X 
Survival status 
H 
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Note: All labs listed here are standard-of-care except those labeled correlative studies and PK. 
Abbreviations: BID = twice daily; C = cycle; CBC = complete blood count; CrCl = creatinine clearance; CT = computed tomography; ECG = electrocardiogram; ECOG 
PS = Eastern Cooperative Oncology Group performance status; HBV = hepatitis B virus; IGHV = immunoglobulin heavy-chain variable; LDH = lactate dehydrogenase; 
MRD = minimal residual disease; PCR = polymerase chain reaction; PK = pharmacokinetics; PO = orally; Q = every; QoL = quality of life; SFU = safety follow-up; wks = weeks. 
Additional footnotes are on the next page. 
 
Footnotes to Table 13: 
1. Subjects will receive 
 of acalabrutinib 
 before beginning obinutuzumab, starting 
 Venetoclax will commence 
 with 
standard 
 dosing for 
 prior to full-dose therapy starting 
 Starting 
 venetoclax should be given first, followed at least 30 minutes 
later by acalabrutinib. Obinutuzumab should be administered last on days of concomitant dosing. 
2. During the physical examination, palpable lymph nodes will be measured, and data will be collected on a separate case report form. 
3. Screening laboratory tests and ECG must be done within 14 days prior to initiating treatment. ECGs may be obtained at unscheduled time points as clinically 
indicated. 
4. Serum or urine HCG for women of child-bearing potential only. 
5. Hepatitis serologies 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 any hepatitis serology must have PCR testing (see exclusion criterion #16). 
6. Subjects who are anti-HBc positive should have a quantitative PCR test for HBV DNA performed during screening. Subjects who receive combination 
therapy with an anti-CD20 monoclonal antibody (i.e., obinutuzumab) should have a quantitative PCR test monthly during treatment and until 12 months 
after the last dose of anti-CD20 therapy. After that, HBV PCR monitoring should continue quarterly (e.g., every 3 months) until at least 12 months after the 
last dose of acalabrutinib. 
7. Laboratory evaluations must be performed on the date specified, ± 3 days. 
8. Does not need to be repeated at Screening if performed within 60 days of registration. 
9. Does not need to be repeated if previously performed. 
10. CT scans and bone marrow biopsies may be performed within 7 days of the specified dates. Screening CT scans may be used if obtained as standard-of-care 
within 42 days prior to initiating treatment provided no prior therapy has been given. Screening bone marrow biopsies may, likewise, be used if obtained as 
standard of care within 90 days prior to initiating treatment provided no prior therapy has been given. 
11. Overall response evaluations will be done every 12 weeks from randomization for the first 24 months, and then every 24 weeks. After Cycle 36, CT scan is 
yearly. Hematology results must be done within 7 days of CT scans. Bone marrow aspirates/biopsies to confirm CR must be done within 4 weeks of the CT 
scan, which showed CR. 
12. LN sample should also be sent for correlative studies at time of progressive disease/relapse, if performed as part of disease analysis. 
13. EORTC QLQ-C30 will be assessed. See Appendix 2. 
 
A. At investigator discretion, subjects who are in CR or CRi and/or MRD negativity may discontinue acalabrutinib after Cycle 24. 
B. 
 
 
C. Specific times and tube types of correlative samples are outlined in Section 13.2. 
D. As outlined in Section 13.3. Drug and metabolite concentrations in plasma will be done by a bioanalytical contract research organization (CRO). 
 
 Refer to the laboratory manual for instructions on 
collection and shipment of PK samples. 
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E. On Day 21, if indicated based on TLS risk. 
F. To confirm CR, bone marrow aspirate/biopsy may be performed at any time. At time of bone marrow (BM) biopsy for CR confirmation, bone marrow 
should also be sent for correlative studies. 
G. To confirm CR, draw PB for flow cytometry MRD at any time point if (i) PE/Lab/CT suggestive of CR OR (ii) there is lone residual splenomegaly and/or 
probable lone reactive lymphadenopathy in absence of other peripheral signs of residual CLL disease. If PB MRD is negative, in 2 to 3 months check BM 
biopsy/aspirate with BM MRD. If PB MRD is positive, PB MRD may be repeated q3 months until negative and then proceed to BM 3 months after negative 
PB MRD. Post-CR/CRi, PB MRD is completed every 6 cycles until PD (per Hallek et al 2008). Site may synchronize this activity with any protocol 
scheduled PB MRD if the blood draws are ±2 months apart. 
H. After disease progression, subjects will be contacted to assess survival status approximately every 12 weeks until death, withdrawal of consent by subject, 
lost to follow-up, or study terminated by sponsor, whichever comes first. 
I. 
If disease progression has not occurred at the time of the 30-day SFU, discontinuation follow-up visits should occur approximately every 12 weeks until 
disease progression. AE and concomitant medication reporting, irrespective of seriousness, ends 30 days after the last dose of study drug(s). 
J. 
CT scans should be performed every 24 weeks. After 2 years in discontinuation follow-up, CT scans will be performed annually. 
K. 
 
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8.1 
Pre-Treatment (Screening) Evaluation 
Subjects will be evaluated prior to registration after signing informed consent. Laboratory 
evaluations and ECG must be done within 14 days, CT scans within 42 days, and bone marrow 
within 90 days provided no prior therapy has been given. Therapy must begin within 28 days 
following registration.  Required pre-treatment evaluation includes: 
• History and physical examination, including medication reconciliation, weight, ECOG 
performance status, and clinical tumor measurement 
• ECG 
• Complete blood count (CBC) with differential 
• Chem 10 panel 
• Lactate dehydrogenase (LDH) 
• Uric acid 
• Calculated CrCl 
• ALT/AST, total and direct bilirubin, albumin, total protein, alkaline phosphatase 
• Direct antiglobulin (Coomb’s test) 
• Quantitative immunoglobulins 
• Peripheral blood flow cytometry 
• Beta 2 microglobulin 
• Zap-70 methylation 
• Stimulated karyotype and FISH analysis (CLL panel) on either blood or bone marrow 
(required within 60 days of registration) 
• CLL mutational screen 
• CT scans of chest/abdomen/pelvis including index lesion measurement 
• Bone marrow biopsy with pathology evaluation and flow cytometry 
• Psychological/behavioral measures Section 13.4) 
8.2 
Study Evaluations 
The schedule of required procedures for each cycle is detailed in the tables in Section 8. 
Laboratory evaluations must be performed on the date specified and within the window specified 
in Section 8. CT scans and bone marrow biopsies may be performed within 7 days of the 
specified dates. Clinical evaluations and laboratory studies may be repeated more frequently if 

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clinically indicated. Such unscheduled assessments will be captured in the protocol-specific 
database as appropriate. 
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. 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). 
 
8.3 
Safety Follow-up 
Each subject should be followed until the safety follow-up (SFU) visit at 30 (+7) days after his or 
her last dose of all study drug(s) to monitor for resolution or progression of AEs and to document 
the occurrence of any new events, regardless of whether the subject receives a new anticancer 
therapy or demonstrates disease progression within this timeframe. Subjects who withdraw 
consent for study treatment should still be encouraged to complete the Safety Follow-up 
assessments before withdrawing consent, but these assessments cannot be mandated if subject 
consent for further study participation is withdrawn. The Schedule of Activities (Section 8) 
describes the procedures required for the Safety Follow-up visits. 
 
8.4 
Discontinuation Follow-up 
After discontinuation of study treatment for any reason (except for death, lost to follow up, or 
withdrawal of consent), each subject should be followed until disease progression. If disease 
progression has not occurred at the time of the 30-day SFU visit, discontinuation follow-up visits 
should occur approximately every 12 weeks until disease progression. During this period, 
subjects will be followed via CT scans (every 24 weeks), CBC with differential, physical 
examinations (including vital signs and weight), serum chemistry, peripheral blood MRD (every 
6 months for subjects in Cohorts 3 and 4 who will be monitored while off study drugs), and bone 
marrow biopsy and aspirate (as clinically indicated); after 2 years in discontinuation follow-up, 
CT scans will be yearly. Refer to the Schedule of Assessments (Section 8) for a full list of 
assessments required during this period. 
 
8.5 
Long-Term Follow-up 
After disease progression, subjects will be contacted to assess survival status approximately 
every 12 weeks until death, withdrawal of consent by subject, lost to follow-up, or study 
terminated by sponsor, whichever comes first. 
 
9 
Criteria for Response, Progression, and Relapse 
Any subject who has confirmed objective evidence of cancer progression while receiving 
regimens of acalabrutinib and obinutuzumab; acalabrutinib, venetoclax, and obinutuzumab; or 

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acalabrutinib, venetoclax, and rituximab should be withdrawn from the study treatment. If there 
is uncertainty regarding whether there is true cancer progression, the subject may continue study 
treatment and remain under close observation (e.g., evaluated at 4-week intervals) pending 
confirmation of progression. In particular, transient worsening of disease early in therapy or 
during temporary interruption of study therapy (e.g., for drug-related toxicity, surgery, or 
intercurrent illness) may not indicate cancer progression. In such circumstances, and if 
medically appropriate, subjects may resume therapy and relevant clinical, laboratory, and/or 
radiologic assessment can be attempted to document whether tumor control can be maintained or 
whether cancer progression has occurred. 
Criteria for response for CLL and prolymphocytic leukemia (PLL) will utilize the IWCLL 2008 
(Hallek et al. 2008, Table 14) for response, which includes clinical, hematologic, and bone 
marrow features. Responses will be classified as follows: 
Complete response: Requires all of the following for a period of at least 2 months: 
• Absence of lymphadenopathy >1.5 cm on physical examination and CT scan 
• No hepatomegaly or splenomegaly on physical examination (a CT scan also may be used to 
assess) 
• Normal CBC as exhibited by polymorphonuclear leukocytes ≥1,500/µL, platelets 
>100,000/µL, hemoglobin >11.0 g/dL (untransfused); absolute lymphocyte count <4,000/µL 
• Bone marrow aspirate and biopsy must be normocellular for age with <30% of nucleated 
cells being lymphocytes. Lymphoid nodules may be present but must be T-cell in origin. If 
these are demonstrated to be clonal B-cells, subjects should be considered to be a PR. 
Additionally, if bone marrow is positive by immunohistochemistry (IHC) for CLL cells, it 
should be considered a PR. If the marrow is hypocellular a bone marrow should be 
performed in 2 to 3 months. If blood counts (polymorphonuclear leukocytes <1,500/µL, 
platelets <100,000/µL) fail to recover at the time of the response evaluation but there is 
otherwise no evidence of CLL, a repeat determination should be performed at the time of 
count recovery (polymorphonuclear leukocytes ≥ 1,500/µL, platelets >100,000/µL) but 
should not exceed 6 months. 
• Subjects who fulfill the criteria for CR with the exception of a persistent cytopenia (i.e., 
anemia, thrombocytopenia, or neutropenia) that is believed to be unrelated to CLL but related 
to drug toxicity will be considered a CR with incomplete marrow recovery (CRi). As stated 
above, subjects falling into this category should ideally undergo a repeat bone marrow when 
counts recover fully. If the bone marrow at full count recovery reveals no CLL, these 
subjects will be considered to be in complete remission at that time. 
• Subjects who fulfill the criteria of CR with exception of having bone marrow lymphoid CLL 
nodules will be considered a nodular PR (nPR), and assessed prospectively for similarity to 
outcome with CR. 

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Partial Response: Requires a ≥50% decrease in peripheral lymphocyte count from 
pre-treatment value or absolute lymphocyte count <5,000/µL, ≥50% reduction in 
lymphadenopathy of as many as 6 measurable lymph nodes, and/or ≥50% reduction in 
splenomegaly/hepatomegaly for a period of at least 2 months. Additionally, these subjects must 
have 1 of the following: 
• Polymorphonuclear leukocytes ≥1,500/µL or 50% improvement from pre-treatment value 
• Platelets >100,000/µL or 50% improvement from pre-treatment value 
• Hemoglobin >11.0 g/dL (untransfused) or 50% improvement from pre-treatment value 
• Subjects who meet the criteria for PR with the exception of having less than a 50% reduction 
in peripheral lymphocyte count AND absolute lymphocyte count >5,000/µL will be 
considered a PRL. These subjects should continue to be followed on therapy and response 
status updated if the lymphocyte count does decrease by ≥50% or absolute lymphocyte count 
<5,000/µL is achieved. 
Progressive Disease: Progressive disease will be characterized by any one of the following 
events: 
• ≥50% increase in the products of at least 2 lymph nodes on 2 consecutive determinations 
2 weeks apart (at least 1 lymph node must be ≥2 cm); appearance of new palpable lymph 
nodes 
• ≥50% increase in the size of the liver and/or spleen as determined by measurement below the 
respective costal margin; appearance of palpable hepatomegaly or splenomegaly, which was 
not previously present 
• Transformation to a more aggressive histology (i.e., Richter’s syndrome or PLL with ≥56% 
prolymphocytes) 
• The progression of any cytopenia (unrelated to autoimmune cytopenia), as documented by a 
decrease of Hgb levels >2 g/dL or to <10 g/dL, or by a decrease of platelet counts >50% or to 
<100,000/µL, which occurs at least 3 months after the initiation of treatment, deﬁnes disease 
progression, if the marrow biopsy demonstrates an inﬁltrate of clonal CLL cells. During 
therapy, cytopenias cannot be used to deﬁne disease progression. 
Stable Disease: Subjects who do not fulfill the criteria for CR or PR as defined above but do not 
exhibit progressive disease will be considered as having stable disease (SD). 

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Table 14: IWCLL Response Assessment Criteria 
 
Response 
Lymphocytes 
Bone Marrow 
Physical Examinationa 
(Nodes, Liver, Spleen) 
Peripheral Blood 
CR* 
Lymphocytes 
<4 x 109/L 
Normocellular 
<30% lymphocytes 
No B-lymphoid 
nodules 
Normal (e.g., no lymph 
nodes >1.5 cm) 
ANC >1.5 x 109/Lb 
Platelets >100 x 109/Lb 
Hemoglobin >11.0 g/dL 
(untransfused)b 
CRi 
Lymphocytes 
<4 x 109/L 
Hypocellular 
<30% lymphocytes 
Normal 
(e.g., no lymph nodes 
>1.5 cm) 
Persistent anemia, 
thrombocytopenia, or neutropenia 
related to drug toxicity 
nPR 
CR with the presence of lymphoid nodules in the bone marrow, which reflect residual disease 
PR* 
Lymphocytes 
<5 x 109/L 
Or 
≥50% decrease from 
baseline 
Not assessed 
≥50% reduction in 
lymphadenopathyc and/or in 
spleen or liver enlargement 
ANC >1.5 x 109/L 
Or 
Platelets >100 x 109/L or 
50% improvement over baselineb 
Or 
Hemoglobin >11.0 g/dL or 
50% improvement over baseline 
(untransfused)b 
PRL* 
Lymphocytes 
≥5 x 109/L 
Not assessed 
≥50% reduction in 
lymphadenopathyc and/or in 
spleen or liver enlargement 
ANC >1.5 x 109/L 
Or 
Platelets >100 x 109/L or 
50% improvement over baselineb 
Or 
Hemoglobin >11.0 g/dL or 
50% improvement over baseline 
(untransfused)b 
SD 
Absence of PD and failure to achieve at least a PR 
PD* 
Lymphocytes ≥50% 
increase over baseline 
Not assessed 
Appearance of any new 
lesion or de novo 
appearance of hepatomegaly 
or splenomegaly Or 
Increase ≥50% in 
lymphadenopathy 
Or 
Increase ≥50% in 
hepatomegaly or 
splenomegaly 
Platelets decrease of ≥50% from 
baseline secondary to CLL 
Or 
Hemoglobin decrease of >2 g/dL 
from baseline secondary to CLL 
Modified from Hallek et al. 2008. 
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 subjects have to lack disease-related constitutional symptoms; PR: at least two of the 
above PR criteria for lymphadenopathy, splenomegaly, hepatomegaly, or lymphocytes plus one of the criteria for ANC, platelets or 
hemoglobin have to be met; PRL: presence of lymphocytosis, plus ≥ 50% reduction in lymphadenopathy and/or in spleen or liver 
enlargement, plus one of the criteria for ANC, platelets or hemoglobin have to be met; PD: at least one of the above PD criteria has to be 
met, or transformation to a more aggressive histology (e.g., Richter’s syndrome). Note: Isolated elevation of treatment-related 
lymphocytosis by itself will not be considered PD unless subject becomes symptomatic from this per Cheson et al 2012. 
a. Computed tomography (CT) scan of abdomen, pelvis, and thorax may be used if previously abnormal 
b. Without need for exogenous growth factors 
c. 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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Response criteria for SLL subjects will use 2007 Revised Response Criteria for Malignant 
Lymphoma (Cheson et al. 2007). Responses will be classified as follows: 
Complete response: Requires all of the following: 
• Complete absence of all detectable clinical evidence of disease and disease-related symptoms 
present prior to therapy 
• Regression of lymphadenopathy to normal size (≤1.5 cm) on physical examination and CT 
scan. Previously involved nodes that were 1.1 to 1.5 cm in long axis and more than 1 cm in 
short axis must have decreased to ≤1 cm in their short axis. 
• No hepatomegaly or splenomegaly on physical examination or CT scan, and nodules related 
to lymphoma should disappear. 
• Bone marrow aspirate and biopsy must be free of disease on an adequate biopsy sample. If 
indeterminate by morphology, IHC must be negative. 
Partial Response: Requires all of the following: 
• ≥50% decrease in sum of product of the diameters of up to 6 largest dominant masses. No 
increase in size of other nodes and no new lesions. 
• ≥50% reduction in sum of product diameters of nodules in spleen/liver with no increase in 
size of liver or spleen. 
Progressive Disease: Progressive disease will be characterized by any 1 of the following events: 
• Appearance of a new lesion >1.5 cm in any axis 
• ≥50% increase in the products of at least 2 lymph nodes 
• ≥50% increase in the longest diameter of a previously identified node >1 cm in short axis 
• ≥50% increase in the size of the liver and/or spleen or previously determined nodules in the 
liver or spleen 
• New or recurrent bone marrow involvement 
Stable Disease: Subjects who do not fulfill the criteria for complete or partial response as 
defined above but do not exhibit progressive disease will be considered as having SD. 
 
10 
Patient Safety and Adverse Event Reporting 
 
10.1 
Reference Safety Information 
For the purpose of reporting AEs and SAEs, the Investigator Brochure for acalabrutinib contains 
the RSI. 

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10.2 
Monitoring of Adverse Events 
After the signing of the Informed Consent Form (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(s) or the start of a new 
anticancer therapy (whichever comes first). After this period, investigators should report SAEs 
or other AEs of concern that are believed to be related to prior treatment with study drug. 
All SAEs that occur during the reporting period should be followed to resolution or until the 
investigator assesses the subject as stable, or the subject is lost to follow-up or withdraws 
consent. Resolution/stable means the subject has returned to baseline state of health or the 
investigator does not expect any further improvement or worsening of the event. 
The events must be detailed to include diagnostic term, severity, causality in relationship to the 
study drug, duration, action taken and outcome. The descriptions and grading scales found in the 
NCI-CTCAE version 4.03 or higher will be utilized for AE reporting. 
 
10.3 
Definitions of Adverse Events and Causality 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational (medicinal) product, regardless of attribution. 
This includes the following: 
• AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with CLL that were not present 
before the AE reporting period 
• Pre-existing medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
• Abnormal laboratory values considered clinically significant by the investigator should be 
reported as AEs. 
The following are NOT considered AEs: 
• Pre-existing condition that has not worsened: A pre-existing condition (documented on 
the medical history CRF) is not considered an AE unless the severity, frequency, or character 
of the event worsens during the study period. 
• Preplanned hospitalization: A hospitalization planned before signing the ICF is not 
considered an SAE, but rather a therapeutic intervention. However, if during the preplanned 

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hospitalization an event occurs, which prolongs the hospitalization or meets any other SAE 
criteria, the event will be considered an SAE. Surgeries or interventions that were under 
consideration, but not performed before signing the ICF in the study, will not be considered 
serious if they are performed after signing the ICF in the study for a condition that has not 
changed from its baseline level. Elective hospitalizations for social reasons, solely for the 
administration of chemotherapy, or due to long travel distances are also not SAEs. 
• Diagnostic testing and procedures: Testing and procedures should not be reported as AEs 
or SAEs, but rather the cause for the test or procedure should be reported. If a test or 
procedure is done to rule out a diagnosis, the sign or symptom leading to the test/procedure 
should be the event term, and the event term should only be updated to the diagnosis if/when 
the diagnosis is confirmed. Testing and procedures performed solely as screening measures 
(e.g., routine screening mammography or colonoscopy) should not be reported as AEs or 
SAEs. 
• Abnormal laboratory results that the investigator considers to not be clinically 
significant: Abnormal laboratory results are not AEs unless they are clinically significant. 
For example, a clinically significant laboratory result is one that requires treatment (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. 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation time points 
during the study. All AEs and SAEs whether volunteered by the subject, discovered by study 
personnel during questioning, or detected through physical examination, or other means will be 
recorded in the subject’s medical record and on the AE eCRF. 
Disease progression itself is not considered an AE; however, signs and symptoms of disease 
progression may be recorded as AEs or SAEs. 
Each recorded AE or SAE will be described by its duration (i.e., start and end dates), severity, 
regulatory seriousness criteria, if applicable, suspected relationship to the study drug (see 

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following guidance), and any actions taken. The causality of AEs to the study drug will be 
assessed by means of the question: ‘Is there a reasonable possibility that the event may have 
been caused by the study drug?’ per FDA guidance on safety reporting requirements. 
 
10.4 
Definition of Serious Adverse Events 
Any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (places the subject at immediate risk of death at the time of the occurrence) 
• Required inpatient hospitalization or prolongation of an existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
• Is an important medical event, that may not be immediately life-threatening or result in death 
or hospitalization, but based upon appropriate medical and scientific judgment, may 
jeopardize the subject or may require medical or surgical intervention to prevent one of the 
other serious outcomes listed in the definition above. 
Any death (other than death due to disease progression; see Section 10.5) occurring within 
30 days of the subject receiving study drug, regardless of the subject having discontinued from 
the study, must be reported as a SAE. Any hospitalization <24 hours or hospitalizations for 
planned procedures will not be considered an SAE. 
 
10.5 
Reporting of Adverse Events 
All SAEs must be reported within 24 hours of discovery. All initial SAE reports and follow-up 
information will be reported using the protocol-specific electronic data capture system, according 
to the instructions provided in the investigator site file. If electronic SAE reporting is not 
available, paper SAE forms must be faxed or emailed to Acerta Pharma, BV, Drug Safety, or 
designee. Acerta Pharma, BV, may request follow-up and other additional information from the 
investigator (e.g., hospital admission/discharge notes, and laboratory results). 
Whenever possible, AEs/SAEs should be reported by diagnosis term not as a constellation of 
symptoms. 
Death due to disease progression should be recorded on the appropriate form in the electronic 
data capture system. If the primary cause of death is disease progression, the death due to 
disease progression should not be reported as an SAE. If the primary cause of death is 
something other than disease progression, then the death should be reported as an SAE with the 
primary cause of death as the event term, as death is typically the outcome of the event, not the 
event itself. The primary cause of death on the autopsy report should be the term reported. 

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Autopsy and postmortem reports must be forwarded to Acerta Pharma, BV, Drug Safety, or 
designee, as outlined for SAEs above. 
If study drug is discontinued because of an SAE, this information must be included in the SAE 
report. 
An SAE may qualify for mandatory expedited reporting to regulatory authorities if the SAE is 
attributable to the study drug (or if a causality assessment is not provided for the SAE, in which 
case a default of ‘related’ may be used for expedited reporting purposes) and the SAE is not 
listed in the current acalabrutinib Investigator Brochure (i.e., an unexpected event). In this case, 
Acerta Pharma, BV, 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 of the SUSAR, as required. 
 
 
 
Drug Safety Contact Information 
eFax: 
 
Email: 
 
 
 
 
10.5.1 
Second Primary Malignancies 
AEs for malignant tumors reported during a study should generally be assessed as SAEs. If no 
other seriousness criteria apply, the “Important Medical Event” criterion should be used. In 
certain situations, however, medical judgment on an individual event basis should be applied to 
clarify that the malignant tumor event should be assessed and reported as a nonserious AE. For 
example, if the tumor is included as medical history and progression occurs during the study but 
the progression does not change treatment and/or prognosis of the malignant tumor, the AE may 
not fulfill the attributes for being assessed as serious, although reporting of the progression of the 
malignant tumor as an AE is valid and should occur. Also, some types of malignant tumors, 
which do not spread remotely after a routine treatment that does not require hospitalization, may 
be assessed as nonserious; examples in adults include Stage 1 basal cell carcinoma and 
Stage 1A1 cervical cancer removed via cone biopsy. 
 
The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (i.e., it is not the tumor for which entry into the study is a criterion and that is 
being treated by the investigational product under study and is not the development of new or 
progression of existing metastasis to the tumor under study). Malignant tumors that—as part of 
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normal, if rare, progression—undergo transformation (e.g., Richter's transformation of B cell 
CLL into diffuse large B cell lymphoma) should not be considered a new malignant tumor. 
 
10.5.2 
Adverse Events of Special Interest 
The following events are adverse events of special interest (AESIs) for subjects randomized to 
the acalabrutinib-containing combinations arm and must be reported to the sponsors 
expeditiously (see Section 10.5 for reporting instructions), irrespective of regulatory seriousness 
criteria or causality: 
• Ventricular arrhythmias (e.g., ventricular extrasystoles, ventricular tachycardia, ventricular 
arrhythmia, ventricular fibrillation) 
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 such as immunosuppression. 
 
 
10.6 
Data Safety Monitoring Plan 
The data and safety monitoring plan will involve the continuous evaluation of safety, data quality 
and data timeliness during the dose escalation phase of Cohorts 1 and 2. During this phase, 
Acerta and investigators will conduct continuous review of data and subject safety at regular 
intervals. This will include the review of frequency and severity of AEs and responses on the 
trial, where applicable, to determine if the risk/benefit ratio of the trial changes. SAEs and 
responses will also be reviewed by The Ohio State University CCC Data Safety Monitoring 
Committee (DSMC). The principal investigator will also submit a progress report quarterly that 
will be reviewed by the committee per the DSMC plan. All reportable SAE will be reported to 
the FDA and IRB of record as per the policies of the IRB. In addition, at the end of each DLT 
review period, mandatory safety meetings will be held with the sponsor. 
For Cohorts 3 and 4, safety data will be reviewed for the first 3 subjects who complete Cycle 3 in 
each cohort. The review will be repeated for additional subjects if needed. Unless a safety 
concern is identified (e.g., dose delays >14 days in 
 enrollment in Cohorts 3 and 4 will 
continue during the safety review until the desired number of subjects is reached. There are no 
DLTs defined for this portion of the study. See Section 5 for study drugs and administration 
guidelines. 
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11 
Withdrawal of Subject from Treatment or Assessment 
 
11.1 
Withdrawal of Subjects from Study Treatment 
The investigator, in consultation with the medical monitor, may withdraw any subject from study 
treatment, if, in the investigator’s opinion, it is not in the subject’s best interest to continue. 
Any subject has the right to withdraw from the study at any time.  In addition, subjects may be 
withdrawn from study treatment for the following reasons: 
• Completed treatment 
• Progressive disease 
• Adverse event 
• Pregnancy 
• Physician decision (includes start of alternative anticancer therapy) 
• Treatment withdrawal by subject 
• Treatment terminated by sponsor 
• Subject lost to follow-up 
• Death 
• Other 
Subjects who discontinue study therapy will continue to be followed on study for follow up of 
safety (Section 8.3), disease progression, and survival unless they withdraw consent for further 
follow-up. Thus, all subjects receiving ≥1 dose of study drug will be followed during the 
immediate post-therapy and long-term follow-up assessments unless the subject withdraws 
consent for such follow-up to be conducted. The date the subject is withdrawn from study 
treatment or from the study (including long-term follow-up) and the reason for discontinuation 
will be recorded and also should be described on the appropriate eCRF. 
 
11.2 
Reasons for Study Exit 
Reasons for study exit include: 
• Death 
• Subject lost to follow-up 
• Study terminated by sponsor 
• Study withdrawal by subject 
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• Other 
12 
Forms to Be Kept 
On-study as well as follow-up data will be recorded on data sheets specific to this study. All 
study participants will sign a written informed consent, which will describe the objectives of the 
study and potential risks. All subject data will be identified by subject initials and study code 
number only. Subjects will not be identified by name. 
 
13 
Correlative Studies 
 
13.1 
Outline of Correlative Laboratory Studies 
Correlative studies associated with this trial will focus on the 
 
 as well as the consequences of BTK inhibition in CLL cells, T cells, and NK 
cells. MRD analysis will be performed to correlate long-term outcomes with MRD negativity. 
Additionally, from subjects who relapse after this combination, samples will be taken at relapse 
to determine mechanisms of resistance. Samples not used immediately will be stored for future 
research specifically investigating acalabrutinib or the combination of acalabrutinib and 
obinutuzumab in CLL. Residual material may be used to study other aspects of CLL related 
biology or other measures of treatment response. Stored samples will be housed in the CLL 
Experimental Therapeutics Laboratory at OSU. Subjects may withdraw consent to use their 
tissue at any time. 
Pharmacokinetic analysis will be performed on samples from the first 8 subjects enrolled in the 
expansion of Cohort 1 as well as the first 8 subjects enrolled in each of Cohorts 3 and 4. 
Pharmacokinetics analysis is outlined in Section 13.3. 
 
At baseline, peripheral blood and bone marrow will be collected as well as buccal cell sample for 
genomic DNA. Unselected or B cell selected peripheral blood cells at this time point will be 
compared with serial samples to determine changes in BTK occupancy and BCR signaling 
protein activation that occur with acalabrutinib alone or in combination with obinutuzumab. 
BTK occupancy analysis and select signaling studies will be performed by Acerta. In Cohorts 3 
and 4, BCL-2 family members (Bcl-2, Mcl-1, and Bcl-xL) will be profiled in peripheral blood 
and/or bone marrow mononuclear cells. Samples for these studies will be batched and sent by 
the laboratory personnel to Acerta Pharma, BV, or designee. 
 
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During serial follow up, we will assess for development of mutations to BTK and PLCG2, the 
most frequent mechanism of resistance to ibrutinib. This will be performed at 3-month intervals 
on blood or bone marrow.
 
 
 
Peripheral blood flow cytometry will be performed serially to analyze how B, T, and NK cell 
total number and subset composition change during the course of this therapy. As well, T cells 
and NK cells will be selected from peripheral blood at baseline and serial time points to 
determine how cytokine expression, cytotoxicity directed by NK cells (direct or antibody 
mediated), NK cell direct cytotoxicity, activation markers of T-cells and NK cells, or T cell 
polarity is changed by acalabrutinib alone or in combination with obinutuzumab, rituximab, or 
venetoclax. 
The expression of cell death pathway proteins such as MCL1, BCL-2 and others will be 
measured from peripheral blood using flow cytometry on serial sample to determine if the level 
of cell death proteins change with treatment and if a profile of cell death proteins is predictive of 
treatment outcomes. 
 
 
 
MRD status will be evaluated in all subjects at prespecified time points. In Cohorts 1 and 2, all 
subjects should have bone marrow biopsy with MRD analysis at Cycle 12 Day 1 (Table 11). 
 
 
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Figure 2: 
 
 
 
 
 
 
Figure 3: 
 
 
 
All samples, except PK samples outlined in Section 13.3, will be delivered to the CLL 
Experimental Therapeutics Laboratory for processing and shipment of selected samples. 
 
13.2 
Correlative Sample Requirements (Exclusive of Pharmacokinetic Samples) 
 
13.2.1 
Cohorts 1 and 2 
Refer to the Schedule of Assessments (Table 11). 
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Screening 
• 10 mL bone marrow in a heparin tube, which will be processed by Ficoll density gradient 
centrifugation and viably frozen 
• 2 buccal swabs 
• Peripheral blood 4 x 8.5 mL acid citrate dextrose (ACD) tubes, which will be processed by 
Ficoll density gradient centrifugation and viably frozen 
• Peripheral blood 2 x 6 mL ethylenediamine tetra-acetic acid (EDTA) tubes that will be 
centrifuged to obtain plasma 
 
• Peripheral blood 4 x 8.5 mL ACD tubes, which will be processed by Ficoll density gradient 
centrifugation and viably frozen 
 
• Peripheral blood 2 x 8.5 mL ACD tubes, which will be processed by Ficoll density gradient 
centrifugation and viably frozen 
 
• Peripheral blood 4 x 8.5 mL ACD tubes, which will be processed by Ficoll density gradient 
centrifugation and viably frozen 
• Peripheral blood 2 x 6 mL EDTA tubes that will be centrifuged to obtain plasma 
 
• Peripheral blood 4 x 8.5 mL ACD tubes, which will be processed by Ficoll density gradient 
centrifugation and viably frozen 
• Peripheral blood 2 x 6 mL EDTA tubes that will be centrifuged to obtain plasma 
 
• Peripheral blood 4 x 8.5 mL ACD tubes, which will be processed by Ficoll density gradient 
centrifugation and viably frozen 
• Peripheral blood 2 x 6 mL EDTA tubes that will be centrifuged to obtain plasma 
 
• Peripheral blood 4 x 8.5 mL ACD tubes, which will be processed by Ficoll density gradient 
centrifugation and viably frozen 
• Peripheral blood 2 x 6 mL EDTA tubes that will be centrifuged to obtain plasma 
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• Peripheral blood 4 x 8.5 mL ACD tubes, which will be processed by Ficoll density gradient 
centrifugation and viably frozen 
 
• 10 mL bone marrow in a heparin tube, which will be processed by Ficoll density gradient 
centrifugation and viably frozen 
• Peripheral blood 4 x 8.5 mL ACD tubes, which will be processed by Ficoll density gradient 
centrifugation and viably frozen 
• Peripheral blood 2 x 6 mL EDTA tubes that will be centrifuged to obtain plasma 
 
• Peripheral blood 4 x 8.5 mL ACD tubes, which will be processed by Ficoll density gradient 
centrifugation and viably frozen 
• Peripheral blood 2 x 6 mL EDTA tubes that will be centrifuged to obtain plasma 
Relapse 
• 10 mL bone marrow in a heparin tube, which will be processed by Ficoll density gradient 
centrifugation and viably frozen 
• Peripheral blood 4 x 8.5 mL ACD tubes, which will be processed by Ficoll density gradient 
centrifugation and viably frozen 
• Peripheral blood 2 x 6 mL EDTA tubes that will be centrifuged to obtain plasma 
• If applicable, sample of lymph node biopsy to confirm transformation or relapse, which will 
be processed to a mononuclear cell suspension using manual disassociation and Ficoll 
density gradient centrifugation or red cell lysis. 
 
13.2.2 
Cohorts 3 and 4 
 
Refer to the Schedules of Assessments (Table 12 and Table 13). 
 
 
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Cell Death Protein Ratio Flow 
 
Blood samples will be collected and analyzed within 48 hours of collection using flow cytometry 
for cell death proteins and pathway and/or disease-related proteins. Samples should consist of a 
10-mL blood draw to be obtained at the following time points: 
• Screening 
• Cycle 1 Day 1, before acalabrutinib dose 
• Cycle 2 Day 1, before anti-CD20 antibody 
• Cycle 3 Day 1, before venetoclax 
• Relapse/PD 
• Safety Follow-up Visit 
Immunophenotyping 
 
Blood samples will be collected to evaluate tumor and immune microenvironment by flow 
cytometry. Samples should consist of a 10-mL blood draw to be obtained at the following time 
points: 
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• Screening 
• Cycle 1 Day 1, before acalabrutinib dose 
• Cycle 2 Day 1, before anti-CD20 antibody 
• Cycle 3 Day 1, before venetoclax 
• Relapse/PD 
• Safety Follow-up Visit 
 
On-treatment Bone Marrow 
 
Remaining bone marrow will be analyzed to confirm findings from correlative analysis from 
peripheral blood samples. If bone marrow is being collected, surplus could be submitted for 
correlative analysis. 
 
13.3 
Pharmacokinetics 
To supplement data from the Phase 1 study, the first 8 subjects accrued to the Phase 1b 
Expansion of Cohort 1 and the first 8 subjects enrolled in each of Cohorts 3 and 4 will have PK 
analysis performed. In Cohorts 3 and 4, subjects who have not previously participated in PK 
analysis will have PK analysis performed at predose and 2 hours postdose, relative to 
acalabrutinib administration. The plasma PK of acalabrutinib, a metabolite ACP-5862 and 
venetoclax will be characterized using noncompartmental analysis. Missing dates or times may 
be imputed for PK samples if the missing values can be established with an acceptable level of 
accuracy based on other information obtained during the visit in question. If PK sampling for a 
given subject is not performed according to protocol instructions that subject may be excluded 
from the PK analyses and an additional subject used. 
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The PK parameters will be tabulated and summarized using descriptive statistics.
 
 
 
At each PK time point one 4 mL lithium heparin tube should be collected and sent to CTPL 
immediately. 
 
Sample should be processed per laboratory manual. 
Samples will be batched for shipment. 
Cohort 1 PK samples will be collected at the following time points on 
 
• Predose 
• 30 minutes 
• 1 hour 
• 2 hours 
• 3 hours 
• 4 hours 
• 6 hours 
• 24 hours 
For Cohorts 3 and 4, PK samples will be collected at the following time points on 
 
 relative to acalabrutinib administration: 
• Predose 
• 30 minutes (±5 minutes) 
• 1 hour (±5 minutes) 
• 2 hours (±15 minutes) 
• 3 hours (±15 minutes) 
• 4 hours (±15 minutes) 
• 6 hours (±15 minutes) 
• 24 hours (±15 minutes) 
In Cohorts 3 and 4, subjects who have not previously participated in PK analysis will have PK 
analysis performed at predose and 2 hours postdose, relative to acalabrutinib administration. 
• Predose 
• 2 hours (±15 minutes) 
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13.4 
Health Related Quality of Life and Emotional Distress Assessment 
Cohorts 1 and 2: 
As part of this study, data regarding health-related quality of life (HR-QOL) will be obtained to 
determine how acalabrutinib plus obinutuzumab affect HR-QOL. Baseline HR-QOL between 
subjects with untreated disease and those with relapsed and refractory CLL will also be 
compared. 
During screening, sociodemographic information (e.g., age, race, marital status) and reports of 
recent stressful events will be obtained. In addition, the assessment will consist of measures of 
CLL specific stress, anxiety and depressive symptoms, social support, other symptoms (fatigue, 
pain, sleep problems), and quality of life. Across cycles, only a subset of measures is used as 
this reduces subject burden. See Appendix 2 for timeline for measure usage and descriptions of 
the psychometric properties of the measures. 
Cohorts 3 and 4: 
 
The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 
Core 30 (EORTC QLQ-C30) is a cancer-specific instrument most frequently used to measure 
quality of life in cancer patients. 
 
14 
Statistical Considerations 
 
14.1 
Study Overview 
This is a Phase 1b study with expansion to evaluate the safety and preliminary efficacy of 
acalabrutinib in combination with obinutuzumab, or with venetoclax and an anti-CD20 antibody 
(rituximab or obinutuzumab) in 4 separate cohorts of subjects: those with relapsed/refractory 
CLL (Cohorts 1 and 3) and those with treatment-naive CLL (Cohorts 2 and 4). Enrollment will 
begin in Cohort 1, where the recommended dose will be based on decision rules from a standard 
3+3 Phase 1 trial design and will proceed as outlined in Figure 4. Both Cohorts 1 and 2 will be 
expanded to better evaluate the toxicity profile of these combination regimens, and also to detect 
moderate to large increases in ORR at 12 months relative to historical control. Cohorts 3 and 4 
will be enrolled to establish the safety profile of the combination of acalabrutinib plus venetoclax 
plus an anti-CD20 antibody. The ORR will be defined as the proportion of treated subjects who 
achieve complete or partial remission at Cycle 16 for Cohorts 3 and 4. The cumulative ORR 
over time will be summarized for each of the 4 cohorts individually. 

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Figure 4: Trial Design 
 
 
CLL = chronic lymphocytic leukemia; R/R = relapsed/refractory 
 
 
 
14.2 
Sample Size 
The sample size for Cohorts 1 and 2 is based on: 1) dose de-escalation rules; and 2) the number 
of subjects required to detect moderate to large increases in ORR relative to historical control 
with sufficient power while constraining Type I error to 0.10. This study is expected to require 
45 subjects, 6 subjects evaluated for safety in each cohort and an additional 20 and 13 subjects 
enrolled in Cohorts 1 and 2, respectively. More subjects may be enrolled if de-escalation of dose 
levels is indicated in the safety evaluation. The sample size of 12 subjects each for Cohorts 3 
and 4 is chosen to provide evaluation for safety and tolerability. 
 
14.3 
Accrual Time and Study Duration 
The anticipated accrual rate is 1 to 2 subjects per month for Cohort 1 and 1 subject per month for 
Cohort 2. It is anticipated that all subjects will be accrued to Cohort 1 within 2 years and accrual 
to Cohort 2 will occur over the course of approximately 3 years, resulting in a study duration of 
approximately 4 years to evaluate the primary endpoint. The anticipated accrual rate for 
Cohorts 3 and 4 is approximately 2 subjects per month. 

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14.4 
Statistical Design 
Cohorts 1 and 2 will use a Phase 1b study design with de-escalation to determine a safe and 
tolerable dose level to be recommended for the expansion portion. Section 6.5 provides the 
details of the study design for dose finding. Each of Cohorts 1 and 2 will be expanded at the 
recommended dose level to include, respectively, 26 and 19 total relapsed/refractory and 
treatment-naive CLL subjects. These sample sizes were chosen to obtain sufficient preliminary 
safety and efficacy information in these populations. With respect to toxicity and ability to 
detect common AEs, there is approximately a 60% chance of observing at least 1 subject with an 
AE occurring at a 5% rate with 19 treatment-naive subjects in Cohort 2, and approximately a 
75% chance in the group of 26 relapsed/refractory CLL subjects in Cohort 1. If toxicity profiles 
are similar and it is appropriate to summarize AEs across all subjects, there is at least a 90% 
chance of detecting a common AE. With respect to clinical efficacy, a 50% ORR (PRL or 
better) (null) at the 12-month evaluation would be considered uninteresting as this can be 
achieved with either of acalabrutinib or obinutuzumab as single agents in both populations. 
However, an ORR of at least 75% in the relapsed/refractory setting for Cohort 2 and an ORR of 
at least 80% in the treatment-naive setting for Cohort 1 would be of considerable interest and 
would warrant further investigation of the combination regimen (alternative). If 16 or fewer 
responses are observed in 26 evaluable subjects with relapsed/refractory CLL in Cohort 1, the 
combination of acalabrutinib with obinutuzumab would not be considered promising; likewise, if 
12 or fewer responses in 19 evaluable subjects who were previously untreated for CLL in Cohort 
2 were observed, the combination would not be considered promising as upfront therapy. Each 
of these designs has at least 90% power with a 1-sided alpha level of 0.10. 
The sample sizes for Cohorts 3 and 4 are chosen to obtain preliminary safety information in the 
relapsed/refractory and treatment-naive CLL populations. With respect to toxicity and ability to 
detect common AEs, there is a 46% chance of observing at least 1 subject with an AE occurring 
at a 5% rate with 12 subjects in each of Cohort 3 and 4. Below is a list of various AE rates with 
the chance of observing at least 1 subject with that AE. 
 
Sample Size 
Adverse Event Rate 
Chance of Observing at Least 1 Adverse Event 
12 
1% 
11% 
12 
2% 
22% 
12 
5% 
46% 
12 
10% 
72% 
 
 
14.5 
Analysis Populations: 
• All-treated Population: All enrolled subjects who receive ≥1 dose of study drug. The 
All-treated Population will be used for the efficacy and safety analyses. 
• Efficacy-evaluable Population: All subjects in the All-treated Population who have 
≥1 evaluable response assessment after the first dose of study drug. The Efficacy-evaluable 
Population will be used for sensitivity analysis. 

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For Cohorts 1 and 2, if in the DLT observation portion, a subject discontinues study prior to 
completing the second cycle of treatment at a dose level for reasons other than toxicity, an 
additional subject may be enrolled at that dose level for purposes of the DLT assessment and 
decision rules. 
 
14.6 
Analysis Plan 
 
14.6.1 
Primary Endpoints 
For Cohorts 1 and 2, the ORR (PR or better) at the 12-month response assessment will be 
calculated and 95% exact binomial CIs will be provided. For Cohorts 1 to 4, toxicities will be 
tabulated by type and grade using NCI-CTCAE version 4.03 criteria or higher and displayed in 
summary form.  In addition, the number of subjects requiring dose reductions, and the reason for 
going off each treatment may be summarized. 
 
14.6.2 
Secondary Endpoints 
All secondary endpoints will be evaluated for each cohort separately. The ORR of the 
combination therapy of acalabrutinib plus venetoclax plus an anti-CD20 antibody at Cycle 16 
(Cohorts 3 and 4) will be calculated and 95% exact binomial CIs will be provided. The CR rate 
and MRD-negative CR rate will be summarized. The degree of response will be summarized as 
well as the number of subjects who achieve CR but remain positive for MRD. Duration of 
response, time to CR, PFS, TTNT, time to response, and OS will be summarized with simple 
descriptive statistics obtained using the Kaplan-Meier method. DOR will be measured from the 
date of initial response to the date of disease progression or death. PFS will be measured from 
the date of first treatment to date of disease progression or death. For DOR and PFS, subjects 
who do not have disease progression or death will be censored at the date of last disease 
assessment. Subjects receiving stem cell transplant will be censored at the date of last disease 
assessment prior to the transplant. Time to next anti-CLL treatment will be measured from date 
of first treatment until date of next treatment or death, censoring those alive who have not started 
another treatment at last follow-up. OS will be measured from date of first treatment until date 
of death or last follow-up. These analyses will be useful in planning future studies. 
Cytogenetic and molecular marker data, including FISH and stimulated karyotype results, 
Zap-70 methylation, and IGHV mutational status will be summarized for all subjects. 
Relationships between these baseline variables and response rate or PFS will be explored 
graphically (e.g., side-by-side boxplots or Kaplan-Meier plots), where estimates with CIs will be 
presented as the primary method of analysis due to the limited number of subjects. If given a 
sufficient number of events, baseline markers may be correlated with response or survival using 
logistic regression or proportional hazards models, respectively, and adjusting for subject cohort 
(i.e., treatment-naive versus relapsed/refractory). 

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Correlative studies will assess the effects of acalabrutinib alone or in combination with other 
study drugs on 
 as well as B, T, and NK cell numbers over the course of therapy. 
With these data collected serially over time, patterns will be explored graphically using box plots 
and/or individual time plots as well as analytically with repeated measures analysis of variance. 
 
 
 
 
 
15 
Ethical and Regulatory Considerations 
 
15.1 
Ethical Principles 
This study will be conducted according to the principles outlined by the Declaration of Helsinki 
and all applicable amendments; the International Council for Harmonization (ICH) Guidelines 
for Good Clinical Practice; the US FDA regulations regarding the conduct of clinical trials and 
the protection of human subjects; the IRB, any applicable local health authority, and the Ethics 
Committee requirements. 
 
15.2 
Institutional Review Board Approval 
This study must obtain the approval of the protocol, the informed consent document and any 
other material used to inform the subject about the nature of the trial by a properly constituted 
IRB. The trial should not start until a copy of this written approval has been received by the 
investigator. The investigator will supply Acerta Pharma BV, with a copy of the IRB approval 
letter stating that the study protocol and any subsequent amendments and informed consent have 
been reviewed and approved. 
The investigator or designee will be responsible for obtaining annual IRB re-approval throughout 
the duration of the study including at completion or termination. 
 
15.3 
Protocol Amendments 
Any changes to this protocol made by the investigator must be in the form of a written 
amendment and the amendment will be appended to the protocol. Approval of amendments by 
the IRB is required prior to their implementation, unless there are overriding safety reasons. 
 
15.4 
Confidentiality 
It is the responsibility of the investigator to ensure that the confidentiality of all subjects 
participating in the trial and all of their medical information is maintained. Identifying 
information must be kept in a secure location with access limited to the study staff directly 
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participating in the trial. The investigator/institution will permit direct access to source data and 
documents to the sponsor’s study monitors, IRB, the FDA and/or other regulatory authorities. 
 
15.5 
Case Report Forms and Record Retention 
Authorized study site personnel will complete eCRFs designed for this study according to the 
completion guidelines that will be provided. The investigator will ensure that the eCRFs are 
accurate, complete, legible, and completed promptly. The investigator will ensure that source 
documents that are required to verify the validity and completeness of data transcribed on the 
eCRFs are never obliterated or destroyed. 
The investigator must maintain all study records, subject files and other source data for the 
duration of the trial and per applicable regulations. 
 
15.5.1 
Record Retention 
The investigator and other appropriate study staff are responsible for maintaining all 
documentation relevant to the study. Mandatory documentation includes copies of study 
protocols and amendments, each FDA Form 1572, IRB approval letters, signed ICFs, drug 
accountability records, SAE forms transmitted to Acerta Pharma, BV, subject files (source 
documentation) that substantiate entries in eCRFs, all relevant correspondence and other 
documents pertaining to the conduct of the study. 
An investigator shall retain records for a period of at least 2 years after the date the last 
marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and regulatory authorities have 
been notified. The investigator must notify Acerta Pharma, BV, and obtain written approval 
from Acerta Pharma, BV, before destroying any clinical study records at any time. Acerta 
Pharma, BV, will inform the investigator of the date that study records may be destroyed or 
returned to Acerta Pharma, BV. 
Acerta Pharma, BV, must be notified in advance of, and Acerta Pharma, BV, 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, BV, to store such documents in sealed containers 
away from the study site so that they can be returned sealed to the investigator for audit 
purposes. 

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15.6 
Study Monitoring Requirements 
Representatives of Acerta Pharma, BV, 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, representatives of Acerta Pharma, BV, its designated 
agents, and authorized employees of the appropriate regulatory agencies to inspect the facilities 
used in this study and, for purposes of verification, allow direct access to the hospital or clinic 
records of all subjects enrolled into this study.  This includes providing by fax, email, or regular 
mail de-identified copies of radiology, pathology, and/or laboratory results when requested by 
the sponsor. A statement to this effect will be included in the informed consent and permission 
form authorizing the use of protected health information. 
 
15.7 
Investigational Study Drug Accountability 
Study drugs must be kept in a locked limited access cabinet or space. The study drugs 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, BV, 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. 

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16 
References 
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Appendix 1. Known Strong In Vivo Inhibitors and Inducers of CYP3A 
 
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 
idelalisib 
erythromycin 
indinavir and ritonavirb 
fluconazole 
itraconazolea 
fluvoxamine 
ketoconazole 
imatinib 
lopinavir and ritonavira,b 
tofisopam 
nefazodone 
verapamila 
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. 
 
Note: After discontinuation of the strong CYP3A inhibitor, wait 3 days before resuming venetoclax or 
acalabrutinib. 

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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. 
 
 
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/DrugInteractionsLa 
beling/ucm093664.htm#inVivo 

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Bile acid sequestrants 
Proton pump inhibitors 
H2-receptor antagonists 
cholestyramine 
dexlansoprazole 
cimetidine 
colestipol 
esomeprazole 
famotidine 
colesevelam 
lansoprazole 
nizatidine 
omeprazole 
ranitidine 
rabeprazole 
pantoprazole 
Source: FDA Established Pharmacologic Class Text Phrase. Web link accessed 18 July 2018: 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/lawsactsandrules/uc 
m428333.pdf 

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Appendix 2. Health-Related Quality of Life and Emotional Distress Survey 
 
The schedule for quality of life assessments is included in Table 15. 
Sociodemographic information 
Single items are used to assess age, race/ethnicity, marital status, education, occupation, 
work-related functioning, and income. 
Medical Comorbidities 
 
The Charlson Comorbidity Index (Charlson et al., 1987) is a method of classifying comorbid 
health conditions. It was designed to capture risk of death from comorbid disease for use in 
longitudinal studies. Various medical conditions are listed, each with a point value (1, 2, 3, or 6) 
that contributes to a total score. More serious medical conditions are weighted more heavily and 
contribute more points to the total score. Higher scores indicate higher risk of death from a 
comorbid medical condition. To be completed by research staff. 
Stressful Life Events 
 
The Life Events Scale was adapted from the Women’s Health Initiative study (Matthews et al., 
1997). Participants indicate if they have experienced any of 5 stressful life events during the 
previous year (death, financial difficulty, divorce or break-up of family member or friend, major 
conflict with children or grandchildren, robberies or accidents). Two scores are calculated: 
presence versus absence of each event (0 = not occurred, 1 = occurred), and the total number of 
events reported (range 0 to 5). Higher scores indicate more frequent life events and greater 
distress. 
Health-Related Quality of Life 
 
The Medical Outcomes Study-Short Form-36 (SF-36; Ware, Kosinski, & Keller, 1996; Ware, 
Kosinski, Turner-Bowker, & Gandek, 2002) is used to assess health-related quality of life during 
the past month. The SF-36 assesses 8 aspects of quality of life including physical functioning, 
role functioning physical, general health perceptions, vitality, social functioning, role 
functioning-emotion, and mental health. Higher scores reflect better quality of life. 
The European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 (EORTC QLQ-C30; Aaronson et al., 1993) is a cancer-specific 
instrument most frequently used to measure quality of life in cancer patients. 
The Generalized Anxiety Disorder 7-item (GAD-7; Spitzer et al., 2006) is a self-reported 
questionnaire for screening and severity measuring of generalized anxiety disorder (GAD). 
GAD-7 has 7 items, which measure severity of various signs of GAD according to reported 
response categories with assigned points. 

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The Brief Pain Inventory (BPI; Cleeland & Ryan, 1994) is a 7-item self-report measure of pain 
severity and daily functional interference. Higher scores indicate greater interference. 
The Fatigue Symptom Inventory (FSI: Hann et al., 1998) disruption index is a 7-item assessment 
of the impact of fatigue on quality of life on an 11-point Likert-type scale ranging from 0 = no 
interference to 10 = extreme interference; higher scores indicating greater interference. 
The Medical Outcomes Study-Sleep Scale (MOS-Sleep; Hays, Martin, Sesti, & Spritzer, 2005) is 
a 12-item measure that will be used to assess sleep disturbance. Participants report how long it 
usually takes them to fall asleep in the past 4 weeks and on average how many hours of sleep 
they got each night in the last 4 weeks. They also report how often they have experienced 
10 specific difficulties with sleep (e.g., “Awaken during your sleep and have trouble falling 
asleep again”) on a 6-point Likert scale (1 = All of the time to 6 = None of the time) to form a 
sleep problems index. Higher scores on the sleep problem index indicate higher levels of sleep 
problems. 
Perceptions of Illness 
 
The Brief Illness Perception Questionnaire (BIPQ; Broadbent et al., 2006) is a 9-item 
questionnaire to assess patients’ perceptions of their illness. The BIPQ uses a single-item scale 
approach to assess perceptions on a continuous linear 0- to 10-point scale. For example, patients 
are asked, “How much control do you feel you have over your illness?” or “How much do you 
experience symptoms from your illness?” Although each item can stand alone as its own scale, a 
sum score can be computed by reverse scoring items 3, 4, and 7, and summing them with 
remaining items 1 through 8. The sum score ranges from 0 to 80, with higher scores 
representing a more negative perception of the illness. 
Depressive Symptoms 
 
The Center for Epidemiological Studies-Depression Scale (CES-D; Radloff, 1977) is a 20-item 
scale that assesses participants’ depressive symptoms in the past week. Participants are asked to 
rate how often each statement applied to them in the previous week on a 4-point scale from 0 
(“rarely or none of the time”) to 3 (“most or all of the time”). Scores range from 0 to 60, with 
higher scores representing greater depressive symptoms. 
The Patient Health Questionnaire (PHQ-9; Spitzer, Kroenke, & Williams, 1999) is a self-report 
scale that assesses symptoms of major depressive disorder as defined by the DSM-IV. The 
domain is depressive symptoms and its accompanying functional impairment. The traditional 
cutoff score for the PHQ-9 is ≥10, with higher scores indicating higher levels of depressive 
symptoms. 

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Anxiety 
 
The state subscale of the State-Trait Anxiety Inventory (STAI; Spielberger et al., 1970) will be 
used to assess symptoms of anxiety. It is a 20-item scale that asks respondents to indicate how 
they are feeling “right now, at this very moment.” Sample items include “I feel at ease” and “I 
feel nervous.” A sum score can be computed, with higher scores indicating higher levels of state 
anxiety. 
Emotional Distress 
 
The Profile of Mood States (McNair et al., 1971) is used to assess patient mood. The POMS is a 
65-item self-report inventory asking the subject how they have felt during the past week, yielding 
six mood subscales: Anxiety, Depression, Anger, Vigor, Fatigue, and confusion. Individual 
scale scores can be computed, as well as an overall mood disturbance score. Higher scores 
indicate higher levels of that particular mood. 
The Impact of Events Scale (Horowitz et al., 1979; Weiss & Marmar, 1996) is a 22-item 
standardized self-report questionnaire used to assess reactions to cancer diagnosis and treatment. 
Responses are rated on a 5-point scale; higher scores indicate greater distress. 

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Appendix 3. Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law 
 
 
ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER BIOCHEMISTRY AND 
EVALUATION OF HY’S LAW 
 
 
INTRODUCTION 
 
This appendix describes the process to be followed to identify and appropriately report potential 
Hy’s law (PHL) cases and Hy’s law (HL) cases. It is not intended to be a comprehensive guide 
to the management of elevated liver biochemistries. 
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets PHL 
criteria at any point during the study. All sources of laboratory data are appropriate for the 
determination of PHL and HL events; this includes samples taken at scheduled study visits and 
other visits, including central and all local laboratory evaluations, even if collected outside of the 
study visits (e.g., PHL criteria could be met by an elevated alanine aminotransferase (ALT) from 
a central laboratory and/or elevated total bilirubin from a local laboratory). The investigator will 
also review adverse event (AE) data (e.g., for AEs that may indicate elevations in liver 
biochemistry) for possible PHL events. 
The investigator participates with the sponsor in the review and assessment of cases meeting 
PHL criteria to agree whether HL criteria are met. HL criteria are met if there is no alternative 
explanation for the elevations in liver biochemistry other than drug-induced liver injury (DILI) 
caused by the investigational medicinal product (IMP). The investigator is responsible for 
recording data pertaining to PHL/HL cases and for reporting AEs and serious adverse events 
(SAEs) according to the outcome of the review and assessment in line with standard 
safety-reporting processes. 
DEFINITIONS 
 
Potential Hy’s Law 
 
Aspartate aminotransferase (AST) or ALT ≥3 x upper limit or normal (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 (ALP). 

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Hy’s Law 
 
AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN, where no reason other than the 
investigational medical product (IMP) can be found to explain the combination of increases (e.g., 
elevated ALP 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. 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
 
Laboratory data must be comprehensively reviewed by the investigator for each subject to 
identify laboratory values meeting the following criteria: 
• 
ALT ≥3 x ULN 
 
• 
AST ≥3 x ULN 
 
• 
Total bilirubin ≥2 x ULN 
 
When the identification criteria are met from central or local laboratory results, the investigator 
will perform the following: 
• 
Notify the sponsor representative/medical monitor by telephone and report the PHL case as 
an SAE of Potential Hy’s law: seriousness criteria “Important medical event” and causality 
assessment “yes/related” or in accordance with the clinical study protocol as appropriate. 
• 
Request a repeat of the test (new blood draw) without delay 
 
• 
Complete the appropriate unscheduled laboratory electronic case report form (eCRF) 
module(s) 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the clinical study protocol, as applicable 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
The instructions in this section should be followed by the investigator for all cases where PHL 
criteria are met. 
As soon as possible after the biochemistry abnormality is initially detected, the study medical 
monitor and the investigator will review available data, to agree whether there is an alternative 
explanation for meeting PHL criteria other than DILI caused by the IMP and to ensure that 

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

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

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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 and IgG anti-CMV 
IgM and IgG anti-HSV 
IgM and IgG anti-EBV 
Alcoholic hepatitis 
Carbohydrate deficient transferrin 
(CD-transferrin) 
Autoimmune hepatitis 
Antinuclear antibody (ANA) 
Anti-Liver/Kidney Microsomal Ab 
(Anti-LKM) 
Anti-Smooth Muscle Ab (ASMA) 
Metabolic diseases 
Alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin 
Transferrin saturation 
Reference 
 
FDA Guidance for Industry (issued July 2009). Drug-induced liver injury: Premarketing clinical 
evaluation https://www.fda.gov/regulatory-information/search-fda-guidance-documents/drug- 
induced-liver-injury-premarketing-clinical-evaluation. 

Page 114 of 114 
 
 
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Table 15: Chronic Lymphocytic Leukemia Health-Related Quality of Life and Emotional Distress Assessment 
 
Screening 
Cycle 1, Day 1 
(Only if not finished 
from screening). 
Cycle 2, 3, 4, Day 1 
Cycle 5, Day1 
Cycle 6, 7, 8, Day 1 
Cycle 9 Day 1 
Cycle 10, 11 Day 1 
Cycle 12, Day 1 
(Cycle 13 Day 1 for 
Cohorts 3 and 4) 
Cycle 18 Day 1 
(Cycle 19 Day 1 for 
Cohorts 3 and 4) 
Cycle 24 Day 1 
End of Study 
(36 months 
complete or off 
prior to this) 
Charlson Comorbidity Index 
(Completed by Study Personnel) 
x 
x 
Sociodemographics 
x 
x 
x 
x 
x 
Life Events 
x 
x 
x 
x 
x 
Social Support 
x 
x 
x 
x 
x 
x 
x 
x 
Social Contacts 
x 
x 
x 
x 
x 
x 
Patient Health Questionnaire (PHQ-9) 
x 
x 
x 
x 
x 
x 
Impact of Events 
x 
x 
x 
x 
x 
x 
x 
x 
Feelings in the Past Month (SF-36) 
x 
x 
x 
x 
x 
x 
x 
x 
EORTC-QLQ-C30 Questionnaire 
x 
x 
x 
x 
x 
x 
x 
x 
GAD-7 Questionnaire 
x 
x 
x 
x 
x 
x 
Anxiety (STAI) 
x 
x 
x 
x 
x 
x 
x 
x 
Depressive Symptoms (CES-D) 
x 
x 
x 
x 
x 
x 
x 
x 
Perception of CLL 
x 
x 
x 
x 
x 
x 
x 
x 
Fatigue 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moods (POMS) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Sleep 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pain 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x