An Open-label, Phase 1b/2 Study of Acalabrutinib Alone or in Combination Therapy in Subjects With B-cell Non-Hodgkin Lymphoma
Phase: PHASE1
Conditions: Non Hodgkin Lymphoma
Sponsor: Acerta Pharma BV

Product: Acalabrutinib
Protocol: ACE-LY-003
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PROTOCOL
TITLE:
An Open-label, Phase 1b/2 Study of Acalabrutinib 
Alone or in Combination Therapy in Subjects with 
B-cell Non-Hodgkin Lymphoma
PROTOCOL NUMBER:
ACE-LY-003
STUDY DRUG:
Acalabrutinib (ACP-196)
IND NUMBER:
118717
EU CT NUMBER
2023-508141-40-00
SPONSOR MEDICAL
MONITOR
Medical Monitor name and contact information will be 
provided separately
SPONSOR:
Acerta Pharma BV
Kloosterstraat 9
5349 AB Oss
The Netherlands
PROTOCOL DATE:
Version 0.0 - 02 June 2014
AMENDMENT 1 DATE:
Version 1.0 - 20 February 2015
AMENDMENT 2 DATE:
Version 2.0 – 08 May 2015
AMENDMENT 3 DATE:
Version 3.0 – 18 March 2016
AMENDMENT 4 DATE
Version 4.0 – 23 Aug 2017
AMENDMENT 5 DATE
Version 5.0 – 05 Jul 2018
AMENDMENT 6 DATE
Version 6.0 – 05 March 2020
AMENDMENT 7 DATE
Version 7.0 – 14 July 2022
AMENDMENT 8 DATE
Version 8.0 – 12 October 2023 (all sites global 
consolidation version for EU-CTR)
Confidentiality Statement
This document contains proprietary and confidential information of the Sponsor 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 the Sponsor.
Redacted for Public Disclosure

Product: Acalabrutinib
Protocol: ACE-LY-003
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PROTOCOL APPROVAL PAGE VERSION 8.0
I have carefully read Protocol ACE-LY-003 entitled “An Open-label, Phase 1b/2 Study 
of Acalabrutinib Alone or in Combination Therapy in Subjects with B-cell Non-Hodgkin 
Lymphoma”. I agree to conduct this study as outlined herein and in compliance with 
Good Clinical Practices (GCP) and all applicable regulatory requirements.
Furthermore, I understand that the Sponsor and the Institutional Review Board
(IRB)/Independent Ethics Committee (IEC) must approve any changes to the protocol 
in writing before implementation.
I agree not to divulge to anyone, either during or after the termination of the study, 
any confidential information acquired regarding the investigational product and 
processes or methods of the Sponsor. All data pertaining to this study will be 
provided to the Sponsor. The policy of the Sponsor requires that any presentation or 
publication of study data by clinical investigators be reviewed by the Sponsor, before 
release, as specified in the protocol.
Principal Investigator’s Signature
Date
Print Name

Product: Acalabrutinib
Protocol: ACE-LY-003
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SUMMARY OF AMENDMENT 8.0
This protocol was amended to include details of a new acalabrutinib formulation 
(acalabrutinib maleate tablet), as approved under NDA 216387. Acalabrutinib maleate 
tablets and acalabrutinib capsules are bioequivalent, and patients may be switched 
between the original capsule formulation and the updated tablet formulation at the 
earliest convenience.
In addition, the protocol has been updated to prepare for the transition to EU-CTR.
Clarifying edits and typographical changes have been made throughout the protocol. 
The following changes were made as part of this amendment:
Sections Impacted Rationale
Substantial / 
Non-substantial
PROTOCOL TITLE 
PAGE
Added EU CT number and Sponsor address.
Non-substantial
STUDY SYNOPSIS Updated to reflect changes in the body of the 
protocol
Substantial
Sections 1.2.1, 
1.3.2, 3.4.1, 3.4.2,
3.4.3, 3.4.4, 3.4.5, 
3.4.6, 3.5.2, 3.5.3, 
and 3.5.4.
Added text/ information relating to acalabrutinib 
tablets.
Substantial
Section 3.2
Clarified definition of the end of study according to 
EU and FDA requirements. For consistency and 
alignment in terms of posting study results and to 
comply with EU CTR.
Substantial
Section 3.7.1
Updates to describe potential risk of hepatotoxicity 
to align with the current IB.
Substantial
Section 3.7.3
Updates to risk associated with lenalidomide
Substantial
Section 3.7.4
Updated text relating to dietary restrictions.
Substantial
Sections 3.6.3 and 
3.7.5
Amended the text on agents that reduce gastric 
acid so that the restrictions are specific to 
acalabrutinib capsules.
Substantial
Section 3.7.7
Added description of reporting of overdose. 
Update required to comply with EU CTR.
Substantial
Section 6.3.1
Clarified the adverse event reporting period.
Substantial
Section 6.3.7
Added description of Medication Error, Drug 
Abuse and Drug Misuse definition and examples. 
Update required to comply with EU CTR.
Substantial
Section 7.1
Added sub-section on regulatory reporting 
requirements for SAEs to comply with regulatory 
requirements (EU CTR) and global company 
requirement.
Substantial

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Protocol: ACE-LY-003
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Section 7.1
Added sub-section on Serious Breaches. Update 
required to comply with regulatory requirements 
(EU CTR) and global company requirement.
Substantial
Section 7.2
Updated section on IRB/IEC to reflect current 
study status.
Non-substantial
Section 7.5
Updated text relating to study monitoring 
requirements and audits and inspections to comply 
with EU CTR.
Substantial
Section 7.6
Updated section describing quality control and 
quality assurance to comply with EU CTR.
Substantial
Section 7.7
New section added describing data handling and 
recordkeeping to comply with EU CTR.
Substantial
Section 7.7
Updated information about retention timelines of 
records and documents to 25 years after study 
archiving or as required by local regulations. 
Update required to comply with EU-CTR.
Substantial
Section 7.11
Section updated describing investigational study 
drug accountability to comply with EU CTR.
Substantial
Appendix 3
Added Seville oranges and starfruit as strong 
inhibitors of CYP3A.
Substantial
Appendix 9
Added description of Medication Error, Drug 
Abuse and Drug Misuse definition and examples. 
Update required to comply with EU CTR.
Substantial
Appendix 10
Added information on Data Quality Assurance. 
Update required to comply with EU CTR
Substantial
Appendix 11
Updated information about timelines for 
submission of trial results summaries to EU CTIS. 
Update required to comply with EU CTR.
Substantial
Appendix 12
Added a summary of country specific changes 
made to the local CSPs. Update required to 
comply with EU CTR.
Substantial
Throughout
Minor editorial, 
formatting, and 
typographical 
updates and 
corrections have 
been made.
Minor corrections made for document clarity
Non-substantial

Product: Acalabrutinib
Protocol: ACE-LY-003
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Table of Contents
1
BACKGROUND INFORMATION.............................................................37
1.1
ROLE OF BTK IN LYMPHOID CANCERS ..............................................37
1.2
NONCLINICAL STUDIES OF ACALABRUTINIB.....................................41
1.2.1 Chemistry.................................................................................................41
1.2.2 Efficacy Pharmacology ............................................................................42
1.2.3 Safety Pharmacology...............................................................................43
1.2.4 Drug-Drug Interaction Potential................................................................43
1.2.5 In Vivo General Toxicology ......................................................................43
1.3
CLINICAL EXPERIENCE WITH ACALABRUTINIB .................................44
1.3.1 Pharmacokinetics and Pharmacodynamics of Acalabrutinib in Healthy 
Volunteers................................................................................................44
1.3.2 Clinical Experience with Acalabrutinib......................................................44
1.4
RITUXIMAB IN LYMPHOID CANCERS...................................................45
1.5
RITUXIMAB COMBINATION THERAPY IN LYMPHOID CANCERS ......46
1.6
LENALIDOMIDE IN LYMPHOID CANCERS ...........................................47
1.7
BENEFIT/RISK ........................................................................................47
1.8
SUMMARY AND CONCLUSIONS...........................................................48
2
STUDY OBJECTIVES .............................................................................49
2.1
PART 1 ....................................................................................................49
2.1.1 Primary Objective.....................................................................................49
2.1.2 Secondary Objectives:.............................................................................49
2.2
PART 2 ....................................................................................................49
2.2.1 Primary Objective.....................................................................................49
2.2.2 Secondary Objectives ..............................................................................49
2.2.3 Exploratory Objectives .............................................................................49
2.3
PART 3 ....................................................................................................50
2.3.1 Primary Objective.....................................................................................50
2.3.2 Secondary Objectives:.............................................................................50
2.3.3 Exploratory Objectives: ............................................................................50
3
STUDY DESIGN......................................................................................50
3.1
DESCRIPTION OF STUDY......................................................................50
3.1.1 Efficacy Parameters.................................................................................57
3.1.2 Safety Parameters ...................................................................................58

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3.1.3 Pharmacokinetic, Pharmacodynamic Parameters, and Molecular Profiling
58
3.2
END OF STUDY......................................................................................59
3.3
RATIONALE FOR STUDY DESIGN AND DOSING REGIMEN...............60
3.4
SELECTION OF STUDY POPULATION .................................................62
3.4.1 Inclusion Criteria Part 1............................................................................62
3.4.2 Exclusion Criteria Part 1...........................................................................62
3.4.3 Inclusion Criteria Part 2............................................................................64
3.4.4 Exclusion Criteria Part 2...........................................................................66
3.4.5 Inclusion Criteria Part 3............................................................................68
3.4.6 Exclusion Criteria Part 3...........................................................................69
3.4.7 Replacement of Subjects .........................................................................71
3.4.8 Enrollment and Procedures......................................................................72
3.5
STUDY DRUG .........................................................................................73
3.5.1 Premedications........................................................................................73
3.5.2 Formulation, Packaging, and Storage......................................................73
3.5.3 Administration of Study Drug....................................................................74
3.5.4 Assuring Subject Compliance ..................................................................75
3.5.5 Definition of Dose-limiting Toxicity (Part 3)...............................................75
3.5.6 Dose Delays ............................................................................................76
3.5.7 Dose Modification and Discontinuation ....................................................77
3.6
CONCOMITANT THERAPY ....................................................................79
3.6.1 Permitted Concomitant Therapy...............................................................79
3.6.2 Prohibited Concomitant Therapy..............................................................79
3.6.3 Cautionary Therapy Considerations Including Drug-Drug Interactions.....79
3.7
RISKS ASSOCIATED WITH STUDY DRUGS.........................................80
3.7.1 Risks Associated with Acalabrutinib Treatment........................................80
3.7.2 Risks Associated with Rituximab (Rituxan/MabThera) Treatment............83
3.7.3 Risks Associated with Lenalidomide (Revlimid) Treatment ......................84
3.7.4 Dietary Restrictions..................................................................................86
3.7.5 Drug-Drug Interactions.............................................................................86
3.7.6 Reproductive Toxicity...............................................................................88
3.7.7 Overdose Instructions..............................................................................90
3.8
WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT ...............91
3.9
REASONS FOR STUDY EXIT.................................................................91
3.10
DATA AND SAFETY MONITORING........................................................92

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4
STUDY ACTIVITIES AND ASSESSMENTS............................................92
4.1
DESCRIPTION OF PROCEDURES ........................................................92
4.1.1 Informed Consent ....................................................................................92
4.1.2 Medical History ........................................................................................92
4.1.3 Adverse Events........................................................................................93
4.1.4 Concomitant Medications and Therapy....................................................93
4.1.5 Confirmation of Eligibility..........................................................................93
4.1.6 ECOG Performance Status......................................................................93
4.1.7 Physical Examination, Vital Signs, Height, and Weight............................93
4.1.8 Bone Marrow Aspirate and Biopsy...........................................................93
4.1.9 Electrocardiogram....................................................................................94
4.1.10 Urine or Serum Pregnancy Test...............................................................94
4.1.11 Hematology..............................................................................................94
4.1.12 Serum Chemistry.....................................................................................94
4.1.13 Thyroid Function Test ..............................................................................95
4.1.14 Hepatitis B and C Testing ........................................................................95
4.1.15 Urinalysis.................................................................................................96
4.1.16 T/B/NK Cell Count....................................................................................96
4.1.17 Serum Immunoglobulin............................................................................96
4.1.18 Endoscopy and 13C Urea Breath Test for Gastric MALT Lymphoma 
Subjects...................................................................................................96
4.1.19 Pharmacokinetics ....................................................................................96
4.1.20 Pharmacodynamics .................................................................................97
4.1.21 Molecular Profiling....................................................................................98
4.1.22 Tumor Assessment..................................................................................98
4.1.23 Study Drug Accountability......................................................................100
4.1.24 Routine Clinical Assessments................................................................100
4.2
INVESTIGATOR’S ASSESSMENT OF RESPONSE TO TREATMENT 100
4.3
SAFETY FOLLOW-UP VISIT.................................................................103
4.4
TIME-TO-NEXT TREATMENT, DISEASE FOLLOW-UP, AND LONG-
TERM FOLLOW-UP ..............................................................................104
4.5
MISSED EVALUATIONS.......................................................................104
5
STATISTICAL METHODS OF ANALYSIS.............................................105
5.1
GENERAL CONSIDERATIONS ............................................................105
5.2
SAMPLE SIZE CONSIDERATIONS ......................................................105

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5.3
DEFINITION OF ANALYSIS SETS........................................................106
5.4
MISSING DATA HANDLING..................................................................106
5.5
ENDPOINT DATA ANALYSIS ...............................................................106
5.5.1 Safety Endpoint .....................................................................................106
5.5.2 Demographics and Baseline Characteristics..........................................107
5.5.3 Study Treatment Administration and Compliance..................................107
5.5.4 Analysis of Efficacy Parameters.............................................................107
5.5.5 Analysis of Pharmacokinetic/Pharmacodynamic Parameters.................108
5.5.6 Explorative or Correlative Analyses .......................................................109
6
ASSESSMENT OF SAFETY..................................................................110
6.1
REFERENCE SAFETY INFORMATION................................................110
6.2
DEFINITIONS........................................................................................110
6.2.1 Adverse Events......................................................................................110
6.2.2 Serious Adverse Event...........................................................................112
6.2.3 Adverse Events of Special Interest ........................................................112
6.2.4 Severity113
6.3
DOCUMENTING AND REPORTING OF ADVERSE AND SERIOUS 
ADVERSE EVENTS ..............................................................................113
6.3.1 Adverse Event Reporting Period............................................................114
6.3.2 Assessment of Adverse Events .............................................................114
6.3.3 Second Primary Malignancies................................................................115
6.3.4 Pregnancy..............................................................................................115
6.3.5 Expedited Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest........................................................116
6.3.6 Type and Duration of Follow-up of Subjects After Adverse Events ........117
6.3.7 Medication Error, Drug Abuse, and Drug Misuse...................................118
7
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS......118
7.1
REGULATORY AND ETHICAL COMPLIANCE.....................................119
7.2
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE .........................................................................................120
7.3
INFORMED CONSENT AND PROTECTED SUBJECT HEALTH 
INFORMATION AUTHORIZATION .......................................................120
7.4
CASE REPORT FORMS .......................................................................121
7.5
STUDY MONITORING REQUIREMENTS.............................................121
7.6
QUALITY CONTROL AND QUALITY ASSURANCE.............................122
7.7
DATA HANDLING AND RECORDKEEPING.........................................123
7.8
PROTOCOL AMENDMENTS ................................................................124

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7.9
PUBLICATION OF STUDY RESULTS ..................................................125
7.10
CLINICAL TRIAL INSURANCE .............................................................125
7.11
INVESTIGATIONAL STUDY DRUG ACCOUNTABILITY ......................125
7.12
GENERAL INVESTIGATOR RESPONSIBILITIES ................................126
8
REFERENCES ......................................................................................127
9
APPENDICES........................................................................................132
In–Text Tables
Table 1
Drug Modification and Discontinuation Actions for Acalabrutinib 
(in Combination with Lenalidomide)....................................................................... 77
Table 2
Drug Modification and Discontinuation Actions for Acalabrutinib 
(Without Lenalidomide) ........................................................................................... 77
Table 3
Dose Modification Actions for Lenalidomide.................................. 78
Table 4
Pharmacokinetic Sample Schedule................................................. 97
Table 5
Sparse PK Sampling Schedule for Part 3 ....................................... 97
Table 6
Response Assessment Criteria for NHL (Cheson et al. 2014) ..... 101
In-Text Figures
Figure 1
Part 2 Study Schema........................................................................ 52
Figure 2
Study Schematic for Part 3.............................................................. 55
Figure 3
Dose-Limiting Toxicity Review and Enrollment for Part 3 ............. 55
Appendices
Appendix 1. Performance Status Scores .............................................................133
Appendix 2. Adverse Event Assessment of Causality..........................................134
Appendix 3. Examples of Coadministered Drugs that Need Additional 
Consideration.........................................................................................135
Appendix 4. Schedule of Assessments Part 1 .....................................................137
Appendix 5. Schedule of Assessments Part 2.....................................................139
Appendix 6. Schedule of Assessments Part 3.....................................................142
Appendix 7. Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ..........................................................................145
Appendix 8. Management of Study Procedures During Pandemic ......................150
Appendix 9.
Medication Error, Drug Abuse, and Drug Misuse .....................155
Appendix 10.
Data Quality Assurance............................................................157
Appendix 11.
Dissemination of Clinical Study Data........................................158
Appendix 12.
Country Specific Requirements................................................159

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Abbreviations
Abbreviation
Definition
λz
terminal elimination rate constant
5PS
5-point scale
ABC
activated B-cell like
ACP-196
acalabrutinib
ACP-5862
acalabrutinib’s active metabolite (M27) 
AE(s)
adverse event(s)
AESI
adverse event of special interest
ALT
alanine aminotransferase
anti-HBc
hepatitis B core antibody 
anti-HBs
hepatitis B surface antibody
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-12
area under the plasma concentration-time curve from 0 to 
12 hours, calculated using linear trapezoidal summation.
AUC0-24calc
area under the plasma concentration-time curve from 0 to 
24 hours, calculated by doubling the value for AUC0-12
AUC0-∞
area under the plasma concentration-time curve from 0 to 
infinity, calculated using the formula: AUC0-∞= AUC0-t + Ct / λz, 
where λz is the apparent terminal elimination rate constant
AUC0-t
area under the plasma concentration-time curve calculated using 
linear trapezoidal summation from time 0 to time t, where t is the 
time of the last measurable concentration (Ct)
AUCinf
area under the plasma concentration-time curve from 0 to infinity 
BCR
B-cell receptor
BID
twice per day (dosing)
BRCP
breast cancer resistance protein
BTK
Bruton tyrosine kinase
BTK-TO
Bruton tyrosine kinase target occupancy
CD
cluster of differentiation
CFR
Code of Federal Regulations
cGMP
current Good Manufacturing Practices
CHOP
cyclophosphamide, doxorubicin, vincristine, and prednisone 
CL/F
oral clearance
CLL
chronic lymphocytic leukemia
Cmax
maximum observed plasma concentration

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CR
complete remission (response)
CSP
Clinical study protocol
CSR
Clinical Study Report
CSSF
Clinical Supplies Shipping Receipt Form
Ct
time of last measurable concentration
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
CTIS
Clinical Trial Information System
CTR
Clinical Trials Regulation
CTT
Clinical Trial Transparency
CYP
cytochrome P450
DES
Data Entry Site
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DOR
duration of response
DVT
deep vein thrombosis
EC50
half-maximal response effective concentration
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EGFR
epidermal growth factor receptor 
EMA
European Medicines Agency 
ESMO
European Society for Medical Oncology 
FDA
Food and Drug Administration
FDG
[18F]fluorodeoxyglucose
FIH
first-in-human (trial)
FL
follicular lymphoma
FSH
follicle-stimulating hormone
GCB
germinal center B-cell like
GCP
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor 
GLP
Good Laboratory Practices
GRAD
Global Retention and Disposal

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HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HDT/ASCT
high-dose chemotherapy with autologous stem cell 
transplantation
IC50
inhibitory concentration 50%
ICF
informed consent form
IEC
Independent Ethics Committee
Ig
immunoglobulin
IHC
immunohistochemistry
IMP
Investigational medicinal product
IRB
Institutional Review Board
IV
intravenous
IVIG
intravenous immunoglobulins
LDi
longest transverse diameter of a lesion
LTFU
long-term follow-up
MALT
mucosa-associated lymphoid tissue
MCL
mantle cell lymphoma
MDS
myelodysplastic syndrome
MRD
minimal residual disease
MRI
magnetic resonance imaging
MZL
marginal zone lymphoma
NHL
non-Hodgkin lymphoma
NIMP
Non-investigational medicinal product
NK
natural killer (cells)
NOAEL
no observed adverse effect level
NFkB
nuclear factor kappa beta
ORR
overall response rate
OS
overall survival
PBMC(s)
peripheral blood mononuclear cells
PCR
polymerase chain reaction
PD
pharmacodynamic
PET
positron-emission topography
PFS
progression-free survival
PI3K
phosphoinositide-3 kinase
PK
pharmacokinetic

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PMBCL
primary mediastinal large B-cell lymphoma
PML
progressive multifocal leukoencephalopathy
PO
per os (mouth)
PPD
cross product of the LDi and perpendicular diameter
PR
partial remission (response)
PTAP
Post Trial Access Program
QD
once per day (dosing)
QTc
corrected QT interval
QTcF
corrected QT interval using Fridericia formula
R-CHOP
Rituximab-CHOP
R-DHAP
rituximab, cisplatin, cytarabine, and dexamethasone
REMS
Risk Evaluation and Mitigation Strategy
R-ICE
rituximab, ifosfamide, carboplatin, and etoposide
R/R
relapsed or refractory
SAE(s)
serious adverse event(s)
SAP
Statistical Analysis Plan
SDi
shortest axis perpendicular to the LDi
SFU
safety follow-up
SPD
sum of the product of the diameters
SUSAR
Suspected Unexpected Serious Adverse Reaction (report)
SYK
spleen tyrosine kinase
t½
terminal elimination half-life
TLS
tumor lysis syndrome
Tmax
time to maximum plasma concentration
TSH
thyroid stimulating hormone
ULN
upper limit of normal
Vz/F
oral volume of distribution
WBC
white blood cell (count)
WHO
World Health Organization
WOCBP
women of childbearing potential

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Study Synopsis
Protocol Number:
ACE-LY-003
Study Drug:
Acalabrutinib (formerly known as ACP-196)
Protocol Title:
An Open-label, Phase 1b/2 Study of Acalabrutinib Alone or in 
Combination Therapy in Subjects with B-cell Non-Hodgkin 
Lymphoma
Phase:
Phase 1b/2
Comparator:
None
Background and 
Rationale for Study
The majority of indolent lymphomas are mature B-cell lymphomas,
including the most common subtype of follicular lymphoma (FL), 
accounting for approximately 25% of all non-Hodgkin lymphomas
(NHLs), followed by marginal zone lymphoma (MZL; 
approximately 12% of all NHLs).
Despite the recent advances in treatments for advanced indolent 
NHLs, the disease is incurable. Although most patients have had 
extended survival, a subset of patients have early relapses after 
therapy or have disease that is refractory to existing therapies.
Therefore, safe and effective drug combinations, particularly 
chemotherapy-free approaches, are being studied in patients with 
relapsed or refractory (R/R) FL.
In contrast to indolent NHLs, a subset of NHLs has an aggressive
course. Diffuse large B-cell lymphoma (DLBCL) is the most 
common form of aggressive NHL in the United States, with an 
annual incidence that has been rising gradually since the 1990s.
A significant proportion of patients with DLBCL are cured with 
standard chemoimmunotherapy including Rituximab-
cyclophosphamide, doxorubicin, vincristine, and prednisone (R-
CHOP). Nonetheless, for those patients not cured by standard 
initial therapy, the prognosis remains generally poor, and DLBCL 
still accounts for the highest number of deaths per year of all the 
NHL histologies.
Acalabrutinib is a potent, highly selective covalent inhibitor of Bruton 
tyrosine kinase (BTK) in clinical development for B-cell 
malignancies. Acalabrutinib inhibits B-cell receptor (BCR) signaling 
by irreversibly inactivating BTK, leading to decreased growth and 
survival signals in B cells and shows greater kinase selectivity for 
BTK than ibrutinib in laboratory studies. In laboratory studies, 
acalabrutinib and its major metabolite, ACP-5862, have limited off-
target kinase activity. The lack of activity against other Tec- and Src-
family kinases, which are important for the function of T cells, NK 
cells, and platelets and against epidermal growth factor receptor 
(EGFR), a kinase important for epithelial cell functions, may
contribute to the safety and efficacy profile of acalabrutinib.

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Acalabrutinib has an acceptable safety profile in clinical studies.
Acalabrutinib has been administered to subjects with hematologic 
malignancies, solid tumors, or rheumatoid arthritis, and healthy 
volunteers or noncancer patients with mild- to moderate-hepatic 
impairment. Acalabrutinib monotherapy has also demonstrated 
clinical activity in patients with chronic lymphocytic leukemia (CLL),
mantle cell lymphoma (MCL), FL, and DLBCL. For more detailed 
information on acalabrutinib clinical experience, refer to the 
Acalabrutinib Investigator Brochure.
Rituximab, an anti-cluster of differentiation 20 (CD20) monoclonal
antibody, is indicated for treatment of CD20+ NHL as a single 
agent and in combination with chemotherapy.
The combination of rituximab and ibrutinib has been evaluated in a 
Phase 2 clinical trial in treatment-naive patients with FL. In patients 
receiving concurrent treatment with ibrutinib and rituximab (n=60), 
the overall response rate (ORR) was 85%, with complete response 
(CR) rate of 35%. The 12-month progression-free survival (PFS) 
was reported as 87%. The drug combination appeared to be well
tolerated based on the lack of new safety signals in patients treated 
with the combination. Moreover, the acceptable safety and efficacy 
results to date for rituximab and the first-generation BTK inhibitor,
ibrutinib, support further evaluation of rituximab with a novel BTK
inhibitor such as acalabrutinib. Safety data from Part 1 of the ACE-
LY-003 trial are included in the current Acalabrutinib Investigator 
Brochure. These data show that the combination of acalabrutinib 
and rituximab is safe and well tolerated in patients with FL.
Lenalidomide is an immunomodulatory agent with anti-
inflammatory and antiangiogenic properties. In combination 
with rituximab, lenalidomide has shown promising activity in
patients with FL and R/R DLBCL.
In an effort to improve clinical benefit, the addition of ibrutinib to the
lenalidomide and rituximab regimen has been explored in recent 
clinical trials. This triplet regimen was evaluated in the frontline 
treatment of FL, and results showed this triplet regimen was not 
superior in efficacy than the lenalidomide-rituximab doublet
regimen.
There are ongoing trials evaluating the triplet combination in R/R 
DLBCL. These studies support the exploration of acalabrutinib in
combination with lenalidomide and rituximab in R/R FL and DLBCL.
The purpose Parts 1 and 2 in this study is to evaluate the safety, 
pharmacokinetics (Part 1), pharmacodynamics, and activity of 
acalabrutinib alone or in combination with rituximab in subjects with 
FL or MZL.
The purpose of Part 3 of this study is to evaluate the safety, activity, 
pharmacokinetics, and pharmacodynamics of acalabrutinib in 
combination with rituximab and lenalidomide in subjects with R/R 
FL.

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Study Design:
This study will be conducted in 3 parts. Note: Text throughout the 
protocol applies to all parts of the study unless otherwise specified.
At the time of Amendment 6, the sponsor made the decision to 
close Part 4 of the study (R/R DLBCL: Acalabrutinib + rituximab 
and lenalidomide).
Part 1
This part of the study is a Phase 1b, multicenter, open-label, 
randomized, parallel group study to be conducted at approximately 
11 centers. Two cohorts will be enrolled in parallel: The 
Relapsed/Refractory Cohort will include approximately 24 subjects 
with R/R FL, and the
Treatment-Naive Cohort will include 12 subjects who have not 
previously been treated for FL. Note: At the time of Amendment 
4, enrollment in Part 1 has been completed.
Relapsed/Refractory Cohort
Arm 1: Acalabrutinib 100 mg by mouth (PO) twice daily (BID) 
administered approximately 12 hours apart (BID dosing=200 mg 
total daily dose) for 28 days
Arm 2: Acalabrutinib 100 mg PO BID administered approximately
12 hours apart (BID dosing=200 mg total daily dose) for 28 days,
plus rituximab 375 mg/m2 intravenous (IV) on Days 1, 8, 15, and 22 
of Cycle 1 and Day 1 of Cycles 2
through 6
Treatment-Naive Cohort: A total of 12 subjects will receive the
combination of acalabrutinib and rituximab: acalabrutinib 100 mg 
PO BID administered approximately 12 hours apart (BID 
dosing=200 mg total daily dose) for 28 days, plus rituximab 375 
mg/m2 IV on Days 1, 8, 15, and 22 of Cycle 1
and Day 1 of Cycles 2 through 6.
Pharmacokinetic (PK)/pharmacodynamic (PD) testing will be 
performed in Cycle 1 and Cycle 2. Tumor assessments will be 
performed at 8- to 24-week intervals during the trial.
Refer to protocol for a comprehensive list of study assessments 
and their timing.
Part 2
This part of the study is a Phase 2, multicenter, open-label, 
study to be conducted at approximately 38 centers. Up to 40
subjects with R/R MZL will be enrolled. Each cycle is 28 days.
At the time of Amendment 6, the decision was made to close 
Cohort 2.
Cohort 1: Acalabrutinib 100 mg PO BID administered approximately
12 hours apart (BID dosing=200 mg total daily dose) for 
28 days
Cohort 2: Acalabrutinib 100 mg PO BID administered approximately
12 hours apart (BID dosing=200 mg total daily dose) for 
28 days, plus rituximab

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375 mg/m2 IV on Days 1, 8, 15, and 22 of Cycle 1
and Day 1 of Cycles 2 through 6 
See protocol for the Part 2 study schema.
Samples for PD and molecular profiling will be collected according
to sampling times in the Schedule of Assessments (see protocol).
Tumor assessments will be performed at
12- week intervals in the first year and every 24 weeks 
thereafter during the study.
Refer to protocol for a comprehensive list of study assessments 
and their timing.
Part 3
This is a dose-finding, Phase 1b, multicenter, open-label study to 
be conducted at approximately 38 centers.
Approximately 26 to 32 subjects with R/R FL will be enrolled and 
treated with acalabrutinib, rituximab, and lenalidomide (each cycle 
is 28 days). Once a safe and tolerable dose of lenalidomide has 
been established, 14 subjects (as part of the 26 to 32 subjects 
total) will be treated on the 3 drugs at that dose of lenalidomide.

Acalabrutinib 100 mg PO BID administered 
approximately 12 hours apart (BID dosing=200 mg total 
daily dose), until disease progression or an 
unacceptable toxicity occurs.

Rituximab 375 mg/m2 IV administered on Days 1, 8, 15, 
and 22 of Cycle 1, and Day 1 of every cycle starting at 
Cycle 2 through Cycle 6, followed by
10 additional doses of maintenance rituximab every other
cycle beginning with Cycle 8 for subjects who have not 
progressed.

Lenalidomide will start at 15 mg PO once a day (QD) for 
the first 6 subjects in Cycle 1. Doses up to 20 mg PO QD 
will be explored. Lenalidomide will be administered on
Days 1 through 21 of a 28-day cycle.
Acalabrutinib
has
been
used
in
combination
with
rituximab at the doses mentioned above and this 
combination has an acceptable safety profile (current 
version of Acalabrutinib Investigator Brochure). There will 
be an inter-subject dose escalation or de-escalation
during the dose-limiting toxicity (DLT) review period to find
the appropriate dose of lenalidomide that can be used in 
combination with acalabrutinib and rituximab.
DLT review and enrollment are presented in a schematic in the
protocol for Part 3 and will be conducted as follows (DLT criteria 
are defined in the protocol):
Six subjects are planned to be enrolled initially and treated with 
acalabrutinib, rituximab, and lenalidomide (15 mg PO QD) in 
Cycle 1. At the end of the cycle, subjects will be evaluated for 
DLTs on a rolling basis.

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
If there are ≥2 subjects with DLTs on 15 mg of 
lenalidomide QD, the dose of lenalidomide will be 
reduced to 10 mg QD, and 6 more subjects are 
planned to be enrolled at this reduced dose of 
lenalidomide.
o
If there are ≥2 subjects with DLTs at the end of Cycle
1 on 10 mg lenalidomide QD, enrollment will close.
o
If there are <2 of 6 subjects with DLTs, then 
approximately 14 additional subjects will be enrolled
and treated with lenalidomide 10 mg QD for Cycles 1 
through 12.

If there are <2 of 6 subjects with DLTs on 15 mg QD, 6 
additional subjects are planned to be enrolled to receive 
an increased dose of lenalidomide at 20 mg QD.
o
If there are ≥2 subjects with DLTs, the dose of 
lenalidomide will be reduced back to 15 mg QD. 
Approximately 14 more subjects will be added to 
complete enrollment at the 15-mg QD dose.
o
If there are <2 of 6 subjects with DLTs, 20 mg of 
lenalidomide will be the dose used for Cycles 2 
through 12. Approximately 14 more subjects will be 
added to complete enrollment.
Note: Subjects will be evaluated for DLTs at the end of the first
cycle, on a rolling basis, when they complete a cycle of treatment.
Refer to protocol for a comprehensive list of study assessments 
and their timing.
Part 4
At the time of Amendment 6, the sponsor made the decision to 
close Part 4 cohort to enrollment. Therefore, Part 4 has been 
removed.
All Parts
Twenty-eight days of study drug administration is 1
cycle. Treatment with acalabrutinib may be continued 
until confirmed disease progression or an unacceptable 
drug-related toxicity occurs.
Dose modification provisions are provided in the protocol. Note:
Temporary withholding of acalabrutinib for as little as 7 days can
cause a transient worsening of disease and/or of constitutional
symptoms. All subjects who discontinue study drug will have a 
safety follow-up visit 30 (+7) days after the last dose of study drug 
until the final data cut-off regardless of whether the subject 
receives a new anticancer therapy or demonstrates disease 
progression within this timeframe.
All subjects will have hematology, serum chemistry, hepatitis 
serology, and urinalysis safety panels performed at screening. For 
Part 1 and Part 2, once dosing commences (Day 1), all subjects 
will be evaluated for safety, including hematology and serum 
chemistry, once weekly for the first

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4 weeks, every 2 weeks in Cycle 2, monthly through Cycle 13,
and then every 3 months thereafter. For Part 3, once dosing 
commences (Day 1), all subjects will be evaluated for safety, 
including hematology and serum
chemistry, once weekly for the first 4 weeks, every 2 weeks in 
Cycle 2, and monthly through Cycle 13, and for Part 3, every 8 
weeks starting Cycle 14 up to cycle 28 (rituximab infusion ends at 
Cycle 26) and every 3 months thereafter.
Part 3
Pregnancy testing will be performed at baseline, weekly for the 
first month, and then monthly for all females of childbearing 
potential receiving lenalidomide until 4 weeks after the last dose of 
lenalidomide. In addition, women of childbearing potential must 
use highly effective methods of contraception or abstain from sex 
during lenalidomide treatment and for 4 weeks after completion of
lenalidomide treatment.
All subjects (males and females) receiving lenalidomide must be 
enrolled in the Revlimid® Risk Evaluation and Mitigation Strategy 
(REMS™) program.
Study Objectives:
Part 1
Primary Objective:

To characterize the safety profile of acalabrutinib alone
or in combination with rituximab in subjects with R/R FL
Secondary Objectives:

To characterize the safety profile of acalabrutinib in 
combination with rituximab in subjects with previously 
untreated FL

To characterize the PK profile of acalabrutinib alone or in 
combination with rituximab

To evaluate the PD effects of acalabrutinib alone or in 
combination with rituximab

To evaluate the activity of acalabrutinib alone or in 
combination with rituximab as measured by ORR, 
duration of response (DOR), time-to-next treatment, and 
PFS
Part 2
Please note that enrollment for Part 2, Cohort 2 (R/R MZL: 
Acalabrutinib + Rituximab) of the ACE-LY-003 study is closed.
Primary Objective

To characterize the activity of acalabrutinib alone or in 
combination with rituximab in subjects with R/R MZL, as 
measured by ORR
Secondary Objectives:

To characterize the safety of acalabrutinib alone or in 

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
DOR

PFS

OS
Safety Parameters:
The safety of acalabrutinib alone or in combination with rituximab or
rituximab and lenalidomide will be characterized by the type, 
frequency, severity, timing of onset, duration, and relationship to 
study drug of any adverse events (AEs); serious adverse events 
(SAEs); or AEs leading to study treatment delay, dose modification, 
or discontinuation.
Definition of Dose-
Limiting Toxicity (Part
3)
A DLT will be defined as the occurrence of any of the following 
study drug-related AEs during the DLT review period. (Note: AEs 
clearly related to disease progression or the subject’s medical 
history and associated comorbidities considered by the investigator
to be unrelated to study drugs, will not be considered DLTs.
Infusion reactions clearly associated with rituximab infusion will not 
be considered DLTs):
1. Non-hematologic DLTs include
a) Grades 3 or 4 nausea, vomiting, or diarrhea 
lasting >7 days despite optimal antiemetic or 
antidiarrheal management or any Grade 3 or 
Grade 4 toxicity
b) Any grade Stevens-Johnson syndrome or toxic 
epidermal necrolysis
c) Aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) >3 × upper limit of normal
(ULN) concurrently with total bilirubin >2 × ULN
d) Clinical tumor lysis syndrome (TLS) not resolving to 
baseline after a 2-week treatment delay
•
Exceptions are deep vein thrombosis (DVT), correctable
electrolyte abnormalities, or Grade 3 or Grade 4 
laboratory abnormalities lasting ≤7 days; Grades 3 or 4 
fatigue, anorexia, non-neutropenic fever, Grade 3 rash 
resolving to Grade 2 within
10 days (allowed therapy with steroids).
2. Hematologic DLTs
a) Grade 3 or Grade 4 neutropenia with fever
≥38.5°C or infection, or Grade 4 neutropenia lasting >7 
days despite adequate
granulocyte-colony stimulating factor (G-CSF) use.
b) Grade 3 or Grade 4 thrombocytopenia with hemorrhage.
If thrombocytopenia improves to Grade ≤2 or to ≥80% of 
the baseline value within 28 days, without a platelet
transfusion, this will not be considered a DLT.
c) Any Grade 4 hematologic toxicity unrelated to the 
underlying disease
3. Any study drug-related Grade 5 AE

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Protocol: ACE-LY-003
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Any study drug-related toxicity leading to an individual drug dose 
delay of >21 consecutive days for acalabrutinib or >14 
consecutive days for lenalidomide will be considered as a DLT.
Subjects should receive at least one dose of rituximab in Cycle 1 
to be evaluable for DLT.
Pharmacokinetic 
Parameters:
Part 1
The plasma pharmacokinetics of acalabrutinib in subjects receiving
acalabrutinib alone or in combination with rituximab will be 
characterized using noncompartmental analysis. The following PK 
parameters will be calculated, whenever possible, from plasma 
concentrations of acalabrutinib:

AUC0-t: Area under the plasma concentration-time curve 
calculated using linear trapezoidal summation from
time 0 to time t, where t is the time of the last measurable 
concentration (Ct).

AUC0-12: Area under the plasma concentration-time curve 
from 0 to 12 hours, calculated using linear trapezoidal 
summation.

AUC0-∞: Area under the plasma concentration-time curve from 
0 to infinity, calculated using the formula:
AUC0-∞=AUC0-t + Ct / λz, where λz is the apparent terminal 
elimination rate constant.

AUC0-24calc: Area under the plasma concentration-time curve 
from 0 to 24 hours, calculated by doubling the value for 
AUC0-12.

Cmax: Maximum observed plasma concentration

Tmax: Time of the maximum plasma concentration 
(obtained without interpolation)

t½: Terminal elimination half-life (whenever possible)

λz: Terminal elimination rate constant (whenever 
possible)

CL/F: Oral clearance

Vz/F: Oral volume of distribution
The PK parameters will be tabulated and summarized using 
descriptive statistics.
Part 2
No PK analysis will be performed in Part 2
Part 3
Plasma concentrations of acalabrutinib and ACP-5862 will be 
tabulated for each subject by arm, visit, and timepoint.
Summary statistics (mean, median, standard deviation, 

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2. Relapsed/Refractory Cohort: A confirmed diagnosis of FL 
Grade 1, 2, or 3a that has relapsed after, or been refractory 
to ≥1 prior therapy for FL and which requires treatment per 
National Cancer Institute or International Working Group 
guidelines. Documented failure to achieve at least partial 
remission (PR) with, or documented disease progression
after, the most recent treatment regimen.
Treatment-Naive Cohort: A confirmed diagnosis of FL Grade 
1, 2, or 3a that requires treatment per National Cancer 
Institute or International Working Group guidelines in subjects
who have not previously received systemic anticancer 
therapy for FL.
3. Presence of radiographically measurable lymphadenopathy or
extranodal lymphoid malignancy (defined as the presence of 
≥1 lesion that measures ≥2.0 cm in the longest dimension and
≥1.0 cm in the longest perpendicular dimension as assessed 
by computed tomography [CT] scan).
4. Eastern Cooperative Oncology Group (ECOG) 
performance status of ≤2.
5. Agreement to use highly effective methods of contraception 
during the study and for 2 days after the last dose of
acalabrutinib or 12 months after the last dose of rituximab, 
whichever is longer, if sexually active and able to bear or beget 
children. Highly effective forms of contraception are defined in 
the protocol.
6. Men must agree to refrain from sperm donation during the 
study and for 3 months after the last dose of rituximab.
7. Willing and able to participate in all required evaluations and 
procedures in this study protocol including swallowing 
capsules or tablets without difficulty.
8. Ability to understand the purpose and risks of the study and 
provide signed and dated informed consent and 
authorization to use protected health information (in 
accordance with national and local patient privacy 
regulations).
Part 2
1. Men and women ≥18 years of age.
2. Histologically confirmed MZL including splenic, nodal, and 
extranodal sub-types
a. Subjects with splenic MZL must have an additional 
measurable lesion, nodal or extranodal, as described 
in inclusion criterion #4;
b. Subjects with gastric mucosa-associated lymphoid 
tissue (MALT) lymphoma must be Helicobacter
pylori-negative (including subjects after successful 
elimination of H. pylori) or refractory to H. pylori 
eradication therapy by a minimum time of 12 months 

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Protocol: ACE-LY-003
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by a pathology confirmation or by a 13C urea test 
(proton-pump inhibitors and H2 blockers should be 
discontinued or withheld for at least 14 days and 
7 days, respectively, and antibiotics for treating H. 
pylori, such as those with anti-helicobacter action and 
bismuth preparations, should be withdrawn at least 
30 days before H. pylori testing).
3. Previous therapy:
a. Cohort 1: Previously received 1 or more lines of 
systemic therapy including at least 1 CD20-directed 
regimen (either as monotherapy or as 
chemoimmunotherapy for MZL) with documented failure
to achieve at least PR, or documented disease 
progression after the most recent treatment regimen.
b. Cohort 2: Previously received 1 or more lines of therapy
including at least 1 prior systemic therapy for MZL or
radiation therapy with documented failure to achieve at 
least PR, or documented disease progression after the
most recent treatment regimen.
4. Presence of radiographically measurable lymphadenopathy
or extranodal lymphoid malignancy (defined as the 
presence of ≥1 lesion that measures
≥2.0 cm in the longest dimension and ≥1.0 cm in the longest 
perpendicular dimension as assessed by CT scan). Lesions in 
anatomical locations, such as extremities or soft tissue lesions, 
that are not well visualized by CT may be measured by 
magnetic resonance imaging (MRI) instead; subjects with
spleen- only disease are considered as not having measurable 
disease.
5. ECOG performance status of ≤2.
6. Women must agree to use highly effective methods of 
contraception during the study and for 2 days after the last
dose of acalabrutinib or 12 months after the last dose of 
rituximab, whichever is longer, if sexually active and able to 
bear or beget children. Highly effective methods of 
contraception are defined in the protocol.
7. Men must agree to refrain from sperm donation during the 
study and for 3 months after the last dose of rituximab.
8. Willing and able to participate in all required evaluations and 
procedures in this study protocol including swallowing 
capsules or tablets without difficulty.
9. Ability to understand the purpose and risks of the study and 
provide signed and dated informed consent and authorization 
to use protected health information (in accordance with 
national patient privacy regulations).
Part 3
1. Men and women ≥18 years of age

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2. For subjects with FL: Pathologically confirmed diagnosis of FL 
Grade 1, 2, or 3a that has relapsed after, or been refractory to 
≥1 prior therapy for FL and which requires treatment per 
National Cancer Institute or European Society for Medical 
Oncology (ESMO) clinical practice guidelines.
3. This criterion was removed under Amendment 6.
4. Subjects must have previously received at least 1 
frontline standard chemoimmunotherapy regimen.
5. Subjects with suspected residual disease after the 
treatment regimen directly preceding study enrollment must 
have biopsy-demonstrated residual FL.
6. Documented R/R disease, defined as either: 1) recurrence of 
disease after a CR or PR, or 2) stable disease or progressive 
disease at completion of the treatment regimen preceding
entry to the study (residual disease).
7. Presence of radiographically measurable lymphadenopathy
or extranodal lymphoid malignancy (defined as the 
presence of ≥1 lesion that measures
≥2.0 cm in the longest dimension and ≥1.0 cm in the longest
perpendicular dimension as assessed by CT scan).
8. ECOG performance status of ≤2.
9. Females of reproductive potential must
a. have 2 negative pregnancy tests prior to initiating 
treatment with lenalidomide. The first should be 
within 10 to 14 days and the second test within 24 
hours prior to first dose of lenalidomide.
b. commit to abstain continuously from heterosexual
sex or use highly effective methods of contraception.
Contraception must be used beginning 4 weeks 
prior to initiating treatment with lenalidomide, during
therapy with any study drug, and during dose 
interruptions for lenalidomide. Contraception must 
be used for 2 days after the last dose of 
acalabrutinib,12 months after the last dose of 
rituximab, or 4 weeks after the last dose of 
lenalidomide, whichever is later
10. Men must agree to use a synthetic or latex condom during 
any sexual contact with female of reproductive potential 
including with pregnant partners while taking lenalidomide 
and for up to 4 weeks after last dose of lenalidomide, even 
if they have undergone a successful vasectomy. Men must 
agree to refrain from sperm donation during the study and 
for 3 months after the last dose of rituximab or 4 weeks 
after the last dose of lenalidomide, whichever is later.
11. Subjects must not donate blood during treatment with 
lenalidomide and for 4 weeks after discontinuation of 
lenalidomide.
12. Willing and able to participate in all required evaluations 
and procedures in this study protocol including swallowing 
capsules or tablets without difficulty.

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13. Ability to understand the purpose and risks of the study 
and provide signed and dated informed consent and 
authorization to use protected health information (in 
accordance with national patient privacy regulations).
Exclusion Criteria:
Subjects will be ineligible for this study if they meet any of the 
following criteria.
Part 1
1. Prior malignancy (other than indolent B-cell NHL), except for 
adequately treated basal cell or squamous cell skin cancer, in 
situ cancer, or other cancer from which the subject has been 
disease free for ≥2 years.
2. Known CNS lymphoma or leptomeningeal disease.
3. A life-threatening illness, medical condition, or organ system 
dysfunction which, in the investigator’s opinion, could
compromise the subject’s safety, interfere with the absorption 
or metabolism of acalabrutinib, or put the study outcomes at 
undue risk.
4. Known history of a bleeding diathesis (e.g., hemophilia, von 
Willebrand disease).
5. Significant cardiovascular disease such as uncontrolled or 
symptomatic arrhythmias, congestive heart failure, or 
myocardial infarction within 6 months of screening, or any Class 
3 or 4 cardiac disease as defined by the New York Heart 
Association Functional Classification, or corrected QT interval 
(QTc) >480 msec.
6. Malabsorption syndrome, disease
significantly
affecting 
gastrointestinal function, or resection of the stomach or small 
bowel, gastric bypass, symptomatic inflammatory bowel
disease, or partial or complete bowel obstruction.
7. Any immunotherapy within 4 weeks of first dose of study drug.
8. Relapsed/Refractory Cohort: The time from the last dose of the
most recent chemotherapy or experimental therapy to the first 
dose of study drug is <5 times the half-life of the previously 
administered agent(s).
9. Prior exposure to a BCR inhibitor (e.g., BTK, 
phosphonositide-3 kinase [PI3K], or spleen tyrosine 
kinase [SYK] inhibitors) or BCL-2 inhibitor (e.g., 
venetoclax).
10. Known history of anaphylaxis or hypersensitivity to rituximab
(Rituxan/MabThera) or any of its components.
11. Ongoing immunosuppressive therapy, including systemic or 
enteric corticosteroids for treatment of FL or other conditions.
Note: Subjects may use topical or inhaled corticosteroids or 
low-dose steroids (≤20 mg of prednisone or equivalent) as 
therapy for comorbid conditions. During study participation, 
subjects may also receive systemic or enteric corticosteroids 

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as needed for treatment-emergent comorbid conditions.
12. Grade ≥2 toxicity (other than alopecia) continuing from prior 
anticancer therapy including radiation.
13. Known history of HIV or active infection with hepatitis C virus
(HCV) or any uncontrolled active systemic infection.
14. Known hepatitis B infection or positive for hepatitis B surface 
antigen (HBsAg) or hepatitis B core antibody (anti-HBc). Since 
intravenous immunoglobulins (IVIG) may cause false positive
hepatitis serology, subjects who are receiving prophylactic IVIG 
and have positive HBsAg or anti-HBc must have negative 
hepatitis B DNA to be eligible.
15. Major surgery within 4 weeks before first dose of 
acalabrutinib.
16. Uncontrolled autoimmune hemolytic anemia or idiopathic 
thrombocytopenia purpura.
17. History of stroke or intracranial hemorrhage within 6 
months before the first dose of acalabrutinib.
18. Requires or receiving anticoagulation with warfarin or 
equivalent vitamin K antagonist (e.g., phenprocoumon) within 
7 days of first dose of study drug.
19. Requires treatment with proton-pump inhibitors (e.g., 
omeprazole, esomeprazole, lansoprazole, 
dexlansoprazole, rabeprazole, or pantoprazole). Note: this 
criterion no longer applies to patients who have switched 
from acalabrutinib capsules to tablets.
20. Received a live virus vaccination within 28 days of first dose 
of study drug.
21. ANC <0.75 × 109/L or platelet count <50 × 109/L. For 
subjects with documented disease involvement in the bone
marrow, ANC <0.50 × 109/L or platelet count
<30 × 109/L.
22. Creatinine >2.5 × institutional ULN; total bilirubin
>2.5 × ULN; and AST or ALT >3.0 × ULN.
23. Breastfeeding or pregnant.
24. Concurrent participation in another therapeutic clinical trial.
25. Presence of a gastrointestinal ulcer diagnosed by 
endoscopy within 3 months before screening.
Part 2
1. Prior malignancy (other than indolent B-cell NHL), except for 
adequately treated basal cell or squamous cell skin cancer, in 
situ cancer, or other cancer from which the subject has been 
disease free for ≥2 years.
2. Known medically apparent CNS lymphoma or 

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leptomeningeal disease.
3. Known evidence of transformation to another aggressive 
lymphoma.
4. A life-threatening illness, medical condition, or organ system 
dysfunction which, in the investigator’s opinion, could
compromise the subject’s safety, interfere with the absorption 
or metabolism of acalabrutinib, or put the study outcomes at 
undue risk.
5. Known history of a bleeding diathesis (e.g., hemophilia, von 
Willebrand disease).
6. Significant cardiovascular disease such as uncontrolled or 
symptomatic arrhythmias, congestive heart failure, or 
myocardial infarction within 6 months of screening, or any Class 
3 or 4 cardiac disease as defined by the New York Heart 
Association Functional Classification, or QTc using Fridericia 
formula (QTcF) >480 msec.
7. Malabsorption syndrome, disease significantly affecting 
gastrointestinal function (excluding gastric MALT), or 
resection of the stomach or small bowel, gastric bypass, 
symptomatic inflammatory bowel disease, or partial or 
complete bowel obstruction.
8. This criterion was removed under Amendment 5.
9. This criterion was removed under Amendment 5.
10. Prior exposure to a BCR inhibitor (e.g., BTK or SYK inhibitors).
11. For Cohort 2, evidence of CD20− MZL and/or known history of 
anaphylaxis or hypersensitivity to rituximab (Rituxan/MabThera) 
or any of its components.
12. Ongoing immunosuppressive therapy, including systemic or 
enteric corticosteroids for treatment or other conditions within 1 
week before the first dose of study drug. Note: Subjects may use 
topical or inhaled corticosteroids or low-dose steroids (≤20 mg of 
prednisone or equivalent for up to 2 weeks) as therapy for 
comorbid conditions. However, subjects requiring systemic 
steroids at daily doses >20 mg prednisone equivalent of 
systemic exposure are not allowed.
13. Grade ≥2 toxicity (other than alopecia or laboratory value 
requirements mentioned in Part 2) continuing from prior 
anticancer therapy including radiation.
14. Uncontrolled active systemic fungal, bacterial, viral, or other 
infection (defined as exhibiting ongoing signs/symptoms related 
to the infection and without improvement, despite appropriate 
antibiotics or other treatment), or intravenous anti-infective 
treatment within 2 weeks before first dose of study drug.
15. Known history of infection with HIV.
16. Serologic status reflecting active hepatitis B or C infection.

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•
Subjects who are anti-HBc positive and who are surface 
antigen negative will need to have a negative hepatitis B 
virus (HBV) DNA polymerase chain reaction (PCR) result 
before enrollment. Subjects who are HBsAg positive or 
hepatitis B PCR positive will be excluded.
•
Subjects who are anti-HCV positive will need to have a 
negative PCR result before enrollment. Subjects who are 
hepatitis C PCR positive will be excluded.
17. History of allogeneic stem cell (or organ) transplantation.
18. This criterion was removed under Amendment 5.
19. Major surgery within 4 weeks before first dose of acalabrutinib.
20. Uncontrolled autoimmune hemolytic anemia or idiopathic 
thrombocytopenia purpura.
21. History of stroke or intracranial hemorrhage within 6 months 
before the first dose of acalabrutinib.
22. Requires or receiving anticoagulation with warfarin or equivalent 
vitamin K antagonist (e.g., phenprocoumon) within 7 days of first 
dose of study drug.
23. Requires treatment with proton-pump inhibitors (e.g., 
omeprazole, esomeprazole, lansoprazole, 
dexlansoprazole, rabeprazole, or pantoprazole). Note: this 
criterion no longer applies to patients who have switched 
from acalabrutinib capsules to tablets.
24. Received a live virus vaccination within 28 days of first dose 
of study drug.
25. ANC <1.0 × 109/L or platelet count <100 × 109/L.
For 
subjects with documented disease involvement in the bone 
marrow, ANC <0.50 × 109/L or platelet count
<30 × 109/L.
26. Creatinine >1.5 × institutional ULN; total bilirubin 
>1.5 × ULN; and AST or ALT >2.5 × ULN.
27. Breastfeeding or pregnant.
28. Concurrent participation in another therapeutic clinical trial.
29. In the absence of gastric MALT (subject to inclusion criterion 
2b) presence of a gastrointestinal ulcer diagnosed by 
endoscopy within 3 months before screening or diagnosed >3
months before screening and without confirmed resolution by 
endoscopy.
30. Received
any
chemotherapy,
external beam radiation 
therapy, anticancer antibodies, or investigational drug within 
30 days before first dose of study drug.
31. History of or ongoing progressive multifocal 
leukoencephalopathy (PML).

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Part 3
1. Prior malignancy, except for adequately treated basal cell or 
squamous cell skin cancer, in situ cancer, or other cancer from 
which the subject has been disease free for
≥2 years.
2. Subjects for whom the goal of therapy is tumor debulking 
before stem cell transplant.
3. Known history or presence of CNS lymphoma or 
leptomeningeal disease.
4. Transformed DLBCL or DLBCL with coexistent histologies 
(e.g., FL or mucosa-associated lymphoid tissue and primary
mediastinal large B-cell lymphoma (PMBCL).
5. A life-threatening illness, medical condition, or organ system 
dysfunction which, in the investigator’s opinion, could
compromise the subject’s safety, interfere with the absorption 
or metabolism of acalabrutinib, or put the study outcomes at 
undue risk.
6. Known history of a bleeding diathesis (e.g., hemophilia, von 
Willebrand disease).
7. Significant cardiovascular disease such as uncontrolled or 
symptomatic arrhythmias, congestive heart failure, or 
myocardial infarction within 6 months of screening, or any 
Class 3 or 4 cardiac disease as defined by the New York 
Heart Association Functional Classification, or QTcF >480
msec. Exception: Subjects with controlled, asymptomatic atrial 
fibrillation during screening are allowed to be enrolled on 
study.
8. Malabsorption syndrome, disease
significantly
affecting 
gastrointestinal function, or resection of the stomach or small 
bowel, gastric bypass, symptomatic inflammatory
bowel
disease, or partial or complete bowel obstruction.
9. Received
any
chemotherapy,
external beam radiation 
therapy, anticancer antibodies, or investigational drug within 
30 days before first dose of study drug.
10. Prior exposure to a BCR inhibitor (e.g., BTK or SYK 
inhibitors), lenalidomide, or CAR-T cell therapy.
11. Known history of anaphylaxis or hypersensitivity to rituximab
(Rituxan/MabThera) or any of its components.
12. Subjects with a prior history of Grade 4 rash associated with 
thalidomide treatment.
13. Ongoing immunosuppressive therapy, including systemic (e.g.,
IV or oral) corticosteroids within 2 weeks before the first dose of 
study drug. Note: Subjects may use topical or inhaled 
corticosteroids or low-dose steroids (≤20 mg prednisone
equivalent/day for ≤2 weeks) as a therapy for comorbid

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conditions. During study participation, subjects may also 
receive systemic (e.g., IV or oral) corticosteroids as needed for 
treatment-emergent comorbid conditions.
14. Grade ≥2 toxicity (other than alopecia or laboratory value 
requirements mentioned in Part 3 exclusion criteria) 
continuing from prior anticancer therapy including radiation.
15. Uncontrolled active systemic fungal, bacterial, viral, or other 
infection (defined as exhibiting ongoing signs or symptoms 
related to the infection and without improvement, despite 
appropriate antibiotics or other treatment), or intravenous
anti-infective treatment within 2 weeks before first dose of 
study drug.
16. Known history of infection with HIV.
17. Serologic status reflecting active hepatitis B or C 
infection.
a. Subjects who are anti-HBc positive and who are surface
antigen negative will need to have a negative PCR result 
before enrollment. Subjects who are HBsAg positive or 
hepatitis B PCR positive will be excluded.
b. Subjects who are HCV antibody (anti-HCV) positive will 
need to have a negative PCR result before enrollment.
Subjects who are HCV PCR positive will be excluded.
18. History of allogeneic stem cell (or organ) transplantation.
19. Major surgery within 4 weeks before first dose of 
acalabrutinib.
20. Uncontrolled autoimmune hemolytic anemia or idiopathic 
thrombocytopenia purpura.
21. History of stroke or intracranial hemorrhage within 6 
months before the first dose of acalabrutinib.
22. Requires or has received anticoagulation with warfarin or 
equivalent vitamin K antagonist (e.g., phenprocoumon) within 7 
days of first dose of study drug.
23. Received a live virus vaccination within 28 days of first dose 
of study drug.
24. ANC <1.0 × 109/L or platelet count <75 × 109/L. Subjects will 
only be considered eligible if peripheral blood counts can be 
maintained independent of growth factors or transfusions 
during screening.
25. Creatinine clearance of <60 mL/min, calculated using the 
formula of Cockcroft and Gault [(140-Age) * Mass (kg)/(72 * 
creatinine mg/dL) * 0.85 if female].
26. Total bilirubin >1.5 × ULN, or AST or ALT >2.5 × ULN, 
unless directly attributable to Gilbert’s syndrome.
27. Total bilirubin >1.5 × ULN, or AST or ALT >2.5 × ULN, 

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unless directly attributable to Gilbert’s syndrome.
28. Requires treatment with proton-pump inhibitors (e.g., 
omeprazole, esomeprazole, lansoprazole, dexlansoprazole,
rabeprazole or pantoprazole). Subject receiving proton-pump 
inhibitors who switch to
H2-receptor antagonists or antacids are eligible for enrollment to 
this study. Note: this criterion no longer applies to patients who 
have switched from acalabrutinib capsules to tablets.
29. Breastfeeding or pregnant.
30. Concurrent participation in another therapeutic clinical trial.
31. History of or ongoing PML.
Dosage Form and 
Strength:
As of Clinical Study Protocol (CSP) Version 8.0, acalabrutinib is 
supplied in 2 formulations (hard gelatin capsules and orange film 
coated tablets) for oral administration, prepared using standard 
pharmaceutical grade excipients. Acalabrutinib capsules and 
tablets are bioequivalent in relation to dosage strength. 
Acalabrutinib will be provided in white, high-density polyethylene
bottles.
Rituximab (Rituxan/MabThera) injection is a commercial product 
(Genentech, Inc., South San Francisco, CA/Roche, Basal
Switzerland). Rituximab is available in 100 mg/10 mL single-use 
vials and 500 mg/50 mL single-use vials.
Lenalidomide (Revlimid) is a commercial product (Celgene, Inc, 
Summit, NJ). Lenalidomide is available as capsules containing 2.5
mg, 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg of drug substance.
Refer to product information from the manufacturers for details on
formulation, packaging, and storage of rituximab and lenalidomide.
Dose Regimen/Route
of Administration:
Acalabrutinib is intended to be administered orally with 8 ounces 
(approximately 240 mL) of water. Acalabrutinib taken with an acidic 
beverage may impact exposure to acalabrutinib (refer to the current 
Acalabrutinib Investigator Brochure). Acalabrutinib may be 
administered without regard to food. The capsules or tablets should
be swallowed intact and subjects should not attempt to open 
capsules or crush tablets, and both formulations should not be 
dissolved in water. Acalabrutinib should be taken BID, 
approximately 12 hours apart.
Rituximab is to be administered as an IV infusion, not an IV push or
bolus. Detailed instructions for the preparation and administration of 
rituximab are provided in the Rituxan/MabThera package insert and 
per institutional standards. No dose reductions for rituximab are 
allowed.
On days when both acalabrutinib and rituximab are administered, 
the rituximab infusion should begin approximately 1 hour after the 
acalabrutinib dose.
Part 3
Lenalidomide is to be administered orally at approximately the 
same time each day, either with or without food. The capsules 

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should be swallowed whole with water. The capsules should not 
be opened, broken, or chewed. Lenalidomide is administered for
the first 21 days of each 28-day cycle. On days that both 
acalabrutinib and lenalidomide are administered, lenalidomide
should be taken approximately 30 minutes prior to the first daily 
dose of acalabrutinib. Dose modification provisions are provided
in the protocol.
Concomitant 
Medications:
The concomitant use of strong inhibitors/inducers of CYP3A (see
protocol) should be avoided when possible.
Acalabrutinib is a substrate of CYP3A4. Drugs inhibiting CYP3A 
may increase exposure of acalabrutinib. If a subject requires short-
term treatment with a strong CYP3A inhibitor (such as anti-
infectives for up to 7 days), interrupt acalabrutinib treatment. If a 
subject requires a moderate CYP3A inhibitor while on study, 
monitor the subject closely for potential toxicities.
Conversely, concomitant administration of a strong inducer of 
CYP3A has the potential to decrease exposure of acalabrutinib and 
could reduce efficacy. Avoid coadministration of strong CYP3A 
inducers. If a subject requires treatment with a strong CYP3A 
inducer, increase the acalabrutinib dose to 200 mg BID during 
concomitant administration with the strong inducer and return to 
recommended dose of 100 mg BID after stopping the strong 
CYP3A inducer.
Use of proton-pump inhibitors, H2 receptor antagonists, or antacids 
while taking acalabrutinib capsules has the potential to decrease 
acalabrutinib exposure. If treatment with a gastric acid-reducing
agent is required, consider using a H2-receptor antagonist (2 hours 
after acalabrutinib capsules) or antacid (2 hours before or 2 hours
after acalabrutinib capsules). Avoid coadministration of proton-
pump inhibitors with acalabrutinib capsules. Acalabrutinib maleate 
tablets can be taken without regards to acid-reducing agents (such 
as antacids, H2-receptor antagonists, or proton-pump inhibitors).
Lenalidomide
Subjects who are concurrently receiving digoxin should have 
periodic monitoring of digoxin plasma levels is due to increased 
Cmax and AUCinf of digoxin with concomitant lenalidomide therapy.
Moreover, subjects taking concomitant therapies such as 
erythropoietin-stimulating agents or estrogen-containing therapies, 
along with lenalidomide, may have an increased risk of venous 
thromboembolic events per package insert.
Rituximab
The only drug-drug interaction with rituximab listed in the 
Rituxan/MabThera package insert is renal toxicity when used in 
combination with cisplatin.
Statistics:
Descriptive statistics (including means, standard deviations, and 
medians for continuous variables and proportions for discrete 
variables) will be used to summarize data as appropriate. All 
analyses will be done by indication, treatment, and overall.

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Part 1
This study will assess acalabrutinib safety, PK, PD, and antitumor
activity when administered alone or in combination with rituximab.
The primary objective of this study is to determine the safety as 
such:

With a total sample size of 36, the probability of 
observing one or more instances of an AE with a 
background rate of 5% and 10% is 84% and 98%, 
respectively.

For each treatment arm (n=12 each), the probability of 
observing one or more instances of an AE with a 
background rate of 5% and 10% is 46% and 72%, 
respectively.
Part 2
The primary objective is to characterize the activity of acalabrutinib
alone in subjects with R/R MZL as measured by the ORR. Up to 
40 subjects in treatment Cohort 1 will provide data for an initial 
assessment of safety and efficacy of acalabrutinib treatment.
Sample size is not based on statistical power consideration.
Part 3
This sample size will provide adequate data for an initial 
assessment of safety and efficacy of acalabrutinib treatment in
combination with lenalidomide and rituximab. This sample size is 
not based on statistical power consideration.

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1
BACKGROUND INFORMATION
1.1
ROLE OF BTK IN LYMPHOID CANCERS
Bruton tyrosine kinase (BTK) is a non-receptor enzyme of the Tec kinase family that 
is expressed among cells of hematopoietic origin, including B cells, myeloid cells, 
mast cells, and platelets, where it regulates multiple cellular processes including 
proliferation, differentiation, apoptosis, and cell migration (Mohamed et al. 2009, 
Bradshaw et al. 2010). Functional null mutations of BTK in humans cause the 
inherited disease, X-linked agammaglobulinemia, which is characterized by a lack of 
mature peripheral B cells (Vihinen et al. 2000). Conversely, BTK activation is 
implicated in the pathogenesis of several B-cell malignancies (Buggy et al. 2012).
Taken together, these findings have suggested that inhibition of BTK may offer an 
attractive strategy for treating B-cell neoplasms.
Non-Hodgkin lymphoma (NHL) is a diverse class of neoplasms that can originate in
B cells, T cells, or natural killer (NK) cells. Estimated new cases and deaths from 
NHL are 72,240 and 20,140, respectively, in the United States in 2017 (National
Cancer Institute 2017). NHL can be divided into two prognostic groups: indolent and 
aggressive lymphomas. Of the NHLs, indolent NHLs account for 40% of all NHL
cases (Leukemia and Lymphoma Society 2008). The majority of indolent lymphomas 
are mature B-cell lymphomas, including the most common subtype of follicular 
lymphoma (FL), accounting for approximately 25% of all NHLs (Sehn 2016), followed 
by marginal zone lymphoma (MZL; approximately 12% of all NHLs; California Cancer
Care 2017). MZL can be classified into 3 subtypes: 1) splenic MZL, 2) nodal MZL, 
and 3) extranodal MZL of mucosa-associated lymphoid tissue (MALT) lymphoma, 
which is further categorized into gastric MALT and nongastric MALT lymphomas 
(Swerdlow et al. 2016). In most cases the etiology for indolent lymphomas is 
unknown, however, associations have been made between indolent NHL and certain 
immune disorders and microbial pathogens, e.g., gastric MALT is strongly associated 
with H. pylori infection and splenic MZL with hepatitis C infection (Arcaini et al. 2016, 
Sehn et al. 2016, Thieblemont et al. 2016, Zucca et al. 2016).
Despite the recent advances in treatments for advanced indolent NHLs, the disease is 
incurable. Although most patients have had extended survival, a subset of patients 
have early relapses after therapy or have disease that is refractory to existing 
therapies (Sehn et al. 2016). Therefore, safe and effective drug combinations, 
particularly chemotherapy-free approaches, are being studied in patients with 

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relapsed or refractory (R/R) FL (Sehn et al. 2016). Current approaches to patients 
with R/R FL vary widely (National Comprehensive Cancer Network 2018), although 
most combinations include an anti-cluster of differentiation (CD) 20 antibody.
Commonly used combination regimens include bendamustine with anti-CD20 
(rituximab or obinutuzumab), rituximab added to an anthracycline-based combination 
chemotherapy (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone 
[CHOP]; National Comprehensive Cancer Network 2018). Single agent PI3-kinase 
inhibitors such as idelalisib and copanlisib are currently Food and Drug Administration 
(FDA)-approved for treatment of patients with FL who have failed 2 prior lines of 
therapy (ZYDELIG® [prescribing information] 2016; Aliqopa package insert 2017).
In contrast to indolent NHLs, a subset of NHLs has an aggressive course. Diffuse 
large B-cell lymphoma is the most common form of aggressive NHL in the United 
States, with an annual incidence that has been rising gradually since the 1990s. A 
significant proportion of patients with diffuse large B-cell lymphoma (DLBCL) are 
cured with standard chemoimmunotherapy including Rituximab-CHOP (R-CHOP) 
(Coiffier et al. 2002, Habermann et al. 2006, Pfreundschuh et al. 2006). Nonetheless, 
for those patients not cured by standard initial therapy, the prognosis remains 
generally poor, and DLBCL still accounts for the highest number of deaths per year of 
all the NHL histologies.
For patients with either refractory or recurrent DLBCL following initial therapy, the 
approach of re-induction chemotherapy, followed by high-dose chemotherapy with 
autologous stem cell transplantation (HDT/ASCT) for responding patients, remains 
the current standard of care. Such an approach was demonstrated to result in 
superior disease-free survival compared with re-induction chemotherapy alone in a 
randomized Phase 3 trial (Philip et al. 1995). However, the results of a more recently 
reported Phase 3 trial comparing rituximab, ifosfamide, carboplatin, and etopside
(R-ICE) to rituximab, cisplatin, cytarabine, and dexamethasone (R-DHAP) as 
re-induction therapy suggests that this standard salvage approach may be less 
efficacious in the era of rituximab-based first-line therapy, as 3-year event-free
survival rates were significantly lower for patients who had received rituximab-based 
first-line therapy (Gisselbrecht et al. 2010). In addition, HDT/ASCT is associated with 
considerable treatment-related morbidity and occasional treatment-related mortality. 
Advanced age and suboptimal baseline pulmonary or cardiac function are risks for 
excessive morbidity during and after HDT/ASCT. Therefore, effective and tolerable 

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therapies are needed in R/R DLBCL, particularly in the era of rituximab-based initial 
chemoimmunotherapy.
There are two major subtypes of DLBCL that are named according to their cell of 
origin and include germinal center B-cell like (GCB) and activated B-cell like (ABC) 
subtypes (approximately15% of patients are not classifiable into either subtype, based 
on gene expression profiling; Alizadeh et al. 2000, Rosenwald et al. 2002). These 
subtypes are postulated to reflect different oncogenic mechanisms and responses to 
treatment (Sehn et al. 2015). For example, ABC subtype has worse outcomes 
following R-CHOP (Lenz et al. 2008). Bortezomib, a proteasome inhibitor of the 
nuclear factor kappa beta (NFkB) pathway, has demonstrated benefit in ABC subtype 
and agents such as lenalidomide appear to have activity in non-GCB DLBCL 
(Dunleavy et al. 2009, Witzig et al. 2011).
Clinical studies have shown that targeting the B-cell receptor (BCR) signaling
pathway by inhibiting BTK produces significant clinical benefit in patients with NHL. A 
first-in-human (FIH) study of ibrutinib in FL showed that 6 of 16 subjects (38%) had an 
objective response (Fowler et al. 2012). In a Phase 2 trial of patients with R/R FL 
treated with ibrutinib, the overall response rate (ORR) was 37.5%, with a complete 
remission (CR) rate of 12.5%, and a median progression-free survival (PFS) of 14 
months (Bartlett et al. 2014; Bartlett). Interim results from a Phase 2 study of ibrutinib 
in subjects with R/R GCB and ABC DLBCL reported an ORR of 41% (CR 17%) for 
subjects with ABC DLBCL versus 5% (no CRs) for subjects with GCB DLBCL
(Wilson et al. 2015). Similar results were observed with ONO-4059, a second 
generation BTK inhibitor in a Phase 1 dose-escalation study in subjects with ABC 
DLBCL (Dyer et al. 2014). In both studies, the BTK inhibitors were well tolerated. In 
recent years, ibrutinib has been approved for the treatment of MZL and Phase 3 
studies for ibrutinib are currently ongoing in FL and DLBCL (NCT02947347, 
NCT01974440, NCT01855750). Moreover, in our experience, acalabrutinib 
monotherapy showed an ORR of 33% in R/R FL and an ORR of 24% in DLBCL 
(Dyer et al. 2018, Fowler et al. 2018). The activity of BTK inhibitors in NHL supports 
the study of acalabrutinib in these NHL histologies.
In a Phase 2, open-label study of ibrutinib, 63 subjects with R/R MZL received 
ibrutinib at 560 mg orally once daily, including subjects with MZL of MALT lymphoma 
(n=32), nodal MZL (n=17), and splenic MZL (n=14) (Inman et al. 2017). All subjects 
had received one or more prior therapies, including an anti-CD20 antibody. All 

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subjects had an Eastern Cooperative Oncology Group (ECOG) performance status of 
≤2 and 33% had bone marrow involvement. Of the 63 patients that were analyzed
for efficacy, the ORR was 46%, including a CR in 2 subjects (3.2%). The ORR for 
the MZL subtypes were as follows: 46.9% (MALT), 41.2% (nodal), and 50% 
(splenic).
The median time to response was 4.5 months (range 2.3 to 16.4 months). The 
median PFS was 14.2 months with ibrutinib (95% CI, 8.3-not reported) and the 
median overall survival (OS) was not yet reached at a median follow-up of 
19.4 months. Based on this study, ibrutinib received an accelerated approval 
for treatment of MZL in patients who have received at least 1 prior anti-CD20
therapy (IMBRUVICA® package insert).
While highly potent in inhibiting BTK, ibrutinib has also shown in vitro activity against 
other kinases with a cysteine in the same position as Cys481 in BTK to which the 
drug covalently binds. The inhibition of epidermal growth factor receptor (EGFR) is 
also observed in cellular assays and may contribute to ibrutinib-related adverse 
events (AEs) of diarrhea and rash (IMBRUVICA® package insert). In addition, 
ibrutinib is a substrate for cytochrome P450 (CYP) 3A; inhibition of CYP3A causes a 
29-fold increase in maximum observed plasma concentration (Cmax) and 24-fold 
increase in area under the curve (AUC) for ibrutinib (IMBRUVICA® package insert). 
This increases the possibility of drug-drug interactions in combination therapies with 
drugs currently used in management of subjects with cancer. These limitations 
support the development of alternative BTK inhibitors for use in the therapy of B-cell 
malignancies.
Chemical optimization, pharmacologic characterization, and toxicologic evaluation 
have led to identification of acalabrutinib, an orally administered, new chemical entity 
that covalently inhibits BTK and shows activity and acceptable safety in nonclinical 
studies. Acalabrutinib is a potent, highly selective covalent inhibitor of BTK in clinical 
development for B-cell malignancies. Acalabrutinib inhibits BCR signaling by 
irreversibly inactivating BTK, leading to decreased growth and survival signals in 
B-cells and shows greater kinase selectivity for BTK than ibrutinib in laboratory 
studies. In laboratory studies, acalabrutinib and its major metabolite, ACP-5862, have 
limited off-target kinase activity (Byrd et al. 2016, Barf et al. 2017). The lack of activity 
against other Tec- and Src-family kinases, which are important for the function of 
T-cells, NK cells, and platelets, and against EGFR, a kinase important for epithelial

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cell functions, may contribute to the safety and efficacy profile of acalabrutinib. Key 
nonclinical differentiators of acalabrutinib versus ibrutinib are:

 
 
 
 

Acalabrutinib and ibrutinib have been evaluated in NK cell functional assays. 
While ibrutinib inhibits NK cell functions including antibody-dependent cellular 
cytotoxicity, lytic granule release, and cytokine production (Kohrt et al. 2014), 
the in vitro functional activity of acalabrutinib-treated NK cells was preserved.

Acalabrutinib has been evaluated against ibrutinib in an in vivo thrombus 
formation model. Platelets from patients with chronic lymphocytic leukemia 
(CLL) treated with acalabrutinib had similar thrombus formation dynamics as 
untreated platelets from healthy volunteers, while platelets from
ibrutinib-treated patients with CLL had impaired thrombus formation (Byrd et
al. 2016).
The nonclinical and toxicology results of acalabrutinib suggest that it may have an 
improved therapeutic window relative to ibrutinib; it may be more readily combined 
with other agents for the treatment of cancer.
1.2
NONCLINICAL STUDIES OF ACALABRUTINIB
Summaries of nonclinical studies are provided below. For more detailed information 
please refer to the Acalabrutinib Investigator Brochure.
1.2.1 Chemistry
Acalabrutinib is an imidazopyrazine analogue with a molecular weight of 465.5 
g/mol. The compound has 1 stereogenic center and acalabrutinib is the S-
enantiomer.
Acalabrutinib is orally bioavailable in animals and is suitable for formulating in 
capsules and tablets (as the maleate salt). For clinical testing, acalabrutinib has 
been manufactured and formulated according to current Good Manufacturing 
Practices (cGMP).
New Formulation: Acalabrutinib Maleate Tablet

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A new film-coated tablet formulation for oral administration, containing acalabrutinib 
maleate equivalent to 100 mg of acalabrutinib, has been developed and was first 
approved by the FDA.
Acalabrutinib maleate tablets were shown to be bioequivalent to acalabrutinib 
capsules in the fasted state in healthy volunteers (Study D8223C00013). Geometric 
mean PK exposures (Cmax and AUClast or AUCinf) of acalabrutinib and its metabolite 
(ACP-5862) were similar (<4% difference) following administration of acalabrutinib 
maleate tablets and acalabrutinib capsules. In addition, the 90% confidence 
intervals for geometric mean ratios (Cmax and AUClast or AUCinf) for acalabrutinib and 
ACP-5862 were well contained within the range of 80.00% and 125.00%, thus 
meeting the pre-defined criteria for the conclusion of bioequivalence.
For acalabrutinib maleate tablets, food reduced acalabrutinib Cmax by approximately 
54%, with no effect on AUC (Study D8220C00018). Similar results were observed 
for ACP-5862. There were no differences in BTK Target Occupancy (BTK-TO) 
across treatments. The decrease in the rate of exposure, without a change in the 
extent of exposure or BTK TO, is not considered clinically significant. Overall, these 
results are consistent with those observed following administration of 100 mg 
acalabrutinib capsule with food (refer to the CALQUENCE label). Thus, 
acalabrutinib maleate tablets can be taken with or without food.
1.2.2 Efficacy Pharmacology
Spontaneous canine B-cell lymphoma shares many characteristics with human NHL, 
including diagnostic classifications and response to BTK inhibition (Honigberg et al.
2010). The life expectancy in untreated animals with aggressive disease is ~6 weeks, 
thus enabling rapid assessment of drug efficacy (Vail et al. 2004). Acalabrutinib was 
evaluated in a dose-escalation study in canine spontaneous B-cell lymphoma 
(Harrington et al. 2016). Twenty dogs were enrolled in the clinical trial and treated with 
acalabrutinib dosages of 2.5 to 20 mg/kg every 12 or 24 hours. Acalabrutinib was 
generally well tolerated, with AEs consisting primarily of Grade 1 or Grade 2 anorexia, 
weight loss, vomiting, diarrhea, and lethargy. Per Veterinary Cooperative Oncology 
Group criteria for assessment of response in peripheral nodal lymphoma (Vail et al. 
2010), the ORR was 25% (5/20 dogs) with a median PFS of 22.5 days.
Clinical benefit was observed in 30% (6/20) of dogs. These findings suggest that 
acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and 
support the use of canine lymphoma as a relevant model for human NHL. These 

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findings are similar to the clinical responses (i.e., 1 dog with partial remission [PR] out 
of 5 dogs treated with suspected or confirmed DLBCL observed with ibrutinib in dogs 
with spontaneous B-cell lymphoma; Honigberg et al. 2010).
1.2.3 Safety Pharmacology
In vitro and in vivo safety pharmacology studies with acalabrutinib have demonstrated 
a favorable nonclinical safety profile. Please refer to the Acalabrutinib Investigator 
Brochure for a detailed review of the nonclinical toxicology program.
1.2.4 Drug-Drug Interaction Potential
For more detailed information on drug-drug interaction potential for acalabrutinib, refer 
to the Acalabrutinib Investigator Brochure.
Please refer to Section 3.7.5 for guidance on drugs that may cause drug-drug 
interactions.
1.2.5 In Vivo General Toxicology
The systemic toxicity of acalabrutinib has been fully evaluated in repeat-dose studies 
in mice, rats, and dogs; reproductive toxicity studies in rats and rabbits; and ongoing 
chronic studies in rats and dogs with durations of up to 28 days, 6 months, and
9 months, respectively; and in reproductive toxicity studies in rats and rabbits. The 
pivotal Good Laboratory Practice (GLP) studies were chronic studies in rats and dogs, 
each with recovery periods to assess the reversibility of observed changes. Please 
refer to the Acalabrutinib Investigator Brochure for a detailed review of the nonclinical 
toxicology program.
In rats, 100 mg/kg/day was selected initially to represent the highest non-severely 
toxic dose; however, 100 mg/kg/day was subsequently determined to be a no 
observed adverse effect level (NOAEL) for male rats, and 30 mg/kg/day was the 
NOAEL for female rats treated chronically (6-month study). In rats, the target organs 
of toxicity were kidney, liver, and heart.
The NOAEL in dogs was 30 mg/kg/day; dose levels higher than 30 mg/kg/day were 
not tolerated. In dogs, the target organs of toxicity, observed only at doses exceeding 
the maximum tolerated dose, were the kidney and liver. Heart findings were also 
observed in 2 dogs with a kidney toxicity, which were interpreted as possibly 
secondary to uremia, as has been reported for this species.
In rats and dogs, no adverse ECG or histopathologic cardiovascular effects were 

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noted at the planned conclusion of the subchronic general toxicity studies or in the rat 
chronic toxicity study. However, in rats that have died prematurely at doses of 200 or 
300 mg/kg/day, slight to moderate necrosis of the myocardium and/or white blood cell 
infiltration/inflammation of the myocardium were noted on microscopic examination of 
the hearts.
1.3
CLINICAL EXPERIENCE WITH ACALABRUTINIB
1.3.1 Pharmacokinetics and Pharmacodynamics of Acalabrutinib in 
Healthy Volunteers
Acalabrutinib has been studied in 10 clinical trials in healthy volunteers. In humans, 
acalabrutinib has a short pharmacokinetic (PK) half-life with a long-lasting 
pharmacodynamic (PD) effect due to covalent binding to BTK after oral 
administration.
In an FIH study in subjects with R/R CLL, acalabrutinib plasma time to maximum 
concentration (Tmax) values were between 0.5 and 1.0 hour for all dose cohorts
(2.5 mg twice per day [BID] to 100 mg once per day [QD]), and the mean half-life 
ranged from 0.97 to 2.1 hours. Acalabrutinib has an absolute oral bioavailability of 
25%, is best taken with water, can be taken with or without food, and does not 
accumulate in plasma upon repeat-dose administration. In healthy subjects, 
exposure was generally linear over the dose range of 15 mg to 100 mg and slightly 
greater than proportional between 100 mg and 400 mg. Variability in exposure to 
acalabrutinib is mainly due to a combination of pH-dependent absorption, and 
predominantly CYP3A-mediated metabolism.
For more detailed information on acalabrutinib clinical pharmacology studies, please 
refer to the Acalabrutinib Investigator Brochure.
1.3.2 Clinical Experience with Acalabrutinib
The Sponsor is developing acalabrutinib for the treatment of patients with cancer or 
autoimmune disorders. Acalabrutinib has an acceptable safety profile in clinical 
studies. Acalabrutinib has been administered to subjects with hematologic 
malignancies, solid tumors, or rheumatoid arthritis, and healthy volunteers or 
noncancer patients with mild- to moderate-hepatic impairment. Acalabrutinib 
monotherapy has also demonstrated clinical activity in patients with CLL (Awan et al.
2016), mantle cell lymphoma (MCL; Awan et al. 2016, Hillmen et al. 2016, Wang
2018; CALQUENCE® package insert), FL, and DLBCL (Dyer et al. 2018, Fowler et al. 

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2018).
For more detailed information on acalabrutinib clinical experience, refer to the 
Acalabrutinib Investigator Brochure.
Acalabrutinib, under the tradename CALQUENCE® has been approved in capsule 
formulation (NDA 210259) in the United States and other markets for the treatment of
adult patients with MCL who have received at least one prior therapy, CLL, and small 
lymphocytic lymphoma (SLL). A new film-coated acalabrutinib maleate tablet 
formulation (NDA 216387) was first approved in the United States for the treatment of 
adult patients with MCL who have received at least 1 prior therapy, CLL, and SLL; 
acalabrutinib tablets and acalabrutinib capsules are bioequivalent.
1.4
RITUXIMAB IN LYMPHOID CANCERS
Rituximab, an anti-CD20 monoclonal antibody, is indicated for treatment of CD20+
NHL as a single agent and in combination with chemotherapy. In a multicenter,
open-label, single-arm study conducted in 166 patients with R/R, low-grade or 
follicular, B-cell NHL who received 375 mg/m2 of rituximab intravenously weekly for 
4 doses (Rituxan/MabThera package insert), the ORR was 48% with a CR rate of
6% and a median duration of response (DOR) of 11.2 months (range 1.9 
to 42.1+ months). The median time to onset of response was 50 days, and 
disease-related signs and symptoms (including B symptoms) resolved in 64%
(25/39) of those patients with such symptoms at study entry. The most common 
adverse reactions reported in ≥25% of subjects with R/R, low grade or follicular 
NHL were infusion reactions, fever (53%), lymphopenia (48% overall, 40% Grade 
3 and Grade 4), chills (33%), infections (31%), and asthenia (26%) 
(Rituxan/MabThera package insert). Moreover, for untreated DLBCL patients
studied in several large randomized studies in combination with anthracycline-
based chemotherapy, patients received 375 mg/m2 of rituximab on Day 1 of each 
cycle of chemotherapy up to 8 infusions.
The CR was significantly higher in the R-chemotherapy group than the group that 
received chemotherapy. With a median follow-up of 2 years or more, OS times were 
significantly higher in the R-chemotherapy group with the most common adverse 
reactions in ≥25% observed were infusion reactions, fever, lymphopenia, chills, 
infection, and asthenia in clinical trials of patients with NHL (Rituxan/MabThera 
package insert).

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1.5
RITUXIMAB COMBINATION THERAPY IN LYMPHOID CANCERS
The combination of rituximab with a BTK inhibitor such as ibrutinib is a promising 
approach that is currently being evaluated in a number of lymphoid cancers, including 
a Phase 2, single-arm clinical trial of ibrutinib/rituximab in subjects with previously 
untreated FL (NCT01980654) and a comparison of ibrutinib versus ibrutinib/rituximab 
in subjects with relapsed CLL (NCT02007044). A completed Phase 2 study of 
rituximab plus ibrutinib in 40 subjects with high-risk CLL (Burger et al. 2014) found the 
combination was well tolerated and induced high rates of remission. Subjects 
received daily ibrutinib plus rituximab weekly during Cycle 1 then once per cycle until 
Cycle 6. The ORR was 95%, including 8% CRs; the median DOR was 15.44 months, 
and at 18 months, the Kaplan-Meier estimate of PFS was 78%. Toxicity was mainly 
of mild to moderate severity (Grade 1 to Grade 2); AEs included diarrhea (25% of 
subjects), bleeding events (35%, including 2.5% Grade 3), nausea (37.5%), and 
fatigue (17.5%). Grade 3 infections occurred in 4 patients (10%), no Grade 4 or 
Grade 5 infections occurred. In MCL, preliminary data have been reported on 
45 subjects in a Phase 2, single-arm trial of the combination of ibrutinib and rituximab 
with a median of 6.5 months of follow-up (Wang et al. 2014). The ORR to date was 
87%, including CR in 38% and PR in 49%. The ORR among the 33 subjects with 
lower Ki-67 (<50%) was 100%, with 48% CR and 52% PR. The median DOR and 
PFS had not yet been reached in this trial. Overall the combination was well 
tolerated; there were no deaths due to therapy, and Grade 3 hematology toxicity 
events included single cases of neutropenia and thrombocytopenia. The most 
common (≥20%) Grade 1 to Grade 2 nonhematologic events regardless of 
relationship to study therapy include fatigue, diarrhea, myalgia, dyspnea, blurred 
vision, nausea, dry eye, and atrial fibrillation. The combination of rituximab and 
ibrutinib has been evaluated in a Phase 2 clinical trial in treatment-naive patients with 
FL (Fowler et al. 2016). In patients receiving concurrent treatment with ibrutinib and 
rituximab (n=60), the ORR was 85%, with CR rate of 35%. The 12-month PFS was 
reported as 87%. The drug combination appeared to be well tolerated based on the 
lack of new safety signals in patients treated with the combination. Moreover, the 
acceptable safety and efficacy results to date for rituximab and the first-generation 
BTK inhibitor, ibrutinib, support further evaluation of rituximab with a novel BTK 
inhibitor such as acalabrutinib. Safety data from Part 1 of the ACE-LY-003 trial are 
included in the current Acalabrutinib Investigator Brochure. These data show that the 

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combination of acalabrutinib and rituximab is safe and well tolerated in patients with 
FL. For R/R DLBCL, an open-label, nonrandomized Phase 2 study, which included 
80 patients (38 ABC, 20 GCB, 17 unclassified, 5 unknown) who received ibrutinib 
orally daily for 4 weeks until disease progression or unacceptable toxicity, responses 
were observed in 25% (20/80) patients, including 12 PR and 8 CR (Wilson et al.
2015). With a median follow-up of 11.53 months, OS and PFS were 6.4 and 1.6 
months, respectively. Fourteen patients (37%) with ABC DLBCL had response 
compared with 1 patient (5%) in the GCB cohort (p=0.0106). The median response 
duration was 4.83 months (range, 1.02–9.26) in the ABC arm. ORR in the ABC group 
included a CR rate of 16% (n=6). Three patients experienced a CR in the ABC arm
had ongoing responses. ORR was 22%. At a median follow-up of 10.1 and 17 
months, PFS was 2 months in the ABC arm versus 1.3 months in the GCB arm 
(p=0.004). Median OS was 10.3 months versus 3.35 months, respectively (p=0.056).
Given the activity of ibrutinib in the ABC subtype of DLBCL (Wilson et al. 2015), a trial 
of R-CHOP with or without ibrutinib is in process (NCT01855750) for untreated 
DLBCL patients. Based on the activity of acalabrutinib in R/R DLBCL (Dyer et al.
2018), acalabrutinib will be studied in combination with rituximab and lenalidomide in
R/R non-GCB DLBCL.
1.6
LENALIDOMIDE IN LYMPHOID CANCERS
Lenalidomide is an immunomodulatory agent with anti-inflammatory and 
antiangiogenic properties. In combination with rituximab, lenalidomide has shown 
promising activity in patients with FL and R/R DLBCL (Wang et al. 2013, Leonard et
al. 2015). In patients with recurrent FL, at a median follow-up of 2.5 years, the ORR 
was 76%, the CR rate was 39%, and the median time to progression was 2 years
(Leonard et al. 2015). Patients with R/R DLBCL, FL, and transformed lymphoma were 
evaluated in a Phase 2 clinical trial that utilized a lenalidomide-rituximab combination
regimen. In this trial, the ORR was 33%, median PFS was 3.7 months, and the 
median OS was 10.7 months (Wang et al. 2013).
These data support the use of the lenalidomide-rituximab combination in patients with 
R/R FL and R/R DLBCL.
1.7
BENEFIT/RISK
Acalabrutinib is a potent, orally administered, small-molecule inhibitor of BTK. In 
Study ACE-CL-001, a study of acalabrutinib in subjects with CLL, including R/R or 

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previously untreated CLL or Richter’s syndrome, no dose-limiting toxicities (DLTs) 
have been reported at dosages of ≤400 mg QD or 100 mg and 200 mg BID. 
Moreover, acalabrutinib has shown activity in other NHL histologies, including DLBCL 
(Dyer et al. 2018). For more detailed information on acalabrutinib clinical experience 
(safety and efficacy), refer to the current Acalabrutinib Investigator Brochure.
Rituximab is a well-established treatment for NHL and has been shown to be well 
tolerated and effective in combination with another BTK inhibitor, ibrutinib, in patients 
with lymphoma (Burger et al. 2014; Wang et al. 2014). In both the treatment-naive 
and R/R setting, rituximab is being given to patients with CD20+ NHL. Based on the 
robust results of acalabrutinib monotherapy in subjects with CLL, MCL, FL, and 
DLBCL and rituximab in NHL, the evaluation of the combination of acalabrutinib and 
rituximab in this study is warranted in these subjects.
In an effort to improve clinical benefit, the addition of ibrutinib to the lenalidomide and 
rituximab regimen has been explored in recent clinical trials. This triplet regimen was 
evaluated in the frontline treatment of FL (Ujjani et al. 2016), and results showed this 
triplet regimen was not superior in efficacy than the lenalidomide-rituximab doublet 
regimen. There was a high incidence of rash (all grades 82%) compared with studies 
of the lenalidomide-rituximab doublet in a similar patient population
(Ujjani et al. 2016), although rash was not a DLT in this study. Of note, patients 
received 90% of the expected dose intensity of rituximab, 93% of ibrutinib, and only 
64% of lenalidomide (Ujjani et al. 2016). There are ongoing trials evaluating the triplet 
combination in R/R DLBCL (NCT02077166). These studies support the exploration of 
acalabrutinib in combination with lenalidomide and rituximab in R/R FL and DLBCL.
1.8
SUMMARY AND CONCLUSIONS
The purpose of Parts 1 and 2 in this study is to evaluate the safety, pharmacokinetics 
(Part 1), pharmacodynamics, and activity of acalabrutinib alone or in combination with 
rituximab in subjects with FL or MZL.
The purpose of Part 3 of this study is to evaluate the safety, activity, 
pharmacokinetics, and pharmacodynamics of acalabrutinib in combination with 
rituximab and lenalidomide in subjects with R/R FL.
The design and conduct of this study is supported by an understanding of the natural 
history and current therapies for subjects with B-cell NHL; knowledge of the efficacy 
and safety of the first-generation BTK inhibitor (e.g., ibrutinib) alone or in combination 

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with rituximab or rituximab and lenalidomide, in subjects with hematologic cancers, 
and the available nonclinical and clinical information regarding acalabrutinib.
2
STUDY OBJECTIVES
2.1
PART 1
2.1.1 Primary Objective

To characterize the safety profile of acalabrutinib alone or in combination with 
rituximab in subjects with R/R FL
2.1.2 Secondary Objectives:

To characterize the safety profile of acalabrutinib in combination with rituximab 
in subjects with previously untreated FL

To characterize the PK profile of acalabrutinib alone or in combination with 
rituximab

To evaluate the PD effects of acalabrutinib alone or in combination with 
rituximab

To evaluate the activity of acalabrutinib alone or in combination with rituximab 
as measured by ORR, DOR, time-to-next treatment, and PFS
2.2
PART 2
Please note that enrollment for Part 2, Cohort 2 (R/R MZL: Acalabrutinib + 
Rituximab) of this study is closed.
2.2.1 Primary Objective

To characterize the activity of acalabrutinib alone or in combination with 
rituximab in subjects with R/R MZL, as measured by ORR
2.2.2 Secondary Objectives

To characterize the safety of acalabrutinib alone or in combination with 
rituximab in subjects with R/R MZL

To evaluate the activity of acalabrutinib alone or in combination with rituximab 
in subjects with R/R MZL, as measured by DOR, PFS, and OS
2.2.3 Exploratory Objectives

 

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
 
 
2.3
PART 3
2.3.1 Primary Objective

To characterize the safety of acalabrutinib in combination with rituximab and 
lenalidomide in subjects with R/R FL
2.3.2 Secondary Objectives:

To characterize the activity of acalabrutinib in combination with rituximab and 
lenalidomide in subjects with R/R FL as measured by ORR, DOR, PFS, and 
OS
2.3.3 Exploratory Objectives:

 
 
 
 
3
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This study will be conducted in 3 parts. Note: Text throughout the protocol applies to 
all parts of the study unless otherwise specified. At the time of Amendment 6, the 
sponsor made the decision to close Part 4 of the study (R/R DLBCL: Acalabrutinib + 
rituximab and lenalidomide).
Part 1
This part of the study is a Phase 1b, multicenter, open-label, randomized, parallel 
group study to be conducted at approximately 11 centers. Two cohorts will be 

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enrolled in parallel: The Relapsed/Refractory Cohort will include approximately 
24 subjects with R/R FL, and the Treatment-Naive Cohort will include 12 subjects
who have not previously been treated for FL. Note: At the time of Amendment 4, 
enrollment in Part 1 has been completed.
Arm 1: Acalabrutinib 100 mg by mouth (PO) BID administered approximately 
12 hours apart (BID dosing=200 mg total daily dose) for 28 days
Arm 2: Acalabrutinib 100 mg PO BID administered approximately 12 hours 
apart (BID dosing=200 mg total daily dose) for 28 days, plus rituximab 
375 mg/m2 intravenous (IV) on Days 1, 8, 15, and 22 of Cycle 1 and Day 1 of 
Cycles 2 through 6
Treatment-Naive Cohort: A total of 12 subjects will receive the combination of 
acalabrutinib and rituximab: acalabrutinib 100 mg PO BID administered 
approximately 12 hours apart (BID dosing=200 mg total daily dose) for 28 days, plus 
rituximab 375 mg/m2 IV on Days 1, 8, 15, and 22 of Cycle 1 and Day 1 of Cycles 2 
through 6.
PK/PD testing will be performed in Cycle 1 and Cycle 2. Tumor assessments will be 
performed at 8- to 24-week intervals during the trial. Refer to Appendix 4 for a 
comprehensive list of study assessments and their timing.
Part 2
This part of the study is a Phase 2, multicenter, open-label, study to be conducted at 
approximately 38 centers. Up to 40 subjects with R/R MZL will be enrolled. Each 
cycle is 28 days. At the time of Amendment 6, the decision was made to close 
Cohort 2.
Cohort 1: Acalabrutinib 100 mg PO BID administered approximately 12 hours 
apart (BID dosing=200 mg total daily dose) for 28 days
Cohort 2: Acalabrutinib 100 mg PO BID administered approximately 12 hours 
apart (BID dosing=200 mg total daily dose) for 28 days, plus rituximab 
375 mg/m2 IV on Days 1, 8, 15, and 22 of Cycle 1 and Day 1 of Cycles 2 through
6.
The study schema for Part 2 of the study is presented in Figure 1.

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administered on Days 1 through 21 of a 28-day cycle.
The study schematic for Part 3 is presented in Figure 2.

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Figure 2
Study Schematic for Part 3
Cycle
1
2
3
4
5
6
8
10
12
14
16
18
20
22
24
26
Acalabrutinib
100 mg PO BID
Until progression or intolerance 
Rituximab
375 mg/m2 IV
Induction regimen
Maintenance regimen
Xa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lenalidomideb
PO D1-21/28d
X
X
X
X
X
X
X
X
X
BID=twice daily; D=day; DLT=dose-limiting toxicity; IV=intravenous; PO=by os (mouth); QD=once a day.
a.
Rituximab will be administered weekly on Day 1 during Cycle 1 and Day 1 of every cycle from Cycles 2 through 6. Subjects who have not progressed will receive 
maintenance rituximab every other cycle starting on Cycle 8 for 10 additional doses until disease progression or intolerance. Lenalidomide is to be taken daily on Days 
1 through 21 of each cycle.
b.
The starting dose of lenalidomide is 15 mg QD and the final dose for the expansion portion of the study will be determined based on the outcome of the DLT review. 
Subjects will receive lenalidomide at the assigned dose or the final dose for up to 12 cycles or until disease progression or intolerance, whichever comes first.

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Acalabrutinib has been used in combination with rituximab at the doses mentioned 
above and this combination has an acceptable safety profile (current version of 
Acalabrutinib Investigator Brochure). There will be an inter-subject dose escalation or 
de-escalation during the DLT review period to find the appropriate dose of lenalidomide 
that can be used in combination with acalabrutinib and rituximab.
DLT review and enrollment are presented in Figure 3 and will be conducted as follows 
(DLT criteria are defined in Section 3.5.5):
Figure 3
Dose-Limiting Toxicity Review and Enrollment for Part 3
DLT=dose-limiting toxicity; QD=once per day.

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Six subjects are planned to be enrolled initially and treated with acalabrutinib, rituximab, 
and lenalidomide (15 mg PO QD) in Cycle 1. At the end of the cycle, subjects will be 
evaluated for DLTs on a rolling basis (Figure 3).

If there are ≥2 subjects with DLTs on 15 mg of lenalidomide QD, the dose of 
lenalidomide will be reduced to 10 mg QD, and 6 more subjects are planned to 
be enrolled at this reduced dose of lenalidomide.
o
If there are ≥2 subjects with DLTs at the end of Cycle 1 on 10 mg 
lenalidomide QD, enrollment will close.
o
If there are <2 of 6 subjects with DLTs, then approximately 14 additional 
subjects will be enrolled and treated with lenalidomide 10 mg QD for Cycles 1 
through 12.

If there are <2 of 6 subjects with DLTs on 15 mg QD, 6 additional subjects are 
planned to be enrolled to receive an increased dose of lenalidomide at 20 mg 
QD.
o
If there are ≥2 subjects with DLTs, the dose of lenalidomide will be reduced 
back to 15 mg QD. Approximately 14 more subjects will be added to 
complete enrollment at the 15-mg QD dose.
o
If there are <2 of 6 subjects with DLTs, 20 mg of lenalidomide will be the 
dose used for Cycles 2 through 12. Approximately 14 more subjects will be 
added to complete enrollment.
Note: Subjects will be evaluated for DLTs at the end of the first cycle, on a rolling basis, 
when they complete a cycle of treatment.
Refer to Appendix 6 for a comprehensive list of study assessments and their timing.
Part 4
At the time of Amendment 6, the sponsor made the decision to close Part 4 cohort to 
enrollment. Therefore, Part 4 has been removed.
All Parts
Twenty-eight days of study drug administration is 1 cycle. Treatment with acalabrutinib 
may be continued until confirmed disease progression or an unacceptable drug-related 
toxicity occurs.
Dose modification provisions are provided in Section 3.5.7. Note: Temporary 
withholding of acalabrutinib for as little as 7 days can cause a transient worsening of 
disease and/or of constitutional symptoms. All subjects who discontinue study drug

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will have a safety follow-up visit 30 (+7) days after the last dose of study drug until 
the final data cut-off regardless of whether the subject receives a new anticancer 
therapy or demonstrates disease progression within this timeframe.
All subjects will have hematology, serum chemistry, hepatitis serology, and urinalysis 
safety panels performed at screening. For Part 1 and Part 2, once dosing commences 
(Day 1), all subjects will be evaluated for safety, including hematology and serum 
chemistry, once weekly for the first 4 weeks, every 2 weeks in Cycle 2, monthly through 
Cycle 13, and then every 3 months thereafter. For Part 3, once dosing commences 
(Day 1), all subjects will be evaluated for safety, including hematology and serum 
chemistry, once weekly for the first 4 weeks, every 2 weeks in Cycle 2, and monthly 
through Cycle 13, and for Part 3, every 8 weeks starting Cycle 14 up to Cycle 28 
(rituximab infusion ends at Cycle 26) and every 3 months thereafter.
Part 3
Pregnancy testing will be performed at baseline, weekly for the first month, and then 
monthly for all females of childbearing potential receiving lenalidomide until 4 weeks 
after the last dose of lenalidomide. In addition, women of childbearing potential must 
use highly effective forms of contraception or abstain from sex during lenalidomide
treatment and for 4 weeks after completion of lenalidomide treatment.
All subjects (males and females) receiving lenalidomide must be enrolled in the 
REVLIMID Risk Evaluation and Mitigation Strategy (REMS) program.
3.1.1 Efficacy Parameters
Standardized response and progression criteria have been established for lymphoma 
(Cheson et al. 2014); assessments of efficacy in this study will be based on these 
criteria. Efficacy endpoints will include:
Part 1

ORR

DOR

PFS

Time-to-next treatment

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Part 2 and Part 3

ORR

DOR

PFS

OS
3.1.2 Safety Parameters
The safety of acalabrutinib alone or in combination with rituximab or rituximab and 
lenalidomide will be characterized by the type, frequency, severity, timing of onset, 
duration, and relationship to study drug of any AEs; serious adverse events (SAEs); or
AEs leading to study treatment delay, dose modification, or discontinuation.
For consistency of interpretation, AEs will be coded using MedDRA, and the severity of 
AEs and laboratory abnormalities will be graded using the Common Terminology Criteria 
for Adverse Events (CTCAE; Part 1 will use Version 4.03 and Parts 2 and 3 will use 
Version 5.0). Standard definitions for seriousness will be applied (see Section 6.2).
3.1.3 Pharmacokinetic, Pharmacodynamic Parameters, and Molecular 
Profiling
Part 1
Standard PK parameters for acalabrutinib in plasma will be evaluated in this study. A full 
description of the PK parameters is provided in Section 5.5.5. The occupancy of BTK by 
acalabrutinib will be measured in peripheral blood mononuclear cells (PBMCs) and bone 
marrow, when available, with the aid of an acalabrutinib analogue probe.
Part 2
No PK analysis will be performed in Part 2. The occupancy of BTK by acalabrutinib will 
be measured in PBMCs and bone marrow, when available, with the aid of an 
acalabrutinib analogue probe.
 
 
Part 3
Sparse acalabrutinib PK samples will be collected and analyzed to investigate the 
relationship between acalabrutinib and its active metabolite (ACP-5862) concentration 
and response. The occupancy of BTK by acalabrutinib will be measured in PBMCs and 
bone marrow, when available, with the aid of an acalabrutinib analogue probe.
 

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3.2
END OF STUDY
The final data cut-off to support final database lock will be based on the projected median 
follow-up of approximately 30 months for subjects in Part 2 which is projected to occur 
approximately 23 months after last subject first dose, this is estimated to be approximately 
25 August 2023. A median follow-up of approximately 30 months is deemed adequate 
follow-up for the FL and MZL population in this study. In addition to the above, a final data 
cut to support Part 1 final database lock will occur approximately 71 months after last 
subject first dose in Part 1; this is expected to provide adequate long-term follow up for the 
FL subjects enrolled in the study. 
A Clinical Study Report (CSR) will be written using the final data cut-off for Part 1 and a 
second CSR will be written using the final data cut-off for Parts 2 and 3.
The end of the study is defined as the final data cut-off for the final analysis. 
AstraZeneca will continue to supply acalabrutinib in the continued access phase of this 
study and after completion of this study while, in the opinion of the investigator, the subject
is benefitting.
In the event that product development reaches a point where alternative product supply 
options become available, then these alternative product supply options will be 
discussed by the Sponsor with the investigator. The Sponsor will work with the 
investigator to transition the subject(s) to alternative supply, where possible.
It is recommended that investigators continue to observe ongoing subjects at the 
frequency employed prior to the primary DCO. 
Protocol dose modification and stopping criteria are to be followed while a subject is 
receiving acalabrutinib. A change in the dose/schedule of acalabrutinib should only 
occur for safety reasons, based on the investigator’s judgement, and should generally 
follow the approach for dose reduction and discontinuation as described in this protocol.
After the final DCO, the clinical database will close to new data, however SAEs must 
continue to be reported.  Subjects may be withdrawn from the study at this time; 
however, they may remain on study treatment beyond closure of the database if, in the 
opinion of the Investigator, the subject continues to receive benefit from study treatment.  
Any subject who is eligible to continue receive acalabrutinib after database closure is 
considered to have completed the study when he/she meets one of the discontinuation 

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criteria listed in Section 3.8.
Dispensation and reconciliation of the investigational product will be handled by the 
study site at each subject’s visit. The investigational product accountability information 
must be collected until all subjects have completed treatment.
For the purpose of Clinical Trial Transparency (CTT) the definition of the end of the 
study differs under FDA and EU regulatory requirements:
European Union requirements define study completion as the last visit of the last subject 
for any protocol related activity.
Food and Drug Administration requirements defines two completion dates:
Primary Completion Date – the date that the final subject is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure 
with different completion dates, this term refers to the date on which data collection is 
completed for all of the primary outcomes.
Study Completion Date – the date the final subject is examined or receives an 
intervention for purposes of final collection of data for the primary and secondary 
outcome measures and AEs (for example, last subject’s last visit), whether the clinical 
study concludes according to the pre-specified protocol or is terminated.
3.3
RATIONALE FOR STUDY DESIGN AND DOSING REGIMEN
As described in Section 1.7, data from an FIH study (ACE-CL-001) in subjects with R/R 
CLL have shown that acalabrutinib is well tolerated at dosages from 100 mg to 400 mg 
QD or 100 mg to 200 mg BID. In addition, data from ACE-CL-001 showed that BTK 
occupancy with acalabrutinib in peripheral blood is >95% at 4 hours after QD dosing but 
decreases to <95% at 24 hours with QD dosing; whereas, with BID dosing, complete 
BTK occupancy (95% to 99%) is maintained over 24 hours at steady state (Byrd et al.
2016). These data suggest that de novo synthesis of BTK can occur within 24 hours in
peripheral blood cells. BID dosing may ensure BTK inhibition for the entire 24 hours, 
which may be beneficial in terms of increased efficacy and/or decreased development of 
resistance to acalabrutinib.
Rituximab is indicated for subjects with a variety of CD20+ NHLs as a single agent and in 
combination with chemotherapy. The Rituxan/MabThera package insert recommends a 
dose of 375 mg/m2 given weekly for 4 or 8 weeks in R/R FL with optional extended 

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dosing. The weekly dosing regimen has been studied in combination with the BTK 
inhibitor, ibrutinib, in CLL and MCL (Burger et al. 2014, Wang et al. 2014). In both 
untreated and R/R FL, ongoing Phase 3 clinical trials of rituximab and lenalidomide are 
utilizing a regimen of 375 mg/m2 rituximab weekly for the first 4 weeks (Cycle 1) and
then once per cycle for the next 4 to 5 cycles (NCT01476787, NCT01650701, 
NCT01938001). Therefore, Part 1 of this study has been designed to evaluate the 
safety, pharmacokinetics, pharmacodynamics, and activity of acalabrutinib alone or in 
combination with rituximab in subjects with R/R FL; Part 2 has been designed to 
evaluate the activity, safety, and pharmacodynamics of acalabrutinib alone or in 
combination with rituximab in subjects with R/R MZL. The dosing regimen will be 
100 mg acalabrutinib BID administered orally and 375 mg/m2 rituximab weekly 
administered intravenously for the first 4 weeks (Cycle 1) and then once per cycle for the 
next 5 cycles for both Part 1 and Part 2 of the study.
In Part 3 of the study, the rituximab regimen will be administered at 375 mg/m2 IV weekly 
for the first 4 weeks in Cycle 1, then on Day 1 of every cycle from Cycles 2 through 6, 
followed by maintenance rituximab every other cycle beginning with Cycle 8 for subjects 
who have not progressed.
Lenalidomide is indicated for subjects with multiple myeloma, myelodysplastic syndrome 
(MDS) with deletion 5q, and MCL (Revlimid package insert). The monotherapy dose 
ranges from 10 mg for MDS to 25 mg for MM and MCL. In the study combining 
lenalidomide with rituximab for R/R FL, lenalidomide was started at 15 mg in Cycle 1 and 
then escalated to 20 mg in Cycles 2 through 12 for 21 of 28 days with an ORR of 76% in 
combination with rituximab compared with 53% for lenalidomide alone (Leonard et al. 
2015). In untreated patients with FL, ibrutinib was added to lenalidomide and rituximab.
Similarly, the starting dose of lenalidomide was 15 mg with dose escalated to 20 mg for 
21 of 28 days with rituximab and ibrutinib. The combination was not more efficacious
than rituximab-lenalidomide. There were no protocol-defined DLTs; however, increased 
toxicity (rash 82%, diarrhea 64%, and fatigue 59%) and dose modifications were 
required in this untreated FL group, so a subsequent study is not planned. Of note, in 
patients with previously untreated FL receiving ibrutinib in combination with rituximab 
and lenalidomide, patients received 90% of the expected dose intensity of rituximab,
93% of ibrutinib, and only 64% of lenalidomide (Ujjani et al. 2016). Given this 
experience, Part 3 of this study will start with 15 mg of lenalidomide to be combined with
acalabrutinib and rituximab. For Part 3, lenalidomide will be given on Days 1 through 21 
of a 28-day cycle up to 12 cycles or until disease progression or an unacceptable toxicity 

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occurs, whichever comes first.
3.4
SELECTION OF STUDY POPULATION
3.4.1 Inclusion Criteria Part 1
Eligible subjects will be considered for inclusion in this study if they meet all of the 
following criteria:
1. Men and women ≥18 years of age.
2. Relapsed/Refractory Cohort: A confirmed diagnosis of FL Grade 1, 2, or 3a that has 
relapsed after, or been refractory to ≥1 prior therapy for FL and which requires 
treatment per National Cancer Institute or International Working Group guidelines. 
Documented failure to achieve at least PR with, or documented disease progression 
after, the most recent treatment regimen.
Treatment-naive Cohort: A confirmed diagnosis of FL Grade 1, 2, or 3a that requires 
treatment per National Cancer Institute or International Working Group guidelines in 
subjects who have not previously received systemic anticancer therapy for FL.
3. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid 
malignancy (defined as the presence of ≥1 lesion that measures ≥2.0 cm in the 
longest dimension and ≥1.0 cm in the longest perpendicular dimension as assessed 
by computed tomography [CT] scan).
4. ECOG performance status of ≤2.
5. Agreement of women of childbearing potential (WOCBP) to use highly effective
methods of contraception during the study and for 2 days after the last dose of 
acalabrutinib or 3 months after the last dose of rituximab, whichever is longer, if 
sexually active and able to bear or beget children. Highly effective forms of 
contraception are defined in Section 3.7.6.
6. Men must agree to refrain from sperm donation during the study and for 3 months 
after the last dose of rituximab.
7. Willing and able to participate in all required evaluations and procedures in this study 
protocol including swallowing capsules or tablets without difficulty.
8. Ability to understand the purpose and risks of the study and provide signed and 
dated informed consent and authorization to use protected health information (in 
accordance with national and local patient privacy regulations).
3.4.2 Exclusion Criteria Part 1

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Subjects will be ineligible for this study if they meet any of the following criteria:
1. Prior malignancy (other than indolent B-cell NHL), except for adequately treated 
basal cell or squamous cell skin cancer, in situ cancer, or other cancer from which 
the subject has been disease free for ≥2 years.
2. Known CNS lymphoma or leptomeningeal disease.
3. A life-threatening illness, medical condition, or organ system dysfunction which, in 
the investigator’s opinion, could compromise the subject’s safety, interfere with the 
absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.
4. Known history of a bleeding diathesis (e.g., hemophilia, von Willebrand disease).
5. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
congestive heart failure, or myocardial infarction within 6 months of screening, or any 
Class 3 or 4 cardiac disease as defined by the New York Heart Association 
Functional Classification, or corrected QT interval (QTc) >480 msec.
6. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or 
resection of the stomach or small bowel, gastric bypass, symptomatic inflammatory 
bowel disease, or partial or complete bowel obstruction.
7. Any immunotherapy within 4 weeks of first dose of study drug.
8. Relapsed/Refractory Cohort: The time from the last dose of the most recent 
chemotherapy or experimental therapy to the first dose of study drug is <5 times the 
half-life of the previously administered agent(s).
9. Prior exposure to a BCR inhibitor (e.g., BTK, phosphonositide-3 kinase [PI3K], or 
spleen tyrosine kinase [SYK] inhibitors) or BCL-2 inhibitor (e.g., venetoclax).
10. Known history of anaphylaxis or hypersensitivity to rituximab (Rituxan/MabThera) or 
any of its components.
11. Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids 
for treatment of FL or other conditions. Note: Subjects may use topical or inhaled 
corticosteroids or low-dose steroids (≤20 mg of prednisone or equivalent) as
therapy for comorbid conditions. During study participation, subjects may also 
receive systemic or enteric corticosteroids as needed for treatment-emergent
comorbid conditions.
12. Grade ≥2 toxicity (other than alopecia) continuing from prior anticancer therapy 
including radiation.
13. Known history of HIV or active infection with hepatitis C virus (HCV) or any 
uncontrolled active systemic infection.

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14. Known hepatitis B infection or positive for hepatitis B surface antigen (HBsAg) or 
hepatitis B core antibody (anti-HBc). Since intravenous immunoglobulins (IVIG) may 
cause false positive hepatitis serology, subjects who are receiving prophylactic IVIG 
and have positive HBsAg or anti-HBc must have negative hepatitis B DNA to be 
eligible.
15. Major surgery within 4 weeks before first dose of acalabrutinib.
16. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.
17. History of stroke or intracranial hemorrhage within 6 months before the first dose of 
acalabrutinib.
18. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonist 
(e.g., phenprocoumon) within 7 days of first dose of study drug.
19. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: this criterion 
no longer applies to subjects who have switched from acalabrutinib capsules to 
tablets. 
20. Received a live virus vaccination within 28 days of first dose of study drug.
21. ANC <0.75 × 109/L or platelet count <50 × 109/L. For subjects with documented 
disease involvement in the bone marrow, ANC <0.50 × 109/L or platelet count
<30 × 109/L.
22. Creatinine >2.5 × institutional upper limit of normal (ULN); total bilirubin >2.5 × ULN; 
and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3.0 × 
ULN.
23. Breastfeeding or pregnant.
24. Concurrent participation in another therapeutic clinical trial.
25. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before 
screening.
3.4.3 Inclusion Criteria Part 2
Eligible subjects will be considered for inclusion in this study if they meet all of the 
following criteria:
1. Men and women ≥18 years of age.
2. Histologically confirmed MZL including splenic, nodal, and extranodal sub-types
a. Subjects with splenic MZL must have an additional measurable lesion, nodal 
or extranodal, as described in inclusion criterion #4;

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b. Subjects with gastric MALT lymphoma must be H. pylori-negative (including 
subjects after successful elimination of H. pylori) or refractory to H.
pylori-eradication therapy by a minimum time of 12 months by a pathology 
confirmation or by a 13C urea test (proton-pump inhibitors and H2 blockers 
should be discontinued or withheld for at least 14 days and 7 days, 
respectively, and antibiotics for treating H. pylori, such as those with anti-
helicobacter action and bismuth preparations, should be withdrawn at least 
30 days before H. pylori testing [Savarino et al. 1999]).
3. Previous therapy:
a. Cohort 1: Previously received 1 or more lines of systemic therapy including 
at least 1 CD20-directed regimen (either as monotherapy or as 
chemoimmunotherapy for MZL) with documented failure to achieve at least 
PR, or documented disease progression after the most recent treatment 
regimen.
b. Cohort 2: Previously received 1 or more lines of therapy including at least
1 prior systemic therapy for MZL or radiation therapy with documented failure 
to achieve at least PR, or document disease progression after the most 
recent treatment regimen.
4. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid 
malignancy (defined as the presence of ≥1 lesion that measures ≥2.0 cm in the 
longest dimension and ≥1.0 cm in the longest perpendicular dimension as assessed 
by CT scan). Lesions in anatomical locations, such as extremities or soft tissue 
lesions, that are not well visualized by CT may be measured by magnetic resonance 
imaging (MRI) instead; subjects with spleen-only disease are considered as not 
having measurable disease.
5. ECOG performance status of ≤2.
6. WOCBP must agree to use highly effective methods of contraception during the
study and for 2 days after the last dose of acalabrutinib or 12 months after the last 
dose of rituximab, whichever is longer, if sexually active and able to bear or beget 
children. Highly effective methods of contraception are defined in Section 3.7.6.
7. Men must agree to refrain from sperm donation during the study and for 3 months 
after the last dose of rituximab.
8. Willing and able to participate in all required evaluations and procedures in this study 
protocol including swallowing capsules or tablets without difficulty.
9. Ability to understand the purpose and risks of the study and provide signed and 

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dated informed consent and authorization to use protected health information (in 
accordance with national patient privacy regulations).
3.4.4 Exclusion Criteria Part 2
Subjects will be ineligible for this study if they meet any of the following criteria:
1. Prior malignancy (other than indolent B-cell NHL), except for adequately treated 
basal cell or squamous cell skin cancer, in situ cancer, or other cancer from which 
the subject has been disease free for ≥2 years.
2. Known medically apparent CNS lymphoma or leptomeningeal disease.
3. Known evidence of transformation to another aggressive lymphoma.
4. A life-threatening illness, medical condition, or organ system dysfunction which, in 
the investigator’s opinion, could compromise the subject’s safety, interfere with the 
absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.
5. Known history of a bleeding diathesis (e.g., hemophilia, von Willebrand disease).
6. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
congestive heart failure, or myocardial infarction within 6 months of screening, or any 
Class 3 or 4 cardiac disease as defined by the New York Heart Association 
Functional Classification, or corrected QT interval using Fridericia formula
(QTcF) >480 msec.
7. Malabsorption syndrome, disease significantly affecting gastrointestinal function 
(excluding gastric MALT), or resection of the stomach or small bowel, gastric bypass, 
symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
8. This criterion was removed under Amendment 5.
9. This criterion was removed under Amendment 5.
10. Prior exposure to a BCR inhibitor (e.g., BTK, or SYK inhibitors).
11. For Cohort 2, evidence of CD20−MZL and/or known history of anaphylaxis or 
hypersensitivity to rituximab (Rituxan/MabThera) or any of its components.
12. Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids 
for treatment or other conditions within 1 week before the first dose of study drug. 
Note: Subjects may use topical or inhaled corticosteroids or low-dose steroids 
(≤20 mg of prednisone or equivalent for up to 2 weeks) as therapy for comorbid 
conditions. However, subjects requiring systemic steroids at daily doses >20 mg 
prednisone equivalent of systemic exposure are not allowed.
13. Grade ≥2 toxicity (other than alopecia or laboratory value requirements mentioned in 

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Part 2) continuing from prior anticancer therapy including radiation.
14. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as 
exhibiting ongoing signs/symptoms related to the infection and without improvement, 
despite appropriate antibiotics or other treatment), or intravenous anti-infective 
treatment within 2 weeks before first dose of study drug.
15. Known history of infection with HIV.
16. Serologic status reflecting active hepatitis B or C infection.
a. Subjects who are anti-HBc positive and who are surface antigen negative will 
need to have a negative hepatitis B virus (HBV) DNA polymerase chain 
reaction (PCR) result before enrollment. Subjects who are HBsAg positive or 
hepatitis B PCR positive will be excluded.
b. Subjects who are anti-HCV positive will need to have a negative PCR result 
before enrollment. Subjects who are hepatitis C PCR positive will be 
excluded.
17. History of allogeneic stem cell (or organ) transplantation.
18. This criterion was removed under Amendment 5.
19. Major surgery within 4 weeks before first dose of acalabrutinib.
20. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.
21. History of stroke or intracranial hemorrhage within 6 months before the first dose of 
acalabrutinib.
22. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonist 
(e.g., phenprocoumon) within 7 days of first dose of study drug.
23. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: this criterion 
no longer applies to subjects who have switched from acalabrutinib capsules to 
tablets.
24. Received a live virus vaccination within 28 days of first dose of study drug.
25. ANC <1.0 × 109/L or platelet count <100 × 109/L. For subjects with documented 
disease involvement in the bone marrow, ANC <0.50 × 109/L or platelet count
<30 × 109/L.
26. Creatinine >1.5 × institutional ULN; total bilirubin >1.5 × ULN; and AST or ALT
>2.5 × ULN.
27. Breastfeeding or pregnant.
28. Concurrent participation in another therapeutic clinical trial.

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29. In the absence of gastric MALT (subject to inclusion criterion 2b) presence of a 
gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening or 
diagnosed >3 months before screening and without confirmed resolution by 
endoscopy.
30. Received any chemotherapy, external beam radiation therapy, anticancer antibodies, 
or investigational drug within 30 days before first dose of study drug.
31. History of or ongoing progressive multifocal leukoencephalopathy (PML).
3.4.5 Inclusion Criteria Part 3
Eligible subjects will be considered for inclusion in this study if they meet all of the 
following criteria.
1. Men and women ≥18 years of age.
2. For subjects with FL: Pathologically confirmed diagnosis of FL Grade 1, 2, or 3a that 
has relapsed after, or been refractory to, ≥1 prior therapy for FL and which requires 
treatment per National Cancer Institute or European Society for Medical Oncology 
(ESMO) clinical practice guidelines.
3. This criterion was removed under Amendment 6.
4. Subjects must have previously received at least 1 frontline standard 
chemoimmunotherapy regimen.
5. Subjects with suspected residual disease after the treatment regimen directly 
preceding study enrollment must have biopsy-demonstrated residual FL.
6. Documented R/R disease, defined as either: 1) recurrence of disease after a CR or 
PR, or 2) stable disease or progressive disease at completion of the treatment 
regimen preceding entry to the study (residual disease).
7. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid 
malignancy (defined as the presence of ≥1 lesion that measures ≥2.0 cm in the 
longest dimension and ≥1.0 cm in the longest perpendicular dimension as assessed 
by CT scan).
8. ECOG performance status of ≤2.
9. Females of reproductive potential must
a. have 2 negative pregnancy tests prior to initiating treatment with lenalidomide. 
The first should be within 10 to 14 days and the second test within 24 hours prior 
to first dose of lenalidomide.
b. commit to abstain continuously from heterosexual sex or use highly effective

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methods of contraception. Contraception must be used beginning 4 weeks prior 
to initiating treatment with lenalidomide, during therapy with any study drug,
and during dose interruptions for lenalidomide. Contraception must be used for 
2 days after the last dose of acalabrutinib,12 months after the last dose of 
rituximab, or 4 weeks after the last dose of lenalidomide, whichever is later.
10. Men must agree to use a synthetic or latex condom during any sexual contact with 
female of reproductive potential or with a pregnant partner while taking lenalidomide
and for up to 4 weeks after last dose of lenalidomide, even if they have undergone a 
successful vasectomy since lenalidomide is present in the semen. Men must agree 
to refrain from sperm donation during the study and for 3 months after the last dose 
of rituximab or 4 weeks after the last dose of lenalidomide, whichever is later.
11. Subjects must not donate blood during treatment with lenalidomide and for 4 weeks 
after discontinuation of lenalidomide.
12. Willing and able to participate in all required evaluations and procedures in this study 
protocol including swallowing capsules or tablets without difficulty.
13. Ability to understand the purpose and risks of the study and provide signed and 
dated informed consent and authorization to use protected health information (in 
accordance with national patient privacy regulations).
3.4.6 Exclusion Criteria Part 3
1. Prior malignancy, except for adequately treated basal cell or squamous cell skin 
cancer, in situ cancer, or other cancer from which the subject has been disease free 
for ≥2 years.
2. Subjects for whom the goal of therapy is tumor debulking before stem cell transplant.
3. Known history or presence of CNS lymphoma or leptomeningeal disease.
4. Transformed DLBCL or DLBCL with coexistent histologies (e.g., FL or 
mucosa-associated lymphoid tissue and primary mediastinal large B-cell lymphoma 
[PMBCL]).
5. A life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety, interfere with the 
absorption or metabolism of acalabrutinib or lenalidomide, or put the study outcomes 
at undue risk.
6. Known history of a bleeding diathesis (e.g., hemophilia, von Willebrand disease).
7. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
congestive heart failure, or myocardial infarction within 6 months of screening, or any 

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Class 3 or 4 cardiac disease as defined by the New York Heart Association 
Functional Classification, or QTcF >480 msec. Exception: Subjects with controlled, 
asymptomatic atrial fibrillation during screening are allowed to be enrolled on study.
8. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or 
resection of the stomach or small bowel, gastric bypass, symptomatic inflammatory 
bowel disease, or partial or complete bowel obstruction.
9. Received any chemotherapy, external beam radiation therapy, anticancer antibodies, 
or investigational drug within 30 days before first dose of study drug.
10. Prior exposure to a BCR inhibitor (e.g., BTK or SYK inhibitors), lenalidomide, or 
CAR-T cell therapy.
11. Known history of anaphylaxis or hypersensitivity to rituximab (Rituxan/MabThera) or 
any of its components.
12. Subjects with a prior history of Grade 4 rash associated with thalidomide treatment.
13. Ongoing immunosuppressive therapy, including systemic (e.g., IV or oral) 
corticosteroids within 2 weeks before the first dose of study drug. Note: Subjects 
may use topical or inhaled corticosteroids or low-dose steroids (≤20 mg prednisone 
equivalent/day for ≤2 weeks) as a therapy for comorbid conditions. During study 
participation, subjects may also receive systemic (e.g., IV or oral) corticosteroids as 
needed for treatment-emergent comorbid conditions.
14. Grade ≥2 toxicity (other than alopecia or laboratory value requirements mentioned in 
Part 3 exclusion criteria) continuing from prior anticancer therapy including radiation.
15. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined
as exhibiting ongoing signs or symptoms related to the infection and without 
improvement, despite appropriate antibiotics or other treatment), or intravenous 
anti-infective treatment within 2 weeks before first dose of study drug.
16. Known history of infection with HIV.
17. Serologic status reflecting active hepatitis B or C infection.
a. Subjects who are anti-HBc positive and who are surface antigen negative will 
need to have a negative PCR result before enrollment. Subjects who are 
HBsAg positive or hepatitis B PCR positive will be excluded.
b. Subjects who are HCV antibody (anti-HCV) positive will need to have a negative 
PCR result before enrollment. Subjects who are HCV PCR positive will be 
excluded.
18. History of allogeneic stem cell (or organ) transplantation.

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19. Major surgery within 4 weeks before first dose of acalabrutinib.
20. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.
21. History of stroke or intracranial hemorrhage within 6 months before the first dose of 
acalabrutinib.
22. Requires or has received anticoagulation with warfarin or equivalent vitamin K 
antagonist (e.g., phenprocoumon) within 7 days of first dose of study drug.
23. Received a live virus vaccination within 28 days of first dose of study drug.
24. ANC <1.0 × 109/L or platelet count <75 × 109/L. Subjects will only be considered 
eligible if peripheral blood counts can be maintained independent of growth factors or 
transfusions during screening.
25. Creatinine clearance of <60 mL/min, calculated using the formula of Cockcroft and 
Gault [(140-Age) * Mass (kg)/(72 * creatinine mg/dL) * 0.85 if female].
26. Total bilirubin >1.5 × ULN, or AST or ALT >2.5 × ULN, unless directly attributable to 
Gilbert’s syndrome.
27. Requires treatment with a strong CYP3a inhibitor/inducer.
28. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole or pantoprazole). Subject receiving 
proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible 
for enrollment to this study. Note: this criterion no longer applies to subjects who 
have switched from acalabrutinib capsules to tablets.
29. Breastfeeding or pregnant.
30. Concurrent participation in another therapeutic clinical trial.
31. History of or ongoing PML.
3.4.7 Replacement of Subjects
Part 1 and Part 2
Any subject who does not complete Cycle 2 may be replaced at the discretion of the 
study investigator and sponsor. Should the decision be made to replace a subject, the 
replacement subject will be assigned to the same treatment combination regimen as the 
original subject.
Part 3
Any subject who does not complete study therapy through Cycle 1 for reasons other 
than the occurrence of a DLT may be replaced at the discretion of the study investigator 
and sponsor. Should the decision be made to replace a subject, the replacement 

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subject will be assigned to the same treatment combination regimen as the original 
subject.
3.4.8 Enrollment and Procedures
Part 1
Enrollment of a subject into the study will be performed according to the following 
procedure:

The study center will notify the sponsor when a clinically eligible subject is 
identified and is ready to screen, to ensure enrollment availability on the study.

After the subject has signed and dated the Informed Consent Form (ICF), all 
screening procedures have been completed, and eligibility has been confirmed, 
the subject can be officially enrolled in the study.

To enroll a subject and confirm eligibility, the study center will fax/email a
completed Enrollment Confirmation Form to the sponsor. The enrollment date 
will be the date that the form is faxed/emailed to the sponsor.

An Enrollment Confirmation Form will be completed and faxed/emailed to the 
study center by the sponsor within 24 hours.

The Enrollment Confirmation Form will contain treatment allocation generated by 
the sponsor.

The sponsor will aim to fax/email a completed Enrollment Confirmation Form to 
the study center within 24 hours of receipt.
Treatment must begin within the screening window (Section 4.1) and after the site has 
received the treatment allocation from the sponsor. Study treatment is not blinded on 
this study.
Part 2 and Part 3
Subjects will be enrolled in Part 2 and Part 3 according to the following procedure:

The Sponsor’s clinical team will inform all sites which part of the study is
open for enrollment.

The study center will notify and obtain an approval of the histology from the 
sponsor when a potential subject is identified and ready to be screened.

After the subject has signed and dated the ICF, all screening procedures have 
been completed, and eligibility has been confirmed, the subject can be officially 
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
To enroll a subject and confirm eligibility, the study center will fax/email a 
completed Enrollment Confirmation Form to the sponsor. The enrollment date 
will be the date that the form is faxed/emailed to the sponsor.

The sponsor will aim to fax/email a signed and completed Enrollment 
Confirmation Form to the study center within 24 hours of receipt.
Study treatment must begin within the screening window (Section 4.1).
3.5
STUDY DRUG
3.5.1 Premedications
No specific premedications or supporting medications are required in conjunction with 
acalabrutinib administration.
Prior to each rituximab infusion, subjects should be premedicated according to the 
Rituxan/MabThera package insert and institutional standard practices (e.g., with 
acetaminophen and an antihistamine). The Rituxan package insert warns that “Rituxan 
administration can result in serious, including fatal infusion reactions. Deaths 
within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal 
infusion reactions occurred in association with the first infusion. Monitor patients 
closely. Discontinue Rituxan infusion for severe reactions and provide medical 
treatment for Grade 3 or 4 infusion reactions.”
Subjects receiving lenalidomide are at risk for venous and arterial thromboembolism and 
should receive low-dose aspirin as prophylaxis. Subjects at high risk for venous and 
arterial thromboembolism should receive additional prophylaxis including low molecular 
weight heparin, per the discretion of the investigator. High-risk subjects are those with a 
family history of venous thromboembolism, smoker, oral contraceptives, history of 
diabetes mellitus or coronary artery disease, and signs and symptoms of 
thromboembolism.
AEs of tumor lysis syndrome (TLS) have been observed in subjects treated with 
lenalidomide. Subjects at risk for TLS should be given TLS prophylaxis per institutional 
standard of care.
3.5.2 Formulation, Packaging, and Storage
Acalabrutinib is manufactured according to cGMP regulations and will be provided to the 
investigational site by the Sponsor or designee. Acalabrutinib should be stored 
according to the instructions on the label that is affixed to the package containing the 
drug product.

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As of Clinical Study Protocol (CSP) Version 8.0, acalabrutinib is supplied in 
2 formulations (hard gelatin capsules or orange film-coated tablets) for oral 
administration. Acalabrutinib capsules and tablets are bioequivalent. Each 
acalabrutinib capsule or tablet contains 100 mg of drug substance and standard
pharmaceutical grade excipients. Acalabrutinib will be provided in white, high-
density polyethylene bottles.
If a drug shipment arrives damaged, or if there are any other drug complaints, a Product 
Complaint Form should be completed and emailed or faxed to the Sponsor or the 
Sponsor’s representative.
Refer to the Acalabrutinib Investigator Brochure for additional information.
Rituximab (Rituxan/MabThera) injection is a commercial product (Genentech, Inc., South 
San Francisco, CA/Roche, Basal Switzerland). Rituximab is available in 100 mg/10 mL 
single-use vials and 500 mg/50 mL single-use vials.
Lenalidomide (Revlimid®) is a commercial product (Celgene, Inc, Summit, NJ). 
Lenalidomide is available as capsules containing 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 
and 25 mg of drug substance.
Refer to product information from the manufacturers for details on formulation, 
packaging, and storage of rituximab and lenalidomide.
3.5.3 Administration of Study Drug
Investigators are prohibited from supplying acalabrutinib to any subjects not properly 
enrolled in this study. The investigator must ensure that subjects receive acalabrutinib 
only from personnel who fully understand the procedures for administering the drug.
Acalabrutinib is intended to be administered orally with 8 ounces (approximately 240 mL) 
of water. Acalabrutinib taken with an acidic beverage may impact exposure to 
acalabrutinib (refer to the current Acalabrutinib Investigator brochure). Acalabrutinib
may be administered without regard to food. The capsules or tablets should be 
swallowed intact and subjects should not attempt to open capsules or crush tablets, and 
both formulations should not be dissolved in water.
Acalabrutinib should be taken BID, approximately 12 hours apart. Dietary restrictions 
are provided in Section 3.7.4.
If a dose is missed, it can be taken within 3 hours after the scheduled time with a return 
to the normal schedule with the following dose. If the time from the scheduled time of 

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administration has been >3 hours, the dose should not be taken, and the subject should 
take the next dose. The missed dose will not be made up and must be returned to the 
site at the next scheduled visit.
Rituximab is to be administered as an IV infusion, not an IV push or bolus. Detailed 
instructions for the preparation and administration of rituximab are provided in the 
Rituxan/MabThera package insert and per institutional standards. No dose reductions 
for rituximab are allowed. On days when both acalabrutinib and rituximab are 
administered, the rituximab infusion should begin approximately 1 hour after the 
acalabrutinib dose.
Subjects will continue on acalabrutinib after completion of rituximab treatment or may do 
so if rituximab is discontinued due to intolerability at any time in the study.
Lenalidomide is to be administered orally at approximately the same time each day, 
either with or without food. The capsules should be swallowed whole with water. The 
capsules should not be opened, broken, or chewed. Lenalidomide is administered for 
the first 21 days of each 28-day cycle. On days that both acalabrutinib and lenalidomide 
are administered, lenalidomide should be taken approximately 30 minutes prior to the 
first daily dose of acalabrutinib. Dose modification provisions are provided in
Section 3.5.7.
3.5.4 Assuring Subject Compliance
Subjects will receive their supply of acalabrutinib in the clinic on Day 1 of Cycle 1 and 
Cycle 2, and Day 1 of subsequent scheduled visits. For treatments that are taken in the 
clinic, subjects should take acalabrutinib from the drug dispensed for them for that 
particular time period. All other acalabrutinib treatments will be taken at home. Subjects 
will receive a diary to record the specific time each dose was taken and to record 
reasons for any missed doses.
Subject compliance will be assessed at every visit. The subject will be instructed to 
bring the diary and any remaining capsules or tablets to the clinic at their next visit.
The administrator will review the diary and ask the subject if all the capsules or tablets 
were administered. Any remaining or returned capsules and tablets will be counted 
and recorded as described in Section 7.11. Returned capsules and tablets must not be 
redispensed to another subject. The study staff will resupply the subject with the
correct number of capsules or tablets needed for use until the next visit.
3.5.5 Definition of Dose-limiting Toxicity (Part 3)
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during the DLT review period. (Note: AEs clearly related to disease progression or the 
subject’s medical history and associated comorbidities considered by the investigator to 
be unrelated to study drugs, will not be considered DLTs. Infusion reactions clearly 
associated with rituximab infusion will not be considered DLTs.):
1. Non-hematologic DLTs include:
a) Grades 3 or 4 nausea, vomiting, or diarrhea lasting >7 days despite optimal 
antiemetic or antidiarrhea management or any Grade 3 or Grade 4 toxicity
b) Any grade Stevens-Johnson syndrome or toxic epidermal necrolysis
c) AST or ALT >3 × ULN concurrently with total bilirubin >2 × ULN
d) Clinical TLS not resolving to baseline after a 2-week treatment delay
•
Exceptions are deep vein thrombosis (DVT), correctable electrolyte 
abnormalities, or Grade 3 or Grade 4 laboratory abnormalities lasting ≤7 days; 
Grades 3 or 4 fatigue, anorexia, non-neutropenic fever, Grade 3 rash resolving to 
Grade 2 within 10 days (allowed therapy with steroids)
2. Hematologic DLTs include:
a) Grade 3 or Grade 4 neutropenia with fever ≥38.5°C or infection, or Grade 4 
neutropenia lasting >7 days despite adequate granulocyte-colony stimulating 
factors (G-CSF) use
b) Grade 3 or Grade 4 thrombocytopenia with hemorrhage. If thrombocytopenia 
improves to Grade ≤2 or to ≥80% of the baseline value within 28 days, 
without a platelet transfusion, this will not be considered a DLT
c) Any Grade 4 hematologic toxicity unrelated to the underlying disease
3. Any study drug-related Grade 5 AE
4. Any study drug-related toxicity leading to an individual drug dose delay of 
>21 consecutive days for acalabrutinib or >14 consecutive days for lenalidomide 
will be considered as a DLT. Subjects should receive at least one dose of 
rituximab in Cycle 1 to be evaluable for a DLT.
3.5.6 Dose Delays
Study treatment with acalabrutinib, rituximab, lenalidomide (if applicable), or combination 
treatment should be held for any unmanageable, potentially study drug-related toxicity 
that is Grade ≥3 in severity. Any other clinically important events where dose delays 
may be considered appropriate by the investigator must be discussed with the medical 
monitor. Study drug may be held for a maximum of 28 consecutive days from expected 

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dose due to toxicity. Study treatment should be discontinued in the event of a toxicity 
lasting >28 days, unless reviewed and approved by the medical monitor.
Note: Temporary withholding of acalabrutinib for as little as 7 days can cause a 
transient worsening of disease and/or of constitutional symptoms.
3.5.7 Dose Modification and Discontinuation
All acalabrutinib dose modifications (Table 1 and Table 2) should be discussed with the 
medical monitor prior to instituting changes. For toxicities that are common to both 
acalabrutinib and lenalidomide, consider adjusting the dose of lenalidomide before 
adjusting the dose of acalabrutinib per the recommendations below:

Grade 4 neutrophil count decreases (ANC <500/μL) for >7 days (hematopoietic 
colony-stimulating factors are permitted per American Society of Clinical 
Oncology [ASCO] guidelines] and use must be recorded on the electronic case 
report form [eCRF])

Grade 3 platelet count decreases in the presence of significant bleeding

Grade 4 platelet count decreases

Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal 
antiemetic and/or antidiarrheal therapy

Any other Grade 4 toxicity or unmanageable Grade 3 toxicity
Table 1
Drug Modification and Discontinuation Actions for Acalabrutinib (in 
Combination with Lenalidomide)
Occurrence
Action
1st–2nd
Hold acalabrutinib until recovery to Grade ≤2 or baseline; may restart at 
original dose level (100 mg BID)
3rd
Hold acalabrutinib until recovery to Grade ≤2 or baseline; restart at 100 mg 
once daily
4th
Discontinue acalabrutinib 
BID=twice daily.
Table 2
Drug Modification and Discontinuation Actions for Acalabrutinib (Without 

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Lenalidomide)
Occurrence
Action
1st–2nd
Hold acalabrutinib until recovery to Grade ≤1 or baseline; may restart at 
original dose level (100 mg BID)
3rd
Hold acalabrutinib until recovery to Grade ≤1 or baseline; restart at 100 mg 
once daily
4th
Discontinue acalabrutinib 
BID=twice daily.
Whenever possible, any dose adjustment of acalabrutinib should be discussed between 
the investigator and the Sponsor’s medical monitor before implementation. The 
appropriate clinic staff should dispense the study drug for the new dose level and
instruct the subject/caregiver about the change in dose level. Any changes to the dosing 
regimen must be recorded on the appropriate eCRF.
Rituximab dose modifications should follow the recommendations in the 
Rituxan/MabThera package insert and institutional standard practices.
Per the lenalidomide label, the dose adjustments listed in Table 3 are acceptable for 
lenalidomide.
Table 3
Dose Modification Actions for Lenalidomide
Toxicity
Dose Adjustment
Platelets <50 × 109/L:
Platelets return to ≥50 × 109/L:
Interrupt and follow CBC weekly
Resume at 5 mg less than previous dose.
Discontinue if dose is reduced to <10 mg.
ANC <1.0 × 109/L × 7 days
or ANC <1.0 × 109/L with an associated
temperature ≥38.5°C
or ANC <0.5 × 109/L:
ANC returns to ≥1.0 × 109/L:
Interrupt and follow CBC weekly
Resume at 5 mg less than previous dose.
Discontinue if dose is reduced to <10 mg.
Other Grade 3/4 toxicities related to lenalidomide:
Hold treatment and restart at the investigator’s 
discretion at the next lower dose when toxicity
has resolved to ≤Grade 2
ANC=absolute neutrophil count; CBC=complete blood count.

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3.6
CONCOMITANT THERAPY
3.6.1 Permitted Concomitant Therapy
Antiemetics are permitted if clinically indicated. Standard supportive care medications 
are permitted as per institutional standards.
For subjects considered at risk for TLS: Administer appropriate hydration, and 
alkalinization of urine, and allopurinol or other prophylaxis for TLS (e.g., rasburicase) per 
institutional standards before initiating treatment. See further precautions about TLS in 
Section 3.7.2.
3.6.2 Prohibited Concomitant Therapy
Any chemotherapy, anticancer immunotherapy, corticosteroids (at dosages equivalent to 
prednisone >20 mg/day for longer than 2 weeks), experimental therapy, or radiotherapy 
for treating NHL are prohibited. Localized, short courses of radiotherapy are allowed for 
the treatment of lesions unrelated to the disease under study, if approved by the medical 
monitor. Subjects may use topical or inhaled corticosteroids or low-dose steroids 
(≤20 mg of prednisone or equivalent) as therapy for comorbid conditions. During study 
participation, subjects may also receive systemic or enteric corticosteroids as needed for 
treatment-emergent comorbid conditions.
Warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) are prohibited.
Do not administer live virus vaccines prior to or during rituximab treatment 
(Rituxan/MabThera package insert).
3.6.3 Cautionary Therapy Considerations Including Drug-Drug
Interactions
Acalabrutinib
The concomitant use of strong inhibitors/inducers of CYP3A (see Appendix 3) should be 
avoided when possible. Acalabrutinib is a substrate of CYP3A4. Drugs inhibiting 
CYP3A may increase exposure of acalabrutinib. If a subject requires short-term 
treatment with a strong CYP3A inhibitor (such as anti-infectives for up to 7 days), 
interrupt acalabrutinib treatment. If a subject requires a moderate CYP3A inhibitor while 
on study, monitor the subject closely for potential toxicities.
Conversely, concomitant administration of a strong inducer of CYP3A has the potential 
to decrease exposure of acalabrutinib and could reduce efficacy. Avoid
coadministration of strong CYP3A inducers. If a subject requires treatment with a strong 
CYP3A inducer, increase the acalabrutinib dose to 200 mg BID during concomitant 

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administration with the strong inducer and return to recommended dose of 100 mg BID 
after stopping the strong CYP3A inducer.
Use of proton-pump inhibitors, H2 receptor antagonists, or antacids while taking 
acalabrutinib capsules has the potential to decrease acalabrutinib exposure. If treatment 
with a gastric acid-reducing agent is required, consider using a H2-receptor antagonist (2
hours after acalabrutinib capsules) or antacid (2 hours before or 2 hours after 
acalabrutinib capsules). Avoid coadministration with proton-pump inhibitors with 
acalabrutinib capsules. Acalabrutinib maleate tablets can be taken without regards to 
acid-reducing agents (such as antacids, H2-receptor antagonists, or proton-pump 
inhibitors). 
Lenalidomide
Subjects who are concurrently receiving digoxin should have periodic monitoring of 
digoxin plasma levels due to increased Cmax and AUCinf of digoxin with concomitant 
lenalidomide therapy. Moreover, subjects taking concomitant therapies such as 
erythropoietin-stimulating agents or estrogen-containing therapies, along with 
lenalidomide, may have an increased risk of venous thromboembolic events per 
package insert.
Rituximab
The only drug-drug interaction with rituximab listed in the Rituxan/MabThera package 
insert is renal toxicity when used in combination with cisplatin.
For additional information on potential drug-drug interactions, refer to the individual 
drug’s package insert and Section 3.7.5.
3.7
RISKS ASSOCIATED WITH STUDY DRUGS
3.7.1 Risks Associated with Acalabrutinib Treatment
Refer to Section 3.5.7 for specific dose modification and discontinuation guidelines.
The following summarizes the experience with acalabrutinib in hematological cancer 
studies. For more detailed information on treatment-emergent AEs and details regarding 
the clinical safety of acalabrutinib, refer to the current Acalabrutinib Investigator 
Brochure.
Contraindications
No contraindications are known for acalabrutinib.
Important Identified Risks

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The following summarizes the important identified risks observed with acalabrutinib in 
hematological cancer studies. Full details regarding the clinical safety of acalabrutinib 
are presented in the acalabrutinib Investigator’s Brochure.
Hemorrhage
Serious hemorrhagic events, including fatal events, have occurred in clinical trials 
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 pre- and post-
surgery.
Subjects with hemorrhage should be managed per institutional guidelines with 
supportive care and diagnostic evaluations as clinically indicated.
Infections
Serious infections (bacterial, viral, and fungal), including fatal events, have occurred in 
clinical studies with acalabrutinib. The most frequently reported Grade ≥3 infection was 
pneumonia (preferred term). Across the acalabrutinib clinical development program 
(including subjects treated with acalabrutinib in combination with other drugs), cases of 
HBV reactivation, aspergillosis, and PML have occurred. Please refer to Section 4.1.14 
for monitoring of HBV and management of subjects with HBV reactivation.
Consider prophylaxis in subjects who are at increased risk for opportunistic infections.
Subjects should be monitored for signs and symptoms of infection and treated as 
medically appropriate.
Subjects with infection events should be managed according to institutional guidelines 
with maximal supportive care and diagnostic evaluations as clinically indicated.
Cytopenias
Treatment-emergent Grade 3 or 4 cytopenias, including neutropenia, anemia, and 
thrombocytopenia have occurred in clinical trials with acalabrutinib. Monitor blood 
counts as specified in the Schedule of Assessments and as medically appropriate. 
Please refer to Section 3.5.7 for study drug modification guidance.
Subjects with cytopenias should be managed according to institutional guidelines with 

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maximal supportive care and diagnostic evaluations as clinically indicated. Subjects
should be closely monitored as appropriate.
Second Primary Malignancies
Events of second primary malignancies, including non-melanoma skin carcinomas, 
have been reported in clinical study patients treated with acalabrutinib. The most 
frequently reported second primary malignancy was skin cancer.
Subjects should be monitored for signs and symptoms of malignancy. Subjects who 
develop a second primary malignancy should be managed according to institutional 
guidelines with diagnostic evaluations as clinically indicated, and it may be necessary
for subjects to permanently discontinue study treatment. Continuation of acalabrutinib 
treatment should be discussed with the medical monitor. Please refer to Section 6.3.3
for second primary malignancy reporting guidance.
Atrial Fibrillation
Events of atrial fibrillation/flutter have occurred in clinical studies with acalabrutinib,
particularly in subjects with cardiac risk factors, hypertension, diabetes mellitus, acute 
infections, or a previous history of atrial fibrillation.
Monitor for symptoms of atrial fibrillation and atrial flutter (e.g., palpitations, dizziness, 
syncope, chest pain, dyspnea) and obtain an ECG as appropriate. Subjects with atrial 
fibrillation should be managed per institutional guidelines or as clinically indicated. 
Important Potential Risks
There is one important potential risk for acalabrutinib monotherapy. Information related 
to this important potential risk is presented below. Full details regarding the clinical 
safety of acalabrutinib are presented in the acalabrutinib Investigator’s Brochure.
Hepatotoxicity
The mechanism underlying hepatotoxicity events of non-infectious etiology is currently 
unknown. The overall frequency of hepatotoxicity events in acalabrutinib monotherapy 
pool is low, with the most frequently reported events being ALT elevations and AST 
elevations. Following a comprehensive review of hepatotoxicity events in the 
acalabrutinib clinical program, there was insufficient evidence to establish an 
association between hepatotoxicity events and acalabrutinib due to the contribution of 
confounding factors, absence of clinical symptoms, and quick recovery without 
treatment for patients with transaminase elevations. There is limited evidence 

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regarding hepatotoxicity of non-infectious etiology from literature for other BTK
inhibitors.
3.7.2 Risks Associated with Rituximab (Rituxan/MabThera) Treatment
For complete information, refer to the local label for the Reference Safety Information
for rituximab for this study and dose modification and discontinuation guidelines 
(Rituxan/MabThera package insert).
Contraindications

Hypersensitivity to the active substance or to murine proteins.

Patients in a severely immunocompromised state.
Warnings and Precautions
The following are a list of warnings and precautions associated with rituximab:

Fatal infusion reactions within 24 hours of rituximab infusion; approximately 80% 
of fatal reactions occurred with first infusion. Infusion reactions may be related 
to release of cytokines and/or other chemical mediators. Cytokine release
syndrome may be clinically indistinguishable from acute hypersensitivity 
reactions

Severe, including fatal, mucocutaneous reactions such as Toxic Epidermal 
Necrolysis and Stevens-Johnson syndrome, can occur in subjects receiving 
rituximab.

HBV reactivation can occur in patients treated with rituximab, in some cases 
resulting in fulminant hepatitis, hepatic failure, and death.

PML, including fatal PML, can occur in subjects receiving rituximab.

TLS: Administer aggressive intravenous hydration, antihyperuricemic agents, 
monitor renal function.

Infections: Withhold rituximab and institute appropriate anti-infective therapy.

Cardiac adverse reactions: Discontinue infusions in case of serious or 
life-threatening events.

Renal toxicity: Discontinue in subjects with rising serum creatinine or oliguria.

Bowel obstruction and perforation: Consider and evaluate for abdominal pain, 
vomiting, or related symptoms.

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
Live virus vaccines: Live virus vaccinations prior to or during rituximab treatment 
is not recommended.

Embryo-fetal toxicity: Can cause neonatal harm. Advise of potential risk to 
neonates and use of effective contraception.
3.7.3 Risks Associated with Lenalidomide (Revlimid) Treatment
Cases of PML, including fatal cases, have been reported in subjects treated with 
lenalidomide in combination with immunosuppressive therapy including dexamethasone. 
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 lenalidomide until PML is 
excluded. If PML is confirmed, lenalidomide will be permanently discontinued.
For complete information refer to the local label Reference Safety Information for
lenalidomide (Revlimid package insert) for this study. Also refer to Section 3.5.7 in this 
protocol for specific dose modification and discontinuation guidelines.
Contraindications
Pregnancy
Lenalidomide can cause fetal harm when administered to a pregnant female. 
Lenalidomide is contraindicated in females who are pregnant per the package insert.
Allergic Reactions
Lenalidomide is contraindicated in patients who have demonstrated hypersensitivity 
(e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to 
lenalidomide.
Revlimid capsules contain lactose. The risk-benefit of Revlimid treatment should be 
evaluated in subjects with lactose intolerance per package insert.
Warnings and Precautions
Embryo-fetal Toxicity
If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal 
death (boxed warning). Pregnancy must be excluded before start of treatment.
Hematologic Toxicity
Lenalidomide can cause significant neutropenia and thrombocytopenia (boxed warning).
Venous and Arterial Thromboembolism

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Venous thromboembolic events (deep vein thrombosis and pulmonary embolism) and 
arterial thromboembolic events (myocardial infarction and stroke) are increased in 
patients treated with lenalidomide and seen in patients treated for multiple myeloma 
(boxed warning).
Myocardial Infarction
Myocardial infarction has been reported in patients receiving lenalidomide, particularly 
in those with known risk factors and within the first 12 months when used in 
combination with dexamethasone. Patients with known risk factors – including prior 
thrombosis – should be closely monitored, and action should be taken to try to 
minimize all modifiable risk factors (eg. smoking, hypertension, and hyperlipidemia).
Increased Mortality
Serious and fatal cardiac adverse reactions occurred in patients with CLL treated with 
lenalidomide.
Second Primary Malignancies
Higher incidences of second primary malignancies were observed in controlled trials of 
patients with multiple myeloma receiving lenalidomide.
Hepatotoxicity
Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide 
in combination with dexamethasone. Monitor liver enzymes as indicated in 
Section 4.1.12 and stop lenalidomide upon elevation of liver enzymes per the package 
insert.
Allergic Reactions
Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome 
and toxic epidermal necrolysis have been reported. These events can be fatal.
Discontinue lenalidomide if allergic reactions are suspected. Do not resume 
lenalidomide if these reactions are verified.
Tumor Lysis Syndrome
Fatal instances of TLS have been reported during treatment with lenalidomide. Monitor 
subjects at risk of TLS (i.e., those with high tumor burden) and take appropriate 
precautions per the package insert.
Tumor Flare Reaction

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Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and 
lymphoma and is characterized by tender lymph node swelling, low grade fever, pain, 
and rash. Tumor flare reaction may mimic progression of disease. Lenalidomide may
be continued in patients with Grade 1 and Grade 2 tumor flare reaction without 
interruption or modification per the package insert.
Viral Reactivation Including Hepatitis B Reactivation
Serious or life-threatening reactivation of viral hepatitis may occur in subjects treated 
with lenalidomide (“Dear Health Care Provider letter November 2016”).
Impaired Stem Cell Mobilization
A decrease in the number of CD34+ cells collected after treatment (>4 cycles) with 
lenalidomide has been reported.
Thyroid Disorders
Both hypothyroidism and hyperthyroidism have been reported.
Pulmonary hypertension
Cases of pulmonary hypertension, some fatal, have been reported in patients treated with 
lenalidomide. Patients should be evaluated for signs and symptoms of underlying 
cardiopulmonary disease prior to initiating and during lenalidomide therapy.
3.7.4 Dietary Restrictions
All subjects should be strongly cautioned against excessive consumption of grapefruit, 
grapefruit juice, Seville orange juice or starfruit (which contain potent CYP3A inhibitors) 
or using herbal remedies or dietary supplements unless approved by the study
physician. In particular, St John’s wort is a potent CYP3A inducer and should be 
avoided in subjects treated with acalabrutinib, which is metabolized by CYP3A.
Acalabrutinib taken with an acidic beverage may impact exposure to acalabrutinib (refer 
to current Acalabrutinib Investigator Brochure and package insert). Acalabrutinib can be 
taken with or without food.
Otherwise, subjects should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea, or vomiting.
3.7.5 Drug-Drug Interactions
Drug-drug interactions for individual study drugs are discussed in Section 3.5.3.
Acalabrutinib is predominantly metabolized by CYP3A enzymes and hence can be a 

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victim of drug-drug interactions. Acalabrutinib is not a clinically relevant inhibitor or 
inducer of CYP3A enzymes; therefore, drug-drug interactions as a perpetrator is not 
expected through this pathway.
In vitro data indicates that acalabrutinib is a P-gp and breast cancer resistance protein 
(BCRP) substrate. However, acalabrutinib is highly permeable and is rapidly and nearly 
completely absorbed. Thus, an effect of P-gp/BCRP inhibitor on acalabrutinib 
absorption through P-gp inhibition is not expected. In addition, acalabrutinib has been 
administered at doses of 200 mg BID and 400 mg QD with acceptable safety and 
tolerability.
Acalabrutinib may increase exposure to BCRP substrates (e.g., methotrexate) by 
inhibition of intestinal BCRP and should be coadministered with caution with narrow 
therapeutic index BCRP substrates.
The effect of agents that reduce gastric acidity (e.g., antacids or proton-pump inhibitors) 
on acalabrutinib capsule absorption was evaluated in a healthy volunteer study 
(ACE-HV-004).
Results from this study indicate that subjects should avoid the use of calcium
carbonate-containing drugs or supplements for a period of at least 2 hours before and at 
least 2 hours after taking acalabrutinib capsules. Use of omeprazole, esomeprazole, 
lansoprazole, or any other proton-pump inhibitors while taking acalabrutinib capsules is 
not recommended due to a potential decrease in study drug exposure. However, the 
decision to treat with proton-pump inhibitors during the study is at the investigator’s 
discretion, with the understanding of the potential benefit to the subject’s gastrointestinal 
condition and a potential risk of decreased exposure to acalabrutinib capsules.
Although the effect of H2-receptor antagonists (such as famotidine or ranitidine) on 
acalabrutinib absorption has not been evaluated, if treatment with an H2-receptor 
antagonist is required, the H2-receptor antagonist should be taken approximately 2 
hours after acalabrutinib capsules. Acalabrutinib maleate tablets can be taken without 
regards to acid-reducing agents (such as antacids, H2-receptor antagonists, or proton-
pump inhibitors).
For more information on potential drug interactions with acalabrutinib, refer to the current 
Acalabrutinib package insert and Investigator Brochure.
Rituximab is a monoclonal antibody given intravenously. It is metabolized by 
catabolism. An effect of rituximab on the pharmacokinetics of the small molecule 
coadministered drugs and vice versa is not anticipated.

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3.7.6 Reproductive Toxicity
Definition of women of non-reproductive potential:
Women will be considered of non-reproductive potential if they are either:
(1) Postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women <45 years of age a high follicle-stimulating hormone 
[FSH] level in the postmenopausal range may be used to confirm a 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. 
Women of Childbearing Potential (WOCBP)
WOCBP are fertile following menarche and until becoming postmenopausal unless 
permanently sterile; permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. Postmenopausal state is defined as no 
menses for at least 12 months without alternative medical cause (FSH in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormone replacement therapy; however, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient).
Definition of highly effective methods of contraception:
Highly effective methods of contraception (to be used during heterosexual activity) are 
defined as methods that can achieve a failure rate of <1% per year when used 
consistently and correctly.
Highly effective methods of contraception are‡:

Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation, which may be oral, intravaginal, or 
transdermal. Note: Estrogens may further increase the risk of thrombosis in 
patients treated with lenalidomide (see Section 3.7.3).

Progestogen-only hormonal contraception associated with inhibition of ovulation, 

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which may be oral, injectable, or implantable

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomy of a female subject’s male partner (with medical assessment and 
confirmation of vasectomy surgical success)

Sexual abstinence (only if refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments)
Hormonal contraception may be susceptible to interaction with study or other drugs, 
which may reduce the efficacy of the contraception method.
†Abstinence (relative to heterosexual activity) can only be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and Institutional Review 
Boards (IRBs)/Independent Ethics Committees (IECs). Periodic abstinence (e.g., 
calendar, ovulation, sympto-thermal, and postovulation methods) and withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method are not acceptable 
methods of contraception.
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for subjects participating at 
sites in this country/region.
Results of definitive reproductive toxicity studies with acalabrutinib are provided in the 
current Acalabrutinib Investigator Brochure.
Women of childbearing potential (see definition of WOCBP potential above) who are 
sexually active must agree to use highly effective forms of contraception during the study 
and 2 days after the last dose of acalabrutinib, 12 months after the last dose of
rituximab, or 4 weeks after the last dose of lenalidomide, whichever is longer.
Male subjects who are sexually active with a WOCBP partner or a pregnant partner 
must use a condom during treatment and until 4 weeks after the last dose of 
lenalidomide or 3 months after the last dose of rituximab. Men must also refrain from 
donating sperm during the study for 3 months after the last dose of rituximab, or 4 
weeks after the last dose of lenalidomide, 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 

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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 (for WOCBP only), 12 months 
after the last dose of rituximab, or 4 weeks after the last dose of lenalidomide, 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 partners, become 
pregnant during this period. If a female subject becomes pregnant during the treatment 
period, she must discontinue study drug immediately. Pregnancy in a female subject or 
a male subject’s partner must be reported as outlined in Section 6.3.4.
Blood Donation
Subjects must not donate blood during treatment with lenalidomide and for 4 weeks after 
discontinuation of lenalidomide because the bloods might be given to a pregnant female 
patient whose fetus must not be exposed to lenalidomide.
3.7.7 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.
For any subject experiencing a study drug overdose, observation for any symptomatic 
side effects should be instituted, and vital signs and biochemical and hematologic 
parameters should be followed closely. 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.
The Sponsor’s medical monitor should be contacted if a study drug overdose occurs.
Reporting of Overdose
If an overdose on an investigational medicinal product (IMP) or AstraZeneca non 
investigational medicinal product (NIMP) occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that 
all relevant information is provided to the AstraZeneca Patient Safety Data Entry Site 

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(DES). This information should be provided within one (initial fatal/life-threatening or 
follow-up fatal/life-threatening) or five (other serious initial and follow-up) calendar days 
for overdoses associated with an SAE (see Section 6.2.2) and within 30 days for all 
other overdoses.
3.8
WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT
Subjects may be withdrawn from study treatment for the following reasons:

Progressive disease

Completed treatment

Start of alternative anticancer therapy

Adverse event

Pregnancy

Investigator’s decision

Subject’s withdrawal of consent from the study

Decision by sponsor to terminate the study

Subject lost to follow-up

Death

Other
Subjects who have received ≥1 dose of study drug and discontinue study therapy will 
continue to be followed on study for follow-up of safety (Section 4.3), disease,
time-to-next therapy, and long-term follow-up (Section 4.4) unless they withdraw consent 
for further follow-up. The date the subject is withdrawn from study treatment or from the 
study and the reason for discontinuation will be recorded and described on the 
appropriate eCRF.
3.9
REASONS FOR STUDY EXIT
Reasons for study exit include:

Subject’s withdrawal of consent from study

Decision by sponsor to terminate the study

Subject lost to follow-up

Death

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3.10 DATA AND SAFETY MONITORING
This trial will be monitored in accordance with the sponsor’s pharmacovigilance 
procedures. AEs and SAEs will be reviewed internally on an ongoing basis to identify 
safety concerns. Periodic conference calls with the investigators and applicable site 
staff will be conducted to discuss study progress, obtain investigator feedback and 
exchange, and discuss "significant safety events" (i.e., AEs leading to dose 
modifications, related SAEs, and deaths).
4
STUDY ACTIVITIES AND ASSESSMENTS
The schedule of assessments is provided in Appendix 4 (Part 1), Appendix 5 (Part 2), 
and Appendix 6 (Part 3). Descriptions of the scheduled evaluations are outlined below 
and complete information on study drug and dosing is provided in Section 3.5.
Before study entry, throughout the study, and at the follow-up evaluation, various clinical 
and diagnostic laboratory evaluations are required. The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments.
Clinical evaluations and laboratory studies may be repeated more frequently if clinically 
indicated. This study will primarily use central laboratory testing for laboratory 
evaluations. Samples from local laboratories will be used if central testing is 
unavailable. All data from local laboratories must be entered in the unscheduled 
assessment eCRFs.
4.1
DESCRIPTION OF PROCEDURES
4.1.1 Informed Consent
The subject must read, understand, and sign the ICF approved by the IRB/IEC, 
confirming his or her willingness to participate in this study before initiating any 
screening activity that is not standard of care. Subjects must also grant permission to 
use protected health information if required by local regulations.
4.1.2 Medical History
Collect and record the subject’s complete history through review of medical records and 
by interview. Concurrent medical signs and symptoms must be documented to establish 
baseline severities. A disease history, including the date of initial diagnosis and list of all 
prior anticancer treatments, and responses and DORs to these treatments, also will be 
recorded.

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4.1.3 Adverse Events
The accepted regulatory definition for an AE is provided in Section 6.2. The AE 
reporting period is described in Section 6.3.1. All medical occurrences from the time of 
first dose that meet this definition must be recorded. Important additional requirements 
for reporting SAEs are explained in Section 6.3.
4.1.4 Concomitant Medications and Therapy
Document all concomitant medications and procedures from within 21 days (Part 1) and 
28 days (Parts 2 and 3) before the start of study drug administration through 30 days 
after the last dose of study drug.
4.1.5 Confirmation of Eligibility
Subject eligibility for enrollment will be assessed per Section 3.4. All screening 
procedures, unless otherwise indicated, should be completed within 21 days (Part 1) and 
28 days (Parts 2 and 3) of the first dose of study drug.
4.1.6 ECOG Performance Status
The ECOG performance index is provided in Appendix 1.
4.1.7 Physical Examination, Vital Signs, Height, and Weight
The physical examination includes height (screening only) and weight, and examination 
of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, 
musculoskeletal, nervous, lymphatic system, and general appearance. The nervous 
system examination will include attention to neurologic signs and symptoms of PML. 
The lymphatic system examination will include examination of palpable lymph nodes 
and spleen and liver below the costal margin on the respective side. Only physicians, 
physician assistants, or oncology nurse practitioners should perform the lymphatic 
system examination. As much as possible, the same person should perform all the 
lymphatic exams for a given subject.
Vital sign measurements (blood pressure, heart rate, respiratory rate, and body 
temperature) will be assessed after the subject has rested in the sitting position.
4.1.8 Bone Marrow Aspirate and Biopsy
Bone marrow aspirate and biopsy will be performed at screening or up to 60 days before 
the first dose of study drug (Part 1) or up to 90 days before the first dose of study drug 
(Parts 2 and 3). Per the current response criteria (Cheson et al. 2014), a bone marrow 

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aspirate/biopsy will also be required at any time on study to confirm CR (if bone marrow 
was involved by lymphoma at baseline). Testing will be performed at the study center’s 
local laboratory or other clinical laboratory listed on the investigator’s form FDA 1572.
De-identified copies of all bone marrow biopsy/aspirate results may be requested by the 
sponsor.
Bone marrow will also be used for MRD testing. See Section 4.1.22. When available, any
unused bone marrow tissue will be used for PD testing or molecular profiling. PD testing will 
be performed by the sponsor.
Part 2 and Part 3
An optional bone marrow aspirate and/or biopsy will be performed at the end of 
treatment for molecular profiling to discover mechanisms of resistance to study 
treatment.
4.1.9 Electrocardiogram
Subjects should be in supine position and resting for ≥10 minutes before study-related 
ECGs. At screening, results from the site’s ECG machine (12-lead; triplicates taken
≥1 minute apart) will be averaged to determine eligibility and must meet the eligibility 
criteria of QTcF ≤480 msec. A single ECG will be performed at the end of treatment and 
safety follow-up visits.
4.1.10 Urine or Serum Pregnancy Test
Pregnancy tests will be required only for women of childbearing potential (a definition for 
women of nonchildbearing potential is provided in Section 3.7.6). Testing will be 
performed locally by use of central laboratory provided kits. Pregnancy testing may be 
performed by local laboratories and can be done more frequently than the
protocol-defined schedule, if required by local regulatory authorities.
4.1.11 Hematology
Hematology laboratory testing must include complete blood count with differential and 
platelet counts. Testing will be performed by the central laboratory at screening and at 
each clinic visit.
4.1.12 Serum Chemistry
Chemistry must include albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood 
urea nitrogen, bone-specific alkaline phosphatase, calcium, chloride, creatinine, glucose, 
LDH, magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin, total 

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protein, and uric acid. If results from an unscheduled ECG are abnormal and considered 
clinically significant at any time, then an electrolyte panel (i.e., calcium, magnesium, and 
potassium) must be obtained to coincide with the ECG testing. Testing will be
performed by the central laboratory at screening and at each clinic visit.
4.1.13 Thyroid Function Test
Part 3
Subjects receiving lenalidomide should be monitored for hyperthyroidism and 
hypothyroidism. Thyroid laboratory testing must include thyroid-stimulating hormone, 
triiodothyroxine, and thyroxine. Testing will be performed by the central laboratory at 
screening and every 12 weeks during treatment with lenalidomide and 12 weeks after 
the last dose of lenalidomide.
4.1.14 Hepatitis B and C Testing
Hepatitis serology testing at screening must include HBsAg, hepatitis B surface antibody 
(anti-HBs), anti-HBc, and HCV antibody. In addition, any subject testing positive for
anti-HBc or HCV antibody, must have additional PCR testing performed during 
screening (see Appendix 4, Appendix 5, and Appendix 6). Testing will be performed by
a local or central laboratory.
Since IVIG may cause false positive hepatitis serology, subjects who are receiving 
prophylactic IVIG and have positive HBsAg or anti-HBc must have negative hepatitis B 
DNA to be eligible. Those who are HBsAg positive or hepatitis B PCR positive and 
those who are hepatitis C PCR positive will be excluded.
Subjects who are anti-HBc positive should have HBV DNA PCR performed during 
screening and monthly thereafter. Monthly monitoring should continue until 12 months 
after last dose of study drug(s). Any subject with a rising viral load (above lower limit of 
detection) should discontinue study drug and have antiviral therapy instituted and a 
consultation with a physician with expertise in managing hepatitis B.
Subjects with a known history of hepatitis C or who are hepatitis C antibody positive 
should be tested by quantitative PCR for HCV RNA during screening. Such subjects 
may be enrolled provided the quantitative PCR is negative (undetectable viral load). No 
further monitoring for HCV RNA during treatment is necessary if initial PCR results are 
negative.
Refer to Section 3.7.1 and Appendix 4, Appendix 5, and Appendix 6 regarding 
monitoring of subjects who are anti-HBc positive or hepatitis C antibody positive or have 
a known history of HBV.

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4.1.15 Urinalysis
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose. 
Testing will be performed by the central laboratory.
4.1.16 T/B/NK Cell Count
Flow cytometry testing will include CD3+, CD4+, CD8+, CD19+, and CD16+/56+ cells. 
Testing will be performed by the central laboratory.
4.1.17 Serum Immunoglobulin
Testing for immunoglobulin (Ig) G, IgM, and IgA will be performed by the central 
laboratory.
4.1.18 Endoscopy and 13C Urea Breath Test for Gastric MALT Lymphoma 
Subjects
Part 2
Subjects with gastric MALT lymphoma will have an endoscopy performed at screening
or up to 90 days before the first dose of study drug. Endoscopies will also be required at 
any time on study to confirm CR. Testing will be performed at the study center.
A 13C urea breath test will be performed at screening only if the subject does not have
H. pylori results from a pathology report. If this test is needed, proton-pump inhibitors 
and H2 blockers must be discontinued or withheld 14 days and 7 days, respectively, and 
antibiotics for treating H. pylori, such as those with anti-helicobacter action and bismuth 
preparations, should be withheld at least 30 days before the test.
4.1.19 Pharmacokinetics
Part 1
Refer to the laboratory binder for instructions on collecting and processing these 
samples. Testing will be performed at a central clinical laboratory. Leftover plasma 
samples may be used for exploratory acalabrutinib metabolite analyses. PK samples 

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will be drawn per Table 4.
Table 4
Pharmacokinetic Sample Schedule
Cycle
Day
Predose
Hours Postdose
0.5
(±5 min)
0.75
(±5 min)
1
(±5 min)
2
(±10 min)
4
(±10 min)
6
(±10 min)
1
1
x
x
x
x
x
x
x
8
x
x
x
x
x
x
x
15,
22
x
x
2
1
x
min=minute.
Part 2
PK sampling will not be performed in this part of the study.
Part 3
PK sampling will be performed, and sparse PK samples will be drawn per Schedule of 
Assessments (Appendix 6). Refer to the laboratory manual for instructions on collecting 
and processing these samples. Testing will be performed at a central clinical laboratory. 
The remaining plasma samples may be used for exploratory biomarker development or 
acalabrutinib metabolite and/or lenalidomide analyses. PK samples will be drawn per 
Table 5.
Table 5
Sparse PK Sampling Schedule for Part 3
Cycle
Day
Record Time of 
Dose
After Acalabrutinib Dose
1 Hour
(±5
minutes)
4 Hours
(±10
minutes)
1
1
x
x
x
8
x
x
x
2
1
x
x
x
4.1.20 Pharmacodynamics
Blood samples and bone marrow, when available, will be used for PD testing (e.g., BTK 
occupancy and BTK function). Refer to Appendix 4, Appendix 5, and Appendix 6 and 
the laboratory binder for sampling times and instructions on collecting and processing 

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these samples. Testing will be performed by the sponsor.
4.1.21 Molecular Profiling
Part 1
No molecular profiling will be performed.
Part 2 and Part 3
 
4.1.22 Tumor Assessment
A pretreatment CT scan with contrast (unless contraindicated) is required of the chest, 
abdomen, and pelvis and any other disease sites (e.g., neck) within 30 days before the 
first dose of study drug. A pretreatment positron-emission tomography (PET)/CT scan 
within 60 days before the first dose is also required. Information on extranodal 
involvement will also be recorded.
During treatment, CT scans with contrast (unless contraindicated) of the chest, 
abdomen, and pelvis and any other disease sites (e.g., neck) will be performed for tumor 
assessments.
For subjects in Part 1, CT scans will be performed at Day 1 of Cycle 3 (±7 days), 
Cycle 5 (±7 days), and Cycle 7 (±7 days); and then every 3 cycles (12 weeks, ±7 days) 
thereafter up to 2 years then every 6 cycles (24 weeks) or more frequently at the 
investigator’s discretion.
For subjects in Part 2 and Part 3, CT scans will be performed for tumor assessments 
every 3 cycles (12 weeks, ±7 days) starting at Day 1 of Cycle 4, Cycle 7, Cycle 10, and 
Cycle 13, then every 24 weeks thereafter or more frequently at the investigator’s 
discretion.
On-study tumor assessments will also include physical examination and laboratory test 
results. Bone marrow (if involved by lymphoma at baseline), endoscopy (for subjects 
with gastric MALT), and PET/CT are required to confirm CR per clinical guidelines (see 
Section 3.2). For subjects participating in Part 3, PET/CT scans will be performed at 
Cycle 4 Day1 (Week 12), and Cycle 7 Day 1 (Week 24), and at CR.
De-identified copies of all radiology results maybe requested by the sponsor.
Subjects should have radiographic tumor measurements performed at the participating 
study center or an acceptable alternate imaging facility using an identical imaging 

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protocol and similar equipment. The same imaging equipment should be used for all 
scans whenever possible. The same radiologist should be assigned to read all the 
scans for a given subject throughout the study.
Up to 6 measurable nodal and extranodal lesions (i.e., per Lugano Classification, 
measurable nodes >1.5 cm in longest diameter and measurable extranodal lesions 
>1.0 cm in longest diameter may be assessed). Measurable sites of disease should be 
chosen such that they are representative of the subject’s disease. In addition, 
selection of target lesions should be from as disparate regions of the body as possible
when these areas are significantly involved. If additional lesions are present but are 
not included in the target lesion assessment, they can be added as non-target lesions 
followed throughout the study. The cranial-caudal measurement of the spleen and 
longest diameter of the liver will be assessed at screening and all subsequent 
response evaluations.
In the event disease progression is suspected due to results from physical examinations 
or laboratory tests, a CT and or PET/CT scan must be performed to confirm disease 
progression. It is required that disease progression identified by PET/CT alone be 
confirmed by an alternative imaging modality (e.g., diagnostic quality CT) or by biopsy. 
There must be radiologically measurable disease at screening (≥1 nodal lesion >2.0 cm 
in the longest diameter, and/or extranodal session >1.0 cm in the longest diameter). If 
the sole lesion lies within the field of prior radiotherapy, there must be evidence of 
disease progression in that lesion.
Subjects with confirmed CR are not required to undergo further PET/CT scans on study. 
If disease progression on CT is suspected but cannot be biopsy-proven, PET/CT may be 
used at the investigator’s discretion.
A central imaging vendor may be used to collect and store imaging data in the event the 
sponsor chooses to perform independent radiologic assessments.
Part 2 and Part 3
Minimal Residual Disease Testing
Minimal residual disease (MRD) testing will be performed on tumor biopsy, peripheral 
blood, and bone marrow samples by a central laboratory. Baseline (pretreatment) tumor 
tissue (i.e., diagnostic/predose archival lymph node, bone marrow, or tumor tissue) will 
be collected from each subject at screening. A blood sample is to be collected within
12 weeks for subjects with radiological confirmation of CR or PR and at the end of treatment
visit for subjects who discontinue study treatment for any reason. For subjects with 

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lymphoma involvement of bone marrow at baseline, the bone marrow biopsy performed for 
CR confirmation should also be collected for MRD evaluation. MRD determination will be an
exploratory analysis for correlation with outcome on trial and the MRD testing results will not 
be used for making any treatment decisions on study. Refer to the laboratory manual for 
processing and shipping of samples.
4.1.23 Study Drug Accountability
See Section 7.11.
4.1.24 Routine Clinical Assessments
Routine clinical assessments include physical examinations, recording of symptoms, and 
laboratory evaluations to evaluate for both AEs and assessment of disease progression 
at times when the CT or PET/CT scan is not obtained. The investigator should report 
any suspected disease progression to the sponsor or designee.
4.2
INVESTIGATOR’S ASSESSMENT OF RESPONSE TO TREATMENT
The investigator must rate the response of the subject’s response to treatment 
consistent with clinical guidelines (Cheson et al. 2014) as listed below in Table 6.
Overall response assessments will include evaluation of physical examinations, bone 
marrow assessments, and radiographic evaluations per the schedule of assessments. 
Subjects who have signs and symptoms of progression outside of the scheduled 
assessment should be evaluated by the investigator with a physical examination and 
response assessments (see Table 6) to determine if disease progression is present. 
Any suspected case of disease progression should be confirmed with a CT and/or 
PET/CT scan if one was not obtained and should be reported to the Sponsor or 
designee via the electronic data capture (EDC) system. Subjects may continue study 
treatment until progression is confirmed.

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Table 6
Response Assessment Criteria for NHL (Cheson et al. 2014)
Response and Site
PET-CT-Based Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic
response (all of the following)
Lymph nodes and 
extra lymphatic sites
Score 1, 2, or 3a with or without a 
residual mass on 5PSb
It is recognized that in Waldeyer’s ring
or extranodal sites with high physiologic 
uptake or with activation within spleen or 
marrow (e.g., with chemotherapy or 
myeloid colony-stimulating factors), 
uptake may be greater than normal 
mediastinum and/or liver. In this 
circumstance, complete metabolic 
response may be inferred if uptake at 
sites of initial involvement is no greater 
than surrounding normal tissue even if 
the tissue has high physiologic uptake.
Target nodes/nodal masses 
must regress to ≤1.5 cm in 
LDi
No extralymphatic sites of 
disease
Nonmeasured lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in the 
marrow
Normal by morphology; if 
indeterminate, IHC negative
Partial
Partial metabolic response
Partial remission (all of the 
following)
Lymph nodes and 
extra lymphatic sites
Score 4 or 5b with reduced uptake 
compared with baseline and residual 
mass(es) of any size
≥50% decrease in SPD of up 
to 6 target measurable nodes 
and extranodal sites
At interim, these findings suggest 
responding disease
At end of treatment, these findings 
indicate residual disease
When a lesion is too small to 
measure on CT, assign
5 mm × 5 mm as the default 
value
When no longer visible, 
0 × 0 mm
For a node >5 mm × 5 mm, 
but smaller than the normal, 
use actual measurement for 
calculation
Nonmeasured 
lesions
Not applicable
Absent/normal, regressed, 
but no increase
Organ enlargement
Not applicable
Spleen must have regressed 
by >50% in length beyond 
normal
New lesions
None
None

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Response and Site
PET-CT-Based Response
CT-Based Response
Bone marrow
No response or stable 
disease
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline (diffuse uptake compatible 
with reactive changes from 
chemotherapy allowed). If there are 
persistent focal changes in the marrow in 
the context of a nodal response, 
consideration should be given to further 
evaluation with MRI or biopsy or an 
interval scan
No metabolic response
Not applicable
Stable disease
Target nodes/nodal
Score 4 or 5 with no significant change in
<50% decrease from
masses, extranodal
FDG uptake from baseline at interim or
baseline in SPD of up to 6
lesions
end of treatment
dominant, measurable nodes
and extranodal sites; no
criteria for progressive
disease are met
Nonmeasured 
lesions
Not applicable
No increase consistent with 
progression
Organ enlargement
Not applicable
No increase consistent with 
progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive disease
Progressive metabolic disease
Progressive disease requires 
at least 1 of the following
Individual target 
nodes/nodal masses
Score 4 or 5 with increase in intensity of 
uptake from baseline and/or
PPD progression:
Extranodal lesions
New FDG-avid foci consistent with 
lymphoma at interim or end-of-treatment 
assessment
An individual node/lesion 
must be abnormal with: 
LDi >1.5 cm and
Increase by ≥50% from PPD 
nadir and
An increase in LDi or SDi 
from nadir
0.5 cm for lesions ≤2cm
1.0 cm for lesions >2 cm
In the setting of 
splenomegaly, the splenic 
length must increase by
>50% of the extent of its prior 
increase beyond baseline 
(e.g., a 15-cm spleen must 
increase to >16 cm). If no 
prior splenomegaly, must 
increase by at least 2 cm 
from baseline
New or recurrent 
splenomegaly
Nonmeasured 
lesions
None
New or clear progression of 
preexisting nonmeasured 
lesions

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Response and Site
PET-CT-Based Response
CT-Based Response
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another etiology 
(e.g., infection, inflammation). If 
uncertain regarding etiology of new 
lesions, biopsy or interval scan may be 
considered
Regrowth of previously 
resolved lesions
A new node >1.5 cm in any 
axis
A new extranodal site >1.0 
cm in any axis; if <1.0 cm in 
any axis, its presence must 
be unequivocal and must be 
attributable to lymphoma
Assessable disease of any 
size unequivocally 
attributable to lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
5PS=5-point scale; CT=computed tomography; FDG=[18F]fluorodeoxyglucose; GI=gastrointestinal; 
IHC=immunohistochemistry; LDi=longest transverse diameter of a lesion; MRI=magnetic resonance 
imaging; PET=positron emission tomography; PPD=cross product of the LDi and perpendicular 
diameter; SDi=shortest axis perpendicular to the LDi; SPD=sum of the product of the perpendicular 
diameters for multiple lesions.
a
A score of 3 in many patients indicates a good prognosis with standard treatment, 
especially if at the time of an interim scan. However, in trials involving PET where de-
escalation is investigated, it may be preferable to consider a score of 3 as inadequate 
response (to avoid undertreatment). Measured dominant lesions: Up to 6 of the largest 
dominant nodes, nodal masses, and extranodal lesions selected to be clearly 
measurable in 2 diameters. Nodes should preferably be from disparate regions of the
body and should include, where applicable, mediastinal and retroperitoneal areas. Non-
nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, and lungs), GI 
involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions:
Any disease not selected as measured, dominant disease and truly assessable disease 
should be considered not measured. These sites include any nodes, nodal masses, and 
extranodal sites not selected as dominant or measurable or that do not meet the 
requirements for measurability but are still considered abnormal, as well as truly 
assessable disease, which is any site of suspected disease that would be difficult to 
follow quantitatively with measurement, including pleural effusions, ascites, bone 
lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be 
confirmed and followed by imaging. In Waldeyer’s ring or in extranodal sites (e.g., GI 
tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with 
complete metabolic response but should be no higher than surrounding normal 
physiologic uptake (e.g., with marrow activation as a result of chemotherapy or myeloid 
growth factors).
b
PET 5PS: 1, no uptake above background; 2. Uptake ≤mediastinum; 3, uptake 
> mediastinum but ≤liver; 4, uptake moderately > liver; 5, uptake markedly higher than 
liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma.
4.3
SAFETY FOLLOW-UP VISIT
Each subject should be followed for 30 (+7) days after his or her last dose of study drug 
(i.e., the “safety follow-up visit”) until the final data cut-off to monitor for resolution or 
progression of AEs (see Section 6.3.6) 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 should still be encouraged to complete the safety follow-up assessments, but
these assessments cannot be mandated once consent is withdrawn. The Schedule of 
Assessments (Appendix 4, Appendix 5, and Appendix 6) describes the procedures 

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required for the safety follow-up.
4.4 TIME-TO-NEXT TREATMENT, DISEASE FOLLOW-UP, AND LONG-
TERM FOLLOW-UP
Part 1
Subjects who discontinue study therapy and complete the 30-day safety follow-up will 
continue on study for follow-up of time-to-next treatment unless they withdraw consent 
for further follow-up (Appendix 4). Thus, all subjects receiving ≥1 dose of study drug will 
be followed during the immediate post-therapy period with long-term follow-up (LTFU) 
assessments unless the subject withdraws consent for such follow-up to be conducted. 
The date the subject is withdrawn from the study and the reason for discontinuation will 
be recorded and described on the appropriate eCRF.
Part 2 and Part 3
Subjects who have received ≥1 dose of study drug, discontinue study therapy, and 
complete the 30-day safety follow-up, will continue on study for follow-up of disease (for 
subjects who discontinued for reasons other than disease progression), time-to-next 
treatment, and survival unless they withdraw consent for further follow-up. All follow-up 
visits should occur approximately every 12 weeks (see Appendix 5 and Appendix 6 for 
detailed information):
1. Disease follow-up: Subjects who discontinue for reasons other than disease 
progression will be followed for disease progression (via CT scans per 
investigator discretion), regardless of whether the subjects receive a new 
anticancer therapy. The time-to-next treatment information will also be collected. 
Subjects will then continue long-term follow-up (see #2 below).
2.
Long-term follow-up: Subjects who have disease progression, regardless of 
whether disease progression occurred during the study treatment period or the 
disease follow-up period, will be followed for time-to-next treatment and survival 
until death, lost to follow-up, or consent withdrawal.
The date the subject is withdrawn from the study and the reason for discontinuation will 
be recorded and described on the appropriate eCRF.
4.5
MISSED EVALUATIONS
Missed evaluations should be rescheduled and performed as close to the original 
scheduled date as possible. An exception is made when rescheduling becomes, in the 

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investigator’s opinion, medically unnecessary or unsafe because it is too close in time to 
the next scheduled evaluation. In that case, the missed evaluation should be 
abandoned.
5 STATISTICAL METHODS OF ANALYSIS
5.1
GENERAL CONSIDERATIONS
Descriptive statistics (including means, standard deviations, and medians for continuous 
variables and proportions for discrete variables) will be used to summarize data as 
appropriate. All analyses will be done by indication, treatment, and overall.
5.2
SAMPLE SIZE CONSIDERATIONS
Part 1
This study will assess acalabrutinib safety, PK, PD, and antitumor activity when 
administered alone or in combination with rituximab. A total of 24 subjects (12 each 
arm) in the Relapsed/Refractory Cohort will be equally randomized into 1 of 2 treatment 
arms (monotherapy and combination therapy). Twelve subjects will be enrolled to the 
Treatment-naive Cohort receiving the combination therapy. The study is not formally 
designed to compare these regimens but rather to obtain descriptive information that can 
be used in support of further acalabrutinib development.
The primary objective of this study is to determine the safety as such:

With a total sample size of 36, the probability of observing one or more instances 
of an AE with a background rate of 5% and 10% is 84% and 98%, respectively.

For each treatment arm (n=12 each), the probability of observing one or more 
instances of an AE with a background rate of 5% and 10% is 46% and 72%, 
respectively.

This provides reasonable assurance for generating preliminary safety data for 
this Phase 1b, proof-of-concept study.
Part 2
Part 2 will enroll up to 40 subjects in Cohort 1. The primary objective is to characterize 
the activity of acalabrutinib alone in subjects with R/R MZL as measured by the ORR. 
Up to 40 subjects in treatment Cohort 1 will provide data for an initial assessment of 
safety and efficacy of acalabrutinib treatment. Sample size is not based on statistical 
power consideration.

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Part 3
A total of approximately 26 to 32 subjects are to be enrolled in Part 3. This sample size 
will provide adequate data for an initial assessment of safety and efficacy of 
acalabrutinib treatment in combination with lenalidomide and rituximab. This sample 
size is not based on statistical power consideration.
5.3
DEFINITION OF ANALYSIS SETS
The following definitions will be used for the efficacy and safety analysis sets.
All-treated population: All randomized or enrolled subjects who receive ≥1 dose 
of study drug.
Efficacy-evaluable population: All subjects in the All-treated population who 
have ≥1 response assessment after the first dose of study treatment.
The safety analyses and primary efficacy analyses for all efficacy endpoints will be 
performed on the All-treated population. Sensitivity analyses for efficacy will be carried 
out on the Efficacy-evaluable population.
5.4
MISSING DATA HANDLING
General Considerations: Subjects lost to follow-up (or who dropped out) will be 
included in statistical analyses up to the point of their last evaluation.
Duration of Response and Progression-Free Survival: Data for subjects without 
disease progression or death will be censored at the date of the last tumor assessment 
and before the initiation of alternative anticancer therapy. The details of the censoring 
rules will be provided in the Statistical Analysis Plan (SAP).
Time-to-Next Treatment: Data from subjects who have not received subsequent 
therapy will be censored at the earliest of death or the last time that lack of 
administration of a new therapy was objectively documented. The details of the 
censoring rules will be provided in the SAP.
Safety: Missing or partial start and end dates for AEs and concomitant medications will 
be imputed according to prespecified, conservative imputation rules. The details will be 
provided in the SAP. No other imputation of values for missing data will be performed.
5.5
ENDPOINT DATA ANALYSIS
5.5.1 Safety Endpoint
Safety summaries will include summaries in the form of tables and listings. The 

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frequency (number and percentage) of treatment emergent AEs will be reported in each 
treatment group by MedDRA System Organ Class and Preferred Term. Summaries will 
also be presented by the severity of the AE (per CTCAE, v4.03 for Part 1 and v5.0 for 
Parts 2 and 3) and by relationship to study drug.
Laboratory shift tables containing counts and percentages will be prepared by treatment 
assignment, laboratory parameter, and time. Summary tables will be prepared for each 
laboratory parameter. Figures of changes in laboratory parameters over time will be
generated.
Results of vital sign assessments and physical exams will be tabulated and summarized.
5.5.2 Demographics and Baseline Characteristics
Additional analyses will include summaries of subject demographics, baseline 
characteristics, medical history, compliance, and prior and concurrent treatments. 
Concomitant medications will be coded according to the World Health Organization 
(WHO) Drug Dictionary and tabulated.
5.5.3 Study Treatment Administration and Compliance 
Descriptive information will be provided regarding the number of acalabrutinib, 
lenalidomide, and rituximab doses prescribed, the total number of doses taken, the 
number of days of treatment, and the number and timing of prescribed dose
reductions and interruptions.
For each subject, acalabrutinib and lenalidomide compliance will be described in terms 
of the proportion of study drug actually taken based on returned pill count relative to the 
amount that was dispensed (taking into account physician-prescribed modifications and 
interruptions).
5.5.4 Analysis of Efficacy Parameters
Overall Response Rate
ORR will be defined as the proportion of subjects who achieve a CR or PR according to 
the Lugano Classification for NHL (Cheson et al. 2014), as assessed by investigators. 
ORR will be calculated, and the corresponding 2-sided confidence interval will be 
derived.
Duration of Response
The DOR is defined as the interval from the first documentation of CR or PR to the 
earlier of the first documentation of definitive disease progression or death from any 
cause. Kaplan-Meier methods will be used to estimate event-free curves and 

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corresponding quantiles (including the median).
Progression-Free Survival
PFS is defined as the interval from the start of acalabrutinib therapy to the earlier of the 
first documentation of objective disease progression or death from any cause.
Kaplan-Meier methods will be used to estimate the event-free curves and corresponding 
quantiles (including the median).
Time-to-Next Treatment
Time-to-next treatment defined as the time from start of acalabrutinib therapy on this 
protocol to the start of the next treatment. Kaplan-Meier methods will be used to 
estimate the event-free curves and corresponding quantiles (including the median). 
Data from subjects who have not received subsequent therapy will be censored at the 
earliest of death or the last time that lack of administration of a new therapy was 
objectively documented.
Time-to-next treatment data will be collected from subjects in Part 2 and Part 3 for an 
exploratory analysis.
Overall Survival
The duration of OS will be measured from the start of acalabrutinib therapy until the date 
of death. Subjects who are known to be alive as of their last known status will be 
censored at their date of last contact. Kaplan-Meier methodology will be used to 
estimate OS curves and corresponding quartiles (including the median).
5.5.5 Analysis of Pharmacokinetic/Pharmacodynamic Parameters
Part 1
The plasma pharmacokinetics of acalabrutinib in subjects receiving acalabrutinib alone 
or in combination with rituximab will be characterized using noncompartmental analysis. 
The following PK parameters will be calculated, whenever possible, from plasma 
concentrations of acalabrutinib:

AUC0-t
Area under the plasma concentration-time curve calculated using 
linear trapezoidal summation from time 0 to time t, where t is the 
time of the last measurable concentration (Ct).

AUC0-12
Area under the plasma concentration-time curve from 0 to 
12 hours, calculated using linear trapezoidal summation.

AUC0-∞
Area under the plasma concentration-time curve from 0 to infinity, 

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calculated using the formula: AUC0-∞ =AUC0-t + Ct / λz, where λz is 
the apparent terminal elimination rate constant.

AUC0-24calc Area under the plasma concentration-time curve from 0 to 
24 hours, calculated by doubling the value for AUC0-12.

Cmax
Maximum observed plasma concentration

Tmax
Time of the maximum plasma concentration (obtained without 
interpolation)

t½
Terminal elimination half-life (whenever possible)

λz
Terminal elimination rate constant (whenever possible)

CL/F
Oral clearance

Vz/F
Oral volume of distribution
The PK parameters will be tabulated and summarized using descriptive statistics.
Part 2: There will be no PK analysis in Part 2.
Part 3
Plasma concentrations of acalabrutinib and ACP-5862 will be tabulated for each subject 
by arm, visit, and timepoint. Summary statistics (mean, median, standard deviation, 
percentage coefficient of variation) and plots will be presented, as appropriate.
Additional analyses, including population PK analysis, may be conducted as appropriate.
Part 1, Part 2, and Part 3
Missing dates or times may be imputed for PK and PD samples if the missing values can 
be established with an acceptable level of accuracy based on other information obtained 
during the visit in question. If PK and PD sampling for a given subject is not performed 
according to protocol instructions, that subject may be excluded from the PK and PD 
analyses.
For each PD variable, the concentration at each assessment will be described. The 
change from baseline to each assessment will be summarized. The best change from 
baseline during the study will also be summarized. As appropriate, the on-treatment 
values will be compared with the pretreatment baseline values using paired t-tests.
P-values of 0.05 will be considered significant.
5.5.6 Explorative or Correlative Analyses
Additional PK or PD analyses may be performed, as deemed appropriate.

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Correlations between subject characteristics and outcome measures and correlations 
among outcomes measures will be explored using regression models or other 
appropriate techniques.
6
ASSESSMENT OF SAFETY
Safety assessments will consist of monitoring and recording AEs and SAEs; 
measurements of protocol-specified hematology, clinical chemistry, urinalysis, and other 
laboratory variables; measurement of protocol-specified vital signs; and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study 
drug(s).
6.1
REFERENCE SAFETY INFORMATION
For the purpose of reporting AEs and SAEs:

The Investigator Brochure contains the Reference Safety Information (RSI) for 
acalabrutinib
6.2
DEFINITIONS
6.2.1 Adverse Events
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational (medicinal) product, regardless of 
attribution of causality.
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 NHL that were not present before the AE reporting period (see
Section 6.3.1).

Pre-existing medical conditions (other than the condition being studied) judged 
by the investigator to have worsened in severity or frequency or changed in 
character during the protocol-specified AE reporting period.
Abnormal laboratory values considered clinically significant by the investigator should be 
reported as an AE. For actions required for liver toxicity, refer to Appendix 7.
The following are NOT considered an AE:

Pre-existing condition that has not worsened: A pre-existing condition 
(documented on the medical history eCRF) is not considered an AE unless the 

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severity, frequency, or character of the event worsens during the reporting 
period.

Preplanned hospitalization: A hospitalization planned before signing the ICF is 
not considered an SAE but rather a therapeutic intervention. However, if during 
the preplanned hospitalization an event occurs, which prolongs the 
hospitalization or meets any other SAE criteria, the event will be considered an 
SAE. Surgeries or interventions that were under consideration, but not 
performed before signing the ICF, will not be considered serious if they are 
performed after signing the ICF for a condition that has not changed from its 
baseline level. Elective hospitalizations for social reasons, solely for the 
administration of chemotherapy, or due to long travel distances are also not 
considered 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 performed 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 a 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 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.

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.

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6.2.2 Serious Adverse Event
The terms “severe” and “serious” are not synonymous. Severity (or intensity) refers to 
the grade of an AE (see below). “Serious” is a regulatory definition and is based on
subject or event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning. Seriousness (not severity) serves as the guide 
for defining regulatory reporting obligations from the sponsor to applicable regulatory 
authorities.
An AE should be classified as an SAE if it meets any 1 of the following criteria:

It results in death (i.e., the AE actually causes or leads to death)

It is life-threatening (i.e., the AE, in the view of the investigator, places the
subject at immediate risk of death at the time of the event. It does not include
an AE that, had it occurred in a more severe form, might have hypothetically 
caused death)

It requires or prolongs inpatient hospitalization

It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions)

It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the investigational product

It is considered a significant medical event by the investigator based on 
medical judgment (e.g., may jeopardize the subject or may require 
medical/surgical intervention to prevent one of the outcomes listed above)
6.2.3 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 Sponsor expeditiously (see Section 6.3.5 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 

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considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings indicating an infection 
in a subject exposed to a medicinal product. This term ONLY applies when a 
contamination of the study drug is suspected, NOT for infections supported by 
the mode of action, e.g., immunosuppression.
6.2.4 Severity
Definitions found in the CTCAE (Version 4.03 for Part 1 and Version 5.0 for Parts 2 and 
3) will be used for grading the severity (intensity) of AEs. The CTCAE displays Grades 1 
through 5 with unique clinical descriptions of severity for each referenced AE. Should a 
subject experience any AE not listed in the CTCAE, the following grading system should 
be used to assess severity:

Grade 1 (Mild AE) – experiences that are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities

Grade 2 (Moderate AE) – experiences that introduce some level of 
inconvenience or concern to the subject, and which may interfere with daily 
activities, but are usually ameliorated by simple therapeutic measures

Grade 3 (Severe AE) – experiences that are unacceptable or intolerable, 
significantly interrupt the subject’s usual daily activities, and require systemic 
drug therapy or other treatment

Grade 4 (Life-threatening or disabling AE) – experiences that cause the subject 
to be in imminent danger of death

Grade 5 (Death due to AE) – experiences that result in subject death
6.3
DOCUMENTING AND REPORTING OF ADVERSE AND SERIOUS 
ADVERSE EVENTS
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, as outlined in the prior sections, are recorded on the eCRF. 
All SAEs also must be reported using the SAE report form (see Section 6.3.5).
All SAEs, overdoses, and pregnancies must continue to be reported after the final data 
cut-off. Follow-up to existing SAEs must be entered in the clinical database. AEs will 
no longer be reported in the clinical database after final data cut-off but will instead be 
recorded in the subject’s medical record. After database lock, all new or follow-up to 
existing SAEs and pregnancies must be reported on the SAE paper form. 

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6.3.1 Adverse Event Reporting Period
AEs and SAEs will be collected by the site from time of signature of ICF throughout the 
treatment period and including the follow-up period. After the signing of the ICF and
prior to the first dose of study drug, all SAEs, regardless of causality, must be reported 
to the Sponsor.
All AEs and SAEs will be reported from first dose of study treatment until 30 days after 
the last dose of study drug(s) or the start of new anticancer therapy (whichever comes
first). After this period, investigators should report SAEs that are believed to be related 
to the study drug(s) or any AEs of concern (deemed by the Sponsor or investigator), 
regardless of causality to the study drug(s) as relevant.
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.
All SAEs/AESIs will be recorded and reported to the sponsor or designee within 
24 hours. The investigator will submit any updated SAE/AESI data to the sponsor 
within 24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE data in former study 
subjects. However, if at any time after a subject’s last visit the investigator learns of 
any SAE, including a death, that is considered to be reasonably related to the study 
treatment or study participation, the investigator may notify the Sponsor.
After the final DCO, the study will transition to the PTAP. Patients will be managed as 
per standard of care. All SAEs, irrespective of attribution of causality, will be collected 
and recorded in the subject’s medical records. SAEs will be reported to the sponsor 
using a paper form via Fax or email. No AEs will be reported during the PTAP phase of 
the study. 
6.3.2 Assessment of Adverse Events
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation 
timepoints during the study. All AEs and SAEs whether volunteered by the subject, 
discovered by study personnel during questioning, or detected through physical 
examination, or other means will be recorded in the subject’s medical record and on the 
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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 diagnostic term, duration (i.e., start 
and end dates), severity, regulatory seriousness criteria, if applicable, suspected 
relationship to the study drug (see following guidance), and any actions taken in regard 
to the event. The causal relationship of AEs to the study drug will be assessed by 
means of the question: "Is there a reasonable possibility that the event may have been 
caused by the study drug?" per FDA guidance on safety reporting requirements (FDA
Safety Reporting Requirements for INDs and BA/BE Studies (December 2012)).
See Appendix 2 for more detail on assessing causality.
6.3.3 Second Primary Malignancies
AEs for malignant tumors reported during a study should generally be assessed as 
SAEs. If no other seriousness criteria apply, the “Important Medical Event” criterion 
should be used. In certain situations, however, medical judgment on an individual event 
basis should be applied to clarify that the malignant tumor event should be assessed 
and reported as a nonserious AE. For example, if the tumor is included as medical 
history and progression occurs during the study but the progression does not change 
treatment and/or prognosis of the malignant tumor, the AE may not fulfill the attributes 
for being assessed as serious, although reporting of the progression of the malignant 
tumor as an AE is valid and should occur. Also, some types of malignant tumors, which 
do not spread remotely after a routine treatment that does not require hospitalization, 
may be assessed as nonserious; examples in adults include Stage 1 basal cell 
carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.
The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (i.e., it is not the tumor for which entry into the study is a criterion and 
that is being treated by the investigational product (IP) under study and is not the 
development of new or progression of existing metastasis to the tumor under study).
Malignant tumors that—as part of normal, if rare, progression—undergo transformation 
(e.g., Richter's transformation of B-cell chronic lymphocytic leukemia into DLBCL) should 
not be considered a new malignant tumor.
6.3.4 Pregnancy
The investigator should report all pregnancies and pregnancies in the partners of 
subjects within 24 hours using the Pregnancy Report Form. This form should be faxed 
or emailed to the Sponsor’s Drug Safety. Any pregnancy-associated SAE must be 

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reported to the Sponsor, using the SAE report form, according to the usual timelines
and directions for SAE reporting (Section 6.3.5).
Any uncomplicated pregnancy that occurs with the subject or with the partner of a 
treated subject during this study will be reported for tracking purposes only, if agreed to 
by the subject or the partner of the subject in this study. All pregnancies and partner 
pregnancies that are identified during or after this study, wherein the estimated date of 
conception is determined to have occurred from the time of consent to 2 days after the 
last dose of acalabrutinib, 12 months after the last dose of rituximab, or 4 weeks after 
the last dose of lenalidomide (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.
Pregnancy itself is not regarded as an AE unless there is suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Likewise, elective abortions without complications are not 
considered AEs. Any SAEs associated with pregnancy (e.g., congenital 
abnormalities/birth defects/spontaneous miscarriages or any other serious events) must 
be reported as such using the SAE report form.
Subjects should be instructed to immediately notify the investigator of any pregnancies. 
Any female subjects receiving study treatment who become pregnant must immediately 
discontinue study drug. The investigator should counsel the subject, discussing any 
risks of continuing the pregnancy and any possible effects on the fetus. Upon 
completion of the pregnancy, additional information on the mother, pregnancy, and baby 
will be collected and sent to DrugSafety@acerta-pharma.com.
Drug Safety Contact Information
+1 866 467 0304 (United States)
Fax:
+1 650 935 4996 (for outside the United
States)
Email:
DrugSafety@acerta-pharma.com
6.3.5 Expedited Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
All SAEs and AESIs must be reported within 24 hours of discovery. Initial SAE/AESI 
reports and follow-up information will be reported using the protocol-specific electronic 
data capture system according to the investigator site file. If electronic SAE reporting is 
not available, paper SAE/AESI forms must be completed and emailed or faxed to the 

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Sponsor’s Drug Safety department, or designee. The Sponsor may request follow-up 
and other additional information from the investigator (e.g., hospital admission/discharge
notes and laboratory results). After final database lock, new or follow-up to existing 
SAEs will be reported using a paper form.
Whenever possible, AEs/SAEs should be reported by diagnosis term not as a 
constellation of symptoms.
Death due to disease progression should be recorded on the appropriate form in the 
EDC system. If the primary cause of death is disease progression, then the death due 
to disease progression should not be reported as an SAE. If the primary cause of death 
is something other than disease progression, then the death should be reported as an
SAE with the primary cause of death as the event AE term, as death is typically the 
outcome of the event, not the event itself. The primary cause of death on the autopsy 
report should be the term reported. Autopsy and postmortem reports must be forwarded 
to the Sponsor’s Drug Safety department, or designee, as outlined above.
If study drug is discontinued because of an SAE, this information must be included in the 
SAE report.
An SAE may qualify for mandatory expedited reporting to regulatory authorities if the 
SAE is attributable to the investigational product and is not listed in the current 
Investigator’s Brochure (i.e., an unexpected event). In this case, the Sponsor’s Drug 
Safety department or designee will forward a formal notification describing the 
Suspected Unexpected Serious Adverse Reaction (SUSAR) to all investigators. Each 
investigator must then notify his or her IRB/IEC of the SUSAR.
Drug Safety Contact Information
+1 866 467 0304 (United States)
Fax:
+1 650 935 4996 (for outside the United
States)
Email:
DrugSafety@acerta-pharma.com
6.3.6 Type and Duration of Follow-up of Subjects After Adverse Events
All AEs and SAEs that are encountered during the protocol-specified AE reporting period 
should be followed to resolution, or until the investigator assesses the event as stable, a 
new anticancer therapy is initiated, or the subject is lost to follow-up or withdraws 
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6.3.7
Medication Error, Drug Abuse, and Drug Misuse
Timelines
If an event of medication error, drug abuse, or drug misuse occurs during the study, 
then the investigator or other site personnel informs the appropriate AstraZeneca 
representatives within one calendar day, ie, immediately but no later than 24 hours of 
when they become aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within one (initial fatal/life-threatening or follow-up 
fatal/life-threatening) or 5 (other serious initial and follow-up) calendar days if there is 
an SAE associated with the event of medication error, drug abuse, or misuse (see 
Section 6.2.2) and within 30 days for all other events.
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or 
mistake in the treatment process for an IMP or AstraZeneca NIMP that either causes 
harm to the subject or has the potential to cause harm to the subject.
The full definition and examples of medication error can be found in Appendix 9.
Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of 
IMP or AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix 9.
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study subject) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorized product information, 
or for unauthorized IMPs or AstraZeneca NIMPs, outside the intended use as specified 
in the protocol and includes deliberate administration of the product by the wrong route.
The full definition and examples of drug misuse can be found in Appendix 9.
7
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS
The Sponsor retains the right to terminate the study and remove all study materials
from a study site at any time. Specific circumstances that may precipitate such 
termination include:

Unsatisfactory subject enrollment with regard to quality or quantity

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
Significant or numerous deviations from study protocol requirements, such as 
failure to perform required evaluations on subjects and maintain adequate study 
records

Inaccurate, incomplete or late data recording on a recurrent basis

The incidence and/or severity of AEs in this or other studies indicating a potential 
health hazard caused by the study treatment
7.1
REGULATORY AND ETHICAL COMPLIANCE
Ethical Conduct of the Study
This clinical study was designed and will be implemented in accordance with the 
protocol, the International Conference on Harmonisation Harmonized Tripartite 
Guidelines for Good Clinical Practices, applicable local regulations (including US Code 
of Federal Regulations (CFR) Title 21 and European Directive 2001/20/EC), and the 
ethical principles laid down in the Declaration of Helsinki (October 2008).
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to AstraZeneca of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the 
safety of a study intervention under clinical investigation are met.
AstraZeneca has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. AstraZeneca will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.
For all studies except those utilizing medical devices, investigator safety reports must 
be prepared for SUSAR according to local regulatory requirements and sponsor policy 
and forwarded to investigators as necessary.
Adherence to European Medical Device Regulation 2017/745 for clinical device 
research (if applicable), and all other applicable local regulations.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from AstraZeneca will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
Regulatory Reporting Requirements for Serious Breaches
Prompt notification by the investigator to the sponsor of any (potential) serious breach 

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of the protocol or regulations is essential so that legal and ethical obligations are met.

A ‘serious breach’ means a breach likely to affect to a significant degree the safety and 
rights of a subject or the reliability and robustness of the data generated in the clinical 
trial.
If any (potential) serious breach occurs in the course of the study, investigators or 
other site personnel will inform the appropriate AstraZeneca representatives 
immediately after he or she becomes aware of it.
In certain regions/countries, the sponsor has a legal responsibility to notify both the 
local regulatory authority and other regulatory agencies about such breaches.

The sponsor will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If EU 
Clinical Trials Regulation 536/2014 applies, the sponsor is required to enter details of 
serious breaches into the European Medicines Agency (EMA) Clinical Trial Information 
System (CTIS). It is important to note that redacted versions of serious breach reports 
will be available to the public via CTIS.
The investigator should have a process in place to ensure that: 

the site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach 

a (potential) serious breach is promptly reported to the sponsor or delegated party, 
through the contacts (e-mail address or telephone number) provided by the sponsor.
7.2
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE
After the final data cut-off, the investigator will continue submitting any amendments to 
the protocol, the informed consent, Investigator Brochure, and any other relevant 
information to the appropriate IRB/IEC for review and approval. A signed protocol 
approval page; a letter confirming IRB/IEC approval of the protocol and informed
consent; and a statement that the IRB/IEC is organized and operates according to 
Good Clinical Practice (GCP) guidelines and the applicable laws and regulations; must 
be forwarded to the Sponsor or representative. Amendments to the protocol must also 
be approved by the local regulatory agency, as appropriate, before the implementation 
of changes in this study.
7.3
INFORMED CONSENT AND PROTECTED SUBJECT HEALTH 

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INFORMATION AUTHORIZATION
A copy of the IRB/IEC-approved ICF must be forwarded to the Sponsor for regulatory 
purposes. The investigator, or designee (designee must be listed on the Study 
Personnel Responsibility/Signature Log, see Section 7.11), must explain to each subject 
the purpose and nature of the study, the study procedures, the possible adverse effects, 
and all other elements of consent as defined in § 21CFR Part 50, and other applicable 
national and local regulations governing informed consent. Each subject must provide a 
signed and dated ICF before enrollment into this study. If allowed by the protocol, a 
legal representative may sign the informed consent form for a subject incapable of giving 
consent. Signed consent forms must remain in each subject’s study file and be available 
for verification by study monitors at any time.
In accordance with individual local and national patient privacy regulations, the 
investigator or designee must explain to each subject that for the evaluation of study 
results, the subject’s protected health information obtained during the study may be 
shared with the Sponsor and its designees, regulatory agencies, and IRBs/IECs. As the
study Sponsor, the Sponsor will not use the subject’s protected health information or 
disclose it to a third party without applicable subject authorization. It is the investigator’s 
or designee’s responsibility to obtain written permission to use protected health 
information from each subject, or if appropriate, the subject’s legal guardian. If a subject 
or subject’s legal guardian withdraws permission to use protected health information, it 
is the investigator’s responsibility to obtain the withdrawal request in writing from the
subject or subject’s legal guardian and to ensure that no further data will be collected 
from the subject. Any data collected on the subject before withdrawal will be used in the 
analysis of study results.
7.4
CASE REPORT FORMS
Authorized study site personnel (see Section 7.11) will complete eCRFs designed for
this study according to the completion guidelines that will be provided. The investigator 
will ensure that the eCRFs are accurate, complete, legible, and completed promptly. For 
record retention policies, refer to Section 7.6.
After the final data cut-off, the clinical database will close to new data collection and will 
be archived accordingly. 
7.5
STUDY MONITORING REQUIREMENTS
Representatives of the Sponsor or its designee will monitor this study until completion.

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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 by the sponsor, 
regulatory authorities, or ethics committees.
Remote Monitoring Visits
The main goal of a Remote Monitoring Visit is to check the status of ongoing patients, 
check IMP supply needs and provide support.
Onsite Monitoring Visits
The main goal of an Onsite Monitoring Visit is site oversight, verification of patient 
safety, verification of regulatory and GCP compliance, verification of IMP supply and 
facilities and collection of any new documents not provided previously.
Every effort will be made to maintain the anonymity and confidentiality of all subjects 
during this clinical study. However, because of the experimental nature of this 
treatment, the investigator agrees to allow the IRB/IEC, representatives of the Sponsor, 
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.
Audits and Inspections
Authorized representatives of the Sponsor, a regulatory authority, an IEC or an IRB may 
visit the site to perform audits or inspections, including source data verification. The 
purpose of a Sponsor audit or inspection is to systematically and independently examine 
all study-related activities and documents to determine whether these activities were 
conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, ICH GCP guidelines, and any applicable regulatory requirements. The 
investigator should contact the Sponsor immediately if contacted by a regulatory agency 
about an inspection.
7.6
QUALITY CONTROL AND QUALITY ASSURANCE
The Sponsor shall implement and maintain quality control and quality assurance 

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procedures to ensure that the study is conducted, and data are generated, documented, 
and reported in compliance with the protocol, GCP, and applicable regulatory 
requirements. This study shall be conducted in accordance with the provisions of the 
Declaration of Helsinki (October 2008) and all revisions thereof, and in accordance with 
FDA regulations (21 CFR Parts 11, 50, 54, 56, and 312, Subpart D – Responsibilities of 
Sponsors and Investigators) and with the ICH guidelines on GCP (ICH E6).
Any revised protocol will require IRB/IEC and applicable Regulatory Authority approval 
before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study subjects.
AstraZeneca will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to 
a CRO, but the accountability remains with AstraZeneca.
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR 312.120, ICH guidelines, the 
IRB/IEC, European Regulation 536/2014 for clinical studies (if applicable), European 
Medical Device Regulation 2017/745 for clinical device research (if applicable), and all 
other applicable local regulations.
7.7
DATA HANDLING AND RECORDKEEPING
Subject Screening Log
The investigator must keep a record that lists all subjects considered for enrollment and
consented (including those who did not undergo screening) in the study. For those 
subjects subsequently excluded from enrollment, record the reason(s) for exclusion.
Inspection of Records
The Sponsor or designee will be allowed to conduct site visits to the investigation 
facilities for the purpose of monitoring any aspect of the study. The investigator agrees 
to allow the monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, subject charts and study source documents, and other records 
relative to study conduct.
Record Retention
The investigator and other appropriate study staff are responsible for maintaining all 
documentation relevant to the study. Mandatory documentation includes copies of study 
protocols and amendments, each FDA Form 1572, IRB/IEC approval letters, signed 
ICFs, drug accountability records, SAE forms transmitted to the Sponsor, subject files 

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(source documentation) that substantiate entries in eCRFs, and 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 the Sponsor and obtain 
written approval from the Sponsor before destroying any clinical study records at any 
time. The Sponsor will inform the investigator of the date that study records may be 
destroyed or return to the Sponsor. In accordance with Canadian regulations, all study 
information collected will be stored for at least 25 years after the end of the study by 
the study sponsor.
The Sponsor must be notified in advance of, and the Sponsor 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 the Sponsor 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.
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for a minimum of 25 years after study archiving or 
as required by local regulations, according to the AstraZeneca Global Retention and 
Disposal (GRAD) Schedule. No records may be destroyed during the retention period 
without the written approval of AstraZeneca. No records may be transferred to another 
location or party without written notification to AstraZeneca.
7.8
PROTOCOL AMENDMENTS
The Sponsor will initiate any change to the protocol in a protocol amendment document.
The amendment will be submitted to the IRB/IEC together with, if applicable, a revised 
model ICF. If the change in any way increases the risk to the subject or changes the 
scope of the study, then written documentation of IRB/IEC approval must be received 
by the Sponsor before the amendment may take effect. Additionally, under this 
circumstance, information on the increased risk and/or change in scope must be 
provided to subjects already actively participating in the study, and they must read, 

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understand, and sign any revised ICF confirming willingness to remain in the trial.
7.9
PUBLICATION OF STUDY RESULTS
Authorship, in general, will follow the recommendations of the International Committee of 
Medical Journal Editors (International Committee of Medical Journal Editors 2014).
7.10
CLINICAL TRIAL INSURANCE
Clinical trial insurance has been obtained according to the laws of the countries where 
the study will be conducted. An insurance certificate will be made available to the 
participating sites at the time of study initiation.
7.11
INVESTIGATIONAL STUDY DRUG ACCOUNTABILITY
Acalabrutinib capsules and tablets must be kept in a locked limited access cabinet or 
space. The study drug must not be used outside the context of this protocol. 
Study drug accountability records must be maintained and readily available for 
inspection by representatives of the Sponsor or regulatory authorities at any time.
Each shipment of study drug will contain a Clinical Supplies Shipping Receipt Form 
(CSSF). If it is used, the Drug Re-Order Form (provided in the pharmacy binder) must 
also be included in the site’s drug accountability records.
Contents of each shipment must be visually inspected to verify the quantity and to 
document the condition of study drug capsules and tablets. Following receipt of study 
drug, the designated recipient completes and signs the CSSF. A copy of the signed 
and dated CSSF must be faxed or emailed to the Sponsor at the fax number/email 
address listed on the form; this completed form should be filed in the pharmacy binder.
An Investigational Drug Accountability Log must be used for drug accountability. For 
accurate accountability, the following information must be noted when drug supplies 
are used during the study:
1. study identification number (ACE-LY-003)
2. subject identification number
3. lot number(s) of acalabrutinib dispensed for that subject
4. date and quantity of drug dispensed
5. any unused drug returned by the subject
At study initiation, the monitor will evaluate and approve the site’s procedure for 
investigational product disposal/destruction to ensure that it complies with  the 
Sponsor’s requirements. If the site cannot meet the Sponsor’s requirements for 

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disposal/destruction, arrangements will be made between the site and the Sponsor or 
its representative, for return of unused investigational product. Before 
disposal/destruction, final drug accountability and reconciliation must be performed by 
the monitor.
All study supplies and associated documentation will be regularly reviewed and verified 
by the monitor.
7.12
GENERAL INVESTIGATOR RESPONSIBILITIES
The principal investigator must ensure that:
1.
He or she will conduct or supervise the study.
2.
His or her staff and all persons who assist in the conduct of the study clearly 
understand their responsibilities and have their names included in the Study 
Personnel Responsibility/Signature Log.
3.
The study is conducted according to the protocol and all applicable regulations.
4.
The protection of each subject’s rights and welfare is maintained.
5.
Signed and dated informed consent and, when applicable, permission to use 
protected health information are obtained from each subject before conducting 
study procedures that are not standard of care. If a subject or subject’s legal 
guardian withdraws permission to use protected health information, the 
investigator will obtain a written request from the subject or subject’s legal 
guardian and will ensure that no further data are collected from the subject.
6.
The consent process is conducted in compliance with all applicable regulations 
and privacy acts.
7.
The IRB/IEC complies with applicable regulations and conducts initial and 
ongoing reviews and approvals of the study.
8.
Any amendment to the protocol is submitted promptly to the IRB/IEC.
9.
Any significant protocol deviations are reported to the Sponsor and the 
IRB/IEC according to the guidelines at each study site.
10. eCRF pages are completed promptly.
11. All IND Safety Reports and SUSAR Reports are submitted promptly to the 
IRB/IEC.
12. All SAEs are reported to the Sponsor’s Drug Safety department or
designee within 24 hours of knowledge and to the IRB/IEC per their 
requirements.

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8
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Leukemia and Lymphoma Society. NHL subtypes: World Health Organization (WHO) 
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9
APPENDICES

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

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Appendix 2. Adverse Event Assessment of Causality
Is there a reasonable possibility that the event may have been caused by study drug? 
No
Yes
The descriptions provided below will help guide the principal investigator in making the 
decision to choose either “yes” or “no”:
No = There is no reasonable possibility that the event may have been caused by study 
drug.
The adverse event:

may be judged to be due to extraneous causes such as disease or environment 
or toxic factors

may be judged to be due to the subject’s clinical state or other therapy being 
administered

is not biologically plausible

does not reappear or worsen when study drug is re-administered

does not follow a temporal sequence from administration of study drug
Yes = There is a reasonable possibility that the event may have been caused by study 
drug.
The adverse event:

follows a temporal sequence from administration of study drug

is a known response to the study drug based on clinical or nonclinical data

could not be explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other therapy administered to the subject

disappears or decreases upon cessation or reduction of dose of study drug

reappears or worsens when study drug is re-administered

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Appendix 3. Examples of Coadministered Drugs that Need Additional 
Consideration
The lists of drugs in these tables are not exhaustive. Any questions about drugs not on 
this list should be addressed to the medical monitor of this study.
Strong Inhibitors of CYP3A
Moderate inhibitors of CYP3A
boceprevir
aprepitant
clarithromycin a
cimetidine
cobicistata
ciprofloxacin
conivaptana
clotrimazole
danoprevir and ritonavir a,b
crizotinib,
diltiazema
cyclosporine
elvitegravir and ritonavir a,b
dronedaronea
grapefruit juice, Seville 
oranges, starfruit
erythromycin
idelalisib
fluconazole
indinavir and ritonavir a,b
fluvoxamine
Itraconazole a
imatinib
Ketoconazole a
tofisopam
lopinavir and ritonavir a,b
verapamila
nefazodone
nelfinavira
paritaprevir and ritonavir a and 
(ombitasvir and/or dasabuvir) b
posaconazole
ritonavir a,b
saquinavir and ritonavir a, b
telaprevira
tipranavir and ritonavir a b
troleandomycin
voriconazole
a.
Inhibitor of P-glycoprotein.
b.
Ritonavir is usually given in combination with other anti-
HIV or anti-HCV drugs in clinical practice. Caution should 
be used when extrapolating the observed effect of 
ritonavir alone to the effect of combination regimens on 
CYP3A activities.
c.
After discontinuation of the strong or moderate CYP3A 
inhibitor, wait 3 days before resuming acalabrutinib.

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Strong Inducers of CYP3A
carbamazepine
enzalutamide
mitotane
phenytoin
rifampin
St. John’s worta
a.
The effect of St. John’s wort varies widely 
and is preparation-dependent.
Proton-Pump Inhibitors
H2-Receptor Antagonists
dexlansoprazole
cimetidine
esomeprazole
famotidine
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/guidancecom
plianceregulatoryinformation/lawsactsandrules/ucm4
28333.pdf

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Appendix 4. Schedule of Assessments Part 1
Screeninga
Cycle 1
Cycle 2
Cycle 3
Cycles
4-6
Cycle
7
Cycles
8-12b
Cycle
≥13c
Safety
Follow-Upd
LTFUe
Day
Days (±2)
Days (±2)
Days 
(±2)
Days 
(±2)
Days 
(±2)
Days 
(±2)
Days 
(±7)
Days (+7)
1
8
15
22
1
15
1
1
1
1
1
Informed consent
x
Confirm eligibility
x
Medical history
x
PEf/Vital signsg/Weight
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG status
x
x
x
x
x
x
x
x
x
x
x
x
x
ECGh
x
x
Lab assessments:
Serum or urine 
pregnancyi
x
x
Hematologyj
x
xk.
x
x
x
x
x
x
x
x
x
x
x
Serum chemistryl
x
xk
x
x
x
x
x
x
x
x
x
x
x
Hepatitis serologym
x
HBV PCRn
x
x
x
x
x
x
x
x
x
HCV PCRn
x
Urinalysiso
x
T/B/NK cell countp
xk
x
x
Serum Igq
xk
x
x
x
Bone marrow 
(aspirate/biopsy)r
x
to confirm CR (if bone marrow was involved by 
lymphoma at baseline)
Pharmacodynamics
xm
xm
xn
xn
x
Pharmacokineticsu
x
x
x
x
x
Acalabrutinib dispensed
x
x
x
x
x
x
x
Rituximab administeredv
x
x
x
x
x
x
x
Study drug compliance
x
x
x
x
x
x
x
x
x
x
x
Tumor assessmentr
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse eventsw
x
x
x
x
x
x
x
x
x
x
x
x
Time-to-next treatment
x
anti-HBc=hepatitis B core antibodies; anti-HBs=hepatitis B surface antibody; CR=complete remission; CT=computed tomography; ECOG=Eastern Cooperative 
Oncology Group, FL=follicular lymphoma; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; Ig=immunoglobulin; IVIG=intravenous 
immunoglobulin; LTFU=long-term follow-up; PCR=polymerase chain reaction; PE=physical examination; PET=positron-emission tomography; T/B/NK=T cell/B 
cell/natural killer.
a.
Screening tests should be performed within 21 days before the first administration of study drug, unless otherwise indicated.
b.
Treatment with acalabrutinib may be continued until disease progression or an unacceptable drug-related toxicity occurs as defined in the protocol. The end of the 
study is defined as the final data cut-off for the final analysis (Section 3.2).
c.
Study assessments (including clinical evaluations, laboratories, and CT) are required on Day 1 of Cycle 13 and every 3 cycles thereafter (i.e., Cycles 16, 19, etc.).
d.
Until the final data cut-off, a 30-day (+7 days) safety follow-up visit is required when subjects discontinue study drug.
e.
Subjects who discontinue study therapy will continue on study for long-term follow-up of time-to-next therapy for FL (every 8-12 weeks) unless they withdraw consent for 
further follow-up.
f.
The physical examination includes height (screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities,

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musculoskeletal, nervous, lymphatic system, and general appearance. The lymphatic system examination will include examination of palpable lymph nodes and spleen and 
liver below the costal margin on the respective side. Only physicians, physician assistants, or oncology nurse practitioners should perform the lymphatic system 
examination. As much as possible, the same person should perform all the lymphatic exams for a given subject.
g.
Vital signs (blood pressure, pulse, respiratory rate, and temperature) will be assessed after the subject has rested in the sitting position.
h.
Subjects should be in supine position and resting for ≥10 minutes before study-related ECGs. A 12-lead ECG will be performed in triplicate (≥1 minute apart) at screening. 
The calculated QTc average of the 3 ECGs must be ≤480 ms for eligibility. If results from an unscheduled ECG are abnormal and considered clinically significant at any 
time, then an electrolyte panel (i.e., calcium, magnesium, and potassium) must be obtained to coincide with the ECG testing.
i.
Women of childbearing potential only.
j.
Hematology includes complete blood count with differential and platelet counts. Cycle 1 Day 1 hematology does not need to be repeated if screening hematology was 
within 5 days.
k.
The indicated samples at this timepoint (Cycle 1 Day 1) must be drawn predose.
l.
Serum chemistry: albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood urea nitrogen, bone-specific alkaline phosphatase, calcium, chloride, creatinine, glucose, 
LDH, magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin, total protein, and uric acid. Cycle 1 Day 1 serum chemistry does not need to be repeated if 
screening serum chemistry was within 5 days.
m.
Hepatitis serology must include HBsAg, anti-HBs, anti-HBc, and HCV antibody. In addition, any subjects testing positive for anti-HBc or HVC antibody, must have additional 
PCR testing during screening (see Section 4.1.14). Subjects who are receiving prophylactic IVIG and have positive HBsAg or anti-HBc must have negative hepatitis B DNA 
to be eligible. Those who are HBsAg positive or hepatitis B PCR positive and those who are hepatitis C PCR positive will be excluded.
n.
Subjects who are anti-HBc positive (or have a known history of HBV infection) should have PCR testing for HBV DNA performed during screening and monthly thereafter. 
Monthly monitoring should continue until 12 months after last dose of study drug. Any subject with a rising viral load (above lower limit of detection) should discontinue 
study drug(s) and have antiviral therapy instituted and a consultation with a physician with expertise in managing hepatitis B. If the HBV DNA PCR is needed during
long-term follow-up, it can be performed at a local laboratory. Subjects with a known history of hepatitis C or who are hepatitis C antibody positive should be tested by 
quantitative PCR for HCV RNA during screening. Such subjects may be enrolled provided the quantitative PCR is negative (undetectable viral load). No further monitoring 
for HCV RNA during treatment is necessary if initial PCR results are negative.
o.
Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.
p.
T/B/NK cell count (i.e., CD3+, CD4+, CD8+, CD19+, CD16+/56+).
q.
Serum immunoglobulin: IgG, IgM, IgA.
r
A pretreatment CT scan with contrast (unless contraindicated) is required of the chest, abdomen, and pelvis and any other disease sites (e.g., neck) within 30 days before 
the first dose of study drug. A pretreatment PET/CT scan within 60 days before the first dose of study drug. During treatment, CT scans will be performed for tumor 
assessments on Day 1 of Cycle 3 (±7 days), Cycle 5 (±7 days), Cycle 7 (±7 days); and then every 3 cycles (12 weeks, ±7 days) thereafter (i.e., Cycles 10, 13, 16, etc.) up to 
2 years then every 6 cycles (24 weeks) or more frequently at the investigator’s discretion. Bone marrow (if bone marrow was involved by lymphoma at baseline) and 
PET/CT are required to confirm CR per clinical guidelines (see Section 4.2). When possible, extra bone marrow tissue may be used for pharmacodynamic evaluation. At all 
other visits, tumor assessments will be performed by physical examination and laboratory results.
s.
Pharmacodynamic samples are drawn predose and 4 hours (±10 minutes) postdose on the days indicated. Timepoints are relative to the morning dose.
t.
Pharmacodynamic samples are drawn predose on the days indicated.
u.
Pharmacokinetic samples are drawn per Table 4.
v.
Rituximab 375 mg/m2 IV on Days 1, 8, 15 and 22 of Cycle 1 and Day 1 of Cycles 2 through 6.
w.
After the end of the protocol-defined adverse event reporting period (see Section 6.3.1), only serious adverse events considered related to study drug(s) or study 
procedures are required to be collected.

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Appendix 5. Schedule of Assessments Part 2
Screeninga
Cycle 1
Cycle 2
Cycle 3
Cycles 
4-6
Cycle 
7
Cycles 
8-12b
Cycles
≥13c
End of
treat-
ment
Safety 
Follow
-upd
DFUe
LTFUf
Day
Days (± 2)
Days (± 2)
Days 
(± 2)
Days 
(± 2)
Days 
(± 2)
Days 
(± 2)
Days 
(± 7)
Days 
(± 7)
Days 
(+ 7)
Days 
(± 7)
Days 
(± 7)
1
8
15
22
1
15
1
1
1
1
1
Informed consent
x
Confirm eligibility
x
Medical history
x
PEg/Vital 
signsh/Weight
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG status
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECGf
x
x
x
Endoscopy (gastric 
MALT)j
x
to confirm CR
Lab assessments:
Serum or urine 
pregnancyk
x
x
x
x
x
x
x
x
x
x
Hematologyl
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum chemistrym
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hepatitis serologyn
x
HBV PCRn
x
x
x
x
x
x
x
x
x
x
HCV PCRn
x
Urinalysiso
x
T/B/NK cell countp
xq
x
x
x
Serum Igr
xq
x
x
x
Bone marrow 
(aspirate/biopsy)j
x
to confirm CR (if bone marrow was involved by 
lymphoma at baseline), optional at end of 
treatment
Pharmacodynamicss
x
x
x
x
13C urea breath 
test (gastric
MALT)t
x
Acalabrutinib 
dispensedu
x
x
x
x
x
x
x
Rituximab 
administeredv
x
x
x
x
x
x
x
Study drug compliance
x
x
x
x
x
x
x
x
x
x
x
x
Tumor assessmentj
x
x
x
x
x
x
x
x
x
x
x
x
x
Archival tumorw
x
Peripheral blood for 
MRDw
Within 12 weeks of confirmation of radiological 
CR or PR
x
Time-to-next treatment
xe
xf

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Screeninga
Cycle 1
Cycle 2
Cycle 3
Cycles 
4-6
Cycle 
7
Cycles 
8-12b
Cycles
≥13c
End of
treat-
ment
Safety 
Follow
-upd
DFUe
LTFUf
Day
Days (± 2)
Days (± 2)
Days 
(± 2)
Days 
(± 2)
Days 
(± 2)
Days 
(± 2)
Days 
(± 7)
Days 
(± 7)
Days 
(+ 7)
Days 
(± 7)
Days 
(± 7)
1
8
15
22
1
15
1
1
1
1
1
Concomitant 
medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse eventsx
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Overall survival
x
anti-HBc=hepatitis B core antibodies; anti-HBs=hepatitis B surface antibody; CR=complete remission; CT=computed tomography; DFU=disease follow-up; 
ECOG=Eastern Cooperative Oncology Group; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; Ig=immunoglobulin; 
IVIG=intravenous immunoglobulin; LTFU=long-term follow-up; MALT=mucosa-associated lymphoid tissue; MRD=minimum residual disease; PCR=polymerase chain 
reaction; PE=physical examination; PET=positron-emission tomography; PR=partial response; T/B/NK=T cell/B cell/natural killer.
a.
Screening tests should be performed within 28 days before the first administration of study drug, unless otherwise indicated.
b.
Treatment with acalabrutinib may be continued until disease progression or an unacceptable drug-related toxicity occurs as defined in the protocol. The end of the study is defined 
as the final data cut-off for the final analysis (Section 3.2).
c.
Study assessments (including clinical evaluations, laboratories, and CT) are required on Day 1 of Cycle 13 and every 3 cycles for clinical visit and every 6 cycles for CT 
scan thereafter.
d.
Until the final data cut-off, a 30-day (+ 7 days) safety follow-up visit is required for all subjects after his or her last dose of study drug to monitor for adverse events 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.
e.
Subjects who discontinue for reasons other than progressive disease will be followed for disease progression (via CT scans per investigator discretion), regardless of
whether the subjects receive a new anticancer therapy. The time-to-next treatment information will also be collected. Subjects will then continue long-term follow-up 
(Section 4.4).
f.
Once subjects discontinue due to disease progression regardless of whether disease progression occurred during the study treatment period or disease follow-up period, 
they will be contacted approximately every 12 weeks by clinic visit or telephone, to obtain the information for the time to start of alternative anticancer therapy and assess 
survival until the subject dies, is lost to follow-up, or withdraws consent.
g.
The physical examination includes height (screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, 
musculoskeletal, nervous, lymphatic system, and general appearance. The lymphatic system examination will include examination of palpable lymph nodes and spleen and 
liver below the costal margin on the respective side. Only physicians, physician assistants, or oncology nurse practitioners should perform the lymphatic system 
examination. As much as possible, the same person should perform all the lymphatic exams for a given subject.
h.
Vital signs (blood pressure, pulse, respiratory rate, and temperature) will be assessed after the subject has rested in the sitting position.
i.
Subjects should be in supine position and resting for ≥10 minutes before study-related ECGs. A 12-lead ECG will be performed in triplicate (≥1 minute apart) at screening. 
The calculated QTcF average of the 3 ECGs must be ≤480 ms for eligibility. If results from an unscheduled ECG are abnormal and considered clinically significant at any 
time, then an electrolyte panel (i.e., calcium, magnesium, and potassium) must be obtained to coincide with the ECG testing.
j.
Tumor assessments: 1) An endoscopy for subjects with gastric MALT lymphoma is required within 90 days before the dose of study drug. 2) A pretreatment CT scan with 
contrast (unless contraindicated) is required of the chest, abdomen, and pelvis and any other disease sites (e.g., neck) within 30 days before the first dose of study drug. A 
pretreatment PET/CT scan within 60 days before the first dose of study drug. During treatment, CT scans will be performed for tumor assessments every 3 cycles
(12 weeks, ±7 days) starting at Day 1 of Cycle 4, Cycle 7, Cycle 10, and Cycle 13, and then every 24 weeks thereafter or more frequently at the investigator’s discretion.
3) A bone marrow aspirate/biopsy is required within 90 days before the first dose of study drug and is optional at the end of treatment for molecular profiling to discover 
mechanisms of resistance to study treatment. Bone marrow aspirate/biopsy (if involved by lymphoma at baseline), endoscopy (for subjects with gastric MALT), and PET/CT 
to confirm CR per clinical guidelines (see Section 4.2). When possible, extra bone marrow tissue may be used for pharmacodynamic evaluation. 4) At all other visits, tumor 
assessments will be performed by physical examination and laboratory test results.
k.
Women of childbearing potential only on Day 1 of each cycle.
l.
Hematology includes complete blood count with differential and platelet counts. Cycle 1 Day 1 hematology does not need to be repeated if screening hematology was 
within 5 days.
m.
Serum chemistry: Albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bicarbonate, blood urea nitrogen, bone-specific alkaline phosphatase, 
calcium, chloride, creatinine, glucose, lactate dehydrogenase, magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin, total protein, and uric acid. Cycle 1 
Day 1 serum chemistry does not need to be repeated if screening serum chemistry was within 5 days.

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n.
Hepatitis serology must include HBsAg, anti-HBs, anti-HBc, and HCV antibody. Subjects who are anti-HBc positive should have PCR testing for HBV DNA performed 
during screening and monthly thereafter. Monthly monitoring should continue until 12 months after last dose of study drug(s). Any subject with a rising viral load (above 
lower limit of detection) should discontinue study drug and have antiviral therapy instituted and a consultation with a physician with expertise in managing hepatitis B. 
Subjects with a known history of hepatitis C or who are hepatitis C antibody positive should be tested by quantitative PCR for HCV RNA during screening. Such subjects 
may be enrolled provided the quantitative PCR is negative (undetectable viral load). No further testing beyond screening is necessary if PCR results are negative.
o.
Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.
p.
T/B/NK cell count (i.e., CD3+, CD4+, CD8+, CD19+, CD16+/56+).
q.
The indicated samples at this timepoint (Cycle 1 Day 1) must be drawn predose. 
r
Serum immunoglobulin: IgG, IgM, IgA.
s.
Pharmacodynamic samples are drawn predose.
t.
A 13C urea breath test will be performed at screening only if the subject does not have H. pylori results from a pathology report. If this test is needed, proton-pump inhibitors 
and H2 blockers must be discontinued or withheld 14 days and 7 days, respectively, and antibiotics for treating H. pylori, such as those with anti-helicobacter action and 
bismuth preparations, should be withheld at least 30 days before the test.
u.
Subjects will receive their supply of acalabrutinib in the clinic on Day 1 of Cycle 1 and Cycle 2, and Day 1 of subsequent scheduled visits. Subjects should take their 
acalabrutinib dose in the clinic on Day 1 of Cycle 1. For treatments taken in the clinic, subjects should take acalabrutinib from the drug dispensed for that particular time 
period. All other acalabrutinib treatments will be taken at home.
v.
Rituximab 375 mg/m2 intravenously on Days 1, 8, 15, and 22 of Cycle 1 and Day 1 of Cycles 2 through 6. On the day when rituximab is administered, acalabrutinib will be 
administered first and rituximab will be administered approximately1 hour after the acalabrutinib dose.
w.
Archival tumor sample are collected for baseline genomics and MRD. For subjects with involved bone marrow, a bone marrow biopsy is acceptable. Molecular profiling and 
MRD testing will be performed on tumor biopsy, peripheral blood samples, and bone marrow samples by a central laboratory. A blood sample is to be collected within
12 weeks for subjects with radiological confirmation of CR or PR and at the end of treatment visit for subjects who discontinue study treatment for any reason. For subjects 
with lymphoma involvement of bone marrow at baseline, the bone marrow biopsy performed for CR confirmation should also be collected for MRD evaluation.
x.
After the end of the protocol-defined adverse event reporting period (see Section 6.3.1), only serious adverse events considered related to study drug(s) or study 
procedures are required to be collected.

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Appendix 6. Schedule of Assessments Part 3
Screeninga
Cycle 1
Cycle 2
Cycle 3
Cycles 
4-6
Cycle 7
Cycles 
8-12b
Cycles 
13c-27
Cycle
≥ 28 
(Q3M)
End of
treat-
ment
Safety 
Follow
-upd
DFUe
LTFUf
Day
Days (± 2)
Days 
(± 2)
Days 
(± 2)
Days 
(± 2)
Days 
(± 2)
Days (± 2)
Days (± 7)
Days 
(± 7)
Days 
(+ 7)
Days 
(± 7)
Days 
(± 7)
1
8
15
22
1
15
1
1
1
1
1
1
Informed consent
x
Confirm eligibility
x
Medical history
x
PEg/Vital 
signsh/Weight
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG status
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECGi
x
x
x
Lab assessments:
Serum or urine 
pregnancyj
xj
x
x
x
x
x
x
x
x
x
x
x
x
x
Hematologyk
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum 
chemistryl
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hepatitis 
serologym
x
HBV PCRm
x
x
x
x
x
x
x
x
x
x
x
HCV PCRm
x
Urinalysisn
x
T/B/NK cell 
counto
x
x
x
x
Serum Igp
x
x
x
x
Bone marrow 
(aspirate/ 
biopsy)q,r
x
to confirm CR and for MRD (if bone marrow was involved by 
lymphoma at baseline), optional at end of treatment
TSH, T3, T4
x
Every 12 weeks during treatment with lenalidomide and 12 weeks after the last dose of 
lenalidomide
Pharmacodynamics
xs
xs
xs
xs
xs
Pharmacokinetics
xs
xs
xs
Acalabrutinib 
dispensedt
x
x
x
x
x
x
x
x
Enroll in REVLIMID 
REMSu
x
Lenalidomide 
dispensedv
x
x
x
x
x
x
Rituximab 
administeredw
x
x
x
x
x
x
x
x
x

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Study drug 
compliance
x
x
x
x
x
x
x
x
x
x
x
x
x
Tumor 
assessmentq
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Archival tumorx
x
Peripheral blood for
baseline molecular 
profiley
x
Peripheral blood for 
ctDNAz
x
x
x
x
x
x
x
Saliva sample for
ctDNAz
x
Peripheral blood for 
MRDr
Within 12 weeks of confirmation of radiological CR or PR
Concomitant 
medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse eventsaa
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
anti-HBc=hepatitis B core antibodies; anti-HBs=hepatitis B surface antibody; CR=complete remission; CT=computed tomography; ctDNA=circulating tumor DNA; 
DFU=disease follow-up, ECOG=Eastern Cooperative Oncology Group, HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus;
Ig=immunoglobulin; IVIG=intravenous immunoglobulin; LTFU=long-term follow-up; MRD=minimum residual disease; PCR=polymerase chain reaction; PE=physical 
examination; PET=positron-emission tomography; PR=partial response; Q3M=every 3 months; SFU=safety follow-up; T3=triiodothyroxine; T4=thyroxine;
T/B/NK=T cell/B cell/natural killer; TSH=thyroid stimulating hormone.
a.
Screening tests should be performed within 28 days before the first administration of study drug, unless otherwise indicated.
b.
Treatment with acalabrutinib may be continued until disease progression or an unacceptable drug-related toxicity occurs as defined in the protocol. The end of the study 
is defined as the final data cut-off for the final analysis (Section 3.2).  
c.
Study assessments (including clinical evaluations, laboratories, and CT) are required on Day 1 of Cycle 13 and every 3 cycles for the clinical visit and every 6 cycles for CT 
scan thereafter. (Pregnancy testing for women of childbearing potential will still be required monthly).
d.
Until the final data cut-off, a 30-day (+7 days) safety follow-up visit is required for all subjects after his or her last dose of study drug to monitor for adverse events 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.
e.
Each subject should be followed until disease progression or the start of alternative anticancer therapy. If neither of these has occurred at the time of the 30-day SFU visit, 
DFU visits should occur approximately every 12 weeks until disease progression or next anticancer treatment. During this period, subjects will be followed via CT scans.
f
Once subjects discontinue due to disease progression regardless of whether disease progression occurred during the study treatment period or disease follow-up period, 
they will be contacted approximately every 12 weeks by clinic visit or telephone, to obtain the information for the time to start of alternative anticancer therapy and assess 
survival until the subject dies, is lost to follow-up, or withdraws consent.
g.
Physical examination includes height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, 
musculoskeletal, nervous, lymphatic system, and general appearance. The lymphatic system examination will include examination of palpable lymph nodes and spleen and 
spleen and liver below the costal margin on the respective side. Only physicians, physician assistant, or oncology nurse practitioners should perform the lymphatic system 
examination. As much as possible, the same person should perform all the lymphatic exams for a given subject.
h.
Vital sign measurements (blood pressure, pulse, respiratory rate, and body temperature) will be assessed after the subject has rested in the sitting position.
i.
Subjects should be in supine position and resting for ≥10 minutes before study-related ECGs. A 12-lead ECG will be performed in triplicate (≥1 minute apart) at screening. 
The calculated QTcF average of the 3 ECGs must be ≤480 ms for eligibility. If results from an unscheduled ECG are abnormal and considered clinically significant at any 
time, then an electrolyte panel (i.e., calcium, magnesium, and potassium) must be obtained to coincide with the ECG testing.
j.
Women of childbearing potential must have two negative pregnancy tests prior to the first dose of lenalidomide. The first pregnancy test should be performed 10 to 14 days 
before the first dose and the second test within 24 hours prior to the first dose of lenalidomide. Pregnancy tests should be performed weekly in the first month and then 
monthly thereafter until 4 weeks after discontinuation of lenalidomide.
k.
Hematology includes complete blood count with differential and platelet counts. Cycle 1 Day 1 hematology does not need to be repeated if screening hematology was 
within 5 days.
l.
Serum chemistry: Albumin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, bicarbonate, blood urea nitrogen, bone-specific alkaline phosphatase, 
calcium, chloride, creatinine, glucose, lactate dehydrogenase, magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin, total protein, and uric acid. Only at 

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baseline: Creatinine clearance >60 mL/min. Cycle 1 Day 1 serum chemistry does not need to be repeated if screening serum chemistry was within 5 days.
m.
Hepatitis serology must include HBsAg, anti-HBs, anti-HBc, and HCV antibody. Subjects who are anti-HBc positive should have PCR testing for HBV DNA performed
during screening and monthly thereafter. Monthly monitoring should continue until 12 months after last dose of study drug(s). Any subject with a rising viral load (above 
lower limit of detection) should discontinue study drug and have antiviral therapy instituted and a consultation with a physician with expertise in managing hepatitis B. 
Subjects with a known history of hepatitis C or who are hepatitis C antibody positive should be tested for HCV RNA during screening. No further testing beyond screening is 
necessary if PCR results are negative.
n.
Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose. Cycle 1 Day 1 urinalysis does not need to be repeated if screening urinalysis was within 
5 days.
o.
T/B/NK cell count (i.e., CD3+, CD4+, CD8+, CD19+, CD16+/56+).
p.
Serum immunoglobulin: IgG, IgM, IgA.
q.
Tumor assessments: 1) A pretreatment CT scan with contrast (unless contraindicated) is required of the chest, abdomen, and pelvis and any other disease sites (e.g., neck) 
within 30 days before the first dose of study drug. 2) A pretreatment PET/CT scan within 60 days before the first dose of study drug is required. During treatment, PET/CT 
scans will be performed at Cycle 4 Day 1 (Week 12), Cycle 7 Day 1 (Week 24), and at CR. CT scans will be performed for tumor assessments every 3 cycles (12 weeks,
±7 days) starting at Day 1 of Cycle 4, Cycle 7, Cycle 10, and Cycle 13, then every 24 weeks thereafter or more frequently at the investigator’s discretion. 3) A bone marrow 
aspirate/biopsy is required within 90 days before the first dose of study drug. 4) To confirm CR, PET/CT must be performed and, if bone marrow was involved by lymphoma 
at baseline, a bone marrow aspirate/biopsy must be performed (see Section 4.1.8). 5) At all other visits, tumor assessments will be performed by physical examination.
r.
Molecular profiling and MRD testing will be performed on tumor biopsy, peripheral blood samples, and bone marrow samples by a central laboratory. 1) A blood sample is 
to be collected within 12 weeks for subjects with radiological confirmation of CR or PR and at the end of treatment visit for subjects who discontinue study treatment for any 
reason. 2) For subjects with lymphoma involvement of bone marrow at baseline, a bone marrow biopsy performed for CR confirmation and a bone marrow aspirate should 
also be collected for MRD evaluation.3) Baseline evaluation of MRD will be based on archival lymph node biopsy or bone marrow biopsy for subjects with involved bone 
marrow, or tissue sample obtained at screening.
s.
Pharmacodynamic samples will be drawn for Cycle 1 Day 1 (predose and 4 hours postdose) and on Cycle 1 Day 8 (predose and 4 hours postdose). Pharmacodynamic 
samples will be taken predose on Cycle 2 Day 1, Cycle 3 Day 1, at disease progression, and at EOT. Pharmacokinetic samples will be drawn for Cycle 1 Day 1 and Day 8, 
and Cycle 2 Day 1 at 1 and 4 hours postdose of acalabrutinib.
t.
Subjects will receive their supply of acalabrutinib in the clinic on Day 1 of Cycle 1 and Cycle 2, and Day 1 of subsequent scheduled visits. Subjects should take their 
acalabrutinib dose in the clinic on Day 1 of Cycle 1. For treatments taken in the clinic, subjects should take acalabrutinib from the drug dispensed for that particular time 
period. All other acalabrutinib treatments will be taken at home.
u.
Lenalidomide is available only under a special restricted program called REVLIMID REMS to avoid fetal exposure because of potential toxicity. Prescribers and pharmacists 
registered with the program can prescribe and dispense the product to subjects who are registered and meet all the conditions of the REVLIMID REMS program. All 
subjects (males and females) receiving lenalidomide must be enrolled in the REVLIMID REMS program.
v.
Lenalidomide is to be taken orally daily on Days 1 through 21 of each cycle for up to 12 cycles or until disease progression or intolerance, whichever comes first. The 
starting dose is 15 mg QD and the final dose for dose expansion will be based on DLT evaluation. On days that both acalabrutinib and lenalidomide are administered, 
lenalidomide should be taken approximately 30 minutes prior to the first daily dose of acalabrutinib. Please note that on PK sample collection days, the time of dosing for all 
study drugs must be recorded in the clinical database (electronic case report form).
w.
Rituximab 375 mg/m2 IV administered on Days 1, 8, 15, and 22 of Cycle 1, and Day 1 of every cycle starting at Cycle 2 through Cycle 6, followed by 10 additional doses of 
maintenance rituximab every other cycle beginning with Cycle 8 for subjects who have not progressed. On the day when rituximab is administered, acalabrutinib will be 
administered first and rituximab will be administered approximately 1 hour later. After the last Rituximab dose on Cycle 26, then visits are to occur every 3 cycles starting on 
Cycle 28 until disease progression or intolerance.
x.
Archival tumor sample are collected for baseline genomics and MRD. For subjects with disease involved bone marrow, a bone marrow biopsy is acceptable.
y.
Baseline peripheral blood sample will be drawn for molecular profiling using genomics.
z.
ctDNA samples will be collected at screening and, at every tumor assessment visit beginning with Cycle 4 and at end of treatment. A 2-mL saliva sample to serve as a 
matched normal control sample will be collected.
aa. After the end of the protocol-defined adverse event reporting period (see Section 6.3.1, only serious adverse events considered related to study drug(s) or study 
procedures are required to be collected.

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

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

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

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

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

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Appendix 8. Management of Study Procedures During Pandemic
This appendix consolidates guidance for subject safety and ongoing access to medical 
care and investigational product during the global COVID-19 pandemic. The measures 
detailed below will be implemented across the Sponsor studies on a temporary basis 
until the pandemic is considered resolved by governmental and public health 
organizations, as applicable. 
Regardless of the guidance below, please consider public health advice in your local 
market and individual risk/benefit in treatment decisions for patients at your study site 
during the pandemic. Please also consider logistical requirements such as the ability of 
patients to travel to the study site, accessibility of public transport, etc.
If the subject is unable or unwilling to visit the study site due to COVID-19 related 
reasons, investigators may ask enrolled subjects to use healthcare facilities local to the 
subject to ensure safety and efficacy measures are done per protocol. If a study 
assessment is not done at either the site or a facility local to the subject, then its 
absence should be documented as a protocol deviation. Any protocol deviations 
resulting from the COVID-19 situation should be recorded and prefixed with COVID-19.
STUDY SUBJECT PARTICIPATION
Conduct of Telephone Visits
Due to the current pandemic, it is conceivable that not all subject visit commitments may 
be able to be fulfilled. If a subject is unable or unwilling to attend a study visit, adaptation 
of the onsite visit to a telephone visit is recommended to ensure continuity of study care 
(as an interim measure; e.g., telephone contacts instead of visits, shipping study 
medication to the subject). Priority should be given to maintaining ongoing safety 
follow-up (even if this is conducted by telephone contacts). Study sites should speak 
with their site monitor before performing a telephone visit so he or she may provide 
guidance regarding logistics that may need consideration. Also, study sites should 
speak with the site monitor if the subject cannot attend more than one onsite visit in 
succession, because multiple incomplete visits may have the potential to impact 
evaluation of study endpoints.
Acalabrutinib Dose Modification Recommendation for COVID-19
The Sponsor recognizes that coronavirus 2019-nCoV (COVID-19) presents an 
increased risk for all patients. Due to the potential impact of COVID-19 on multiple organ 
systems, the Sponsor recommends the following dose modification and management 
plan for patients with confirmed or suspected COVID-19 while receiving treatment with 

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

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

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

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visit. 
3.
If the visit requires procedures that cannot be performed via telephone contact 
(e.g., MRI or CT scan), this should be discussed with the site monitor because this 
procedure may impact primary efficacy or safety analyses.
ACALABRUTINIB SITE-TO-SUBJECT DRUG SHIPMENT INSTRUCTIONS DURING 
PANDEMIC CONTAINMENT OR IN CASE OF FORCE MAJEURE
If a subject is definitively unable to physically go to the study site or unable to be 
represented by a third person because of pandemic containment or other force majeure, 
the study site's pharmacy may ship the study drug to the home of the subject following 
approval by the Sponsor. 
For such a shipment, the following conditions must be met:

The Sponsor is responsible for delivery of the study drug to the study site. Any 
shipments made from the site to the subject will be the responsibility of the study 
site.

The subject is informed about the shipment method, confirms the address for 
receipt of the drug, and agrees that his or her personal information (i.e., name and 
address) may be given to a professional carrier.

The pharmacy securely packages the drug for shipment. 

A professional carrier is used by the pharmacy to ship the drug securely and
maintain chain of custody, with evidence provided. Acalabrutinib must be stored 
and shipped at room temperature (15°C to 30°C). The professional carrier must 
ensure that temperature monitoring is conducted for all shipments.

To respect patient confidentiality, the carrier should only be given the name and 
address of the subject. The Sponsor should not receive any personal information 
about the subject.

A procedure is defined with the carrier to confirm the receipt of the drug by the 
subject and that it is received in good condition.

The site contacts the subject to confirm the receipt and integrity of the drug and 
gives instructions about the drug administration.

The pharmacy completes its accountability with each shipment made directly to a 
subject.

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Appendix 9. Medication Error, Drug Abuse, and Drug Misuse
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or 
mistake in the treatment process for an IMP or AstraZeneca NIMP that either causes 
harm to the subject or has the potential to cause harm to the subject.
A medication error is not lack of efficacy of the drug, but rather a human or process 
related failure while the drug is in control of the study site staff or subject.
Medication error includes situations where an error:

Occurred

Was identified and intercepted before the subject received the drug

Did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error, eg, medication prepared incorrectly, even if it was not actually given 
to the subject

Drug not administered as indicated, eg, wrong route or wrong site of administration

Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a 
solid tablet

Drug not stored as instructed, eg, kept in the refrigerator when it should be at room 
temperature

Wrong subject received the medication (excluding IRT/RTSM errors)

Wrong drug administered to subject (excluding IRT/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT/RTSM - including those which led to one of the 
above listed events that would otherwise have been a medication error

Subject accidentally missed drug dose(s), eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Subject failed to return unused medication or empty packaging
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic 

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intentional, non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived 
reward or desired non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and 
forwarded to the DES using the Drug Abuse Report Form. This form should be used 
both if the drug abuse happened in a study subject or if the drug abuse involves a 
person not enrolled in the study (such as a relative of the study subject).
Examples of drug abuse include but are not limited to:

The drug is used with the intent of getting a perceived reward (by the study subject or 
a person not enrolled in the study

The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study subject) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorized product information, 
or for unauthorized IMPs or AstraZeneca NIMPs, outside the intended use as specified 
in the protocol and includes deliberate administration of the product by the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and 
forwarded to the DES using the Drug Misuse Report Form. This form should be used 
both if the drug misuse happened in a study subject or if the drug misuse regards a 
person not enrolled in the study (such as a relative of the study subject).
Examples of drug misuse include but are not limited to:

The drug is used with the intention to cause an effect in another person

The drug is sold to other people for recreational purposes

The drug is used to facilitate assault in another person

The drug is deliberately administered by the wrong route

The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole

Only half the dose is taken because the study subject feels that he/she is feeling better 
when not taking the whole dose

Someone who is not enrolled in the study intentionally takes the drug.

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Appendix 10.
Data Quality Assurance
All subject data relating to the study will be recorded on eCRF unless transmitted to 
AstraZeneca or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
At the final data cut-off, the clinical database will be closed to new data collection, 
however SAEs must continue to be reported via paper form. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy, methods, responsibilities and requirements, 
including handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are included in the Monitoring Plan. 
AstraZeneca assumes accountability for actions delegated to other individuals (eg, 
CROs). 
Record retention must align with GRAD (code 0102 Investigator Site File). In some 
markets the local requirement is less than 25 years e.g. Canada 15 years. If you are 
running a study in these countries please align to the local requirement and apply the 
appropriate GRAD exception.

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Appendix 11.
Dissemination of Clinical Study Data
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS 
within a year from global End of Trial Date in all participating countries, due to scientific 
reasons as otherwise statistical analysis is not relevant.
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the study results when they are available. The clinical study and/or 
summary of study results may also be available on other websites according to the 
regulations of the countries in which the study is conducted.

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Appendix 12.
Country Specific Requirements
Canada specific Amendments
Version 6.1 - 22 February 2021
This amendment was considered non-substantial as the rational for all changes were for 
clarification. Clarifying edits and typographical changes were made throughout the protocol. 
The following substantive changes were made as part of this amendment:
Sections Impacted
Rationale
Synopsis, Section 3.1, Appendix 6
Clarified that subjects in Canada are not required 
to participate in the lenalidomide REMS program
For country-specific reasons, this 
requirement does not and will not apply 
to subjects in Canada
Section 4.0
Added sentence to reference new appendix for 
management of study procedures during 
pandemic. 
Reference to new appendix was added. 
Section 6.3.4, Section 6.3.5, and Section 7.1.2
Updates were made to the designee for receipt of 
serious adverse events and pregnancy reporting 
from Acerta Pharma Drug Safety to AstraZeneca 
Representative
Updated contact information
Appendix 5,
Added ± 2 day window for Cycle 1 Day 1
Defined the time window for capturing 
the blood sample and pregnancy test 
within 48 hours prior to C1D1.
Appendix 6
Added ± 2 day window for Day 1
Added column header for Cycle 2 to include ± 2 
day window
For logisitic reasons, challenge for 
dosing on same day as the visit 
assessments are performed. 
Appendix 7 Management of Study Procedures 
During Pandemic
Added appendix to consolidate 
guidance for subject safety and ongoing 
access to medical care and 
investigational product during the global 
COVID-19 pandemic.
Version 7.0 - 14 July 2022
This protocol was amended to update the safety language from the most recent 
acalabrutinib Investigator’s Brochure (version 11), to implement commercial drug transition 
language, and update the end of study definition.
Clarifying edits and typographical changes were made throughout the protocol. The 
following substantive changes were made as part of this amendment:
Sections Impacted
Rationale
Substantial / 
Non-substantial
Study Synopsis; Section 3.1 DESCRIPTION OF 
STUDY; Section 3.4.1 Inclusion Criteria Part 1; 
Section 3.4.3 Inclusion Criteria Part 2; Section 3.4.5 
Inclusion Criteria Part 3; Section 3.7.2 Risks 
Associated with Rituximab (Rituxan/MabThera) 
Treatment; Section 3.7.6 Reproductive Toxicity; 
Section 6.2.3 Adverse Events of Special Interest
To align with the 
current local 
labels for 
lenalidomide and 
rituximab
Non-substantial

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Updated contraceptive recommendations for 
lenalidomide and rituximab, rituximab 
contraindications, and rituximab warnings and 
precautions to align with the current local label 
recommendations. In addition, added suspected 
transmission of an infectious agent as an adverse 
event of special interest due to the use of rituximab 
in this study.
Study Synopsis; Section 3.1 DESCRIPTION OF 
STUDY; Section 3.2 END OF STUDY; Section 4.3 
SAFETY FOLLOW-UP VISIT; Section 6.3 
DOCUMENTING AND REPORTING OF ADVERSE 
AND SERIOUS ADVERSE EVENTS; Section 6.3.5 
Expedited Reporting Requirements for Serious 
Adverse Events and Adverse Events of Special 
Interest; Appendix 4. Schedule of Assessments Part 
1; Appendix 5. Schedule of Assessments Part 2; 
Appendix 6. Schedule of Assessments Part 3
Clarified timings of final data cut-offs, end of study 
definition and added text to describe the continued 
treatment and monitoring of subjects still on 
acalabrutinib at the time of final data cut-off who are 
deriving clinical benefit from acalabrutinib 
treatment.   
To provide 
clarification on 
continued 
treatment at the 
time or final data 
cut-off.
Non-substantial
Study Synopsis; Section 3.6.3 Cautionary Therapy 
Considerations Including Drug-Drug Interactions
Added guidance for when acalabrutinib is used with 
a strong or moderate CYP3A inhibitor.
To align with 
guidance in local 
labels (such as 
the US 
Prescribing 
Information) on 
acalabrutinib dose 
adjustment when 
given with a 
strong or 
moderate CYP3A 
inhibitor.
Substantial
Section 3.7.1 Risks Associated with Acalabrutinib 
Treatment
Text updated to advise that institutional guidelines 
should be followed in the management of infections, 
and atrial fibrillation. Previous PML and Hepatitis B 
Reactivation text removed as incorporated under 
the important identified risk of Infections. In addition, 
a new section for “Contraindications” added, for 
which there are none for acalabrutinib, and a new 
section for “Important Potential Risks” added with 
an overview on hepatotoxicity events.
To align with the 
acalabrutinib 
Investigator’s 
Brochure version 
10 and version 
11.
Substantial
Section 4.1.7 Physical Examination, Vital Signs, 
To align with 
Non-substantial

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Height, and Weight
Text updated to note nervous system examination 
will include attention to neurologic signs and 
symptoms of PML.
project-specific 
standards.
Section 6.3.1 Adverse Event Reporting Period
Text revised for clarity.
To align with 
project-specific 
adverse event 
collection 
standards.
Non-substantial
Throughout
Minor editorial, formatting, and typographical 
updates and corrections have been made.
Minor corrections 
made for 
document clarity
Non-substantial

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