A Phase 2, Open-Label Study of Acalabrutinib in Combination With R-ICE For Relapsed or Refractory Non-Germinal Center Diffuse Large B Cell Lymphoma, Transformed Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia or Transformed Marginal Zone Lymphoma
Phase: PHASE2
Conditions: Diffuse Large B Cell Lymphoma, Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia, Marginal Zone Lymphoma
Sponsor: University of Miami

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IRB Study Number: 20190706
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eProst #: 20190706 
IND #: TBD
                                                                        NCT04189952
A Phase 2, Open-Label Study of Acalabrutinib in Combination with R-ICE For Relapsed or 
Refractory Non-Germinal Center Diffuse Large B Cell Lymphoma, Transformed Chronic 
Lymphocytic Leukemia/Small Lymphocytic Leukemia or Transformed Marginal Zone Lymphoma
Lead Principal Investigator
Craig Moskowitz, MD 
University of Miami
Sylvester Comprehensive Cancer Center
Funding Collaborator
AstraZeneca
Study Drug Name
Acalabrutinib
Version
3.0
Version Date
24 June, 2021
Confidentiality Statement: The information contained in this document, especially unpublished data, 
is confidential property. The information in this document may not be disclosed to others unless federal 
or state law or regulations require such disclosure. Subject to the foregoing, this information may be 
disclosed only to those persons involved in the study who have a need to know, with the obligation not 
to further disseminate this information.
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INVESTIGATOR AGREEMENT
I confirm that I have read this protocol, I understand it, and I will work according to this protocol and to 
the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable ICH 
guidelines for good clinical practices, and the applicable federal, state, and local laws, rules, and 
regulations relating to the conduct of the protocol.
I have read and understand the information in the Investigators’ Brochure (and/or other such pertinent 
safety information) regarding the risks and potential benefits.
I agree to inform all those who assist/collaborate with me in the conduct of this study of their 
responsibilities and obligations.
Once the protocol has been reviewed and approved by the Institutional Review Board (IRB) I 
understand that any change(s) made during the course of the study must also (first) be approved by the 
IRB prior to implementation, except when such modification is made to remove any immediate 
hazard(s) to the subject(s).
I certify that I and the study staff responsible, have received the requisite training to conduct this 
research protocol.
I agree to maintain adequate and accurate records in accordance with the University of Miami policies, 
federal, state and local laws and regulations.
I agree to maintain the confidentiality of all information received and/or developed in connection with 
this protocol.
eProst Number:
20190706
Protocol Version Number: 3.0
Protocol Version Date: 24 June, 2021
Signature of Investigator:
Date:
Name of Investigator (printed):
Institution:
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PROTOCOL REVISION HISTORY
Version Number
Version Date
Summary of Revisions Made
2.0
8 June, 2020
1.
Section 1.4.2.1-1.4.2.5 was updated with the latest language 
from the Investigational Brochure, version 9.0, dated 19 
February, 2020.
2.
Section 3.10.3:The old version of contraception language was 
replaced with the latest version of contraception template 
language from the HSRO published ICF template.
3.
Section 4.0 Replaced incorrect reference from “Section 3.4” to 
“Section 3.5”
4.
Section 4.1.7 Added directed physical exam to be performed 
every day while participants are receiving R-ICE treatment.
5.
Section 4.1.11 Added that chemistry (potassium) will be 
performed every day while participants are receiving R-ICE 
treatment
6.
Section 4.1.12 Added that urinalysis will be performed every 
day while participants are receiving R-ICE treatment.
7.
Appendix 1:

Added a treatment window of day 1+ 7 or – 3 days to 
Cycles 2-3

Added treatment window of 14-28 days to end of 
treatment visit

Added a treatment window of + or – 1 week to the 
follow up visits that will be performed every 12 weeks

Replaced reference of Section 3.4 to Section 3.5.3

Added chemistry (potassium)

Added urinalysis

Added footer for directed physical exam, chemistry 
and urinalysis to be performed every day while 
participants are receiving R-ICE treatment.
8.
Appendix 5: Added instructions on taking medication to the 
patient diary
9.
Appendix 6 Collection and processing of pre-treatment and
end of treatment blood samples for BCR clonotyping was 
added.
3.0
24 June, 2020
Global Changes

Replaced “sponsor-investigator” with “lead investigator” and 
clarified that each site sub-investigator was the “study site 
principal investigator”.

Clarified that the University of Miami is the coordinating study 
center.

Replaced “investigational drug sponsor” with “supplier of the 
study medication”
Changes to Specific Sections:
1.
Section 3.0. Added language to indicate that this is a multi- 
center, open-label, single arm trial.
2.
Section 3.1.3. References to MedRA were removed and 
replaced with NCI CTCAE 5.0.
3.
Section 3.3.3. Added recruitment and enrollment language, 
consistent with the local addendum language.
4.
Section 3.4. Added definitions for participant discontinuation 
procedures and criteria and definitions for patients lost to 
follow up.
5.
Section 3.14. Added standard study auditing and monitoring 
language.
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6.
Sections 6.2.5, 6.2.6, 6.2.7. Updated AE/SAE reporting 
requirements for study sites to UM (coordinating center), 
coordinating center requirements to the FDA and 
pharmaceutical company.
7.
Section 7.4. Added references to the manual of procedures.
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TABLE OF CONTENTS
LIST OF STUDY CENTERS ......................................................................................2
INVESTIGATOR AGREEMENT ................................................................................3
PROTOCOL REVISION HISTORY ............................................................................4
TABLE OF CONTENTS .............................................................................................6
ABBREVIATIONS.....................................................................................................10
STUDY SYNOPSIS..................................................................................................13
1
BACKGROUND INFORMATION...................................................................19
1.1
Salvage Therapy for Autologous Stem Cell Transplant Eligible Patients with rel/ref 
DLBCL...........................................................................................................19
1.2
Bruton Tyrosine Kinase Inhibition in B cell Lymphomas and DLBCL, including 
combination with R-ICE.................................................................................19
1.2.1
BTK inhibition with ibrutinib as a single agent in DLBCL .................20
1.2.2
R-ICE for relapsed and refractory B cell lymphoma.........................20
1.2.3
Phase I ibrutinib + R-ICE .................................................................20
1.3
acalabrutinib (ACP-196) ................................................................................21
1.3.1
Mechanism of Action........................................................................21
1.3.2
Safety Pharmacology.......................................................................22
1.3.3
Drug-drug Interaction Potential ........................................................22
1.4
Clinical Experience – acalabrutinib................................................................22
1.4.1
Clinical Efficacy................................................................................22
1.4.2
Adverse Events................................................................................23
1.4.2.1
Hemorrhage.......................................................................23
1.4.2.2
Infection.............................................................................23
1.4.2.3
Cytopenias.........................................................................23
1.4.2.4
Second Primary Malignancies ...........................................23
1.4.2.5
Atrial Fibrillation .................................................................24
1.5
R-ICE.............................................................................................................24
2
STUDY OBJECTIVES...................................................................................24
2.1
Primary Objective ..........................................................................................24
2.2
Secondary Objective(s) .................................................................................24
2.3
Exploratory Objective(s) ................................................................................24
3
STUDY DESIGN............................................................................................24
3.1
Study Parameters..........................................................................................25
3.1.1
Efficacy Parameters.........................................................................25
3.1.2
Safety Parameters ...........................................................................25
3.1.3
Pharmacodynamic, Pharmacokinetic and Biomarker Parameters...25
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3.2
Rationale for Study Design and Dosing Regimen .........................................25
3.3
Selection of Study Population........................................................................26
3.3.1
Inclusion Criteria ..............................................................................26
3.3.2
Exclusion Criteria .............................................................................26
3.3.3
Recruitment......................................................................................28
3.4
Study intervention discontinuation and Participant discontinuation/withdrawal28 
3.4.1
Discontinuation of Study Intervention ..............................................28
3.4.2
Participant Discontinuation/Withdrawal from the Study....................28
3.4.3
Data Retention When Subjects Withdraw from FDA-Regulated Clinical Trials
....................................................................................................... 29
3.4.4
Participant Replacement Criteria .....................................................29
3.4.5
Screen Failures................................................................................29
3.4.6
Lost to follow up...............................................................................29
3.5
STUDY DRUG...............................................................................................30
3.5.1
Premedications ................................................................................30
3.5.2
Formulation, Packaging, and Storage..............................................30
3.5.3
Administration of Study Drug ...........................................................30
3.5.4
Assuring Subject Compliance ..........................................................30
3.6
Study Treatment Schedule............................................................................30
3.7
Duration of Therapy.......................................................................................30
3.8
Dosing Delays and Modifications...................................................................31
3.9
Concomitant Therapy ....................................................................................33
3.9.1
Permitted Concomitant Therapy ......................................................33
3.9.2
Prohibited or Restricted Concomitant Therapy ................................33
3.9.2.1
CYP Inhibiting/Inducing Drugs...........................................34
3.9.2.2
QT Prolonging Agents .......................................................34
3.9.2.3
Drugs That May Have Their Plasma Concentration Altered by 
Acalabrutinib....................................................................34
3.9.2.4
Antiplatelet Agents and Anticoagulants .............................34
3.9.2.5
Surgery..............................................................................34
3.10
PRECAUTIOns..............................................................................................35
3.10.1
Dietary Restrictions..........................................................................35
3.10.2
Drug-drug Interactions & Infusion Reactions ...................................35
3.10.3
Contraception Requirements ...........................................................35
3.10.4
Overdose Instructions ......................................................................36
3.11
Withdrawal of Subjects From Study Treatment .............................................36
3.12
Removal from study.......................................................................................37
3.13
Data and Safety Monitoring ...........................................................................37
3.14
Study Auditing and Monitoring.......................................................................37
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3.14.1
Trial Monitoring, Auditing, and Inspecting ........................................37
3.15
Quality Assurance and Quality Control..........................................................38
4
STUDY ACTIVITIES AND ASSESSMENTS..................................................38
4.1
Description of Procedures .............................................................................38
4.1.1
Informed Consent and Permission to Use Protected Health Information
38
4.1.2
Medical History.................................................................................38
4.1.3
Adverse Events................................................................................38
4.1.4
Concomitant Medications and Therapy............................................38
4.1.5
Confirmation of Eligibility...................................................................39
4.1.6
ECOG Performance Status..............................................................39
4.1.7
Physical Examination, Height & Weight, & Vital Signs.....................39
4.1.8
Electrocardiogram ............................................................................39
4.1.9
Urine or Serum Pregnancy Test.......................................................39
4.1.10
Hematology......................................................................................39
4.1.11
Serum Chemistry ..............................................................................39
4.1.12
Urinalysis..........................................................................................39
4.1.13
Hepatitis B and C Testing ................................................................39
4.1.14
Coagulation Panel............................................................................39
4.1.15
Pharmacodynamics/Pharmacokinetics and Biomarker Studies .......39
4.1.16
Tumor Assessments ........................................................................41
4.1.17
Study Drug Accountability ................................................................42
4.2
Assessment of Response to Treatment.........................................................42
4.3
End of Treatment and Treatment Termination Visits .....................................42
4.4
Follow-up for Progression and Survival .........................................................42
4.5
Missed Evaluations........................................................................................42
5
STATISTICAL METHODS OF ANALYSIS.....................................................42
5.1
General Considerations .................................................................................42
5.2
Endpoint Data Analysis..................................................................................43
5.2.1
Efficacy Endpoint(s) .........................................................................43
5.2.2
Safety Endpoint(s)............................................................................43
5.2.3
Study Treatment Administration and Compliance ............................43
5.2.4
Analysis of Efficacy Parameters........................................................43
5.2.5
Primary Efficacy Endpoint................................................................43
5.2.6
Secondary Efficacy Endpoint ...........................................................43
5.2.7
PK, PD or Biomarker Analyses ........................................................43
6
ASSESSMENT OF SAFETY .........................................................................44
6.1
Definitions......................................................................................................44
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6.1.1
Adverse Events................................................................................44
6.1.2
Serious Adverse Event.....................................................................45
6.1.3
Severity............................................................................................45
6.2
Documenting and Reporting of Adverse and Serious Adverse Events..........45
6.2.1
Adverse Event Reporting Period......................................................46
6.2.2
Assessment of Adverse Events .......................................................46
6.2.3
Overdose .........................................................................................46
6.2.4
Pregnancy........................................................................................46
6.2.5
AE/SAE Reporting ...........................................................................47
6.2.5.1
AE/SAE Reporting by Study Sites to Lead Principal Investigator47
6.2.6
Expedited Reporting Requirements for Serious Adverse Events.....48
6.2.7
AE/SAE Reporting by Lead PI to U.S. Regulatory Authorities .........48
6.2.8
Type and Duration of Follow-up of Subjects after Adverse Events. 49
7
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS .............49
7.1
Institutional Review Board and Independent Ethics Committee ....................49
7.2
Subject Screening Log ..................................................................................49
7.3
Case Report Forms .......................................................................................50
7.4
Investigational Study Drug Accountability......................................................50
7.5
Record Retention...........................................................................................50
7.6
Disclosure and publication policy...................................................................50
8
REFERENCES..............................................................................................51
APPENDIX 1. SCHEDULE OF ASSESSMENTS....................................................53
APPENDIX 2. PERFORMANCE STATUS SCORES..............................................55
APPENDIX 3. KNOWN STRONG IN VIVO INHIBITORS OR INDUCERS OF CYP3A
56
APPENDIX 4. ADVERSE EVENT ASSESSMENT OF CAUSALITY.......................57
APPENDIX 5. COLLECTION AND PROCESSING AND END-OF-TREAMENT BLOOD 
SAMPLES FOR BCR CLONOTYPING.........................................................58
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ABBREVIATIONS
λz
terminal elimination rate constant
AE
adverse event
AESI
adverse events of special interest
Akt
protein kinase b
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BID
twice per day (dosing)
BOR
best overall response
BTK
Bruton tyrosine kinase
BUN
blood urea nitrogen
CBC
complete blood count
CD
cluster of differentiation (cell surface marker)
CFR
Code of Federal Regulations
cGMP
current Good Manufacturing Practice
CIs
confidence intervals
CL/F
oral clearance
CLL
chronic lymphocytic leukemia
Cmax
maximum concentration
COPD
chronic obstructive pulmonary disease
CR
complete response (remission)
CRF
case report form
CSSF
Clinical Supplies Shipping Receipt Form
CT
ctDNA
computed tomography 
circulating tumor DNA
CTCAE
Common Terminology Criteria For Adverse Events
CTLA-4
cytotoxic t-lymphocyte-associated protein 4
CYP
cytochrome p450
DCR
disease control rate
DLT
dose-limiting toxicity
DOR
duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EGFR
epidermal growth factor receptor
FDA
Food and Drug Administration
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GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBV
hepatitis B virus
HCV
hepatitis C virus
hERG
human ether-à-go-go-related gene
HIV
human immunodeficiency virus
HNSTD
highest non-severely toxic dose
IC50
half-maximal inhibitory concentration
ICF
informed consent form
IEC
independent ethics committee
Ig
Immunoglobulin
IRB
institutional review board
ir
immune-related
irAE
immune-related adverse event
irRECIST
immune-related response criteria
IV
intravenous or intravenously
Jak
Janus kinase
LDH
lactate dehydrogenase
KRAS
V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
MDSC
myeloid-derived suppressor cells
MedDRA 
MRD
Medical Dictionary for Regulatory Activities 
minimal residual disease
MTD
MTV
maximum tolerated dose
metabolic tumor volume
mTOR
mammalian target of rapamycin
NE 
NGS
Nonevaluable
next-generation sequencing
NK
natural killer (cells)
NOAEL
no observed adverse effect level
NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cells
PFS
progression-free survival
PD
pharmacodynamic, pharmacodynamics, or progressive disease
PD-1
programmed death-1 (receptor)
PD-L1
programmed death ligand-1
PD-L2
programmed death ligand-2
P-gp
p-glycoprotein 1 (transporter)
PI3K
phosphatidylinositol-3 kinase
PK
pharmacokinetic or pharmacokinetics
PP
per protocol
PR
partial response (remission)
Q3M
every 3 months
Q3W
every 3 weeks
Q12W
every 12 weeks
QD
once per day (dosing)
QTc
corrected QT interval
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SD
stable disease or standard deviation
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SUSAR
suspected unexpected serious adverse reaction
Syk
spleen tyrosine kinase
t½
terminal elimination half-life
T3
Triiodothyronine
T4
Thyroxine
TAM
tumor-associated macrophage
Tmax
time to maximum concentration
TSH
thyroid-stimulating hormone (thyrotropin)
Treg
regulatory T cells
ULN
upper limit of normal
Vz/F
oral volume of distribution
WHODRUG
World Health Organization Drug Dictionary
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STUDY SYNOPSIS
Study Title
A Phase 2, open-label study of acalabrutinib in combination with R-ICE for 
relapsed or refractory non-germinal center diffuse large B cell lymphoma, 
transformed chronic lymphocytic leukemia/small lymphocytic leukemia or 
transformed marginal zone lymphoma
Protocol Number
20190706
Study Drug
ACALABRUTINIB (ACP-196), rituximab, ifosfamide, etoposide, carboplatin
Phase
2
Coordinating and 
Study Center
Sylvester Comprehensive Cancer Center
Additional Study 
Centers

Moffitt Cancer Center

City of Hope
Study Objectives
Primary Objective

Improve complete remission (CR) rate of R-ICE for rel/ref non-GC 
DLBCL and transformed histologies from 29% to 50% with 
acalabrutinib + R-ICE for 3 cycles by RECIL.1
Secondary Objectives

Safety and tolerability of acalabrutinib with R-ICE in patients with rel/ref 
DLBCL

(partial remission) PR, CR, overall response rate (ORR) of 
acalabrutinib + R-ICE

Ability to mobilize > 2 x106 CD34+ cells/kg

Event-free survival (EFS), progression-free survival (PFS) and overall- 
survival (OS) at 1 year
Exploratory Objective

Correlate efficacy endpoints (ORR, PFS, OS) with: baseline metabolic 
tumor volume (MTV), circulating cell-free tumor DNA (ctDNA), and the 
results of next-generation sequencing (NGS) of tumor. NGS in 
diagnostic biopsy if available.
Study Design
This is a phase II study of acalabrutinib in combination with R-ICE in rel/ref 
non-GC DLBCL per Hans criteria,2 Each cycle will begin day 1 and last for 
21 days. Acalabrutinib will be administered day 1-21 of every cycle for 3 
cycles, in conjunction with 3 cycles of R-ICE. R-ICE will be administered 
per standard institutional policy.
In addition to a baseline PET-CT scan, confirmatory scans will be obtained 
post cycle 2 per cross sectional imaging criteria by CT and post cycle 3 per 
RECIL criteria.1 If patients have progressive disease after cycle 2, they will 
be removed from study treatment.
An EOT (EOT) visit within 14 days of the last dose of study drug is 
required for any patients who permanently discontinue study drug for any 
reason, including disease progression. Patients will then be followed for 
52 weeks for EFS, PFS, and OS after removal from or completion of study 
treatment, or until death, whichever occurs first. Patients removed from
study treatment for adverse events will be followed until resolution or 
stabilization of the adverse event.
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Efficacy and Safety 
Parameters
Efficacy Parameters
EFS, PFS, OS
Safety Parameters
The safety of acalabrutinib in combination with R-ICE will be characterized 
by the type, frequency, severity, timing of onset, duration, and relationship 
to study drug of any treatment emergent AEs or abnormalities of laboratory 
tests; SAEs; DLTs, or AEs leading to discontinuation of study treatment, or 
death.
For consistency of interpretation, AEs and laboratory results will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA), and the 
severity of AEs and selected laboratory parameters will be graded using 
the Common Terminology Criteria for Adverse Events (CTCAE), Version 
5.0.
Pharmacodynamic, 
Pharmacokinetic and 
Biomarker 
Parameters
Exploratory correlative studies may include characterization of tumor 
subtypes by NGS, including comparing pre- and post- study treatment 
biopsies in patients without a clinical response and/or progression of
disease.31 Baseline and end of treatment (EOT) PET scan will be 
assessed for response by MTV as a correlative biomarker.
Sample Size
In the first stage, we will enroll 20 eligible patients. If 6 or fewer patients 
achieve CR after 3 cycles, no additional patients will be enrolled. If 7 or 
more patients achieve CR, then an additional 26 patients will be enrolled 
for the second stage.
Inclusion Criteria
1.
Men and women ≥ 18 years of age.
2.
Patients must have histologic confirmation of relapsed or refractory 
lymphoma.
3.
Baseline FDG-PET scans must demonstrate positive lesions 
compatible with CT defined anatomical tumor sites.26
a) CT scan showing at least:
i)
2 or more clearly demarcated lesions/nodes with a long axis
>1.5cm and short axis ≥1.0cm, or
ii)
1 clearly demarcated lesion/node with a long axis >2.0cm and
short axis ≥1.0cm.
4.
Patient must have been previously treated for B cell non-Hodgkin 
lymphoma with any of the allowable below:
a) First-line treatment with rituximab and an anthracycline-based 
chemotherapy.
b) Monotherapy rituximab, dosed prior to first-line rituximab combined 
with anthracycline containing chemotherapy, or as maintenance 
therapy.
c)
Radiotherapy as part of the first-line treatment plan including 
anthracycline and rituximab.
5.
Eastern Cooperative Oncology Group (ECOG) performance status of ≤
2 (See Appendix 2)
6.
Life expectancy of greater than 6 weeks.
7.
Patients must have normal organ and marrow function as defined 
below,
a) absolute neutrophil count ≥1000/mcL (unless due to lymphoma
involvement of the bone marrow)
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b) platelets ≥75,000/mcL (unless due to lymphoma involvement of the
bone marrow)
c)
total bilirubin < 1.5 x within normal institutional limits (unless due to 
lymphoma involvement of liver or a known history of Gilbert’s 
disease)
d) AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
(unless due to lymphoma involvement of liver)
e) creatinine within normal institutional limits, or
f)
creatinine clearance ≥40 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal. (unless due to 
lymphoma)
8.
Major surgical procedure within 28 days of first dose of study drug. If a 
subject had major surgery, they must have recovered adequately from 
any toxicity and/or complications from the intervention before the first 
dose of study drug.
9.
Women who are sexually active and can bear children must agree to 
use highly effective forms of contraception during the study and for 90 
days after the last dose of acalabrutinib + R-ICE.
10. Men who are sexually active and can beget children must agree to use 
highly effective forms of contraception during the study and for 90 days 
after the last dose of acalabrutinib + R-ICE.
11. Men must agree to refrain from sperm donation during the study and 
for 90 days after the last dose of study drug.
12. Willing and able to participate in all required evaluations and 
procedures in this study protocol, including swallowing capsules 
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 and local subject 
privacy regulations).
Exclusion Criteria
1.
Germinal-center cell-of-origin DLBCL
2.
Patients who have had chemotherapy or radiotherapy < 21 days prior 
to first administration of study treatment or those who have not 
recovered from adverse events due to agents administered more than 
4 weeks earlier.
3.
Patients who are receiving any other investigational agents.
4.
Patients with known central nervous system involvement of lymphoma.
5.
History of allergic reactions attributed to compounds of similar 
chemical or biologic composition to acalabrutinib or R-ICE with the 
exception of first-infusion reaction to rituximab.
6.
Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements. Recent 
infections requiring systemic treatment need to have completed 
therapy > 7 days before the first dose of study drug.
7.
Pregnant women are excluded from this study because an 
acalabrutinib R-ICE is a chemotherapy program with the potential for 
teratogenic or abortifacient effects. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to
treatment of the mother with acalabrutinib R-ICE, breastfeeding should 
be discontinued if the mother is treated with acalabrutinib R-ICE.
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8.
HIV-positive patients on combination antiretroviral therapy are eligible, 
unless the patient’s CD4 count is below the institutional lower limit of 
normal, or the patient is taking prohibited CYP3A4/5 strong inhibitors 
or inducers.
9.
Patients may not have received any anti-cancer therapy for their 
primary rel/ref DLBCL with the exception of palliative RT.
10. Uncontrolled Autoimmune Hemolytic Anemia or ITP resulting in (or as 
evidenced by) declining platelet or Hgb levels within the 4 weeks prior 
to first dose of study drug.
11. Presence of transfusion-dependent thrombocytopenia.
12. Prior exposure to a BTK inhibitor.
13. History of prior malignancy, with the exception of the following:
a) Malignancy treated with curative intent felt to be at low risk for 
recurrence by treating physician
b) Adequately treated non-melanomatous skin cancer or lentigo 
maligna melanoma without current evidence of disease
c)
Adequately treated cervical carcinoma in situ without current 
evidence of disease.
14. Currently active clinically significant cardiovascular disease such as 
uncontrolled arrhythmia, congestive heart failure, or Class 3 or 4 
congestive heart failure as defined by the New York Heart Association 
Functional Classification, or history of myocardial infarction, unstable 
angina, or acute coronary syndrome within 6 months prior to first dose 
with study drug.
15. Unable to swallow capsules, or disease significantly affecting 
gastrointestinal function or, resection of the stomach or small bowel, 
malabsorption syndrome or symptomatic inflammatory bowel disease 
or ulcerative colitis, or partial or complete bowel obstruction.
16. Serologic status reflecting active hepatitis B or C infection. Patients 
that are positive for hepatitis B core antibody, hepatitis B surface 
antigen (HBsAg), or hepatitis C antibody will need a negative 
polymerase chain reaction (PCR) prior to enrollment. (PCR positive 
patients will be excluded.) Hepatitis C antibody positive patients are 
eligible if PCR is negative. Hepatitis B core antibody (+) patients 
without evidence of HBsAg or Hep B PCR (+) are eligible with 
appropriate Hepatitis B reactivation prophylaxis.
17. History of stroke or intracranial hemorrhage within 6 months prior to 
enrollment.
18. Current life-threatening illness, medical condition, or organ system 
dysfunction which, in the Investigator’s opinion, could compromise the 
patient’s safety, or put the study at risk.
19. Received anticoagulation therapy with Coumadin or equivalent vitamin 
K antagonists within the last 28 days.
20. Vaccinated with live, attenuated vaccines within 4 weeks of first dose 
of study drug.
21. Unresolved toxicities from prior anti-cancer therapy, defined as having 
not resolved to Common Terminology Criteria for Adverse Event 
(CTCAE, version 4), grade ≤1, or to the levels dictated in the 
inclusion/exclusion criteria with the exception of alopecia.
22. Known bleeding disorders (e.g., von Willebrand’s disease), elevated 
PT/INR/aPTT > 2x normal, active bleeding or hemophilia.
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23. Unwilling or unable to participate in all required study evaluations and 
procedures.
24. Currently active, clinically significant hepatic impairment (≥ moderate
hepatic impairment according to the NCI/Child Pugh classification.
25. Breastfeeding or pregnant.
26. Concurrent participation in another therapeutic clinical trial.
27. Patients who require proton pump inhibitors at baseline (prior to fist 
dose of study drug) or strong CYP3A4 inhibitor or inducer and are not 
able to switch to another medication
Dose Regimen/Route 
of Administration
Acalabrutinib is provided as hard gelatin capsules for oral administration 
approximately every 12 hours.
R-ICE will be administered as per standard institutional policy.
Concomitant 
Medications
Permitted Concomitant Therapy
Antiemetics are permitted if clinically indicated. Standard supportive care 
medications are permitted as per institutional standards.
Supportive medications in accordance with standard practice (such as for 
emesis, diarrhea, etc.) are permitted. Use of neutrophil growth factors 
(filgrastim and pegfilgrastim) or red blood cell growth factors 
(erythropoietin) is permitted per institutional policy and in accordance with 
the ASCO guidelines. 3 Transfusions may be given in accordance with 
institutional policy.
Short courses (≤14 days) of steroid treatment for non-cancer related 
medical reasons (e.g., joint inflammation, asthma exacerbation, rash, 
antiemetic use and infusion reactions) at doses that do not exceed 100 mg 
per day of prednisone or equivalent are permitted.
Treatment for autoimmune cytopenias are permitted for <14 days at doses 
that do not exceed 100 mg per day of prednisone or equivalent.
The following may be considered: localized hormonal or bone sparing 
treatment for non-B-cell malignancies, and localized radiotherapy for 
medical conditions other than the underlying B-cell malignancies.
Prohibited Concomitant Therapy
The concomitant use of strong inhibitors/inducers of CYP3A4 (see 
Appendix 3) should be avoided when possible (see Section 3.10.2). If a 
subject requires a strong CYP3A inhibitor while on study, monitor the 
subject closely for potential toxicities. For additional information on drugs 
with potential drug-drug interactions, refer to Section 3.10.2.
Any non-study related chemotherapy, anticancer immunotherapy, 
corticosteroids (at dosages equivalent to prednisone > 20 mg/day for 
longer than 2 weeks), experimental therapy, or radiotherapy for treating 
DLBCL are prohibited.
Warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) are 
prohibited.
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Acalabrutinib and Concomitant Therapy
The effect of agents that reduce gastric acidity (eg, proton pump inhibitors, 
H2-receptor antagonists or antacids) on acalabrutinib absorption was 
evaluated in a healthy volunteer study. 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 2 hours after 
taking acalabrutinib, and acalabrutininb should be taken 2 hours before 
short-acting H2-receptor antagonists. Use of omeprazole or esomeprazole 
or any other proton pump inhibitors while taking acalabrutinib is not 
recommended due to a potential decrease in study drug exposure.
However, if a subject must take a proton pump inhibitor (for example, for 
an ulcer that develops on study), please discuss treatment options with the 
medical monitor.
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1
BACKGROUND INFORMATION
1.1
SALVAGE THERAPY FOR AUTOLOGOUS STEM CELL TRANSPLANT ELIGIBLE 
PATIENTS WITH REL/REF DLBCL
The standard treatment for relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) 
is high-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT)4, provided that 
chemosensitive disease is established with salvage therapy (ST). With the use of modern supportive 
care, transplant-related mortality is minimal and long-term event-free survival (EFS) is approximately 
50%, with variability attributable to pre-transplantation prognostic factors. For the past decade, the 
lymphoma service at MSKCC has defined pre-treatment clinical and biologic prognostic factors in the 
setting of ICE5,6, the most commonly used ST program in the world which was developed at MSKCC.
It has been recognized that the most important factor predictive of outcomes for rel/ref DLBCL 
prior to ASCT is the depth and quality of response to ST5,7-10. In the pre-rituximab era, our group reported 
the initial ICE experience for rel/ref non-Hodgkin lymphoma, the vast majority of the patients (72%) having 
DLBCL. The overall response rate (complete [CR] or partial [PR] remission) was 66.3% 5. Those patients 
in CR at the time of ASCT had significant improvement in EFS compared to those in PR, 54% compared 
to 29% at 40 months (p <0.001). Sequentially, our group reported significant improvement in CR to ST 
compared to historical controls with the incorporation of rituximab into the ICE program, 53% CR with R- 
ICE compared to 27% CR with ICE alone11. Of particular importance, none of the patients received 
rituximab with initial anthracycline-based combination chemotherapy; thus were “rituximab-naïve” at the 
time of R-ICE ST. Recently, the large, multi-institutional international Collaborative Trial in Relapsed 
Aggressive Lymphoma (CORAL) trial comparing R-ICE to R-DHAP demonstrated no difference in 
response rate between the two ST arms12. Disappointingly, the overall response rate was 63% with a 
CR/CRu rate of 38% with no difference between R-DHAP and R-ICE; much lower than previous 
rituximab-naïve historic controls. Of importance, patients previously exposed to rituximab experienced a 
CR/CRu rate of 29% on the CORAL study (personal communication, Gisselbrecht). These poor results 
were further translated to a disappointing 53% EFS at 3 years for chemosensitive patients who proceeded 
to ASCT, and a sobering 31% EFS at 3 years by intent-to-treat. Clearly, the magnitude of benefit 
rituximab added to previously rituximab-naïve rel/ref patients has been nearly completely blunted in the 
current-era of ubiquitous rituximab exposure during initial induction chemotherapy in rel/ref patients. 
Given that the most significant prognostic factor prior to ASCT for rel/ref DLBCL is CR rate, the need for 
improvement in efficacy of ST is of utmost importance to outcomes in rel/ref DLBCL going forward.
1.2
BRUTON TYROSINE KINASE INHIBITION IN B CELL LYMPHOMAS AND DLBCL, 
INCLUDING COMBINATION WITH R-ICE
BTK is a tyrosine kinase involved in B cell signaling through the B cell receptor (BCR)13. The 
importance of this signaling pathway in normal B cell function is evidenced by X-linked 
agammaglobulinemia (XLA) where mutation in the BTK gene results in the absence of mature B cells 
and subsequent function. The primary function is antigen receptor signaling in B cells, where it is 
preferentially expressed compared to other lymphocytes (ie T cells and natural killer (NK) cells). In XLA, 
there are no demonstrable quantitative or qualitative T cell and NK cell defects.
There is emerging evidence of the importance of signaling through BTK in propagating B cell 
lymphomas. The expression of a functional BCR is maintained during progression of B cell lymphoma.14 
Additionally, the knockdown of BCR proteins by RNA interference results in apoptosis of multiple B cell 
lymphoma lines.15
Recently, the pathogenic chronic activation of BCR has been critical in cell survival of activated 
B-cell like (ABC) phenotype of DLBCL.16,17 This subtype of DLBCL has demonstrated poor-response to
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initial induction therapy,18 and thus represents the largest subset of patients with rel/ref DLBCL.19 In ABC 
phenotypic cell lines of DLBCL, short-hairpin inhibition of RNA (shRNA) involved in BCR receptor 
signaling resulted in apoptosis in cells that possessed wild-type (WT) CARD11.17 Roughly 90% of ABC 
DLBCLs have WT CARD11.17 WT BTK is a key proximal kinase in the BCR signaling pathway which, 
upon activation via BCR, phosphorylates downstream to NF-κB resulting in cell survival.
1.2.1 BTK inhibition with ibrutinib as a single agent in DLBCL
Most recently a multi-center phase II study of single-agent ibrutinib administered at a dose of 560 
mg PO daily for rel/ref DLBCL was reported20. Tolerability in 80 evaluable patients was similar to the 
original phase I study with no new safety concerns. The overall response rate (ORR) was 25% (20/80). 
Importantly, ORR was 37% in ABC-subtype patients with median response duration of 4.8 months. One 
of 20 GCB-subtype patients responded to therapy, thus conferring the ABC-subtype selectivity for the 
BTK-dependent mechanism of action of ibrutinib.
1.2.2 R-ICE for relapsed and refractory B cell lymphoma
As R-ICE has been compared to R-DHAP in the salvage setting without demonstrable difference 
in response rates as mentioned above,12 R-DHAP was associated with significantly more grade 3 to 4 
hematologic and non-hematologic toxicity. Most notably, 6% grade 4 nephrotoxicity was seen in the R- 
DHAP group compared to 1% in the ICE group.12 This is attributable to the nephrotoxicity of cisplatin in 
the R-DHAP regimen. This nephrotoxicity can have critical implications to further therapy; including 
allogeneic stem cell transplantation wherein the use of potentially nephrotoxic calcineurin-inhibitor based 
graft-versus-host disease prophylaxis may be contraindicated. Perhaps more importantly, the Bio- 
CORAL correlative study suggested a potential signal of improved chemosensitivity with R-ICE compared 
to R-DHAP in ABC-subtype rel/ref DLBCL by gene expression profiling. 19 This provides clear rationale 
for selectively studying R-ICE in ABC-subtype rel/ref DLBCL in combination with the selective BTK 
inhibitor iburitinib.
1.2.3 Phase I ibrutinib + R-ICE
In this phase I a standard 3 x 3 dose escalation of ibrutinib at 420 mg (dose level [DL] #1), 560 
mg (DL #2) and 840 mg (DL #3) days 1-21 with R-ICE for 3 cycles, every 21 days for rel/ref DLBCL, all 
cells of origin and phenotypes including transformed histologies.29 The primary objective was to 
determine safety and the maximum tolerated dose (MTD) of ibrutinib with R-ICE. Secondary objectives 
included response rate according to CT and PET per Deauville score (DS). Twenty-one patients at a 
median age of 59 years (range 19-75 years). There were no dose-limiting toxicities (DLTs) seen at DL 
#1 (n=3), 2 (n=3), or 3 (n=15). One patient was removed for rapid progression of disease and was not 
evaluated for toxicity or response without completing one cycle of therapy, though was graded as an 
event in KM calculations. Ninety-four percent (15/16) of patients experienced expected and transient 
grade 3 or 4 hematologic toxicities with hematopoietic recovery prior to each cycle. The median number 
of cumulative platelet transfusions per patient over 3 cycles was 2 (range 0-11). Eleven of the 16 patients 
evaluable for response underwent chemotherapy-primed CD34+ hematopoietic progenitor cells (HPCs) 
apheresis procedures on study; 10 of the 11 patients successfully collected HPCs with a median of 5.6 x 
106 CD34+/kg (range 1.7-8.6). The only patient that failed to collect HPCs was an HIV(+) patient at DL 
#3 in the setting of febrile illness. One patient with non-GCB DLBCL experienced grade 3 atrial 
fibrillation/flutter during cycle #1 and was subsequently removed from study per the treating physician’s 
decision. This patient was evaluable toward response and survival by ITT. Other notable events on 
study include: one patient removed following end-of-cycle #2 for asymptomatic pneumatosis coli on 
restaging imaging (CR) and one patient that self discontinued study for grade 2 nausea following cycle 
#2 also a CR. Both of these patients proceeded to HDT-ASCT and remain progression-free.
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Efficacy
Of the 20 patients evaluable for a response, 11 achieved and CR and 7 achieved a PR for an 
overall response rate of 90%. By ITT, 8/9 patients with non-GC DLBCL achieved a CR (89%), with one 
aforementioned patient removed from study for toxicity (grade 3 atrial fibrillation). Thus, all 8 patients 
with non-GC DLBCL that completed 3 cycles of therapy achieved a complete metabolic remission. 
Additionally, all 5 patients with rel/ref Richter’s transformed CLL/SLL achieved a response (CR=2, PR=3). 
In univariate analysis, rel/ref non-GC DLBCL demonstrated a significantly increased rate of CR compared 
to other subtypes (p = 0.008).
At a median follow-up of 14 months for survivors, the one-year event-free (EFS), progression-free 
(PFS) and overall survival (OS) by ITT was 0.51 (95% CI: 0.33-0.79), 0.62 (95% CI: 0.43-0.9) and 0.65 
(95% CI: 0.46-0.93), respectively. Of the 18 patients that achieved a response on study, n=14 and n=2 
proceeded to HDT-ASCT and allogeneic hematopoietic transplantation (allo-HCT), respectively. The 
one-year PFS and OS of transplanted patients on study are 0.73 (95% CI: 0.51-0.99) and 0.82 (95% CI: 
0.62-0.99), respectively.
1.3
ACALABRUTINIB (ACP-196)
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 humans and is suitable for formulating in capsules. Acalabrutinib is approved in the US 
for the treatment of adult patients with MCL who have received at least 1 prior therapy. It is also being 
evaluated for the treatment of patients with other B-cell malignancies.
1.3.1 Mechanism of Action
Acalabrutinib is a potent inhibitor of BTK in vitro and in vivo. Pharmacology models have been 
used to define kinase selectivity of acalabrutinib in comparison to other BTK inhibitors, and to 
investigate functional effects of on-target and off-target activities. Acalabrutinib shows improved 
selectivity for BTK compared with ibrutinib.30 Functional inhibition of non-target cells (eg, T cells, NK 
cells, platelets) was not observed for acalabrutinib at clinically relevant concentrations.
In Table 1-1 the group of 3F-Cys kinases are listed with the IC50 for acalabrutinib and ibrutinib. 
For acalabrutinib, the strongest inhibition was observed for Btk with less activity against Tec, Bmx, and 
ErbB4. However, ibrutinib showed inhibition of all 10 kinases. One kinase potently inhibited by ibrutinib 
is EGFR, which may explain the ibrutinib-related incidence of diarrhea and rash reported for ibrutinib in 
clinical trials of hematologic malignancies (IMBRUVICA prescribing information).
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Table 1-1. Potency of acalabrutinib and Ibrutinib on Group of 3F-Cys Kinases
IC50 (nM)
Acalabrutinib1
Ibrutinib2
Btk
3.1
0.5
Tec
29
78
Bmx
39
0.80
Itk
>1000
10.7
Txk
291
2.01
EGFR
>1000
5.6
ErbB2
912
9.4
ErbB4
13.2
2.71
Blk
>1000
0.5
Jak3
>1000
16.1
IC50 = inhibitory concentration causing half-maximal inhibition 
Profiling at Life Technology
Honigberg 2010; ibrutinib data for Txk and ErbB4 profiled at Life Technology
1.3.2 Safety Pharmacology
In vitro and in vivo safety pharmacology studies with acalabrutinib have demonstrated a favorable 
nonclinical safety profile; for detailed information on the safety pharmacology of acalabrutinib, refer to 
the Investigator Brochure.
1.3.3 Drug-drug Interaction Potential
For more detailed information on drug-drug interaction potential for acalabrutinib, refer to the 
Investigator Brochure.
Please refer to Section 3.9.2 for guidance on drugs that may cause drug-drug interactions.
1.4
CLINICAL EXPERIENCE – ACALABRUTINIB
For more detailed information on the clinical experience for acalabrutinib, please refer to the 
Investigator Brochure.
1.4.1 Clinical Efficacy –
In study LY-002, a phase Ib study of single-agent acalabrutinib for B cell lymphomas, in non-GCB 
DLBCL (by IHC), n=21, responders n = 5 (24%, 3 ABC, 1 GCB, and 1 indetermined by 
NanoString). The CR rate was 19%. The ORR for patients with ABC-subtype (non-GCB) by
NanoString was 33% (3/9) with 22% (2/9) achieving a CR. The most common > grade 3 adverse event 
was anemia. Median steady-state BTK target occupancy was 97-99% in 5 patients analyzed at 
acalabrutinib 100 mg orally twice-daily. (Dyer et al ASCO Annual Meeting 2018 abstract #7547).
This section briefly summarizes data from ACE-CL-001 (NCT02029443), an ongoing non-randomized, 
sequential group, dose-escalation Phase 1/2 study in subjects with relapsed/refractory or previously 
untreated chronic lymphocytic leukemia (CLL), Richter’s syndrome, or prolymphocytic leukemia.
Acalabrutinib has been well tolerated at all dose levels evaluated. No DLTs have occurred at any dose 
level. The MTD was not reached in this study, and the dose escalation was stopped at 400 mg.
Preliminary Day 1 PK data revealed variable and dose-linear PK. There was no accumulation of 
acalabrutinib in plasma upon repeat dosing. For detailed information on the safety and PK of 
acalabrutinib, refer to the Investigator Brochure.
Preliminary PD data from ACE-CL-001 show that Btk occupancy with acalabrutinib, in peripheral blood 
cells, is ≥ 90% at 4 hours after dosing but declines over 24 hours with QD dosing, while with 100 mg 
BID dosing, full Btk occupancy (94% to 97%) is maintained over 24 hours. These data suggest that 
synthesis of de novo Btk may occur within 24 hours.
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1.4.2 Adverse Events –
Safety analysis of acalabrutinib monotherapy was conducted to assess safety for acalabrutinib-exposed 
subjects with hematologic malignancies without confounding toxicity from combination therapy drugs.
Overall, the safety of monotherapy acalabrutinib in subjects with hematologic malignancies has been 
acceptable in the integrated analysis – refer to section 6.3.1 of the Investigator Brochure 9.0.
1.4.2.1 Hemorrhage
Serious hemorrhagic events, including fatal events, have occurred in clinical studies with 
acalabrutinib (see Table 24 of the Investigator’s Brochure).
The mechanism for hemorrhage is not well understood. Patients receiving antithrombic agents 
may be at increased risk of hemorrhage. Use caution with antithrombotic agents and consider 
additional monitoring for signs of bleeding when concomitant use is medically necessary.
Consider the benefit-risk of withholding acalabrutinib for at least 3 days pre- and post-surgery.
Subjects with hemorrhage should be managed per institutional guidelines with supportive care 
and diagnostic evaluations as clinically indicated.
1.4.2.2 Infection
Serious infections (bacterial, viral, and fungal) including fatal events, have occurred in clinical 
studies with acalabrutinib. The most frequently reported Grade ≥3 infection was pneumonia 
(preferred term). Across the acalabrutinib clinical development program (including subjects 
treated with acalabrutinib in combination with other drugs), cases of hepatitis B virus 
reactivation, aspergillosis, and progressive multifocal leukoencephalopathy (PML) have 
occurred (see Table 24 of the Investigator’s Brochure).
Consider prophylaxis in patients 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.
1.4.2.3 Cytopenias
Grade 3 or 4 cytopenias including neutropenia, anemia, and thrombocytopenia have occurred in 
clinical studies with acalabrutinib. Monitor blood counts as medically appropriate (seeTable 24 
of the Investigator’s Brochure).
Subjects with cytopenias should be managed according to institutional guidelines with 
maximalsupportive care and diagnostic evaluations as clinically indicated. Subjects should be 
closely monitored as appropriate.
1.4.2.4 Second Primary Malignancies
Events of second primary malignancies, including non-skin carcinomas, have occurred in 
clinical studies with acalabrutinib. The most frequently reported second primary malignancy 
was skin cancer (see Table 24 of the Investigator’s Brochure).
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.
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1.4.2.5 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 (see Table 24 of the Investigator’s Brochure).
Monitor for symptoms of atrial fibrillation and atrial flutter (e.g., palpitations, dizziness, syncope, 
chest pain, dyspnea) and obtain an ECG as clinically indicated. Subjects with atrial fibrillation 
should be managed per institutional guidelines with supportive care and diagnostic evaluations 
as clinically indicated.
1.5
R-ICE
R-ICE is one of the most common implemented salvage chemotherapy for r/r DLBCL with CR rate of 
63.5%. Hematologic toxicity is universal with 57% of patients requiring transfusion of blood products. 
Grade 3 and 4 toxicities include neutropenic fever and infections. Subjects should be closely monitored 
for infection and need for blood products. As describe on section 3.6 all subjects included in the study 
will require G-CSF on day 5 after chemotherapy.
.
2
STUDY OBJECTIVES
2.1
PRIMARY OBJECTIVE:
The primary objective is to improve CR rate of R-ICE for rel/ref non-GC DLBCL from 29% to 50% with 
acalabrutinib + R-ICE for 3 cycles by RECIL.1
2.2
SECONDARY OBJECTIVE(S):

Safety and tolerability of acalabrutinib with R-ICE in patients with rel/ref DLBCL

PR, CR, ORR of acalabrutinib + R-ICE

Ability to mobilize > 2 x106 CD34+ cells/kg

EFS, PFS and OS at 1 year
2.3
EXPLORATORY OBJECTIVE(S)
Correlate efficacy endpoints (ORR, PFS, OS) with: baseline metabolic tumor volume (MTV), circulating 
cell-free tumor DNA (ctDNA), and the results of next-generation sequencing (NGS) of tumor. NGS in 
diagnostic biopsy if available.
3
STUDY DESIGN
This is a multi-center, open-label, single arm phase II study of acalabrutinib in combination with R-ICE 
in rel/ref non-GC DLBCL per Hans criteria,2 transformed CLL/SLL (tCLL/SLL) and transformed marginal 
zone lymphoma (MZL). Please see schema below.
The study schema is provided below (Figure 3-1).
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Figure 3-1. Study Schema
3.1
STUDY PARAMETERS
3.1.1 Efficacy Parameters
EFS, PFS, OS
PFS is defined as the time from start of study entry until disease progression or death. EFS is 
measured from the time from study entry to the event. Events are defined by: progression of disease, 
death, or removal from study for any reason. OS is defined as the time from study entry or initial 
diagnosis until death from any cause.
3.1.2 Safety Parameters
The safety of acalabrutinib in combination with R-ICE will be characterized by the type, frequency, 
severity, timing of onset, duration, and relationship to study drug of any treatment-emergent AEs or 
abnormalities of laboratory tests; SAEs; DLTs, or AEs leading to discontinuation of study treatment or 
death.
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting.
(see Section 6).
3.1.3 Pharmacodynamic, Pharmacokinetic and Biomarker Parameters
Exploratory correlative studies of tumor tissue, when available, may include characterization of tumor 
subtypes by NGS, including comparing pre- and post- study treatment biopsies in patients without a 
clinical response and/or progression of disease. Baseline and end of treatment (EOT) PET scan will be 
assessed for response by MTV as a correlative biomarker.
3.2
RATIONALE FOR STUDY DESIGN AND DOSING REGIMEN
As described in Section 1.4, acalabrutinib is currently being evaluated in a Phase 1/2 study in 
subjects with CLL, Richter’s syndrome, or prolymphocytic leukemia (ACE-CL-001). In this study, 
subjects have received oral dosages of 100 to 400 mg QD and 100 to 200 mg BID of acalabrutinib. All 
tested dose levels have been well tolerated. No DLT has occurred at any dose level and the MTD was 
not reached. PD results from this study also show 100 and 200 mg BID have the highest Btk 
occupancy at 24 hours of all the regimens evaluated. Robust clinical responses have been observed 
(Investigator Brochure 9.0 section 5.2.3.1).
The dosing of R-ICE has been extensively studied including in phase I with the BTK inhibitor 
ibrutinib.21
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3.3
SELECTION OF STUDY POPULATION
3.3.1 Inclusion Criteria
Eligible subjects will be considered for inclusion in this study if they meet all of the following criteria:
1.
Men and women ≥ 18 years of age.
2.
Patients must have histologic confirmation of relapsed or refractory lymphoma.
3.
Baseline FDG-PET scans must demonstrate positive lesions compatible with CT defined 
anatomical tumor sites.
a) CT scan showing at least:
i)
2 or more clearly demarcated lesions/nodes with a long axis >1.5cm and short axis ≥1.0cm,
or
ii)
1 clearly demarcated lesion/node with a long axis >2.0cm and short axis ≥1.0cm.
4.
Patient must have been previously treated for B cell non-Hodgkin lymphoma with any of the 
allowable below:
a) First-line treatment with rituximab and an anthracycline-based chemotherapy.
b) Monotherapy rituximab, dosed prior to first-line rituximab combined with anthracycline 
containing chemotherapy, or as maintenance therapy.
c)
Radiotherapy as part of the first-line treatment plan including anthracycline and rituximab.
5.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (See Appendix 2)
6.
Life expectancy of greater than 6 weeks.
7.
Patients must have normal organ and marrow function as defined below,
a) absolute neutrophil count ≥1000/mcL (unless due to lymphoma involvement of the bone 
marrow)
b) platelets ≥75,000/mcL (unless due to lymphoma involvement of the bone marrow)
c)
total bilirubin <1.5 x within normal institutional limits (unless due to lymphoma involvement of 
liver or a known history of Gilbert’s disease)
d) AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal (unless due to lymphoma
involvement of liver)
e) creatinine within normal institutional limits, or
f)
creatinine clearance ≥40 mL/min/1.73 m2 for patients with creatinine levels above institutional 
normal. (unless due to lymphoma)
8.
Major surgical procedure within 28 days of first dose of study drug. If a subject had major surgery, 
they must have recovered adequately from any toxicity and/or complications from the intervention 
before the first dose of study drug.
9.
Women who are sexually active and can bear children must agree to use highly effective forms of 
contraception during the study and for 90 days after the last dose of acalabrutinib + R-ICE.
10. Men who are sexually active and can beget children must agree to use highly effective forms of 
contraception during the study and for 90 days after the last dose of acalabrutinib + R-ICE.
11. Men must agree to refrain from sperm donation during the study and for 90 days after the last dose 
of study drug.
12. Willing and able to participate in all required evaluations and procedures in this study protocol 
including swallowing capsules 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 and local 
subject privacy regulations).
3.3.2 Exclusion Criteria
Subjects will be ineligible for this study if they meet any of the following criteria:
1.
Germinal-center cell-of-origin DLBCL22
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2.
Patients who have had chemotherapy or radiotherapy < 21 days prior to first administration of study 
treatment or those who have not recovered from adverse events due to agents administered more 
than 4 weeks earlier.
3.
Patients who are receiving any other investigational agents.
4.
Patients with known central nervous system involvement of lymphoma.
5.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to 
acalabrutinib or R-ICE with the exception of first-infusion reaction to rituximab.
6.
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. Recent infections 
requiring systemic treatment need to have completed therapy > 7 days before the first dose of study 
drug.
7.
Pregnant women are excluded from this study because an acalabrutinib R-ICE is a chemotherapy 
program with the potential for teratogenic or abortifacient effects. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother with 
acalabrutinib R-ICE, breastfeeding should be discontinued if the mother is treated with acalabrutinib 
R-ICE.
8.
HIV-positive patients on combination antiretroviral therapy are eligible, unless the patient’s CD4 
count is below the institutional lower limit of normal, or the patient is taking prohibited CYP3A4/5 
strong inhibitors or inducers.
9.
Patients may not have received any anti-cancer therapy for their primary rel/ref DLBCL with the 
exception of palliative RT.
10. Uncontrolled Autoimmune Hemolytic Anemia or ITP resulting in (or as evidenced by) declining 
platelet or Hgb levels within the 4 weeks prior to first dose of study drug.
11. Presence of transfusion-dependent thrombocytopenia.
12. Prior exposure to a BTK inhibitor.
13. History of prior malignancy, with the exception of the following:
a) Malignancy treated with curative intent felt to be at low risk for recurrence by treating physician
b) Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current 
evidence of disease
c)
Adequately treated cervical carcinoma in situ without current evidence of disease.
14. Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, 
congestive heart failure, or Class 3 or 4 congestive heart failure as defined by the New York Heart 
Association Functional Classification, or history of myocardial infarction, unstable angina, or acute 
coronary syndrome within 6 months prior to first dose with study drug.
15. Unable to swallow capsules, or disease significantly affecting gastrointestinal function or, resection 
of the stomach or small bowel, or symptomatic inflammatory bowel disease or ulcerative colitis, or 
partial or complete bowel obstruction.
16. Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B 
core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody will need a negative 
polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.) 
Hepatitis C antibody positive patients are eligible if PCR is negative. Hepatitis B core antibody (+) 
patients without evidence of HBsAg or Hep B PCR (+) are eligible with appropriate Hepatitis B 
reactivation prophylaxis.
17. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
18. Current life-threatening illness, medical condition, or organ system dysfunction which, in the 
Investigator’s opinion, could compromise the patient’s safety, or put the study at risk.
19. Received anticoagulation therapy with Coumadin or equivalent vitamin K antagonists within the last 
28 days.
20. Vaccinated with live, attenuated vaccines with 4 weeks of first does of study drug.
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21. Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common 
Terminology Criteria for Adverse Event (CTCAE, version 5), grade ≤1, or to the levels dictated in 
the inclusion/exclusion criteria with the exception of alopecia.
22. Known bleeding disorders (e.g., von Willebrand’s disease) or hemophilia.
23. Unwilling or unable to participate in all required study evaluations and procedures.
24. Currently active, clinically significant hepatic impairment (≥ moderate hepatic impairment according
to the NCI/Child Pugh classification.
25. Breastfeeding or pregnant.
26. Concurrent participation in another therapeutic clinical trial.
27.
Patients who require proton pump inhibitors at baseline (prior to fist dose of study drug) or strong 
CYP3A4 inhibitor or inducer and are not able to switch to another medication
3.3.3 Recruitment
Investigators and designated personnel from the research study team at University of Miami Sylvester 
Comprehensive Cancer Center (SCCC) and if applicable other sites (for multi-center studies) will 
identify, recruit, enroll and treat eligible patients for the study. This study will access electronic medical 
record or other protected health information without obtaining a signed HIPAA authorization from the 
subject to identify potential subjects for recruitment and to obtain study data. At the University of Miami 
SCCC, subjects will be recruited via clinical practice offices. Additional study sites will recruit subjects 
as per institutional guidelines.
3.4
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
3.4.1 Discontinuation of Study Intervention
Discontinuation from protocol treatment does not mean discontinuation from the study, and remaining 
study procedures should be completed as indicated by the protocol. If a clinically significant finding is 
identified (including, but not limited to changes from baseline) after enrollment, the Investigator or 
qualified designee will determine if any change in participant management is needed. Any new clinically 
relevant finding will be reported as an adverse event (AE).
The data to be collected at the time of study intervention discontinuation will include the data collected 
during the safety evaluation visit and follow-up information.
3.4.2 Participant Discontinuation/Withdrawal from the Study
Participants are free to withdraw from participation in the study at any time upon request. An 
Investigator may discontinue or withdraw a participant from the study for the following reasons:

Pregnancy

Significant study intervention non-compliance

If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant

Disease progression which requires discontinuation of the study intervention

If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation

Participant unable to receive investigational treatment for 21 days/weeks.
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF).
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3.4.3 Data Retention When Subjects Withdraw from FDA-Regulated Clinical Trials
An investigator may ask a subject who is withdrawing whether the subject wishes to provide continued 
follow-up and further data collection subsequent to their withdrawal from the interventional portion of 
the study. Under this circumstance, the discussion with the subject would distinguish between study- 
related interventions and continued follow-up of associated clinical outcome information, such as 
medical course or laboratory results obtained through non-invasive chart review, and address the 
maintenance of privacy and confidentiality of the subject’s information.
If a subject withdraws from the interventional portion of the study, but agrees to continued follow-up of 
associated clinical outcome information as described in the previous bullet, the investigator must obtain 
the subject’s informed consent for this limited participation in the study (assuming such a situation was 
not described in the original informed consent form). In accordance with FDA regulations, IRB approval 
of informed consent documents would be required (21 CFR 50.25, 56.109(b), 312.60, 312.66,
812.100).
3.4.4 Participant Replacement Criteria
Subjects who sign the informed consent form and are enrolled but do not receive the investigational 
treatment may be replaced. Subjects who sign the informed consent form, receive the protocol 
treatment, and subsequently withdraw, or are withdrawn or discontinued from the study, will not be 
replaced.
3.4.5 Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently entered in the study. Screen failures will be rescreened if they are eligible at a later time.
3.4.6 Lost to follow up
A participant will be considered lost to follow-up if he or she fails to return for three scheduled visits and 
is unable to be contacted by the study site staff.
The following actions must be taken if a participant fails to return to the clinic for a required study visit:

For Missed Treatment Visits: The site will attempt to contact the participant and reschedule 
the missed treatment visit as soon as possible and counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain if the participant wishes to and/or should 
continue in the study.

For Missed Post-Treatment Follow-Up Visits: The site will attempt to contact the participant 
and reschedule the missed post-treatment follow visit within <14 days and counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the Investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
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3.5
STUDY DRUG
3.5.1 Premedications
R-ICE will be administered per standard institutional procedures with appropriate hydration and 
premedication per institutional standards.
3.5.2 Formulation, Packaging, and Storage
Acalabrutinib
The investigational product, acalabrutinib capsules for oral administration, is supplied as yellow and 
blue, opaque hard gelatin capsules, with 100 mg of acalabrutinib as the active ingredient. The capsules 
will be supplied by the supplier of the study medication and provided to participants at no cost. Each 
capsule also contains compendial inactive ingredients: silicified microcrystalline cellulose, which is 
composed of microcrystalline cellulose and colloidal silicon dioxide, partially pregelatinized starch, 
sodium starch glycolate, and magnesium stearate. The capsule shell contains gelatin, titanium dioxide, 
yellow iron oxide and indigotine (FD&C Blue 2).
Acalabrutinib will be provided in white, high-density polyethylene bottles.
Refer to the acalabrutinib Investigator Brochure for additional information regarding the drug product to 
be used in this trial.
3.5.3 Administration of Study Drug
Acalabrutinib capsule is to be taken orally approximately every 12 hours.
The capsules should be swallowed intact with water. Subjects should not attempt to open capsules or 
dissolve them in water. Acalabrutinib can be taken with or without food.
If a dose is missed, it can be taken up to 3 hours after the scheduled time with a return to the normal 
schedule with the next dose. If it has been > 3 hours, the dose should not be taken and the subject 
should take the next dose at the scheduled time. The missed dose will not be made up and must be 
returned to the site at the next scheduled visit.
Guidance on co-administration of acalabrutinib with agents that affect gastric pH is provided in Section 
3.10.2.
R-ICE will be administered as per standard institutional policy.
3.5.4 Assuring Subject Compliance
For treatments that are taken in the clinic, subjects should take the dose from the drug dispensed for 
them for that particular time period. All other acalabrutinib treatments will be taken at home. Subjects 
will receive a medication diary to record the specific time each dose was taken and to record reasons 
for any missed doses (Appendix 6).
Subject compliance with acalabrutinib dosing will be assessed at every clinic visit. The subject will be 
instructed to bring the diary and any remaining capsules to the clinic at their next visit. The study staff 
will review the diary and ask the subject if all of the capsules were administered. Any remaining or 
returned capsules will be counted and recorded as described in Section 7.6. Returned capsules must 
not be redispensed to another subject.
3.6
STUDY TREATMENT SCHEDULE
This is a phase II study of acalabrutinib in combination with R-ICE for rel/ref DLBCL non-GC-subtype. 
R-ICE will be administered as per standard institutional policy.
3.7
DURATION OF THERAPY
In the absence of treatment delays due to adverse event(s), treatment may continue for 3 cycles or until 
one of the following criteria applies:

Disease progression,

Intercurrent illness that prevents further administration of treatment,

Unacceptable adverse event(s),

Patient decides to withdraw from the study, or
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
General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator.
Patients that achieve a partial or complete remission following 3 cycles of therapy, per criteria outlined 
in Section 4.1.16, and have mobilized > 2 x 106 CD34+/kg, will be eligible to proceed to autologous 
transplantation at the discretion of the treating physician. Patients will have completed study following 
3 cycles of therapy and will be subject to follow-up per Section 4.2 and 4.3.
3.8
DOSING DELAYS AND MODIFICATIONS
Treatment modifications
Treatment-emergent adverse events of R-ICE therapy predominantly comprise of hemato-toxicities 
(such as neutropenia, leukopenia, thrombocytopenia, and anemia). Nonhematologic disorders include 
asthenia, sensory disturbance, mucositis, alopecia, sepsis, dyspnea, back pain, hyperglycemia, 
hypersensitivity, and cardiac disorders. Tumor lysis syndrome will be managed as per institutional 
guidelines. Renal and hepatic adverse reactions will be managed as per institutional guidelines.
Treatment modifications are not permitted for R-ICE.
Cycle delay
After completion of each 21-day cycle, the start of a new cycle could be delayed for up to one 1 week (7 
days) in cases of toxicity necessitating a dose delay. A subject whose cycle is delayed should be 
assessed within a week for resolution or recovery of toxicity and a decision regarding further delay.
There is no limit on the number of cycle delays that each subject may experience, as long as delays do 
not exceed one week or 28 days from the beginning of a cycle.
The following parameters must be met on the first day of a new cycle (after cycle 1):

Platelet count  50 x 109/L

ANC  1.0 x 109/L

Non-hematologic toxicity of ≥ grade 3 must have recovered to baseline or Grade ≤ 1
For severe hematologic toxicity (grade  3), laboratory evaluations may be repeated more frequently as 
necessary until the retreatment requirements are met. In the event of severe renal toxicity or 
hepatotoxicity, laboratory tests may be repeated more frequently as necessary until the toxicity 
resolves.
Dose modifications and dose limiting toxicities (DLT) acalabrutinib + RICE
Given that acalabrutinib has not been studied in phase I combination with R-ICE, a 3-6 patient lead-in 
will be conducted at the acalabrutinib 100 mg PO BID dosing. If one DLTs is observed within the first 3 
patients, or if two DLTs are observed within the first 6 patients, a dose level (-)1 of acalabrutinib at 100 
mg PO daily will be instituted for the next 3-6 patients. If > 2 DLTs are observed within the next 6 
patients, the study will be terminated.
Dose Limiting Toxicity: acalabrutinib + R-ICE
The DLT evaluation period begins with the first dose of acalabrutinib and ends immediately prior to the 
initiation of the second cycle. Only toxicities that occur during the DLT period will be used for the 
purposes of defining DLT. However, toxicities that occur in all cycles will be considered in the overall 
decisions of the investigators. The first 3-6 subjects will be evaluated for DLTs per above. Subjects 
considered non-evaluable for DLT may be replaced, but the safety profile of these subjects will be 
included in the investigator review. Subjects considered non-evaluable for DLT are subjects who do not 
complete Cycle 1 for reasons other than toxicity. Subjects who experience a DLT may continue 
treatment on the study at a lower dose of acalabrutinib.
The following will be considered DLTs after confirmation by the investigators:

Complete treatment interruption of more than 7 days (28 days of the cycle) for acalabrutinib-RICE-
related Grade ≥ 2 toxicities within Cycle 1
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
Any Grade 3 or Grade 4 non-hematological toxicity that is at least possibly related to the study 
drugs

excluding:
o
Grade 3 nausea or vomiting responsive to anti-emetic treatment,
o
Grade 3 diarrhea responding to anti-diarrheal treatment,
o
Grade 3 fatigue/asthenia unless persisting for 7 days after stopping acalabrutinib and 
absent at baseline
o
alopecia

including:
o
persistent Grade ≥ 2 nausea and/or vomiting despite prolonged (more than 7 days 
continuously) anti-emetic treatment (5 HT3 antagonist, antihistamine, metoclopramide)

Grade ≥ 2 hemorrhagic events requiring medical intervention

Grade 4 hematological toxicity defined as:

Febrile neutropenia (ANC < 500 cells/µL with fever [body temperature ≥ 38.5C] or sepsis) or 
Grade 4 neutropenia (ANC < 500 cells/µL) requiring at least 1 week delay of the next 
treatment cycle

Grade 4 thrombocytopenia (Platelet count < 25,000 cells/µL) requiring at least 1 week delay of 
next treatment cycle
Based on the specific adverse event observed, 1 dose level reduction is permitted for acalabrutinib (see 
Table below). If acalabrutinib is withheld for < 1 week due to acalabrutinib-related toxicity; study drug 
should be resumed with a dose reduction when treatment resumes following recovery from the toxicity. 
If there is unacceptable toxicity despite 1 dose reduction the treatment should be discontinued. If 
treatment must be withheld for an acalabrutinib-related adverse event that fails to resolve to an 
acceptable level (eg, ≤ Grade 1 nonhematologic toxicity) within 1 week after the date acalabrutinib was 
withheld, treatment with acalabrutinib should be permanently discontinued. In this event, the subject will 
be discontinued from the treatment, and End-of-Treatment Visit assessments will be performed 
including through the protocol-specified AE reporting window and have follow-up for ongoing SAEs to 
resolution or stability unless the subject lost to follow-up. (see section 6.2.6)
Acalabrutinib dose adjustments also apply to cycle 1.
Acalabrutinib dose will not be reduced for hematological toxicities unless the hematologic toxicities fail 
to recover by day 21 of a cycle.
The actions in the table below should be taken for the following toxicities at day 21 of the cycle:

Grade 4 ANC (<500/µL) for >7 days

Grade 3 thrombocytopenia (<50,000/mcL) in the presence of clinically significant bleeding 
events

Grade 4 thrombocytopenia (<25,000/mcL)

Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent, despite optimal antiemetic and/or 
anti-diarrheal therapy

Any other Grade 4 or unmanageable Grade 3 toxicity.
For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks and 
benefits of acalabrutinib treatment. If clinically indicated, the use of anticoagulants or antiplatelet agents 
may be considered for the thromboprophylaxis of atrial fibrillation.
Dose Reduction Schedule for Acalabrutinib
Starting dose (mg/day)
Dose reduction 1 (mg/day)
200 (100 mg BID)
100 (100 mg QD)
Dose reductions below 100 mg/day are not permitted.
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Non-hematological grade 3 or higher toxicities

For Grade 3 possible or probable acalabrutinib-related non-hematologic toxicities (other than the 
adverse events specifically described in this section), therapy (acalabrutinib and R-ICE) is to be 
held for a maximum of 1 week (and d28 of a cycle) until the toxicity returns to Grade 1 or less. If 
grade 2 during the first cycle, this will be considered a DLT.

For any Grade 4 non-hematologic toxicity attributed to acalabrutinib, discontinue acalabrutinib and 
chemotherapy for all remaining cycles; subject is discontinued from study treatment and must 
complete protocol-specified AE reporting along with follow-up for ongoing SAEs to resolution 
unless the subject is lost to follow-up.

If Grade 3 toxicity returns to Grade 1 or less by Day 28, then proceed with next cycle of therapy 
with acalabrutinib reduced to the next lower dose level.
Overdose
Any dose of study drug administered in excess of that specified in this protocol is considered to be an 
overdose. Signs and symptoms of an overdose that meet any SAE criterion must be reported as a SAE 
in the appropriate time frame ( see Section 6.2.2) and documented as clinical sequelae to an overdose.
There is no specific experience in the management of acalabrutinib overdose in patients.
Dose Modification for Hepatic Impaired Subjects (Child-Pugh Criteria)
Acalabrutinib is metabolized in the liver. Please see the Child-Pugh scoring system outlined in 
Appendix G to determine whether dose modifications are warranted according to the following 
instructions. For patients who develop mild-moderate liver impairment while on study (Child-Pugh 
class A), the recommended dose is acalabrutinib 100 mg daily. Patients who develop severe hepatic 
impairment (Child-Pugh class C) must hold study drug until resolved to moderate impairment (Child- 
Pugh class B) or better and may be re-treated according to resolved hepatic conditions. Monitor 
patients for signs of toxicity and follow dose modification guidance as needed.
3.9
CONCOMITANT THERAPY
3.9.1 Permitted Concomitant Therapy
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) are 
permitted. Use of neutrophil growth factors (filgrastim and pegfilgrastim) or red blood cell growth 
factors (erythropoietin) is permitted per institutional policy and in accordance with the ASCO guidelines. 
23 Transfusions may be given in accordance with institutional policy.
Short courses (≤14 days) of steroid treatment that do not exceed 100 mg per day of prednisone or 
equivalent are permitted.
Treatment for autoimmune cytopenias are permitted for <14 days at doses that do not exceed 100 mg 
per day of prednisone or equivalent.
The following may be considered: localized hormonal or bone sparing treatment for non-B-cell 
malignancies, and localized radiotherapy for medical conditions other than the underlying B-cell 
malignancies.
3.9.2 Prohibited or Restricted Concomitant Therapy
Any non-study related chemotherapy, anticancer immunotherapy, corticosteroids (at dosages 
equivalent to prednisone >100 mg/day for longer than 2 weeks), experimental therapy, or radiotherapy 
for treating DLBCL are prohibited.
Warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) are prohibited.
For additional information on drugs with potential drug-drug interactions, refer to Section 3.10.2.
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3.9.2.1 CYP Inhibiting/Inducing Drugs
Based on available nonclinical and clinical data, acalabrutinib is almost completely metabolized 
by multiple CYP and non CYP metabolic pathways. CYP3A-mediated oxidation is the major 
route of metabolism in humans. Additional studies were performed in a human liver microsomal 
system with specific chemical inhibitors of individual CYP isoforms. Inhibition of acalabrutinib 
metabolism by specific CYP3A4/5 inhibitors (ketoconazole and troleandomycin) indicate that 
CYP3A4/5 is the predominant CYP isoform responsible for metabolism of acalabrutinib.
PBPK modeling predicted the magnitude of changes in acalabrutinib and active metabolite 
exposure due to a variety of moderate CYP3A inducers and inhibitors. Avoid coadministration 
of strong CYP3A inhibitors (such as itraconazole and rifampin) with acalabrutinib on study, if 
possible. If moderate or strong CYP3A inhibitors are required on study, monitor subjects for 
toxicity (refer to IB section 6.7). A list of common CYP3A4/5 inhibitors or inducers is provided at 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx.

If acalabrutinib must be administered with a strong or moderate CYP3A4/5 inhibitor, 
the Medical Monitor should be consulted before use, and a dose reduction of 
acalabrutinib to 100 mg PO daily or temporarily holding acalabrutinib should be 
considered. Patients should be closely monitored for potential treatment-related 
toxicities.

There was minimal involvement of CYP1A2, CYP2E1, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, or CYP2D6 in the metabolism of acalabrutinib in human liver 
microsomes.. Therefore drugs that are known to be CYP1A2, CYP2E1, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, or CYP2D6 inhibitors or inducers are not restricted.
3.9.2.2
QT Prolonging Agents
Therapeutic plasma acalabrutinib concentrations after a 100-mg dose or supratherapeutic 
plasma acalabrutinib concentrations after a 400-mg dose in healthy subjects did not prolong the 
QTc interval in a thorough QT study.
Medications known to cause Torsades des Pointes should be avoided. Refer to the Arizona 
CERT website (http://www.azcert.org/medical-pros/drug-lists/list-01.cfm?sort=Generic_name) or 
similar websites for a list of these medications. If no alternative treatment is available, the 
Medical Monitor must be consulted.
Any medications known to cause QT prolongation may be used with caution; periodic 
monitoring with electrocardiograms (ECGs) and electrolytes should be considered.
3.9.2.3
Drugs That May Have Their Plasma Concentration Altered by Acalabrutinib 
Acalabrutinib is a substrate for breast cancer-related protein (BCRP). Acalabrutinib 
coadministration may increase exposure to BCRP substrates by inhibition of intestinal BCRP. 
Use caution with coadministered, oral, narrow therapeutic index BCRP substrates.
3.9.2.4
Antiplatelet Agents and Anticoagulants
Patients receiving antiplatelet or anticoagulant therapies in conjunction with acalabrutinib may 
be at increased risk of hemorrhage and should be monitored for signs of bleeding, as described 
in section 1.4.2.1.
3.9.2.5
Surgery
Patients who require surgery for any reason while on study are recommended to withhold 
acalabrutinib for 3-7 days pre- and post-surgery, depending upon the type or surgery and the
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risk of bleeding. Patients must have recovered adequately from any toxicity and/or 
complications from the intervention before the first dose or before restarting acalabrutinib.
3.10 PRECAUTIONS
3.10.1 Dietary Restrictions
Acalabrutinib can be taken with or without food. There are no dietary restrictions for R-ICE.
3.10.2 Drug-drug Interactions & Infusion Reactions
Acalabrutinib is metabolized by CYP3A. At the systemic exposure levels expected in this study, 
acalabrutinib inhibition of CYP metabolism is not anticipated.
Concomitant administration of acalabrutinib with a strong CYP3A and P-glycoprotein (P-gp) inhibitor, 
itraconazole increased exposure by approximately 5-fold. Conversely, concomitant administration of 
acalabrutinib with a strong CYP3A inducer, rifampin decrease acalabrutinib exposure and could reduce 
efficacy. Consequently, the concomitant use of strong inhibitors/inducers of CYP3A (see Appendix 3) 
should be avoided when possible.
If medically justified, subjects may be enrolled if such inhibitors or inducers can be discontinued or 
alternative drugs that do not affect these enzymes can be substituted within 7 days before first dose of 
study drug. If a subject requires a strong CYP3A4 while on study, the subject should be monitored 
closely for any potential toxicities.
The effect of agents that reduce gastric acidity (eg, proton pump inhibitors or antacids) on acalabrutinib 
absorption was evaluated in a healthy volunteer study (ACE-HV-004). Results from this study indicate 
that subjects should avoid the use of calcium carbonate-containing drugs or supplements for a period of 
at least 2 hours before and at least 2 hours after taking acalabrutinib. Use of omeprazole, 
esomeprazole, lansoprazole or any other proton pump inhibitors while taking acalabrutinib is not 
recommended due to a potential decrease in study drug exposure. However, the decision to treat with 
proton-pump inhibitors during the study is at the investigator’s discretion, with an understanding of the 
potential benefit to the subject’s gastrointestinal condition and a potential risk of decreased exposure to 
acalabrutinib.
Although the effect of H2-receptor antagonists (such as famotidine or ranitidine) on acalabrutinib 
absorption has not been evaluated, if treatment with an H2-receptor antagonist is required, the H2- 
receptor antagonist should be taken approximately 2 hours after an acalabrutinib dose.
Infusion reactions related to rituximab, etoposide, ifosfamide, or carboplatin should be managed 
according to the package insert and/or institutional standard of care.
3.10.3 Contraception Requirements
Contraception Requirements for Women:
The following are acceptable measures to avoid becoming pregnant:

Abstinence (not having sexual relations with a person of the opposite sex)

Implantable hormone (e.g. Norplant)

Intrauterine Device (IUD)

Male partner has had a vasectomy

Female sterilization

Hormonal injection

Oral contraceptives

GnRH Agonists (zoladex, triptorelin, leuprolide)-these agents are only effective if they have 
been in continuous use for at least 3 months
Participants must use contraception, at least starting at screening, before starting study treatment 
unless they abstain from sexual intercourse. Participants must use contraception during study 
treatment and for at least 90 days after stopping study treatment.
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Female participants should not become pregnant, breastfeed, or donate an egg for at least 90 days 
after the last dose of study medication. If female participants become pregnant while participating in the 
study or within 1 year of completing study treatment, they should inform their study doctor immediately.
Contraception Requirements for Men:
One of the following forms of contraception should be used by men or their female partner of 
childbearing potential:

Abstinence (not having sexual relations with a person of the opposite sex)

Implantable hormone (e.g. Norplant)

Intrauterine Device (IUD)

Vasectomy

Female sterilization

Hormonal injection

Oral contraceptives
Male participants must use contraception during study treatment and for at least 90 days after stopping 
study treatment. Participants should also refrain from donating semen during therapy and for at least 1 
year after stopping the therapy.
There is theoretical concern that study treatment can result in sperm abnormalities and/or can transmit 
harmful substances in their semen during sex. Therefore, males must remain abstinent or use a 
condom, even if they have undergone a vasectomy.
If a female partner becomes pregnant or suspects becoming pregnant during study treatment or within 
1 year after completing study treatment, the Study Doctor must be informed immediately. The study 
Doctor may want to follow the pregnancy and may ask the female partner to sign a consent form so 
they can collect information about the outcome of the pregnancy.
3.10.4 Overdose Instructions
Clinical information relevant to overdose is not available. For results from nonclinical overdose studies 
in rats and dogs, please refer to the Investigator Brochure.
Study drug overdose is the accidental or intentional use of the drug in an amount higher than the dose 
being studied. An overdose or incorrect administration of study drug is not an AE unless it results in 
untoward medical effects.
Any study drug overdose or incorrect administration of study drug should be noted on the appropriate 
CRF.
All AEs associated with an overdose or incorrect administration of study drug should be recorded on 
the CRF and reported to Acerta/AZ per contractual guidelines (See Section 6.2.1 for Adverse Event 
Reporting Period).
In the event of subject ingestion of more than the recommended acalabrutinib dosage, observation for 
any symptomatic side effects should be instituted, and vital signs, biochemical and hematologic 
parameters should be followed closely (consistent with the protocol or more frequently, as needed).
Appropriate supportive management to mitigate adverse effects should be initiated. If the overdose 
ingestion of acalabrutinib is recent and substantial, and if there are no medical contraindications, use of 
gastric lavage or induction of emesis may be considered.
3.11 WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT
The investigator may withdraw any subject from study treatment, if, in the investigator’s opinion, it is not 
in the subject’s best interest to continue.
Any subject has the right to withdraw from the study at any time. In addition, subjects may be 
withdrawn from study treatment for the following reasons:
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
Study treatment should be discontinued in the event of a toxicity lasting > 28 days as described 
in Section 3.8.

Any subject who has confirmed objective evidence of cancer progression while receiving study 
treatment should be withdrawn from the study treatment. If there is uncertainty regarding 
whether there is true cancer progression, the subject may continue study treatment and remain 
under close observation (eg, evaluated at 4-week intervals) pending confirmation of 
progression.

Any subject whose medical condition substantially changes after entering the study should be 
carefully evaluated by the investigator. Such subjects should be withdrawn from study 
treatment if continuing would place them at risk.

Any subject who becomes pregnant or begins breastfeeding should be removed from study 
treatment.

Any subject who becomes significantly noncompliant with study drug administration, study 
procedures, or study requirements should be withdrawn from study treatment in circumstances 
that increase risk or substantially compromise the interpretation of study results.
3.12 REMOVAL FROM STUDY
Reasons for removal of a subject from the study are:

Subject’s withdrawal of consent from study

Decision by sponsor to terminate the study

Subject lost to follow-up

Death
3.13 DATA AND SAFETY MONITORING
The Sylvester Comprehensive Cancer Center (SCCC) Data and Safety Monitoring Committee (DSMC) 
will monitor this clinical trial according to the Cancer Center’s Data and Safety Monitoring Plan (DSMP). 
In its oversight capacity, the DSMC bears responsibility for suspending or terminating this study.
DSMC oversight of the conduct of this trial includes ongoing review of accrual and adverse event (AE) 
data, and periodic review of the study therapy. The guidelines appearing in the Section 3.8 are offered 
for DSMC consideration in assessing AEs and pathologic objective response. In addition, the DSMC 
will review reports from all audits, site visits, or study reviews pertaining to this clinical trial and take 
appropriate action. The SCCC DSM Plan to which this study is subject can also be found at 
WWW.SYLVESTER.ORG.
3.14 STUDY AUDITING AND MONITORING
This study will be monitored (as applicable) and may be audited according to the University of Miami 
requirements. See also
http://research.med.miami.edu/clinical-research/crors/monitoring
Following the monitoring plan, the monitors will verify that the clinical trial is conducted and data are 
generated and biological specimens are collected, documented (recorded), and reported in compliance 
with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and 
applicable regulatory requirements.
3.14.1 Trial Monitoring, Auditing, and Inspecting
The investigator will permit trial-related monitoring, quality audits, and inspections by, government 
regulatory authorities, of all trial-related documents (e.g., source documents, regulatory documents, 
data collection instruments, case report forms). The investigator will ensure the capability for 
inspections of applicable trial-related facilities. The investigator will ensure that the trial monitor or any
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other compliance or QA reviewer is given access to all trial-related documents and trial-related 
facilities.
Participation as an investigator in this trial implies the acceptance of potential inspection by government 
regulatory authorities.
3.15 QUALITY ASSURANCE AND QUALITY CONTROL
In addition to the Clinical Monitoring component of this protocol, Quality Assurance (QA) will be 
implemented to assess compliance with GCP and applicable regulatory requirements. Data or 
documentation audited shall be assessed for compliance to the protocol, accuracy in relation to source 
documents and compliance to applicable regulations.
4
STUDY ACTIVITIES AND ASSESSMENTS
The schedule of events is provided in Appendix 1.
Scans and x-rays must be done <4 weeks prior to the start of therapy. In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of 
the next cycle of therapy.
Descriptions of the scheduled evaluations are outlined below and complete information on study drug 
and dosing is provided in Section 3.5.
Before study entry, throughout the study, and at the follow-up evaluation, various clinical and diagnostic 
laboratory evaluations are outlined. The purpose of obtaining these detailed measurements is to 
ensure adequate safety and tolerability assessments. Clinical evaluations and laboratory studies may 
be repeated more frequently if clinically indicated.
4.1
DESCRIPTION OF PROCEDURES
4.1.1 Informed Consent and Permission to Use Protected Health Information
It is the responsibility of the investigator to obtain written informed consent from each subject 
participating in this study after adequate explanation, in lay language, of the methods, objectives, 
anticipated benefits, and potential hazards of the study. The investigator must also explain that the 
subject is completely free to refuse to enter the study or to discontinue participation at any time (for any 
reason) and receive alternative conventional therapy as indicated. Prior to study participation, each 
subject will sign an IRB approved informed consent form and receive a copy of same (and information 
leaflet, if appropriate). For subjects not qualified or able to give legal consent, consent must be 
obtained from a parent, legal guardian, or custodian. The investigator or designee must explain to the 
subject before enrollment into the study that for evaluation of study results, the subject’s protected 
health information obtained during the study may be shared with the study sponsor, regulatory 
agencies, and the IRB. It is the investigator’s (or designee’s) responsibility to obtain permission to use 
protected health information per HIPAA from each subject, or if appropriate, the subjects’ parent or 
legal guardian.
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 duration of response to these treatments, also will be recorded.
4.1.3 Adverse Events
The accepted regulatory definition for an AE is provided in Section 6.1. 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 6.2.
4.1.4 Concomitant Medications and Therapy
All concomitant medications and procedures from within 21 days before the start of study drug 
administration through 30 days after the last dose of study drug must be documented.
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4.1.5 Confirmation of Eligibility
Subject eligibility for enrollment will be assessed per Section 3.3. All screening procedures, unless 
otherwise indicated, should be completed within 28 days of the first dose of study drug.
4.1.6 ECOG Performance Status
The ECOG performance index is provided in Appendix 2.
4.1.7 Physical Examination, Height & Weight, & Vital Signs
The physical examination will include, at a minimum, the general appearance of the subject, height 
(screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, 
abdomen, extremities, musculoskeletal system, nervous system, and lymphatic system with lymphoma 
symptoms reviewed and recorded.
Vital signs (blood pressure, heart rate, and body temperature) will be assessed after the subject has 
rested in the sitting position.
Directed physical exam will be performed every day while participant is receiving R-ICE treatment.
4.1.8 Electrocardiogram
Subjects should be in supine position and resting for at least 10 minutes before any study-related 
ECGs.
4.1.9 Urine or Serum Pregnancy Test
Pregnancy tests will be required only for women of childbearing potential. Testing will be done by a 
local or central laboratory as listed on the investigator’s Form FDA 1572.
4.1.10 Hematology
Hematology studies must include complete blood count (CBC) with differential including, but not limited 
to white blood cell count, hemoglobin, hematocrit, platelet count, absolute neutrophil count (ANC), and 
absolute lymphocyte count (ALC). Testing will be done by a local laboratory as listed on the 
investigator’s Form FDA 1572.
4.1.11 Serum Chemistry
Chemistry will include albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), bicarbonate, blood urea nitrogen (BUN), calcium, chloride, creatinine, glucose, 
lactate dehydrogenase (LDH), magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin, 
total protein, and uric acid.
If an unscheduled ECG is done at any time, then an electrolyte panel (i.e., calcium, magnesium, and 
potassium) must be done to coincide with the ECG testing. Testing will be done by a local laboratory 
as listed on the investigator’s Form FDA 1572.
Chemistry (potassium) will be performed every day while the participant is receiving R-ICE treatment.
4.1.12 Urinalysis
Urinalysis will be performed every day while the participant is receiving R-ICE treatment.
4.1.13 Hepatitis B and C Testing
Hepatitis serology testing must include hepatitis B surface antigen (HBsAg), hepatitis B surface 
antibody (anti-HBs), hepatitis B core antibody (anti-HBc), and HCV antibody. In addition, any subjects 
testing positive for any hepatitis serology must have PCR testing during screening and on study (see 
exclusion criterion #15).
4.1.14 Coagulation Panel
Coagulation panel will include prothrombin time (PT), activated partial thromboplastin time (aPTT), and 
international normalized ratio (INR). Testing will be done by a local laboratory as listed on the 
investigator’s Form FDA 1572.
4.1.15 Pharmacodynamics/Pharmacokinetics and Biomarker Studies
TUMOR BIOPSY and ctDNA:
Identification of Tumor-Specific BCR Clonotype from pre-treatment tumor biopsy and tracking of MRD: 
The specimens collected at pre-treatment (typically, lymph node biopsy) archival tissue will be shipped 
to Foundation One Heme. Details regarding recommended specimens are outlined in the Manual of 
Procedures
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ctDNA CORRELATES
Pre-treatment blood samples can be used as an adjunct specimen to identify DLBCL specific B cell 
receptor (BCR) clonotypes. Briefly, 400 ng of total RNA isolated from buffy coat will be used to prepare 
BCR IGH plus IGL (κ+γ) sequencing libraries using ArcherDx Immunoverse BCR All Chains panel.
Libraries will be sequenced on an Illumina MiSeq to a depth of 1M read-pairs (2x300bp) per sample, 
sufficient to identify dominant clones using a frequency threshold of 5%. Archer Analysis pipeline will be 
used for preprocessing (sample demultiplexing, alignment and molecular index counting for bias 
correction) and BCR repertoire analysis to identify major BCR clones (clone, clonotype, and segment 
usage analysis). MRD assessment using BCR repertoire analysis of peripheral blood buffy coat will 
follow an identical workflow but using 1,600 ng of input RNA and sequencing to a depth of 4M read- 
pairs per sample to permit tracking of low frequency BCR clones. The DLBCL derived BCR clones 
identified in each pre-treatment sample will be used to assess the presence of MRD in post-treatment 
samples with a sampling limit of of >75,000 clonotypes per assay. MRD determined in this manner, as 
DLBCL-derived BCR clone counts within the B cell compartment, will be normalized to total cells or 
standard blood volume using single platform clinical flow cytometry (Laboratory of Flowcytometry, 
Department of Pathology and Laboratory Medicine, University of Miami). The BCR immune repertoire 
approach will also permit screening of the expansion of novel high frequency BCR clones should they 
emerge.
Response Criteria: Response will be evaluated in this study using the RECIL criteria and will be applied 
to define complete response. Response will be evaluated first at pre-treatment, and subsequently at 
interim CT after two cycles of therapy, and at EOT PET. We will follow patients who achieve a complete 
metabolic response after completion of study therapy during surveillance for 52 weeks with CT or 
PET/CT per standard of care until progression of disease by imaging.
As an exploratory objective we will collect circulating cell free DNA (ccfDNA) at each assessment to 
support analysis of circulating tumor DNA (ctDNA). ctDNA analysis will require the targeted sequencing 
of known mutant alleles which may not be apparent for all cases. In cases where genomic alterations in 
the DNA components of the FoundationOne Heme panel are identified pre-treatment, orthologous 
ctDNA-optimized assays using either commercial or custom targeted sequencing panels will be used to 
retrospectively track ctDNA variant allele frequencies. In addition, these ccfDNA samples could also be 
used for comparative retrospective analysis of BCR clonotypes if assays become available.
Refer to the laboratory manual for instructions on collection and shipment of the PD and biomarker 
samples. All testing will be done by the supplier of the study medication or designee. Leftover blood 
and tumor samples may also be used for genomic analyses to study mechanisms of action.
MTV CORRELATE:
Screening and EOT scans for each patient enrolled will be sent to UM for central review. 
PET/CT scans at enrollment and EOT from mid-skull to upper thighs will be obtained ~90 minutes after 
injection on Philips Gemini TF PET/CT systems (Philips Medical Systems, Cleveland, Ohio). A clinical 
imaging protocol will be applied with an injection of approximately 555 +/- 10% MBq FDG after at least 
4 hours of fasting and documentation of blood glucose <200 mg/dL. A low-dose, attenuation correction 
CT scan (120 kV, approximately 100 mA) will be acquired, following by PET emission images. All 
images will be reviewed on Thinking Systems software. Region of interest will be set by manual 
adjustment in 3 planes to exclude adjacent physiologic FDG avid structures. SUV max will be defined 
as the maximum voxel intensity within the volumetric region of interest. A threshold of 41% of the 
maximum signal intensity will be used to delineate the metabolic tumor volume (MTV) however, other 
thresholds will be evaluated. Patient MTV represents the sum of every individual lesion MTV. The TLG 
will be calculated as the product of MTV and the SUV mean using Hermes Hybrid 3D Tumor Finder for 
MTV software.
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4.1.16 Tumor Assessments
Response will be evaluated in this study per RECIL criteria.1
Complete Response (CR):

CR is defined as a complete resolution of all target lesions by CT scans with complete 
normalization of FDG-PET uptake in all areas (Deauville score of 1–3), and bone 
marrow biopsy negativity (if it was positive or unknown at baseline). If pretreatment PET 
scan was negative, lymph nodes that measured ≥15 mm in the long axis should regress 
to < 10 mm.

CR is also defined as achievement of a partial remission by CT scan criteria (reduction 
in sum of longest diameters by CT imaging by >30%) with normalization (Deauville score 
1–3) of FDG-PET activity in FDG-avid lymphoma (Table 1). Because many novel 
targeted agents may alter glucose uptake and/or metabolism, normalizing of FDG-PET 
imaging alone is not sufficient by itself to determine CR status unless accompanied with 
a significant (>30%) decrease in the sum of diameters. Accordingly, a reduction in the 
sum of diameters by ≤30% with normalization of FDG-PET uptake should not be 
considered a CR unless documented by a negative tissue biopsy.

Deauville Criteria 5-point scale32:
1. No uptake.
2. Uptake < mediastinum.
3. Uptake > mediastinum but < liver.
4. Uptake moderately more than liver uptake, at any site.
5. Markedly increased uptake at any site and new sites of disease.

In cases where pretreatment baseline tumor burden is low, with only a few lesions 
measuring around 2 cm in longest diameter, treatment effect may shrink the long axis of 
a target lymph node to a normal values of <10 mm.
Partial Response (PR):

PR is defined as a reduction of the sum of longest diameters of target lesions by ≥30%, 
but without meeting the definition of CR. If one or more target lesions grew in size but 
the sum of the diameters remains ≤30% of the baseline measurement, and no new 
lesions appear, the response should be designated PR.
Minor Response (MR):

Using single diameter long-axis measurements, MR is defined as a reduction in the SLD 
of target lesions by ≥10% but <30%, without the appearance of any new lesions, and 
irrespective of PET scan results.
Stable Disease (SD):

SD is defined as changes in the SLD of targeted lesions ranging between reduction of
<10% to an increase by ≤20% without the appearance of a new lesion, and irrespective
of PET results.
Progressive Disease (PD):

PD is defined as an increase in the sum of longest diameters of target lesions by >20%, 
and/or appearance of a new lesion (lymph node ≥ or a soft tissue mass ≥10 mm of the 
longest diameter), irrespective of FDG-PET results. An increase in the size of previously 
involved small lymph nodes by >20% while other lesions are decreasing, especially at 
the beginning of treatment with investigational agents, may represent a tumor flare and 
should not be designated a PD, unless there is continued increase in size on
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subsequent imaging studies.

Response assessment in patients receiving agents that mobilize lymphoma cells 
from lymph nodes and bone marrow into the blood
o Some agents can inhibit adhesion mechanisms in tumor cells causing 
redistribution of tumor cells from lymph nodes and/or bone marrow into the blood. 
Thus, while lymph node size decrease in response to therapy, the tumor cell 
count increases in the blood, creating another form of “pseudo-progression”. With 
continued therapy, blood lymphocytosis decrease as tumor cells start to die. 
Increased lymphocytosis in the setting of a decrease in lymph node 
measurement is not considered PD, and response designation should depend on 
lymph nodes and extra-nodal disease measurement. Lymphocytosis can be 
included as annotation. For example, PR with increased lymphocytosis.
4.1.17 Study Drug Accountability
See Section 7.6
4.2
ASSESSMENT OF RESPONSE TO TREATMENT
For the purposes of this study, patients should be re-evaluated per the study calendar. In addition to a 
baseline scan, confirmatory scans will also be obtained post cycle 2 per cross sectional imaging criteria 
by CT,, as well as post cycle 3 per RECIL criteria1 following initial documentation of an objective 
response following cycle 2. If patients have progressive disease after cycle 2, they will be removed from 
study.
4.3
END OF TREATMENT AND TREATMENT TERMINATION VISITS
An end of treatment (EOT) visit is required for all subjects within 14 days after the last dose of study 
drug.
The Schedule of Assessments (Appendix 1) describes the procedures required for EOT visit.
4.4
FOLLOW-UP FOR PROGRESSION AND SURVIVAL
Patients will be followed every 12 weeks for 52 weeks for EFS and PFS after the EOT visit, removal 
from study, or until death, whichever occurs first. Follow up can include CBC, CMP, LDH and CT and/or 
PET/CT per standard of care. Patients removed from study for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event.
Patients who discontinue study treatment because of PD will enter overall survival (OS) follow-up and 
will be contacted every 12 weeks for 52 weeks for survival status.
4.5
MISSED EVALUATIONS
Missed evaluations should be rescheduled and performed as close to the original scheduled date as 
possible. An exception is made when rescheduling becomes, in the investigator’s opinion, medically 
unnecessary or unsafe because it is too close in time to the next scheduled evaluation. In that case, 
the missed evaluation should be abandoned.
5
STATISTICAL METHODS OF ANALYSIS
5.1
GENERAL CONSIDERATIONS
The primary objective of phase II study is to evaluate the CR rate of acalabrutinib + R-ICE x 3 cycles 
according to fluorine18 -fluorodeoxyglucose PET imaging criteria. The CR/CRu rate of R-ICE in 
previously rituximab exposed patients on the CORAL study was 29% (personal communication with 
Christian Gisselbrecht, CORAL PI). To this end, an optimal Simon two-stage design will be utilized. 
Given the historic control, we will set the desirable CR rate as 50% or higher for the proposed new 
treatment regimen, and 30% or lower as undesirable. In the first stage, we will enroll 20 eligible patients. 
If 6 or fewer patients achieve CR after 3 cycles, no additional patients will be enrolled and the regimen 
will be considered not promising. If 7 or more patients achieve CR, then an additional 26 patients will be 
enrolled for the second stage. Among the total 46 patients, if 18 or more patients are able to achieve CR
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then this treatment regimen will be considered promising. This decision rule has a one-sided type I error 
(declaring the new treatment regimen promising while it is actually not) rate as 0.10 and a type II error 
(declaring the new treatment regimen not promising while it actually is) rate as 0.10.
The study includes a number of secondary objectives. Descriptive statistics will be used to summarize 
the safety profile of the treatment regimen, and summarize the mobilization rates. Kaplan-Meier 
methodology will be used to estimate overall and progression-free survival. The association between 
genetic markers, MTV, ctDNA, and disease response will be assessed.
5.2
ENDPOINT DATA ANALYSIS
5.2.1 Efficacy Endpoint(s)
The primary endpoint is complete response rate at the end of cycle 3 of treatment. Secondary 
endpoints are toxicity and adverse event rates, PR and OR rates at the end of cycle 3, as well as PFS, 
EFS, and OS at 1 year.
5.2.2 Safety Endpoint(s)

Safety and tolerability of acalabrutinib with R-ICE in patients with rel/ref DLBCL
5.2.3 Study Treatment Administration and Compliance
Descriptive information will be provided regarding the number of acalabrutinib doses prescribed, the 
total number of doses taken, the number of days of treatment, and the number and timing of prescribed 
dose delay, reductions and interruptions.
For each subject, acalabrutinib compliance will be described in terms of the proportion of study drug 
actually taken.
5.2.4 Analysis of Efficacy Parameters
Analysis of efficacy parameters will be evaluated using the efficacy parameters defined in section 3.1.1 
using the RECIL response criteria outlined in 4.1.16.
5.2.5 Primary Efficacy Endpoint
CR rate will be calculated along with an exact 95% CI based on binomial distribution.
5.2.6 Secondary Efficacy Endpoint
ORR and PR rates will be calculated along with exact 95% Cis based on binomial distribution. 
PFS is defined as the time from first dose to documented disease progression, or death from 
any cause, whichever occurs first. Data for subjects who are still alive and free from 
progression at the time of data cutoff date, lost to follow-up, or have discontinued the study will 
be censored on last assessment (or, if no post-baseline tumor assessment, at the time of first 
dose plus 1 day). Duration of PFS will be estimated using Kaplan-Meier methodology.
Approximate 95% CIs for median duration of PFS will be computed using the formula proposed 
by Brookmeyer and Crowley.
EFS is defined as the time from first dose to documented disease progression, death from any 
cause, or study dropout, whichever occurs first. Duration of EFS will be estimated using
Kaplan-Meier methodology. Approximate 95% CIs for median duration of EFS will be computed 
using the formula proposed by Brookmeyer and Crowley.
OS is defined as the time from first dose to death from any cause. Data for subjects who are 
still alive at the time of data cutoff date, lost to follow-up, have discontinued the study (or, if no 
post-baseline assessment, at the time of first dose plus 1 day) will be censored. Duration of OS 
will be estimated using Kaplan-Meier methodology. Approximate 95% CIs for median duration 
of OS will be computed using the formula proposed by Brookmeyer and Crowley.
5.2.7 PK, PD or Biomarker Analyses
Baseline MTV, end of treatment MTV, and baseline ctDNA will be associated with CR, PR, and ORR by 
Wilcoxon rank sum tests. Baseline and post treatment mutations detected by NGS will be associated
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with CR, PR, and ORR by Fisher’s exact tests. MTV (baseline and end of treatment) and mutations 
(baseline and post treatment) will be associated with EFS, PFS, and OS using Cox regression treating 
MTV as time-dependent covariate. Baseline ctDNA will be associated with EFS, PFS, and OS by log- 
rank tests.
6
ASSESSMENT OF SAFETY
Safety assessments will consist of monitoring and recording DLTs, AEs, and SAEs; measurements of 
protocol-specified hematology, clinical chemistry, urinalysis, and other laboratory variables; 
measurement of protocol-specified vital signs; and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study drug(s).]
6.1
DEFINITIONS
6.1.1 Adverse Events
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the 
use of an investigational (medicinal) product, regardless of attribution. This includes the following:

AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the condition being studied that 
were not present before the AE reporting period.

Pre-existing medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period.

Abnormal laboratory values considered clinically significant by the investigator should be 
reported as an AE.
The following are NOT considered an AE:

Pre-existing condition that has not worsened: A pre-existing condition (documented on the 
medical history CRF) is not considered an AE unless the severity, frequency, or character of the 
event worsens during the study period.

Preplanned hospitalization: A hospitalization planned before signing the ICF is not considered 
an SAE, but rather a therapeutic intervention. However, if during the preplanned hospitalization 
an event occurs, which prolongs the hospitalization or meets any other SAE criteria, the event 
will be considered an SAE. Surgeries or interventions that were under consideration, but not 
performed before signing the ICF, will not be considered serious if they are performed after 
signing the ICF for a condition that has not changed from its baseline level. Elective 
hospitalizations for social reasons, solely for the administration of chemotherapy, or due to long 
travel distances are also not SAEs.

Diagnostic testing and procedures: Testing and procedures should not be reported as AEs or 
SAEs, but rather the cause for the test or procedure should be reported. If a test or procedure 
is done to rule out a diagnosis, the sign or symptom leading to the test/procedure should be the 
event term, and the event term should only be updated to the diagnosis if/when the diagnosis is 
confirmed. Testing and procedures performed solely as screening measures (eg, routine 
screening mammography or colonoscopy) should not be reported as AEs or SAEs.

Abnormal laboratory results that the investigator considers to not be clinically 
significant: Abnormal laboratory results are not AEs unless they are clinically significant. For 
example, a clinically significant laboratory result is one that requires treatment (for example a 
blood transfusion for low hemoglobin) or requires a change in study drug (eg, 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
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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.
Symptomatic deterioration may occur in some subjects. Symptomatic deterioration is when 
progression is evident in the subject’s clinical symptoms and the investigator may elect not to perform 
further disease assessments. If there is any uncertainty about an AE being due only to the disease 
under study, it should be reported as an AE or SAE.]
6.1.2 Serious Adverse Event
The terms “severe” and “serious” are not synonymous. Severity (or intensity) refers to the grade of an 
AE (see below). “Serious” is a regulatory definition and is based on subject or event outcome or action 
criteria usually associated with events that pose a threat to a subject’s life or functioning. Seriousness 
(not severity) serves as the guide for defining regulatory reporting obligations from the supplier of the 
study medication 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 (ie, the AE actually causes or leads to death).

It is life-threatening (ie, the AE, in the view of the investigator, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death).

It requires or prolongs inpatient hospitalization.

It results in persistent or significant disability/incapacity (ie, 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 
(eg, may jeopardize the subject or may require medical/surgical intervention to prevent 1 of 
the outcomes listed above).]
6.1.3 Severity
Definitions found in the CTCAE version 5 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 which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities

Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures

Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment

Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be in 
imminent danger of death

Grade 5 (Death related to AE) – experiences which result in subject death]
6.2
DOCUMENTING AND REPORTING OF ADVERSE AND SERIOUS ADVERSE 
EVENTS
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported during 
the study, as outlined in the prior sections, are recorded on the CRF.
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6.2.1 Adverse Event Reporting Period
The AE reporting period for this study begins when the subject receives the first dose of study drug and 
ends 30 days after the last dose. An exception to this reporting period is any AE occurring due to a 
protocol-defined screening procedure. If any SAE occurs beyond 30 days after the last dose of 
acalabrutinib AND it is assessed by the investigator as related to acalabrutinib, it must be reported as 
an SAE.
6.2.2 Assessment of Adverse Events
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation time points during 
the study. All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, or other means, will be recorded in the subject’s 
medical record and on the AE CRF.
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 (eg, start and end dates), 
severity, regulatory seriousness criteria, if applicable, suspected relationship to the study drug (see 
following guidance), and any actions taken. The 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 Guidance 2012).
See Appendix 4 for more detail on assessing relationship.
6.2.3 Overdose
Clinical information relevant to overdose is not available. For results from nonclinical overdose studies 
in rats and dogs, please refer to the Investigator Brochure.
Study drug overdose is the accidental or intentional use of the drug in an amount higher than the dose 
being studied. An overdose or incorrect administration of study drug is not an AE unless it results in 
untoward medical effects.
Any study drug overdose or incorrect administration of study drug should be noted on the appropriate 
CRF. All AEs associated with an overdose or incorrect administration of study drug should be recorded 
on the CRF. For multi-center studies: If the associated AE fulfills serious criteria, Investigators should 
report the event to the supplier of the study medication within 24 hours using the SAE Reporting Form. 
The supplier of the study medication should report any SAEs to the IRB and Regulatory Authorities per 
institutional and/or regulatory guidelines, and to Acerta-Pharma per contractual guidelines.
In the event of subject ingestion of more than the recommended acalabrutinib dosage, observation for 
any symptomatic side effects should be instituted, and vital signs, biochemical and hematologic 
parameters should be followed closely (consistent with the protocol or more frequently, as needed).
Appropriate supportive management to mitigate adverse effects should be initiated. If the overdose 
ingestion of acalabrutinib is recent and substantial, and if there are no medical contraindications, use of 
gastric lavage or induction of emesis may be considered.]
6.2.4 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 Acerta Pharma Drug 
Safety. Any pregnancy-associated SAEs must be reported to Acerta Pharma, according to the usual 
timelines and directions for SAE reporting (Section 6.2.6).
Any uncomplicated pregnancy that occurs with the subject or with the partner of a treated subject 
during this study will be reported. All pregnancies and partner pregnancies that are identified during or 
after this study, wherein the estimated date of conception is determined to have occurred from the time 
of consent to 2 days [2-day guidance applicable to acalabrutinib monotherapy only] after the last dose 
of study medication will be reported, followed to conclusion, and the outcome reported.
A pregnancy itself is not regarded as an AE unless there is suspicion that the investigational product 
under study may have interfered with the effectiveness of a contraceptive medication. Likewise, 
elective abortions without complications are not considered AEs. Any SAEs associated with pregnancy
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information may be transmitted using a follow-up report and should not delay the initial report. The 
Sponsor may contact the investigational site to solicit additional information or follow up on the event.
The Investigator must take all therapeutic measures necessary for resolution of the SAE. Any 
medications or procedures necessary for treatment of the SAE must be recorded on the applicable 
pages of the subject’s eCRF.
UM OVPRS will report to Food and Drug Administration (FDA) any applicable SAEs.
6.2.6 Expedited Reporting Requirements for Serious Adverse Events
The LEAD PRINCIPAL INVESTIGATOR shall be solely responsible for complying, within the required 
timelines, any safety reporting obligation to competent Health Authorities, IRB/ECs and any 
participating (co or sub) investigators, as defined in applicable laws and regulations. For the purposes 
of this section, safety data includes adverse events, product quality complaints (PQCs), and special 
situations including pregnancies.
All SAEs must be reported to Acerta Pharma/Astra Zeneca within 7 days of discovery for fatal and life- 
threatening reports (15 days for other SAE and special situation reports) and to the IRB/IEC <<per their 
requirements.>> Acerta Pharma/Astra Zeneca may request follow-up and other additional information 
from the investigator.
Whenever possible, SAEs should be reported by diagnosis term not as a constellation of symptoms. 
All deaths should be reported with the primary cause of death as the 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 and reports will be forwarded to AZ.
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 Brochure (i.e., an unexpected 
event).
Drug Safety Contact Information
Fax:
+1 866 467 0304 or +1 650 965 4996
Email:
AEMailboxClinicalTrialTCS@astrazeneca.com
The lead principal investigator should report all SAEs to the IRB and Regulatory Authorities per 
institutional and/or regulatory guidelines, and to Acerta Pharma/AstraZeneca per contractual guidelines. 
For Sponsors with subsites: Investigators should report any SAEs to investigational Sponsor within 24 
hours using the SAE Reporting Form.
Generally, any AE considered serious by the PI or Sub-investigator or which meets the 
definition of an SAE included in Section 6.1.2, Serious Adverse Events.
SAEs will be captured on the appropriate case report form (CRF) as well as in the Serious Adverse 
Event reporting section in Velos, a HIPAA AND 21 CFR part 11 compliant database and will be 
reported to the University of Miami’s IRB per institutional requirements.
6.2.7 AE/SAE Reporting by Lead PI to U.S. Regulatory Authorities
According to 21 CFR 312.32(c)(1), “the sponsor [lead PI] must notify FDA in an IND safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later
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than 15 calendar days after the sponsor [lead PI] determines that the information qualifies for reporting. 
In each IND safety report, the sponsor [lead PI] must identify all IND safety reports previously submitted 
to FDA concerning a similar suspected adverse reaction and must analyze the significance of the 
suspected adverse reaction in light of previous, similar reports or any other relevant information. The 
sponsor [lead PI] must report any suspected adverse reaction that is both serious and unexpected. The 
sponsor [lead PI] must report an adverse event as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the drug and the adverse event, such as:
(A) A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome);
(B) One or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture);
(C) An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events that 
commonly occur in the study population independent of drug therapy) that indicates those 
events occur more frequently in the drug treatment group than in a concurrent or historical 
control group.”
Furthermore, according to 21 CFR 312.32(c)(2), “the sponsor [lead PI] must also notify FDA of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later 
than 7 calendar days after the sponsor's [lead PI’s] initial receipt of the information.”
6.2.8 Type and Duration of Follow-up of Subjects after Adverse Events
All AEs and SAEs that are encountered during the protocol-specified AE reporting period should be 
followed to resolution, or until the investigator assesses the subject as stable, or the subject is lost to 
follow-up or withdraws consent.
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 are:

Unsatisfactory subject enrollment with regard to quality or quantity

Significant or numerous deviations from study protocol requirements, such as failures to perform 
required evaluations on subjects and maintain adequate study records

Inaccurate, incomplete and/or late data recording on a recurrent basis

The incidence and/or severity of AEs in this or other studies indicating a potential health hazard 
caused by the study treatment
7.1
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS COMMITTEE
The investigator will submit this protocol, the informed consent, current Investigator Brochure, and any 
other relevant supporting information (eg, all advertising materials) to the appropriate IRB/IEC for 
review and approval before study initiation. Amendments to the protocol must also be approved by the 
IRB/IEC and local regulatory agency, as appropriate, before the implementation of changes in this 
study.
This clinical study was designed and will be implemented in accordance with the protocol, the 
International Conference on Harmonisation (ICH) Harmonised 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.
7.2
SUBJECT SCREENING LOG
The investigator will keep a record that lists all subjects considered for enrollment (including those who 
did not undergo screening) in the study. For those subjects subsequently excluded from enrollment, 
record the reason(s) for exclusion.
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7.3
CASE REPORT FORMS
Authorized study site personnel will complete CRFs designed for this study according to the completion 
guidelines that will be provided within the clinical database. The investigator will ensure that the CRFs 
are accurate, complete, legible, and completed promptly.
7.4
INVESTIGATIONAL STUDY DRUG ACCOUNTABILITY
Acalabrutinib capsules will be supplied to the site research or investigational pharmacy department. 
The study drug must not be used outside the context of the protocol. Refer to the Manual of Procedures 
for further information.
7.5
RECORD RETENTION
The investigator and other appropriate study staff are responsible for maintaining all documentation 
relevant to the study. Mandatory documentation includes copies of study protocols and amendments, 
each Form FDA 1572, IRB/IEC approval letters, signed ICFs, drug accountability records, SAE 
information, subject files (source documentation) that substantiate entries in CRFs, all relevant 
correspondence and other documents pertaining to the conduct of the study.
The investigator shall retain study records in accordance with institutional and/or national/local 
regulations, whichever is longer.
All patients will be requested to maintain a medication diary of each dose of acalabrutinib (Appendix 6). 
Medication diaries and pill bottles (including remaining or missed capsules) will be returned to research 
staff at the end of each cycle for reconciliation and completion of drug return forms.
7.6
DISCLOSURE AND PUBLICATION POLICY
All information provided regarding the trial, as well as all information collected/documented 
during the course of the trial, will be regarded as confidential.
The financial disclosure information will be completed prior to trial participation from all PIs and 
Sub-Investigators who are involved in the trial and named on the FDA 1572 form.
The lead principal investigator will register the trial on www.clinicaltrials.gov. In addition, the 
lead principal investigator will publish the results of the trial.
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8
REFERENCES
1.Younes A, Hilden, P, Coiffier, B., et al.: International Working Group consensus response evaluation 
criteria in lymphoma (RECIL 2017) Annals of Oncology 28:1436-1447, 2017
2.Hans CP, Weisenburger DD, Greiner TC, et al: Confirmation of the molecular classification of diffuse 
large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103:275-82, 2004
3.Smith TJ, Khatcheressian J, Lyman GH, et al: 2006 Update of Recommendations for the Use of 
White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline. Journal of Clinical 
Oncology 24:3187-3205, 2006
4.Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with 
salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 
333:1540-5, 1995
5.Moskowitz CH, Bertino JR, Glassman JR, et al: Ifosfamide, carboplatin, and etoposide: a highly 
effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible 
patients with non-Hodgkin's lymphoma. J Clin Oncol 17:3776-85, 1999
6.Hamlin PA, Zelenetz AD, Kewalramani T, et al: Age-adjusted International Prognostic Index predicts 
autologous stem cell transplantation outcome for patients with relapsed or primary refractory diffuse 
large B-cell lymphoma. Blood 102:1989-96, 2003
7.Derenzini E, Musuraca G, Fanti S, et al: Pretransplantation positron emission tomography scan is the 
main predictor of autologous stem cell transplantation outcome in aggressive B-cell non-Hodgkin 
lymphoma. Cancer 113:2496-503, 2008
8.Dickinson M, Hoyt R, Roberts AW, et al: Improved survival for relapsed diffuse large B cell lymphoma 
is predicted by a negative pre-transplant FDG-PET scan following salvage chemotherapy. Br J 
Haematol 150:39-45, 2010
9.Moskowitz CH, Zelenetz A, Schoder H: An update on the role of interim restaging FDG-PET in 
patients with diffuse large B-cell lymphoma and Hodgkin lymphoma. J Natl Compr Canc Netw 8:347-52, 
2010
10.Sauter CS, Matasar MJ, Meikle J, et al: Prognostic value of FDG-PET prior to autologous stem cell 
transplantation for relapsed and refractory diffuse large B-cell lymphoma. Blood 125:2579-81, 2015
11.Kewalramani T, Zelenetz AD, Nimer SD, et al: Rituximab and ICE as second-line therapy before 
autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. 
Blood 103:3684-8, 2004
12.Gisselbrecht C, Glass B, Mounier N, et al: Salvage Regimens With Autologous Transplantation for 
Relapsed Large B-Cell Lymphoma in the Rituximab Era. J Clin Oncol, 2010
13.Satterthwaite AB, Witte ON: The role of Bruton's tyrosine kinase in B-cell development and function: 
a genetic perspective. Immunol Rev 175:120-7, 2000
14. Kuppers R: Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer 5:251-62, 2005
15.Gururajan M, Jennings CD, Bondada S: Cutting edge: constitutive B cell receptor signaling is critical 
for basal growth of B lymphoma. J Immunol 176:5715-9, 2006
16. Lenz G, Staudt LM: Aggressive lymphomas. N Engl J Med 362:1417-29, 2010
17.Davis RE, Ngo VN, Lenz G, et al: Chronic active B-cell-receptor signalling in diffuse large B-cell 
lymphoma. Nature 463:88-92, 2010
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18.Wilson WH, Dunleavy K, Pittaluga S, et al: Phase II study of dose-adjusted EPOCH and rituximab in 
untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center 
biomarkers. J Clin Oncol 26:2717-24, 2008
19.Thieblemont C, Briere J, Mounier N, et al: The Germinal Center/Activated B-Cell Subclassification 
Has a Prognostic Impact for Response to Salvage Therapy in Relapsed/Refractory Diffuse Large B-Cell 
Lymphoma: A Bio-CORAL Study. J Clin Oncol, 2011
20.Wilson WH, Young RM, Schmitz R, et al: Targeting B cell receptor signaling with ibrutinib in diffuse 
large B cell lymphoma. Nat Med 21:922-6, 2015
21.Sauter C.S. M, M.J., Schoder, H., et al.: A phase 1 study of ibrutinib in combination with R-ICE in 
patients with relapsed or primary refractory DLBCL. Blood 131:1805-1808, 2018
22.Swerdlow SH, Campo E, Pileri SA, et al: The 2016 revision of the World Health Organization 
classification of lymphoid neoplasms. Blood 127:2375-90, 2016
23.Smith TJ, Khatcheressian, J., Lyman, G.H., et al.: 2006 Update of Recommendations for the Use of 
White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline. Journal of Clinical 
Oncology 24:3187-3205, 2006
24.Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize 
response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin 
Oncol 17:1244, 1999
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IRB Study Number: 2019070-6
Study #: 20190706
Effective Date: 7/1V4e/2rs0i2o1n #3.0, Date: 24 June, 2021
APPENDIX 1. SCHEDULE OF ASSESSMENTS
Parameter
Pre-treatment
Period 
Screening
Open-Label Treatment Period
Follow-Upn
In Clinic
Up to 28 
days before 
enrollment
Cycle 1, Day 1
Cycles 2 to 3
(Day 1,+ 7 or – 3 
days)
Response Evaluation 
Cycle 2
End of Treatment 
Visita
(14 – 28 days after
last dose of study 
drug)
Every 12 weeks (+ 
or – 1 week) for 52 
weeks
Screening/Administrative
Informed Consent
X
Demographics/ Medical 
History
X
Inclusion/Exclusion
X
Staging and sAAIPI
X
Patient diary will be 
provided
Xo
Check patient medication 
diary for treatment
compliance
X
Study Drug Administration
Acalabrutinib 
administration
Refer to Dose and Administration – Section 3.5 3
R-ICE administration
Refer to Dose and Administration – Section 3.5 3
Safety Assessments
Complete physical 
examination
Xk
Directed physical 
examination with
lymphoma symptoms 
reviewed and recordedb
Xb, l
X
Performance status (ECOG)
Xk
X
X
Vital Signs (heart rate, 
temperature, BP)
Xk
X
X
Weight
Xk
X
X
Height
Xk
BSA
X
ECG
X
X
Echocardiogram/MUGA 
scanc
X
Concomitant Medications
X
Adverse Events
X
X
Clinical Laboratory Assessments
Hematology (CBC with 
differential: WBC, HGB, 
HCT, platelet count, ANC,
ALC)
Xk
Xe
X
Chemistry (albumin, ALP, 
ALT, AST, CO2, BUN, Ca,
Cl, creatinine, glucose, 
LDH, Mg,
phosphate/phosphorus, K, 
Na, total bilirubin, total
protein, uric acid)d
Xk
Xf
X
Chemistry (K)
Xl
Urinalysis
Xl
Coagulation panel (PT, 
aPTT, INR)
X
HBV surface antigen and 
HCV (antibodies)
X
Serum or urine -HCG 
pregnancy test
(for females with 
childbearing potential)
Xe
X
Total cell count, B cell 
count
X
X
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Parameter
Pretreament 
Period
Screening
Open-Label Treatment Period
Follow-Upn
In Clinic
Up to 28
days before 
enrollment
Cycles 1 to 3
(Day 1)
Response Evaluation 
Cycle 2
End of Treatment 
Visita
Efficacy Assessments
CT imaging (neck, chest, 
abdomen, and pelvis) with 
IV or oral contrast
Xh
Xh
Xi
Whole body FDG-PET 
scanh, i
Xh
Xi
Evaluation of other sites of 
diseaseh, i
X
X
Bone marrow biopsyj
X
ctDNA assessmentm
X
X
Survival
X
ALC=absolute lymphocyte count; ALP=alkaline phosphatase; ALT=alanine aminotransferase; ANC=absolute neutrophil count; 
AP=alkaline phosphatase; aPTT= activated partial thromboplastin time; AST=aspartate aminotransferase; -HCG=beta-human chorionic 
gonadotropin; BP=blood pressure; BSA=body surface area; BUN-blood urea nitrogen; Ca=calcium; Cl=chloride; CO2=bicarbonate; 
CT=computed tomography; ctDNA= circulating tumor DNA; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
FDG=fluorodeoxyglucose; HBV=hepatitis B virus; HCV=hepatitis C virus; IHC=immunohistochemistry; INR= international normalized 
ratio; IV=intravenous; K=potassium; LDH=lactate dehydrogenase; Mg=magnesium; MUGA=multiple-gated acquisition scan; Na= 
sodium; PD=progressive disease; PET=positron emission tomography; PK=pharmacokinetics; PT=prothrombin time; R-ICE=rituximab,
ifosfamide, carboplatin, and etoposide; sAAIPI= age-adjusted international prognostic index at the initiation of second-line 
therapy;WBC=white blood count.
a
This visit is required for all subjects. It should take place 14-28 days after the last dose of study drug.
b
Directed physical examination includes all organ systems that were previously abnormal or involved with disease and 
documentation of any clinically relevant abnormalities in any organ. Lymphoma symptoms reported at screening should be reviewed 
and recorded during the directed physical examination. Subjects should be questioned regarding changes in ocular status and
referred to an ophthalmologist for a formal exam if any positive findings (Grade ≥2) are reported.
c
Echocardiography or MUGA scan is mandatory at baseline; thereafter it can be repeated optionally at any time during the study if 
clinically relevant, or in case of cardiac adverse events, using the same modality as at baseline.
d
Calculated creatinine clearance of ≥60 mL/minute/1.73 m2 within 14 days before enrollment.
e
Samples can be taken on the day of or day prior to dosing, provided that results are available before the dose of study drug is given. 
Hematology should be done on Days 1, between Days 7 and 10, and on Day 14 of each cycle with a window of ±1 day. For pregnancy 
tests, if the pregnancy test during screening is within 28 days of Cycle 1 Day 1, it does not need to be repeated.
f
Samples can be taken on the day of or day prior to dosing. The results do not need to be available before the dose of study drug is 
given.
g
Computed tomography and PET scans obtained for standard subject evaluations before signing ICF can be used for screening, but 
should not be older than 28 days prior to enrollment.
h
Computed tomography scan and PET scans will be performed at screening and at the end of Cycle 3. CT scan will occur Day 15-21 
of Cycle 2 to demonstrate lack of progression of disease (PD)24. If PD, patient will be removed from study. Positron emission 
tomography scans must be done between Days 15 to 21 of Cycle 3.
i
Computed tomography and PET scans are required at early withdrawal. Computed tomography and PET scans performed after Cycle 
3 are considered the End-of-Treatment disease efficacy assessment (or earlier if <3 cycles administered as per investigator discretion).
If early withdrawal prior to the end of Cycle 3, CT and PET scans are to be repeated.
j
Morphological and IHC examination of the bone marrow is required and should be performed within 28 days prior to the first dose 
of study drug. In subjects with bone marrow involvement prior to treatment, bone marrow biopsy must be repeated once during the
study for confirmation of CR (preferentially within 30 days of initial documentation of CR). Bone marrow obtained for standard 
subject evaluations before signing ICF can be used for screening, but should not be older than 28 days prior to treatment.
k
If this visit occurs within 7 days of Cycle 1 Day 1. It may be used for the screening and Cycle 1 Day 1 treatment evaluations.
l
A directed physical exam, chemistry (potassium) and urinalysis assessments will be performed every day while participants are 
receiving R-ICE treatment.
m RNB for patients with evaluable clonotype determined on pretreatment tumor specimen. Required ctDNA assessment time points: 
pre-treatment, and at EOT.
n
Follow-up every 12 weeks for 52 weeks after EOT visit, until removal from study, or until death. SAEs considered related to study 
drug should be documented
o
A patient diary will be provided to participants and study team members will advise participants on how to record information in the 
diary.
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Appendix 2. Performance Status Scores
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity. Fully active, able to 
carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of
disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
2
In bed <50% of the time. 
Ambulatory and capable of all self- 
care, but unable to carry out any 
work activities. Up and about more
than 50% of waking hours.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care and
assistance.
3
In bed >50% of the time. Capable 
of only limited self-care, confined to 
bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated. Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any self- 
care. Totally confined to bed or 
chair.
10
Moribund, fatal processes
progressing rapidly.
5
Dead.
0
Dead.
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APPENDIX 3. KNOWN STRONG IN VIVO INHIBITORS OR INDUCERS OF CYP3A
Strong Inhibitors of CYP3Aa
Strong Inducers of CYP3Ad
boceprevir
carbamazepinee
clarithromycinb
phenytoine
conivaptinb
rifampine
indinavir
St John's worte
itraconazoleb
ketoconazoleb
lopinavir/ritonavirb (combination drug)
mibefradilc
nefazodone
nelfinavir
posaconazole
ritonavirb
saquinavir
telaprevir
telithromycin
voriconazole
a.
A strong inhibitor is defined as an inhibitor that increases the AUC of a substrate by ≥ 5-fold.
b.
In vivo inhibitor of P-glycoprotein.
c.
Withdrawn from the United States market because of safety reasons.
d.
A strong inducer is defined as an inducer that results in ≥ 80% decrease in the AUC of a substrate.
e.
In vivo inducer of P-glycoprotein.
Note: The list of drugs in these tables is not exhaustive. Any questions about drugs not on this list should be 
addressed to the Sponsor of the protocol.
Source:
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers . Web link Accessed 
11 June 2015:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm09 
3664.htm#inVivo
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Appendix 4. Adverse Event Assessment of Causality
Adverse Event:
Is there a reasonable possibility that the event may have been caused by study drug? No
 
Yes
The descriptions provided below will help guide the principal investigator in making the decision to 
choose either “yes” or “no”:
No = There is no reasonable possibility that the event may have been caused by study drug. 
The adverse event:

may be judged to be due to extraneous causes such as disease or environment or toxic 
factors

may be judged to be due to the subject’s clinical state or other therapy being administered

is not biologically plausible

does not reappear or worsen when study drug is re-administered

does not follow a temporal sequence from administration of study drug
Yes = There is a reasonable possibility that the event may have been caused by study drug. 
The adverse event:

follows a temporal sequence from administration of study drug

is a known response to the study drug based on clinical or preclinical data

could not be explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other therapy administered to the subject

disappears or decreases upon cessation or reduction of dose of study drug

reappears or worsens when study drug is re-administered
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APPENDIX 5. COLLECTION AND PROCESSING AND END-OF-TREAMENT BLOOD 
SAMPLES FOR BCR CLONOTYPING
Materials

BD Vacutainer® Molecular Cell Preparation Tube, 8 mL (BD362761)

DMSO (Sigma Cat. No D2650)

IMDM- Iscove’s Modified Dulbecco’s Medium (Thermo Scientific Cat. No 12440-053)

Fetal bovine serum- FBS (Thermo Scientific Cat. No 26140-079)

HBSS- Hank’s Balanced Salt Solution (Thermo Scientific Cat. No 14170-112)

2.0mL Cryo Storage Vial (VWR Cat. No 66008-728)

15mL Centrifuge Tubes (VWR Cat. No 21008-918)
Procedure
1.
Blood Collection
1.1. Collect whole blood in two (2) pre-labeled BD Vacutainer Molecular Cell Preparation Tubes 
(CPT), 8 mL each.
1.2. Invert each tube 8-10 times at store at room temperature (18-25°C).
2.
Shipping and Receiving blood samples in cell preparation tubes
2.1. Sylvester sites will coordinate with the BioSpecimen Shared Resource (BSSR; Melinda 
Boone and Elena Cortizas) for drop off/pick up of blood samples. CPT processing should 
occur within 2 hours of collection.
2.2. For non-Sylvester sites: Ship CPT tubes the same day via FedEx First Overnight to: 
ATTN: Melinda Boone
SCCC Biospecimen Shared Resources 
1550 NW 10th Ave, Fox 436
Miami, Florida 33136
Samples should be kept and shipped at room temperature. Shipments should be sent Monday – 
Wednesday only to avoid being delayed in transit during the weekend.
3.
Freezing Medium Preparation (If necessary)
3.1. Freezing medium consists of 70% FBS, 20% IMDM, and 10% DMSO.
3.2. To prepare 50mL of freezing medium
3.2.1.
Add 35mL FBS to a clean 50mL conical tube.
3.2.2.
Add 10mL IMDM to the conical tube and gently invert.
3.2.3.
Add 5mL DMSO to the conical tube, invert 5 times.
3.2.4.
Aliquot 5mL into 10-15mL conicals and store at -20º C until ready for use.
4.
CPT Processing
4.1. Upon arrival, make sure that CPT tube is maintained in an upright position, and kept at 
room temperature until centrifugation.
4.2. For optimal results, processing should be started within 2 hours of blood collection; cell 
degradation will occur if tubes are stored for longer than four hours.
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4.3. Centrifuge CPT tubes at 1800 x g for 40 minutes at room temperature. Turn the centrifuge 
brake off by setting the deceleration to zero.
4.4. After centrifugation, place the CPT tube in biological safety cabinet and carefully remove 
the top.
4.5. Using a sterile 5mL transfer pipet, gently pipette the plasma up and down against the gel 
plug to dislodge cells that are stuck to the top of the gel. Avoid vigorous pipetting that 
would disintegrate the gel plug itself.
4.6. Transfer the cell suspension from each CPT tube (2) from a single patient time point to a 
15mL conical polypropylene tube. Bring cell suspension to a final volume of 12mL with 
HBSS.
4.7. Transfer one aliquot of cell suspension (1 million PBMC suspended in 1 ml RPMI with 10% 
bovine serum) into a tube for clinical flow (see below for procedure).
4.8. Centrifuge 15mL tubes at 250 x g for 10 minutes at room temperature.
5.
Cell Resuspension/Cryopreservation
5.1. When centrifugation is complete, aspirate the supernatant and gently flick the tube to 
break up the pellet.
5.2. Gently swirl cell suspension in 15mL tube and 1mL freezing media gradually.
5.3. Place the tube on ice and avoid any further mixing or agitation of the cells.
5.4. Using a sterile 5mL transfer pipet, transfer the cell suspension into a 2.0mL cryovial.
5.5. Place aliquots in a Mr. Frosty™ freezing container filled with 100% isopropyl alcohol that 
has been pre-cooled at -80º C and return to -80 º C. This will achieve a cooling rate of 
close to -1 º C/minute.
5.6. Store samples at -80º C for 24 hours, then transfer to permanent storage in liquid 
nitrogen.
5.7. The BSSR will store plasma/mononuclear cell layer. When enough samples have been 
processed and stored to batch for RNA extraction, the BSSR will contact the Onco- 
Genomics Shared Resource (OGSR) to coordinate pickup of samples.
5.8. The OGSR will pick up samples on dry ice and process for RNA extraction (procedure 
below) immediately.
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RNA extraction and BCR clonotyping of pre-treatment and end-of-treatment blood samples
Materials

RNeasy Mini Kit 50 rxns (Qiagen 74104)

Fragment Analzyer HS/SS RNA Kit

Qubit HS/BR RNA Kit

ArcherDx Immunoverse HS BCR IGH/K/L kit

Fragment Analzyer HS DNA Kit

Qubit HS DNA Kit

MiSeq Reagents
Procedure
1.
RNA Extraction of isolated plasma/mononuclear cell layer following manufacturer’s 
protocol.
1.1. RNeasy Mini Kit (100 ug RNA) (Qiagen 74104)
2.
RNA Quantification and QC
2.1. Run 2 ul of extracted total RNA on Fragment Analyzer using the High Sensitivity/Standard 
Sensitivity RNA Kit.
2.2. Visualize quality and record RIN score.
2.3. Run 2 ul of extracted total RNA on Qubit Fluorometer to determine concentration.
3.
Prepare sequencing library using the ArcherDx Immunoverse HS BCR IGH/K/L kit 
following the manufacturer’s protocol.
3.1. For pre-treatment samples, the input is 400 ng of RNA.
3.2. For end-of-treatment samples, the input is 1600 ng of RNA.
4.
Library Quantification and QC
4.1. Run 2 ul of library on Fragment Analyzer using the High Sensitivity DNA kit.
4.2. Visualize quality of library and record average fragment size.
4.3. Run 2 ul of library on Qubit Fluorometer to determine concentration.
5.
Sequencing
5.1. Libraries will be pooled and sequenced on an Illumina MiSeq (2x300 bp).
5.2. Pre-treatment libraries will be sequenced at 1 million read-pairs per sample.
5.3. Post-treatment libraries will be sequence at 4 million read-pairs per sample.
6.
Data Analysis
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MRD assessment for normalization with blood samples
Procedure
1) An aliquot from the plasma/mononuclear cell layer will be immediately transfer to 
Hematopathology by the Biospecimen Shared Resource.
2) Hematopathology will run clinical flow cytometry procedure.
Collection of circulating cell free DNA (ccfDNA) of pre-treatment and end-of-treatment 
samples
Materials

PAXgene ccfDNA blood tube (PreAnalytix 768115)

QIAamp MinElute ccfDNA Mini (Qiagen 55204)

Fragment Analyzer HS DNA Kit

Qubit HS DNA Kit
Procedure
1.
Pre-label two (2) PAXgene ccfDNA blood tubes (10mL) per patient.
1.1. Collect whole blood in a PAXgene ccfDNA blood tube to its’ maximum volume.
1.2. Invert tube 8 times to mix blood and additive.
1.3. Immediately store at 4°C. (The whole blood sample can be stored for up to 10 days at 
temperatures from 2°C to 25°C, 7 days at up to 30°C, and 3 days at up to 37°C prior to 
processing. Do not store below 2°C)
2.
Shipping and receiving blood samples in PAXgene tubes
2.1. For Sylvester sites, collected samples will be received by the BSSR along with the above 
CPT blood tubes for plasma/mononuclear cells isolation.
2.2. For Non-Sylvester sites, …
2.3. The BSSR will store the PAXgene ccfDNA blood tubes at 4°C.
2.4. Due to time restrictions on processing these tubes, the BSSR will contact the OGSR upon 
arrival and storage of samples to arrange retrieval.
2.5. The OGSR will receive the samples from the BSSR and store at 4°C until processing 
within the time frame based on sampling date and temperature storage.
3.
ccfDNA Isolation
3.1. The whole blood sample will following the manufacturer’s protocol for Plasma Preparation 
Isolation of ccfDNA in PAXgene ccfDNA blood tube prior to ccfDNA isolation.
3.2. ccfDNA Isolation will following the manufacturer’s protocol
3.2.1.
QIAamp MinElute ccfDNA Mini (Qiagen 55204)
4.
ccfDNA Quantification and QC
4.1. Run 2 ul of ccfDNA on Fragment Analyzer using the High Sensitivity DNA kit.
4.2. Visualize quality of ccfDNA.
4.3. Run 2 ul of ccfDNA on Qubit Fluorometer to determine concentration.
5.
The ccfDNA will be stored at -20°C.
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