Clinical trial NCT04402138
Conditions: Mantle Cell Lymphoma
Keywords: Acalabrutinib Non Hodgkin's lymphoma Blood or Marrow transplant BMT Maintenance therapy Bruton's Tyrosine Kinase Inhibitor
Sponsor: SCRI Development Innovations, LLC
Start date: 2020-08-07; Completion date: 2024-04-05
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase II study to evaluate efficacy of Acalabrutinib as a maintenance therapy following blood or marrow transplant (BMT) in patients who have been diagnosed with mantle cell lymphoma.

Detailed description:
Mantle cell lymphoma (MCL) is one of approximately 100 different types of non-Hodgkin's lymphoma (NHL). Due to the aggressive and heterogeneous nature of MCL, majority of patients are diagnosed with advanced stage disease that requires immediate, diverse and aggressive courses of therapy to improve the outcome of the disease. The addition of blood or bone marrow transplantation (BMT) to the chemotherapy regimens is a critical factor to prolong duration of response in patients, however, the benefit of combination chemotherapy followed by BMT is often temporary as patients experience disease progression and mortality and this underscores the need for novel therapies as well as additional maintenance therapy strategies to prevent relapse post-BMT.

Acalabrutinib, a selective, irreversible small molecule inhibitor of Bruton's tyrosine kinase (BTK) is approved for the treatment of adult patients with MCL who have received at least 1 prior therapy

This study is a single arm, multi-center, phase 2 study of participants who will receive acalabrutinib as maintenance therapy post-BMT. Participants will undergo a standard of care BMT with conditioning regimen determined by the treating physician per institutional guidelines.The BMT procedure is not considered part of this study. Following completion of the BMT, maintenance therapy with acalabrutinib will begin on Day 100 in 28-day cycles. Participants will self-administer 129 mg acalabrutinib twice daily (BID) until they reach 2 years post-BMT (approximately 22 cycles). Participants will be followed for up to 5 years post-BMT for Progression Free Survival.

Arms: arm 1: Acalabrutinib will be self-administered orally for up to approximately 2 years post-BMT.
Interventions: intervention 1: Acalabrutinib
Intervention descriptions: intervention 1: Acalabrutinib 129 mg will be self-administered orally twice daily (BID) starting from 100 day (+/- 7 days) Post-BMT on a 28-day schedule, with or without food, until the patient has reached approximately 2 years post-BMT.

Protocol documents:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
This document is confidential and is the property of Sarah Cannon Development Innovations, LLC.  No part of this 
document may be transmitted, reproduced, published, or used by other persons without prior written authorization 
from Sarah Cannon Development Innovations, LLC. 
 
LYM 155 
Single Arm, Phase II Study of Acalabrutinib as Post-Autologous Blood or 
Marrow Transplant (BMT) Maintenance Therapy in Subjects with Mantle 
Cell Lymphoma 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER: 
LYM 155 
STUDY DRUG: 
Acalabrutinib 
ACERTA PHARMA PROTOCOL NUMBER: 
ESR-18-13673 
SPONSOR: 
Sarah Cannon Development Innovations, LLC 
1100 Dr. Martin L. King Jr. Blvd. 
Suite 800 
Nashville, TN 37203 
844-710-6157 
CANN.InnovationsMedical@sarahcannon.com 
 
STUDY CHAIR: 
Michael Tees, MD 
Sarah Cannon Research Institute at Colorado Blood 
Institute (CBCI) at HealthOne’s Presbyterian/St. Luke 
Medical Center 
1721 East 19th Ave, Suites 200 & 300 
Denver, CO 80218 
720-754-4800 
DATE FINAL: 
24 July 2019 
AMENDMENT 1 
30 March 2020 
AMENDMENT 2 
22 December 2020 
AMENDMENT 3 
29 September 2023 


 
 
INNOVATIONS STUDY NUMBER: LYM 155 
STUDY DRUG:  ACALABRUTINIB 
CONFIDENTIAL 
Page 2 of 76 
PROTOCOL DATE: 29 SEP 2023 
AMENDMENT 3.0, VERSION 4.0 
 
 
Clinical Study Statement of Compliance 
LYM 155 
Single Arm, Phase II Study of Acalabrutinib as Post-Autologous Blood or 
Marrow Transplant (BMT) Maintenance Therapy in Subjects with Mantle 
Cell Lymphoma 
 
This clinical study shall be conducted in compliance with the protocol, as referenced herein, 
and all applicable local, national, and international regulatory requirements to include, but 
not be limited to: 
• 
International Council for Harmonisation (ICH) Guidelines on Good Clinical 
Practice (GCP) 
• 
Ethical principles that have their origins in the Declaration of Helsinki 
• 
Food and Drug Administration (FDA) Code of Federal Regulation (CFR): 
o 
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human Subjects 
o 
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators 
o 
Title 21CFR Part 56, Institutional Review Boards (IRBs) 
o 
Title 21CFR Part 312, Investigational New Drug Application 
o 
Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA) 
 
As the Study Chair and/or Principal Investigator, I understand that my signature on the 
protocol constitutes my agreement and understanding of my responsibilities to conduct the 
clinical study in accordance with the protocol and applicable regulations.  Furthermore, it 
constitutes my understanding and agreement that any changes initiated by myself, without 
prior agreement in writing from the Sponsor, shall be defined as a deviation from the 
protocol, and shall be formally documented as such. 


 
 
INNOVATIONS STUDY NUMBER: LYM 155 
STUDY DRUG:  ACALABRUTINIB 
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AMENDMENT 3.0, VERSION 4.0 
 
Clinical Study Protocol Approval Page 
Single Arm, Phase II Study of Acalabrutinib as Post-Autologous Blood or 
Marrow Transplant (BMT) Maintenance Therapy in Subjects with Mantle 
Cell Lymphoma 
 
INNOVATIONS STUDY NUMBER: 
LYM 155 
STUDY DRUG: 
Acalabrutinib 
DATE FINAL: 
24 July 2019 
AMENDMENT 1 
30 March 2020 
AMENDMENT 2 
22 December 2020 
AMENDMENT 3 
29 September 2023 
 
 
 
Study Chair 
Michael Tees, MD 
Sarah Cannon Research Institute at 
Colorado Blood Institute (CBCI) at 
HealthOne’s Presbyterian/St. Luke 
Medical Center 
1721 East 19th Ave, Suites 200 & 300 
Denver, CO 80218 
720-754-4800 
Study Chair Signature 
 
Date 
 
 
 
 
 
 
Sarah Cannon Development 
Innovations, LLC 
Vice President, Development Innovations 
Sarah Cannon Development Innovations 
1100 Dr. Martin L. King Jr. Blvd. 
Suite 800 
Nashville, TN 37203 
Sarah Cannon Development Innovations, 
LLC Representative Signature 
 
Date 
 
 
 


 
 
INNOVATIONS STUDY NUMBER: LYM 155 
STUDY DRUG:  ACALABRUTINIB 
CONFIDENTIAL 
Page 4 of 76 
PROTOCOL DATE: 29 SEP 2023 
AMENDMENT 3.0, VERSION 4.0 
 
 
Clinical Study Principal Investigator Signature Form 
Single Arm, Phase II Study of Acalabrutinib as Post-Autologous Blood or 
Marrow Transplant (BMT) Maintenance Therapy in Subjects with Mantle 
Cell Lymphoma 
 
INNOVATIONS STUDY NUMBER: 
LYM 155 
DATE FINAL: 
24 July 2019 
AMENDMENT 1 
30 March 2020 
AMENDMENT 2 
22 December 2020 
AMENDMENT 3 
29 September 2023 
 
By signing this protocol acceptance page, I confirm I have read, understand, and agree to conduct the 
study in accordance with the current protocol. 
 
 
 
___________________________            _______________________________     _______  
Principal Investigator Name 
(Please Print) 
 
Principal Investigator Signature 
 
Date 
 
Please retain a copy of this page for your study files and return the original signed and dated 
form to: 
 
Sarah Cannon Development Innovations, LLC 
1100 Dr. Martin L. King Jr. Blvd., Suite 800 
Attention:  LYM 155 Study Team 
Nashville, TN 37203 


 
INNOVATIONS STUDY NUMBER: LYM 155 
STUDY DRUG:  ACALABRUTINIB 
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AMENDMENT 3.0, VERSION 4.0 
 
LYM 155 Summary of Changes 
AMENDMENT NUMBER: 
3.0 
AMENDMENT DATE:       29 September 2023 
Additions are noted by bolding. Deletions are noted by cross outs. 
Title Page, Clinical Study Protocol Approval Page, and Contact Information 
Study Chair transitioned from Ian Flinn, MD, PhD, to Michael Tees, MD. 
 
Ian Flinn, MD, PhD 
Director, Lymphoma Program 
Sarah Cannon Research Institute 
Sarah Cannon Center for Blood Cancer 
250 25th Ave North 
Suite 412 
Nashville, TN 37203 
615-986-7600 
iflinn@tnonc.com 
 
Michael Tees, MD 
Sarah Cannon Research Institute at Colorado Blood Institute (CBCI) at HealthOne’s 
Presbyterian/St. Luke Medical Center 
1721 East 19th Ave, Suites 200 & 300 
Denver, CO 80218 
720-754-4800 
Michael.Tees@HealthONECares.com 
Contact Information 
Regulatory email updated. 
SCRIRegulatory@scri-innovations.com 
CANN.SCRIRegulatory@SCRI-Innovations.com 
Synopsis 
Define the conversion rate from minimal residual disease positive (MRD+) to MRD negative 
(MRD-) during therapy for up to 2 years post-BMT 
Beginning at Day +100 (±7 days) post-BMT, subjects will receive 129100 mg acalabrutinib 
twice daily (BID) until they reach 2 years post-BMT. 
Acalabrutinib 129100 mg will be self-administered orally BID for up to 2 years (approximately 
22 cycles) on a 28-day cycle (approximately 22 cycles). 
Synopsis and Section 3.2 
5. Willing and able to participate in all required evaluations and procedures in this study 
protocol including swallowing tabletscapsules without difficulty. 


 
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Synopsis and Section 3.3 
14. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).  Subjects receiving proton-
pump inhibitors who switch to histamine 2-receptor antagonists or antacids are eligible 
for enrollment to this study. 
20. The inability to swallow tabletscapsules. 
Section 1.4.2 
Acalabrutinib absorption may be lower in individuals being treated with proton-pump inhibitors, 
histamine 2 (H2) receptor antagonists, or antacids.   
Section 1.6 
In this study, we propose the use of acalabrutinib 129100 mg PO BID as maintenance therapy 
post-BMT to prolong PFS. 
Section 5 
Subjects will self-administer 129100 mg acalabrutinib BID until they reach 2 years post-BMT 
(approximately 22 cycles). 
Figure 1 
Subjects will self-administer acalabrutinib 129100 mg BID on a 28-day cycle. 
Section 5.1  
Acalabrutinib 129100 mg will be self-administered orally BID on a 28-day schedule, with or 
without food, until the patient has reached approximately 2 years post-BMT. 
Section 5.3 
The effect of agents that reduce gastric acidity (i.e., 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 after taking acalabrutinib.  Use of 
omeprazole, esomeprazole, lansoprazole or any other proton-pump inhibitors while taking 
acalabrutinib is not recommended due to a potential decrease in study drug exposure. However, 
the decision to treat with proton-pump inhibitors during the study is at the Investigator’s 
discretion, with an understanding of the potential benefit to the subject’s gastrointestinal 
condition and a potential risk of decreased exposure to acalabrutinib. 
Although the effect of H2-receptor antagonists (e.g. 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. 
Section 6.3 
• Complete blood count (CBC), and clinical chemistry panel, and coagulation testing 
Section 6.4.1, Section 6.4.2, Section 6.4.3, and Section 6.4.4 
• Treatment with acalabrutinib 129100 mg PO BID 


 
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AMENDMENT 3.0, VERSION 4.0 
 
Section 6.5.5 
Coagulation testing will include PT/INR or aPTT. 
Section 7 
7.1 
Acalabrutinib 
Investigational Product 
Dosage Form and Strength 
Manufacturer 
Acalabrutinib 
129100 mg tabletscapsules 
Acerta Pharma 
7.2 
Acalabrutinib Treatment Duration 
Acalabrutinib tabletscapsules will be self-administered BID approximately every 12 hours.  The 
tabletscapsules should be swallowed intact with approximately 1 cup of water.  Patients should 
not chew the tablets and should try to swallow tablets whole. Patients should not attempt to 
open capsules or dissolve them in water.   
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 
patient should take the next dose at the scheduled time.  The missed dose will not be made up 
and must be returned to the site at the next scheduled visit. 
Guidance on co-administration of acalabrutinib with agents that affect gastric pH is provided in 
Section 5.3. 
7.2.1 Labeling, Packaging, and Supply of Acalabrutinib 
The investigational product, acalabrutinib maleate tablet, is supplied as an orange film-
coated tablet containing 129 mg of acalabrutinib maleate (equivalent to 100 mg of 
acalabrutinib) drug substance.   
Each tablet also contains the following compendial inactive ingredients: mannitol, 
microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and sodium stearyl 
fumarate.  The tablet coating contains hypromellose, copovidone, titanium dioxide, 
polyethylene glycol, caprylic/capric triglyceride, yellow iron oxide, and red iron 
oxide.Acalabrutinib is supplied as yellow and blue, opaque hard gelatin capsules filled with 100 
mg of 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).   
Acalabrutinib will be provided in white, high-density polyethylene bottles.  The recommended 
storage condition for acalabrutinib capsules is below 30°C (86°F).Acalabrutinib maleate 
tablets are packed in white, high-density polyethylene (HDPE) bottles containing a silica 
gel desiccant and should be stored according to the storage conditions as indicated on the 
label.  The recommended storage condition for acalabrutinib maleate tablets is below 30°C 
(86°F). 


 
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Section 7.4 
The subject will be instructed to bring the diary and any remaining tabletscapsules to the clinic 
at his/her next visit.  The study staff will review the diary and ask the subject if all the 
tabletscapsules were administered.  Any remaining or returned tabletscapsules will be counted 
and documented.  Returned tabletscapsules must not be redispensed to another subject.   
Table 1 
Acalabrutinib Dose Reduction Options 
Starting Dose 
1st Dose Reduction 
2nd Dose Reduction 
129100 mg BID 
129100 mg QD 
discontinue 
Section 8.1 
The maximum dose of acalabrutinib is 129100 mg BID. 
Section 8.2 
If the acalabrutinib dose should be reduced and the subject is receiving acalabrutinib 129100 mg 
QD, acalabrutinib should be discontinued. 
Appendix D: Schedule of Assessments 
Coagulation testingu 
129100 mg twice daily continuously for 2 years post-BMT (~22 cycles). 
Appendix D: Schedule of Assessments footnote u 
u 
Coagulation testing will include PT/INR or aPTT. 
 


 
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AMENDMENT 3.0, VERSION 4.0 
 
LYM 155 PROTOCOL SYNOPSIS 
Title of Study: 
Single Arm, Phase II Study of Acalabrutinib as Post-Autologous Blood or Marrow 
Transplant (BMT) Maintenance Therapy in Subjects with Mantle Cell Lymphoma 
Innovations Study 
Number: 
LYM 155 
Sponsor: 
Sarah Cannon Development Innovations, LLC 
Study Duration: 
The total duration of the study is planned to be 
approximately 7 years (2 years for recruitment). 
Phase of Study:  II 
Number of Study 
Centers: 
This study will be conducted at approximately 10 sites in the United States. 
Number of Patients: 
Approximately 50 patients are planned to be enrolled in this study. 
Objectives: 
Primary Objective 
The primary objective of this study is to: 
• 
Determine the progression-free survival (PFS) rate of subjects who received at least 
one dose of acalabrutinib and are alive and free of disease progression or relapse at 
2 years post-blood or marrow transplant (BMT). 
Secondary Objectives 
The secondary objectives of this study are to: 
• 
Define the conversion rate from minimal residual disease positive (MRD+) to MRD 
negative (MRD-) during therapy for up to 2 years post-BMT 
• 
Assess how MRD correlates with PFS 
• 
Assess the incidence of adverse events (AEs)  
Exploratory Objectives 
The exploratory objectives of this study are to: 
• 
Determine how mutations correlate with disease relapse using next-generation 
sequencing 
• 
Determine the MRD correlation of bone marrow compared to blood 
Study Design: 
This is a single arm, multi-center, Phase II study of subjects with mantle cell lymphoma 
(MCL) who will receive acalabrutinib as maintenance therapy post-BMT.  The BMT is 
not considered part of this study.  Beginning at Day +100 (±7 days) post-BMT, subjects 
will receive 129 mg acalabrutinib twice daily (BID) until they reach 2 years post-BMT.  
All subjects will be followed for up to 5 years post-BMT for progression-free survival.  
Study Drug, Dose, and 
Mode of 
Administration: 
Acalabrutinib 129 mg will be self-administered orally BID for up to 2 years 
(approximately 22 cycles) on a 28-day cycle.  Acalabrutinib will be self-administered 
until disease progression, unacceptable toxicity, or the subject discontinues treatment for 
any other reason. 
Inclusion Criteria for 
Initial Enrollment 
(Screening #1) : 
1. Written informed consent according to local guidelines, signed by the subject or by 
a legal guardian prior to the performance of any study-related procedures. 
2. Men and women ≥18 years-of-age. 
3. A diagnosis of MCL confirmed by one of the following: 
- t(11;14) detected by fluorescence in situ hybridization (FISH), conventional 
cytogenetics, or other molecular evaluation 
- expression of cyclin D1 confirmed by immunohistochemistry  
4. Subject must have completed induction chemotherapy and plan to and be eligible to 
receive their first BMT per standard of care 
5. Availability of an archival paraffin-embedded tumor block for MRD testing 


 
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AMENDMENT 3.0, VERSION 4.0 
 
6. The Investigator anticipates that the subject will meet the appropriate lab 
requirements listed in Screening #2 by Day 100 
7. Patients who received prior therapy with a Bruton’s tyrosine kinase (BTK) inhibitor 
are eligible to enroll. 
Inclusion Criteria after 
BMT, Prior to Day 100 
(Screening #2) 
1. Adequate organ system functions defined as: 
- Absolute neutrophil count ≥1,000/mm3.  
- Platelet count ≥75,000/mm3.  Platelet infusions to meet eligibility criteria are 
not allowed within 3 days of study enrollment. 
- Calculated creatinine clearance (CrCl) ≥30 mL/min as calculated by the 
Cockcroft-Gault method. 
Estimated CrCl (glomerular filtration rate) = (140-age [years]) x (weight [kg]) x Fa 
(72 x serum creatinine [mg/dL]) 
a where F = 0.85 for females and F = 1 for males 
- Total bilirubin ≤1.5 x the upper limit of normal (ULN) (except for previously 
documented Gilbert's syndrome) 
- Alanine aminotransferase/aspartate aminotransferase ≤2.5 x ULN 
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 
3. Subjects who did not receive an anti-cancer therapy (including surgery, 
radiotherapy, chemotherapy, immunotherapy, or investigational therapy) during the 
time between their transplant and the start of study therapy.  Subjects must have 
recovered (e.g. Grade ≤1 or baseline) from AEs associated with prior cancer 
therapy.  Note:  Subjects with Grade ≤2 neuropathy or Grade ≤2 alopecia are an 
exception to the latter criterion and may qualify for the study. 
4. Women of childbearing potential (WoCBP) who are sexually active with male 
partners must use highly effective methods of contraception during treatment and 
for 2 days after the last dose of acalabrutinib.  For male subjects with a pregnant or 
non-pregnant WoCBP partner, no contraception measures are required.  A WoCBP 
must have a negative pregnancy test (urine or serum) at the time of screening and 72 
hours before starting the study drug or have evidence of non-childbearing potential 
by fulfilling one of the following criteria: 
- Post-menopausal women, defined as either women aged >50 years and 
amenorrheic for ≥12 months following cessation of all exogenous hormonal 
treatments or women <50 years old who have been amenorrheic for ≥12 
months following the cessation of exogenous hormonal treatments, and have 
serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels 
in the post-menopausal range for the institution. 
- Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy, but not tubal ligation. 
- Medically confirmed, irreversible premature ovarian failure. 
5. Willing and able to participate in all required evaluations and procedures in this 
study protocol including swallowing tablets without difficulty. 
6. Ability to understand the purpose and risks of the study and provide signed and 
dated informed consent and authorization to use protected health information. 


 
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AMENDMENT 3.0, VERSION 4.0 
 
Exclusion Criteria : 
1. Subjects who have relapsed or progressed at any time prior to BMT 
2. Subjects with known mutations that confer resistance to a BTK inhibitor. 
3. Confirmed clinical disease progression since the time of BMT 
4. Prior malignancy (or any other malignancy requiring active treatment), except for 
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or 
other cancer from which the subject has been disease free for ≥2 years or that will 
not limit survival to <2 years. The exceptions are: 
- Subjects treated with curative intent <2 years prior to enrollment and have a 
low probability of recurrence. 
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 (Appendix B). 
6. Malabsorption syndrome, disease significantly affecting gastrointestinal function, 
resection of the stomach or small bowel that is likely to affect absorption, 
symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or 
gastric restrictions and bariatric surgery, such as gastric bypass. 
7. Known history of infection with human immunodeficiency virus (HIV) or any 
uncontrolled active systemic bacterial, fungal, parasitic or viral infection. Infections 
are considered controlled if appropriate therapy has been instituted and, at the time 
of screening, no signs of infection progression are present. 
8. Known history of drug-specific hypersensitivity or anaphylaxis to study drug 
(including active product or excipient components).  
9. Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand 
disease). 
10. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic 
purpura. 
11. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer 
(see Appendix G).  
12. Requires or is receiving anticoagulation treatment with warfarin or equivalent 
vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study 
drug. 
13. Prothrombin time (PT)/international normalized ratio (INR) or activated partial 
thromboplastin time (aPTT) >2 x ULN (in the absence of lupus anticoagulant). 
14. History of significant cerebrovascular disease/event, including stroke or intracranial 
hemorrhage, within 6 months before the first dose of study drug. 
15. 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. 
16. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-
HBc) positive and who are hepatitis B surface antigen (HbsAg) negative will need 
to have a negative polymerase chain reaction (PCR) result.  Those who are 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. 


 
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AMENDMENT 3.0, VERSION 4.0 
 
17. Breastfeeding or pregnant. 
18. Concurrent participation in another therapeutic clinical trial.   
19. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol. 
20. The inability to swallow tablets.  
Statistical 
Methodology: 
The primary endpoint is the percentage of subjects who are alive and free of disease 
progression or relapse at 2-years post-BMT. A sample size of 45 subjects produces a 
two-sided 95% confidence interval of 65%-95% when the observed percentage is 80%. 
To account for a 10% non-evaluable rate, the total sample size will be 50 patients. 


 
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AMENDMENT 3.0, VERSION 4.0 
 
LYM 155 CONTACT INFORMATION 
Sponsor 
Contact Information: 
Sarah Cannon Development Innovations 
1100 Dr. Martin Luther King Jr. Blvd. 
Suite 800 
Nashville, TN 37203 
844-710-6157 
 
CANN.InnovationsMedical@sarahcannon.com 
Study Chair: 
Michael Tees, MD 
Sarah Cannon Research Institute at Colorado Blood 
Institute (CBCI) at HealthOne’s Presbyterian/St. Luke 
Medical Center 
1721 East 19th Ave, Suites 200 & 300 
Denver, CO 80218 
720-754-4800 
 
Michael.Tees@HealthONECares.com 
Safety Dept. Fax #: 
Safety Dept. Email: 
866-807-4325 
CANN.SAE@scri-innovations.com 
Medical Support Center Phone # 
Regulatory Email: 
844-710-6157 
CANN.SCRIRegulatory@SCRI-Innovations.com 
Innovations Enrollment Fax #: 
Innovations Enrollment Email #: 
1-866-346-1062 or 615-524-4012 
CANN.SCRIInnovationsEnr@scri-innovations.com 


 
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LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
autoSCT 
Autologous stem cell transplant 
BID 
Twice per day (dosing) 
BM 
Bone marrow (or bortezomib maintenance, depending on context) 
BMT 
Blood or marrow transplant 
BTK  
Bruton’s tyrosine kinase 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CR 
Complete response 
CT 
Computed tomography 
CYP 
Cytochrome p450 
ECG 
Electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group  
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose positron emission tomography 
GCP 
Good Clinical Practice 
H2 
Histamine 2 
HBc 
Hepatitis B core antibody 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIPPA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
Innovations 
Sarah Cannon Development Innovations 
IRB 
Institutional Review Board 
IVIG 
Intravenous immunoglobulin 
MCL 
Mantle cell lymphoma 
MRD 
Minimal residual disease 
MRI 
Magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NGS 
Next-generation sequencing  
OS 
Overall survival 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression-free survival 


 
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PHI 
Protected health information 
PI 
Principal Investigator 
PML 
Progressive multifocal leukoencephalopahthy 
PR 
Partial response 
QD 
Once per day (dosing) 
RECIL 
Response Evaluation Criteria in Lymphoma 
R/R 
Relapsed/refractory 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SD 
Stable disease 
SUSAR 
Suspected unexpected serious adverse reactions 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
WoCBP 
Women of child bearing potential 


 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ................................................................................................. 21 
1.1 
Background ........................................................................................................... 21 
1.2 
Relevance of Minimal Residual Disease ............................................................... 21 
1.3 
Maintenance Therapy for Mantle Cell Lymphoma ............................................... 21 
1.4 
Acalabrutinib ......................................................................................................... 22 
1.4.1 
Mechanism of Action ............................................................................................ 22 
1.4.2 
Pharmacokinetics and Pharmacodynamics of Acalabrutinib ................................ 23 
1.4.3 
Safety Pharmacology ............................................................................................. 23 
1.5 
Acalabrutinib Monotherapy in Mantle Cell Lymphoma ....................................... 23 
1.6 
Rationale for the Study .......................................................................................... 24 
2. 
STUDY OBJECTIVES ......................................................................................... 24 
2.1 
Primary Objective.................................................................................................. 24 
2.2 
Secondary Objectives ............................................................................................ 24 
2.3 
Exploratory Objectives .......................................................................................... 25 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION ...................... 25 
3.1 
Inclusion Criteria for Initial Enrollment (Screening #1) ....................................... 25 
3.2 
Inclusion Criteria Post-BMT, Prior to Day 100 (Screening #2)............................ 25 
3.3 
Exclusion Criteria .................................................................................................. 26 
3.4 
Discontinuation from Study Drug ......................................................................... 28 
3.5 
Study-wide Stopping Rules ................................................................................... 28 
4. 
STUDY REGISTRATION.................................................................................... 28 
5. 
STUDY DESIGN .................................................................................................. 29 
5.1 
Treatment Plan ...................................................................................................... 30 
5.2 
Concomitant Medications...................................................................................... 30 
5.2.1 
Permitted Concomitant Medications ..................................................................... 30 
5.2.2 
Prohibited or Restricted Concomitant Medications .............................................. 31 
5.3 
Drug-Drug Interactions ......................................................................................... 31 
5.4 
Exploratory Correlatives ....................................................................................... 31 
6. 
STUDY ASSESSMENTS AND EVALUATIONS .............................................. 32 
6.1 
Overview ............................................................................................................... 32 
6.2 
Baseline Study Assessments, Screening #1 Prior to BMT .................................... 32 
6.3 
Baseline Study Assessments, Screening #2 Post-BMT – Day 80 to Day 100 ...... 32 
6.4 
Study Assessment Timing ..................................................................................... 32 


 
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6.4.1 
Cycle 1, Days 1 and 15 (~ 4 months post-BMT) .................................................. 33 
6.4.2 
Cycles 2-6, Day 1 (~ 5-9 months post-BMT) ....................................................... 33 
6.4.3 
Cycles 7-12, Day 1 (~ 10-15 months post-BMT) ................................................. 33 
6.4.4 
Cycle 13 and Beyond, Day 1 (≥16 months post-BMT) ........................................ 33 
6.4.5 
End of Treatment/Early Termination Visit ........................................................... 34 
6.4.6 
Long-Term Follow-up/End of study ..................................................................... 34 
6.5 
Study Assessments ................................................................................................ 34 
6.5.1 
Medical History and Demographics ...................................................................... 34 
6.5.2 
Physical Examinations (Including Performance Scale and Vital Signs) ............... 34 
6.5.3 
12-Lead Electrocardiogram ................................................................................... 35 
6.5.4 
Pregnancy Testing ................................................................................................. 35 
6.5.5 
Laboratory Assessments ........................................................................................ 35 
6.5.6 
HIV and Hepatitis B and C Testing....................................................................... 35 
6.5.7 
Clonality (ID) Sample ........................................................................................... 36 
6.5.8 
Tracking (MRD) Sample ....................................................................................... 36 
6.5.9 
Fresh Lymphoma Biopsy Sample ......................................................................... 36 
6.5.10 
Response and Activity Assessments ..................................................................... 36 
6.5.11 
Adverse Event Assessments .................................................................................. 36 
6.5.12 
Prior and Concomitant Medications ...................................................................... 37 
6.5.13 
Minimal Residual Disease Assessment ................................................................. 37 
6.5.14 
Radiologic Assessments ........................................................................................ 37 
7. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION ............................................................................... 39 
7.1 
Acalabrutinib ......................................................................................................... 39 
7.2 
Acalabrutinib Treatment Duration ........................................................................ 39 
7.2.1 
Labeling, Packaging, and Supply of Acalabrutinib ............................................... 39 
7.3 
Accountability for the Study Drug ........................................................................ 39 
7.4 
Assuring Subject Compliance ............................................................................... 40 
7.5 
Toxicity of Study Drug and Study Regimen ......................................................... 40 
7.5.1 
Precautions and Risks Associated with Acalabrutinib .......................................... 40 
8. 
DOSE MODIFICATIONS .................................................................................... 42 
8.1 
Criteria and Procedures for Dose Interruptions and Adjustments of 
Acalabrutinib ......................................................................................................... 42 
8.2 
Dose Modifications for Hematologic Toxicities ................................................... 43 
8.3 
Dose Modifications for Non-hematologic Toxicities ............................................ 45 
8.4 
Management of Acalabrutinib-Related Adverse Events ....................................... 45 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS .................................. 45 
9.1 
Progression-free Survival ...................................................................................... 45 
9.2 
Complete Response ............................................................................................... 45 


 
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9.3 
Minimal Residual Disease ..................................................................................... 45 
10. 
STATISTICAL CONSIDERATIONS .................................................................. 46 
10.1 
Statistical Design ................................................................................................... 46 
10.2 
Sample Size Considerations .................................................................................. 46 
10.3 
Analysis Population ............................................................................................... 46 
10.4 
Data Analysis ........................................................................................................ 46 
10.4.1 
Demographics and Baseline Characteristics ......................................................... 46 
10.4.2 
Efficacy Analysis .................................................................................................. 47 
10.4.3 
Safety Analysis ...................................................................................................... 47 
10.5 
Analysis Time Points............................................................................................. 47 
10.5.1 
Final Analysis ........................................................................................................ 47 
11. 
SAFETY REPORTING AND ANALYSES ......................................................... 48 
11.1 
Definitions ............................................................................................................. 48 
11.1.1 
Adverse Events ...................................................................................................... 48 
11.1.2 
Serious Adverse Events ......................................................................................... 48 
11.1.3 
Adverse Reaction .................................................................................................. 49 
11.1.4 
Suspected Adverse Reaction ................................................................................. 49 
11.1.5 
Adverse Events of Special Interest ........................................................................ 49 
11.1.6 
Recording and Reporting of Adverse Events ........................................................ 49 
11.1.7 
Assessment of Adverse Events.............................................................................. 50 
11.2 
Serious Adverse Event Reporting by Investigators ............................................... 50 
11.3 
Recording of Adverse Events and Serious Adverse Events .................................. 51 
11.3.1 
Diagnosis versus Signs and Symptoms ................................................................. 51 
11.3.2 
Persistent or Recurrent Adverse Events ................................................................ 51 
11.3.3 
Abnormal Laboratory Values ................................................................................ 52 
11.3.4 
Deaths .................................................................................................................... 52 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery ........................................ 52 
11.3.6 
Pre-Existing Medical Conditions .......................................................................... 53 
11.3.7 
New Cancers.......................................................................................................... 53 
11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies ................................. 53 
11.3.9 
Overdose ................................................................................................................ 53 
11.4 
Funding Partner Serious Adverse Event Reporting Requirements ....................... 53 
11.4.1 
Sponsor Assessment of Unexpected Events .......................................................... 54 
11.4.2 
Funding Partner Reporting for Clinical Studies Under an Investigational New 
Drug Application ................................................................................................... 55 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .................................... 55 
12.1 
Study Monitoring, Auditing, and Inspecting ......................................................... 55 
13. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ............ 55 
13.1 
Institutional Review Board Approval.................................................................... 55 


 
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13.2 
Regulatory Approval ............................................................................................. 56 
13.3 
Informed Consent .................................................................................................. 56 
13.3.1 
Confidentiality ....................................................................................................... 56 
13.4 
Financial Information ............................................................................................ 57 
14. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY ........ 57 
14.1 
Amendments to the Protocol ................................................................................. 57 
14.2 
Documentation Required to Initiate the Study ...................................................... 58 
14.3 
Study Documentation and Storage ........................................................................ 58 
14.4 
Data Collection ...................................................................................................... 60 
14.5 
Disclosure and Publication Policy ......................................................................... 60 
15. 
REFERENCES ...................................................................................................... 62 
16. 
APPENDICES ....................................................................................................... 65 
 
LIST OF TABLES 
 
Table 1 
Acalabrutinib Dose Reduction Options ................................................... 42 
Table 2 
Dose Modifications for Hematologic Toxicities ...................................... 44 
Table 3 
Dose Modification Guidance for Grade 3 Non-hematologic 
Toxicities, Except Liver Dysfunction ...................................................... 45 
LIST OF FIGURES 
Figure 1 
Study Schema........................................................................................... 30 
 
LIST OF APPENDICES 
Appendix A: 
ECOG Performance Status Criteria ......................................................... 65 
Appendix B: 
New York Heart Association (NYHA) Classification of Cardiac 
Disease ..................................................................................................... 66 
Appendix C: 
Guidelines for Female Patients of Childbearing Potential and Fertile 
Male Patients ............................................................................................ 67 
Appendix D: 
Schedule of Assessments ......................................................................... 70 


 
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Appendix E 
RECIL 2017: Response Categories Based on Assessment of Target 
Lesions ..................................................................................................... 73 
Appendix F 
Response Designation Incorporating Best Response of Target 
Lesions and Nontarget Lesions ................................................................ 74 
Appendix G 
Cytochrome P450 3A4 Inhibitors and Inducers....................................... 75 
Appendix H 
Management of Acalabrutinib-Related Adverse Events .......................... 76 


 
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1. 
INTRODUCTION 
1.1 
Background 
Mantle cell lymphoma (MCL) is one of approximately 100 different types of non-Hodgkin’s 
lymphoma (NHL) and represents about 6% of new cases of NHL in the United States. Mantle 
cell lymphoma results from a malignant transformation of B lymphocytes in the outer edge of a 
lymph node follicle (the mantle zone). A minority of subjects (10% to 15%) are diagnosed with 
indolent disease and may not need therapy for several years; however, due to the aggressive and 
heterogeneous nature of MCL, the majority of subjects with MCL are diagnosed with advanced 
stage disease that requires immediate, diverse and aggressive courses of therapy to improve the 
outcome of the disease. 
Younger patients with MCL, those ≤65 years of age, are often treated with several rituximab plus 
chemotherapy combinations followed by a blood or bone marrow transplant (BMT). The 
addition of BMT to the treatment regimen is a critical factor to prolong the duration of first 
complete remission (CR1). There has been significant progress in the development of novel 
agents for MCL, including the recent approvals of acalabrutinib, bortezomib, lenalidomide, and 
ibrutinib. Unfortunately, MCL still remains an incurable disease and the benefit of combination 
chemotherapy followed by BMT, is often temporary as patients experience disease progression 
(PD) and mortality.  
This underscores the need for novel chemotherapy combinations as well as additional 
maintenance therapy strategies to prevent relapse post-BMT in patients with MCL.   
1.2 
Relevance of Minimal Residual Disease 
Traditionally, the most important predictor of long-term remission after treatment in patients has 
been the achievement of complete response (CR). However, with the use of more sensitive 
polymerase chain reaction (PCR)-based/analytical techniques such as flow cytometry and next 
generation sequencing (NGS), many patients who achieve CR are found to have low-level 
disease in the absence of clinical signs or symptoms. This is called minimal residual disease 
(MRD). Several studies have reported MRD as a stronger predictor of progression-free survival 
(PFS) and overall survival (OS) than conventional CR; therefore, new trial designs favor MRD 
negativity (MRD-) rate as the primary endpoint over conventional CR rates.   
In three published studies, MRD- rates post-transplant have been analyzed with significant 
results, ranging from 22% to 58% of MCL patients achieving MRD- status before transplant and 
improving to 53% to 93% MRD- status post-transplant (Brugger et al 2004, Armand et al 2016, 
Kolstad et al 2016). 
Given that several studies have now shown MRD status to be predictive of outcome across the 
board, MRD- is expected to become a key endpoint in future MCL trials (Eskelund et al 2016).  
1.3 
Maintenance Therapy for Mantle Cell Lymphoma 
Disease relapse is the number one cause of post-BMT therapy failure and mortality in subjects 
with MCL.  This presents the need for additional studies looking at the prevention of post-BMT 
therapy failure through novel maintenance strategies. Studies of rituximab maintenance have 
resulted in improved PFS and OS among subjects with MCL (Damon et al 2009, Dietrich et al 


 
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2014, Graf et al 2015, Kaplan et al 2015, Kaplan et al 2018, Le Gouill et al 2017). Dietrich et al 
report a median time from autologous stem cell transplant (autoSCT) to relapse of 20 months 
(range: 0.4 to 117 months) in patients who either underwent autoSCT as first-line therapy, 
received rituximab and high-dose ARA-C, or had refractory disease prior to autoSCT. In the 
relapse group, 33% experienced PD within the first year post-autoSCT, whereas only 6% of 
patients relapsed >5 years post-autoSCT.  Le Gouill et al. found that patients who received 
rituximab maintenance post-autologous transplant had a 4-year PFS rate of 83% (95% 
confidence interval [CI], 73 to 88) compared to 64% (95% CI, 55 to 73) in those who did not 
receive treatment post-transplant.  In a study by Damon et al 2009 analysing the Cancer and 
Leukemia Group B (CALGB) 59909 regimen of high-dose chemotherapy and autoSCT with 
rituximab maintenance for newly diagnosed MCL, the authors reported a 2-year PFS rate of 76% 
(95% CI, 64%-85%) and a 5-year PFS rate of 56% (95% CI, 43%-68%).  Utilizing the same 
CALGB 59909 treatment regimen of Damon et al, Kaplan et al randomized patients to receive 
either bortezomib maintenance (BM) or consolidation (BC) post-rituximab.  Median PFS was 
significantly greater than the null hypothesis (4 years) for both arms, with 5-year PFS rates of 
70% (55-81%) for BM and 69% (54-80%) for BC and 8-year PFS estimates of 77% (95% CI 66-
90%) for BM and 58% (95% CI 44-75%) for BC.  However, due to adverse events (AEs), BM is 
almost never used. 
Acalabrutinib is a novel Bruton’s tyrosine kinase (BTK) inhibitor that has shown positive results 
in lymphoma and may have fewer off-target effects compared to ibrutinib. Furthermore, 
acalabrutinib monotherapy increased PFS and OS in relapsed or refractory (R/R) MCL while 
maintaining a favorable safety profile (Wang et al 2018).  Therefore, given acalabrutinib’s 
increased efficacy compared to rituximab, acalabrutinib may prove to be a better maintenance 
therapy. 
1.4 
Acalabrutinib 
Acalabrutinib, a selective, irreversible small molecule inhibitor of BTK, is approved for the 
treatment of adult patients with MCL who have received at least 1 prior therapy. 
1.4.1 
Mechanism of Action 
Acalabrutinib inactivates BTK by forming a covalent bond with a cysteine residue in the kinase 
active site in vitro and in vivo.  This leads to inhibition of signaling through the B-cell receptor 
(BCR) in sensitive cells.  In nonclinical and clinical studies, acalabrutinib inhibited BTK-
mediated activation of downstream signaling proteins CD86 and CD69 and inhibited malignant 
B-cell proliferation and survival. 
Acalabrutinib shows encouraging activity, including improved selectivity for BTK compared to 
ibrutinib (Barf et al 2017, Byrd et al 2016) and an acceptable safety profile in nonclinical and 
clinical studies.  In addition, laboratory studies have shown that acalabrutinib and ACP-5862 (an 
acalabrutinib metabolite) have limited off-target kinase activity, with specific inhibition of only 2 
kinases (erb-b2 receptor tyrosine kinase 4 [ErbB4] and bone marrow tyrosine kinase gene in 
chromosome X [BMX]) at clinically relevant concentrations (Byrd et al 2016, Acalabrutinib IB, 
Armand et al 2016, Barf et al 2017).  The lack of activity against other Tec- and Src-family 
kinases may contribute to the safety and efficacy profile of acalabrutinib. 


 
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1.4.2 
Pharmacokinetics and Pharmacodynamics of Acalabrutinib 
Acalabrutinib has a short pharmacokinetic (PK) half-life with a long-lasting pharmacodynamic 
(PDc) effect due to covalent binding to BTK.  In a first-in-human (FIH) study in healthy 
subjects, acalabrutinib plasma time to maximum concentration (Tmax) values were between 0.5 
and 1.0 hour for all dose cohorts (2.5 mg twice daily [BID] to 100 mg once daily [QD]), and 
mean half-life ranged from 0.97 hours to 2.1 hours.  Acalabrutinib has an absolute oral 
bioavailability of 25%, is best taken with water, can be taken with or without food, and does not 
accumulate in plasma upon repeat-dose administration.  Based on population PK analysis, 
acalabrutinib PK was linear over the 75 to 250 mg dose range.  Variability in exposure to 
acalabrutinib is mainly due to a combination of gastric pH-dependent absorption and 
predominantly cytochrome P450 (CYP)3A mediated metabolism.   
Acalabrutinib is extensively and almost completely metabolized.  The most abundant circulating 
metabolite in humans was ACP-5862, which was formed by CYP3A-mediated oxidation and 
accounted for more than 10% of total acalabrutinib-related material.  Within the Tec family of 
kinases, activities of acalabrutinib and ACP-5862 were quite similar. 
ACP-5862 plasma area under the plasma-concentration time curve (AUC) was approximately 2- 
to 3-fold the AUC of acalabrutinib in healthy subjects, with a median half-life of 6.9 hours.  
Based on plasma profiling of radioactive metabolites, ACP-5862 exposure was higher in rats at a 
no observable adverse effect level (NOAEL) dose than in human subjects at a 100 mg dose.  
Excretion of [14C] acalabrutinib-related radioactivity was essentially complete by 48 to 96 hours 
post-dose, with predominantly biliary-fecal excretion in rats, dogs, and humans. 
Co-administration of acalabrutinib with strong inhibitors and strong inducers of CYP3A should 
be avoided; however, coadministration with grapefruit juice did not increase acalabrutinib 
exposure in healthy subjects.  Therapeutic and supratherapeutic plasma acalabrutinib 
concentrations did not prolong the corrected QT (QTc) interval in a thorough QT study. 
1.4.3 
Safety Pharmacology 
In vitro and in vivo safety pharmacology studies with acalabrutinib have demonstrated a 
favorable nonclinical safety profile. For detailed information on the safety pharmacology of 
acalabrutinib, refer to the acalabrutinib Investigator’s Brochure (IB) (Acalabrutinib IB).   
1.5 
Acalabrutinib Monotherapy in Mantle Cell Lymphoma 
As of 03 September 2017, acalabrutinib has been administered to over 2,000 subjects in clinical 
studies, including subjects with hematologic malignancies, solid tumors, or rheumatoid arthritis, 
and subjects who were healthy or had mild to moderate hepatic impairment. 
In a single-arm, Phase II study of 124 subjects with MCL who had relapsed after ≥1 (but not >5) 
prior treatment regimens, acalabrutinib (100 mg PO BID) demonstrated durable responses and an 
encouraging safety profile (Wang et al 2018). At a median follow-up of 15.2 months, 81% of 
subjects achieved an overall response: 40% achieved CR, and 41% achieved partial response 
(PR). The 12-month rates for duration of response, PFS, and OS were 72%, 67% and 87%, 
respectively. The estimated medians were not reached (Wang et al 2018).  
Nearly all subjects (98%) experienced AEs, the most frequently reported being: headache 
(37.9%), diarrhea (30.6%), fatigue (28.2%), cough (21.0%), and myalgia (21.0%).  Sixty-four 


 
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(51.6%) subjects had at least 1 Grade ≥3 AE.  The most frequently reported Grade ≥3 AEs were 
neutropenia (10.5%), anemia (8.9%), pneumonia (4.8%), thrombocytopenia (4.0%), and diarrhea 
(3.2%). Three (2.4%) subjects had one Grade 5 (fatal) AE each that included non-small cell lung 
cancer, pulmonary embolism and aortic stenosis.  All three Grade 5 events were considered not 
related to acalabrutinib. 
Serious AEs (SAEs) occurred in 52 (41.9%) subjects.  The most frequently reported SAEs were 
pneumonia (4.0%) and anemia (3.2%).  SAEs reported as related to acalabrutinib occurred in a 
total of 15 (12.1%) subjects, and included colitis and vomiting (2 subjects each).  Additional 
SAEs included headache, tumor lysis syndrome, interstitial lung disease, sepsis, anemia, 
leukostasis syndrome, respiratory syncytial virus infection, bacterial arthritis, abdominal pain, 
nausea, hematuria, acute coronary syndrome, B-cell lymphoma (verbatim term second 
malignancy of large B cell lymphoma), arthralgia, and pulmonary fibrosis (1 subject each).   
For more detailed information on the clinical experience with acalabrutinib, please refer to the 
acalabrutinib IB. 
1.6 
Rationale for the Study 
Minimal residual disease is the main cause of disease relapse and death post-BMT in subjects 
with MCL. Rituximab maintenance in subjects with MCL has demonstrated improved PFS and 
OS (Dietrich et al 2014, Graf et al 2015, Le Gouill et al 2017). However, acalabrutinib has 
demonstrated increased efficacy while maintaining a favorable safety profile in patients with R/R 
MCL. Therefore, we hypothesize that acalabrutinib will prove to be a more efficacious single 
agent for maintenance therapy.  
In this study, we propose the use of acalabrutinib 129 mg PO BID as maintenance therapy 
post-BMT to prolong PFS. Moreover, built-in assessments of MRD will determine its impact on 
achieving an MRD- status post-BMT and after maintenance therapy with acalabrutinib. 
2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to: 
• Determine the PFS rate of subjects who received at least one dose of acalabrutinib and 
are alive and free of PD or relapse 2 years post-BMT. 
2.2 
Secondary Objectives 
The secondary objectives of this study are to: 
• Define the conversion rate from minimal residual disease positive (MRD+) to MRD- 
during therapy for up to 2 years post-BMT. 
• Assess how MRD correlates with PFS 
• Assess the incidence of AEs 


 
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2.3 
Exploratory Objectives 
The exploratory objectives of this study are to: 
• Determine how mutations correlate with disease relapse using NGS. 
• Determine the MRD correlation of bone marrow compared to blood 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION 
3.1 
Inclusion Criteria for Initial Enrollment (Screening #1) 
Patients must meet all of the following criteria in order to be included in this research study: 
1. Written informed consent, according to local guidelines, signed by the subject or by a 
legal guardian prior to the performance of any study-related screening procedures. 
2. Men and women ≥18 years-of-age at the time of signature of the informed consent form 
(ICF). 
3. A diagnosis of MCL confirmed by one of the following: 
- t(11;14) detected by fluorescence in situ hybridization (FISH), conventional 
cytogenetics, or other molecular evaluation 
- expression of cyclin D1 confirmed by immunohistochemistry  
4. Subject must have completed induction chemotherapy and plan to and be eligible to 
receive their first BMT per standard of care. 
5. Availability of an archival paraffin-embedded tumor block for MRD testing. 
6. The Investigator anticipates that the subject will meet the appropriate lab requirements 
listed in Screening #2 by Day 100 
7. Patients who received prior therapy with a BTK inhibitor are eligible to enroll. 
3.2 
Inclusion Criteria Post-BMT, Prior to Day 100 (Screening #2) 
1. Adequate organ system function defined as: 
- Absolute neutrophil count (ANC) ≥1,000/mm3.  
- Platelet count ≥75,000/mm3.  Platelet infusions to meet eligibility criteria are not 
allowed within 3 days of study enrollment. 
- Calculated creatinine clearance (CrCl) ≥30 mL/min as calculated by the Cockcroft-
Gault method. 
Estimated CrCl (glomerular filtration rate [GFR]) = (140-age [years]) x (weight [kg]) x Fa 
(72 x serum creatinine [mg/dL]) 
a where F = 0.85 for females and F = 1 for males 
- Total bilirubin ≤1.5 x the upper limit of normal (ULN) (except for previously 
documented Gilbert’s syndrome) 
- Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 x ULN 


 
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2. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 
(Appendix A). 
3. Subjects who did not receive an anti-cancer therapy (including surgery, radiotherapy, 
chemotherapy, immunotherapy, or investigational therapy) during the time between their 
transplant and the start of study therapy.  Subjects must have recovered (e.g., Grade ≤1 or 
baseline) from AEs associated with prior cancer therapy.  Note:  Subjects with Grade ≤2 
neuropathy or Grade ≤2 alopecia are an exception to the latter criterion and may qualify 
for the study. 
4. Woman of childbearing potential (WoCBP) who are sexually active with male partners 
must use highly effective methods of contraception during treatment and for 2 days after 
the last dose of acalabrutinib.  For male subjects with a pregnant or non-pregnant 
WoCBP partner, no contraception measures are required.  A WoCBP must have a 
negative pregnancy test (urine or serum) at the time of screening and 72 hours before 
starting the study drug or have evidence of non-childbearing potential by fulfilling one of 
the following criteria: 
- Post-menopausal women, defined as either women aged >50 years and amenorrheic 
for ≥12 months following cessation of all exogenous hormonal treatments or women 
<50 years old who have been amenorrheic for ≥12 months following the cessation of 
exogenous hormonal treatments, and have serum follicle-stimulating hormone (FSH) 
and luteinizing hormone (LH) levels in the post-menopausal range for the institution. 
- Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy, but not tubal ligation. 
- Medically confirmed, irreversible premature ovarian failure. 
5. Willing and able to participate in all required evaluations and procedures in this study 
protocol including swallowing tablets without difficulty. 
6. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information (PHI). 
3.3 
Exclusion Criteria  
Patients who meet any of the following criteria will be excluded from study entry: 
1. Subjects who have relapsed or progressed at any time prior to BMT 
2. Subjects with known mutations that confer resistance to a BTK inhibitor. 
3. Confirmed clinical PD since the time of BMT  
4. Prior malignancy (or any other malignancy requiring active treatment), except for 
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other 
cancer from which the subject has been disease free for ≥2 years or that will not limit 
survival to <2 years. The exceptions are: 
- Subjects treated with curative intent >2 years prior to enrollment and have a low 
probability of recurrence. 


 
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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 (Appendix B). 
6. Malabsorption syndrome, disease significantly affecting gastrointestinal function, 
resection of the stomach or small bowel that is likely to affect absorption, symptomatic 
inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions 
and bariatric surgery, such as gastric bypass. 
7. Known history of infection with human immunodeficiency virus (HIV) or any 
uncontrolled active systemic bacterial, fungal, parasitic or viral infection.  Infections are 
considered controlled if appropriate therapy has been instituted and, at the time of 
screening, no signs of infection progression are present. 
8. Known history of drug-specific hypersensitivity or anaphylaxis to study drug (including 
active product or excipient components). 
9. Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand 
disease). 
10. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura. 
11. Requires treatment with a strong CYP3A4 inhibitor/inducer (Appendix G). 
12. Requires or is receiving anticoagulation treatment with warfarin or equivalent vitamin K 
antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug. 
13. Prothrombin time (PT)/international normalized ratio (INR) or activated partial 
thromboplastin time (aPTT) >2 x ULN (in the absence of lupus anticoagulant). 
14. History of significant cerebrovascular disease/event, including stroke or intracranial 
hemorrhage, within 6 months before the first dose of study drug. 
15. 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. 
16. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) 
positive and who are hepatitis B surface antigen (HbsAg) negative will need to have a 
negative PCR result.  Those who are 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. 
17. Breastfeeding or pregnant. 
18. Concurrent participation in another therapeutic clinical trial. 
19. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol and/or follow-up procedures outlined in the protocol. 
20. The inability to swallow tablets. 


 
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3.4 
Discontinuation from Study Drug 
Patients will be discontinued from the study drug for any of the following reasons: 
• 
PD 
• 
Completed treatment 
• 
Start of alternative anticancer therapy 
• 
Irreversible or intolerable toxicity or abnormal laboratory values thought to be related to 
drug toxicity 
• 
Conditions requiring therapeutic intervention not permitted by the protocol 
• 
Intercurrent illness (this will be at the Investigator’s discretion) 
• 
Inability of the patient to comply with study requirements 
• 
Patient requests to discontinue treatment 
• 
Patient withdraws consent from the study or study participation altogether 
• 
Patient lost to follow-up 
• 
Pregnancy  
• 
Study termination 
After discontinuation from protocol treatment, patients must be followed for AEs for 30 days 
after their last dose of study drug.  All new AEs occurring during this period must be reported 
and followed until resolution, unless, in the opinion of the Investigator, these values are not 
likely to improve because of the underlying disease.  In this case, the Investigator must record his 
or her reasoning for this decision in the patient’s medical records. 
All patients who have Grade 3 or 4 laboratory abnormalities (per National Cancer Institute  
Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 5.0) at the time of 
discontinuation must be followed until the laboratory values have returned to Grade 1 or 2, 
unless it is, in the opinion of the Investigator, not likely that these values are to improve.  In this 
case, the Investigator must record his or her reasoning for making this decision in the patient’s 
medical records. 
3.5 
Study-wide Stopping Rules 
If after 20 patients have been accrued to the study, 30% or more are unable to stay on 
acalabrutinib due to AEs, enrollment will be stopped, and a comprehensive review of safety will 
be performed by the study chair, primary investigators, and representatives of Acerta 
Pharma/AstraZeneca.  
4. 
STUDY REGISTRATION 
The patient must willingly consent to participate after being informed of the procedures to be 
followed, the experimental nature of the treatment, potential benefits, treatment alternatives, 
side-effects, risks, and discomforts.  Institutional Review Board (IRB) approval of this protocol 


 
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and any associated ICFs are required.  Eligible patients who wish to participate in the study will 
be enrolled into the study. 
Registration must occur prior to the initiation of protocol therapy.  Patients eligible to participate 
in the study may be enrolled by each site following the patient registration instructions provided 
by the Sarah Cannon Development Innovations (Innovations) study contact.  Patient registration 
follow-up and/or confirmation will be provided via email within approximately 24 hours or by 
the next business day. 
5. 
STUDY DESIGN 
This is a single arm, multi-center, Phase II study of subjects with MCL who will receive 
acalabrutinib as maintenance therapy post-BMT.  In general, subjects will provide informed 
consent prior to BMT to collect the required central labs. However, a limited number of subjects 
may be allowed to provide informed consent following BMT, determined on a case-by-case basis 
by the Principal Investigator (PI).  In this event, any of the study assessments required prior to 
BMT not performed for standard of care will not be required.  
Subjects will undergo a standard of care BMT with conditioning regimen determined by the 
treating physician per institutional guidelines.  The BMT is not considered part of this study.  
Following completion of the BMT, a second screening will begin between Day 80 and Day 100. 
Maintenance therapy with acalabrutinib will begin on Day 100 in 28-day cycles. Subjects will 
self-administer 129 mg acalabrutinib BID until they reach 2 years post-BMT (approximately 
22 cycles).  Subjects who experience PD while on study will be encouraged to provide a fresh 
biopsy to assess lymphoma genome alterations. All subjects will be followed for up to 5 years 
post-BMT for PFS.  
Approximately 50 subjects are planned to be enrolled after receiving BMT.  


 
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Figure 1 
Study Schema 
 
Subjects will self-administer acalabrutinib 129 mg BID on a 28-day cycle. 
Abbreviations: BM, bone marrow; BMT, blood or marrow transplant; MRD, minimal residual disease; 
SOC, standard-of-care. 
5.1 
Treatment Plan 
In this clinical trial, the study drug only refers to acalabrutinib. The BMT is a non-investigational 
medicinal product and is not the study drug.  
Acalabrutinib 129 mg will be self-administered orally BID on a 28-day schedule, with or without 
food, until the patient has reached approximately 2 years post-BMT.   
Acalabrutinib will be administered until PD, unacceptable toxicity, or the subject discontinues 
treatment for any other reason. 
5.2 
Concomitant Medications 
Patients will be instructed not to take any additional medications during the course of the study 
without prior consultation with the research team.  At each visit, the patient will be asked about 
any new medications he/she is taking or has taken after the start of the study drug. 
5.2.1 Permitted Concomitant Medications 
Standard post-BMT therapy is permitted and encouraged.  Prophylaxes for pneumocystis 
jirovecii pneumonia (PJP) and herpes simplex/varicella zoster viruses (HSV/VZU) are 
recommended for 6 months and 1 year, respectively.  Antiemetics are permitted if clinically 
indicated.  Supportive medications in accordance with standard practice are permitted (such as 
for emesis, diarrhea, and nausea [Appendix H]).   
Use of granulocyte growth factors (filgrastim and pegfilgrastim) or red blood cell growth factors 
(erythropoietin) are permitted per institutional policy and in accordance with the American 
Society of Clinical Oncology (ASCO) guidelines (Smith et al 2006, Smith et al 2015).  Blood 
and platelet transfusions may be given in accordance with institutional policy. 
For subjects at risk for infectious pneumonitis based on prior history or comorbid 
conditions:   
Infection control should be considered for select subjects (e.g., those with a history of recurrent 
pneumonias). Initiation of antibiotic prophylaxis against pneumocystis infection (e.g., with 
trimethoprim-sulfamethoxazole, dapsone, aerosolized pentamidine, or atovaquone) beginning 
before study drug administration may be warranted.  Such support may also offer the benefit of 


 
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reducing the risk for other bacterial infections (Stern et al 2014).  Prophylaxis with intravenous 
immunoglobulins (IVIG) may be appropriate in subjects with low immunoglobulin levels 
(Raanani et al 2009).  Local practices or guidelines regarding infection prophylaxis may be 
followed.   
For infections:   
Bacterial/viral/fungal prophylaxis is allowed per institutional standards (see Appendix H). 
5.2.2 Prohibited or Restricted Concomitant Medications 
The following treatments are prohibited during the treatment period of the study: 
• Any chemotherapy, anticancer immunotherapy, experimental therapy, radiotherapy, 
warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon), or corticosteroids (at 
dosages equivalent to prednisone >20 mg/day for longer than 2 weeks) are prohibited. 
• The concomitant use of strong inhibitors/inducers of CYP3A4 (Appendix G) should be 
avoided when possible (Section 5.3).  If a subject requires a strong CYP3A inhibitor while 
on study, monitor the subject closely for potential toxicities.  For additional information on 
drugs with potential drug-drug interactions, refer to Section 5.3. 
• At study entry, subjects may be using topical or inhaled corticosteroids or low-dose 
steroids (≤10 mg of prednisone or equivalent per day) as therapy for comorbid conditions, 
but use of corticosteroids as therapy for the lymphoid cancer, other than palliative, is not 
permitted.  During study participation, subjects may also receive corticosteroids at any 
required dosage as needed for treatment-emergent adverse events (TEAEs). 
5.3 
Drug-Drug Interactions 
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 increases exposure by 
approximately 5-fold.  Conversely, concomitant administration of acalabrutinib with a strong 
CYP3A inducer, rifampin, decreases acalabrutinib exposure and could reduce efficacy.  
Consequently, the concomitant use of strong inhibitors/inducers of CYP3A (Appendix G) 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 inhibitor or inducer while on study, 
monitor the subject closely for potential drug-related toxicities.    
5.4 
Exploratory Correlatives  
Testing for circulating tumor DNA (ctDNA), lymphoma biopsies, and exploratory blood samples 
may be performed to evaluate MRD and lymphoma genome alterations. 
Adaptive Biotechnologies will perform the MRD analysis to investigate potential changes in 
MRD status (MRD+ to MRD-) in response to acalabrutinib therapy as well as MRD correlations 
to bone marrow (BM) compared to whole blood as outlined in Section 6.5.12. 


 
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6. 
STUDY ASSESSMENTS AND EVALUATIONS 
6.1 
Overview 
All patients should visit the study center on the days specified within this protocol.  The 
complete Schedule of Assessments for this study is presented in Appendix D. 
6.2 
Baseline Study Assessments, Screening #1 Prior to BMT 
The following information will be collected and procedures will be performed for each patient at 
a baseline study assessment. This screening assessment will take place following written 
informed consent (see Section 13.3) and within 3 days prior to taking the study drug.  
• Medical history and demographics 
• Physical examination (including height [screening only] and weight) 
• Serum or urine pregnancy test for women of child-bearing potential (WoCBP) 
• Archival lymphoma sample collection 
6.3 
Baseline Study Assessments, Screening #2 Post-BMT – Day 80 to Day 100 
• Physical examination (including weight) 
• ECOG performance status 
• Vital signs (pulse, blood pressure, oxygen saturation, and body temperature) 
• 12-lead electrocardiogram (ECG) 
• Complete blood count (CBC), clinical chemistry panel, and coagulation testing 
• Urinalysis 
• Serum or urine pregnancy test for WoCBP 
• Screening for HIV, Hepatitis B (HBV) and Hepatitis C (HCV) viruses (see Section 3.3 
[exclusion criteria #7 and #17)  
• Archival lymphoma biopsy collection, if not collected during Screening #1 
• Blood sample collection and bone marrow aspirate for MRD analysis  
• Computed tomography (CT)/ magnetic resonance imaging (MRI)/ positron emission 
tomography (PET) scans 
• Concomitant medication review and AE evaluation 
6.4 
Study Assessment Timing 
The maintenance treatment period begins on the day the patient receives the first administration 
of acalabrutinib (Day 100).  Dates for study visits and assessments will be determined based 
upon the first day after the BMT and should occur based on the timing parameters outlined in 
this protocol.   


 
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6.4.1 
Cycle 1, Days 1 and 15 (~ 4 months post-BMT) 
• Physical examination and vital signs (including weight) 
• ECOG performance status 
• CBC and clinical chemistry panel 
• Concomitant medication review and AE monitoring 
• Treatment with acalabrutinib 129 mg PO BID 
6.4.2 
Cycles 2-6, Day 1 (~ 5-9 months post-BMT) 
• Physical examination and vital signs (including weight) 
• ECOG performance status 
• CBC and clinical chemistry panel 
• Screening for viruses (see Section 6.5.6) 
• Blood sample collection for MRD analysis 
• CT/MRI/PET scans (6 months post-BMT) 
• Treatment with acalabrutinib 129 mg PO BID 
• Concomitant medication review and AE monitoring 
6.4.3 
Cycles 7-12, Day 1 (~ 10-15 months post-BMT) 
• Physical examination and vital signs (including weight) 
• ECOG performance status 
• CBC and clinical chemistry panel 
• Screening for viruses (see Section 6.5.6) 
• Blood sample collection and bone marrow aspirate for MRD analysis 
• CT/MRI/PET scans (12 months post-BMT) 
• Treatment with acalabrutinib 129 mg PO BID 
• Concomitant medication review and AE monitoring 
6.4.4 
Cycle 13 and Beyond, Day 1 (≥16 months post-BMT) 
• Physical examination and vital signs (including weight) 
• ECOG performance status 
• CBC and clinical chemistry panel 
• Screening for viruses (see Section 6.5.6) 
• Blood sample collection for MRD analysis 


 
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• CT/MRI/PET scans (18 and 24 months post-BMT) 
• Treatment with acalabrutinib 129 mg PO BID 
• Concomitant medication review and AE monitoring 
6.4.5 
End of Treatment/Early Termination Visit 
Please refer to Section 3.4 for the reasons for study drug discontinuation/early termination.  If 
either the study drug or observations are discontinued, the reason will be recorded in the 
electronic case report form (eCRF) and source document. Patients who complete or discontinue 
the study drug should have the following evaluations performed as soon as possible.  
• Screening for viruses (see Section 6.5.6) 
• Fresh lymphoma biopsy (at PD) 
• Concomitant medication review and AE monitoring 
Patients prematurely discontinuing from the study drug must be followed for AEs and 
concomitant medication use for 30 days following the last administration of study drug or until 
resolution/stabilization of any ongoing AEs attributed to the medication.  
Patients who discontinue from the study drug may be treated with other therapies at the 
discretion of the Investigator. 
6.4.6 
Long-Term Follow-up/End of study  
At 2 years post-BMT, a follow-up visit will be performed for all MRD- and MRD+ subjects every 
3 months until the time of PD, death, withdrawal of consent, start of another anticancer therapy, 
the study is terminated, or the 5-year post-BMT time point is reached. The following procedures 
and tests will be done at each follow-up visit: 
• Fresh lymphoma biopsy (at PD) 
• PFS status 
6.5 
Study Assessments 
6.5.1 Medical History and Demographics 
A complete medical history will be taken.  Information to be documented includes 
demographics, prior medical illnesses and conditions, prior surgical procedures, date and stage of 
original diagnosis and details of prior chemotherapy/radiotherapy administered and other 
treatments for cancer (including type of drugs, dosages, schedule or administration, response and 
response duration) and Mantle Cell Lymphoma International Prognostic Index (MIPI). 
Concurrent medical signs and symptoms must be documented to establish baseline severities. 
6.5.2 Physical Examinations (Including Performance Scale and Vital Signs) 
A complete physical examination will be done at baseline, at each visit, at the end-of-treatment 
visit, and long-term follow-up visit as well as at the discretion of the Investigator.  Examinations 
will include documentation of height (at screening only), weight, vital signs, and ECOG 


 
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performance status (Appendix A).  Any abnormal or clinically significant findings from the 
physical examination must be recorded on the appropriate eCRF page. 
6.5.3 12-Lead Electrocardiogram 
ECGs will be done according to Appendix D and at the discretion of the Investigator.  Each will 
be performed with the patient in a supine position having rested in this position for at least 10 
minutes before the reading. 
6.5.4 Pregnancy Testing 
In WoCBP, a serum beta human chorionic gonadotropin or urine pregnancy test must be 
performed at the time of screening and 72 hours prior to the start of treatment.   
6.5.5 Laboratory Assessments 
Laboratory samples (CBC, clinical chemistry, urinalysis, and virology) are to be collected as 
outlined in Appendix D.  Laboratory results will be graded using NCI CTCAE Version 5.0. 
Hematology studies must include CBC with differential including, but not limited to, white 
blood cell count, hemoglobin, hematocrit, platelet count, ANC, and absolute lymphocyte count. 
Coagulation testing will include PT/INR or aPTT. 
Serum chemistry will include albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood urea 
nitrogen (BUN), calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), 
magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin, total protein, and uric 
acid.   
If an unscheduled ECG is done at any time, then an electrolyte panel (e.g., calcium, magnesium, 
and potassium) must be done to coincide with the ECG testing. 
A urinalysis will include pH, ketones, specific gravity, bilirubin, protein, blood and glucose. 
6.5.6 HIV and Hepatitis B and C Testing 
Patients with a known history of HIV or who are HIV antibody positive should be tested for HIV 
ribonucleic acid (RNA) during screening. No further testing beyond screening is necessary if 
PCR results are negative, except if clinically indicated. 
Patients who are anti-HBc positive, or have a known history of HBV, should have quantitative 
PCR testing for HBV DNA performed during screening and every 3 months thereafter.  
Monitoring (every 3 months) should continue until 12 months after last dose of acalabrutinib.  
Any patient with a rising viral load (above lower limit of detection) should discontinue 
acalabrutinib and have antiviral therapy instituted and a consultation with a physician with 
expertise in managing hepatitis B.  As IVIG may cause false positive hepatitis serology, monthly 
PCR testing is not required in patients who are currently receiving or received prophylactic IVIG 
within 3 months before study enrollment and have a documented negative anti-HBc test before 
the initiation of IVIG therapy.  PCR testing should be performed when clinically indicated (e.g., 
in the setting of rising transaminase levels).  
Patients with a known history of HCV or who are hepatitis C antibody positive should be tested 
for HCV RNA during screening.  No further testing beyond screening is necessary if PCR results 
are negative, except if clinically indicated. 


 
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6.5.7 Clonality (ID) Sample 
The clonoSEQ Clonality (ID) Test determines the clonal diversity of a sample and can also be 
used to identify the trackable immune receptor sequence(s) of a lymphoid clone.  Please ensure 
slide box and individual slides are each labeled with Subject ID and Collection Date. 
Details of sample collection, processing, shipping, and storage will be described in the laboratory 
manual. 
6.5.8 
Tracking (MRD) Sample 
The clonoSEQ Tracking (MRD) Test uses follow-up samples for the purposes of following the 
immune receptor sequence(s) identified by the clonoSEQ Clonality (ID) Test.  Please ensure 
individual samples are labeled with Subject ID and Collection Date. 
Details of sample collection, processing, shipping, and storage will be described in the laboratory 
manual. 
6.5.9 Fresh Lymphoma Biopsy Sample 
When feasible, collection of a lymphoma biopsy at relapse is encouraged, but will not be 
considered a protocol deviation if the patient withdraws consent.  This sample will be used to 
investigate changes in pathway signaling and potential mechanisms of resistance (i.e., genetic 
alterations or evidence of alternative pathway activation).  For this reason, a relapse lymphoma 
biopsy is encouraged in patients who achieve an objective response to the study drug, but later 
relapse. 
All fresh lymphoma biopsies will be formalin-fixed and paraffin-embedded slides.  Failure to 
obtain a sufficient lymphoma sample after making best efforts to biopsy the lymphoma will not 
be considered a protocol deviation. 
If additional lymphoma molecular profiling is required to further understand any response to the 
study drug, the Sponsor may request a sample of the most recent lymphoma biopsy for additional 
research. 
The results of this exploratory research will be reported separately and will not form part of the 
clinical study report (CSR). 
Details of sample collection, processing, shipping, and storage will be described in the laboratory 
manual. 
6.5.10 Response and Activity Assessments 
See Section 6.5.12, Section 6.5.13 and Section 9. 
6.5.11 Adverse Event Assessments  
Information regarding the occurrence of AEs, including infections, will be collected from the 
time the patient signs the ICF throughout their participation in the study, including a period of 
30 days after the last dose of study drug.  Adverse event severity will be determined using the 
CTCAE Version 5.0 grading scale. See Section 11 for more details. 


 
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6.5.12 Prior and Concomitant Medications 
All concomitant medications are to be collected and recorded from the time the patient signs the 
ICF throughout the patient’s participation in the study.  
6.5.13 Minimal Residual Disease Assessment 
Adaptive Biotechnologies will use the clonoSEQ® assay to investigate potential changes in 
MRD status (MRD+ to MRD-) in response to acalabrutinib therapy.  Bone marrow aspirate will 
be collected at Day +100 (Screening #2) and 1 year post-BMT (~Cycle 10 Day 1).  Blood 
samples will be collected at Day +100 (Screening #2), 6 months (~Cycle 4 Day 1), 1 year 
(~Cycle 10 Day 1) and 2 years post-BMT (~Cycle 22 Day 1). For time points where both blood 
and BM are tested, if a patient has an MRD+ result from either sample source (blood or BM), 
then the patient is considered MRD+. If the limit of detection and the limit of quantitation are not 
met and the MRD results are indeterminate, indicating an inadequate sample was used, then the 
patient will have a follow-up test performed at the discretion of the Investigator 
(see Section 9.3).  
Next-generation sequencing (NGS) will be conducted on all bone marrow and blood samples. 
6.5.14 Radiologic Assessments 
Response assessments will be evaluated based on recent International Working Group consensus 
criteria Response Evaluation Criteria in Lymphoma (RECIL 2017) (Younes et al 2017), outlined 
in Appendix E and Appendix F. 
Tumor assessments will be performed using radiologic imaging by CT scan with contrast 
covering neck, chest, abdomen, and pelvis and [18F]2-fluoro-2-deoxy-D-glucose-positron 
emission tomography (FDG-PET) scan covering from base of skull to mid-thigh within 28 days 
before the first dose of study drug and as outlined in Appendix D.  In certain cases, 
measurements may be performed on the CT component of a combined PET-CT image, provided 
that is of adequate resolution.  In the latter instance, approval by the sponsor is required. 
Magnetic resonance imaging (MRI) may be used for imaging assessments if a contrast CT scan 
is contraindicated or undesirable.  In cases where MRI is desirable, the MRI must be obtained at 
baseline and at all subsequent response evaluations. 
CT/MRI measurements 
Assessment of tumor burden will use the sum of the longest diameters.  In subjects with 
disseminated disease, a maximum of 3 target lesions should be selected to estimate tumor 
response.   
Target lesions should be selected per the following: 
• They should be selected from those of the largest size that can be measured reproducibly 
and preferably representing multiple sites and organs. 
• Lymph nodes: 
- Lymph nodes can be considered target lesions if the lymph node longest diameter 
measures ≥15 mm. 


 
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- A lymph node measuring between 10 and 14 mm is considered abnormal but should 
not be selected as a target lesion. 
- Lymph nodes measuring <10 mm in diameter are considered normal and cannot be 
used as target lesions. 
- In certain anatomical sites (inguinal, axillary, and portacaval), normal lymph nodes 
may exist in a narrow, elongated form, and such nodes should not be selected as 
target lesions if alternatives are available. 
• Extranodal lesions can be selected as target lesions if they have a soft tissue component, 
based on their size and the ease of reproducibility of repeated measurements, with a 
minimum measurement of the longest diameter of ≥15 mm. 
• Nontarget lesions: 
- All other lesions should be identified as nontarget lesions and should be recorded at 
baseline, without the need to measure them. 
- Nontarget lesions should be followed and reported as present, absent, or clear 
progression. 
FDG-PET measurements 
Scoring is semi-quantitative using the Deauville 5-point scale (Deauville 5PS).  It is a simple tool 
based on visual interpretation of [18F]2-fluoro-2-deoxy-D-glucose (FDG) uptake.  It takes 
advantage of two reference points on the individual subject which have demonstrated relatively 
constant uptake on serial imaging.  The two reference organs are the mediastinum and the liver.  
The scale ranges from 1 to 5, where 1 is “no FDG uptake” and 5 is “markedly increased FDG 
uptake”.  Each FDG-avid (or previously FDG-avid) lesion is rated independently. 
1. No uptake or no residual uptake (when used interim)  
2. Slight uptake, but below blood pool (mediastinum)  
3. Uptake above mediastinal, but below or equal to uptake in the liver 
4. Uptake slightly to moderately higher than liver 
5. Markedly increased uptake or any new lesion (on response evaluation) 


 
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7. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION 
7.1 
Acalabrutinib 
Investigational Product 
Dosage Form and Strength 
Manufacturer 
Acalabrutinib 
129 mg tablets 
Acerta Pharma 
7.2 
Acalabrutinib Treatment Duration 
Acalabrutinib tablets will be self-administered BID approximately every 12 hours.  The tablets 
should be swallowed intact with approximately 1 cup of water.  Patients should not chew the 
tablets and should try to swallow tablets whole.  
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 
patient 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. 
7.2.1 Labeling, Packaging, and Supply of Acalabrutinib 
The investigational product, acalabrutinib maleate tablet, is supplied as an orange film-coated 
tablet containing 129 mg of acalabrutinib maleate (equivalent to 100 mg of acalabrutinib) drug 
substance.   
Each tablet also contains the following compendial inactive ingredients: mannitol, 
microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and sodium stearyl 
fumarate.  The tablet coating contains hypromellose, copovidone, titanium dioxide, polyethylene 
glycol, caprylic/capric triglyceride, yellow iron oxide, and red iron oxide.  
Acalabrutinib maleate tablets are packed in white, high-density polyethylene (HDPE) bottles 
containing a silica gel desiccant and should be stored according to the storage conditions as 
indicated on the label. The recommended storage condition for acalabrutinib maleate tablets is 
below 30°C (86°F). 
Study drug will arrive commercially labeled as CALQUENCE®.  Innovations will affix labels 
reading “LYM 155 – For Investigational Use Only” before distribution.  
7.3 
Accountability for the Study Drug 
The PI (or designee) is responsible for accountability of all used and unused study drug supplies 
at the site.  Innovations representatives must be granted access on reasonable request to check 
drug storage, dispensing procedures, and accountability records. 
All study drug inventories must be made available for inspection by Innovations or its 
representatives and regulatory agency inspectors upon request. 
Throughout the study and at its completion, Innovations Drug Accountability Record Form(s) 
will be completed by the site and sent to the Innovations Regulatory Department.  Study drug 
supplies must not be destroyed unless prior approval has been granted by Innovations.  Please 
contact Innovations regarding disposal of any study drug. 


 
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7.4 
Assuring Subject Compliance 
Most acalabrutinib doses will be taken by the subjects at home.  Therefore, subjects will receive 
an acalabrutinib drug diary to record the specific time each dose was taken and to record reasons 
for any missed doses.  Subject compliance with acalabrutinib dosing will be assessed at every 
visit and recorded in the eCRF.  The subject will be instructed to bring the diary and any 
remaining tablets to the clinic at his/her next visit.  The study staff will review the diary and ask 
the subject if all the tablets were administered.  Any remaining or returned tablets will be 
counted and documented.  Returned tablets must not be redispensed to another subject.  The 
investigational products should only be used as directed in this protocol and as detailed in the 
pharmacy manual and handling instructions.  
The study personnel at the investigational site will account for all drugs dispensed and for 
appropriate destruction or return of unused drugs to the sponsor or designee.  All study supplies 
and associated documentation will be regularly reviewed and verified by the Site Monitor before 
destruction or return to the sponsor or designee.  Certificates of delivery and destruction/return 
should be signed and copies must be retained by the sponsor. 
7.5 
Toxicity of Study Drug and Study Regimen 
7.5.1 Precautions and Risks Associated with Acalabrutinib 
7.5.1.1 
Hemorrhage 
Hemorrhagic events, including central nervous system, respiratory, and gastrointestinal 
hemorrhages, have been reported in clinical trials with acalabrutinib.  Some of these bleeding 
events resulted in fatal outcomes.   
The mechanism for hemorrhage is not well understood. Subjects receiving antiplatelet or 
anticoagulant therapies may be at increased risk of hemorrhage and should be monitored for 
signs of bleeding.  Consider the benefit-risk of withholding acalabrutinib for at least 3 days pre- 
and post-surgery. Subjects with haemorrhage should be managed per institutional guidelines with 
supportive care and diagnostic evaluations as clinically indicated. 
7.5.1.2 
Infection 
Serious infections, including fatal events, 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 HBV reactivation (resulting in liver failure and death in 
1 case) and cases of progressive multifocal leukoencephalopathy (PML) have occurred in 
subjects with hematologic malignancies. 
Subjects should be monitored for signs and symptoms of infections and treated as medically 
appropriate. Subjects with infection events should be managed according to institutional 
guidelines with maximal supportive care and diagnostic evaluations as clinically indicated. 
7.5.1.3 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias including neutropenia, anemia, and 
thrombocytopenia have occurred in clinical studies with acalabrutinib.  Monitor blood counts as 
medically appropriate. 


 
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7.5.1.4 
Second Primary Malignancies 
Events of second primary malignancies, including non-skin carcinomas, have been reported in 
clinical studies with acalabrutinib.  The most frequently reported second primary malignancy 
was skin cancer.   
Subjects with a second primary malignancy should be managed according to institutional 
guidelines with maximal supportive and therapeutic care and diagnostic evaluations as clinically 
indicated. 
7.5.1.5 
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. 
Subjects with atrial fibrillation should be managed per institutional guidelines with supportive 
care and diagnostic evaluations as clinically indicated. 
7.5.1.6 
Overdose 
Clinical information relevant to overdose is not available.  For results from nonclinical overdose 
studies in rats and dogs, please refer to the IB. 
In the event of subject ingestion of more than the recommended acalabrutinib dosage, the subject 
should be observed for any symptomatic side effects, and vital signs and biochemical and 
hematologic parameters should be followed closely (consistent with the protocol or more 
frequently, as needed).  Appropriate supportive management to mitigate adverse effects should 
be initiated.  If the overdose ingestion of acalabrutinib is recent and substantial, and if there are 
no medical contraindications, use of gastric lavage or induction of emesis may be considered. 
7.5.1.7 
Pregnancy, Breastfeeding, and Contraception 
In acalabrutinib nonclinical reproductive toxicity studies, including definitive embryo-fetal 
development studies, oral acalabrutinib at ≥100 mg/kg/day produced maternal toxicity, and at 
100 mg/kg/day resulted in decreased fetal body weights and delayed skeletal ossification in 
rabbits. Please refer to the current acalabrutinib IB for further details. 
There has been one reported pregnancy in a subject exposed to acalabrutinib, in which the 
subject was exposed during the first trimester. Acalabrutinib was discontinued, and the subject 
gave birth to a live, full term male infant by Caesarean section. 
The potential for acalabrutinib to be excreted in breast milk of nursing mothers is unknown. In 
studies of lactating rats, acalabrutinib and its metabolite ACP-5862 were measured in milk and in 
the plasma of nursing pups on postnatal Day 12. 
There have been no positive genotoxicity findings during development of acalabrutinib. 
Additionally, based on modeled estimates of fetal exposures to active product ingredient levels in 
ejaculated material using assumptions for small molecules, direct embryofetal exposure (i.e., 
female partner exposure following a vaginal dose of estimated seminal concentration) and male-
mediated developmental risk with acalabrutinib treatment is considered to be very low, and risk 


 
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mitigation measures for male-mediated developmental risk are therefore not required for 
acalabrutinib. 
For further guidance and definitions, see Appendix C. 
8. 
DOSE MODIFICATIONS 
If toxicity occurs, the toxicity will be graded using the NCI CTCAE Version 5, and appropriate 
supportive care treatment will be administered to decrease the signs and symptoms thereof. Dose 
adjustments will be based on the organ system exhibiting the greatest degree of toxicity. 
8.1 
Criteria and Procedures for Dose Interruptions and Adjustments of 
Acalabrutinib 
Subjects should be followed closely for AEs or laboratory abnormalities that might indicate 
acalabrutinib-related toxicity.  If a subject experiences a treatment-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 TEAEs are provided in Table 1. 
• Grade 4 neutropenia (<500/μL) for >7 days (neutrophil growth factors are permitted per 
ASCO guidelines [Smith et al 2006, Smith et al 2015] and use must be recorded on the 
eCRF) 
• Grade 3 thrombocytopenia (<50,000/μL) in the presence of significant bleeding. 
• Grade 4 thrombocytopenia (<25,000/μL) 
• Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal antiemetic and/or 
anti-diarrheal therapy 
• Any other Grade 4 AE or unmanageable Grade 3 AE 
Table 1 
Acalabrutinib Dose Reduction Options 
Starting Dose 
1st Dose Reduction 
2nd Dose Reduction 
129 mg BID 
129 mg QD 
discontinue 
Temporarily withholding acalabrutinib for as little as 7 days can cause a transient worsening of 
disease and/or of constitutional symptoms.  Transient worsening of disease during temporary 
interruption of study therapy (e.g. for drug-related toxicity, surgery, or intercurrent illness) may 
not indicate PD.  In such circumstances, and if medically appropriate, following discussion with 
the Medical Monitor, subjects may resume therapy and relevant clinical, laboratory, and/or 
radiologic assessments should be done to document whether lymphoma control can be 
maintained or whether actual PD has occurred. 
As appropriate, certain laboratory abnormalities may warrant more frequent monitoring (i.e., 
once per week) until abnormalities have recovered to Grade ≤1.  If acalabrutinib is reduced for 
apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or 


 
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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 PI.  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 129 mg BID. 
Treatment with acalabrutinib should be withheld for any unmanageable, potentially study drug-
related toxicity that is Grade ≥3 in severity.  Any other clinically important events where dose 
delays may be considered appropriate must be discussed with the PI. 
8.2 
Dose Modifications for Hematologic Toxicities 
If the acalabrutinib dose should be reduced and the subject is receiving acalabrutinib 129 mg 
QD, acalabrutinib should be discontinued.  Refer to Table 2 for dose modifications due to 
hematologic toxicities. 


 
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Table 2 
Dose Modifications for Hematologic Toxicities 
NCI CTCAE Grade 
Acalabrutinib Action 
Febrile neutropenia Grade 3 or 4 
Withhold acalabrutinib until infection is resolved, 
antibiotics no longer required and ANC Grade ≤2 or 
baseline. Then, restart acalabrutinib at the same dose. 
2nd episode: febrile neutropenia 
Grade 3 or 4 
Withhold acalabrutinib until infection is resolved, 
antibiotics no longer required and ANC Grade ≤2 or 
baseline. Then, restart acalabrutinib with 1 level dose 
reduction or discontinue (Table 1). 
3rd episode: febrile neutropenia 
Grade 3 or 4 
Discontinue acalabrutinib 
 
 
Neutrophil count decrease Grade 4 
lasting >7 days despite growth factor 
support 
Withhold acalabrutinib until Grade ≤2 or baseline. Then, 
restart acalabrutinib at the same dose. 
2nd episode: neutrophil count 
decrease Grade 4 lasting >7 days 
despite growth factor support 
Withhold acalabrutinib until Grade ≤2 or baseline. Then, 
restart acalabrutinib with 1 level dose reduction or 
discontinue (Table 1). 
3rd episode: neutrophil count 
decrease Grade 4 lasting >7 days 
despite growth factor support 
Discontinue acalabrutinib 
 
 
Platelet count decrease Grade 4 
without bleeding requiring blood or 
platelet transfusion 
Withhold acalabrutinib until Grade ≤2 or baseline. Then, 
restart acalabrutinib at the same dose (Table 1). 
2nd episode: platelet count decrease 
Grade 4 without bleeding requiring 
blood or platelet transfusion 
Withhold acalabrutinib until Grade ≤2 or baseline. Then, 
restart acalabrutinib with 1 level dose reduction or 
discontinue (Table 1). 
3rd episode: platelet count decrease 
Grade 4 without bleeding requiring 
blood or platelet transfusion 
Discontinue acalabrutinib 
 
 
Platelet count decrease Grade 3 or 4 
with bleeding requiring blood or 
platelet transfusion 
Withhold acalabrutinib until Grade ≤2 or baseline. Then, 
restart acalabrutinib with 1 level dose reduction or 
discontinue (Table 1). 
2nd episode: platelet count decrease 
Grade 3 or 4 with bleeding requiring 
blood or platelet transfusion 
Discontinue acalabrutinib 
 


 
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8.3 
Dose Modifications for Non-hematologic Toxicities 
In case of Grade 4 treatment-related non-hematologic toxicity, discontinue acalabrutinib. 
Grade 3 toxicities require dose modifications, temporary treatment interruptions or 
discontinuation of acalabrutinib (Table 3). 
Table 3 
Dose Modification Guidance for Grade 3 Non-hematologic Toxicities, Except 
Liver Dysfunction 
Occurrence 
Acalabrutinib Action 
First 
Withhold acalabrutinib until recovery to Grade ≤2 or baseline. Then, restart acalabrutinib at 
the same dose (Table 1). 
Second 
Withhold acalabrutinib until recovery to Grade ≤2 or baseline. Then, restart acalabrutinib 
with 1 level dose reduction or discontinue (Table 1). 
Third 
Withhold acalabrutinib until recovery to Grade ≤2 or baseline. Then, restart acalabrutinib 
with 1 level dose reduction or discontinue (Table 1). 
 
8.4 
Management of Acalabrutinib-Related Adverse Events 
Management for acalabrutinib-related AEs are located in Appendix H. 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS 
9.1 
Progression-free Survival 
Progression-free survival is defined as the time from Day 0 of BMT until the date of objective 
radiological PD according to RECIL or death (by any cause in the absence of PD).  Patients who 
are alive and free from PD will be censored at the date of last tumor assessment.  Patients who 
begin subsequent therapy prior to PD or death will be censored at the date of last tumor 
assessment prior to the start of subsequent therapy.   
9.2 
Complete Response 
Any RECIL assessments determined to be a CR will be confirmed by no morphologic, 
immunohistochemical, or flow cytometric evidence of disease by BM biopsy or aspirate 
(Brugger et al 2004).  
9.3 
Minimal Residual Disease 
Minimal residual disease (MRD) is defined as the minimal traceable persistence of lymphoma 
after treatment with acalabrutinib. The clonoSEQ® assay, developed by Adaptive 
Biotechnologies, is an NGS-based immunosequencing platform that will be used for the 
detection, quantification and analysis of MRD. The assay uses multiplex PCR, high throughput 
sequencing and a proprietary algorithm for evaluating lymphoid clonal distribution and 
expansions in genomic DNA. MRD positive or negative results will be determined by detection 


 
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of residual clonal cells (with assay sensitivity of 10-6) per Adaptive Technologies’ reporting 
methods. 
An MRD- status will be defined as all results from whole blood and BM that meet the assay 
testing requirements and are negative for the presence of residual clonal cells. An MRD+ status 
will be defined as all results from whole blood or BM that are positive for residual clonal cells 
per Adaptive Biotechnologies’ reporting methods. In addition to MRD positivity or negativity, 
MRD level will be captured by recording the number of residual clonal cells detected. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Statistical Design 
This is a Phase II, single arm, multi-center trial designed to assess the safety and efficacy of 
acalabrutinib as maintenance therapy post-BMT in subjects with MCL.  The primary objective of 
this trial is to determine the percentage of subjects who receive at least one dose of acalabrutinib 
and who are alive and free of PD or relapse at 2 years post-BMT.  
10.2 
Sample Size Considerations 
The primary endpoint is the percentage of patients who are alive and free of PD or relapse at 
2 years post-BMT. A sample size of 45 patients produces a two-sided 95% CI of 65%-90% when 
the observed percentage is 80%. To account for a 10% non-evaluable rate, the total sample size 
will be 50 patients. 
10.3 
Analysis Population 
The following analysis populations will be used: 
• The Safety Analysis Set is defined as all patients who receive at least one dose of 
acalabrutinib. 
• The Efficacy Analysis Set is defined as all patients who receive at least one dose of 
acalabrutinib, who have an adequate baseline disease assessment and an adequate post-
baseline assessment, and those who discontinue due to death or PD prior to their first 
assessment. 
10.4 
Data Analysis 
Descriptive statistics, including mean, median, standard deviation, and range for all continuous 
measures, will be tabulated and reported. Percentages and frequencies for all categorical 
measures will also be presented. Time-to-event endpoints will be reported using Kaplan-Meier 
estimates, with 95% CIs for median time to event. A full description of the analysis will be 
included in the Statistical Analysis Plan. 
10.4.1 
Demographics and Baseline Characteristics 
Demographic and baseline disease characteristics will be summarized using descriptive statistics. 
Data to be tabulated will include demographic features such as age, sex, and race, as well as 
disease-specific characteristics. 


 
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The number and percentages of patients enrolled, treated, completed the treatment/study and 
withdrawn from treatment/study for any reason will be presented. 
10.4.2 
Efficacy Analysis 
All efficacy analyses will be performed using the Efficacy Analysis Set. 
• PFS is defined as the time from Day 0 of BMT to objective radiological PD or death on 
study. PFS will be evaluated as Kaplan-Meier estimates of the percentage of subjects who 
receive at least one dose of study drug and who are alive and free of PD or relapse at 
2 years post-BMT according to RECIL (Younes et al 2017). Data for subjects who are 
still alive and free from progression at the time of data cut-off date, are lost to follow-up, 
have discontinued the study, or have initiated a subsequent protocol therapy will be 
censored on last assessment (or, if no post-baseline tumor assessment, at the time of first 
dose plus 1 day).  Approximate 95% CI for median duration of PFS will be computed 
using the formula proposed by Brookmeyer and Crowley. 
• Minimal residual disease status will be examined by NGS on all bone marrow aspirate 
and blood samples collected up to 2 years post-BMT to determine the conversion rate 
from MRD+ to MRD- while taking acalabrutinib, correlate MRD status with PFS, and 
identify mutations that correlate with disease relapse. An MRD- status will be defined as 
all results from whole blood and BM that are negative for the presence of residual clonal 
cells (with assay sensitivity of 10-6). An MRD+ status will be defined as all results from 
whole blood or BM that are positive for residual clonal cells per Adaptive 
Biotechnologies’ reporting methods.  
10.4.3 
Safety Analysis 
Safety will be assessed through the analysis of the reported incidence of treatment-emergent 
AEs.  Treatment-emergent AEs are those with an onset on or after the initiation of therapy, and 
will be graded according to NCI CTCAE Version 5.0.  A copy of the CTCAE scoring system 
may be downloaded from: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf. 
The AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
summarized using system organ class and preferred term for all patients in the Safety Analysis 
Set.  In addition, summaries of SAEs, AEs leading to treatment discontinuation, AEs by 
maximum NCI CTCAE grade, and AEs related to the study drug will also be presented. 
Other safety endpoints including laboratory results, vital signs, ECG findings, and other 
protocol-specified tests will be listed and/or summarized for all patients in the Safety Analysis 
Set. 
Concomitant medications will be coded using the WHO Drug Dictionary and they will be listed 
and summarized. 
10.5 
Analysis Time Points 
10.5.1 
Final Analysis 
The final analysis of the study will occur following the last visit of the last patient. 


 
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11. 
SAFETY REPORTING AND ANALYSES 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs, 
and measurement of protocol-specified hematology, clinical chemistry, and urinalysis variables, 
and measurement of protocol-specified vital signs. 
The PI is responsible for recognizing and reporting SAEs to the Innovations Safety Department 
(Section 11.1.5).  It is Innovations’ responsibility to report relevant SAEs to the applicable local, 
national, or international regulatory bodies.  In addition, Investigators must report SAEs and 
follow-up information to their responsible IRBs according to the policies of each IRB. 
The PI is also responsible for ensuring that every staff member involved in the study is familiar 
with the content of this section. 
11.1 
Definitions 
11.1.1 
Adverse Events 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related.  An AE can be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the 
use of a drug, without any judgment about causality.  An AE can arise with any use of the drug 
(e.g., off-label use, use in combination with another drug) and with any route of administration, 
formulation, or dose, including overdose. 
11.1.2 
Serious Adverse Events 
An AE or a suspected adverse reaction (SAR) is considered “serious” if it results in any of 
the following outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization of at least 24 hours or prolongation of existing 
hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
• Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of such medical events include: 
o allergic bronchospasm requiring intensive treatment in an emergency room 
or at home,  
o blood dyscrasias or convulsions that do not result in hospitalization, or  
o development of drug dependency or drug abuse. 


 
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It is important to distinguish between “serious” and “severe” AEs, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered “serious.”  Seriousness serves as the guide for defining regulatory 
reporting obligations and is based on patient/event outcome or action usually associated with 
events that pose a threat to a patient’s life or vital functions.  For example, nausea which persists 
for several hours may be considered “severe” nausea, but may not be considered an SAE.  On the 
other hand, a stroke which results in only a limited degree of disability may be considered only a 
mild stroke, but would be considered an SAE.  “Severity” and “seriousness” should be 
independently assessed when recording AEs on the eCRF and SAEs on the SAE Report Form. 
11.1.3 
Adverse Reaction 
An adverse reaction (AR) means any AE caused by a drug.  Adverse reactions are a subset of all 
SARs where there is a reason to conclude that the drug caused the event. 
11.1.4 
Suspected Adverse Reaction 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE.  “Reasonable possibility” means that there is evidence to suggest a causal 
relationship between the drug and the AE.  An SAR implies a lesser degree of certainty about 
causality than an AR, which means any AE caused by a drug. 
11.1.5 
Adverse Events of Special Interest 
The following events are adverse events of special interest (AESIs) for subjects exposed to 
acalabrutinib, and must be reported to the sponsors expeditiously (see Section 11.1.6.2 for 
reporting instructions), irrespective of regulatory seriousness criteria or causality. 
• Ventricular arrhythmias (e.g., ventricular extrasystoles, ventricular tachycardia, 
ventricular arrhythmia, ventricular fibrillation, etc.). 
11.1.6 
Recording and Reporting of Adverse Events 
11.1.6.1 Recording of Adverse Events 
All AEs of any patient during the course of the research study will be recorded in the eCRF, and 
the Investigator will give his or her opinion as to the relationship of the AE to the study drug 
(e.g., whether the event is related or unrelated to study drug administration). 
All AEs should be documented. A description of the event, including its date of onset and 
resolution, whether it constitutes an SAE or not, any action taken (e.g., changes to study drug), 
and outcome should be provided along with the Investigator’s assessment of causality (e.g., the 
relationship to the study drug).  For an AE to be a suspected TEAE there should be at least a 
reasonable possibility of a causal relationship between the protocol treatment and the AE.  
Adverse events will be graded according to the NCI CTCAE Version 5.0, and changes will be 
documented. 
If the AE is serious, it should be reported immediately to the Innovations Safety Department.  
Other untoward events occurring in the framework of a clinical study are to be recorded as AEs 
(e.g., AEs that occur prior to assignment of the study drug that are related to a protocol-mandated 
intervention, including invasive procedures such as biopsies, medication washout, or no 
treatment run-in). 


 
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Any clinically significant signs and symptoms, abnormal test findings, changes in physical 
examination, hypersensitivity, and other measurements that occur will be reported as AEs and 
collected on the relevant eCRF screen. 
Test findings will be reported as an AE if: the test result requires an adjustment in the study 
drug(s) or discontinuation of treatment; test findings require additional testing or surgical 
intervention; a test result or finding is associated with accompanying symptoms; and/or a test 
result is considered to be an AE by the Investigator. 
11.1.6.2 Reporting Period for Adverse Events 
All AEs regardless of seriousness or relationship to the study drug spanning from the first dose 
of acalabrutinib until 30 calendar days after discontinuation or completion of study drug, as 
defined by this clinical study protocol, are to be recorded on the corresponding screen(s) 
included in the eCRF. 
All AEs resulting in discontinuation from the study should be followed until resolution or 
stabilization.  All new AEs occurring during the AE reporting period must be reported and 
followed until resolution unless, in the opinion of the Investigator, the AE or laboratory 
abnormality is not likely to improve because of the underlying disease.  In this case, the 
Investigator must record his or her reasoning for this decision in the patient’s medical record. 
Thirty days or more after completion of protocol-specific treatment or discontinuation, only AEs, 
SAEs, or deaths assessed by the Investigator as treatment-related are to be reported. 
11.1.7 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately.  Each reported AE or SAE will be described by its duration (e.g., start 
and end dates), regulatory seriousness criteria if applicable, suspected relationship to the study 
drug (see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, Investigators should apply the 
following general guideline: 
YES:  There is a plausible temporal relationship between the onset of the AE and 
administration of the study treatment, and the AE cannot be readily explained by the 
patient’s clinical state, intercurrent illness, or concomitant therapies, and/or the AE 
follows a known pattern of response to the study drug, and/or the AE abates or resolves 
upon discontinuation of the study drug or dose reduction and, if applicable, reappears 
upon re-challenge. 
NO:  Evidence exists that the AE has an etiology other than the study drug (e.g., pre-
existing medical condition, underlying disease, intercurrent illness, or concomitant 
medication), and/or the AE has no plausible temporal relationship to study drug 
administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
11.2 
Serious Adverse Event Reporting by Investigators 
Adverse events classified by the treating Investigator as “serious” require expeditious handling 
and reporting to the Innovations Safety Department in order to comply with regulatory 


 
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requirements.  Determination of “life-threatening” or “serious” is based on the opinion of either 
the Sponsor or the Investigator. 
Serious AEs may occur at any time from the first dose of acalabrutinib through the 30-day 
follow-up period after the last dose of study drug.  The Innovations Safety Department must 
be notified of all SAEs, regardless of causality, within 24 hours of the first knowledge of the 
event by the treating physician or research personnel. 
To report an SAE, the SAE Report Form should be completed with the necessary information. 
The SAE Report Form should be sent to the Innovations Safety Department via fax or e-mail 
using the following contact information (during both business and non-business hours): 
Sarah Cannon Innovations Safety Department 
Safety Dept. Fax #:      1-866-807-4325 
Safety Dept. Email:     CANN.SAE@SCRI-Innovations.com 
Transmission of the SAE report should be confirmed by the site personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to the Innovations Safety Department as soon as it is available; these reports 
should also be submitted using the Innovations SAE Report Form.  The detailed SAE reporting 
process will be provided to the sites in the SAE reporting guidelines contained in the study 
reference manual. 
11.3 
Recording of Adverse Events and Serious Adverse Events 
11.3.1 
Diagnosis versus Signs and Symptoms 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the PI or designated physician, the AEs constitute components of a recognized 
condition, disease, or syndrome.  In the latter case, the condition, disease, or syndrome should be 
named rather than each individual sign or symptom.  If a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded as an AE or SAE as appropriate on the relevant form(s) 
(SAE Report Form and/or AE eCRF screen).  If a diagnosis is subsequently established, it should 
be reported as follow-up information is available.  If a diagnosis is determined subsequent to the 
reporting of the constellation of symptoms, the signs/symptoms should be updated to reflect the 
diagnosis. 
Progression of malignancy (including fatal outcomes), if documented by use of an appropriate 
method (e.g., as per RECIL), should not be reported as an SAE. 
11.3.2 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points.  Such events should only be recorded once on the SAE Report Form and/or the AE 
eCRF screen.  If a persistent AE becomes more severe or lessens in severity, it should be 
recorded on a separate SAE Report Form and/or AE eCRF screen. 


 
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A recurrent AE is one that occurs and resolves between patient evaluation time points and 
subsequently recurs.  All recurrent AEs should be recorded on an SAE Report Form and/or AE 
eCRF screen. 
11.3.3 
Abnormal Laboratory Values 
If an abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, 
the sign or symptom should be reported as an AE or SAE, and the associated laboratory value or 
vital sign should be considered additional information that must be collected on the relevant 
eCRF screen.  If the laboratory abnormality is a sign of a disease or syndrome, only the diagnosis 
needs to be recorded on the SAE Report Form and/or AE eCRF screen. 
Abnormal laboratory values will be reported as an AE if: the laboratory result requires an 
adjustment in the study drug(s) or discontinuation of treatment, and/or laboratory findings 
require additional testing or surgical intervention, a laboratory result or finding is associated with 
accompanying symptoms, or a laboratory result is considered to be an AE by the Investigator. 
11.3.4 
Deaths 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
Investigator solely to PD will be recorded on the “End of Study” eCRF screen.  All other on-
study deaths, regardless of attribution, will be recorded on an SAE Report Form and 
expeditiously reported to the Innovations Safety Department. 
When recording an SAE with an outcome of death, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the SAE 
Report Form and AE eCRF screen.  If the cause of death is unknown and cannot be ascertained 
at the time of reporting, record “Death NOS” (“death cause unknown”) on the AE eCRF screen.  
During post-study survival follow-up, deaths attributed to PD will be recorded on the “Follow-up 
Summary” and “Death Page” eCRF screens. 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization of >24 hours or prolongation of pre-existing 
hospitalization should be documented and reported as an SAE unless specifically instructed 
otherwise in this protocol.  There are some hospitalizations that do not require reporting as an 
SAE. 
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“inpatient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
• Emergency department or emergency room 
• Outpatient or same-day surgery units 
• Observation or short-stay unit 
• Rehabilitation facility 
• Hospice or skilled nursing facility 
• Nursing homes, custodial care, or respite care facility 


 
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Hospitalization during the study for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the study) does not require reporting as an SAE. 
11.3.6 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  Such conditions 
should be recorded on the General Medical History eCRF screen.  A pre-existing medical 
condition should be recorded as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study.  When recording such events on an SAE Report Form and/or 
AE eCRF screen, it is important to convey the concept that the pre-existing condition has 
changed by including applicable descriptors. 
11.3.7 
New Cancers 
The development of a new primary cancer should be regarded as an AE, with the exception of 
early non-melanoma cancers, and will generally meet at least one of the seriousness criteria (see 
Section 11.1.2).  New primary cancers are those that are not the primary reason for the 
administration of the study drug and have developed after the inclusion of the patient in the 
study.  They do not include metastases of the original cancer.  Symptoms of metastasis or the 
metastasis itself should not be reported as an AE/SAE, as they are considered to be PD. 
11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
If a patient becomes pregnant while enrolled in the study, a Pregnancy Form (a paper report 
form, not available within the eCRF) should be completed and faxed to the Innovations Safety 
Department.  The Innovations Safety Department should be notified expeditiously, irrespective 
of whether or not it meets the criteria for expedited reporting.  Abortions (spontaneous, 
accidental, or therapeutic) must also be reported to the Innovations Safety Department. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, this must be reported to the Innovations Safety Department immediately.  Every effort 
should be made to follow the pregnancy for the final pregnancy outcome. 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting.  A 
Pregnancy Form should also have been previously completed, and will need to be updated to 
reflect the outcome of the pregnancy. 
11.3.9 
Overdose 
Symptomatic and non-symptomatic overdose must be reported in the eCRF.  Any accidental or 
intentional overdose with the study drug that is symptomatic, even if not fulfilling a seriousness 
criterion, is to be reported to the Innovations Safety Department no greater than 24 hours from 
first knowledge of the event using the corresponding screens in the eCRF and following the same 
process described for SAE reporting (Section 11.2) if the overdose is symptomatic. 
For information on how to manage an overdose of acalabrutinib, see Section 7.5.1.6 and the IB. 
11.4 
Funding Partner Serious Adverse Event Reporting Requirements 
The Innovations Safety Department will forward SAE information regarding acalabrutinib to 
Acerta Pharma/AstraZeneca at AEMailboxClinicalTrialTCS@astrazeneca.com within 7 calendar 
days (for life-threatening/fatal SAEs) of the Innovations Safety Department personnel becoming 


 
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aware of the SAE or 15 calendar days for other SAEs, Suspected Unexpected Serious Adverse 
Reactions (SUSARs), pregnancy (unless fatal/life-threatening) and special situations. 
Innovations is responsible for reporting relevant SAEs to the competent authority, other 
applicable regulatory authorities, and participating Investigators, in accordance with 
International Council for Harmonisation (ICH) guidelines and US Food and Drug Administration 
(FDA) regulations in parallel with Acerta Pharma/AstraZeneca. 
New information will be submitted to Acerta Pharma 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 PD should be recorded on the appropriate form in the electronic data 
capture (EDC) system. If the primary cause of death is PD, the death due to PD should not be 
reported as an SAE. If the primary cause of death is something other than PD, then the death 
should be reported as an SAE with the primary cause of death as the event AE term, as death is 
typically the outcome of the event, not the event itself. The primary cause of death on the 
autopsy report should be the term reported. Autopsy and post-mortem reports must be forwarded 
to AEMailboxClinicalTrialTCS@astrazeneca.com. If study drug is discontinued because of an 
SAE, this information must be included in the SAE report. 
11.4.1 
Sponsor Assessment of Unexpected Events 
The Sponsor is responsible for assessing an AE or SAR as “unexpected.”  
An AE or SAR is considered “unexpected” when the following conditions occur: 
• Event(s) is not mentioned in the IB  
• Event(s) is not listed at the specificity or severity that has been observed 
• An event(s) is not consistent with the General Investigative Plan or in the current 
application 
• Includes AEs or SARs that may be anticipated from the pharmacological properties of the 
study drug, or that occur with members of the drug class, but that have not previously 
been observed under investigation 
When applicable, an unexpected AE may also apply to an event that is not listed in the current IB 
or an event that may be mentioned in the IB, but differs from the event because of greater 
severity or specificity.    
Known as SUSARs, these events suspected (by the Investigator or Sponsor) to be related to the 
study drug, are unexpected (not listed in the IB), and are serious (as defined by the protocol) and 
require expedient submission to relevant health authorities within 7 days (for fatal or life-
threatening event) or 15 days (for all serious events), or as defined by law.  The term SUSAR is 
used primarily in the reporting of events to regulatory authorities. 
Expected AEs are those events that are listed or characterized in the current IB. 


 
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11.4.2 
Funding Partner Reporting for Clinical Studies Under an Investigational New 
Drug Application 
All written investigational new drug (IND) Safety Reports submitted to the FDA by the 
Innovations Safety Department are not required to be distributed to pharmaceutical company(ies) 
that are supporting the study with either funding or drug supply. 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
12.1 
Study Monitoring, Auditing, and Inspecting 
The Investigator will permit study-related monitoring, quality audits, and inspections by 
Innovations, or its representative(s), government regulatory authorities, and the IRB(s) of all 
study-related documents (e.g., source documents, regulatory documents, data collection 
instruments, CRFs).  The Investigator will ensure the capability for inspections of applicable 
study-related facilities.  The Investigator will ensure that the study monitor or any other 
compliance or Quality Assurance reviewer is given access to all study-related documents and 
study-related facilities. 
At the discretion of Innovations, Source Document Verification (SDV) may be performed on 
partial or all data items as defined in study documents and/or plans. 
Participation as an Investigator in this study implies the acceptance of potential inspection by 
government regulatory authorities, the IRB(s), and/or Innovations or its representative(s). 
13. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This research study will be conducted according to the standards of Good Clinical Practice 
(GCP) outlined in the ICH E6 Tripartite Guideline and the Code of Federal Regulations (CFR) 
Title 21 part 312, applicable government regulations, institutional research policies and 
procedures, and any other local applicable regulatory requirement(s). 
13.1 
Institutional Review Board Approval 
The clinical study protocol, ICF, IB, available safety information, patient documents (e.g., study 
diary), patient recruitment procedures (e.g., advertisements), information about payments (e.g., 
PI payments) and compensation available to the patients, and documentation evidencing the PI’s 
qualifications should be submitted to the IRB for ethical review and approval if required by local 
regulations, prior to the study start. 
The PI/Sponsor and/or designee will follow all necessary regulations to ensure appropriate, 
initial, and on-going IRB study review.  The PI/Sponsor (as appropriate) must submit to and, 
where necessary, obtain approval from the IRB for all subsequent protocol amendments and 
changes to the ICF.  Investigators will be advised by the Sponsor or designee whether an 
amendment is considered substantial or non-substantial and whether it requires submission for 
approval or notification only to an IRB. 
Safety updates will be prepared by the Sponsor or its representative as required, for distribution 
to the Investigator(s) and submission to the relevant IRB. 


 
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13.2 
Regulatory Approval 
As required by local regulations, the Sponsor will ensure all legal aspects are covered and 
approval of the appropriate regulatory bodies obtained prior to study initiation.  If required, the 
Sponsor will also ensure that the implementation of substantial amendments to the protocol and 
other relevant study documents happen only after approval by the relevant regulatory authorities. 
13.3 
Informed Consent 
Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular study after having been informed of all aspects of the study that are 
relevant to the patient's decision to participate.  Informed consent is documented by means of a 
written, signed, and dated ICF. 
The ICF will be submitted for approval to the IRB that is responsible for review and approval of 
the study.  Each ICF must include all of the relevant elements currently required by the FDA, as 
well as local country authority or state regulations and national requirements. 
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the research study.  Once the essential information has been provided to the 
prospective candidate, and the Investigator is sure that the individual candidate understands the 
implications of participating in this research study, the candidate will be asked to give consent to 
participate in the study by signing an ICF.  A notation that written informed consent has been 
obtained will be made in the patient’s medical record.  A copy of the ICF, to include the patient’s 
signature, will be provided by the Investigator to the patient. 
If an amendment to the protocol substantially alters the study design or the potential risks to the 
patients, the patient’s consent to continue participation in the study should be obtained. 
13.3.1 
Confidentiality 
13.3.1.1 Patient Confidentiality 
Confidentiality of patients’ personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  HIPAA regulations require that, 
in order to participate in the study, a patient must sign an authorization form for the study that he 
or she has been informed of the following: 
• What PHI will be collected from patients in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal 
or state privacy laws 
• That the information collected about the research study will be kept separate from the 
patient’s medical records, but the patient will be able to obtain the research records after 
the conclusion of the study 
• Whether the authorization contains an expiration date 


 
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• The rights of a research patient to revoke his or her authorization. 
In the event that a patient revokes authorization to collect or use his or her PHI, the Investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (e.g., that the patient is alive) at the 
end of their scheduled study period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that 
the Investigator and institution permit authorized representatives of Innovations, the regulatory 
authorities, and the IRB direct access to review the patient’s original medical records at the site 
for verification of study-related procedures and data. 
One measure to protect confidentiality is that only a unique study number will identify patients 
in the eCRF or other documents submitted to Innovations.  This information, together with the 
patient’s year of birth, will be used in the database for patient identification.  Patient names or 
addresses will not be entered in the eCRF.  No material bearing a patient’s name will be kept on 
file by Innovations.  Patients will be informed of their rights within the ICF. 
13.3.1.2 Investigator and Staff Information 
Personal data of the Investigators and sub-Investigators may be included in the Innovations 
database, and shall be treated in compliance with all applicable laws and regulations.  When 
archiving or processing personal data pertaining to the Investigator or sub-Investigator, 
Innovations shall take all appropriate measures to safeguard and prevent access to this data by 
any unauthorized party. 
13.4 
Financial Information 
The finances for this clinical study will be subject to a separate written agreement between Sarah 
Cannon Development Innovations, LLC and applicable parties.  Any Investigator financial 
disclosures as applicable to 21 CFR Part 54 shall be appropriately provided. 
14. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY 
14.1 
Amendments to the Protocol 
Amendments to the protocol shall be planned, documented, and signature authorized prior to 
implementation. 
If an amendment to the protocol is required, the amendment will be originated and documented 
by Innovations.  All amendments require review and approval of all pharmaceutical companies 
providing funding for the study and of the PI supporting the study.  The written amendment must 
be reviewed and approved by Innovations, and submitted to the IRB at the Investigator’s facility 
for the board’s approval. 
Items requiring a protocol amendment approved by the IRB of record for the Investigator’s 
facility and the FDA or other regulatory authorities include, but are not limited to, the following: 
• Change to study design 
• Risk to patients 


 
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• Increase to dose or patient exposure to drug 
• Patient number increase 
• Addition or removal of tests and/or procedures 
• Addition/removal of an Investigator 
The amendment will be submitted formally to the IRB and the FDA or other regulatory 
authorities by Innovations. 
It should be further noted that, if an amendment to the protocol substantially alters the study 
design or the potential risks to the patients, the patient’s consent to continue participation in the 
study should be obtained. 
14.2 
Documentation Required to Initiate the Study 
Before the study may begin, certain documentation required by FDA regulations and ICH GCP 
must be provided by the Investigator.  The required documentation should be submitted to: 
Sarah Cannon Development Innovations 
Regulatory Department 
1100 Dr. Martin L. King Jr. Blvd.,  
Suite 800 
Nashville, TN 37203 
Documents at a minimum required to begin a study in the US include, but are not limited to, the 
following: 
• A signature-authorized protocol and contract 
• A copy of the official IRB approval of the study and the IRB members list 
• Current curricula vitae for the PI and any associate Investigator(s) who will be involved 
in the study 
• Indication of appropriate accreditation for laboratories (as required) to be used in the 
study and the normal ranges for tests to be performed by those laboratories 
• Original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed 
• A copy of the IRB-approved ICF containing permission for audit by representatives of 
Innovations, the IRB, and the FDA and other regulatory agencies (as applicable) 
• Financial disclosure forms for all Investigators listed on Form FDA 1572 (if applicable) 
• Verification of PI acceptability from local and/or national debarment list(s). 
14.3 
Study Documentation and Storage 
The PI must maintain a list of appropriately qualified persons to whom he/she has delegated 
study duties and should ensure that all persons assisting in the conduct of the study are informed 
of their obligations.  All persons authorized to make entries and/or corrections on the eCRFs are 
to be included on this document.  All entries in the patients’ eCRFs are to be supported by source 
documentation where appropriate. 


 
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Source documents are the original documents, data, records, and certified copies of original 
records of clinical findings, observations, and activities from which the patient’s eCRF data are 
obtained.  These can include, but are not limited to, hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, diaries, microfiches, ECG 
traces, copies or transcriptions certified after verification as being accurate and complete, 
photographic negatives, microfilm or magnetic media, x-rays, and correspondence. 
The PI and study staff members are responsible for maintaining a comprehensive and centralized 
filing system (e.g., regulatory binder or Investigator study file [ISF]) of all essential study-related 
documentation, suitable for inspection at any time by representatives from the Sponsor and/or 
applicable regulatory authorities.  The ISF must consist of those documents that individually or 
collectively permit evaluation of the conduct of the study and the quality of the data produced.  
The ISF should contain at a minimum all relevant documents and correspondence as outlined in 
ICH GCP Section 8 and 21 CFR Part 312.57, including key documents such as the IB and any 
amendments, the protocol and any amendments, signed ICFs, copies of completed eCRFs, IRB 
approval documents, Financial Disclosure forms, patient identification lists, enrollment logs, 
delegation of authority log, staff qualification documents, laboratory normal ranges, and records 
relating to the study drug including accountability records.  Drug accountability records should, 
at a minimum, contain information regarding receipt, shipment, and disposition.  Each form of 
drug accountability record, at a minimum, should contain PI name, date the drug 
shipped/received, and the date, quantity, and batch/code or lot number for the identity of each 
shipment.  In addition, all original source documents supporting entries in the eCRF must be 
maintained and readily available. 
Innovations shall maintain adequate investigational product and financial interest records as per 
21 CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing application has 
been approved by FDA; or, in the event that the marketing application has not been approved by 
FDA, for no less than 2 years after the last shipment/delivery of the drug for investigational use 
or the drug is discontinued and the FDA has been notified of the discontinuation. 
The Investigator shall maintain adequate records of drug disposition, case histories, and any 
other study-related records as per 21 CFR Part 312.62, for no less than 2 years after the last 
marketing application has been approved by FDA; or, in the event that the marketing application 
has not been approved by FDA, no less than 2 years after the last shipment/delivery of the drug 
for investigational use or the drug is discontinued and FDA has been notified of the 
discontinuation.  
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the Investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records, e.g., eCRF records and medical 
records), all original signed ICFs, copies of all eCRF records, SAE Reporting forms, source 
documents, detailed records of treatment disposition, and related essential regulatory documents.  
The documents listed above must be retained by the Investigator for as long as needed to comply 
with national and international regulations (generally 2 years after discontinuing clinical 
development or after the last marketing approval).  Sponsor will notify the 
Investigator(s)/institutions(s) when the study-related records are no longer required. 
If the Investigator relocates, retires, or for any reason withdraws from the study, Innovations 
must be prospectively notified.  The study records must be transferred to an acceptable designee, 


 
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such as another Investigator, another institution, or to Innovations.  The Investigator must obtain 
Innovations’ written permission before disposing of any records, even if retention requirements 
have been met.  All study files will be maintained by Innovations throughout the study, and will 
be held by Innovations at the conclusion of the study. 
14.4 
Data Collection 
The study eCRF is the primary data collection instrument for the study.  Case report forms will 
be completed using the English language and should be kept current to enable Innovations to 
review the patients’ status throughout the course of the study. 
In order to maintain confidentiality, only study number, patient number, and year of birth will 
identify the patient in the eCRF.  If the patient’s name appears on any other document (e.g., 
laboratory report), it must be obliterated on the copy of the document to be supplied to 
Innovations and be replaced instead with the patient number and other identifier (e.g., patient 
initials) as allowed per institutional policy.  The Investigator will maintain a personal patient 
identification list (patient numbers with corresponding patient identifiers) to enable records to be 
identified and verified as authentic.  Patient data/information will be kept confidential, and will 
be managed according to applicable local, state, and federal regulations. 
All data requested in the eCRF system must be supported by and be consistent with the patient’s 
source documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the eCRF, 
a note should be created verifying that the test was “Not Done” or the result was “Unknown.”  
For any entry errors made, the error(s) must be corrected, and a note explaining the reason for 
change should be provided.  The Investigator will electronically sign and date the patient eCRF 
casebook indicating that the data in the eCRF has been assessed.  Each completed eCRF will be 
signed and dated by the PI, once all data for that patient is final. 
14.5 
Disclosure and Publication Policy 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential.  The Sponsor reserves the right 
to release literature publications based on the results of the study.  Results from the study will be 
published/presented as per the Sponsor’s publication process. 
Inclusion of the Investigator in the authorship of any multi-center publication will be based upon 
substantial contribution to the study design, the analysis, or interpretation of data, or the drafting 
and/or critically revising of any manuscript(s) derived from the study.  The Investigator 
acknowledges that the study is part of a multi-center study and agrees that any publication by the 
Investigator of the results of the study conducted at the research site shall not be made before the 
first multi-center publication.   
In the event there is no multi-center publication within fifteen (15) months after the study has 
been completed or terminated at all study sites, and all data has been received, the Investigator 
shall have the right to publish his/her results from the study, subject to the notice requirements 
described herein and subject to acknowledgement of the Sponsor as appropriate.  The 
Investigator shall provide the Sponsor thirty (30) days to review a manuscript or any poster 
presentation, abstract or other written or oral material which describes the results of the study for 
the purpose only of determining if any confidential or patentable information is disclosed 


 
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thereby.  If the Sponsor requests in writing, the Investigator shall withhold any publication or 
presentation an additional sixty (60) days solely to permit the Sponsor to seek patent protection 
and to remove any Innovations confidential information from all publications. 


 
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15. 
REFERENCES 
Acalabrutinib IB 
Acalabrutinib Investigator’s Brochure. Acerta Pharma BV. Edition Number 7.1. Release date: 15 
February 2018. 
Armand et al 2016 
Armand P, Redd R, Bsat J, Mayuram S, Giardino A, Fisher DC, et al. A phase 2 study of 
rituximab-bendamustine and rituximab-cytarabine for transplant eligible patients with mantle 
cell lymphoma. Br J Haematol. 2016;173:89-95. 
Barf et al 2017 
Barf T, Covey T, Izumi R, van de Kar B, Gulrajani M, van Lith B, et al. Acalabrutinib (ACP-
196): A covalent Bruton tyrosine kinase (BTK) inhibitor with a differentiated selectivity and in 
vivo potency profile. J Pharmacol Exp Ther. 2017;363:240-52. 
Brugger et al 2004 
Brugger W, Hirsch J, Grünebach F, Repp R, Brossart P, Vogel W, et al. Rituximab consolidation 
after high-dose chemotherapy and autologous blood stem cell transplantation in follicular and 
mantle cell lymphoma: a prospective, multicenter phase II study. Ann Oncol. 20404;15:1691-8. 
Byrd et al 2016 
Byrd JC, Harrington B, O’Brien S, Jones JA, Schuh A, Devereux S, et al. Acalabrutinib (ACP-
196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;37:323-32. 
Damon et al 2009 
Damon LE, Johnson JL, Niedzwiecki D, et al. Immunochemotherapy and autologous stem-cell 
transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol 
2009;27:6101-8. 
Dietrich et al 2014 
Dietrich S, Weidle J, Rieger M, Meissner J, Radujkovic A, Ho AD, et al. Rituximab maintenance 
therapy after autologous stem cell transplantation prolongs progression free survival in patients 
with mantle cell lymphoma. Leukemia. 2014;28:708-9. 
Eskelund et al 2016 
Eskelund CW, Kolstad A, Jerkeman M, Räty R, Laurell A, Eloranta S, et al. 15-year follow-up 
of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without 
survival plateau. Br J Haematol. 2016;175:410-8. 
Graf et al 2015 
Graf SA, Stevenson PA, Holmberg LA, Till BG, Press OW, Chauncey TR, et al. Maintenance 
rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma. Ann 
Oncol. 2015 Nov;26:2323-8. 


 
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STUDY DRUG:  ACALABRUTINIB 
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AMENDMENT 3.0, VERSION 4.0 
 
Kaplan et al 2015 
Kaplan LD, Jung SH, Stock W, Bartlett NL, Pitcher B, Byrd JC, et al. Bortezomib maintenance 
(BM) versus consolidation (BC) following aggressive immunochemotherapy and autologous 
stem cell transplant (ASCT) for untreated mantle cell lymphoma (MCL): CALGB (Alliance) 
50403. Blood. 2015;126:337. 
Kaplan et al 2018 
Kaplan LD, Maurer MJ, Stock W, et al. Bortezomib maintenance (BM) or consolidation (BC) 
following aggressive immunochemotherapy and autologous stem cell transplant (ASCT) for 
untreated mantle cell lymphoma (MCL): 8 year follow up of CALGB 50403 (Alliance). Blood. 
2018;132:146; doi: https://doi.org/10.1182/blood-2018-99-112655. 
Kolstad et al 2016 
Kolstad A, Pedersen LB, Eskelund CW, Husby S, Grønbæk K, Jerkeman M, et al. Molecular 
monitoring after autologous stem cell transplantation and preemptive rituximab treatment of 
molecular relapse; results from the Nordic Mantle Cell Lymphoma Studies (MCL2 and MCL3) 
with median follow-up of 8.5 years. Biol Blood Marrow Transplant. 2017;23:428-35. 
Le Gouill et al 2017 
Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, et al. Rituximab 
after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 
2017;377:1250-60. 
Raanani et al 2009 
Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. Immunoglobulin 
prophylaxis in chronic lymphocytic leukemia and multiple myeloma: systematic review and 
meta-analysis. Leuk Lymphoma. 2009;50:764-72. 
Smith et al 2006 
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al.  2006 update of 
recommendations for the use of white blood cell growth factors: an evidence based clinical 
practice guideline. J Clin Oncol. 2006;24:3187-205. 
Smith et al 2015 
Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al.  Recommendations for 
the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice 
Guideline update. J Clin Oncol. 2015;33:3199-212. 
Stern et al 2014 
Stern A, Green H, Paul M, Vidal L, Leibovici L. Prophylaxis for Pneumocystis pneumonia 
(PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev. 2014 Oct 
1;10:CD005590. 


 
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AMENDMENT 3.0, VERSION 4.0 
 
Wang et al 2018 
Wang M, Rule S, Zinzani PL, Goy A, Casasnovas O, Smith SD, et al. Acalabrutinib in relapsed 
or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. 
Lancet 2018;391:659-667. 
Younes et al 2017 
Younes A, Hilden P, Coiffier B, Hagenbeek A, Salles G, Wilson W, et al.  International Working 
Group consensus response evaluation criteria in lymphoma (RECIL 2017).  Ann Oncol. 
2017;28:1436-47. 
 


 
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AMENDMENT 3.0, VERSION 4.0 
 
16. 
APPENDICES 
 
Appendix A: ECOG Performance Status Criteria 
 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to carry 
on all pre-disease performance without 
restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
70 
Cares for self, unable to carry on normal 
activity or to do active 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% of waking hours. 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated.  Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead 
0 
Dead 


 
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AMENDMENT 3.0, VERSION 4.0 
 
 
Appendix B: New York Heart Association (NYHA) Classification of Cardiac Disease 
The following table presents the NYHA classification of cardiac disease. 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of physical 
activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort.  Symptoms of heart failure or the anginal 
syndrome may be present even at rest.  If any physical activity is undertaken, 
discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 1994:253-256. 
 


 
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AMENDMENT 3.0, VERSION 4.0 
 
Appendix C: Guidelines for Female Patients of Childbearing Potential and Fertile Male 
Patients 
Acceptable Contraception Methods: 
Women of childbearing potential (WoCBP), defined as all women physiologically capable of 
becoming pregnant, must use highly-effective contraception during the study and until 2 days 
following the last dose of acalabrutinib. For male subjects with a pregnant or non-pregnant 
WoCBP partner, no contraception measures are required. 
Highly effective contraception is defined as either: 
True Abstinence 
When this is in line with the preferred and usual lifestyle of the patient 
during the entire period of risk associated with the study drug.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
Sterilization  
When a WoCBP has had surgical bilateral oophorectomy (with or 
without hysterectomy) or tubal ligation at least six weeks prior to study 
entry.  In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow-up hormone level 
assessment. 
Female condom 
Barrier methods of contraception: condom or an occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository. 
Male Partner Sterilization With the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate. 
Intrauterine device 
Placement of an intrauterine device (IUD) or intrauterine system 
(IUS) 
Hormonal contraception 
Combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation, which may 
be oral, intravaginal, or transdermal. Progestogen-only hormonal 
contraception associated with inhibition of ovulation, which may 
be oral, injectable, or implantable. 
Hormonal contraception may be susceptible to interaction with the study drug or other drugs, 
which may reduce the efficacy of the contraception method. 
If a contraceptive method is restricted by local regulations/guidelines, then it does not qualify 
as an acceptable highly effective method of contraception for subjects participating at sites in 
the relevant country/region. 
Subjects should promptly notify the Investigator if they, or for male subjects their partner, 
become pregnant during this study, or within 2 days after the last dose of acalabrutinib.  If a 
female subject becomes pregnant during the treatment period, she must discontinue 
acalabrutinib immediately.  Pregnancy in a female subject or a male subject’s partner must be 
reported as outlined in Section 11.3.8.   


 
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AMENDMENT 3.0, VERSION 4.0 
 
Acceptable forms of barrier contraception include: 
• Latex condom, diaphragm or cervical/vault cap when used with spermicidal 
foam/gel/film/cream/suppository 
Unacceptable methods of contraception include: 
• Periodic abstinence 
• Natural family planning (rhythm method) or breastfeeding 
• Fertility awareness 
• Withdrawal 
• Triphasic combined oral contraceptives 
• All progesterone only pills, except Cerazette™ 
• All barrier methods, if intended to be used alone 
• Non-copper containing intrauterine devices 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on the study drug must be reported to the 
Innovations Safety Department within 24 hours of learning of its occurrence.  The pregnancy 
should be followed up for 3 months after the termination of the pregnancy to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence 
or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
Investigator to the Innovations Safety Department.  Pregnancy follow-up should be recorded 
on the same form and should include an assessment of the possible relationship to the study 
drug of any pregnancy outcome.  Any SAE experienced during pregnancy must be reported on 
the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took the 
study drug in this study.  Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
Women Not of Childbearing Potential are Defined as Follows: 
• Women are considered post-menopausal and not of childbearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(i.e., age appropriate, history of vasomotor symptoms).  
• Women <45 years of age a high follicle-stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not 
using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient. 


 
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• Women who are permanently sterilized at least 6 weeks before screening (e.g., bilateral 
tubal ligation/occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy). 
• Women who are >45 years-of-age, not using hormone-replacement therapy and who 
have experienced total cessation of menses for at least 1 year OR who have a FSH 
value >40 mIU/mL and an estradiol value <40 pg/mL (140 pmol/L). 
• Women who are >45 years-of-age, using hormone-replacement therapy and who have 
experienced total cessation of menses for at least 1 year OR who have had documented 
evidence of menopause based on FSH >40 mIU/mL and estradiol <40 pg/mL prior to 
initiation of hormone-replacement therapy. 
• Women who had have a congenital or acquired condition that prevents childbearing. 
 


 
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AMENDMENT 3.0, VERSION 4.0 
 
Appendix D: Schedule of Assessments 
ASSESSMENTS 
Screening 
Acalabrutinib Maintenance post-BMTa 
 
 
 
Pre- 
BMT 
Post-
BMTb 
Cycle1c  
~4 mos. 
Post-BMT 
 
Cycles 2-6d  
~5-9 mos. 
post-BMT 
 
Cycles 7-12e  
~10-15 mos. 
post-BMT 
 
Cycles 13 & beyondf  
≥16 mos. 
post-BMT 
 
End of 
treatment 
visitg 
Follow-
Uph 
 
 
 
D1 
D15 
D1 (±7 days) 
D1 (±7 days) 
D1 
 
 
Medical history & 
demographics 
X 
 
 
 
 
 
 
 
 
Physical examination & 
weight 
X 
X 
X 
X 
X 
X 
X  
 
 
ECOG PS 
 
X 
X 
 
X 
X 
X 
 
 
Vital signsi 
 
X 
X 
 
X 
X 
X 
 
 
ECGj 
 
X 
 
 
 
 
 
 
 
CBC & CMP 
 
X 
X 
X 
X 
X 
X 
 
 
Coagulation testingu 
 
X 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
Pregnancy testk 
X 
X 
 
 
 
 
 
 
 
HIV testl 
 
X 
 
 
 
 
 
 
 
Hepatitis B virus PCRm 
 
X 
 
 
Xm 
Xm 
Xm 
Xm 
 
Hepatitis C virus PCRn 
 
Xn 
 
 
 
 
 
 
 
Archival tumor sampleo 
X 
Xo 
 
 
 
 
 
 
 
Fresh tumor biopsies p 
 
 
 
 
 
 
 
Xp 
Xp 
MRD analysis (blood)q 
 
Xq 
 
 
X q 
X q 
X q 
 
 
MRD analysis (BM 
aspirate)r 
 
Xr 
 
 
 
Xr 
 
 
 
CT/MRI/PETs 
 
X 
 
 
Xs 
Xs 
Xs 
 
 
Acalabrutinib (oral) & 
drug compliance 
 
 
129 mg twice daily continuously for 2 years post-BMT (~22 cycles) 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE evaluationst 
 
 
X 
X 
X 
X 
X 
X 
 
PFS follow-up 
 
 
 
 
 
 
 
 
X 


 
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AMENDMENT 3.0, VERSION 4.0 
 
a. 
Acalabrutinib maintenance therapy begins on Day 100 post-BMT 
b. 
Post-BMT screening should occur between Day +80 and Day +100 
c. 
Begin between Day +100 and Day +120 
d. 
Clinic visits will be monthly on Day 1 for Cycles 2-6 only (See Planned Clinic Visits table below) 
e. 
Cycles 7-12 only: clinic visits will occur every 2 months for 6 months (See Planned Clinic Visits table below) 
f. 
Cycle 13 and beyond until 5 years post-BMT: clinic visits will occur every 3 months (See Planned Clinic Visits table below) 
g. 
Within 30 days of last dose of acalabrutinib    
h. 
A telephone call to assess PFS every 3 months can be made in lieu of an office visit 
i. 
Blood pressure, pulse, oxygen saturation, and temperature 
j. 
Subjects should be in supine position and resting for at least 10 minutes before any study-related ECGs are taken.   
k. 
For women of childbearing potential only at the time of screening (post- and prior to BMT) and 72 hours before the start of treatment.  Urine or serum 
pregnancy tests are acceptable. 
l. 
Patients with a known history of human immunodeficiency virus (HIV) or who are HIV antibody positive should be tested for HIV RNA during screening.  
No further testing beyond screening is necessary if PCR results are negative, except if clinically indicated (see Section 6.5.6). 
m. 
Only patients who are anti-HBc positive, or have a known history of HBV, should have quantitative PCR testing for HBV DNA performed during 
screening and every 3 months thereafter.  Monitoring (every 3 months) should continue until 12 months after last dose of acalabrutinib. As IVIG may cause 
false positive hepatitis serology, monthly PCR testing is not required in patients who are currently receiving or received prophylactic IVIG within 3 months 
before study enrollment and have a documented negative anti-HBc test before the initiation of IVIG therapy (see Section 6.5.6). 
n. 
Patients with a known history of hepatitis C virus (HCV) or who are hepatitis C antibody positive should be tested for HCV RNA during screening.  No 
further testing beyond screening is necessary if PCR results are negative, except if clinically indicated (see Section 6.5.6). 
o. 
If not obtained during Screening #1 (prior to BMT) 
p. 
Collect a fresh lymphoma biopsy at disease progression 
q. 
MRD analysis with blood sample: Collect a blood sample prior to beginning maintenance on Day +100 (Screening #2), 6 months (~Cycle 4 Day 1), 1 
year (~Cycle 10 Day 1) and 2 years post-BMT (~Cycle 22 Day 1).  
r. 
MRD analysis with bone marrow biopsy and aspirate: Collect a bone marrow biopsy and aspirate prior to beginning maintenance on Day +100 
(Screening #2) and at 1 year post-BMT (~Cycle 10 Day 1).  
s. 
CT/MRI/FDG-PET scans will be done post-BMT (Day 80-100), at 6 months, 12 months, 18 months and 24 months.  Thereafter, scans will be done per 
institutional standard operating procedures. 
t. 
Record all AEs regardless of seriousness or relationship spanning from the first dose of acalabrutinib until 30 calendar days after discontinuation or 
completion of study drug. 
u. 
Coagulation testing will include PT/INR or aPTT. 


 
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AMENDMENT 3.0, VERSION 4.0 
 
Planned Clinic Visits 
Cycle 1 
d. Cycles 2-6 only: 
clinic visits will occur every month 
e.  Cycles 7-12 only: 
clinic visits will occur every 2 months 
f.  Cycle 13 and beyond until 5 years post-BMT: 
clinic visits will occur every 3 months 
C1 
D1 
C1 
D15 
C2 
D1 
C3 
D1 
C4 
D1 
C5 
D1 
C6 
D1 
C7 
D1 
C8 
D1 
C9 
D1 
C10 
D1 
C11 
D1 
C12 
D1 
C13 
D1 
C14 
D1 
C15 
D1 
C16 
D1 
C17 
D1 
C18 
D1 
C19 
D1 
C20 
D1 
C21 
D1 
C22 
D1 
Visit 
Visit 
Visit 
Visit 
Required 
for 
6 mo 
imaging 
Visit 
Visit 
No 
Visit 
Begin 
every 
2 mo 
visits 
No 
Visit 
Required 
for 
12 mo 
imaging 
No 
Visit 
Visit 
Begin 
every 
3 mo 
visits 
No 
Visit 
No 
Visit 
Required 
for 
18 mo 
imaging 
No 
Visit 
No 
Visit 
Visit 
No 
Visit 
No 
Visit 
Required 
For 
24 mo 
imaging 


 
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AMENDMENT 3.0, VERSION 4.0 
 
Appendix E RECIL 2017: Response Categories Based on Assessment of Target Lesions 
 
 
% Change in sum of diameters of target lesions from nadir 
 
CR 
PR 
MRa 
SD 
PD 
% change from 
baseline  
Complete 
disappearance of all 
target lesions and all 
nodes with long axis 
<10mm. 
≥30% decrease in the 
sum of longest 
diameters of target 
lesions (PR) with 
normalization of FDG-
PET 
≥30% 
decrease in 
the sum of 
longest 
diameters of 
target lesions 
but not a CR 
≥10% decrease 
in the sum of 
longest 
diameters of 
target lesions 
but not a PR 
(<30%) 
<10% decrease 
or ≤ 20% 
increase in the 
sum of longest 
diameters of 
target lesions 
>20% increase 
in the sum of 
longest 
diameters of 
target lesions  
For small 
lymph nodes 
measuring 
<15 mm post 
therapy, a 
minimum 
absolute 
increase of 
5 mm and the 
long diameter 
should exceed 
15 mm 
Appearance of a 
new lesion  
FDG-PET 
Normalization of FDG-
PET (Deauville score 1-
3) 
Positive 
(Deauville 
score 4-5) 
Any 
Any 
Any 
Bone marrow 
involvement 
Not involved 
Any 
Any 
Any 
Any 
New lesions  
No 
No 
No 
No 
Yes or No 
a A provisional category 
Abbreviations: CR, complete response; CT, compute tomography; FDG-PET, [18F]2-fluoro-2-deoxy-D-glucose; 
MR, minor response; PD, disease progression; PR, partial response; SD, stable disease. 
Source: Younes et al 2017 


 
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AMENDMENT 3.0, VERSION 4.0 
 
Appendix F Response Designation Incorporating Best Response of Target Lesions and 
Nontarget Lesions 
 
Target lesion  
Nontarget lesion 
New lesion 
Response designation 
CR 
CR 
No 
CR 
CR 
PR, MR, or SD  
No 
PRa 
CR 
UE 
No 
UE 
PR 
UE 
No 
UE 
PR 
CR 
No 
PR 
PR 
PR, MR, or SD 
No 
PR 
MR 
UE 
No 
UE 
MR 
CR 
No 
MR 
MR 
PR, MR, or SD 
No 
MR 
SD 
UE 
No 
UE 
SD 
CR, PR, or MR 
No 
SD 
SD 
SD 
No 
SD 
PD 
Any 
Yes/No 
PD 
Any 
PD 
Yes/No 
PD 
Any 
Any 
Yes 
PD 
CR 
No 
No 
CR 
PR 
No 
No 
PR 
MR 
No 
No 
MR 
SD 
No 
No 
SD 
a Compute tomography scan-based PR with complete normalization of [18F]2-fluoro-2-deoxy-D-glucose positron 
emission tomography activity is considered CR 
Abbreviations: CR, complete response; MR, minor response; PD, disease progression; PR, partial response; SD, 
stable disease; UE, unevaluable 
Source: Younes et al 2017 
 
 


 
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Appendix G Cytochrome P450 3A4 Inhibitors and Inducers 
Source:  http://www.mayomedicallaboratories.com/it-
mmfiles/Cytochrome_P450_3A4_and_3A5_Known_Drug_Interaction_Chart.pdf 
CYP3A4 Inhibitors 
CYP3A4 Inducers 
Strong Inhibitors 
Barbiturates 
Clarithromycin 
Carbamazepine 
Indinavir 
Efavirenz 
Itraconazole 
Glucocorticoids 
Ketoconazole 
Modafinil 
Nefazodone 
Nevirapine 
Posaconazole 
Oxcarbazepine 
Ritonavir 
Phenobarbital 
Saquinavir 
Phenytoin  
Suboxone 
Pioglitazone  
Telithromycin 
Rifabutin  
Voriconazole 
St. John's Wort 
Conivaptin 
Troglitazone 
Lopinavir/ritonavir 
 
Nefazodone 
 
Nelfinavir 
 
Intermediate Strength Inhibitors 
 
Aprepitant 
 
Erythromycin 
 
Fluconazole 
 
Isavuconazole 
 
Verapamil 
 
Diltiazem 
 
Weak Inhibitors 
 
Cimetidine 
 
Other Possible Inhibitors 
 
Amiodarone 
 
Boceprevir 
 
Chloramphenicol 
 
Ciprofloxacin 
 
Delaviridine 
 
Diethyl-dithiocarbamate 
 
Fluvoxamine 
 
Gestodene 
 
Imatinib 
 
Mibefradil 
 
Mifepristone 
 
Norfloxacin 
 
Norfluoxetine 
 
Starfruit 
 
Telaprevir 
 


 
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AMENDMENT 3.0, VERSION 4.0 
 
Appendix H Management of Acalabrutinib-Related Adverse Events 
Progressive multifocal leukoencephalopathy (PML) 
Cases of PML have been reported in subjects treated with acalabrutinib.   
Signs and symptoms of PML may include cognitive and behavioral changes, language 
disturbances, visual disturbances, sensory deficits, weakness, and coordination and gait 
difficulties. 
If PML is suspected, hold further treatment with acalabrutinib until PML is excluded. A 
diagnostic evaluation may include (but is not limited to): 
• Neurologic consultation 
• Brain MRI 
• PCR analysis for John Cunningham (JC) virus DNA in cerebrospinal fluid 
If PML is confirmed, permanently discontinue acalabrutinib. 
Infections 
Subjects receiving treatment with acalabrutinib may be at an increased risk of infection.  
Subjects should be made aware of the risk of possible overlapping toxicities of infections while 
receiving the study drug.  This should be managed as per clinical practice. In case of Grade 3 
infections, the guidelines provided in Table 3 should be followed.