Conditions: Chronic Lymphocytic Leukemia and Relapsed and Refractory Mantle Cell Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 103
Healthy volunteers: no

Brief summary:
This study is plan to assess the safety and efficacy of Acalabrutinib in Indian patients with chronic lymphocytic leukaemia (CLL) and relapsed and refractory mantle cell lymphoma (MCL)

Detailed description:
A prospective, multi-centre, phase IV clinical trial of Acalabrutinib capsules in Indian adult patients with chronic lymphocytic leukaemia (CLL) and relapsed and refractory mantle cell lymphoma (MCL). As per recommendation from Indian health authority, the current phase-IV study is planned with the aim to assess the safety and efficacy profile of Acalabrutinib in Indian patients with CLL/SLL, and patients with MCL who have received at least one prior therapy. The data obtained from the study will help to understand the safety and efficacy profile of Acalabrutinib in Indian patients. Patients will be monitored throughout the study period for Adverse Events of Acalabrutinib

Arms:
arm 1: Single-arm study

Interventions: intervention 1: Acalabrutinib capsule
Intervention descriptions: intervention 1: The recommended dose of Acalabrutinib is 100 mg given per oral (PO) twice daily

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol  
Drug Substance - ACALABRUTINIB 
AstraZeneca 
Study Code        - D8220C00022 
Version  1.0, Date: 01 Sep 2020 
CONFIDENTIAL AND PROPRIETARY 
Page 1 of 60 
Clinical Study Protocol 
Drug Substance 
ACALABRUTINIB 
Study Code 
D8220C00022 
Version 
1.0 
Date 
01/09/2020 
A prospective, multi-centre, phase IV clinical trial to assess the safety and 
efficacy of Acalabrutinib capsules in Indian adult patients with chronic 
lymphocytic leukaemia and relapsed and refractory mantle cell lymphoma 
Sponsor: 
AstraZeneca Pharma India Limited 
Block N1, 12th Floor, Manyata Embassy Business Park 
Rachenahalli, Outer Ring Road, Bangalore-560045. 
Redacted for Public Disclosure




Clinical Study Protocol  
Drug Substance - ACALABRUTINIB  
AstraZeneca 
Study Code        - D8220C00022 
Version  1.0, Date: 01 Sep 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
  
 
 
 
Page 3 of 60 
TABLE OF CONTENTS 
TITLE PAGE ......................................................................................................................... 1 
VERSION HISTORY .............................................................................................................. 2 
TABLE OF CONTENTS ......................................................................................................... 3 
1. 
PROTOCOL SUMMARY....................................................................................... 6 
1.1 
Schedule of Activities (SoA) ................................................................................... 6 
1.2 
Synopsis ................................................................................................................... 8 
Rationale 9 
Objectives and Endpoints ....................................................................................................... 10 
Overall design ........................................................................................................................ 10 
Patient Population .................................................................................................................. 11 
Study Drug, dosage, and mode of administration .................................................................. 13 
Duration of treatment ............................................................................................................. 13 
Post-trial access ...................................................................................................................... 13 
Safety Evaluations .................................................................................................................. 14 
Efficacy Evaluations .............................................................................................................. 14 
Statistical methods: ................................................................................................................ 14 
1.3 
Schema ................................................................................................................... 14 
2. 
INTRODUCTION ................................................................................................. 15 
2.1 
Study rationale ....................................................................................................... 15 
2.2 
Background ............................................................................................................ 15 
2.2.1 
Acalabrutinib ......................................................................................................... 15 
2.2.2 
Chronic Lymphocytic Leukaemia and Small Lymphocytic Lymphoma .............. 16 
2.2.3 
Mantle Cell Lymphoma ......................................................................................... 18 
2.3 
Benefit/risk assessment .......................................................................................... 19 
3. 
OBJECTIVES AND ENDPOINTS ....................................................................... 19 
4. 
STUDY DESIGN .................................................................................................. 20 
4.1 
Overall design ........................................................................................................ 20 
4.1.1 
Screening Phase (Visit 1)....................................................................................... 21 
4.1.2 
Treatment Phase (Visit 2 To 7) .............................................................................. 21 
4.1.3 
End–of–Treatment Visit (EOT) ............................................................................. 22 
4.1.4 
Follow-Up Phase (End-Of-Study) ......................................................................... 22 
4.2 
Scientific rationale for study design ...................................................................... 22 
4.3 
Justification for dose .............................................................................................. 23 
4.4 
End of study definition .......................................................................................... 23 
5. 
STUDY POPULATION ........................................................................................ 23 
5.1 
Inclusion criteria .................................................................................................... 23 
5.2 
Exclusion criteria ................................................................................................... 25 
5.3 
Lifestyle restrictions .............................................................................................. 26 
5.4 
Screen failures ....................................................................................................... 26 


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6. 
STUDY TREATMENTS ...................................................................................... 26 
6.1 
Treatments administered ........................................................................................ 26 
6.1.1 
Duration of treatment ............................................................................................. 27 
6.1.2 
Administration ....................................................................................................... 27 
6.2 
Handling/storage/accountability ............................................................................ 27 
6.3 
Measures to minimise bias: randomisation and blinding ...................................... 27 
6.4 
Treatment compliance ........................................................................................... 28 
6.5 
Concomitant therapy .............................................................................................. 28 
6.5.1 
Other concomitant treatment/s ............................................................................... 28 
6.5.2 
Rescue medication/s .............................................................................................. 29 
6.6 
Dose modification .................................................................................................. 29 
7. 
DISCONTINUATION OF STUDY DRUG .......................................................... 29 
7.1 
Discontinuation of study treatment ........................................................................ 29 
7.2 
Withdrawal from the study .................................................................................... 29 
8. 
STUDY ASSESSMENTS AND PROCEDURES................................................. 30 
8.1 
Efficacy and Safety assessments ........................................................................... 31 
8.1.1 
Efficacy Assessment .............................................................................................. 31 
8.1.2 
Safety assessments ................................................................................................. 33 
8.2 
Collection of adverse events .................................................................................. 36 
8.2.1 
Method of detecting AEs and SAEs ...................................................................... 36 
8.2.2 
Time period and frequency for collecting AE and SAE information .................... 36 
8.2.3 
Follow-up of AEs and SAEs.................................................................................. 37 
8.2.4 
Adverse event data collection ................................................................................ 37 
8.2.5 
Causality collection ............................................................................................... 38 
8.2.6 
Adverse events based on signs and symptoms ...................................................... 38 
8.2.7 
Adverse events based on examinations and tests .................................................. 38 
8.3 
Safety reporting and medical management............................................................ 39 
8.3.1 
Reporting of serious adverse events ...................................................................... 39 
8.3.2 
Pregnancy .............................................................................................................. 40 
8.3.3 
Overdose ................................................................................................................ 41 
9. 
STATISTICAL CONSIDERATIONS .................................................................. 41 
9.1 
Statistical hypotheses ............................................................................................. 41 
9.2 
Sample size determination ..................................................................................... 41 
9.3 
Populations for analyses ........................................................................................ 42 
9.4 
Statistical analysis .................................................................................................. 42 
10. 
REFERENCES ...................................................................................................... 43 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................. 45 
 


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AstraZeneca 
Study Code        - D8220C00022 
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LIST OF TABLES 
Table 1: Schedule of Activities (SoA) ..................................................................................... 6 
Table 2: Study objectives ....................................................................................................... 19 
Table 3: Study Treatments ..................................................................................................... 26 
Table 4: Response (CR and PR) definition after treatment of CLL/SLL patients 
(Hallek et al., 2018) .................................................................................. 32 
Table 5: Response Assessment Criteria for MCL patients .................................................... 32 
Table 6: Haematology ............................................................................................................ 34 
Table 7: Clinical chemistry (serum or plasma) ...................................................................... 34 
Table 8: Estimated Incidence and Precision .......................................................................... 42 
Table 9: Recommended Dose Adjustments for Adverse Reactions* ..................................... 52 
 
LIST OF FIGURES 
Figure 1. Study design ............................................................................................................ 15 
Figure 2: Study Flow .............................................................................................................. 21 
LIST OF APPENDICES 
Appendix A 
Regulatory, ethical and study oversight considerations ........................... 45 
Appendix B 
Adverse event definitions and additional safety information................... 48 
Appendix C         Recommended Treatment Modifications for Acalabrutinib and 
Management Recommendations .............................................................. 52 
Appendix D:        EORTC QLQ-C30 .................................................................................... 53 
Appendix E:         Abbreviations .......................................................................................... 55 








Clinical Study Protocol  
Drug Substance - ACALABRUTINIB  
AstraZeneca 
Study Code        - D8220C00022 
Version  1.0, Date: 01 Sep 2020 
 
 
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No. of total enrolled patients: Approximately 100 
No. of study sites: 10 
Total planned study period 
 
Estimated date of the first patient in 
Q4 2020 
Estimated date of the last patient in 
Q2 2021 
Estimated date of last patient last visit 
Q4 2021 
Estimated date of database lock 
Q2 2022 
Clinical study report  
Q3 2022 
Rationale 
Chronic lymphocytic leukaemia (CLL) is a malignancy of B cells that predominantly affects an 
elderly population. It is the most prevalent form of adult leukaemia, with an age-adjusted 
incidence of 3.3–6.4 per 100,000 person-years and a median age at diagnosis of 70 years (Noone 
AM, April 2018). The diagnosis of CLL is established using peripheral blood and immune-
phenotyping and requires the presence of a minimum of 5 x 109/L monoclonal B cells that co-
express the surface antigens CD5, CD19, CD20, and CD23. In routine practice, patients with 
asymptomatic early-stage disease should be monitored without therapy unless they have 
evidence of disease progression or disease-related symptoms. Treatment of CLL is initiated once 
there is evidence of progressive or symptomatic/active disease as defined by iwCLL guidelines 
(Hallek et al., 2018; Hallek et al., 2008). Despite the relatively long life expectancy for early-
stage disease, CLL remains an incurable disease. 
The incidence of CLL in India is 0.41 per 100,000 person-years; not as common as in the western 
countries. However, estimates of the incidental cases are 5000 per year with a prevalence of 
25000 patients (one-third that of the estimate for the United States)(Lad et al., 2018). In India, 
CLL accounts for 3-5% of all leukaemia types. CLL is a disease of the elderly and the median 
age of CLL presentation is >60yrs in India. The high-risk CLL is defined, by a genetic aberration 
of the TP53 gene [i.e., del(17p) or TP53 mutation]. The incidence of high-risk characteristics 
(del 17p) increase up to 50% in patients with relapsed and refractory CLL (Gogia, Gupta, Kumar, 
Sharma, & Soni, 2019). An Indian study showed that high-risk cytogenetic abnormalities like 
del(17p) and del(11q) were seen in 13.3% patients, which are more common in India than that 
reported in the West. (Saxena, Kumar, Sazawal, & Mahapatra, 2016)   
The Scientific Expert Committee (SEC) of Oncology and Haematology, nominated by Central 
Drugs Standard Control Organisation (CDSCO), met on 12-Feb-2020. The committee provided 
recommendations to obtain marketing authorization for Acalabrutinib in the treatment of patients 
with CLL/SLL, and patients with MCL who have received at least one prior therapy. The 
marketing authorization was provided with a condition to conduct a phase IV clinical trial as per 
the requirements in the latest New Drug and Clinical Trial Rules (2019) in India. The phase IV 
trial will be a part of the marketing authorization condition, which will be issued for the 
additional indication of CLL for Acalabrutinib in India.  
In line with the SEC recommendation and to comply with the marketing authorization condition, 
the current phase IV study plans to assess the safety and efficacy of Acalabrutinib in Indian 
patients. The data obtained from the study will help to understand the safety and efficacy profile 
of Acalabrutinib in Indian patients with CLL/SLL, and patients with MCL who have received at 


Clinical Study Protocol  
Drug Substance - ACALABRUTINIB  
AstraZeneca 
Study Code        - D8220C00022 
Version  1.0, Date: 01 Sep 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
  
 
 
 
Page 10 of 60 
least one prior therapy. The study will add information to currently available safety and efficacy 
data on Acalabrutinib. 
Objectives and Endpoints 
Primary objective 
To investigate the safety of Acalabrutinib 
among patients with treatment naïve and 
R/R CLL/ SLL, and relapsed & refractory 
MCL in Indian patients   
Outcome measures 
Adverse Events (AEs), Serious Adverse 
Events (SAEs), and AEs of Special Interest 
(AESI) including Arrhythmias (Atrial 
Fibrillation), Anaemia, Hypertension, 
Bleeding, Infections,  
Reasons for discontinuation  and second 
primary malignancies   
Secondary objectives 
To assess the efficacy of Acalabrutinib in 
patients of CLL/SLL and relapsed & 
refractory MCL in Indian patients   
Patient-reported outcome (PRO)  
Secondary Outcome measures 
Objective response to treatment. 
 
Health related quality of life (EORTC QLQ-
C30 Questionnaire) 
Overall design 
The study is a phase IV, open-label, single-arm, multi-centre, prospective study to be conducted 
in India. The study will evaluate the safety and efficacy of Acalabrutinib in Indian adult patients 
with CLL/SLL and patients with MCL who have received at least one prior therapy. The 
Investigator will be trained on the locally approved Prescribing Information (PI) before the 
enrolment of the first patient at their site to ensure compliance and proper dosing of the study 
drug. Patients will be monitored throughout the study period for AEs /SAEs/AESI of 
Acalabrutinib.  
Patients with CLL/SLL and MCL who are eligible to receive Acalabrutinib treatment as per 
locally approved PI and ratified by an independent clinical judgment of treating physician will 
be evaluated for inclusion into the current phase IV trial. To enrol approximately 100 patients 
(90 patients of TN & R/R CLL and 10 R/R MCL patients) into the study, it is expected that 
approximately 150 patients will need to be screened. 
The study will be initiated after approval by the Ethics Committee. Patients will undergo the 
following phases: Screening/Enrolment Phase, Treatment Phase, and Follow-up Phase.  
The decision of patients to participate in this study must not, in any way, impact the standard of 
care they are receiving or any benefits to which they are otherwise entitled.   Prior to data 
collection, all patients must sign an Informed Consent Form (ICF), allowing for data collection 
and source data verification to be performed in accordance with local requirements and Sponsor 
policy. 
Two cohorts of patients will be included in the current study (a) patients with CLL/SLL who are 
treatment naïve or have received at least one prior therapy (N= 90) and (b) patients with MCL 


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AstraZeneca 
Study Code        - D8220C00022 
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Page 11 of 60 
who have received at least one prior therapy (N= 10). Potential patients will undergo screening 
phase within 07 days prior to the first dose. Patients who meet the protocol-defined 
inclusion/exclusion criteria will be prospectively enrolled in the study.  
Acalabrutinib capsules 100 mg are administered twice daily (BID) for 06 cycles, starting from 
Cycle 1, Day 1, and continuing up to Cycle 6, Day 28; or until study drug discontinuation due to 
either disease progression or, unacceptable toxicity, or other reasons, whichever occurs earlier. 
Acalabrutinib will be provided by the Sponsor to patients in the Treatment Phase. The Sponsor 
shall also conduct laboratory investigations for safety and efficacy evaluations, including 
haematology, biochemistry, radiology, and electrocardiography (ECG), as mentioned in the SoA 
table. 
Patient Population 
Inclusion criteria 
Patients are eligible to be included in the study only if all of the following inclusion criteria and 
none of the exclusion criteria apply: 
1. Men and Women aged 18yrs or more. 
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0,1, or 2 
3. Able to receive all outpatient treatments, all laboratory monitoring, and all radiologic 
evaluations. 
4. The following laboratory parameters: 
a. Absolute neutrophil count (ANC) ≥750 cells/μL or ≥500 cells/μL in patients with 
documented bone marrow involvement, and independent of growth factor support 
07 days before the assessment 
b. Platelet count ≥50,000 cells/μL or ≥30,000 cells/μL in patients with documented 
bone marrow involvement, and without transfusion support 07 days before the 
assessment 
c. Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤2.0 x ULN 
d. Total bilirubin ≤1.5 x ULN 
e. Estimated creatinine clearance of ≥30 mL/min 
5. Refractory disease defined as achieving less than partial response with the most recent 
treatment within 6 months before study entry 
6. Provision of signed, written and dated informed consent prior to any study-specific 
Procedures 
7. The patients of either CLL or MCL: 
a. CLL patients: 
i. Treatment naïve or ≥1 prior systemic therapy for CLL 
ii. Diagnosis of CD20+ CLL that meets published diagnostic criteria (Hallek 
et al. 2018) 
iii. An active disease that meets ≥1 of the following iwCLL 2018 criteria for 
requiring treatment: 
1) Evidence of progressive marrow failure as manifested by the 
development 
of, 
or 
worsening 
of, 
anaemia 
and/or 
thrombocytopenia. Cut-off levels of Hb <10 g/dL or platelet 


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counts <100 × 109/L are generally regarded as an indication for 
treatment. However, in some patients, platelet counts <100 × 
109/L may remain stable over a long period; this situation does not 
automatically require therapeutic intervention. 
2) Massive (i.e., ≥6 cm below the left costal margin) or progressive 
or symptomatic splenomegaly. 
3) Massive nodes (i.e., ≥10 cm in longest diameter) or progressive or 
symptomatic lymphadenopathy. 
4) Progressive lymphocytosis with an increase of ≥50% over a 2-
month period or Lymphocyte Doubling Time (LDT) in <6 months. 
LDT can be obtained by linear regression extrapolation of absolute 
lymphocyte counts obtained at intervals of 2 weeks over an 
observation period of 2 to 3 months; patients with initial blood 
lymphocyte counts <30 × 109/L may require a longer observation 
period to determine the LDT. Factors contributing to 
lymphocytosis other than CLL (e.g., infections, steroid 
administration) should be excluded. 
5) Autoimmune 
complications, 
including 
anaemia 
or 
thrombocytopenia poorly responsive to corticosteroids. 
6) Symptomatic or functional extra-nodal involvement (e.g., skin, 
kidney, lung, spine). 
7) Disease-related symptoms as defined by any of the following: 
a) Unintentional weight loss of ≥10% within the previous 06 
months. 
b) Significant fatigue (i.e., ECOG performance scale 02 or 
worse; cannot work or unable to perform usual activities). 
c) Fever ≥100.5°F or 38.0°C for 02 or more weeks without 
evidence of infection. 
d) Night sweats for ≥1 month without evidence of infection. 
 
b. MCL Patients:  
i. Confirmed MCL with translocation t(11;14) (q13;q32) and/or 
overexpressed cyclin D1 
ii. Measurable nodal disease (one or more lesions measuring ≥2 cm in the 
longest diameter) 
iii. Relapsed after, or were refractory to, 1-5 previous treatments 
 
Exclusion criteria  
1. Known prolymphocytic leukaemia, Central Nervous System (CNS) lymphoma or 
leukaemia; or known history of (or currently suspected) Richter’s syndrome 
2. Treatment with chemotherapy, external beam radiation therapy, anticancer antibodies, or 
investigational drug within 30 days of the first dose of study drug 
3. Prior radio-conjugated or toxin-conjugated antibody therapy 


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4. Anticoagulation therapy (e.g., warfarin or equivalent vitamin K antagonists) within 07 
days of the first dose of study drug. 
5. Major surgery ≤30 days before the first dose of study drug 
6. History of stroke or intracranial haemorrhage ≤6 months before the first dose of study 
drug 
7. History of bleeding diathesis 
8. Prior exposure to a B-cell lymphoma-2 (Bcl-2) inhibitor or B-cell receptor inhibitor like 
BTKs 
9. Active Cytomegalovirus (CMV) infection or serologic status reflecting active Hepatitis 
B or C infection or known history of infection with Human Immunodeficiency Virus 
(HIV), or any uncontrolled active systemic infection. 
10. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
Congestive Heart Failure, or Myocardial Infarction within 06 months of screening, or 
any Class 3 or 4 cardiac diseases as defined by the New York Heart Association 
Functional Classification, or QTcB >480 msec at screening. 
11. Requiring treatment with proton-pump inhibitors (e.g., Omeprazole, Esomeprazole, 
Lansoprazole, Dexlansoprazole, Rabeprazole, or Pantoprazole). 
12. Breastfeeding or pregnant. 
13. Current life-threatening illness, medical condition, or organ/system dysfunction which, 
in the Investigator’s opinion, could have compromised the subject’s safety or put the 
study at risk. 
14. Concurrent participation in another therapeutic clinical trial. 
Study Drug, dosage, and mode of administration 
The recommended dose of Acalabrutinib is 100 mg given per oral (PO) twice daily (BID) (each 
treatment cycle is 28 days) until disease progression or unacceptable toxicity. Dose escalation or 
reduction is recommended. Dose withholding or discontinuation may be required based on 
individual safety and tolerability. 
Duration of treatment 
The Treatment Phase will be from the start of Cycle 1, Day 1 to end of Cycle 6, Day 28, or until 
study drug discontinuation due to either disease progression or unacceptable toxicity, or other 
reasons whichever occurs earlier, as listed in Section 7.1.  
Post-trial access  
Patients who are observed to receive clinical benefit from Acalabrutinib after completion of 
treatment phase, may continue to receive Acalabrutinib, if in the opinion of their treating 
physician they are continuing to derive clinical benefit from continued treatment or have not 
progressed clinically. The patients may continue treatment via drug supply (provided by 
AstraZeneca) until disease progression or withdraw of drug due to side effects or investigators 
decision whichever comes first.  
These subjects shall receive the study drug free of cost in case if there is no coverage / 
reimbursement through a separate patient support program and will not receive the medication 
via the clinical trial supply for this study. These subjects shall not be actively monitored for AE’s 
and it will be the responsibility of the treating physician to ensure reporting of all SAE’s, 


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Page 14 of 60 
pregnancies, overdose and medication errors to the relevant authorities as per the standard 
spontaneous safety reporting practice in India. 
Safety Evaluations 
Safety evaluations will include adverse event monitoring, physical examinations, ECG 
monitoring, clinical laboratory investigations (haematology and biochemistry), vital sign 
measurements, ECOG performance status, and death as observed by the Investigator. Based on 
previous in vitro studies, animal toxicological findings, and human studies with Acalabrutinib, 
arrhythmias (which includes atrial fibrillation), anaemia, hypertension, bleeding, infections, and 
second primary malignancies will be closely monitored. Any of the safety monitoring 
assessments may be performed more frequently, and adverse events should be evaluated by the 
Investigator according to the standard practice if clinically indicated. 
Efficacy Evaluations 
All patients who receive Acalabrutinib capsule 100 mg BID will be evaluated for efficacy once 
every 03 months during the treatment phase. Efficacy will be assessed based on iwCLL 2018 
criteria for CLL/SLL (Hallek et al., 2018) and for MCL (Cheson et al., 2014). Efficacy will be 
based on objective response [Complete Remission (CR) + Partial Remission (PR) and partial 
response with lymphocytosis (PRL)] via Computed Tomography (CT) scans or Magnetic 
Resonance Imaging (MRI). 
Statistical methods: 
Sample Size Justification 
The primary endpoint of the trial is to demonstrate the safety profile of Acalabrutinib in routine 
clinical practice as assessed by the incidence of adverse events (AEs) (Serious and Non-serious 
AEs) observed during the trial. As per the Health Authority requirement, the total sample size of 
the study will be approximately 100.   
Hypothesis 
No formal hypothesis testing will be conducted.  
Statistical Analysis 
Categorical data will be summarized using frequencies and percentages. Continuous data will be 
summarized with descriptive statistics, including mean, standard deviation, median, minimum, 
and maximum. Confidence intervals will be supplied for key proportions (including objective 
response rate) using the Clopper-Pearson method. 
1.3 
Schema 
The general study design is summarised in Figure 1.  


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Figure 1. Study design 
 
2. 
INTRODUCTION 
2.1 
Study rationale 
The Scientific Expert Committee (SEC) of Oncology and Haematology, nominated by Central 
Drugs Standard Control Organisation (CDSCO), met on 12-Feb-2020. The committee provided 
recommendations to obtain marketing authorization for Acalabrutinib in the treatment of patients 
with CLL/SLL, and patients with MCL who have received at least one prior therapy. The 
marketing authorization was provided with a condition to conduct a phase IV clinical trial as per 
the requirements in the latest New Drug and Clinical Trial Rules (2019) in India. The phase IV 
trial will be a part of the marketing authorization condition, which will be issued for the 
additional indication of CLL for Acalabrutinib in India.  
In line with the SEC recommendation and to comply with the marketing authorization condition, 
the current phase IV study plans to assess the safety and efficacy of Acalabrutinib in Indian 
patients. The data obtained from the study will help to understand the safety and efficacy profile 
of Acalabrutinib in Indian patients with CLL/SLL, and patients with MCL who have received at 
least one prior therapy. The study will add information to currently available safety and efficacy 
data on Acalabrutinib. 
2.2 
Background 
2.2.1 
Acalabrutinib 
B cell antigen receptor (BCR) expression is essential for B-cell function, and loss of expression 
leads to rapid cell death. (Buchner & Müschen, 2014) The BCR over-expression contributes to 
the majority of B-cell malignancies. Several downstream protein kinases such as BTK (Bruton 
Tyrosine Kinase) are critical in the BCR signalling cascade. Due to the influence of BTK on cell 
proliferation and survival, it is an attractive target for inhibition to treat diseases such as CLL 
and other B-cell lymphomas. (Isaac & Mato, 2020) 


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Acalabrutinib is a selective small-molecule inhibitor of BTK. BTK is a signalling molecule of 
the BCR and cytokine receptor pathways. In B cells, BTK signalling results in B-cell survival 
and proliferation and is required for cellular adhesion, trafficking, and chemotaxis. 
Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue 
in the BTK active site, leading to irreversible inactivation of BTK (IC50 ≤ 5 nM) with minimal 
off-target interactions. In a screen of 380 mammalian wild-type kinases, the only additional 
kinase interactions at clinically relevant concentrations of Acalabrutinib and ACP-5862 were 
with BMX and ERBB4, with 3- to 4-fold less potency than BTK. In non-clinical studies, 
Acalabrutinib inhibited BTK-mediated activation of downstream signalling proteins CD86 and 
CD69, inhibited malignant B-cell proliferation and survival, and had minimal activity on other 
immune cells (T cells and Natural Killer cells). (PI, 2020) 
In patients with B-cell malignancies dosed with Acalabrutinib 100 mg twice daily, median 
steady-state BTK occupancy of ≥ 95% in peripheral blood was maintained over 12 hours, 
resulting in inactivation of BTK throughout the recommended dosing interval. 
2.2.2 
Chronic Lymphocytic Leukaemia and Small Lymphocytic Lymphoma  
CLL and SLL are characterized by a progressive accumulation of leukemic cells in the peripheral 
blood, bone marrow, and lymphoid tissues. Morphologically, these leukemic cells appear as 
small, mature lymphocytes that may be found admixed with occasional larger or atypical cells, 
or pro-lymphocytes. CLL and SLL are different manifestations of the same disease and are 
managed in much the same way. The major difference is that in CLL, a significant number of 
the abnormal lymphocytes are found in the peripheral blood in addition to bone marrow and 
lymphoid tissue, and in SLL, the bulk of disease is in lymph nodes, bone marrow, and other 
lymphoid tissues, and there are few (if any) abnormal lymphocytes circulating in the peripheral 
blood. (Wierda et al., 2020) 
Chronic lymphocytic leukaemia is a malignancy of B cells that predominantly affects an elderly 
population. It is the most prevalent form of adult leukaemia, with an age-adjusted incidence of 
3.3–6.4 per 100,000 person-years and a median age at diagnosis of 70 years (Noone AM, April 
2018). The diagnosis of CLL is established using peripheral blood and immune-phenotyping and 
requires a minimum of 5 x 109/L monoclonal B cells that co-express the surface antigens CD5, 
CD19, CD20, and CD23. In routine practice, patients with asymptomatic early-stage disease 
should be monitored without therapy unless they have evidence of disease progression or 
disease-related symptoms. Treatment of CLL is initiated once there is evidence of progressive 
or symptomatic/active disease as defined by iwCLL guidelines (Hallek et al., 2018; Hallek et al., 
2008). Despite the relatively long life expectancy for early-stage disease, CLL remains an 
incurable disease. 
The incidence of CLL in India is 0.41 per 100,000 person-years not; as common as in the western 
countries.  However, estimates of the incidental cases are 5000 per year with a prevalence of 
25000 patients (one-third that of the estimate for the United States). (Lad et al., 2018) In India, 
CLL accounts for 3-5% of all leukaemia types. CLL is a disease of the elderly and the median 
age of CLL presentation is >60yrs in India. The high-risk CLL is defined, at least in part, by a 
genetic aberration of the TP53 gene [i.e., del(17p) or TP53 mutation]. The incidence of high-risk 
characteristics (del 17p) increase up to 50% in patients with relapsed and refractory CLL (Gogia 
et al., 2019). An Indian study showed that high-risk cytogenetic abnormalities like del(17p) and 


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del(11q) were seen in 13.3% patients, which are more common in India than that reported in the 
West. (Saxena et al., 2016)  
The safety and efficacy of Acalabrutinib in previously untreated CLL were evaluated in a 
randomised, multi-centre, open-label Phase 3 study (ELEVATE-TN) of 535 patients. Patients 
received Acalabrutinib plus Obinutuzumab, Acalabrutinib monotherapy, or Obinutuzumab plus 
Chlorambucil. Patients 65 years of age or older or between 18 and 65 years of age with coexisting 
medical conditions were included in ELEVATE-TN. The trial also allowed patients to receive 
antithrombotic agents other than warfarin or equivalent vitamin K antagonists. (PI, 2020) 
Patients were randomised in a 1:1:1 ratio into 03 arms to receive  
 Acalabrutinib plus Obinutuzumab (Acalabrutinib+G): Acalabrutinib 100 mg was 
administered twice daily, starting on Cycle 1 Day 1 until disease progression or unacceptable 
toxicity. Obinutuzumab was administered starting on Cycle 2 Day 1 for a maximum of 
6 treatment cycles. Obinutuzumab 1000 mg was administered on Days 1 and 2 (100 mg on 
Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 2 followed by 1000 mg on Day 1 of Cycles 
3 up to 7. Each cycle was of 28 days.   
 Acalabrutinib monotherapy: Acalabrutinib 100 mg was administered twice daily until 
disease progression or unacceptable toxicity. 
 Obinutuzumab plus Chlorambucil (GClb): Obinutuzumab and Chlorambucil were 
administered for a maximum of 6 treatment cycles. Obinutuzumab 1000 mg was 
administered on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 1 
followed by 1000 mg on Day 1 of Cycles 2 up to 6. Chlorambucil 0.5 mg/kg was 
administered on Days 1 and 15 of Cycles 1 up to 6. Each cycle was of 28 days. 
 
Patients were stratified by 17p deletion mutation status (presence versus absence), ECOG 
performance status (0 or 1 versus 2), and geographic region (North America and Western Europe 
versus other). After confirmed disease progression, 45 patients randomised on the GClb arm 
crossed over to Acalabrutinib monotherapy.  
The primary endpoint was progression-free survival (PFS) as assessed by an Independent 
Review Committee (IRC) per iwCLL 2008 criteria with the incorporation of the clarification for 
treatment-related lymphocytosis (Cheson 2012). With a median follow-up of 28.3 months, PFS 
by IRC indicated a 90% statistically significant reduction in the risk of disease progression or 
death for previously untreated CLL patients in the Acalabrutinib + G arm compared to the GClb 
arm. At the time of analysis, median overall survival had not been reached in any arm with a 
total of 37 deaths: 9 (5%) in the Acalabrutinib +G arm, 11 (6.1%) in the Acalabrutinib 
monotherapy arm, and 17 (9.6%) in the GClb arm.  
PFS results for Acalabrutinib with or without Obinutuzumab were consistent across subgroups, 
including high-risk features in the high-risk CLL population (17p deletion, 11q deletion, TP53 
mutation, and un-mutated IGHV), the PFS hazard ratios of Acalabrutinib with or without 
Obinutuzumab versus Obinutuzumab plus Chlorambucil were 0.08 [95% CI (0.04, 0.15)] and 
0.13 [95% CI (0.08, 0.21)], respectively. 
Patients with CLL who received at least one prior therapy (PI, 2020) 
The safety and efficacy of Acalabrutinib in relapsed or refractory CLL were evaluated in a 
randomised, multi-centre, open-label phase 3 study (ASCEND) of 310 patients who received at 


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least one prior therapy. Patients received Acalabrutinib monotherapy or Investigator’s choice of 
either Idelalisib plus Rituximab or Bendamustine plus Rituximab. The trial allowed patients to 
receive antithrombotic agents other than warfarin or equivalent vitamin K antagonists. 
Patients were randomised 1:1 to receive either: Acalabrutinib 100 mg twice daily until disease 
progression or unacceptable toxicity, or Investigator’s choice: 
 Idelalisib 150 mg twice daily until disease progression or unacceptable toxicity in 
combination with ≤8 infusions of rituximab (375 mg/m2/500 mg/m2) on Day 1 of each 28-
day cycle for up to 6 cycles 
 Bendamustine 70 mg/m2 (Day 1 and 2 of each 28-day cycle) in combination with rituximab 
(375 mg/m2/500 mg/m2) on Day 1 of each 28-day cycle for up to 6 cycles 
Patients were stratified by 17p deletion mutation status (presence versus absence), ECOG 
performance status (0 or 1 versus 2), and a number of prior therapies (1 to 3 versus ≥ 4). After 
confirmed disease progression, 35 patients randomised on the Investigator’s choice of either 
Idelalisib plus Rituximab or Bendamustine plus Rituximab crossed over to Acalabrutinib.  
The primary endpoint was PFS as assessed by IRC iwCLL 2008 criteria with the incorporation 
of the clarification for treatment-related lymphocytosis (Cheson 2012). With a median follow-
up of 16.1 months, PFS indicated a 69% statistically significant reduction in the risk of death or 
progression for patients in the Acalabrutinib arm. At the time of analysis, median overall survival 
had not been reached in any arm with a total of 33 deaths: 15 (9.7%) in the Acalabrutinib 
monotherapy arm and 18 (11.6%) in the Investigator’s choice of either Idelalisib plus rituximab 
or Bendamustine plus rituximab arm.  
PFS results for Acalabrutinib were consistent across subgroups, including high-risk features. In 
the high risk CLL population (17p deletion, 11q deletion, TP53 mutation, and un-mutated 
IGHV), the PFS HR was 0.27 [95% CI (0.17, 0.44)]. 
2.2.3 
Mantle Cell Lymphoma 
MCL is a distinct sub-type of non-Hodgkin’s lymphoma (NHL) comprising approximately 7% 
of all adult NHL, with a moderately aggressive clinical course and poor outcome. The primary 
cell of origin of MCL is thought to be a naive B cell of pre-germinal centre origin within the 
mantle zone of the lymph node. The incidence of MCL increases with age and an increase in 
incidence has been observed over time. (Zhou et al., 2008) The disease is characterized by the 
chromosomal translocation t(11;14)(q13·3; q32·33), resulting in over‐expression of the cell 
cycle protein cyclin D1. (McKay, Leach, Jackson, Robinson, & Rule, 2018) the role of BTK 
inhibitors was demonstrated to manage relapse and refractory cases of MCL. (Schieber, Gordon, 
& Karmali, 2018) 
The safety and efficacy of Acalabrutinib in MCL were evaluated in an open-label, multi-centre, 
single-arm Phase 2 study (ACE-LY-004) of 124 previously treated patients. All patients received 
Acalabrutinib 100 mg orally twice daily until disease progression or unacceptable toxicity. The 
trial did not include patients who received prior treatment with BTK inhibitors. The primary 
endpoint was Investigator-assessed overall response rate (ORR) per the Lugano classification 
for non-Hodgkin’s lymphoma (NHL). Duration of Response (DoR) was an additional outcome 
measure. (PI, 2020) 


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The median age was 68 (range 42 to 90) years, 79.8% were male, and 74.2% were Caucasian. 
At baseline, 92.8% of patients had an ECOG performance status of 0 or 1. The median time since 
diagnosis was 46.3 months, and the median number of prior treatments was 02 (range 1 to 5), 
including 17.7% with prior stem cell transplant. The most common prior regimens were CHOP-
based (51.6%) and ARA-C (33.9%).  At baseline, 37.1% of patients had at least one tumour with 
the longest diameter ≥5 cm, 72.6% had extra-nodal involvement, including 50.8% with bone 
marrow involvement. The simplified Mantle Cell Lymphoma International Prognostic Index 
(MIPI) score, (which includes age, ECOG score, and baseline lactate dehydrogenase and white 
cell count) was intermediate in 43.5% and high in 16.9% of patients. (PI, 2020) 
As per recommendation by the Regulatory Authority, the current phase-IV study is planned with 
the aim to assess the safety and efficacy of Acalabrutinib in Indian patients as a post-marketing 
requirement. The data obtained from the present study will help to understand the safety and 
efficacy profile of Acalabrutinib in Indian patients with CLL and MCL. 
2.3 
Benefit/risk assessment 
Patients with CLL/SLL and patients with MCL who have received at least one prior therapy will 
be treated with Acalabrutinib 100 mg BID from Day1 Cycle 1 for 06 cycles (each treatment 
cycle is 28 days). During this time, the patient will be monitored for safety and efficacy according 
to the assessment frequency presented in Table 1. The efficacy and safety of Acalabrutinib is 
established in various studies in CLL/SLL and MCL patients (refer Section 2).  
Overall, Acalabrutinib monotherapy demonstrated satisfactory safety profile in various studies 
conducted in patients of CLL/SLL, and MCL (Table 3). Most AEs are low-grade (Grade 1 to 2) 
with relatively few related high-grade (Grade 3 to 4) AEs.  
More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of Acalabrutinib may be found in the Acalabrutinib India PI. 
3. 
OBJECTIVES AND ENDPOINTS 
Table 2: Study objectives 
Primary objective 
Outcome measures 
To investigate the safety of Acalabrutinib 
among patients with CLL/ SLL, and relapsed 
& refractory MCL in Indian patients   
Adverse Events (AEs), Serious Adverse 
Events (SAEs), and AEs of Special Interest 
(AESI) including Arrhythmias (Atrial 
Fibrillation), Anaemia, Hypertension, 
Bleeding, Infections,  
Reasons for discontinuation  and second 
primary malignancies   
Secondary objectives 
Secondary Outcome measures 


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To assess the efficacy of Acalabrutinib in 
patients of CLL/SLL and relapsed & 
refractory MCL in Indian patients   
Patient-reported outcome (PRO)  
Objective response to treatment. 
 
Health related quality of life (EORTC QLQ-
C30 Questionnaire) 
 
4. 
STUDY DESIGN 
4.1 
Overall design 
The study is a phase IV, open-label, single-arm, multi-centre, prospective study to be conducted 
in India. The study will evaluate the safety and efficacy of Acalabrutinib in Indian adult patients 
with CLL/SLL, and patients with MCL who have received at least one prior therapy. The 
Investigator will be trained on the locally approved Prescribing Information before the enrolment 
of the first patient at their site to ensure compliance and proper dosing of the study drug. Patients 
will be monitored throughout the study period for AEs /SAEs/AESI of Acalabrutinib.  
Patients with CLL/SLL and MCL who are eligible to receive Acalabrutinib treatment as per 
locally approved prescribing information and ratified by an independent clinical judgment of 
treating physician, will be evaluated for inclusion into the current phase IV trial. To enrol 
approximately 100 patients into the study, it is expected that approximately 150 patients will 
need to be screened. 
The study will be initiated after approval by the Ethics Committee. Patients will undergo the 
following phases: Screening/Enrolment Phase, Treatment Phase, and Follow-up Phase.  
The decision of patients to participate in this study must not, in any way, impact the standard of 
care they are receiving or any benefits to which they are otherwise entitled. Prior to data 
collection, all patients must sign an ICF, allowing for data collection and source data verification 
to be performed in accordance with local requirements and Sponsor policy. 
Two cohorts of patients will be included in the current study (a) patients with CLL/SLL who are 
treatment naïve or have received at least one prior therapy (N= 90) and (b) patients with MCL 
who have received at least one prior therapy (N= 10). Potential patients will undergo screening 
phase within 07 days prior to the first Acalabrutinib dose. Patients who meet the protocol-defined 
inclusion/exclusion criteria will be prospectively enrolled into the study.  
Acalabrutinib capsules 100 mg administered orally twice daily (BID) for 06 cycles, starting from 
Cycle 1, Day 1, and continuing up to Cycle 6, Day 28; or until study drug discontinuation due to 
either disease progression or, unacceptable toxicity, or other reasons, whichever occurs earlier. 
Acalabrutinib will be provided by the Sponsor to patients in the Treatment Phase. The Sponsor 
shall also conduct laboratory investigations for safety and efficacy evaluation, including 
haematology, biochemistry, radiology, and electrocardiography (ECG), as mentioned in the SoA 
table. 


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Figure 2: Study Flow 
 
4.1.1 
Screening Phase (Visit 1) 
Patients, or their Legally Acceptable Representative (LAR), will provide written informed 
consent before any trial-specific procedures are performed. If the patient and/or LAR are unable 
to read, an impartial witness should be present during the entire informed consent discussion. 
During the Screening Phase, eligibility criteria will be reviewed, and a complete clinical 
evaluation will be performed as specified in the SoA (Table 1). Screening procedures will be 
performed up to 07 days prior to Cycle 1, Day 1. All baseline disease characteristics will be 
captured based on the evaluation performed as a part of routine clinical practice. The 
investigations that are required before the consideration of the patient for Acalabrutinib treatment 
must have been performed before the first dose (Cycle 1, Day 1). The NGS tests should be 
performed before the start of the treatment as per SoA (Table 1). Next-generation sequencing 
will be conducted to understand the genetic profile in Indian settings. Molecular cytogenetics 
(FISH) for del(13q), del(11q), del(17p), trisomy 12 in peripheral blood lymphocytes; TP53 
mutation; immunoglobulin variable heavy chain (IGHV) mutational status will be assessed 
before the start of treatment in CLL/SLL-naïve patients, or CLL/SLL patients who did not have 
their report. However, MCL patients are Relapsed/Refractory and their previous report data will 
be used. A six months old report can be considered for both the conditions. 
4.1.2 
Treatment Phase (Visit 2 To 7) 
The Treatment Phase will start from Cycle 1, Day 1 to Cycle 6, Day 28, or until study drug 
discontinuation due to either disease progression, unacceptable toxicity; or other reasons, 
whichever occurs earlier. Each cycle of treatment is defined as 28 days of twice-daily 
Acalabrutinib treatment.  


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Details of the procedures performed during the Treatment Phase are outlined in the Schedule of 
Activity table. Patients will be closely monitored for adverse events and other safety evaluations, 
including laboratory investigations, concomitant medications etc. as provided in SoA table. If 
disease progression is diagnosed before Day 168, then the patient will discontinue the study drug. 
The End-of-Treatment Visit evaluations will be completed on the day of progression and patient 
will enter the safety Follow-up Phase. 
4.1.3 
End–of–Treatment Visit (EOT) 
An End-of-Treatment Visit will be scheduled on Day 170 (Visit 8) of the study. All patients who 
will complete the Treatment phase will be assessed for EOT. In the event where a patient 
discontinues the study treatment for any reason listed in Section 7.1 before Day 168, the last visit 
of the patient will be considered as the End-of-Treatment Visit and the patient will be assessed 
as per EOT visit.  
4.1.4 
Follow-Up Phase (End-Of-Study) 
The Follow-up Phase will begin once a patient discontinues study drug or completes the 
Treatment Phase. The follow-up phase will continue until 28 days after last dose, loss to follow 
up, withdrawal of consent for study participation, or end of the study, whichever occurs earlier. 
A follow-up will be conducted 28 days after the EOT visit via a phone call. This will be 
considered as End-of-Study Visit. Every effort should be made to conduct the End-of-Study 
Visit. 
Patients who are observed to receive clinical benefit from Acalabrutinib after completion of 
treatment phase, may continue to receive Acalabrutinib, if in the opinion of their treating 
physician they are continuing to derive clinical benefit from continued treatment or have not 
progressed clinically. The details on “Post-Trial Access” are provided in section 1.2. 
For details on treatments given during the study, refer Section 6.1 Treatments Administered.   
For details on what is included in the efficacy and safety endpoints, refer Section 3 and 8.    
4.2 
Scientific rationale for study design 
The present study will be conducted to assess the safety and efficacy of Acalabrutinib in the 
Indian population of CLL/SLL and MCL. The efficacy and safety of Acalabrutinib 100 mg BID 
dose is established in CLL/SLL and refractory & relapsed MCL patients for 6 cycles (refer 
Section 2). Hence the present phase IV trial is planned to assess the safety and efficacy of 
Acalabrutinib 100 mg BID monotherapy for a treatment period of 168 days in Indian patients.   
In the combined safety database with Acalabrutinib monotherapy, the commonest adverse events 
in patients receiving Acalabrutinib monotherapy as a treatment for haematological malignancies 
are related to blood and lymphatic system disorders, cardiac disorders, nervous system disorders, 
and gastrointestinal disorders. The current phase IV trial includes a treatment phase of 168 days, 
which would enable us to detect the incidence of adverse events and the objective response to 
treatment in an eligible Indian patient population. As the primary objective of the study will be 
an assessment of safety, the study design is a single arm, prospective open-label one.  


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The safety analysis (N = 1040) showed that the most common treatment-emergent AEs were 
anaemia, neutropenia, thrombocytopenia, headache, diarrhoea, bruising, rash, infections, and 
musculoskeletal pain.  
4.3 
Justification for dose 
The dose used in the current study is based on the locally approved Prescribing Information. 
4.4 
End of study definition 
The end of the study is defined as the last expected visit/contact of the last patient undergoing 
the study. 
A patient is considered to have completed the study when he/she has completed his/her last 
scheduled visit or last scheduled procedure shown in the SoA 
Refer Appendix A 6 for guidelines for the dissemination of study results. 
5. STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomised to study intervention.  Under no circumstances can 
there be exceptions to this rule.  
5.1 Inclusion criteria 
Patients are eligible to be included in the study only if all of the following inclusion criteria and 
none of the exclusion criteria apply: 
1. 
Men and Women aged 18 yrs or more. 
2. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0,1, or 2 
3. 
Able to receive all outpatient treatments, all laboratory monitoring, and all radiologic 
evaluations. 
4. 
The following laboratory parameters: 
a. Absolute neutrophil count (ANC) ≥750 cells/μL or ≥500 cells/μL in patients with 
documented bone marrow involvement, and independent of growth factor support 
07 days before the assessment 
b. Platelet count ≥50,000 cells/μL or ≥30,000 cells/μL in patients with documented 
bone marrow involvement, and without transfusion support 07 days before the 
assessment 
c. Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤2.0 x ULN 


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d. Total bilirubin ≤1.5 x ULN 
e. Estimated creatinine clearance of ≥30 mL/min 
5. 
Refractory disease defined as achieving less than partial response with the most recent 
treatment before study entry 
6. 
Provision of signed, written and dated informed consent prior to any study-specific 
procedures 
7. 
The patients of either CLL or MCL: 
a. CLL patients: 
i. Treatment naïve or ≥1 prior systemic therapy for CLL 
ii. Diagnosis of CD20+ CLL that meets published diagnostic criteria (Hallek 
et al. 2018) 
iii. An active disease that meets≥1 of the following iwCLL 2018 criteria for 
requiring treatment 
1) Evidence of progressive marrow failure as manifested by the 
development 
of, 
or 
worsening 
of, 
anaemia 
and/or 
thrombocytopenia. Cut-off levels of Hb <10 g/dL or platelet 
counts <100 × 109/L are generally regarded as an indication for 
treatment. However, in some patients, platelet counts <100 × 
109/L may remain stable over a long period; this situation does not 
automatically require therapeutic intervention. 
2) Massive (i.e., ≥6 cm below the left costal margin) or progressive 
or symptomatic splenomegaly. 
3) Massive nodes (i.e., ≥10 cm in longest diameter) or progressive or 
symptomatic lymphadenopathy. 
4) Progressive lymphocytosis with an increase of ≥50% over a 2-
months period or lymphocyte doubling time (LDT) in <6 months. 
LDT can be obtained by linear regression extrapolation of absolute 
lymphocyte counts obtained at intervals of 2 weeks over an 
observation period of 2 to 3 months; patients with initial blood 
lymphocyte counts <30 × 109/L may require a longer observation 
period to determine the LDT. Factors contributing to 
lymphocytosis other than CLL (e.g., infections, steroid 
administration) should be excluded. 
5) Autoimmune 
complications, 
including 
anaemia 
or 
thrombocytopenia poorly responsive to corticosteroids. 
6) Symptomatic or functional extra-nodal involvement (e.g., skin, 
kidney, lung, spine). 


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7) Disease-related symptoms as defined by any of the following: 
a) Unintentional weight loss of ≥10% within the previous 06 
months. 
b) Significant fatigue (i.e., ECOG performance scale 02 or 
worse; cannot work or unable to perform usual activities). 
c) Fever ≥100.5°F or 38.0°C for 02 or more weeks without 
evidence of infection. 
d) Night sweats for ≥1 month without evidence of infection. 
b. MCL Patients:  
i. Confirmed MCL with translocation t(11;14) (q13;q32) and/or 
overexpressed cyclin D1 
ii. Measurable nodal disease (one or more lesions measuring ≥2 cm in the 
longest diameter) 
iii. Relapsed after, or were refractory to, 1-5 previous treatments 
5.2 Exclusion criteria  
1. 
Known prolymphocytic leukaemia, Central Nervous System (CNS) lymphoma or 
leukaemia; or known history of (or currently suspected) Richter’s syndrome 
2. 
Treatment with chemotherapy, external beam radiation therapy, anticancer antibodies, 
or investigational drug within 30 days of the first dose of study drug 
3. 
Prior radio-conjugated or toxin-conjugated antibody therapy 
4. 
Anticoagulation therapy (e.g., warfarin or equivalent vitamin K antagonists) within 07 
days of the first dose of study drug. 
5. 
Major surgery ≤30 days before the first dose of study drug 
6. 
History of stroke or intracranial haemorrhage ≤6 months before the first dose of study 
drug 
7. 
History of bleeding diathesis 
8. 
Prior exposure to a B-cell lymphoma-2 (Bcl-2) inhibitor or B-cell receptor inhibitor like 
BTKIs 
9. 
Active Cytomegalovirus (CMV) infection or serologic status reflecting active Hepatitis 
B or C infection, known history of infection with Human immunodeficiency virus 
(HIV), or any uncontrolled active systemic infection. 
10. 
Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
Congestive Heart Failure, or Myocardial Infarction within 6 months of screening, or 


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any Class 3 or 4 cardiac diseases as defined by the New York Heart Association 
Functional Classification, or QTcB >480 msec at screening. 
11. 
Requiring treatment with proton-pump inhibitors (e.g., Omeprazole, Esomeprazole, 
Lansoprazole, Dexlansoprazole, Rabeprazole, or Pantoprazole). 
12. 
Breastfeeding or pregnant. 
13. 
Current life-threatening illness, medical condition, or organ system dysfunction which, 
in the Investigator’s opinion, could have compromised the subject’s safety or put the 
study at risk. 
14. 
Concurrent participation in another therapeutic clinical trial. 
5.3 
Lifestyle restrictions 
Not Applicable 
5.4 
Screen failures 
Screen failures are defined as patients who sign the informed consent form to participate in the 
clinical study but are not subsequently entered in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure patients to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, and eligibility criteria. The reason/s for screen failure for these patients 
should be recorded in the electronic Case Report Form (eCRF). 
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be rescreened.    
6. 
STUDY TREATMENTS 
Study treatment is defined as any investigational product(s) (including marketed product, 
comparator, and placebo) or medical device(s) intended to be administered to a study participant 
according to the study protocol. Study treatment in this study refers to Acalabrutinib. 
6.1 
Treatments administered 
Table 3: Study Treatments 
 
             Treatment  
Study treatment name: 
Acalabrutinib 
Dosage formulation: 
Capsule 
Route of administration  
Per Oral (PO) 


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Dosing instructions: 
The recommended dose is 100 mg (1 capsule) twice daily. 
Acalabrutinib should be swallowed whole with water at 
approximately the same time each day. Acalabrutinib can be 
taken with or without food. The capsule should not be 
chewed, dissolved or opened. 
Packaging and labelling 
 
Study treatment will be provided and labelled in accordance 
with Good Manufacturing Practice (GMP) Annex 13 and per 
country regulatory requirement. 
Provider 
AstraZeneca/ delegate will be providing the Investigational 
Medicinal Product (IMP) to site. 
 
The recommended dose of Acalabrutinib is 100 mg given PO twice daily for 06 cycles (each 
cycle is 28 days) until disease progression or unacceptable toxicity. Dose escalation or reduction 
is not recommended. Dose withholding or discontinuation may be required based on individual 
safety and tolerability. 
6.1.1 
Duration of treatment 
The Treatment Phase will be from the start of Cycle 1, Day 1 to end of Cycle 6, Day 28, or until 
study drug discontinuation due to either disease progression or unacceptable toxicity, or other 
reasons whichever occurs earlier, as listed in Section 7.1. as continue  
6.1.2 
Administration 
The recommended dose of Acalabrutinib is 100 mg (1 capsule) twice daily. Acalabrutinib should 
be swallowed whole with water at approximately the same time each day. Acalabrutinib can be 
taken with or without food. The capsule should not be chewed, dissolved, or opened. 
6.2 
Handling/storage/accountability 
Acalabrutinib does not require any special storage conditions.  
Only patients enrolled in the study may receive study treatment, and only authorised site staff 
may supply or administer study treatment.  All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the Investigator and authorised site staff. 
The Investigator, Institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
6.3 
Measures to minimise bias: randomisation and blinding 
Since the present study is an open-label phase IV trial, blinding and randomisation are not 
applicable. 


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6.4 
Treatment compliance 
Any change from the dosing schedule: dose interruptions, dose reductions, dose discontinuations 
should be recorded in the eCRF. There should be 100% compliance with the study medication. 
No drug interruptions and missed doses will be permitted in the study.  
The Investigational Product Storage Manager(Investigator/delegate) is responsible for managing 
the IMP from receipt by the study site until the destruction or return of all unused IMP. The 
Investigator(s) is responsible for ensuring that the patient has returned all unused IMP. 
6.5 
Concomitant therapy 
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the patient is receiving at the time of enrolment or receives during 
the study must be recorded along with: 
 Reason for use 
 Dates of administration including start and end dates 
 Dosage information including dose and frequency 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care except 
for those medications identified as “excluded” as listed below: 
 Any investigational anticancer therapy 
 Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic, or hormonal 
therapy for cancer treatment. Concurrent use of hormones for non-cancer-related 
conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable. 
NOTE: Local treatment of isolated lesions, excluding target lesions, for palliative intent 
is acceptable (e.g., by local surgery or radiotherapy). 
 Strong inducers of CYP3A activity (e.g., Phenytoin, Rifampin, Carbamazepine). 
 Strong CYP3A inhibitors (e.g., Clarithromycin, Telithromycin, Nefazodone, 
Itraconazole, Ketoconazole, Atazanavir, Darunavir, Indinavir, Lopinavir, Nelfinavir, 
Ritonavir, Saquinavir, Tipranavir). 
 Proton 
pump 
inhibitors 
(e.g., 
Omeprazole, 
Esomeprazole, 
Lansoprazole, 
Dexlansoprazole, Rabeprazole, Or Pantoprazole). 
NOTE: If treatment with an acid-reducing agent is required, consider using an antacid 
(e.g., calcium carbonate), or an H2-receptor antagonist (e.g., Ranitidine). 
6.5.1 
Other concomitant treatment/s 
Other medication/s other than that described above, which is/are considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the Investigator and recorded in 
the appropriate sections of the electronic Case Report Form. 


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6.5.2 
Rescue medication/s 
Rescue medication/s, if required, will be provided by the Investigator as per the Standard of Care. 
The date and time of rescue medication administration, as well as the name and dosage regimen 
of the rescue medication, will be recorded 
6.6 
Dose modification 
Dose escalation or reduction are recommended in the study. In addition, there are certain 
circumstances in which the study drug should be permanently discontinued (refer Appendix C 
and Section 7). 
Acalabrutinib discontinuation will not be required for AEs that are clearly not attributed to study 
drug (such as an accident) or for laboratory abnormalities that are not deemed to be clinically 
significant.  
7. 
DISCONTINUATION OF STUDY DRUG 
7.1 
Discontinuation of study treatment  
Patients may be discontinued from the investigational product in the following situations: 
 Patient decision. The patient is at any time free to discontinue treatment without prejudice 
to further treatment. 
 Adverse Event that in the opinion of the Investigator or the Sponsor contraindicates 
further dosing 
 Severe non-compliance to study protocol that, in the opinion of the Investigator or 
Sponsor, warrants withdrawal, e.g., refusal to adhere to scheduled visits etc. 
 Any AE that meets criteria for discontinuation, as defined in Appendix D  
 Initiation of alternative anticancer therapy including another investigational agent 
 Disease progression as per the Investigator’s clinical and imaging assessment. 
 Pregnancy or intent to become pregnant. 
If the patient is discontinued from the study, the patient will be followed up until the start of 
subsequent anti-cancer intervention or up to a duration of 28 days, whichever is earlier. 
7.2 
Withdrawal from the study 
A patient may withdraw from the study (e.g., withdraw consent), at any time at his/her own 
request, without prejudice to further treatment. 
A patient who considers withdrawing from the study must be informed by the Investigator that 
the day of withdrawal will be considered as the end of the study phase for the patient. However, 
the patient will still have the provision of spontaneous AE reporting. 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, he/she may request the destruction of any samples taken, 
and the Investigator must document this in the site study records.   


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A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  The Investigator will follow up with patients, as medically indicated.  
AstraZeneca or its delegate will request Investigators to collect information on patients’ vital 
status (dead or alive; date of death when applicable) at the end of the study from publicly 
available sources, in accordance with local regulations.  Knowledge of the vital status of all 
patients at the end of the study is crucial for the integrity of the study.  
Refer SoA, Table 1, for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed.  
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarised in the SoA, Table 1.   
Written informed consent for participation in the study must be obtained before performing any 
study specific screening tests or evaluations.  Informed Consent Forms for enrolled patients and 
for patients who are not subsequently enrolled will be maintained at the study site.   
Documented evidence of CLL/SLL and MCL positive status from previous testing is acceptable, 
otherwise it has to be assessed at a local laboratory that is experienced/certified in CLL/SLL and 
MCL testing using an accurate and validated assay. 
Women with child bearing potential and male patients with partners of child bearing potential 
who are sexually active will have to agree to use a highly effective, non-hormonal form of 
contraception (such as surgical sterilization) or two effective forms of non-hormonal 
contraception (such as a barrier method of contraception in conjunction with spermicidal jelly) 
during and for at least 6-months post-study treatment. 
Screening tests and evaluations will be performed within 7 days prior to the first study 
medication administration (dosing). CT or MRI scans will be performed prior to the first study 
medication administration (dosing). CT or MRI scans are applicable for the patients with 
lymphadenopathy or organomegaly. Patients with abnormalities of blood parameters without any 
lymphadenopathy or organomegaly will not undergo CT or MRI scans. Patients who will be 
undergoing CT, should have baseline and every 3-months reports.   
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before enrolment.  The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening failure, 
as applicable. 
The safety assessments during the treatment visit will be performed at the start of each treatment 
cycle. However, efficacy assessments will be scheduled every three months during the study 
treatment period and EOT. 
The Investigator will ensure that data are recorded in the eCRF. 


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The Investigator ensures the accuracy, completeness for eCRFs that includes: timeliness of the 
data recorded and query resolution according to the Clinical Study Agreement. The Investigator 
will sign the completed eCRFs.  
Immediate safety concerns should be immediately discussed with the Sponsor upon occurrence 
or awareness to determine if the patient should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
patients screened, confirm their eligibility for the trial, or record reasons for screening failure, as 
applicable.   
Procedures conducted as part of the patient’s routine clinical management (e.g., blood count) 
and obtained before signing of the ICF may be utilised for screening or baseline purposes 
provided the procedures meet the protocol-specified criteria and were performed within the time 
frame defined in the SoA. 
The maximum amount of blood collected from each patient will not exceed approximately 10 
mL/visit. Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples 
8.1 
Efficacy and Safety assessments  
8.1.1 
Efficacy Assessment 
Objective Response 
All patients who receive Acalabrutinib capsule 100 mg BID will be evaluated for efficacy once 
every 03 months during the treatment phase. The following assessments must be performed 
every three treatment cycles: tumour assessment, ECOG performance status, and partial 
remission (PR), partial response with lymphocytosis (PR-L) and complete remission (CR).  
A characteristic feature of BTK inhibitor is that it may transiently increase the peripheral 
lymphocyte count while the lymph nodes are shrinking and patients are improving. Some 
patients were taken off study very early in ibrutinib trials because their lymphocyte count began 
to go up and it was assumed that they were progressing. The transient lymphocytosis is now 
understood to be an effect of redistributing parts of the disease into the blood. It is not considered 
as a sign of disease progression. There is now a response criterion known as PRL, which refers 
to patients who have a greater than 50% shrinkage of nodal disease and who fulfil all criteria of 
partial response (PR) except for a persistent lymphocytosis. (Woyach et al., 2014) In the present 
study the objective response will evaluate PR, PR-L, and CR. 
The efficacy endpoint will be objective response, defined as the proportion of patients achieving 
either a PR or CR per the iwCLL 2018 criteria for CLL/SLL (Hallek et al., 2018) and Lugano 
classification for NHL for MCL (Cheson et al., 2014) as presented in Table 4 and Table 5, 
respectively. Efficacy will be based on objective response [Complete Remission (CR) + Partial 
Remission (PR)] via Computed Tomography (CT) scans or Magnetic Resonance Imaging (MRI).  


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Table 4: Response (CR and PR) definition after treatment of CLL/SLL patients (Hallek 
et al., 2018) 
Parameter 
Complete Remission (CR) 
Partial Remission (PR) 
Lymph nodes 
None ≥1.5 cm 
Decrease ≥50% from 
baseline* 
Liver and/or 
spleen size† 
Spleen size <13 cm; 
liver size normal 
Decrease ≥50% from 
baseline 
Constitutional 
symptoms 
None 
any 
Circulating 
lymphocyte count 
Normal 
Decrease ≥50% from 
baseline 
Platelet count 
≥100 x 109L 
≥100 x 109/L or increase 
≥50% over baseline 
Haemoglobin 
≥11.0 g/dL (untransfused and 
without erythropoietin) 
≥11.0 g/dL or increase 
≥50% over baseline 
*Sum of the products of 6 or fewer lymph nodes (as evaluated by CT scans and physical examination in clinical 
trials or by physical examination in general practice). 
†Spleen size is considered normal if, it is <13 cm. There is no firmly established international consensus of the 
size of a normal liver; therefore, liver size should be evaluated by imaging and manual palpation  
 
A CT-based Response Assessment Criteria for MCL will be assessed as per Table 5 (Cheson et 
al., 2014). Patients with abnormalities of blood parameters without any lymphadenopathy or 
organomegaly will not undergo CT or MRI scans. Patients who will be undergoing CT, should 
have baseline and every 3-months reports.   
Table 5: Response Assessment Criteria for MCL patients 
Response and Site 
Complete Response 
Partial Response 
Lymph 
nodes 
and 
extra 
lymphatic sites 
Target nodes/nodal masses 
must regress to ≤1.5 cm in 
LDi  
No extra lymphatic sites of 
disease 
≥ 50% decrease in SPD of up 
to 6 target measurable nodes 
and extra-nodal sites 
When a lesion is too small to 
measure on CT, assign 5 mm 
×5 mm as the default value  
When no longer visible, 0 × 
0mm  
For a node >5 mm × 5 mm, 
but smaller than the normal, 
use the actual measurement 
for calculation 
Non-measured lesion 
Absent 
Absent/normal, 
regressed, 
but no increase 


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Response and Site 
Complete Response 
Partial Response 
Organ enlargement 
Regress to normal 
Spleen must have regressed 
by > 50% in length beyond 
normal 
New lesions 
None 
None 
LDi: longest transverse diameter of a lesion; SPD: sum of the product of the greatest diameters 
Patient-Reported Outcome 
A health-related quality of life questionnaire i.e., QLQ-C30 Questionnaire will be administered 
to each subject at screening/visit 1 before the dosing, every three months during the treatment 
period and at the end of the study. Most of the items in the questionnaire use a “past week” recall 
period. The patients will be assessed on the functional, symptoms, and global quality of life scale.   
8.1.2 
Safety assessments  
Safety evaluations will include clinical laboratory parameters (haematology and biochemistry), 
physical examinations, vital sign measurements, ECG monitoring, ECOG performance status, 
adverse event monitoring, and death, as observed by the Investigator. Based on the previous in 
vitro studies, animal toxicological findings, and human studies with Acalabrutinib, arrhythmias 
(which includes atrial fibrillation), anaemia, hypertension, bleeding, infections, and second 
primary malignancies will be closely monitored. Any of the safety monitoring assessments may 
be performed more frequently, and adverse events should be evaluated by the Investigator 
according to the standard practice if clinically indicated. 
Clinical safety laboratory assessments 
The list of clinical safety laboratory tests to be performed are provided in Table 6 and Table 7.  
All protocol-required laboratory assessments, as defined in the table, must be conducted in 
accordance with the laboratory manual and the timing and frequency outlined in the SoA.   
The Investigator should assess the available results with regard to clinically relevant 
abnormalities. The laboratory results should be signed, dated, and retained at the site as source 
data for laboratory variables.   
For information on how AEs based on laboratory tests should be recorded and reported, refer 
Section 8.2.7. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  The date, time of collection, and results (values, units, and reference ranges) should 
be appropriately recorded in the eCRF. 
The haematology (Table 6), clinical chemistry (Table 7) and urinalysis (routine and microscopy) 
measurements will be performed at a local laboratory at or near the Investigator site.   
A complete blood cell count will be conducted as per SoA (Table 1). It includes white blood cell 
count, haemoglobin, haematocrit, reticulocyte, platelet count and differential leukocyte count, 
including both percent and an absolute number of lymphocytes.  


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Table 6: Haematology 
Haematocrit 
Haemoglobin 
Basophils  
Eosinophils  
Monocytes 
Lymphocytes 
Reticulocytes 
Absolute Neutrophil Count 
Platelet count 
Total leucocyte count 
 
Table 7: Clinical chemistry (serum or plasma) 
Albumin  
Glucose 
Amylase 
Lipase  
Alkaline phosphatase  
Lactate dehydrogenase 
Alanine aminotransferase   
Aspartate aminotransferase   
Potassium 
Bicarbonate  
Sodium 
Calcium  
Total bilirubin  
Chloride  
Total protein 
Creatinine (creatinine clearance)  
Urea or Blood Urea Nitrogen, depending on local practice 
Gamma-glutamyl transferase  
Magnesium 
Haptoglobin 
b2-microglobulin 
 
Note: CMV serology, HIV (anti-HIV1 Ab, anti-HIV2 Ab), Hepatitis serology testing will be 
conducted at the screening that includes hepatitis B surface antigen (HBsAg), hepatitis B surface 
antibody (HBsAb), anti-HBc, and HCV antibody. 
The local GLP certified laboratory will perform haematology and clinical chemistry tests. 
Additional analyses may be performed if clinically indicated. 
Any clinically significant abnormal laboratory values should be repeated as clinically indicated 
and recorded in the eCRF.  


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All patients who have any Common Toxicity Criteria (CTC) Grade 3 or 4 laboratory values at 
the time of completion or discontinuation from study must have further tests performed until the 
laboratory values have returned to CTC Grade 1 or 2, unless these values are not likely to 
improve because of the underlying disease. 
Urine Pregnancy Test 
Urine pregnancy tests will be required only for women of childbearing potential. Urine 
pregnancy tests will be performed at Screening; on Cycle 1 Day 1; on Day 28 of Cycles 1-6; and 
at the early termination or End of study visit.  
Physical examinations 
For timing of individual measurements refer to the schedule outlined in (Table 1). 
A complete physical examination will be performed and will include an assessment of the 
following (as clinically indicated): general appearance, respiratory, cardiovascular, abdomen, 
skin, head, neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal 
(including spine and extremities), and genital/rectal and neurological systems. 
Symptom-directed physical exams, including tumour assessments by palpation, will be done 
during the treatment period and at the EOT visit. 
Lymph nodes: The bi-dimensional diameters of the largest palpable lymph node/s in each of the 
following sites should be recorded: cervical, axillary, and inguinal. The dimensions of the liver 
and spleen below their respective costal margins, as assessed by palpation, should also be 
recorded.  
Performance status will be assessed using ECOG performance status. 
Vital signs 
The timings of assessments for vital signs are provided in Table 1 (SoA). Patients will be 
monitored with the assessment of vital signs (Blood Pressure, pulse, respiratory rate, and 
temperature) at screening and at each subsequent visit in the treatment phase. Additional 
monitoring with the assessment of vital signs is at the discretion of the Investigator per standard 
clinical practice or as clinically indicated. The date and time of collection and measurement will 
be recorded in the eCRF.  
Electrocardiograms (ECG) 
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study. ECGs should be obtained after the patient has been rested in a supine position for at least 
5 minutes and recorded while the patient remains in that position. In case of clinically significant 
ECG abnormalities, including a QTc value >480 ms, 2 additional 12-lead ECGs should be 
obtained over a brief period (e.g., 30 minutes) to confirm the finding. 
All ECGs should be assessed by the Investigator for clinically significant abnormalities. If there 
is a clinically significant abnormal finding, the Investigator will record it as an AE on the eCRF. 


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At screening, the mean QTc with Bazett’s correction (QTcB = QT/√R) must be <480 msec as 
per the eligibility criteria of the study. 
Chest X-Ray 
Patients with signs and symptoms of Pneumonia will be allowed to go for chest X-ray 
investigation.  A symptom directed chest X-ray will be conducted at screening and all subsequent 
visits during the study duration.  
8.2 
Collection of adverse events 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. The definitions of an AE or SAE can be found in 
Appendix B. 
All adverse events occurring during the study will be recorded and reported. AEs observed/ 
elicited by the Physician/ Site Investigator during physical examination and vital signs recording 
or derived from safety assessments; reported by patients during site visits will be documented in 
the source notes and in the AE log of eCRF. AEs can be reported by the patient (or, when 
appropriate, by a caregiver, surrogate, or the patient's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow-up AEs, refer 
Section 8.2.3.   
The nature of adverse events will be recorded in the eCRF. This will include reporting of duration, 
severity, seriousness, causality/ relationship with the study drug, action taken in terms of any 
medication or any other intervention and outcome of the event. These assessments will be 
performed by the Physician/Site Investigator. In the event an AE is being assessed in real time 
and a Co-Investigator (other than the Site Investigator) is evaluating the event, then the final 
conclusion on the nature of AE can be revised based on the judgement arrived at by the Site 
Investigator.  
The events will be coded by the data management team using Medical Dictionary for Regulatory 
Activities (MedDRA) version 20.0 or above. 
8.2.1 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and non-
leading verbal questioning of the patient is the preferred method to inquire about AE occurrences.   
8.2.2 
Time period and frequency for collecting AE and SAE information  
Adverse events and SAEs will be collected from the time of signature of informed consent, 
throughout the treatment period (168 days), End of study visit (Day 170) and including the 
follow-up period (28 days after the last dose of study drug) in patients who discontinue before 
168 days. 
If a patient discontinues from study drug for reasons other than disease progression, drug-related 
SAEs must be captured until the patient is initiated on an alternate intervention or up to 28 days, 
whichever is earlier. 


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All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix B.  The Investigator will submit any updated SAE data to the Sponsor within 24 
hours of it being available. 
Investigators are not obligated to actively seek AE or SAE in former study patients. However, if 
the Investigator learns of any SAE, including death, at any time after a patient’s last visit and 
he/she considers the event to be reasonably related to the study treatment or study participation, 
the Investigator may notify the Sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix B. 
8.2.3 
Follow-up of AEs and SAEs 
During the course of the study, all AEs and SAEs should be proactively followed up for each 
patient. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion. 
AEs that are unresolved at the patient’s last visit in the study must be followed up by the 
Investigator for as long as medically indicated. 
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study if judged necessary.  
8.2.4 
Adverse event data collection 
'The following variables will be collected for each AE; 
 AE (verbatim). 
 The date and time when the AE started and stopped. 
 CTCAE grade 3 or more: whether the AE is serious or not 
 Investigator’s causality rating against the Investigational Product (yes or no). 
 Action taken with regards to Investigational Product(s). 
 Select the appropriate as required: AE caused patient’s withdrawal from study (yes or 
no). 
 Outcome. 
In addition, the following variables will be collected for SAEs: 
 Date AE met criteria for serious AE 
 Date Investigator became aware of serious AE 
 Reason for AE becoming serious 
 Date of hospitalisation 
 Date of discharge 
 Probable cause of death 
 Date of death 


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 Autopsy performed 
 Causality assessment in relation to study procedure(s) 
 Causality assessment to other medication/s 
8.2.5 
Causality collection 
The Investigator will assess the causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’ 
For SAEs, a causal relationship will also be assessed for other medication/s and study 
procedures.  Note that for SAEs that could be associated with any study procedure, the causal 
relationship is implied as ‘yes.’ 
A guide to the interpretation of the causality questions is found in Appendix B to the Clinical 
Study Protocol. 
8.2.6 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or care provider or reported in response to open 
question/s from the study site staff: or revealed by observation will be collected and recorded in 
the eCRF.  When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms. However, if a diagnosis is known, and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis, and each sign or 
symptom will be recorded separately. 
8.2.7 
Adverse events based on examinations and tests 
The results from the Clinical Study Protocol-mandated laboratory tests and vital signs will be 
summarised in the CSR.  Deterioration as compared to baseline in protocol-mandated laboratory 
values, vital signs should, therefore, only be reported as AEs if they fulfil any of the SAE criteria 
or are the reason for discontinuation of treatment with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE, and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible, the reporting Investigator will 
use the clinical, rather than the laboratory term (e.g., anaemia versus low haemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally related 
to the disease under study. 
Disease progression can be considered as a worsening of a patient’s condition attributable to the 
disease for which the investigational product is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of new, or progression of existing metastasis to primary cancer under study should 


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be considered as disease progression and not an AE. Events, which are unequivocally due to 
disease progression, should not be reported as an AE during the study. 
New cancers 
The development of new cancer should be regarded as an SAE. New primary cancers are those 
that are not the primary reason for the administration of the study drug and have been identified 
after the patient’s inclusion in this study. 
Deaths 
All deaths that occur during the study, or within the protocol-defined follow-up period after the 
administration of the last dose of study drug, must be reported as follows: 
 Death clearly the result of disease progression should be reported to the study monitor 
at the next monitoring visit and should be documented in the eCRF but should not be 
reported as an SAE. 
 Where death is not due (or not clearly due) to Progressive Disease (PD) under study, 
the AE causing the death must be reported to the study monitor as an SAE within 24 
hours. The report should contain a comment regarding the co-involvement of PD, if 
appropriate, and should assign main and contributory causes of death. 
 Deaths with an unknown cause should always be reported as an SAE. A post-mortem 
maybe helpful in the assessment of the cause of death, and if performed, a copy of 
the post-mortem results should be forwarded to AstraZeneca or its representative 
within the usual timeframes. 
8.3 
Safety reporting and medical management 
8.3.1 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s).  All SAEs will be recorded in the eCRF. 
If any SAE occurs during the study, the Investigator or other site personnel should inform the 
appropriate AstraZeneca representatives within one day, i.e., immediately but no later than 24 
hours of when he or she becomes aware of it. 
The Investigator will also inform the chairperson of Institutional Ethics Committee (IEC) and 
Licensing Authority (LA) i.e., Drugs Controller General (India), about the SAE within 24 hours. 
In addition, the Investigator will provide a detailed report on the SAE after due analysis to the 
IEC chairperson, the Head of Institute and the LA within 14 calendar days of its occurrence.  
The IEC will forward its report on the SAE along with its opinion on the financial compensation, 
if any, (to be paid by Sponsor) within 30 calendar days of occurrence of SAE to LA. The 
timeline for the order from Licensing Authority on the quantum of compensation to be paid will 
be within 150 calendar days of occurrence of SAE or receiving report. Sponsor will pay the 
compensation to subject within 30 calendar days of order from LA. 
In case the Investigator fails to report any SAE within stipulated period, he shall furnish the 
reason for the delay to the satisfaction of the Licensing Authority along with the SAE report. 


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The designated AstraZeneca representative will co-ordinate with the Investigator to ensure that 
all the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
01 calendar day of the initial receipt for fatal and life-threatening events and within 05 
calendar days of initial receipt for all other SAEs. 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE within 
one calendar day, i.e., immediately but no later than 24 hours of when he or she becomes aware 
of it. 
Once the Investigator or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative. 
If the EDC system is not available, then the Investigator or other study site staff reports an SAE 
to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the Investigator/study site staff on how to proceed.   
Investigators or other site personnel will then send relevant eCRF modules by fax to the 
designated AstraZeneca representative. For further guidance on the definition of an SAE, please 
refer to Appendix B of the Clinical Study Protocol. 
8.3.2 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for: 
 
If the pregnancy is discovered before the patient has received the study drug 
 
Pregnancies in the partner of male patients. 
If pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.3.2.1 
Maternal exposure 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
will inform the appropriate AstraZeneca representatives within one day, i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative will co-ordinate with the Investigator to ensure that 
all relevant information is provided to the AstraZeneca Patient Safety data entry site within 01 
or 05 calendar days for SAEs (refer Section 8.3.1) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 


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8.3.3 
Overdose 
The use of Acalabrutinib in excess dose than specified in the protocol is considered to be an 
overdose. There is currently no specific treatment in the event of an overdose of Acalabrutinib, 
and possible symptoms of overdose are not established. 
 An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose Case Report Form module. 
 An overdose without associated symptoms is only reported on the Overdose CRF module 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel must inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with an SAE, the standard reporting timelines apply, refer Section 
8.2.2.  For other overdoses, reporting must occur within 30 days. 
9. 
STATISTICAL CONSIDERATIONS  
9.1 
Statistical hypotheses 
No formal hypothesis testing will be conducted. 
9.2 
Sample size determination  
The primary endpoint of the trial is to demonstrate the safety profile of Acalabrutinib in routine 
clinical practice as assessed by the incidence of adverse events (AEs) (Serious and Non-serious) 
observed during the trial. As per the Health Authority requirement, the total sample size of the 
study is approximately 100.  
The table below illustrates the estimated incidence and the precision of the estimate that could 
be expected for a variety of sample sizes (indicative of possible subgroup and total sample) for 
an observed numbered of patients with a particular event. 


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Table 8: Estimated Incidence and Precision  
 
9.3 
Populations for analyses 
The Full Analysis Set (FAS) will consist of all enrolled patients who received at least one dose 
of Acalabrutinib. The FAS will be used for all analyses of safety and efficacy. 
9.4 
Statistical analysis 
Categorical data will be summarized using frequencies and percentages. Continuous data will be 
summarized with descriptive statistics, including mean, standard deviation, median, minimum, 
and maximum. Confidence intervals will be supplied for key proportions (including objective 
response rate) using the Clopper-Pearson method. The details will be provided into statistical 
analysis plan.   
 
Number of observed 
events
n=10
n=20
n=50
n=90
n=100
0.0%
0.0%
0.0%
0.0%
0.0%
(0.00%, 30.85%)
(0.00%, 16.84%)
(0.00%, 7.11%)
(0.00%, 4.02%)
(0.00%, 3.62%)
10.0%
5.0%
2.0%
1.1%
1.0%
(0.25%, 44.50%)
(0.13%, 24.87%)
(0.05%, 10.65%)
(0.03%, 6.04%)
(0.03%, 5.45%)
20.0%
10.0%
4.0%
2.2%
2.0%
(2.52%, 55.61%)
(1.23%, 31.70%)
(0.49%, 13.71%)
(0.27%, 7.80%)
(0.24%, 7.04%)
30.0%
15.0%
6.0%
3.3%
3.0%
(6.67%, 65.25%)
(3.21%, 37.89%)
(1.25%, 16.55%)
(0.69%, 9.43%)
(0.62%, 8.52%)
40.0%
20.0%
8.0%
4.4%
4.0%
(12.16%, 73.76%)
(5.73%, 43.66%)
(2.22%, 19.23%)
(1.22%, 10.99%)
(1.10%, 9.93%)
100.0%
50.0%
20.0%
11.1%
10.0%
(69.15%, 100%)
(27.20%, 72.80%)
(10.03%, 33.72%)
(5.46%, 19.49%)
(4.90%, 17.62%)
100.0%
40.0%
22.2%
20.0%
(83.16%, 100%)
(26.41%, 54.82%)
(14.13%, 32.21%)
(12.67%, 29.18%)
60.0%
33.3%
30.0%
(45.18%, 73.59%)
(23.74%, 44.05%)
(21.24%, 39.98%)
80.0%
44.4%
40.0%
(66.28%, 89.97%)
(33.96%, 55.30%)
(30.33%, 50.28%)
100.0%
55.6%
50.0%
(92.89%, 100%)
(44.70%, 66.04%)
(39.83%, 60.17%)
Estimated incidence/precision*
* Clopper-Pearson exact 95% confidence interval
0
1
2
3
4
10
20
30
40
50


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10. 
REFERENCES 
 
Buchner, M., & Müschen, M. (2014). Targeting the B-cell receptor signaling pathway in B 
lymphoid malignancies. Current opinion in hematology, 21(4), 341-349. doi: 
10.1097/MOH.0000000000000048 
Cheson, B. D., Fisher, R. I., Barrington, S. F., Cavalli, F., Schwartz, L. H., Zucca, E., & Lister, 
T. A. (2014). Recommendations for initial evaluation, staging, and response assessment 
of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol, 
32(27), 3059-3068. doi: 10.1200/jco.2013.54.8800 
Gogia, A., Gupta, R., Kumar, L., Sharma, A., & Soni, L. (2019). Chronic lymphocytic leukemia 
with deletion 17p: An Indian scenario. South Asian J Cancer, 8(1), 40. doi: 
10.4103/sajc.sajc_287_18 
Hallek, M., Cheson, B. D., Catovsky, D., Caligaris-Cappio, F., Dighiero, G., Dohner, H., . . . 
Kipps, T. J. (2018). iwCLL guidelines for diagnosis, indications for treatment, response 
assessment, and supportive management of CLL. Blood, 131(25), 2745-2760. doi: 
10.1182/blood-2017-09-806398 
Hallek, M., Cheson, B. D., Catovsky, D., Caligaris-Cappio, F., Dighiero, G., Dohner, H., . . . 
Kipps, T. J. (2008). Guidelines for the diagnosis and treatment of chronic lymphocytic 
leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia 
updating the National Cancer Institute-Working Group 1996 guidelines. Blood, 111(12), 
5446-5456. doi: 10.1182/blood-2007-06-093906 
Isaac, K., & Mato, A. R. (2020). Acalabrutinib and Its Therapeutic Potential in the Treatment of 
Chronic Lymphocytic Leukemia: A Short Review on Emerging Data. Cancer Manag 
Res, 12, 2079-2085. doi: 10.2147/cmar.s219570 
Lad, D. P., Tejaswi, V., Malhotra, P., Varma, N., Sachdeva, M. S., Naseem, S., . . . Varma, S. 
(2018). Establishment of a comprehensive chronic lymphocytic leukemia clinic at a 
tertiary referral center in India. Blood advances, 2(Suppl 1), 33-34. doi: 
10.1182/bloodadvances.2018GS110801 
McKay, P., Leach, M., Jackson, B., Robinson, S., & Rule, S. (2018). Guideline for the 
management of mantle cell lymphoma. British Journal of Haematology, 182(1), 46-62. 
doi: 10.1111/bjh.15283 
Noone AM, H. N., Krapcho M, et al (eds). . (April 2018). SEER Cancer Statistics Review, 1975-
2015, National Cancer Institute. Bethesda, MD,.   Retrieved April 16, 2020, from 
https://seer.cancer.gov/csr/1975_2015/ 
PI. (2020). Calquence® (Acalabrutinib) capsules [prescribing information]. Banglore: 
AstraZeneca Pharma India Limited, Inc. 
Saxena, R., Kumar, R., Sazawal, S., & Mahapatra, M. (2016). CLL in India May Have a Different 
Biology 
from 
That 
in 
the 
West. 
Blood, 
128(22), 
5574-5574. 
doi: 
10.1182/blood.V128.22.5574.5574 
Schieber, M., Gordon, L. I., & Karmali, R. (2018). Current overview and treatment of mantle 
cell 
lymphoma. 
F1000Research, 
7, 
F1000 
Faculty 
Rev-1136. 
doi: 
10.12688/f1000research.14122.1 
Wierda, W. G., Byrd, J. C., Abramson, J. S., Bilgrami, S. F., Bociek, G., Brander, D., . . . Sundar, 
H. (2020). Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 
4.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 
18(2), 185-217. doi: 10.6004/jnccn.2020.0006 
Woyach, J. A., Smucker, K., Smith, L. L., Lozanski, A., Zhong, Y., Ruppert, A. S., . . . Byrd, J. 
C. (2014). Prolonged lymphocytosis during ibrutinib therapy is associated with distinct 


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molecular characteristics and does not indicate a suboptimal response to therapy. Blood, 
123(12), 1810-1817. doi: 10.1182/blood-2013-09-527853 
Zhou, Y., Wang, H., Fang, W., Romaguer, J. E., Zhang, Y., Delasalle, K. B., . . . Wang, M. 
(2008). Incidence trends of mantle cell lymphoma in the United States between 1992 and 
2004. Cancer, 113(4), 791-798. doi: 10.1002/cncr.23608 
 
 
 


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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
Appendix A Regulatory, ethical and study oversight considerations 
A 1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
 
Applicable laws and regulations 
The protocol, protocol amendments, Informed Consent Document (ICD), Investigator Brochure, 
and other relevant documents (e.g., advertisements) must be submitted to an Institutional Review 
Board (IRB)/ Institutional Ethics Committee (IEC) by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.   
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate hazard 
to study patients.   
The Investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
The study will be performed in accordance with the AstraZeneca policy on Bioethics and Human 
Biological Samples. 
A 2 
Financial disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit a complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators are 
responsible for providing information on financial interests during the course of the study and 
for a year after completion of the study. 


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A 3 
Informed consent process 
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorised representative and answer all questions regarding the study.   
Patients must be informed that their participation is voluntary.  Patients or their legally authorised 
representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, ICH-GCP guidelines, and New Drugs & Clinical Trials Rules, 2019 
(India) 
where applicable, and the IRB/IEC or study centre.   
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study with a mention of the date and time of the same. The 
authorised person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study as applicable.   
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorised 
representative.   
A 4 
Data protection 
Each patient will be assigned a unique identifier by the Sponsor.  Any patient records or data sets 
transferred to the Sponsor will contain only the identifier; patient names or any information 
which would make the patient identifiable will not be transferred.   
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law.  The level of disclosure must also be explained to 
the patient.   
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorised personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities, without his/her identity being 
revealed 
A 5 
Committees structure 
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the Clinical Study Protocol and letters 
to Investigators. 
A 6 
Dissemination of clinical study data 
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com,  and 
CTRI (http://ctri.nic.in/Clinicaltrials), as will the summary of the study results when they are 
available. The clinical trial summary of study results may also be available on other websites 
according to the regulations of India in which the study is conducted. 


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A 7 
Data quality assurance 
All patient data pertaining to the study will be recorded in an eCRF and transferred to the Sponsor 
or designee electronically at the end of the study. The Investigator will be responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF.   
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.   
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.   
The Clinical Research Organization (CRO) or designee is responsible for the data management 
of this study, including the quality checking of the data.   
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements.   
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the Sponsor.  No records may be transferred to 
another location or party without written notification to the Sponsor.  
A 8 
Source documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected.  Source documents are filed at the Investigator’s site. 
Data reported on the e-CRF that are transcribed from source documents must be consistent with 
the source documents, or the discrepancies must be explained.  The Investigator may need to 
request previous medical records or transfer records, depending on the study.  Also, current 
medical records must be available. 
A 9 
Publication policy 
The results of this study may be published or presented at scientific meetings.  If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission.  
This allows the Sponsor to protect proprietary information and to provide comments.   
The Sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the Sponsor will generally support the publication of 
multicentre studies only in their entirety and not as individual site data.  In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with the International Committee 
of Medical Journal Editors' authorship requirements. 


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Appendix B Adverse event definitions and additional safety information 
B 1 
Definition of adverse event 
An adverse event is the development of any untoward medical occurrence in a patient or clinical 
study patient administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.   An AE can, therefore, be any unfavourable and unintended 
sign (e.g., an abnormal laboratory finding), symptom (for example, nausea, chest pain), or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.   
The term AE is used to include both serious and non-serious AEs and can include a deterioration 
of a pre-existing medical occurrence.  An AE may occur at any time, including run-in or washout 
periods, even if no study treatment has been administered. 
B 2 
Definition of serious adverse event 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
 
Results in death 
 
Is immediately life-threatening 
 
Requires inpatient hospitalisation or prolongation of existing hospitalisation  
 
Results in persistent or significant disability or incapacity   
 
Is a congenital abnormality or birth defect 
 
Is an important medical event that may jeopardise the patient or may require medical 
treatment to prevent one of the outcomes listed above. 
B 3 
Life threatening 
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred, or it is suspected that use or continued use of the product would result in the patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it might 
have caused the death (e.g., hepatitis that resolved without hepatic failure). 
B 4 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons for 
it may be (e.g., bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
B 5 
Important medical event or medical treatment 


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Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious.  These 
should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
B 6 
For oncology studies, the following may be used instead  
The grading scales found in the revised National Cancer Institute CTCAE version 5.0 or above 
will be utilised for all events with an assigned CTCAE grading.  For those events without 
assigned CTCAE grades, the recommendation in the CTCAE criteria that converts mild, 
moderate, and severe events into CTCAE grades should be used.  A copy of the CTCAE can be 
downloaded from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The 
applicable version of CTCAE should be described clearly. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity, 
whereas seriousness is defined by the criteria in Appendix B 2.  An AE of severe intensity need 
not necessarily be considered serious.  For example, nausea that persists for several hours may 
be considered severe nausea, but not an SAE unless it meets the criteria shown in Appendix B 2. 
On the other hand, a stroke that results in only a limited degree of disability may be considered 
a mild stroke but would be an SAE when it satisfies the criteria shown in Appendix B 2. 
B 7 
A Guide to Interpreting the Causality Question 
When assessing causality, the following factors must be considered when deciding if there is a 
‘reasonable possibility’ that an AE may have been caused by the drug: 
 
Time Course.  Exposure to suspect drug.  Has the patient actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug? 
 
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
 
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
 
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge. 
 
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host, or environmental factors. 


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 
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship. 
In difficult cases, other factors should be considered, such as: 
 
Is this a recognized feature of an overdose of the drug? 
 
Is there a known mechanism? 
The causality of ‘related’ is made if following a review of the relevant data, there is evidence for 
a ‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are facts 
(evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data, including enough information 
to make an informed judgment.  With limited or insufficient information in the case, it is likely 
that the event(s) will be assessed as ‘not related.’ 
Causal relationship in cases where the disease under study has deteriorated due to lack of effect 
should be classified as no reasonable possibility. 
B 8 
Medication Error 
For the purposes of this clinical study, a medication error is an unintended failure or mistake in 
the treatment process for the study drug that either causes harm to the participant or has the 
potential to cause harm to the participant.   
A medication error is not a lack of efficacy of the drug, but rather a human or process-related 
failure while the drug is in control of the study site staff or participant. 
Medication error includes situations where an error.   
 
occurred 
 
was identified and intercepted before the participant received the drug 
 
did not occur, but circumstances that could have led to an error were recognized 
Examples of events to be reported in clinical studies as medication errors: 
 
Drug name confusion 
 
Dispensing error e.g., medication dispensed incorrectly 
 
Drug not administered as indicated, for example, wrong dose/frequency/duration 
 
Drug not stored as instructed  
Examples of events that do not require reporting as medication errors in clinical studies:  
 
Participant accidentally missed drug dose(s), e.g., forgot to take medication 


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 
Accidental overdose (will be captured as an overdose) 
 
Participant failed to return unused medication or empty packaging 
 
Errors related to background and rescue medication/s, or standard of care medication 
in open-label studies, even if an AZ product  
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error. 
 


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Appendix C Recommended Treatment Modifications for Acalabrutinib and 
Management Recommendations 
Recommended dose modifications of Acalabrutinib for Grade ≥3 adverse reactions are provided 
in Table 9. 
The administration of Acalabrutinib must be temporarily interrupted to manage a Grade ≥3 non-
haematological treatment-related adverse reaction, Grade 3 thrombocytopenia with significant 
bleeding, Grade 4 thrombocytopenia, or Grade 4 neutropenia lasting longer than 07 days. Upon 
resolution of the adverse reaction to Grade 1 or baseline (recovery), administration of 
Acalabrutinib must  be restarted as recommended in Table 9. 
Table 9: Recommended Dose Adjustments for Adverse Reactions* 
Adverse Reaction 
Occurrence 
Dose Modification 
(Starting dose = 100 mg twice daily) 
1st and 2nd 
Restart at 100 mg twice daily 
3rd 
Restart at 100 mg daily 
4th 
Discontinue Acalabrutinib 
*Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) version 4.03. 
 
 
 


Clinical Study Protocol  
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Appendix D: EORTC QLQ-C30 
 


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Clinical Study Protocol  
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Appendix E: Abbreviations  
Abbreviation or 
special term 
Explanation 
AE 
Adverse Event 
AESI 
AEs of special interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ARA-C 
Cytosine Arabinoside 
BCR 
B cell antigen receptor 
BID 
Twice daily 
BP 
Blood Pressure 
BTK 
Bruton Tyrosine Kinase 
BUN 
Blood Urea Nitrogen 
CDSCO 
Central Drugs Standard Control Organisation 
CHOP 
Cyclophosphamide, Hydroxy-daunorubicin, Oncovin, and Prednisone 
CLL 
Chronic Lymphocytic Leukaemia 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
CONSORT 
Consolidated Standards of Reporting Trials 
eCRF 
electronic Case Report Form 
CR 
Complete Remission 
CSA 
Clinical Study Agreement 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
DAE 
Discontinuation of investigational product due to Adverse Event 
DNA 
Deoxyribonucleic Acid  
DoR 
Duration of Response 
ECG 
Electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of Treatment 
EOS 
End of Study 
GGT 
Gamma-glutamyl transferase 
GMP 
Good Manufacturing Practice 
Hb 
Haemoglobin 


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Abbreviation or 
special term 
Explanation 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
IEC 
Institutional Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IGHV 
Immunoglobulin Variable Heavy Chain 
iwCLL 
International Workshop on Chronic Lymphocytic Leukaemia 
LAR 
Legally Acceptable Representative 
LDT 
Lymphocyte Doubling Time 
MCL 
Mantle Cell Lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
Minimal Residual Disease 
MRI 
Magnetic Resonance Imaging 
NGS 
Next-Generation Sequencing   
NHL 
Non-Hodgkin’s Lymphoma 
ORR 
Overall Response Rate 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PO 
Per Oral 
PI 
Principal Investigator  
PR 
Partial Remission 
PRL 
Partial Response with Treatment-Induced Lymphocytosis 
PRO 
Patient-reported outcome 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
SEC 
Scientific Expert Committee 
SLL 
Small Lymphocytic Lymphoma 
SoA 
Schedule of Activities 
SPD  
Sum of The Product Of The Greatest Diameters  
 
 
 


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ASTRAZENECA SIGNATURE(S)  
A prospective, multi-centre, Phase-IV clinical trial to assess the safety 
and efficacy of Acalabrutinib capsules in Indian adult patients with 
chronic lymphocytic leukaemia and relapsed and refractory mantle cell 
lymphoma 
 
This Clinical Study Protocol has been subjected to an internal AstraZeneca review  
 
I agree to the terms of this Study protocol.  
 
 
AstraZeneca representative                  
                                     
  
 
 
 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from AstraZeneca. Investigators are 
cautioned that the information in this protocol may be subject to change and revision.  
 
 
 
PPD


Clinical Study Protocol  
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AstraZeneca 
Study Code        - D8220C00022 
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ASTRAZENECA SIGNATURE(S)  
A prospective, multi-centre, Phase-IV clinical trial to assess the safety 
and efficacy of Acalabrutinib capsules in Indian adult patients with 
chronic lymphocytic leukaemia and relapsed and refractory mantle cell 
lymphoma 
 
This Clinical Study Protocol has been subjected to an internal AstraZeneca review  
 
I agree to the terms of this Study protocol.  
 
 
AstraZeneca representative                  
                                     
 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from AstraZeneca. Investigators are 
cautioned that the information in this protocol may be subject to change and revision.  
 
 
 
PPD


Clinical Study Protocol  
Drug Substance - ACALABRUTINIB  
AstraZeneca 
Study Code        - D8220C00022 
Version  1.0, Date: 01 Sep 2020 
 
 
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Page 59 of 60 
ASTRAZENECA SIGNATURE(S)  
A prospective, multi-centre, Phase-IV clinical trial to assess the safety 
and efficacy of Acalabrutinib capsules in Indian adult patients with 
chronic lymphocytic leukaemia and relapsed and refractory mantle cell 
lymphoma 
 
This Clinical Study Protocol has been subjected to an internal AstraZeneca review  
 
I agree to the terms of this Study protocol.  
 
 
AstraZeneca representative                  
                                     
 
 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from AstraZeneca. Investigators are 
cautioned that the information in this protocol may be subject to change and revision.  
 
 
 
PPD


Clinical Study Protocol  
Drug Substance - ACALABRUTINIB  
AstraZeneca 
Study Code        - D8220C00022 
Version  1.0, Date: 01 Sep 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
  
 
 
 
Page 60 of 60 
ASTRAZENECA SIGNATURE(S)  
A prospective, multi-centre, Phase-IV clinical trial to assess the safety 
and efficacy of Acalabrutinib capsules in Indian adult patients with 
chronic lymphocytic leukaemia and relapsed and refractory mantle cell 
lymphoma 
 
This Clinical Study Protocol has been subjected to an internal AstraZeneca review  
 
I agree to the terms of this Study protocol.  
 
 
AstraZeneca representative                  
                                    
 
 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from AstraZeneca. Investigators are 
cautioned that the information in this protocol may be subject to change and revision.  
 
PPD

SAP_001.pdf: