Phase II Study of Rituximab and Acalabrutinib in Newly Diagnosed B Cell Post Transplant Lymphoproliferative Disorder (PTLD)
Phase: PHASE2
Conditions: Post-transplant Lymphoproliferative Disorder
Sponsor: Deepa Jagadeesh

 
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STUDY NUMBER: CASE 3419  
 
ClinicalTrials.gov NCT #: NCT04337827 
 
Protocol Date: 7/2/2021 
 
STUDY TITLE: Phase II Study of Rituximab and Acalabrutinib in Newly Diagnosed B Cell 
Post Transplant Lymphoproliferative Disorder (PTLD) 
 
 
 
PRINCIPAL INVESTIGATOR: 
Deepa Jagadeesh MD, MPH 
Cleveland Clinic 
Taussig Cancer Institute 
9500 Euclid Avenue 
Cleveland, OH  44195 
 
 
 
 
Cleveland Clinic Sub-Investigators: 
 
 
 
 
 Brad Pohlman, MD 
Rob Dean, MD 
Brian Hill, MD 
Christopher D'Andrea, PA-C 
Allison Winter, MD 
Omer Koc, MD 
Genevieve Crane, MD 
 
 
 
STATISTICIAN:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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STUDY COORDINATOR: 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
  
 
SPONSOR:  
 
 
Case Comprehensive Cancer Center  
 
 
 
 
 
 
SUPPORT/FUNDING: 
 
AstraZeneca  
 
SUPPLIED AGENT: 
 
Acalabrutinib 
 
IND #:  
 
 
 
 
 
 
 
 
OTHER AGENT:  
 
Rituximab 

 
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SUMMARY OF CHANGES 
 
Protocol 
Date 
Section 
Change 
11/13/2019  
Initial PRMC approval 
4/3/2020 
throughout 
Minor formatting and grammatical updates 
4/3/2020 
1.1 
Added some information to the background of PTLD 
4/3/2020 
4.1.1 
Added the histological diagnoses of PTLD in the inclusion criteria per 
WHO 2016 criteria 
4/3/2020 
4.1.4; 
appendix 4 
Added creatinine clearance eligibility criteria for renal function 
4/3/2020 
4.2.21 & 
4.2.22 
Revised the exclusion criteria to exclude patients with acute GVHD 
and/or transplant organ rejection 
4/3/2020 
6.1 
Clarified that subjects are not required to fail the trial of  
immunosuppression prior to starting study treatment 
4/3/2020 
6.1.1 
Added hematologic criteria required to initiate each treatment cycle 
4/3/2020 
6.4 
Added the development of second primary malignancy to the criteria 
for removal from the study 
4/3/2020 
7.1 
Revised the dose delay/modification criteria for acalabrutinib 
4/3/2020 
9.2 
Clarified that rituximab administration should be done per local 
institutional standard of care 
4/3/2020 
10.0 
Revised the instructions for specimen collection for correlative studies 
4/3/2020 
11.1.1;  
11.1.2; 
11.2; 12.0 
Clarified that PET scan is preferred for patients is insurance only 
allows one type of scan and that the same radiologic imaging that was 
obtained at screening will be used to assess response 
4/3/2020 
11.1.1 
Added that if baseline tissue is not available, approval from the 
sponsor-investigator is required to enroll 
4/3/2020 
14.4 
Added toxicity monitoring rules 
4/18/2020 
Cover Page Added NCT number 
4/18/2020 
Schema 
and 
throughout 
Changed the Interim Response Assessment to take place during days 
39-42 (instead of day 36 ± 5 days) and for cycle 2 to start within 2 
weeks (instead of 3 weeks) of the end of cycle one treatment 
4/18/2020 
4.1.5 
Added highly effective methods of contraception 
4/18/2020 
8.1.1.1 
Updated the language for second primary malignancies and removed 
pregnancy and breastfeeding from the warning and precautions section 
4/18/2020 
8.3; 8.4; 
8.5 
Added the definition of AESI and included AESIs in the reporting 
requirements to go along with SAEs 
12/28/2020 Cover Page Remove University Hospitals; Update Cleveland Clinic sub-
investigators and study coordinator 
12/28/2020 5.0 
Registration contact information changed from Ben Pannell to the 
Study Coordinator provided on page 2 
12/28/2020 8.5.1 
SAE/AESI Reporting Requirements: study coordinator added to list of 
people included in notification 
12/28/2020 6.1.3; 9.2 
Adding biosimilar use of Rituximab is permitted for this study per 
treating investigator discretion 
12/28/2020 10.3 
Change Cleveland Clinic Biorepository shipping title and ATTN to 
Genevieve Crane, MD 

 
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Protocol 
Date 
Section 
Change 
12/28/2020 6.5; 11.1.2; 
11.2 
Allowing virtual visits for long-term follow up visits 
7/2/2021 
Cover page Updated study staff 
7/2/2021 
Abbrevia-
tions 
Removed unused abbreviations 
7/2/2021 
Table of 
contents 
Added missing section numbers 
7/2/2021 
throughout 
Corrected typos 
7/2/2021 
Schema; 
11.1.1; 
11.2 
Added required PT/INR at screening to align with inclusion criteria 
7/2/2021 
9.1 
Corrected storage temperature of acalabrutinib 
7/2/2021 
11.1.1 
Removed requirement to receive approval for missing tissue samples 
prior to enrollment 
7/2/2021 
13.1 
Replaced references to Forte EDC with the new name Adverra EDC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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PROTOCOL SUMMARY 
 
Protocol Number/Title 
CASE 3419/ Phase II Study of Rituximab and 
Acalabrutinib in Newly Diagnosed B Cell Post Transplant 
Lymphoproliferative Disorder (PTLD) 
Study Phase 
Phase II  
Brief Background/Rationale 
 
 
 
Post-transplant lymphoproliferative disorders (PTLD) are 
rare pathologically and clinically heterogeneous diseases 
that occur in both solid organ and bone marrow transplant 
(BMT) patients.  The frequency of PTLD in solid organ 
transplant (SOT) varies from 1-20% with highest incidence 
seen among heart, lung, intestinal and multi organ 
transplantation 1-5 
Currently there is no approved therapy for PTLD. Single 
agent rituximab is commonly used and the overall response 
rate (ORR) has ranged from 37% to 69% 6-11.  In a subset of 
patients’ inadequate response necessitates addition of 
chemotherapy to improve response rate and outcomes. The 
morbidity and mortality with combination chemotherapy is 
reported to be high in this population 8.  In one analysis 
52% patients treated with chemotherapy required hospital 
admission for complications and treatment related mortality 
was 26% 8. Due to these reasons treatment with novel 
targeted agents needs to be explored to improve outcomes 
and to minimize toxicity.  
Acalabrutinib is a well-tolerated Bruton’s Tyrosine Kinase 
Inhibitor (BTK).  BTK plays an important role in B cell 
development and function thus its inhibition is a treatment 
strategy in B cell lymphomas. Acalabrutinib has been 
approved in the treatment of R/R mantle cell lymphoma 
(MCL) and is being studied in other B cell malignancies 12-
15.  
Primary Objective  
To determine the overall response rate to combination 
treatment with rituximab and acalabrutinib in patients with 
PTLD.  To be measured 8 weeks after treatment 
completion.   
Secondary Objective(s) 
To determine the following in patients with PTLD treated 
with combination rituximab and acalabrutinib.   
 Complete response rate (CRR) 
 Partial response rate (PRR) 
 Duration of response (DOR) 
 Progression free survival (PFS) 
 Overall survival (OS) 
 Time to treatment failure (TTF) 
 Safety of rituximab and acalabrutinib 
Sample Size 
62 patients 
Disease sites/Conditions 
Post-transplant lymphoproliferative disorder 

 
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Interventions 
 Rituximab weekly x 4 weeks PLUS acalabrutinib 
100mg BID x 4 weeks (28  
day cycle)  
 Response assessment with CT scans on days 39-42 
after end of cycle 1 treatment.  
 If complete response, then proceed with one 
additional 28 day cycle.  
 If partial response, then proceed with 3 additional 
28 day cycles. 
 If stable disease or progression of disease, then go 
off study treatment and proceed onto LTFU. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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ABBREVIATIONS  
 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BCR 
B cell receptor 
BID 
twice per day (dosing) 
BOR 
best overall response 
BR 
Bendamustine and Rituximab  
BTK 
Bruton tyrosine kinase 
BMT 
Bone marrow transplant 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CCCC 
Case Comprehensive Cancer Center 
CCF 
Cleveland Clinic Foundation 
CFR 
Code of Federal Regulations 
CIs 
confidence intervals 
CLL 
chronic lymphocytic leukemia 
CR 
complete response (remission) 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria For Adverse Events 
CYP 
cytochrome p450 
DOR 
duration of response 
DSTC 
Data Safety and Toxicity Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
IB 
Investigator’s brochure  
IEC 
independent ethics committee 
Ig 
immunoglobulin 
IRB 
institutional review board 

 
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IV 
intravenous or intravenously  
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCL 
mantle cell lymphoma 
NE 
nonevaluable 
NHL 
Non-Hodgkin lymphoma 
ORR 
overall response rate 
OS 
overall survival 
PFS 
progression-free survival 
PLL 
prolymphocytic leukemia  
PR 
partial response (remission) 
PRL 
partial response with lymphocytosis 
PRMC 
Protocol Review and Monitoring Committee 
PTLD 
post-transplant lymphoproliferative disorders  
R/R 
relapsed/refractory 
SAE 
serious adverse event 
SD 
stable disease or standard deviation 
SOC 
Standard of Care 
SOT 
solid organ transplant 
SUSAR 
suspected unexpected serious adverse reaction 
TTF 
time to treatment failure 
ULN 
upper limit of normal 
 

 
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TABLE OF CONTENTS 
 
1.0  
INTRODUCTION  
 
1.1 
Background of PTLD  
1.2  
Name and description of Acalabrutinib 
 
1.2.1     Preclinical Data 
 
1.2.2     Clinical Efficacy Data 
 
1.2.3     Clinical Pharmacokinetics 
1.3  
Name and description of Rituximab 
 
1.3.1     Preclinical Data 
 
1.3.2     Clinical Efficacy Data 
 
1.3.3     Clinical Pharmacokinetics 
1.4  
Rationale   
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 
2.2  
Secondary Objectives 
 
3.0 
STUDY DESIGN 
3.1 
Study design 
3.2 
Number of Subjects 
3.3 
Replacement of Subjects 
3.4 
Expected Duration of Treatment and Subject Participation 
 
 
4.0  
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
5.0 
REGISTRATION  
 
 
6.0  
TREATMENT PLAN 
6.1 
Treatment Regimen Overview 
 
6.1.1     Criteria for starting a new cycle 
 
6.1.2     Acalabrutinib Administration 
 
6.1.3     Rituximab Administration 
6.2 
Duration of Therapy  
6.3  
General Concomitant Medications and Supportive Care Guidelines 
 
6.3.1     Drug-Drug Interactions with Acalabrutinib 
 
6.3.2     Drug-Drug Interactions with Rituximab  
6.4 
Criteria for Removal from Study 
6.5 
Duration of Follow Up 
 
7.0 
DOSE DELAYS / DOSE MODIFICATIONS 
7.1    Acalabrutinib 
7.2 
Rituximab 
 
8.0 
ADVERSE EVENTS AND POTENTIAL RISKS 
8.1  
Acalabrutinib  
 
8.1.1     Warnings and Precautions 
 
  
8.1.1.1     Hemorrhage 

 
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8.1.1.2     Infection 
 
 
8.1.1.3     Cytopenias 
 
 
8.1.1.4     Second Primary Malignancies 
 
 
8.1.1.5     Atrial Fibrillation 
8.2 
Rituximab  
 
8.2.1    Warnings and Precautions 
 
  
8.2.1.1     Tumor Lysis Syndrome 
 
 
8.2.1.2     Infection 
 
 
8.2.1.3     Cardiovascular Adverse Reactions 
 
 
8.2.1.4     Renal Toxicity 
 
 
8.2.2.5     Bowel Obstruction and Perforation 
 
 
8.2.1.6     Immunization 
 
 
8.2.1.7     Embryo-Fetal Toxicity 
 
 
8.2.1.8     Concomitant Use with Other Biologic Agents and DMARDS other  
 
 
                 than Methotrexate in RA, GPA and MPA, PV 
 
 
8.2.1.9     Infusion-related Reactions 
 
 
8.2.1.10   Mucocutaneous Reactions 
 
 
8.2.1.11   Progressive multifocal leukoencephalopathy 
8.3 
Definitions 
 
8.3.1     Adverse Event 
 
8.3.2     Serious Adverse Events 
 
8.3.3     Adverse Events of Special Interest 
 
8.3.4     Adverse Event Evaluation 
8.4 
Serious Adverse Event Report Form 
8.5 
Reporting Procedures for Serious Adverse Event  
 
8.5.1     SAE reporting Requirements 
8.6 
Serious Adverse Events and OnCoreTM    
8.7 
Data Safety Toxicity Committee 
8.8 
Data and Safety Monitoring Plan 
 
9.0 
PHARMACEUTICAL INFORMATION  
9.1 
Acalabrutinib 
 
9.2 
Rituximab 
9.3 
Rituximab-hyaluronidase human 
 
10.0  CORRELATIVE STUDIES 
10.1 
Tissue Procurement 
10.2 
Blood Sample 
10.3 
Shipment 
 
11.0 
STUDY PARAMETERS AND CALENDAR 
11.1 
Study Parameters 
 
11.1.1     Screening Evaluation day -28 to 1 
 
11.1.2     Treatment Period 
11.2 
Calendar 
 
12.0 
MEASUREMENT OF EFFECT  
12.1 
Definitions 
 
12.1.1     Overall Response Rate 
 
12.1.2     Complete Response Rate 
 
12.1.3     Partial Response Rate 

 
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12.1.4     Duration of Response 
 
12.1.5     Progression Free Survival 
 
12.1.6     Overall Survival 
 
12.1.7     Time to Treatment Failure 
 
 
13.0 
DATA REPORTING/REGULATORY CONSIDERATIONS 
13.1 
Data Reporting 
13.2 
Regulatory Considerations 
 
13.2.1     Written Informed Consent 
 
13.2.2     Subject Data Protection 
 
13.2.3     Retention of Records 
 
13.2.4     Audits and Inspections  
 
 
14.0 
STATISTICAL CONSIDERATIONS 
14.1 
General Considerations 
14.2 
Rational for Sample Size 
14.3 
Futility Monitoring Rule 
14.4 
Toxicity Monitoring 
14.5 
Analysis Population 
14.6 
Missing Data Handling 
14.7 
Endpoint Data Analysis 
 
REFERENCES 
 
  
APPENDICES  
APPENDIX 1.     Performance Status Criteria 
APPENDIX 2.     Known Strong in Vivo Inhibitors or Inducers of CYP3A 
APPENDIX 3.     Assessment of Responses based on Lugano Criteria 
APPENDIX 4.     Cockcroft Gault Formula to Estimate Renal Function Using Serum Creatinine 
APPENDIX 5.     Subject Pill Diary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1.0 
Introduction  
 
1.1 
Background of PTLD  
Post-transplant lymphoproliferative disorders (PTLD) are rare pathologically and clinically 
heterogeneous diseases that occur in both solid organ and bone marrow transplant (BMT) 
patients. The main determinant risk factors in the development of PTLD are the degree and 
duration of the immunosuppression. Suppression of the normal T cell function by the 
immunosuppressants enables the proliferation of EBV infected B cells leading to the 
development of PTLD.   
The frequency of PTLD in solid organ transplant (SOT) varies from 1-20% with highest 
incidence seen among heart, lung, intestinal and multi organ transplantation 1-5.  The higher 
incidence of PTLD among these SOTs has been attributed to higher degree and longer duration 
of immunosuppression.  The incidence is much less (1-5%) in SOT that requires lower 
immunosuppression like liver and renal transplants 4,5. The incidence in BMT patients is low 
approximately 0.5-1% with T cell depletion being a risk factor 16-18.  
The highest incidence of PLTD is in 1-2 years following the transplant. Early PTLD are mostly 
EBV positive, while the late PTLDs have shown to be EBV negative 19,20. According to the 2016 
WHO classification, PTLD is classified into 6 categories: plasmacytic hyperplasia PTLD, 
infectious mononucleosis PTLD, florid follicular hyperplasia PTLD, polymorphic PTLD, 
monomorphic PTLD and classical Hodgkin lymphoma PTLD 21. Due to paucity of data and 
rarity of the disease there is no well-established standard of care for PTLD.  
Currently, PTLD is treated with either single agent rituximab or with rituximab containing 
chemotherapy. The overall response rate (ORR) to single-agent rituximab has ranged from 37% 
to 69% 6-11. The first prospective phase II study by Choquet et al evaluated single-agent 
rituximab in 43 SOT-related PTLD recipients who failed tapering of immunosuppression 7.  
They demonstrated an ORR of 34%, event free survival (EFS) of 72%, and overall survival (OS) 
of 67% at 1 year. Complete response (CR) rate in this trial after 4 doses of rituximab was 28%. 
Rituximab was well tolerated with only 2 grade 3 or 4 events related to rituximab – hypertension 
and purpura with myalgia.  Neutropenia was reported in two patients 7.  Another prospective 
study evaluated the efficacy of extended use of rituximab in 38 patients with PTLD 11. After the 
first course of rituximab, 34% had a CR, which was further augmented to 61% when partial 
responders were given 4 additional doses. One episode of grade 4 neutropenia was the only 
serious adverse event observed.  Elstrom et al retrospectively reviewed 35 patients with PTLD 
treated with rituximab and showed an ORR of 68% and median OS of 31 months with rituximab 
8.   
Currently there is no approved therapy for PTLD. Although single agent rituximab is commonly 
used to treat B cell PTLD, the overall response rate is around 60% with approximately 30% of 
the subjects attaining a complete response. In a subset of patients’ inadequate response 
necessitates addition of chemotherapy to improve response rate and outcomes. The morbidity 
and mortality with combination chemotherapy is reported to be high in this population 8.  In one 
analysis 52% patients treated with chemotherapy required hospital admission for complications 
and treatment related mortality was 26% 8. Due to these reasons treatment with novel targeted 
agents needs to be explored to improve outcomes and to minimize toxicity.  
 
 
 
 
 
 

 
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1.2  
Name and Description of Acalabrutinib 
 
1.2.1  Preclinical Data  
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 22.  Functional inhibition of non-target 
cells (eg, T cells, NK cells, platelets) was not observed for acalabrutinib at clinically relevant 
concentrations.  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 mantle cell 
lymphoma (MCL) who have received at least 1 prior therapy.  It is also being evaluated for the 
treatment of patients with other B-cell malignancies.     
Please refer to the Investigator’s Brochure (IB) for detailed preclinical data.  
  
1.2.2 Clinical Efficacy Data   
There have been several studies and are several ongoing studies that have evaluated the efficacy 
of acalabrutinib in B cell malignancies and even solid tumors.  Acalabrutinib is approved for R/R 
mantle cell lymphoma and undergoing a phase III studies for use in chronic lymphocytic 
leukemia (CLL).  A summary of results from studies evaluating acalabrutinib is below however, 
please see the Investigator Brochure for full details.   
 
In a phase II study (ACE-LY-004) using single agent acalabrutinib to treat R/R MCL the ORR in 
124 patients was 80.6% with 39.5% achieving a CR 23.  More than half of patients (56.6%) 
continued on treatment at a median follow up of 15 months.  The median duration of response, 
PFS and OS were not reached, but the 1-year PFS and OS were 67% and 87% respectively 23 
Most adverse events (AE) were grade 1-2, with only a small proportion of the patients 
experiencing grade ≥3 AE, which included neutropenia (10%), anemia (9%) and pneumonia 
(5%). Only 1 patient had grade 3 bleeding, while no atrial fibrillation was noted. Other notable 
AEs include grade 2 pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV) 
reactivation in 1 patient 23. Acalabrutinib is being evaluated with Bendamustine and Rituximab 
(BR) for the treatment of MCL in a Phase 1b, multicenter, open label study (ACE-LY-106) 24 .  
The study includes two cohorts – treatment-naïve and R/R patients.  The ORR was 94.4% (n=18) 
in the treatment-naïve cohort and 80.0% (n=20) in the R/R cohort. The phase III randomized 
placebo-controlled study evaluating BR vs BR + acalabrutinib in newly diagnosed MCL is 
currently accruing (clinicaltrials.gov #NCT02972840).  
 
ACE-CL-001 is a phase I/II study of single agent acalabrutinib in 134 patients with R/R CLL, 99 
patients with treatment-naïve CLL, 33 patients with CLL that were ibrutinib-intolerant, and 29 
patients with Richter’s syndrome or prolymphocytic leukemia transformation (PLL) 25.  
Acalabrutinib 100 mg twice-daily dose demonstrated 99% BTK occupancy.  In the R/R CLL 
cohort, ORR (including PR and PRL) was 96.9% with most responses being PR (86.8%) at a 
median follow up of 19.8 months.  The rate of PFS at 12 months was 95.4% 13,14.  In the 
treatment-naïve and ibrutinib intolerant cohorts the ORRs were 99% and 80.6%, respectively.  In 
the Richter’s syndrome or PLL group the ORR was 37%. Ongoing studies are evaluating 
acalabrutinib in combination with chemotherapy in various subtypes of B cell malignancies.  
  
1.2.3 Clinical Pharmacokinetics  
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.  See the IB for further 
details regarding pharmacokinetics.  In brief, Acalabrutinib is absorbed rapidly in non-clinical 

 
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species.  It is almost completely metabolized by multiple CYP and non CYP metabolic pathways 
with CYP3A-mediated oxidation being the major route of metabolism.  The half-life of the active 
metabolite (ACP-5862) is 6.9 hours.  Acalabrutinib is excreted mostly in the feces (84%) and a 
small amount in the urine (12%).  
 
1.3  Name and Description of Rituximab 
Rituximab has been approved for the use in Non-Hodgkin’s Lymphoma (NHL), Chronic 
Lymphocytic Leukemia (CLL), Rheumatoid Arthritis, Granulomatosis with Polyangiitis and 
Microscopic Polyangiitis, and Pemphigus Vulgarius 26.  While not approved for PTLD, it has 
become the mainstay of treatment (see Section 1.1 for further details) 
 
1.3.1 Preclinical Data 
 
Rituximab is a genetically engineered, chimeric murine/human monoclonal antibody directed 
against the CD20 antigen found on the surface of normal and malignant pre-B and mature B 
cells. The antibody is an IgG1 κ immunoglobulin containing murine light-and heavy-chain 
variable region sequences and human constant region sequences. Rituximab is composed of two 
heavy chains of 451 amino acids and two light chains of 213 amino acids (based on cDNA 
analysis) and has an approximate molecular mass of 145 kD.  The Fab domain of rituximab 
binds to the CD20 antigen on B-lymphocytes with a binding affinity of ~8.0nM.  The Fc domain 
recruits immune effector functions.   Upon binding to CD20, rituximab mediates B-cell lysis. 
Possible mechanisms of cell lysis include complement dependent cytotoxicity (CDC) and 
antibody dependent cell mediated cytotoxicity (ADCC).  The biological effect is manifested by 
B-cell depletion in peripheral blood, lymph nodes, and bone marrow 26. 
 
1.3.2 Clinical Efficacy Data 
See section 1.1 for discussion of rituximab use in patients with PTLD.   
 
1.3.3 Clinical Pharmacokinetics  
Per the rituximab package insert, pharmacokinetics were characterized in 203 NHL patients 
receiving 375 mg/m2 rituximab weekly by intravenous infusion for 4 doses. Rituximab was 
detectable in the serum of patients 3 to 6 months after completion of treatment. The 
pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m2 in 
combination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone. 
Based on a population pharmacokinetic analysis of data from 298 NHL patients who received 
rituximab once weekly or once every three weeks, the estimated median terminal elimination 
half-life was 22 days (range, 6.1 to 52 days). Patients with higher CD19-positive cell counts or 
larger measurable tumor lesions at pretreatment had a higher clearance. However, dose 
adjustment for pretreatment CD19 count or size of tumor lesion is not necessary. Age and gender 
had no effect on the pharmacokinetics of rituximab.  
Pharmacokinetics were characterized in 21 patients with CLL receiving rituximab according to 
the recommended dose and schedule. The estimated median terminal half-life of rituximab was 
32 days (range, 14 to 62 days) 26.  
 
1.4 
Rationale  
 
As stated in the Section 1.1, there is currently no approved therapy for PTLD.  Single 
agent rituximab and combination chemotherapy (R-CHOP) are the treatments used in clinical 
practice. Single agent rituximab yields a response rate of around 60% and combination 
chemotherapy is associated with significant morbidity and mortality8. As there are no approved 
treatment for newly diagnosed or relapsed PTLD, it’s an area of unmet need. Due to these 

 
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reasons treatment with novel targeted agents needs to be explored to improve outcomes and to 
minimize toxicity. 
Bruton’s tyrosine kinase (BTK) is a non-receptor enzyme in the Tec kinase that plays an 
important role in B-cell development and function.  It is in the B-cell receptor (BCR) signaling 
pathway and leads to the activation of nuclear factor kB and thus cell migration, proliferation and 
survival.  Abnormal signaling of the BCR pathway is important in the pathogenesis of B-cell 
malignancies. Thus, inhibition of the BTK has been implicated in the treatment of B-cell 
malignancies 12,15 
Acalabrutinib is a highly selective, irreversible second-generation Bruton’s tyrosine 
kinase (BTK) inhibitor that is approved for the treatment of mantle cell lymphoma (MCL), a B 
cell malignancy. It is also active in CLL and studies are ongoing evaluating its efficacy in other 
B cell lymphomas. This drug is rapidly absorbed and eliminated reaching the mean peak plasma 
level between 0.6 to 1.1 hours with a mean half-life of 1 hour in CLL patients 13. This short half-
life compared to 4-6 hours for ibrutinib 27 could be partially responsible for its better safety 
profile. Unlike ibrutinib, published data suggests lack of inhibition of epidermal growth factor 
receptor (EGFR), interleukin-2 inducible T cell kinase (ITK) and tyrosine kinase expressed in 
hepatocellular carcinoma (TEC) by acalabrutinb 13. An aggregate safety analysis of acalabrutinib 
monotherapy was conducted and included data from 7 studies.  This pooled data included 614 
acalabrutinib-exposed subjects with a median exposure of 21.9 months.  The most frequently 
reported Grade ≥3 AEs were neutropenia (10.4%), anemia (7.5%), pneumonia (6.5%), 
thrombocytopenia (3.7%), and hypertension (3.1%).  Evidence of clinical activity with improved 
toxicity profile has led to clinical studies with this agent in B cell malignancies.  
Ongoing studies are evaluating combination of acalabrutinb in various subtypes of B cell 
malignancies. Some of which include acalabrutinb with bendamustine and rituximab (BR) in RR 
MCL (NCT02717624), and in combination with R-CHOP in DLBCL (ACCEPT trial). An 
ongoing trial in United Kingdom is evaluating the outcome of ibrutinib with R-CHOP in PTLD 
patients (https://bloodwise.org.uk/research/clinical-trials/ptld-ibrutinib-i-and-rituximab-r-and-ir-
chop). Based on emerging data of clinical efficacy of acalabrutinib in B cell malignancies and an 
unmet need for novel therapies in PTLD, we propose a phase II study of rituximab and 
acalabrutinib in newly diagnosed B cell PTLD.  
 
2.0  
Objectives 
 
2.1  
Primary Objective  
To determine the overall response rate to combination treatment with rituximab and acalabrutinib 
in patients with newly diagnosed B-cell PTLD.   
 
2.2 
Secondary Objectives 
To determine the following in patients with PTLD treated with combination rituximab and 
acalabrutinib.   
 Complete response rate (CRR) 
 Partial response rate (PRR) 
 Duration of response (DOR) 
 Progression free survival (PFS) 
 Overall survival (OS) 
 Time to treatment failure (TTF) 
 Safety of rituximab and acalabrutinib 
 
 

 
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3.0 
Study Design 
 
3.1  
Study design   
This is a non-randomized phase II study of acalabrutinib plus rituximab in newly diagnosed B-
cell PTLD in both SOT and BMT patients. All subjects who meet the eligibility criteria 
described below will be enrolled to participate in the study.  
 
Refer to Section 11 for a comprehensive list of study assessments and their timing.  The study 
schema is provided in Figure 1 at the beginning of this document 
 
3.2 
Number of Subjects 
 
We plan to enroll 62 patients.   
 
3.3  
Replacement of Subjects 
 
If a subjects signs consent and meets eligibility criteria, but withdraws from the study prior to 
receiving the study treatment, the subject will be replaced. No subject will be replaced after 
receiving study treatment. 
 
3.4  
Expected Duration of Treatment and Subject Participation 
 
Duration of treatment will depend on patients’ response to therapy.  Initial treatment (cycle 1) for 
all patients, will be 28 days in length. Between days 39-42 after the end of cycle 1 treatment, 
patients will undergo CT scan for response assessment. Patients with a complete response will 
receive one additional 28 day cycle of therapy. Patients with a partial response will receive 3 
additional 28 day cycles of therapy. Patients with stable disease or progressive disease will come 
off study treatment and go directly on to long-term follow-up. Patients will receive a minimum 
of 1 cycle of therapy and a max of 4 cycles depending on their response. Cycle 2 should start 
within 2 weeks after the end of cycle 1 treatment.    
 
Table 1: Total Duration of Treatment Based on Disease Response 
 
Response to Cycle 1 
Duration of 
Treatment 
Complete Response 
56 days 
Partial Response 
112 days 
Stable or Progressive 
Disease 
28 days 
 
4.0 
Subject Selection 
Each of the criteria in the sections that follow must be met in order for a subject to be considered 
eligible for this study. Use the eligibility criteria to confirm a subject’s eligibility.  
 
4.1 
Inclusion Criteria 
 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment:  
 
4.1.1 Subjects must have a biopsy confirmed newly diagnosed CD20 positive B cell PTLD. 
The histological diagnosis may include: 

 
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 Plasmacytic hyperplasia PTLD  
 Infectious mononucleosis PTLD  
 Florid follicular hyperplasia PTLD 
 Polymorphic PTLD  
 Monomorphic PTLD (B- cell types)  
 Classical Hodgkin lymphoma PTLD 
4.1.2 Patients ≥ 18 years of age. 
4.1.3 Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.  ECOG 3 
will be permitted if the decline in performance status is due to lymphoma. [See 
Appendix 1] 
4.1.4 Subjects must have adequate hematologic, hepatic, and renal function as defined below:  
o Hemoglobin ≥ 8 gm/dL 
o Absolute neutrophil count ≥1000/mcL (unless documented bone marrow 
involvement with lymphoma) 
o Platelet count ≥50000/mcL (unless there is documented bone marrow 
involvement with lymphoma)  
o Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) < 2x 
ULN. 
o Total bilirubin ≤1.5X upper limit of normal (ULN)  
o Creatinine ≤2.5X upper limit of normal (ULN) or creatinine clearance ≥40 ml/min 
using the Cockcroft-Gault equation (Appendix 4)  
o ALT/AST < 2.5 X or ≤5X ULN for patients with documented hepatic 
involvement with lymphoma 
4.1.5 Women of childbearing potential and men must agree to use highly effective methods 
of contraception during treatment and for 12 months after last dose of study 
treatment. Such methods include: 
o Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation, which may be oral, intravaginal, or 
transdermal 
o Progestogen-only hormonal contraception associated with inhibition of ovulation, 
which may be oral, injectable, or implantable 
o Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
o Bilateral tubal occlusion 
o Vasectomy of a female subject’s male partner (with medical assessment and 
confirmation of vasectomy surgical success 
o Sexual abstinence (only if refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments) 
Women who have undergone surgical sterilization or who have been postmenopausal 
for at least 2 years are not considered to be of childbearing potential. 
4.1.6 Subjects must be willing and able to participate in all required evaluations and 
procedures in this study protocol including swallowing capsules without difficulty 
4.1.7 Subjects must have the ability to understand the purpose and risks of the study and 
provide signed and dated informed consent and authorization to use protected health 
information 
4.2 
Exclusion Criteria 
 
The presence of any of the following will exclude a subject from study enrollment: 
 
4.2.1 Prior treatment with any BTK inhibitor 

 
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4.2.2 Subjects receiving any other investigational agents or participating in another 
therapeutic clinical trial. 
4.2.3 Subjects with active (treated or untreated) brain metastases/ central nervous system 
(CNS) disease (including but not limited to CNS PTLD) will be excluded from this 
clinical trial 
4.2.4 Prior malignancy (or any other malignancy that requires active treatment), except for 
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, 
early stage prostate cancer or other cancer from which the subject has been disease 
free for ≥ 3 years 
4.2.5 Clinically significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of 
screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart 
Association Functional Classification.  Subjects with controlled, asymptomatic atrial 
fibrillation during screening can enroll in the study. 
4.2.6 Has difficulty with or is unable to swallow oral medication, or has significant 
gastrointestinal disease that would limit absorption of oral medication. 
4.2.7 Known history of infection with HIV. HIV-positive subjects on combination 
antiretroviral therapy are ineligible because of the potential for pharmacokinetic 
interactions with acalabrutinib. 
4.2.8 Patients with uncontrolled concurrent illness like active infection (eg, bacterial, viral, 
or fungal) requiring IV antibiotics or psychiatric illness/social situations that would 
limit compliance with study requirements 
4.2.9 Known history of drug-specific hypersensitivity or anaphylaxis to acalabrutinib or 
rituximab (including active product or excipient components). 
4.2.10 Active bleeding, history of bleeding diathesis (eg, hemophilia or von Willebrand 
disease). 
4.2.11 Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic 
thrombocytopenic purpura). 
4.2.12 Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer 
4.2.13 Requires or receiving anticoagulation with warfarin or equivalent vitamin K 
antagonists (eg, phenprocoumon) 
4.2.14 Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).  Subjects receiving 
proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible 
for enrollment to this study. 
4.2.15 History of significant cerebrovascular disease or event, including stroke or 
intracranial hemorrhage, within 6 months before the first dose of study drug. 
4.2.16 Major surgical procedure within 28 days of first dose of study drug.  Note:  If a 
subject had major surgery, they must have recovered adequately from any toxicity 
and/or complications from the intervention before the first dose of study drug. 
4.2.17 Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-
HBc) positive and who are surface antigen negative will need to have a negative 
polymerase chain reaction (PCR).  Those who are hepatitis B surface antigen 
(HbsAg) positive or hepatitis B PCR positive will be excluded.  Subjects who are 
hepatitis C antibody positive will need to have a negative PCR result.  Those who are 
hepatitis C PCR positive will be excluded. 
4.2.18 History of progressive multifocal leukoencephalopathy (PML) 
4.2.19 Breastfeeding or pregnant. Pregnant or breastfeeding women are excluded from this 
study because it is unknown how acalabrutinib and rituximab can affect the fetus or 
infant. Rituximab can cross the placenta and is found in breast milk.  Acalabrutinib 

 
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has been found in the breast milk of animals and there is not significant data 
regarding its effect during pregnancy. 
4.2.20 Vaccination with live virus vaccines is not allowed within 4 weeks of study treatment 
of or during treatment. 
4.2.21 Active GVHD requiring treatment  
4.2.22 Patients with biopsy proven transplant organ rejection that is clinically significant as 
determined by transplant team 
 
4.3 
Inclusion of Women and Minorities  
Men, women and members of all races and ethnic groups are eligible for this trial. 
 
5.0 
Registration 
All subjects who have been consented are to be registered in the OnCore™ Database. For those 
subjects who are consented, but not enrolled, the reason for exclusion must be recorded. 
 
All subjects will be registered through Cleveland Clinic and will be provided a study number by 
emailing the Study Coordinator with the contact information provided on page 2 of this 
document.  
 
6.0  
Treatment Plan 
 
6.1 
 
 
Table 2: Treatment Regimen Overview 
 
Cycle  
Agent 
Suggested 
Premedication3 
Dose 
Route 
Schedule 
Cycle 
Length 
Cycle 1 
Rituximab 
Acetaminophen 
(650 mg) PO and 
diphenhydramine 
(50 mg) PO or IV, 
30 -60 minutes 
prior to each 
infusion1.  
 
375mg/m2 IV 
or flat dose 
1400mg SC 
IV or 
subcutaneous 
(SC) 
Days 
1,8,15,22 
28 days 
Cycle 2 for 
subjects in 
CR 
Rituximab 
Acetaminophen 
(650 mg) PO and 
diphenhydramine 
(50 mg) PO or IV, 
30 -60 minutes 
prior to each 
infusion1. 
375mg/m2 IV 
or flat dose 
1400mg SC 
IV or 
subcutaneous 
(SC) 
Days 
1,8,15,22 
Cycles 2-4 
for subjects 
in PR 
Rituximab 
Acetaminophen 
(650 mg) PO and 
diphenhydramine 
(50 mg) PO or IV, 
30 -60 minutes 
prior to each 
infusion1. 
375mg/m2 IV 
or flat dose 
1400mg SC 
IV or 
subcutaneous 
(SC) 
Day 1 
Cycles 1-4 
Acalabrutinib none 
100mg BID 
PO 
Days 1-
28 
1. Hydroxyzine may be substituted in patients intolerant of diphenhydramine  
2. First dose of rituximab will be given IV and subsequent doses can be either IV or SC based on institutional 
guidelines.  
3. Premedication can be per institutional standards or as suggested above  
 

 
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If a patient is on immunosuppressants, the treating physician will discuss with the transplant 
team about reducing immunosuppression according to local institutional standard of care. If the 
transplant team decides to reduce the immunosuppression, the study treatment can be started 
simultaneously and it is not required to fail the trial of immunosuppression to start the study 
treatment. If the transplant team deems that it is not safe to reduce the immunosuppression, 
eligible patients can start study treatment.   
 
6.1.1  Criteria for starting a new cycle 
 
The following treatment parameters should be met on D1 prior to initiating a new cycle (starting 
with cycle 2): 
 ANC ≥500/mcL  
 Platelets ≥50,000/mcL (if there is documented bone marrow involvement or 
hypersplenism, then platelets ≥ 25,000/mcL)  
 Any non-hematologic grade 3 or 4 AE that is considered at least possibly related to study 
treatment that has resolved to Grade ≤1.  
  
Growth factors can be used as per institutional standard to treat/prevent neutropenia. The use of 
growth factors should be documented in the CRF.  
 
6.1.2 Acalabrutinib Administration 
Patients will receive acalabrutinib 100mg BID orally on days 1-28. See Table 2 above for further 
details. Also refer to the drug diary (appendix IV) for further directions. On days with rituximab 
administration, acalabrutinib may be taken first in order to allow 12 hours between dosing.  
 
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. 
 
Drug interactions for Acalabrutinib are described in Section 6.3. 
 
Appropriate dose modifications for Acalabrutinib are described in Section 7.0.  
 
Reported adverse events and potential risks of Acalabrutinib are described in Section 8.0.  
 
6.1.3 Rituximab Administration 
Patients will receive Rituximab on days 1, 8, 15, and 22 of 28 day cycles during cycle 1 and day 
1 (for PR responders) or days 1, 8, 15, and 22 (for CR responders) of subsequent cycles (see 
Table 2 above).  First dose will be administered IV per institutional standard and subsequent 
doses can be given either IV or SQ per institutional guidelines. CAUTION: DO NOT 
ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. See Table 2 above for further 
details.  
Rituximab biosimilar use is permitted for this study per treating investigator discretion or per 
insurance mandate. 
Appropriate dose modifications for Rituximab are described in Section 7.0.  Reported adverse 
events and potential risks of Rituximab are described in Section 8.0.  
 

 
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6.2 
Duration of Therapy 
 
See Section 3.4 
 
6.3 
General Concomitant Medications and Supportive Care Guidelines 
Subjects should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, etc when appropriate. 
 
Patients with hepatitis B core antibody positive and HBV viral DNA PCR negative should receive 
prophylaxis with either lamuvidine or entecavir (per institutional standard) while receiving 
rituximab and for 6 months after last dose of rituximab 
 
Any chemotherapy, anticancer immunotherapy (other than Rituximab), corticosteroids (at 
dosages equivalent to prednisone > 20 mg/day for longer than 2 weeks), experimental therapy 
(other than acalabrutinib), or radiotherapy for treating PTLD are prohibited. 
 
Warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) are prohibited. 
 
The concomitant use of strong inhibitors/inducers of CYP3A4 (see Appendix 2) should be 
avoided when possible.  If a subject requires a strong CYP3A inhibitor while on study, monitor 
the subject closely for potential toxicities.   
 
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. H2-receoptor antagonists 
should be avoided or taken hours after taking acalabrutinib. H2-receptor antagonists should be 
taken approximately 2 hours after an acalabrutinib dose. 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 risks and benefits 
reviewed.   
 
6.3.1 Drug-Drug Interactions with Acalabrutinib 
At the systemic exposure levels expected in this study, acalabrutinib inhibition of CYP metabolism 
is not anticipated. 
However, acalabrutinib is metabolized by CYP3A.  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 2) 
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 

 
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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. 
 
6.3.2   Drug-Drug Interactions with Rituximab 
No known drug-drug interactions.  However, limited data are available on the safety of the use of 
biologic agents or disease modifying antirheumatic drugs (DMARDs) other than methotrexate in 
RA patients exhibiting peripheral B-cell depletion following treatment with rituximab. Observe 
patients closely for signs of infection if biologic agents and/or DMARDs are used concomitantly 
 
6.4 
Criteria for Removal from Study 
Treatment may continue for 2-4 cycles or until one of the following criteria applies: 
• 
Disease progression 
• 
Development of second primary malignancy 
• 
Intercurrent illness that prevents further administration of treatment 
• 
The investigator considers it, for safety reasons, to be in the best interest of the subject 
• 
Unacceptable adverse event(s)  (Any toxicity or other issue that causes a delay of study 
drug administration by more than 4 weeks) 
• 
Subject decision to withdraw from treatment (partial consent) or from the study (full 
consent), 
• 
Pregnancy during the course of the study for a child-bearing participant 
• 
Death 
• 
Sponsor reserves the right to temporarily suspend or prematurely discontinue this study. 
The date and reason for discontinuation must be documented. Every effort should be made to 
complete the appropriate assessments.  
 
6.5 
Duration of Follow Up 
 
End of Treatment Response Assessment: End of treatment scans and visit will be completed 
within 8 weeks (±7 days) of treatment termination. Subjects with stable or progressive disease 
after Cycle 1 Day 36 scans will go directly onto LTFU.  
 
If there is an adverse event related to study drug, the clinical course of each event will be 
followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause with a cut off of 24 months after completion of therapy.  
 
Serious adverse events that are still ongoing at the end of the study period will necessitate follow-
up to determine the final outcome. Any serious adverse event that occurs after the study period 
and is considered to be possibly related to the study treatment or study participation will be 
recorded and reported immediately. 
 
Long-Term Follow Up 
Each subject should be followed for a total of 3 years after study treatment has ended, Follow up 
visits will occur at 6, 12, 18, 24 and 36 months after completion of treatment.  During this 
period, subjects will be followed via physical exam and laboratory analysis. CT scans will be 
repeated at 6, 12, and 24 months. If the patient is unable to follow up in person, virtual visits may 
be used to capture applicable procedures during long-term follow up only. Subjects who 

 
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experience disease progression are not required to come in for clinic follow up. Study team will 
make every effort to contact them via phone to obtain information specified in the protocol (see 
section 11.1.2).  
 
 
7.0  
Dose Delays/Dose Modifications 
 
7.1    Acalabrutinib 
 
Subjects should be followed closely for AEs or laboratory abnormalities that might indicate 
acalabrutinib-related toxicity.  If a subject experiences an acalabrutinib-related toxicity or other 
intolerable AE during the course of therapy, then acalabrutinib should be withheld, as necessary, 
until the AE resolves or stabilizes to an acceptable degree.  
 
Dose modifications for the following acalabrutinib-emergent toxicities are provided in Table 3: 
 Grade 4 neutropenia (< 500/μL) for > 7 days  
 Grade 3 thrombocytopenia in presence of significant bleeding. 
 Grade 4 thrombocytopenia.  
 Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal antiemetic and/or 
anti-diarrheal therapy. 
 Any other Grade 4 toxicity or unmanageable Grade 3 toxicity. 
 
Table 3: Drug Modification Actions for Acalabrutinib 
Occurrence 
Action 
1st  
Hold acalabrutinib until recovery to Grade 1 or baseline; may restart at original 
dose level 
2nd  
Hold acalabrutinib until recovery to Grade 1 or baseline; restart at lower dose 
100 mg daily 
3rd 
For non-hematologic AE’s, discontinue acalabrutinib.  
 
For thrombocytopenia with significant bleeding, discontinue acalabrutinib.  
 
For other hematologic AEs, hold acalabrutinib until recovery to Grade 1 or 
baseline; restart at lower dose 100 mg daily . 
4th 
For hematologic AEs, discontinue acalabrutinib  
 
Acalabrutinib may be held for a maximum of 28 consecutive days from expected dose due to 
toxicity. During this period, appropriate laboratory monitoring should be performed per 
institutional guidelines. As appropriate, certain laboratory abnormalities may warrant more 
frequent monitoring (eg, once per week) until abnormalities have recovered to Grade 1.  
Acalabrutinib should be discontinued in the event of a grade 3 or 4 toxicity considered at least 
possibly related lasting >28 days. 
 
If acalabrutinib is reduced for apparent acalabrutinib-related toxicity, the dose need not be 
re-escalated, even if there is minimal or no toxicity with the reduced dose.  However, if the 
subject tolerates a reduced dose of acalabrutinib for ≥ 4 weeks then the dose may be increased to 
the next higher dose level, at the discretion of the investigator and after discussion with the 
sponsor-investigator.  Such re-escalation may be particularly warranted if further evaluation 
reveals that the AE that led to the dose reduction was not treatment-related.  The maximum dose 
of acalabrutinib is 100 mg BID. 
 

 
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Treatment with acalabrutinib should be withheld for any unmanageable, potentially 
acalabrutinib-related toxicity that is Grade ≥ 3 in severity.  Any other clinically important events 
where dose delays may be considered appropriate must be discussed with the Sponsor-
Investigator, Dr. Deepa Jagadeesh.   
 
Consider the benefit-risk of withholding acalabrutinib for 3-7 days pre- and post-surgery 
depending on the surgery and the risk of bleeding.   
 
7.2    Rituximab 
Because rituximab is known to cause hypersensitivity and infusion reactions, it will be infused 
with graduated incremental rates depending on whether it is being given as an initial dose (cycle 
1) or subsequent dose (2-4), per institutional guidelines. As the severity of infusion reactions 
increase, the infusion of rituximab will be either slowed or held, as indicated in table 4.  
 
Table 4: Management of Rituximab Hypersensitivity/Infusion Reactions 
Grade of 
Event 
Management/Next Dose for 
Rituximab 
Treatment 
Grade 1 
Decrease infusion rate by one 
dose level (see section 9.2 for rate 
information) 
 
Treatment of infusion-related symptoms 
with diphenhydramine and acetaminophen 
is recommended. Additional treatment with 
bronchodilators or IV saline may be 
indicated.  
 
Grade 2 
Hold until ≤ Grade 1. The infusion 
can be resumed at one-half the 
previous rate when symptoms 
abate.  
 
Grade 3 
Hold until ≤ Grade 1. The infusion 
can be resumed at one-half the 
previous rate when symptoms 
abate.  
 
Grade 4 
Off protocol therapy. 
 
Epinephrine for subcutaneous injection, 
diphenhydramine hydrochloride for IV 
injection, corticosteroids as needed and 
resuscitation equipment for the emergency 
management of anaphylactic reactions will 
be available at the bedside prior to rituximab 
administration.  
 
 
 
8.0 
Adverse Events and Potential Risks  
 
8.1 
Acalabrutinib   
See Section 5.3.2 of the Investigator Brochure for further information.  A summary is provided 
here.  An aggregate safety analysis of acalabrutinib monotherapy was conducted and included 
data from 7 studies.  This pooled data included 614 acalabrutinib-exposed subjects with a median 
exposure of 21.9 months.  Almost all subjects (609 [99.2%]) had at least 1 AE, and about half 
(334 [54.4%]) had at least 1 Grade ≥3 AE. The most commonly reported AEs of any grade were 
headache (42.3%), diarrhea (40.4%), fatigue (24.6%), nausea (23.6%), contusion (23.5%), cough 
(22.1%), and upper respiratory tract infection (21.7).  Atrial fibrillation of any grade was seen in 

 
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22 (3.6%) patient, grade 3 events were seen in 8 (1.3%) patients, and grade 4 or 5 events were 
seen in 0 patients.  The most frequently reported Grade ≥3 AEs were neutropenia (10.4%), 
anemia (7.5%), pneumonia (6.5%), thrombocytopenia (3.7%), and hypertension (3.1%).  Grade 5 
AEs were reported for 27 (4.4%) patients with the most common severe AE being infection 
(2.1%).   
 
8.1.1  Warnings and Precautions 
 
 
8.1.1.1     Hemorrhage 
Serious hemorrhagic events, including central nervous system, respiratory, and gastrointestinal 
hemorrhage, have been reported in clinical trials with acalabrutinib; some of these bleeding 
events resulted in fatal outcomes.  Grade 3 or higher bleeding events, including gastrointestinal, 
intracranial, and epistaxis have been reported in 2% of patients. Overall, bleeding events 
including bruising and petechiae of any grade occurred in approximately 50% of patients with 
hematological malignancies. The mechanism for hemorrhage is not well understood.  
Acalabrutinib may further increase the risk of hemorrhage in patients receiving antiplatelet or 
anticoagulant therapies and patients should be monitored for signs of bleeding.  Consider the 
benefit-risk of withholding acalabrutinib for 3-7 days pre- and post-surgery depending on the 
surgery and the risk of bleeding.   
 
 
8.1.1.2     Infection 
Serious infections (bacterial, viral or fungal), including fatal events and opportunistic infections, 
have been reported in clinical studies with acalabrutinib.  The most frequently reported Grade 3 
or 4 infection was pneumonia.  Across the acalabrutinib clinical development program (including 
subjects treated with acalabrutinib in combination with other drugs), cases of hepatitis B virus 
(HBV) reactivation (resulting in liver failure and death in 1 case) and cases of progressive 
multifocal leukoencephalopathy have occurred in subjects with hematologic malignancies.  
Monitor patients for signs and symptoms of infection and treat as medically appropriate. 
 
 
8.1.1.3     Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias including neutropenia, anemia, and 
thrombocytopenia have occurred in clinical studies with acalabrutinib.   Subjects should be 
closely monitored as appropriate. 
 
 
8.1.1.4     Second Primary Malignancies 
Second primary malignancies, including solid tumors and skin cancers, have been reported in 
patients treated with acalabrutinib. The most frequent second primary malignancy was skin 
cancer (basal cell carcinoma). Subjects should be monitored for signs and symptoms of 
malignancy. Subjects who develop a second primary malignancy should be managed according 
to institutional guidelines with diagnostic evaluations as clinically indicated, and it may be 
necessary for subjects to permanently discontinue study treatment. Continuation of acalabrutinib 
treatment should be discussed with the principal investigator.   
 
 
8.1.1.5     Atrial Fibrillation 
Events of atrial fibrillation/flutter have been reported in clinical studies with acalabrutinib, 
particularly in subjects with cardiac risk factors, hypertension, diabetes mellitus, acute infections, 
and a previous history of atrial fibrillation. 
The mechanism for atrial fibrillation is not well understood 
 
8.2  
Rituximab 

 
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See Section 6 of the package insert for a detailed discussion of adverse events.  In NHL the most 
common (>25%) adverse reactions in clinical trials were infusions reactions, fever, lymphopenia, 
chills, infection, and asthenia 26.  In CLL the most common (>25%) adverse reactions in clinical 
trials were infusions reactions and neutropenia 26.   
 
8.2.1 Warnings and Precautions 
 
8.2.1.1     Tumor Lysis Syndrome 
Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from 
tumor lysis, sometimes fatal, can occur within 12-24 hours after the first infusion of rituximab in 
patients with NHL. A high number of circulating malignant cells (>25,000/mm3) or high tumor 
burden, confers a greater risk of TLS 26. Correct electrolyte abnormalities; monitor renal function 
and hydration status, and administer supportive care as indicated. 
 
 
8.2.1.2     Infection 
Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur 
during and following the completion of rituximab-based therapy. Infections have been reported 
in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia 
>11 months after rituximab exposure). New or reactivated viral infections included 
cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, 
and hepatitis B and C. Discontinue rituximab for serious infections and institute appropriate anti-
infective therapy.  Rituximab is not recommended for use in patients with severe, active 
infections 26. 
 
 
8.2.1.3     Cardiovascular Adverse Reactions 
Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and 
cardiogenic shock may occur in patients receiving RITUXAN. Discontinue infusions for serious 
or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions 
of RITUXAN for patients who develop clinically significant arrhythmias, or who have a history 
of arrhythmia or angina 26. 
 
 
8.2.1.4     Renal Toxicity  
Severe, including fatal, renal toxicity can occur after rituximab administration in patients with 
NHL. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in 
patients with NHL administered concomitant cisplatin therapy during clinical trials. Monitor 
closely for signs of renal failure and discontinue rituximab in patients with a rising serum 
creatinine or oliguria 26. 
 
 
8.2.1.5     Bowel Obstruction and Perforation  
Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in 
patients receiving rituximab in combination with chemotherapy. In postmarketing reports, the 
mean time to documented gastrointestinal perforation was 6 (range 1-77) days in patients with 
NHL. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur 26. 
 
 
8.2.1.6     Immunization  
The safety of immunization with live viral vaccines following rituximab therapy has not been 
studied and vaccination with live virus vaccines is not recommended before or during treatment 
26.  
 
8.2.1.7     Embryo-Fetal Toxicity 
Based on human data, rituximab can cause fetal harm due to B-cell lymphocytopenia in infants 
exposed to rituximab in-utero.  Advise pregnant women of the risk to a fetus. Females of 

 
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childbearing potential should use effective contraception while receiving rituximab and for 12 
months following the last dose of rituximab 26. 
 
 
8.2.1.8     Concomitant Use with Other Biologic Agents and DMARDS other than 
Methotrexate in RA, GPA and MPA, PV 
Limited data are available on the safety of the use of biologic agents or disease modifying 
antirheumatic drugs (DMARDs) other than methotrexate in RA patients exhibiting peripheral B-
cell depletion following treatment with rituximab. Observe patients closely for signs of infection 
if biologic agents and/or DMARDs are used concomitantly. Use of concomitant 
immunosuppressants other than corticosteroids has not been studied in GPA or MPA or PV 
patients exhibiting peripheral B-cell depletion following treatment with rituximab 26. 
 
 
8.2.1.9        Infusion-Related Reactions 
[US Boxed Warning]: Serious (including fatal) infusion-related reactions have been reported, 
usually with the first infusion; fatalities have been reported within 24 hours of infusion; monitor 
closely during infusion; discontinue for severe reactions and provide medical intervention for 
grades 3 or 4 infusion-related reactions. Reactions usually occur within 30 to 120 minutes and 
may include hypotension, angioedema, bronchospasm, hypoxia, urticaria, and, in more severe 
cases, pulmonary infiltrates, acute respiratory distress syndrome, MI, ventricular fibrillation, 
cardiogenic shock, and/or anaphylactoid events. Closely monitor patients with a history of prior 
cardiopulmonary reactions or with preexisting cardiac or pulmonary conditions and patients with 
high numbers of circulating malignant cells (≥25,000/mm3). Prior to infusion, premedicate 
patients with acetaminophen and an antihistamine (and methylprednisolone for patients with 
rheumatoid arthritis [RA] and PV). Medications for the treatment of hypersensitivity reactions 
(eg, bronchodilators, epinephrine, corticosteroids, oxygen) should be available for immediate 
use; treatment is symptomatic. If infusion-related reaction occurs, temporarily or permanently 
discontinue infusion (depending on the severity of the reaction and required interventions). After 
symptoms resolve, infusion may be resumed with at least a 50% infusion rate reduction 26. 
 
 
8.2.1.10      Mucocutaneous Reactions 
[US Boxed Warning]: Severe and sometimes fatal mucocutaneous reactions (lichenoid 
dermatitis, paraneoplastic pemphigus, Stevens-Johnson syndrome, toxic epidermal necrolysis, 
and vesiculobullous dermatitis) have been reported; onset has been variable but has occurred as 
early as the first day of exposure. Discontinue in patients experiencing severe mucocutaneous 
skin reactions 26.  
 
 
8.2.1.11      Progressive multifocal leukoencephalopathy  
[US Boxed Warning]: Progressive multifocal leukoencephalopathy (PML) due to JC virus 
infection has been reported with rituximab; may be fatal. Clinical findings included 
confusion/disorientation, motor weakness/hemiparesis, altered vision/speech, and poor motor 
coordination with symptoms progressing over weeks to months. Promptly evaluate any patient 
presenting with neurological changes; consider neurology consultation, brain MRI, and lumbar 
puncture for suspected PML. Discontinue rituximab in patients who develop PML; consider 
reduction/discontinuation of concurrent chemotherapy or immunosuppressants 26. 
 
 
8.3 
Definitions  
 
8.3.1 
Adverse Event   
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with a research study, which causes harm or injury to a research participant as a result 

 
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of the participant’s involvement in a research study. The event can include abnormal laboratory 
findings, symptoms, or disease associated with the research study. The event does not necessarily 
have to have a causal relationship with the research, any risk associated with the research, the 
research intervention, or the research assessments.  
 
Adverse events may be the result of the interventions and interactions used in the research; the 
collection of identifiable private information in the research; an underlying disease, disorder, or 
condition of the subject; and/or other circumstances unrelated to the research or any underlying 
disease, disorder, or condition of the subject.  
 
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 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. 
 

 
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8.3.2   Serious Adverse Events  
A serious adverse event (SAE) is any adverse experience occurring at any dose that results in any 
of the following outcomes:  
 Results in death.  
 Is a life-threatening adverse experience.  The term life-threatening in the definition of 
serious refers to an adverse event in which the subject was at risk of death at the time 
of the event.  It does not refer to an adverse event which hypothetically might have 
caused death if it were more severe.  
 Requires inpatient hospitalization or prolongation of existing hospitalization.  Any 
adverse event leading to hospitalization or prolongation of hospitalization will be 
considered as Serious, UNLESS at least one of the following expectations is met: 
o The admission results in a hospital stay of less than 24 hours OR 
o The admission is pre-planned (e.g., elective or scheduled surgery arranged 
prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However it should be noted that invasive treatment during any hospitalization may fulfill 
the criteria of “medically important” and as such may be reportable as a serious adverse 
event dependent on clinical judgment.  In addition where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedent.  
 Results in persistent or significant disability/incapacity.  The definition of disability 
is a substantial disruption of a person’s ability to conduct normal life’s functions. 
 Is a congenital anomaly/birth defect.  
 Is an important medical event.  Important medical events that may not result death, 
be life-threatening, or require hospitalization may be considered a serious adverse 
experience when, based upon appropriate medical judgment, they may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
disease or disorders, or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. The development of a new cancer is 
always considered an important medical event. 
 
8.3.3    Adverse Events of Special Interest 
The following events are adverse events of special interest (AESIs) and must be reported to the 
sponsors expeditiously, irrespective of regulatory seriousness criteria or causality: 
o Ventricular arrhythmias (e.g., ventricular extrasystoles, ventricular tachycardia, ventricular 
arrhythmia, ventricular fibrillation, etc.) 
 
8.3.4 Adverse Event Evaluation  
The investigator or designee is responsible for ensuring that all adverse events (both serious and 
non-serious) observed by the clinical team or reported by the subject which occur on or after 
cycle 1 day 1 are fully recorded in the subject’s medical records. Source documentation must be 
available to support all adverse events.  
 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations, result 
in a delay or dose modification of study treatment, or judged relevant by the investigator), should 
be reported as an adverse event.   

 
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The investigator or sub-investigator (treating physician if applicable) will provide the following 
for all adverse events (both serious and non-serious): 
 Event term (as per CTCAE v5.0) 
 Description of the event 
 Date of onset and resolution 
 Expectedness of the toxicity 
 Grade of toxicity (as per CTCAE) 
 Attribution of relatedness to the investigational agent- (this must be assigned by an 
investigator, sub-investigator, or treating physician) 
 Action taken as a result of the event, including but not limited to; no changes, dose 
interrupted, reduced, discontinued, etc. or action taken with regard to the event, i.e. no 
action, received conmed or other intervention, etc. 
 Outcome of event 
 
Descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5 will be utilized for AE reporting. If the event term is not listed in 
CTCAE v5.0, then the general grading scale shown here will be used. 
 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 
 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol. For regulatory reporting purposes, only events listed in the Investigator Brochure’s 
Reference Safety Information will be considered expected. 
 
An unexpected adverse event is an adverse event not previously known or anticipated to result 
from the research study or any underlying disease, disorder, or condition of the subject.  
 
Attribution is the relationship between an adverse event or serious adverse event and the study 
drug.  Attribution will be assigned as follows: 
 
 Definite – The AE is clearly related to the study drug. 
 Probable – The AE is likely related to the study drug. 
 Possible – The AE may be related to the study drug. 
 Unlikely – The AE is doubtfully related to the study drug. 
 Unrelated – The AE is clearly NOT related to the study drug. 
 
Protocol must specify if attribution is required for individual components of the treatment regimen 
or the treatment regimen as a whole. 

 
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8.4  
SAE/AESI Report Form 
SAEs/AESIs will be recorded on the FDA Form 3500A (MedWatch) but should only be reported 
as instructed below.  The electronic FDA SAE reporting forms should not be used.   
 
8.5  
Reporting Procedures for Serious Adverse Events and AESIs 
For the purposes of safety reporting, all adverse events will be reported that occur on or after 
Cycle 1 Day 1 through the End of Treatment Response Assessment. Adverse events, both serious 
and non-serious, and deaths that occur during this period will be recorded in the source 
documents. All SAEs/AESIs should be monitored until they are resolved or are clearly 
determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). Related 
AEs will be followed until resolution to baseline or grade 1 or stabilization.  
 
8.5.1 SAE/AESI Reporting Requirements 
 Participating investigators (all sites) must report all serious adverse events and AESIs to 
the Lead Site Principal Investigator (e.g. Sponsor-Investigator) within 1 business day of 
discovery or notification of the event. The participating investigator must also provide 
follow-up information on the SAE/AESI until final resolution.  
o Please send all SAE/AESI reports to cancersaeinbox@ccf.org and cc: 
jagaded@ccf.org and the study coordinator listed on page 2.  
 The Lead Site Principal Investigator will review the SAE and report the event to the 
FDA, external collaborator(s), and Cleveland Clinic IRB as applicable. 
 It is the Sponsor-Investigator’s responsibility (e.g. lead site PI) to ensure that ALL 
serious adverse events that occur on the study (e.g. ALL SAEs that occur at each 
enrolling institution) are reported to all participating sites. 
 
Drug Supplier / Manufacturer / Financial Supporter Reporting Requirements:  
 The investigator is responsible for ensuring that all AEs and SAEs/AESIs that are 
observed or reported during the study, as outlined in the prior sections, are recorded on 
the CRF 
 It is the responsibility of the Sponsor-Investigator (Cleveland Clinic Principal 
Investigator) to report safety data to the drug supplier (AstraZeneca Data Entry Site 
[DES]). 
 The Sponsor will submit appropriate reports to applicable local regulatory agencies and 
to ethics committees (ECs) as per local regulations. The Sponsor will notify Acerta 
Pharma/AstraZeneca in parallel with submission to the IRB (if applicable) and concerned 
Regulatory Authority for Suspected Unexpected Serious Adverse Reactions (SUSARs) 
and within fifteen (15) calendar days of awareness for other SAEs or Special Situation 
Reports using Form FDA 3500A (MedWatch). New information will be submitted to 
Acerta Pharma/AstraZeneca within the same time frame as initial reports.  
 Whenever possible, SAEs should be reported by diagnosis term not as a constellation of 
symptoms.   
 Death due to disease progression should be recorded on the appropriate form in the 
electronic data capture (EDC) system.  If the primary cause of death is disease 
progression, the death due to disease progression should not be reported as an SAE to 
Acerta Pharma/AstraZeneca. If the primary cause of death is something other than 
disease progression, then the death should be reported as an SAE with the primary cause 

 
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of death as the event AE term, as death is typically the outcome of the event, not the 
event itself.  The primary cause of death on the autopsy report should be the term 
reported.  Autopsy and postmortem reports will be forwarded if readily available to 
Acerta Pharma/AstraZeneca DES as outlined above. 
 If study drug is discontinued because of an SAE/AESI, this information must be included 
in the SAE report. 
 
All SAEs/AESIs will be submitted by the lead site to the AstraZeneca Product Safety 
mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com 
Institutional Review Board Reporting Requirements: 
 Investigative sites will report adverse events to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events.  
 
Pregnancy 
Investigators should report all pregnancies and pregnancies in the partners of subjects to the 
Sponsor within 24 hours. The Sponsor should report any occurrences to the Cleveland Clinic 
IRB and Regulatory Authorities per institutional and/or regulatory guidelines, and to Acerta 
Pharma/AstraZeneca per contractual guidelines. Each participating site should follow their local 
institutional IRB reporting policies. 
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 the last dose of study medication will be reported, followed to conclusion, and the 
outcome reported. 
Subjects should be instructed to immediately notify the investigator of any pregnancies.  Any 
female subjects receiving study drug who become pregnant must immediately discontinue study 
drug. The investigator should counsel the subject, discussing any risks of continuing the 
pregnancy and any possible effects on the fetus. 
 
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 and the sponsor-investigator should be notified immediately. 
 
8.6 
SAEs and OnCore 
 All SAEs will be entered into OnCore.   
 A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded into 
Oncore. 
 

 
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8.7  
Data Safety and Toxicity Committee 
It is the responsibility of each site PI to ensure that ALL SAEs occurring on this trial (internal or 
external) are reported to the Case Comprehensive Cancer Center’s Data and Safety Toxicity 
Committee. This submission is simultaneous with their submission to the sponsor and/or other 
regulatory bodies.  
 
The sponsor-investigator is responsible for submitting an annual report to the DSTC as per 
CCCC Data and Safety Monitoring Plan. 
  
8.8 
Data and Safety Monitoring Plan (DSMP) 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and 
Safety Monitoring Plan in accordance with NCI guidelines.  
 
9.0 
PHARMACEUTICAL INFORMATION  
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Sections 8.1 and 8.2. 
 
 
9.1 Acalabrutinib 
 
Other Names: ACP-196 
 
Product description: Acalabrutinib capsules for oral administration, are supplied as yellow and 
blue, opaque hard gelatin capsules, 100 mg strength (size 1), and with acalabrutinib as an active 
ingredient. 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). 
 
Storage requirements: Acalabrutinib capsules are packaged in white, high-density polyethylene 
bottles and should be stored according to the storage conditions as indicated on the label. The 
recommended storage condition for acalabrutinib capsules is below 86°F. 
 
Route of administration: Oral administration 
 
Drug Procurement: Acalabrutinib will be supplied for this study by Acerta Pharma.   
 
Drug Accountability: The investigator or designated study personnel are responsible for 
maintaining accurate dispensing records of the study drug. All study drugs must be accounted 
for, including study drug accidentally or deliberately destroyed. Under no circumstances will the 
investigator allow the investigational drug to be used other than as directed by the protocol. If 
appropriate, drug storage, drug dispensing, and drug accountability may be delegated to the 
pharmacy section of the investigative site.  
 
Drug Destruction:  At the completion of the study, there will be a final reconciliation of drug 
shipped, drug consumed, and drug remaining. This reconciliation will be logged on the drug 
reconciliation form, signed and dated. Any discrepancies noted will be investigated, resolved, 
and documented prior to return or destruction of unused study drug. Drug destroyed on site will 
be documented in the study files. 

 
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9.2  
Rituximab 
 
 
Other Names:  Rituxan™, Mabthera™ 
 
Product description:  Rituximab is a sterile, clear, colorless, preservative-free liquid 
concentrate for intravenous (IV) administration.  The product is formulated for intravenous 
administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL 
polysorbate 80, and Sterile Water for Injection. The pH is adjusted to 6.5. Rituximab biosimilar 
use is permitted for this study per treating investigator discretion or per insurance mandate. 
 
Solution preparation: Using appropriate aseptic technique, withdraw the necessary amount of 
rituximab and dilute to a final concentration of 1 to 4 mg/mL into an infusion bag containing 
either 0.9% Sodium Chloride or 5% Dextrose in Water. Gently invert the bag to mix the solution. 
Discard any unused portion left in the vial. Caution should be taken during the preparation of the 
drug, as shaking can cause aggregation and precipitation of the antibody. Do not mix or dilute 
with other drugs.  
 
Storage requirements:  Once reconstituted into IV bags, rituximab is chemically stable for up 
to 24 hours at 2°C to 8°C (36°F to 46°F), followed by up to 24 hours at room temperature 
(23°C). However, since rituximab solutions do not contain preservative, diluted solutions should 
be stored refrigerated (2°C to 8°C). No incompatibilities between rituximab and 
polyvinylchloride or polyethylene bags have been observed. Rituximab vials should be protected 
from direct sunlight. 
 
Stability:  Rituximab is biologically and chemically stable at 2°C to 8°C (36°F to 46°F) and has 
a proposed shelf life stability of 30 months. Rituximab vials are intended for single use only. Do 
not use beyond the expiration date stamped on the carton. 
 
Route of administration:  
DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. Do not infuse rituximab 
concurrently with another IV solution or other IV medications. Premedication, consisting of 
acetaminophen 650 mg to 1000 mg PO and diphenhydramine 25 to 50 mg IV or PO, will be 
administered before each infusion of rituximab. Premedication may attenuate infusion-related 
events. Since transient hypotension may occur during rituximab infusion, anti-hypertensive 
medications will be withheld 12 hours prior to rituximab infusion.  
 
Rituximab will be administered intravenously per institutional standard. An in-line filter is not 
required.  
 
Rituximab infusion must be interrupted for severe reactions. If the patient experiences fever and 
rigors, the antibody infusion is discontinued. The severity of the side effects will be evaluated. In 
most cases, the infusion can be resumed at a 50% reduction in rate (e.g., from 100mg/hr to 
50mg/hr) when symptoms have completely resolved. Most patients who have experienced non-
life-threatening infusion-related reactions have been able to complete the full course of rituximab 
therapy.  
 
NOTE: In addition, alternative rituximab infusion rates (i.e., “rapid rituximab infusion”) can be 
used per institutional guidelines as long as the total number of milligrams of rituximab is the 

 
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same and that “rapid infusion” is not administered with the patient’s first rituximab cycle. 
Further, a rituximab infusion time should not be less than 90 minutes in duration. 
 
9.3  
Rituximab-hyaluronidase human 
 
Other names: Rituxan Hycela, MabThere S.C. 
 
Product Description:  rituximab-hyaluronidase injection is a colorless to yellowish, clear to 
opalescent solution supplied in sterile, preservative-free, single-dose vials for subcutaneous 
administration. Each mL of solution contains rituximab (120 mg), hyaluronidase human (2,000 
Units), L-histidine (0.53 mg), L-histidine hydrochloride monohydrate (3.47 mg), L-methionine 
(1.49 mg), polysorbate 80 (0.6 mg), α,α-trehalose dihydrate (79.45 mg), and Water for Injection. 
 
Solution Preparation: Draw up 11.7 mL of rituximab-hyaluronidase injection into a syringe. To 
avoid clogging, attach administration needle, or catheter, only when the patient is ready for 
injection. 
 
Storage Requirements: Vials should be stored in the refrigerator at 2◦C–8◦C (36◦F–46◦F) in the 
original carton to protect from light. Do not freeze. 
 
Stability: If not used immediately, prepared syringe may be stored in the refrigerator at 2-8◦C for 
up to 48 hours and subsequently for 8 hours at room temp up to 30◦C 
 
Route of administration: Patient must have received at least one dose of rituximab IV, without 
serious infusion reaction, before starting rituximab- hyaluronidase. DO NOT ADMINISTER AS 
AN INTRAVENOUS PUSH OR BOLUS. Premedicate patients with acetaminophen 650mg and 
diphenhydramine 50mg, prior to each dose.  
 
The dose should be administered over 5 minutes, into the subcutaneous tissue of the abdomen. 
Never inject into areas where the skin is red, bruised, tender or hard, or areas where there are 
moles or scars. If administration is interrupted, continue administering at the same site, or at a 
different site, but restricted to the abdomen. Patients must be observed for at least 15 minutes 
following administration. 
 
Drug Procurement: Rituximab must be obtained from commercial sources. 
 
 
10.0 
CORRELATIVE STUDIES 
 
10.1 
Tissue Procurement 
 
The following materials should be sent for each patient that signs consent. The slides should be 
done after the patient has signed the consent form to participate in the study and within 4 weeks 
of starting study treatment. 
 
1. Fifteen 4 micron unstained sections on charged (plus) slides 
2. Four 10 micron sections (if an incisional or excisional biopsy) or eight 10 micron sections 
(if needle biopsy) on slides or in a tube 
 

 
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10.2 
Blood Sample 
 
20 ml of peripheral blood will be obtained at the time of sample collection (baseline, after C1, 
and then end of treatment) in heparinized green top tubes. 
 
The green top heparin tubes will be processed into aliquots of plasma and viable mononuclear 
cells.  
 
10.3 
Shipment 
 
Please ship the slides/tube to the Cleveland Clinic Biorepository at the address provided below: 
 
Robert J. Tomsich Pathology and Laboratory Medicine Institute (RT-PLMI) 
ATTN: Dr. Genevieve Crane 
2119 East 93 Street, L25 
Cleveland, Ohio 44106 
 
Please ship the blood samples to the Cleveland Clinic Pharmacology Lab. The Manual of 
Operating Procedures (MOP) contains more detailed instructions on shipment of the slides and 
blood samples. 
 
Information about the planned analyses concerning these correlative studies will be added in a 
protocol amendment. 
 
11.0  STUDY PARAMETERS AND CALENDAR  
 
11.1 
Study Parameters 
 
11.1.1 Screening Evaluation day -28 to 1  
Screening studies and evaluations will be used to determine the eligibility of each subject for 
study inclusion. All evaluations must be completed ≤28 days prior to administration of protocol 
therapy, except where otherwise indicated.  
 Informed Consent  
 Demographics  
 Medical History  
 Physical Examination  
 IPI score 
 Height  
 Weight  
 Vital signs including: blood pressure, pulse, respiratory rate and temperature.  
 Concurrent Medications Assessment including prescription medications, over-the-counter 
(OTC) medications and supplements.  
 ECOG Performance Status  
 Urinalysis 
 Baseline Symptoms Assessment  
 Complete Blood Count (CBC) with differential  
 PT/INR 

 
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 Serum chemistry panel: sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
calcium, glucose, total protein, albumin, alkaline phosphatase, total bilirubin, SGOT 
[AST], and SGPT [ALT] 
 Lactate dehydrogenase (LDH) level, uric acid, phosphorus 
 Pregnancy test for women of childbearing potential (within 72 hrs of study of study 
treatment). Women who have undergone surgical sterilization or who have been 
postmenopausal for at least 2 years are not considered to be of childbearing potential. 
 Peripheral blood Epstein Barr Virus (EBV) PCR (if not done within 1 month of 
diagnosis)  
 Remote Hepatitis Panel (Hepatitis B Surface Antigen, Hepatitis B Surface Antibody, 
Hepatitis B Core Antibody, Hepatitis C antibody)* (no need to repeat if done within 3 
months of start of study treatment) 
 HIV (no need to repeat if done within 3 months of start of study treatment) 
 Electrocardiogram (EKG)  
 PET and CT scan of neck, chest, abdomen, and pelvis with IV and PO contrast. Neck CT 
can be omitted at the investigator’s discretion, if no suspicion for involvement. If insurance 
only allows one type of scan, PET scan is preferred at baseline.  
 Bone marrow aspiration and biopsy. This can be omitted at investigator’s discretion, if 
there is low or no suspicion of involvement 
 Send tumor biopsy slides to CCF for correlative studies. Biopsy slides should be sent within 
4 weeks of start of study treatment. Please see section 10 for detailed information. If tissue 
is not available, approval from the sponsor-investigator must be received. 
 Peripheral blood sample for correlative studies 
 
* Hepatitis B and C Testing 
Hepatitis serology testing must include hepatitis B surface antigen (HBsAg), hepatitis B surface 
antibody (anti-HBs), anti-HBc, and HCV antibody. In addition, any subjects testing positive for 
any hepatitis serology must have PCR testing during screening. Subjects with a known history of 
hepatitis C should be tested for HCV RNA during screening and monthly. See exclusion 
criterion 4.2.17.  
 
Subjects who are anti-HBc positive should have quantitative PCR testing for HBV DNA 
performed during screening and may be repeated as per institutional practices. Patients with 
detectable viral load are not eligible for participation.  
 
11.1.2 Treatment Period 
Cycle 1 is 28 days followed by interim response assessment at day 42 (- 3 day window) 
Cycle 2 (in patients with CR is 28 days) 
Cycles 2-4 (in patients with PR is 28 days) 
 
Cycle 1, Day 1 
 Physical Examination  
 Weight  
 Vital signs including: blood pressure, pulse, respiratory rate and temperature.  
 Concurrent Medications Assessment including prescription medications, over-the-counter 
(OTC) medications and natural/herbal supplements.  
 ECOG performance status   
 Laboratory Studies:  
o Complete Blood Count (CBC) with differential and platelets.  

 
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o Serum Chemistries: Serum chemistry panel: sodium, potassium, chloride, 
bicarbonate, BUN, creatinine, calcium, glucose, total protein, albumin, alkaline 
phosphatase, total bilirubin, SGOT [AST], SGPT [ALT] 
o LDH, uric acid, phosphorous 
 Rituximab IV administration 
 Acalabrutinib started (days 1 – 28) 
 Adverse event evaluation and documentation 
 
Cycle 1, Day 8 ± 2 days 
 Vital signs including: blood pressure, pulse, respiratory rate and temperature.  
 Laboratory Studies:  
o Complete Blood Count (CBC) with differential  
 Rituximab administration 
 Adverse event evaluation and documentation 
 
Cycle 1, Day 15 ± 2 days 
 Vital signs including: blood pressure, pulse, respiratory rate and temperature.  
 Laboratory Studies:  
o Complete Blood Count (CBC) with differential  
o Serum Chemistries: Serum chemistry panel: sodium, potassium, chloride, 
bicarbonate, BUN, creatinine, calcium, glucose, total protein, albumin, alkaline 
phosphatase, total bilirubin, SGOT [AST], SGPT [ALT] 
 Rituximab administration 
 Adverse event evaluation and documentation 
 
Cycle 1, Day 22 ± 2 days 
 Vital signs including: blood pressure, pulse, respiratory rate and temperature.  
 Laboratory Studies:  
o Complete Blood Count (CBC) with differential  
 Rituximab administration  
 Adverse event evaluation and documentation 
 
Cycle 1, Day 42 (-3 day window)  
 CT scan of neck, chest, abdomen, and pelvis with IV and PO contrast. CT neck can be 
omitted if there was no involvement at baseline 
 Interim disease response assessment 
 Peripheral blood EBV PCR if positive at baseline  
 Adverse event evaluation and documentation 
 Peripheral blood sample for correlative studies 
 
Cycle 2, Day 1 (for CR responders ONLY) 
Cycle 2 should start within 2 weeks after the end of cycle 1 treatment. 
 Physical Examination  
 Weight  
 Vital signs including: blood pressure, pulse, respiratory rate and temperature  
 Concurrent Medications Assessment including prescription medications, over-the-counter 
(OTC) medications and natural/herbal supplements.  
 ECOG Performance Status  
 Adverse event evaluation and documentation 

 
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 Laboratory Studies: 
o Complete Blood Count (CBC) with differential and platelets  
o Serum Chemistries: Serum chemistry panel: sodium, potassium, chloride, 
bicarbonate, BUN, creatinine, calcium, glucose, total protein, albumin, alkaline 
phosphatase, total bilirubin, SGOT [AST], SGPT [ALT]  
o Lactate dehydrogenase (LDH) 
 Rituximab administration on days 1, 8, 15, and 22 
 Acalabrutinib on days 1-28 
 
Cycles 2-4, Day 1 (for PR responders ONLY) 
Cycle 2 should start within 2 weeks after the end of cycle 1 treatment. There is a ± 3 day window 
for the start of cycles 3 and 4. 
 Physical Examination  
 Weight  
 Vital signs including: blood pressure, pulse, respiratory rate and temperature  
 Concurrent Medications Assessment including prescription medications, over-the-counter 
(OTC) medications and natural/herbal supplements.  
 ECOG Performance Status  
 Adverse event evaluation and documentation 
 Laboratory Studies: 
o Complete Blood Count (CBC) with differential and platelets  
o Serum Chemistries: Serum chemistry panel: sodium, potassium, chloride, 
bicarbonate, BUN, creatinine, calcium, glucose, total protein, albumin, alkaline 
phosphatase, total bilirubin, SGOT [AST], SGPT [ALT]  
o Lactate dehydrogenase (LDH) only on cycle 2 day 1 (not required on cycles 3-4) 
 Rituximab administration on day 1 
 Acalabrutinib started (continue days 1-28) 
 
End of Treatment Response Assessment – 8 weeks ± 7 days after treatment completion (this 
visit does not apply to subjects with stable/progressive disease after cycle 1) 
 Physical Examination  
 Weight  
 Vital signs including: blood pressure, pulse, respiratory rate and temperature.  
 Concurrent Medications Assessment including prescription medications, over-the-counter 
(OTC) medications and natural/herbal supplements.  
 ECOG Performance Status  
 Adverse Event Evaluation  
 Laboratory Studies:  
o Complete Blood Count (CBC) with differential and platelets.  
o Serum Chemistries: albumin, alkaline phosphatase, total bilirubin, bicarbonate, 
BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT 
[AST], SGPT [ALT], sodium 
o Lactate dehydrogenase (LDH) 
o Peripheral blood EBV PCR if positive at baseline  
 PET and diagnostic CT of neck, chest, abdomen, and pelvis with IV and PO contrast for 
response assessment. Neck CT can be omitted if no involvement at baseline. If insurance 
only allows one type of scan, PET scan is preferred for end of treatment assessment.  
 Disease response assessment 

 
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 Bone marrow aspiration and biopsy if positive at baseline 
 Peripheral blood sample for correlative studies 
 
Duration of Follow Up  
After completion of the study treatment the subjects will be followed for a total of 3 years. The 
follow up visits will be done at 6, 12, 18, 24 and 36 months after the last cycle of therapy. There 
is a ± 14 day window for these visits. If the patient is unable to follow up in person, virtual visits 
may be used to capture applicable procedures during long-term follow up only.  
 
The follow up visits should include the following: 
 Survival/Disease Status 
 Physical Examination 
 Vital signs 
 CBC with differential  
 Serum chemistry panel  
 Diagnostic CT neck, chest, abdomen and pelvis scan with IV and PO contrast will be 
done at 6, 12 and 24 months if no disease progression. Neck CT can be omitted if no 
involvement at baseline 
 Peripheral blood EBV PCR if positive at baseline will be done at 6, 12 and 24 months 
 Current lymphoma treatment 
 
Patients who have stable/progressive disease are not required to come in for clinical follow up. 
These patients can be contacted over the phone by the study personnel to obtain the following 
information 
 
 Survival/Disease Status 
 Current lymphoma treatment 
 
Patients will be followed for toxicity until the End of Treatment Response Assessment study visit 
or until death, whichever occurs first. The clinical course of each event will be followed until 
resolution, stabilization, or until has been determined that the study treatment or participation is 
not the cause.  
 
Serious adverse events (SAE) that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation will 
be recorded and reported immediately. 
 
11.2 
Calendar

 
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a. Sodium, potassium, chloride, bicarbonate, BUN, creatinine, calcium, glucose, total protein, albumin, alkaline phosphatase, total bilirubin, 
SGOT [AST], SGPT [ALT]  
b. Neck CT can be omitted at baseline at the discretion of the investigator if there was no suspicion for involvement 
c. PET and diagnostic CT scan preferred, but PET alone is preferred, if unable to obtain both.  
d. Acalabrutinib given on days 1-28 
e. CT neck can be omitted if there was no baseline involvement 
f. For subject in a CR after cycle 1, rituximab will be administered on the same schedule as cycle 1 (see Table 2). For these patients, no 
other study assessment will be done on days 8, 15, and 22. 
g. Pregnancy test to be done within 72 hours of starting the study drug. This only applies to women of childbearing potential. 
h. Patients with disease progression only need to have survival follow-up and current lymphoma treatment captured (see section 11.1.2). 
Virtual visits may be used to capture applicable procedures during long-term follow up only if the patient is unable to follow up with the 
in person. 
i. Cycle 1 Day 1 pre-dose assessment do not need to be repeated if being done same day as screening. If the same assessments are being 
used for both screening and day 1, the data should be entered at screening in the database. 
j. EBV PCR at baseline if not done within 1 month of diagnosis  
k. EBV PCR if positive at baseline 
l. LDH to be done only on Cycle 2 Day 1 (does not apply to Cycle 3 or 4) 
m. This can be omitted at investigator’s discretion, if there is low or no suspicion of involvement  
n. Bone marrow aspiration and biopsy if positive at baseline 
o. Blood pressure, pulse, respiratory rate and temperature 
Bone marrow 
biopsy/aspiration 
Xm 
 
 
 
 
 
 
Xn 
 
 
 
 
 
Disease Response 
Assessment 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
Acalabrutinibd 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Rituximab 
 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
Survival/Disease 
Status 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 

 
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12.0  MEASUREMENT OF EFFECT  
Response assessments will be evaluated based on Lugano Criteria (refer to Appendix 3).  
Patients who achieve a CR or PR after cycle 1 treatment will have a CT scan approximately 8 
weeks after the end of study treatment. Please see section 11 for the schedule of the imaging 
studies. Patients will have pre-treatment and end of treatment FDG-PET and/or CT to monitor 
their response to treatment. For each patient, every effort will be made to use the same radiologic 
imaging that was obtained at screening to be used to assess response. Interim response will be 
assessed after cycle 1 using CT scans. During follow up patients will have CT scans done at 6, 
12, and 24 months after the last cycle of therapy. 
 
All patients will be evaluable for toxicity from the time of their first treatment with rituximab and 
acalabrutinib.   
 
The following guidelines are to be used for establishing tumor measurements at baseline and for 
subsequent comparison:  
 The six largest dominant nodes or extranodal masses must be identified at baseline.  
 If there are 6 or fewer nodes and extranodal masses, all must be listed as dominant.  
If there are more than 6 involved nodes or extranodal masses, the 6 largest dominant 
nodes or extranodal masses should be selected according to the following features: 
 nodes should be clearly measurable in at least two perpendicular measurements  
 nodes should be from as disparate regions of the body as possible  
 Measurements for all dominant nodes and extranodal masses will be reported at baseline. 
Measurements on non-dominant nodes are not required. The lymph nodes or extranodal 
masses selected for measurement should be measured in two perpendicular diameters, 
one of which is the longest perpendicular diameter. The lymph nodes should be measured 
in centimeters to the nearest one tenth of a centimeter (e.g. 2.0 cm, 2.1cm, 2.2 cm, etc.)  
 
 
12.1 
Definitions 
12.1.1 Overall Response Rate 
Overall response rate (ORR) is defined as all patients that achieve a CR or PR based on end of 
treatment scans, using the Lugano Criteria. 
   
12.1.2 Complete Remission Rate 
Complete response rate (CRR) is defined as all patients that achieve a CR based on end of 
treatment scans, using the Lugano Criteria. 
    
12.1.3 Partial Remission Rate 
Partial response rate (PRR) is defined as all patients that achieve a PR based on end of treatment 
scans, using the Lugano Criteria. 
    
12.1.4 Duration of Response 
Duration of response (DOR) is only measured in responders. DOR is defined as the time from 
documented response (CR or PR) to the time of confirmed disease progression or death due to 
any cause, whichever occurs first.  Subjects who are still alive and free from progression at the 
time of data cutoff date, lost to follow-up, have discontinued study, or have initiated other non-
protocol anti-tumor therapy (NPT) will be censored at the last tumor assessment when subjects 
are progression-free. 
 
 
 

 
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12.1.5 Progression Free Survival 
Progression free survival (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, have 
discontinued the study, or have initiated NPT will be censored on last assessment (or, if no post-
baseline tumor assessment, at the time of first dose plus 1 day). 
   
12.1.6 Overall Survival  
Overall survival (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 
on last assessment. 
 
12.1.7 Time to Treatment Failure 
Time to treatment failure (event-free survival) is measured from the time from study entry to any 
treatment failure including discontinuation of treatment for any reason, such as disease 
progression, toxicity, patient preference, initiation of new treatment without documented 
progression, or death. This composite endpoint is generally not encouraged by regulatory 
agencies because it combines efficacy, toxicity and patient withdrawal. 
 
13.0 
DATA REPORTING / REGULATORY CONSIDERATIONS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Data Reporting  
The Adverra EDC™ and OnCore™ databases will be utilized, as required by the Case 
Comprehensive Cancer Center and Cleveland Clinic, to provide data collection for both accrual 
entry and trial data management. Adverra EDC and OnCore™ are Clinical Trials Management 
Systems housed on secure servers. Access to data through Adverra EDC and OnCore™ is 
restricted by user accounts and assigned roles. Once logged into the Adverra EDC or OnCore™ 
system with a user ID and password, Adverra EDC™ and OnCore™ define roles for each user 
which limits access to appropriate data. User information and password can be obtained by 
contacting the OnCore™ Administrator at OnCore-registration@case.edu for OnCore™ access, 
and taussigoncore@ccf.org for Adverra EDC™ access. 
 
Adverra EDC™ is designed with the capability for study setup, activation, tracking, reporting, 
data monitoring and review, and eligibility verification. When properly utilized, Adverra EDC™ 
is 21 CFR 11 compliant. This study will utilize electronic Case Report Form completion in the 
Adverra EDC™ database. A calendar of events and required forms are available in Adverra 
EDC™. 
 
13.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws. 
13.2.1 Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related procedures. 
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study as well as the 
subject’s financial responsibility. Subjects must also be notified that they are free to discontinue 

 
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from the study at any time. The subject should be given the opportunity to ask questions and be 
allowed time to consider the information provided.  
The original, signed written Informed Consent Form must be kept with the Research Chart in 
conformance with the institution’s standard operating procedures. A copy of the signed written 
Informed Consent Form must be given to the subject. Additionally, documentation of the 
consenting process should be located in the research chart. 
13.2.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or allow the 
sponsor, a regulatory authority, or Institutional Review Board access to subject’s medical 
information that includes all hospital records relevant to the study, including subjects’ medical 
history.  
 
13.2.3  Retention of records 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention of 
all documentation of adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence for as long as needed to comply with local, national and international 
regulations. No records will be destroyed until the Principal Investigator confirms destruction is 
permitted.  
 
13.2.4  Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform audits or 
inspections, including source data verification. The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analysed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP), guidelines of the 
International Conference on Harmonization (ICH), and any applicable regulatory requirements.  
For multi-center studies, participating sites must inform the sponsor-investigator of pending 
audits.  
 
14.0 STATISTICAL CONSIDERATIONS  
 
14.1  
General Considerations 
This is an open-label, single-arm, phase II trial of Rituximab in combination with Acalabrutinib 
treating newly diagnosed B cell post-transplant lymphoproliferative disorder. The primary 
objective is to assess the efficacy of the combination regimen. The primary endpoint is overall 
response rate (ORR) 8 weeks after treatment completion. Secondary endpoints include complete 
response rate (CRR), partial response rate (PRR), duration of response (DoR), overall survival 
(OS), progression-free survival (PFS), time to treatment failure (TTF) and toxicity profile. 
 
14.2   Rational for Sample Size 
The null ORR of single agent Rituximab is 60% based on literature 6-11. We expect the ORR (CR 
+PR) of combination regimen be at least 75%. Using one-sample exact binomial test, 62 patients 
will ensure a power of 80% at two-sided type I error rate of 10% to detect such a difference. The 
trial will be considered a success if 44 or more CRs/PRs are observed out of 62 patients.  
 

 
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14.3 
Futility Monitoring Rule 
We expect the ORR of Rituximab + Acalabrutinib will be 15% or higher than Rituximab alone. 
We will monitor the ORR and stop the trial early for futility if observed ORR is unlikely to 
achieve the target (75%). A Bayesian method 31 will be used to monitor futility. The reference 
ORR was assumed to follow a Beta(60,40) distribution, which corresponds to an expected ORR 
of 60% with an effective sample size of 100. The prior distribution of true ORR was set as 
Beta(0.6,0.4), which also has an expected ORR of 60%, but with an effective sample size of 1. 
Futility monitoring will start from the 10th patient and in cohorts of 10 thereafter. We will stop 
the trial early if Pr (ORR < 0.60 + 0.15|data) > 0.9, i.e. stop the trial early if the posterior 
probability of experimental ORR missing target (75%) is high (>0.9) given data. Table 5 
summarizes early stopping boundaries, and table 6 summarizes operating characteristics. 
 
Table 5. Summary of futility stopping boundaries using Bayesian monitoring rule. Futility 
monitoring will start from the 10th patient and in cohorts of 10. Trial will stop early if the 
number of CRs/PRs observed is less than or equal to the boundaries. For example, if we 
observed 5 or less CRs/PRs out of the first 10 patients, we will stop the trial early. Similarly, 
if we observed less than or equal to 12/20, 18/30, 25/40, or 32/50 CRs/PRs, we will stop the 
trial early for futility. 
Total Number of 
Patients Treated 
10 
20 
30 
40 
50 
Number of CRs/PRs 
Observed <= 
5 
12 
18 
25 
32 
 
Table 6. Summary of operating characteristics based on 10,000 simulations using early 
stopping boundaries in table 5. E.g. If the true ORR is 75%, the early stopping probability is 
0.17; if the true ORR is 60% (same as Rituximab alone), the early stopping probability is 
0.84; if the true ORR is 50% (worse than Rituximab alone), the trial will stop early with 
probability 0.99. MultcLean v2.1 from MDACC was used to calculate the stopping 
boundaries and operation characteristics 
Scenario 
True ORR 
Pr(Early Stopping) 
Average #Patients 
Enrolled 
Average 
#CR/PR 
Observed 
1 
0.80 
0.06 
57.5 
46.0 
2 
0.75 
0.17 
53.0 
39.8 
3 
0.60 
0.84 
26.9 
16.1 
4 
0.50 
0.99 
15.9 
7.9 
 
14.4 Toxicity Monitoring 
Toxicity is defined as any grade 4 adverse event or treatment related death. We will do interim 
looks for toxicity after every 15 patients have been treated and assessed for toxicity. If the 
estimated toxicity rate is higher than 20%, we will pause the study and a comprehensive safety 
assessment will be performed. 
 
14.5 Analysis Populations 
All efficacy and safety analysis will be performed using the treated population, which consists of 
all subjects who receive any amount of study treatment.  The analysis of DOR will only include 
subjects who have achieved objective response and will be measured from the first observation 
of DOR until date of progressive disease. 
 
14.6 
Missing Data Handling 

 
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No imputation of values for missing data will be performed except that missing or partial start 
and end dates for AEs and concomitant medication will be imputed according to prespecified, 
conservative imputation rules.  Subjects lost to follow-up (or drop out) will be included in 
statistical analyses to the point of their last evaluation. 
 
 
14.7  Endpoint Data Analysis 
Patient characteristics will be summarized using mean, SD, range, frequencies, and percentages 
where appropriate. ORR will be estimated along with 90% CIs, and compared against the null 
using exact binomial test. Logistic regression model will be used to identify factors associated 
with response status. Survival endpoints will be estimated using Kaplan-Meier method and 
compared using log-rank test. Cox proportional hazard model will be used to identify factors 
associated with survival endpoint. Other analyses will be carried out as appropriate. 
 
 

 
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journal of the American Society of Clinical Oncology 1998;16:2052-9. 
21. 
Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health 
Organization classification of lymphoid neoplasms. Blood 2016;127:2375-90. 
22. 
Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): A Covalent Bruton Tyrosine 
Kinase Inhibitor with a Differentiated Selectivity and In Vivo Potency Profile. The Journal of 
pharmacology and experimental therapeutics 2017;363:240-52. 
23. 
Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell 
lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet 2018;391:659-67. 
24. 
Phillips TJ, Smith SD, Jurczak W, et al. Safety and Efficacy of Acalabrutinib Plus 
Bendamustine and Rituximab (BR) in Patients with Treatment-Naive (TN) or 
Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL). Blood 2018;132:4144-. 
25. 
Byrd JC, Wierda WG, Schuh A, et al. Acalabrutinib Monotherapy in Patients with 
Relapsed/Refractory Chronic Lymphocytic Leukemia: Updated Results from the Phase 1/2 ACE-
CL-001 Study. Blood 2017;130:498-. 
26. 
Rituxan (rituximab) [package insert]. Biogen and Genetech, San Fancisco, CA. 2018. 
27. 
Imbruvica (ibrutinib) [package insert].  Pharmacyclics, Inc., Sunnyvale, CA. 2013. 
28. 
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 : official journal of the American Society of Clinical Oncology 2006;24:3187-
205. 
29. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. American journal of clinical oncology 1982;5:649-55. 
30. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 2014;32:3059-68. 
31.       Peter F. Thall, Richard M. Simon, and Elihu H. Estey,  Bayesian sequential monitoring 
designs for single-arm clinical trials with multiple outcomes, Statistics in Medicine, vol 14, 357-
379 (1995). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX 1 
 
Performance Status Criteria 29 
 
ECOG Performance Status Scale 
Grade 
Description 
 
0 
Normal activity. Full active, able to 
carry on all pre-disease performance 
without restriction.  
 
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). 
 
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% if waking 
hours. 
 
3 
In bed > 50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX 2 
 
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/DrugInter
actionsLabeling/ucm093664.htm#inVivo 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX 3 
 
Assessment of Responses based on Lugano Criteria as defined by Cheson et al 30 
   

 
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APPENDIX 4 
 
 
Cockcroft Gault Formula to Estimate Renal Function Using Serum Creatinine 
 
Estimated creatinine clearance (ClCr) by the Cockcroft-Gault (C-G) equation (Cockcroft 
and Gault, 1976).  
 
CLcr (ml.min) = [140-age (years)] x weight (kg) x [0.85 if female) 
                             72 x serum creatinine (mg/dL) 
 
 
 
Reference: 
1. Cockcroft, D.W. and M.H. Gault.  (1976). Prediction of creatinine clearance from serum 
creatinine.  Nephron.  16:31-41. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX 5 
 
Subject Pill Diary 
  
Subject Name ______________________ Subject Study ID __________   Today’s date ___/___/___ 
Drug _
 Cycle #:
      
INSTRUCTIONS FOR THE SUBJECT: 
  1.  Complete one form every 4 weeks (one treatment cycle). 
  2.  You will take one Acalabrutinib capsule twice each day about 12 hours apart.  Take the capsules with a full 
glass (8 oz) of water and with or without food, as you wish. If a dose is missed by more than 3 hours, please 
skip that dose and take the next dose at the next scheduled time. 
       Morning dose:  take # of   ____ mg capsule  
       Evening dose:  take # of    ____ mg capsule 
  3.  Record the date, the number of capsules of each size that you took, and what time you took them.  
  4.  If you have any comments or notice any side effects, please record them in the “Comments” column. 
  5.  Please bring this form and your bottle(s) of acalabrutinib to your physician when you return for each 
appointment.   
  6.  Please sign your name at the bottom of the diary. 
Day 
Date 
Time of 
morning 
dose 
# of capsules taken 
Time of 
evening 
dose 
# of capsules 
taken 
 
Comments 
___ 
mg 
___ 
mg 
 
___ 
mg 
___ 
mg 
 
1 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
 
Subject’s Signature: ________________________________________ Date: _____________ 

 
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Reviewed by Signature: 
 Date: 
 
 
Date: 
Date: