Conditions: Leukemia, Lymphocytic, Chronic, B-Cell Lymphoma, Mantle-Cell
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 75
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to evaluate the post-marketing safety of ImbruvicaTM (ibrutinib capsule 140 milligram \[mg\]) under actual conditions of use, and to understand the incidence of adverse events (AEs) (serious and non-serious AEs).

Detailed description:

Arms:
arm 1: Participants will receive ibrutinib 420 milligram (mg) (three 140 mg capsules) as a single daily dose for chronic lymphocytic leukemia (CLL) and 560 mg (four 140 mg capsules) as a single daily dose for mantle cell lymphoma (MCL) for up to 12 months or till disease progression, whichever is earlier.

Interventions: intervention 1: Ibrutinib 420 mg intervention 2: Ibrutinib 560 mg
Intervention descriptions: intervention 1: Ibrutinib capsule administered orally at a dose of 420 mg for CLL participants. intervention 2: Ibrutinib capsule administered orally at a dose of 560 mg for MCL participants.

Protocol document:
Prot_000.pdf: 
1 
Status: Approved,  Date: 20 October 2022 
Johnson & Johnson Private Limited 
Phase IV Clinical Trial Protocol 
A prospective, multicenter, open label single arm Phase IV clinical trial to assess safety of 
ImbruvicaTM (Ibrutinib capsules 140 mg) in Indian patients with chronic lymphocytic 
leukemia or mantle cell lymphoma who have received at least one prior therapy or chronic 
lymphocytic leukemia with 17p deletion   
Protocol 54179060LYM4005; Phase [   IV ] 
 54179060   Imbruvica (Ibrutinib capsule 140 mg) 
is approved for marketing in India for:  
(a) ImbruvicaTM  is indicated for the treatment of adult patients with mantle cell lymphoma who have
received at least one prior therapy.
(b) ImbruvicaTM is indicated for the treatment of patients with chronic lymphocytic leukemia who have
received at least one prior therapy.
(c) ImbruvicaTM is indicated for the treatment of patients with chronic lymphocytic leukemia with 17p
deletion.
Status:      
Approved (Version 2.0) 
Date: 
20 October 2022 
Prepared by:     Johnson & Johnson Private Limited 
EDMS number: 
EDMS-ERI-133399729, 2.0 
GCP Compliance:  This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.  
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
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Approved, Date: 20 October 2022  
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .......................................................................................................................... 2 
LIST OF ATTACHMENTS ....................................................................................................................... 3 
LIST OF IN-TEXT FIGURES ................................................................................................................... 4 
SYNOPSIS .............................................................................................................................................. 5 
TIME AND EVENTS SCHEDULE. ................................................. ERROR! BOOKMARK NOT DEFINED. 
ABBREVIATIONS ................................................................................................................................. 11 
1. 
INTRODUCTION .......................................................................................................................... 12 
1.1. 
Background............................................................................................................................... 12 
1.2. 
Overall Rationale for the Study .................................................................................................. 13 
2. 
OBJECTIVES AND HYPOTHESIS ............................................................................................... 21 
2.1. 
Objectives ................................................................................................................................. 21 
2.1.1. 
Objectives .............................................................................................................................. 21 
2.2. 
Hypothesis ................................................................................................................................ 21 
3. 
STUDY DESIGN AND RATIONALE ............................................................................................. 21 
3.1. 
Overview of Study Design ......................................................................................................... 22 
3.2. 
Study Design Rationale ............................................................................................................. 23 
4. 
SUBJECT POPULATION ............................................................................................................. 24 
4.1. 
Inclusion Criteria ....................................................................................................................... 25 
4.2. 
Exclusion Criteria ...................................................................................................................... 25 
5. 
TREATMENT ALLOCATION ........................................................................................................ 25 
6. 
DOSAGE AND ADMINISTRATION .............................................................................................. 27 
7. 
TREATMENT COMPLIANCE ....................................................................................................... 28 
8. 
CONCOMITANT THERAPY ......................................................................................................... 28 
9. 
STUDY EVALUATIONS ............................................................................................................... 29 
9.1. 
Efficacy Evaluations .................................................................................................................. 29 
9.2. 
Safety Evaluations .................................................................................................................... 30 
9.3. 
Sample Collection and Handling ................................................................................................ 31 
10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ...................................................................................................................... 31 
10.1. 
Completion ............................................................................................................................... 31 
10.2. 
Discontinuation of Study Treatment/Withdrawal from the Study ................................................. 32 
11. 
STATISTICAL METHODS ............................................................................................................ 32 
11.1. 
Subject Information ................................................................................................................... 33 
11.2. 
Sample Size Determination ....................................................................................................... 33 
11.3. 
Efficacy Analyses ...................................................................................................................... 33 
11.4. 
Safety Analyses ........................................................................................................................ 33 
12. 
ADVERSE EVENT REPORTING .................................................................................................. 34 
12.1. 
Definitions ................................................................................................................................. 35 
12.1.1. 
Adverse Event Definitions and Classifications ........................................................................ 35 
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
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Approved, Date: 20 October 2022  
12.1.2. 
Attribution Definitions ............................................................................................................. 36 
12.1.3. 
Severity Criteria ..................................................................................................................... 36 
12.2. 
Special Reporting Situations ..................................................................................................... 37 
12.3. 
Procedures ............................................................................................................................... 37 
12.3.1. 
All Adverse Events ................................................................................................................. 38 
12.3.2. 
Serious Adverse Events ......................................................................................................... 39 
12.3.3. 
Pregnancy ............................................................................................................................. 40 
12.4. 
Contacting Sponsor Regarding Safety ....................................................................................... 40 
13. 
PRODUCT QUALITY COMPLAINT HANDLING........................................................................... 40 
13.1. 
Procedures ............................................................................................................................... 40 
13.2. 
Contacting Sponsor Regarding Product Quality ......................................................................... 41 
14. 
STUDY DRUG INFORMATION .................................................................................................... 41 
14.1. 
Physical Description of Study Drug(s)........................................................................................ 41 
14.2. 
Packaging ................................................................................................................................. 41 
14.3. 
Labeling .................................................................................................................................... 41 
14.4. 
Drug Accountability ................................................................................................................... 41 
15. 
STUDY-SPECIFIC MATERIAL ..................................................................................................... 41 
16. 
ETHICAL ASPECTS .................................................................................................................... 42 
16.1. 
Study-Specific Design Considerations ....................................................................................... 42 
16.2. 
Regulatory Ethics Compliance................................................................................................... 42 
16.2.1. 
Investigator Responsibilities ................................................................................................... 42 
16.2.2. 
Independent Ethics Committee or Institutional Review Board ................................................. 42 
16.2.3. 
Informed Consent .................................................................................................................. 44 
16.2.4. 
Privacy of Personal Data ........................................................................................................ 44 
17. 
ADMINISTRATIVE REQUIREMENTS .......................................................................................... 45 
17.1. 
Protocol Amendments ............................................................................................................... 45 
17.2. 
Regulatory Documentation ........................................................................................................ 45 
17.2.1. 
Regulatory Approval/Notification ............................................................................................ 45 
17.2.2. 
Required Prestudy Documentation ......................................................................................... 45 
17.3. 
Subject Identification, Enrollment, and Screening Logs .............................................................. 46 
17.4. 
Source Documentation .............................................................................................................. 46 
17.5. 
Case Report Form Completion .................................................................................................. 47 
17.6. 
Data Quality Assurance/Quality Control ..................................................................................... 47 
17.7. 
Record Retention ...................................................................................................................... 48 
17.8. 
Monitoring ................................................................................................................................. 48 
17.9. 
Study Completion/Termination .................................................................................................. 49 
17.9.1. 
Study Completion/End of Treatment ....................................................................................... 49 
17.9.2. 
Study Termination .................................................................................................................. 49 
17.10. On-Site Audits ........................................................................................................................... 49 
17.11. Use of Information and Publication ............................................................................................ 50 
x 
REFERENCES ............................................................................................................................. 51 
x 
ATTACHMENTS .......................................................................................................................... 53 
INVESTIGATOR AGREEMENT ............................................................................................................ 59 
 
LIST OF ATTACHMENTS 
Attachment 1:  
EORTC OLQ C-30 (Specimen Sample) .................................................................... 53 
Attachment 2:  
Functional Assessment of Chronic Illness Therapy-Fatigue....................................... 55 
Attachment 3:       Dose Modifications for Adverse Reactions…………………………………………...57 
 
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LIST OF IN-TEXT FIGURES 
FIGURES 
Figure 1: 
Schematic Overview of the phase IV clinical trial for a single patient .................................... 23 
 
PROTOCOL AMENDMENTS 
 
SUMMARY OF CHANGES 
 
Protocol Version  
 
Issue Date 
Original Protocol  
 
27-Sep-2016 
Amendment 1  
 
20-Oct-2022 
 
Amendments below are listed beginning with the most recent amendment. 
Amendment -1 (20-Oct-2022) 
 
Protocol Section 
Description of Change 
SYNOPSIS 
Added description regarding referring to attachment 3 for dose modification 
guidelines “Refer to the locally approved prescribing information for 
ImbruvicaTM and Attachment 3 regarding the updated dose modification 
guidelines, special warnings, precautions for use, and other important 
information.” 
1.2 Overall Rationale 
for study 
Added description regarding referring to attachment 3 for dose 
modification guidelines “For atrial fibrillation which persists, consider 
the risks and benefits of ibrutinib treatment and follow the dose 
modification guidelines as per Attachment 3 in conjunction with local 
prescribing information” 
6.0 Dosage and 
Administration 
Added description regarding referring to attachment 3 for dose 
modification guidelines “Refer to the locally approved prescribing 
informationfor ImbruvicaTM and Attachment 3 regarding the updated 
dose modification guidelines, special warnings, precautions for use, 
and other important information.” 
 
Attachments  
Added attachment 3 
Investigator 
Agreement (Last Page) 
Change in Sponsor's Responsible Medical Officer: 
 to 
 
 
 
PPD
PPD
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
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SYNOPSIS 
Protocol Title 
A prospective, multicenter, open label single arm Phase IV clinical trial to assess safety of ImbruvicaTM 
(Ibrutinib capsules 140 mg) in Indian patients with chronic lymphocytic leukemia or mantle cell lymphoma 
who have received at least one prior therapy or chronic lymphocytic leukemia with 17p deletion   
Sponsor's Responsible Medical Officer: 
, Medical Advisor, Johnson & Johnson 
Private Limited, India. 
The term "sponsor" used throughout this document refers to the entities listed in the Contact Information 
page(s), which will be provided separately.  
BACKGROUND AND RATIONALE 
Ibrutinib is a first-in-class potent, orally-administered, covalently-binding small molecule inhibitor of 
Bruton’s tyrosine kinase (BTK) currently approved by the United States (US) FDA for the treatment of 
adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy; for the 
treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior 
therapy; and for the treatment of patients with CLL with 17p deletion. Drug Controller General (India) first 
approved ibrutinib for the treatment of patients with CLL or MCL who have received at least one prior 
therapy or CLL with 17p deletion in October 2015. 
Post-marketing study is useful in identifying new safety issues and trends, which were not observed in 
previously conducted clinical studies. The data obtained from the present study will help to understand the 
safety profile of ibrutinib in a real-world Indian scenario compared with that obtained in a controlled clinical 
environment. 
OBJECTIVES 
The aim of the present phase IV clinical trial is to assess the safety of ibrutinib in a routine clinical set-up 
in Indian patients to address the regulatory requirement. 
Objective 
Primary Objective 
The primary objective of this study is to evaluate the post-marketing safety of ImbruvicaTM (ibrutinib 
capsule 140 mg) under actual conditions of use, and to understand the following: 
x 
Incidence of adverse events (AEs) (Serious and Non-serious AEs); 
Exploratory Objective(s) 
To analyse the following outcomes with ibrutinib:  
x 
Baseline patient and disease characteristics 
x 
Response assessment and progression  
x 
Change in patient reported outcomes as measured by  
o Quality of Life by EORTC QLQ C-30 instrument (European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaires Core 30) 
o Fatigue by FACIT Fatigue instrument (Functional Assessment of Chronic Illness Therapy 
Fatigue)  
PPD
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
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PHASE IV CLINICAL STUDY DESIGN 
This is a prospective open label, single arm, multicentre, phase IV interventional study to describe the safety 
of ImbruvicaTM in Indian subjects. Approximately, 75 subjects, selected by investigators and determined to 
be eligible for ibrutinib treatment as per protocol eligibility criteria will be enrolled into the study, after 
written informed consent is obtained. Subjects will be monitored for AEs during treatment of ImbruvicaTM. 
Participating investigators will be trained on the locally approved prescribing information of ImbruvicaTM 
by the sponsor designee before the enrolment of first patient  
The decision of subjects to participate in this study must not, in any way, impact upon the standard of care 
that they are receiving or any benefits to which they are otherwise entitled. Prior to data collection, all 
subjects must sign an informed consent form (ICF) allowing data collection and source data verification in 
accordance with local requirements and/or sponsor policy. Sponsor shall provide reimbursement for the 
investigations haematological profile and coagulation profile to monitor the safety as per protocol throughout 
the study period. Commercial stocks of Ibrutinib affixed with additional investigational labels ( to meet 
local regulatory requirements) will be provided free of cost by the sponsor to clinical trial subject from the 
existing distribution channel as per the mentioned duration in the study protocol.  
 
Screening cum Enrolment Visit (Day 1): 
Data collected at this visit may include but not limited to demographics, medical history, disease related 
history, concomitant medications, patient-reported outcomes (PROs), laboratory investigations 
(hematological and coagulation profile) etc. The use of ImbruvicaTM is expected to follow the locally 
approved prescribing information. 
Treatment Period: Subjects will be observed for up to 12 months from the treatment initiation. During the 
study period, data will be collected at monthly intervals for the first 6 months, (monthly visit ± 7 days; Visit 
1 to 6) . Subsequent visit would be at 9 months ± 7 days [Visit 7], Data collected at this visit will include 
demographics, medical history, disease related history, AEs, disease progression assessment, concomitant 
medications, patient-reported outcomes (PROs), laboratory investigations (haematological and coagulation 
profile) as listed in the TIME AND EVENTS SCHEDULE. The End-of-Treatment (EOT) visit will be 
conducted after the completion of 12-months ImbruvicaTM treatment (at Visit 8) or on the day at which the 
patient discontinued the ImbruvicaTM treatment or study. The rationale for such schedule is that in the 
RESONATE Trial, on long term follow up it was found that the prevalence rates for infection, diarrhoea, 
and bleeding events were highest for the first 6 months and gradually declined thereafter. Subjects will have 
post-trial access to ImbruvicaTM for at least one year or as decided by EC whichever is more as per the 
recommendations of Subject Expert Committee (Oncology & Haematology) made in its 70th meeting held 
on 23rd May 2018 at Central Drugs Standard Control Organization HQ, New Delhi communicated vide F.N. 
12-10/2017-DC (Pt-Johnson-snd). 
Follow up period (End of Study Visit): A telephonic follow-up will be conducted 30 days after the EOT 
Visit.  
The observation period including the Enrolment Visit and telephonic follow-up will be up to a maximum 
duration of 13 months for each patient. The subjects can continue with their prescribed ImbruvicaTM 
treatment after the end of treatment in consultation with the participating physician. The overall duration 
of the study, including recruitment [and/or follow up], is expected to be 36 months.  
The expected frequency and timing of data collection in this phase IV clinical trial are summarized in the 
Error! Reference source not found.Error! Reference source not found.   presented after the synopsis. 
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
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SUBJECT POPULATION 
The phase IV clinical trial population will include Indian subjects with CLL or MCL who have received at 
least one prior therapy or CLL with 17p deletion who are newly initiated on ImbruvicaTM treatment based 
on the independent clinical judgment of the treating physician in clinical practice setting.  
Participating sites will be encouraged to enrol subjects in a consecutive manner when subjects  come for 
their regular consultation, in order to minimize bias in patient selection. All eligible patients should be 
offered enrolment for data collection within the phase IV clinical trial.  
Each potential patient must satisfy the following criteria to be eligible for participation in this study:  
1. Patient of either sex and >18 years of age 
2. CLL or MCL patients being newly initiated on ImbruvicaTM treatment (Ibrutinib capsule 140 mg) 
based on independent clinical judgment of treating physicians as per locally approved prescribing 
information 
3. Must give written informed consent indicating that they understand the purpose and are willing to 
participate in the study and allowing data collection and source data verification in accordance with 
regulatory requirements 
Potential patients who meet any of the following criteria will not be eligible for this study: 
1. Patients who are not eligible to receive ImbruvicaTM as per the locally approved prescribing 
information. 
2. Patients participating or planning to participate in any interventional drug trial during the course of 
this study.  
TREATMENT WITH IMBRUVICATM 
ImbruvicaTM will be prescribed to the subjects as per locally approved Prescribing Information. The 
recommended dose of ImbruvicaTM is 420 mg (three 140 mg capsules) as a single daily dose for CLL and 
560 mg (four 140 mg capsules) as a single daily dose for MCL.  
ImbruvicaTM should continue until disease progression or no longer tolerated by the patient. 
Refer to the locally approved prescribing information for ImbruvicaTM and Attachment 3 regarding the 
updated dose modification guidelines, special warnings, precautions for use, and other important 
information. 
DATA SOURCES AND COLLECTION METHODS 
The primary data source for this phase IV interventional study will be the medical records of each patient. 
Source documentation should be in subjects’ medical records for all data entered into the CRF. 
Additionally, patient- completed questionnaires requested by the sponsor will be recorded and will be 
considered source data. 
At each participating site, the same physician must do assessments for an individual patient through the 
course of study, if possible. Response assessment and progression criteria will be recorded  
Patient-reported outcomes will be measured by 2 questionnaires. The EORTC QLQ-C30 is a general cancer 
assessment, and the FACIT Fatigue Scale specifically assesses aspects of fatigue. Samples of the PRO 
scales are provided in Attachments 1, and 2. The PRO questionnaires will be collected at the beginning of 
the clinic visits prior to any procedures or physician interactions according to the Error! Reference source n
ot found. 
Safety Assessment 
All AEs, with the exception of progression of CLL/MCL, will be reported from the time a signed and dated 
informed consent form is obtained until 30 days following the end of treatment period or until the start of 
a subsequent systemic antineoplastic therapy, if earlier. All non-haematological AEs including laboratory 
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
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Approved, Date: 20 October 2022  
AEs and AEs leading to dose reductions or discontinuation will be graded and reported according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0. 
All haematological AEs will be graded and reported according to the International Workshop on Chronic 
Lymphocytic Leukemia (IWCLL) 2008 criteria for grading of haematological toxicities in CLL studies. 
Results of physical examinations including vital signs and clinical laboratory investigations if performed 
during routine clinical visit will also be recorded. 
Clinical Response Measures 
Response assessment and progression criteria will be recorded as per IWCLL criteria for CLL and revised 
response criteria for malignant lymphoma for MCL as per participating physicians’ routine clinical practice. 
Patient-Reported Outcomes 
Patient-reported outcomes (PROs) will be measured by 2 questionnaires. The EORTC QLQ-C30 is a 
general cancer assessment, and the FACIT Fatigue Scale specifically assesses aspects of fatigue. The PRO 
questionnaires will be collected at the beginning of the clinic visits prior to any procedures or physician 
interactions. Data will be collected using electronic Case Report Form (eCRF). The EORTC QLQ-C30 
includes 30 separate items with a recall period of last 1 week. Administration time is approximately 11 
minutes. FACIT Fatigue is an instrument for use as a measure of the effect of fatigue in patients with 
cancer and other chronic diseases  
STATISTICAL METHODS 
The primary objective of this study is to estimate the incidence of AEs in Indian subjects under 
actual conditions of use of ImbruvicaTM. A sample size of 75 subjects is as per the 
recommendations of Subject Expert Committee (Oncology & Haematology) made in its 70th 
meeting held on 23rd May 2018 at Central Drugs Standard Control Organization HQ, New Delhi 
communicated vide F.N. 12-10/2017-DC (Pt-Johnson-snd). 
 
Parameters of Interest 
Primary Endpoint:  
x 
The number and type of AEs reported by the investigator or the patient 
The safety variables to be analysed include AEs and clinical laboratory tests  
Exploratory Endpoints 
x 
Proportion of participants experiencing clinical response as per assessment criteria defined in 
section 9.1 
x 
Change from baseline in patient-reported outcomes as per EORTC QLQ C-30 and FACIT Fatigue 
The safety analysis population will include all subjects who sign the ICF and receive at least one dose of 
ImbruvicaTM. The verbatim terms used by participating physicians to document AEs in the CRF will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA). For each adverse event, the 
percentage of subjects who experience at least 1 occurrence of the given event will be summarized. Adverse 
events and serious adverse events will be summarized for the study duration by body system, preferred 
term, intensity, and relationship to ImbruvicaTM using descriptive statistics. Where appropriate, additional 
summaries, listings, or narratives may be provided for any deaths, serious adverse events, or any adverse 
events of clinical interest. Changes from baseline to the worst AE grade experienced by a patient during the 
study will be provided as shift tables. Results of investigations data including vital signs, if any, will be 
summarized using descriptive statistics. 
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
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Approved, Date: 20 October 2022  
d. 
May include but not limited to blood pressure, pulse rate, respiratory rate, body temperature, and weight 
including ECOG performance status. 
e. 
Based on the criteria described in Section 9.1 implemented by the participating physician 
f. 
All AEs and special situations following exposure to ibrutinib will be to be recorded in the CRF, regardless of 
seriousness or causality. AE collection should start from the time a signed and dated informed consent form is 
obtained and will apply to all adverse events that occur up until 30 days after a patient’s last use within the 
study. It includes the incidence of deaths, AEs, and AEs reported/observed any time during the course of the 
study, either during any study visit or through any other mode of communication. AE follow-up required for 30 
days after last dose to determine if any new or ongoing drug-related AEs or any SAEs regardless of 
relationship to ImbruvicaTM exists. Follow-up would be conducted by participating site via telephone contact. 
g. 
Investigations including haematological and  coagulation profile  
h. 
A discontinuation visit is the visit at which the participating physician is discontinuing ImbruvicaTM or first 
routine clinic visit after the patient stopped taking ImbruvicaTM on his own. At the discontinuation visit 
information on date and reason(s) for ImbruvicaTM discontinuation will be collected, if available. 
i. 
For follow-up assessments, a telephonic follow-up call will be made by the participating physician 30 days (±7 
days) after last dose of ImbruvicaTM or 30 days (±7 days) after completion of 12 months of ImbruvicaTM 
treatment (whichever is earlier), to inquire about any AEs observed. 
 
Abbreviation: 
EORTC QLQ C-30: 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaires Core 30 
FACIT Fatigue:  
Functional Assessment of Chronic Illness Therapy-Fatigue 
 
 
 
 
 
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ABBREVIATIONS 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
BTK 
Bruton’s Tyrosine Kinase 
CLL 
Chronic Lymphocytic Leukaemia 
CR 
Complete Response 
CRF 
Case Report Form 
del17p 
deletions in the short arm of chromosome 17 
ECOG 
Eastern Cooperative Oncology Group 
eDC 
Electronic Data Capture 
EORTC QLQ C-30 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaires Core 30 
EOT 
End-Of-Treatment 
FACIT 
Functional Assessment of Chronic Illness Therapy 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form/Document 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
IWCLL 
International Workshop on Chronic Lymphocytic Leukaemia 
MCL 
Mantle Cell Lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR 
Overall Response Rate 
PD 
Progressive Disease 
PQC 
Product Quality Complaint 
PR 
Partial Response 
PRO 
Patient-Reported Outcome 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SLL 
Small Lymphocytic Lymphoma 
TEAE 
Treatment-Emergent Adverse Event 
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1. 
INTRODUCTION 
 
Ibrutinib (PCI-32765; JNJ-54179060) is a first-in-class potent, orally-administered, covalently-
binding small molecule inhibitor of Bruton’s tyrosine kinase (BTK) currently under development 
for the treatment of B-cell malignancies. Ibrutinib is being co-developed by Pharmacyclics, Inc. 
and Janssen Research & Development, LLC (JRD). The term "sponsor" used throughout this 
document refers to the entities listed in the Contact Information page(s), which will be provided 
as a separate document. 
Ibrutinib is an oral formulation in a hard gelatin capsule form containing micronized ibrutinib. The 
initial approval of ibrutinib by the United States (US) FDA for the treatment of an adult patient 
with mantle cell lymphoma (MCL) who has received at least one prior therapy was received on 13 
November 2013. This indication is based on overall response rate. Subsequently it received 
approval in the US for the treatment of patient with chronic lymphocytic leukemia (CLL) who has 
received at least one prior therapy, and for the treatment of CLL patient with 17p deletion. It is 
also approved in the EU for the treatment of adult patients with CLL who have received at least 
one prior therapy, or in first line in the presence of 17p deletion or TP53 mutation in patients 
unsuitable for chemo-immunotherapy. Approvals have also been obtained in a number of other 
countries worldwide. Drug Controller General (India) first approved Ibrutinib for the treatment of 
patients of CLL or MCL who have received at least one prior therapy or CLL with 17p deletion 
on October 2015. 
The following nonclinical and clinical information summarizes ImbruvicaTM (Ibrutinib capsule 
140 mg) (Appendix 1). The term “sponsor” used throughout this document refers to the entities 
listed in the Contact Information page(s), which will be provided as a separate document. 
1.1. 
Background 
The generation and maintenance of normal and malignant B cells is controlled by biochemical 
signals transmitted by the BCR. Bruton’s tyrosine kinase is an enzyme required for BCR 
signalling. Selective BTK inhibition is a novel approach to target diseases driven by BCR 
activation, such as CLL/SLL (Small Lymphocytic Lymphoma).  
In vitro studies have shown that ibrutinib binds covalently to a cysteine residue (Cys-481) in the 
BTK active site, leading to potent and irreversible inhibition of BTK enzymatic activity.1 In 
cellular signal transduction assays with a B-cell lymphoma cell line, ibrutinib inhibited auto-
phosphorylation of BTK, phosphorylation of BTK’s physiological substrate, phospholipaseCγ 
(PLCγ), and phosphorylation of a further downstream kinase, extracellular signal-regulated kinase 
(ERK). Ibrutinib also inhibited the growth of a subset of B-cell lymphoma derived cell lines, with 
50% growth inhibition (GI50) values ranging from 0.1 to 5.5 μM.2 When added directly to human 
whole blood, ibrutinib inhibits signal transduction from the B-cell receptor and blocks primary B-
cell activation (IC50 = 80 nM) as assayed by anti-IgM stimulation followed by CD69 expression.3 
 
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1.2. 
Overall Rationale for the Study 
CLL is a progressive hematologic disease characterized by an accumulation of monoclonal mature 
B cells (CD5+ CD23+) in the blood, bone marrow, and secondary lymph organs; diagnosis 
requires the presence of ≥ 5000 B-lymphocytes/μL in the peripheral blood. The clinical course for 
CLL ranges from asymptomatic lymphocytosis to aggressive disease involving lymphatic and 
myelopoietic organs.  
Although there have been impressive gains in treatment and in the understanding of the biology of 
CLL, the disease is incurable using chemotherapy or CIT. Stem cell transplant may be curative, 
but few patients are able to undergo this treatment. The more relapses patients incur, the more 
resistant patients become to therapy. Therefore, there is a need for further development of therapies 
for CLL. The most recent guidelines on the management of CLL states that the biological 
parameters useful for guiding treatment for CLL are deletions in the short arm of chromosome 17 
(del17p), p53, and in the long arm of chromosome 11 (del11q). In particular, patients with the 
del17p abnormality have an increased risk of relapse and death; the median life expectancy is 2 to 
3 years from first-line treatment, and no standard treatment exists for this patient group.  
While a minority of patients with CLL will have del17p at the time of diagnosis, the proportion 
increases with successive chemotherapy treatments to between 30% and 50% of patients having 
del17p in the relapsed setting. This chromosomal defect results in a loss of functional p53, which 
thereby confers resistance to subsequent salvage treatments. 
CLL has been categorized under lymphoid leukaemia (as C91 in ICD-10) in Consolidated report 
of Hospital-Based Cancer Registry of India for year 2007-2011.4 Exact number of cases is not 
reported in the reported but overall number of lymphoid leukaemia cases is as followed: 
 
HBCR 
Male 
N (% of total cancer cases) 
Female 
N (% of total cancer cases) 
Mumbai 
662 (2.9) 
251 (1.4) 
Bangalore 
390 (3.5) 
207 (1.6) 
Chennai 
450 (2.9) 
232 (1.3) 
Thiruvananthapuram 
739 (3.8) 
446 (2.4) 
Dibrugarh 
27 (0.9) 
7 (0.3) 
Guwahati 
26 (0.4) 
19 (0.4) 
Chandigarh 
155 (5.9) 
41 (2.0) 
 
MCL is a rare and incurable subtype of non-Hodgkin Lymphoma (NHL). It accounts for about 
6% of all NHL cases in the Western world. At the molecular level, MCL is uniquely characterized 
by overexpression of the cell cycle regulator protein cyclin D1. This is due to the chromosomal 
translocation t(11;14)(q13;q32), which puts the cyclin D1 gene, B-cell leukaemia/lymphoma-1 
(bcl-1), under the control of the immunoglobulin heavy chain enhancer with subsequent 
overexpression of cyclin D1. In association with overexpression of cyclin D1, other markers such 
as CD20 and CD5 are also evident in MCL. 
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
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Approved, Date: 20 October 2022  
Current initial therapy for the treatment of MCL includes cyclophosphamide, doxorubicin, 
vincristine, and prednisone (CHOP) or hyperfractionated cyclophosphamide, vincristine, 
doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (Hyper-CVAD), 
often in combination with rituximab (R-CHOP or R-Hyper CVAD). However, many other 
chemotherapeutic regimens have been evaluated. Younger patients with good performance status 
are frequently considered for more intensive induction therapy with combinations such as R-Hyper 
CVAD or alternating R-CHOP and rituximab, dexamethasone, high-dose cytarabine, and cisplatin 
(R-DHAP) followed by consolidation therapy with autologous stem cell transplant (SCT). 
Intensive therapy is not an option for most patients with MCL because of their age and 
comorbidities. Once the disease has progressed after first-line therapy, the prognosis is dismal. 
Many agents/regimens have been studied and are used. However, there is no globally accepted 
standard treatment for patients with MCL who progress after initial therapy. 
MCL has been categorized under NHL (as C83.1 in ICD-10) in “Consolidated report of Hospital-
Based Cancer Registry of India for year 2007-2011”.4 Exact number of MCL cases is not reported 
in the reported but overall number of NHL cases is as followed: 
HBCR 
Male 
N (% of total cancer cases) 
Female 
N(% of total cancer cases) 
Mumbai 
1381 (6.1) 
647(3.5) 
Bangalore 
520 (4.6) 
254 (1.9) 
Chennai 
655 (4.2) 
301 (1.7) 
Thiruvananthapuram 
954 (5.0) 
516 (2.7) 
Dibrugarh 
83 (2.9) 
33 (1.4) 
Guwahati 
127 (1.9) 
60 (1.3) 
Chandigarh 
114 (4.3) 
45 (2.2) 
MCL represents around 2-3% of all cases of non-Hodgkin’s lymphoma in India [2.1% by Gujral 
S et al.11, 3.4% by Naresh KN et al.12, 1.8% by Nimmagadda RB13]. 
 
Efficacy in CLL 
Extensive pharmacokinetic (PK) sampling has been performed on approximately 186 subjects 
across 4 studies [Studies PCYC-047535, PCYC-1102-CA6, PCYC-1104-CA7, and PCYC-1109-
CA8]. Results show that plasma concentrations of ibrutinib generally increased with increasing 
dosages from 1.25 to 12.5 mg/kg/day. An increase in ibrutinib AUC was approximately 
proportional to dose. The coefficient of variation for the AUC ranged from 60% to 107% across 
all studies. The mean apparent terminal half-life of ibrutinib ranged from 4.3 to 8.9 hours, with 
median Tmax of 2 hours. There was no apparent accumulation of ibrutinib exposure after repeated 
daily dosing.5,6 
In Study PCYC-1102-CA, ibrutinib was administered as a fixed dosage of 420 mg/day to subjects 
with relapsed/refractory CLL/SLL. Approximately 95% of subjects had steady-state ibrutinib 
AUC values ≥160 ng∙h/mL, indicating that the 420-mg/day dose is adequate to achieve exposures 
yielding full BTK active-site occupancy. 
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54179060   Imbruvica (Ibrutinib capsule 140 mg)  
 
 
 
Clinical Protocol 54179060LYM4005 (Amendment-1) 
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Approved, Date: 20 October 2022  
Study PCI-32765CLL1002 was an open-label drug-drug interaction study of 18 men, in which 
ibrutinib was administered alone at a 120-mg dose or in combination with ketoconazole at a 40-
mg dose. Results demonstrated a 24-fold increase in ibrutinib area under the plasma concentration-
time curve (AUC0-last) and a 29-fold increase in Cmax following co-administration with 
ketoconazole. Terminal half-life was not increased. Ibrutinib single-dose administration was well 
tolerated. No drug-related adverse events (AEs) were reported. No Grade 3 or 4 toxicities or 
serious adverse events (SAEs) were reported. 
Patients with various B-cell malignancies have received ibrutinib across 7 clinical studies, 4 of 
which included patients with CLL/SLL. Patients with CLL or SLL have received single-agent 
ibrutinib across 2 clinical studies: Study PCYC-04753, a Phase 1 dose-finding study in patients 
with recurrent B-cell lymphoma, and Study PCYC-1102-CA, a Phase 1b/2 study in patients with 
CLL/SLL. Two additional Phase 1b/2 studies are ongoing to evaluate the safety and efficacy of 
ibrutinib in combination with chemoimmunotherapy (CIT) or CD20 monoclonal antibody therapy 
in patients with relapsed or refractory CLL/SLL, specifically with BR or FCR in Study PCYC-
1108-CA, and with ofatumumab in Study PCYC-1109-CA. 
In Study 1112, a Phase 3 randomized, comparator-controlled, pivotal study in subjects with 
CLL/SLL ibrutinib improved efficacy outcomes in subjects with previously treated CLL/SLL 
compared to that ofatumumab. Analysis of PFS (per the Independent Review Committee [IRC]) 
demonstrated a statistically significant reduction in the risk of disease progression or death in the 
ibrutinib arm compared to the ofatumumab arm (HR=0.215, p<0.0001). Analysis of OS showed 
that subjects in the ibrutinib arm had a statistically significant reduction in the risk of death 
(HR=0.434, p=0.0049). The ORR (per the IRC) was significantly higher (p<0.0001) for subjects 
in the ibrutinib arm (42.6%) than those in the ofatumumab arm (4.1%). The ORR, when including 
partial response with lymphocytosis (PR-L) (per IRC assessment), was 62.6% for the ibrutinib arm 
and 4.1% for the ofatumumab arm (p<0.0001). 
Study PCYC-04753 was a Phase 1, multicentre, dose-escalation study of ibrutinib in subjects with 
surface immunoglobulin positive B-cell Non-Hodgkin’s Lymphoma (NHL).5 Subjects were 
observed for dose-limiting toxicities (DLTs) and other AEs as well as for laboratory and physical 
examination changes. Fifty subjects were evaluable for efficacy. The ORR was 60%, with 7 CRs 
and 23 PRs. The maximum tolerated dose (MTD) of ibrutinib was not reached.5 
Study PCYC-1102-CA is a Phase 1b/2, open-label, multicentre study. One hundred seventeen 
subjects with CLL/SLL were enrolled into 1 of 5 treatment groups, each receiving 1 of 2 fixed 
dose levels (420 mg/day or 840 mg/day) of ibrutinib. Of the 61 subjects in Groups 1 
(relapsed/refractory; 420 mg) and 3 (relapsed/refractory; 840 mg) with relapsed or refractory 
disease had received a median of 4 (range: 1 to 12) prior therapies, with all subjects receiving 
nucleoside analogues. The median age for subjects in Groups 1 and 3 was 64 years. Thirty-nine 
percent of subjects had an ECOG performance score of 0 and 61% had a score of 1 or 2.6  
Molecular, clinical, and prior treatment characteristics reflected a poor-risk population. 28 (46%) 
subjects from Groups 1 and 3 were considered refractory to purine analogue therapy (ie, <12-
month treatment-free interval following purine analogue regimen). 54% had bulky disease 
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
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(defined as single lymph nodes measuring ≥5 cm). 79% of subjects had at least 1 molecular poor-
risk feature. (immunoglobulin variable heavy gene [IgVH] unmutated, del [17p], del [11q], or β2 
microglobulin >3 mg/L), with 36% of subjects having del (17p).6 
The ORR was 67% with 2% CRs. An additional 23% of subjects had >50% shrinkage of 
lymphadenopathy (nodal response) and 3% had stable disease. The 840-mg cohort was stopped 
after comparable efficacy and safety between 420 mg and 840 mg was shown. The 12-month PFS 
estimate for Group 1 was 88% and for Group 3 was 82%.6 
Study PCYC-1108-CA is an ongoing combination CIT Phase 1b/2 study which has completed 
enrolment. Among 33 subjects with relapsed and refractory CLL/SLL enrolled, 30 have received 
BR and ibrutinib and 3 have received FCR and ibrutinib.9 The FCR cohort enrolment was 
suspended due to slow enrolment related to the lack of subjects at participating sites with relapsed 
CLL in whom the FCR regimen was considered appropriate. For subjects receiving the BR 
combination, bendamustine 70 mg/m2 was administered on Day 1 and Day 2, combined with 
rituximab at 375 mg/m2 on Day 1 of Cycle 1 and 500 mg/m2 on Day 1 for all subsequent courses 
for a maximum of 6 cycles. Ibrutinib was administered as a continuous daily oral dose of 420 mg. 
The median number of prior therapies was 2 (range 1 to 4). There were 37% and 13% of subjects, 
respectively, who were considered either refractory to a purine analogue-containing regimen or to 
BR (treatment-free interval prior to enrolment was <12 months). Bulky disease was present in 52% 
of subjects.9  
At a median follow-up of 4.9 months (range 2.7 to 8.3 months), the ORR was 90% (CR 10%, 
partial response [PR] 80%). Two additional subjects achieved a nodal response with residual 
lymphocytosis. Responses appear to be independent of high-risk clinical or genomic features. 
Ninety percent of subjects currently remain on study. Three subjects have discontinued, 2 for 
progressive disease (PD) and 1 in pursuit of a stem cell transplant.9 
Study PCYC-1109-CA is an ongoing Phase 1b/2 study combining ibrutinib with ofatumumab. 
Based on preliminary data from 27 subjects with relapsed or refractory CLL/SLL/prolymphocytic 
leukaemia (PLL) (n=24) or Richter’s transformation (RT, n=3), all subjects achieved a PR (100% 
ORR). The median follow-up is 6.5 months (range: 5.3 to 10.2 months).8,10 
In Study 1112, a Phase 3 randomized, comparator-controlled, pivotal study in subjects with 
CLL/SLL ibrutinib improved efficacy outcomes in subjects with previously treated CLL/SLL 
compared to that ofatumumab. Efficacy results from Studies PCYC-04753, PCYC-1102-CA, 
PCYC-1108-CA, and PCYC-1109-CA demonstrate that ibrutinib has robust activity in CLL both 
as a single agent and in combination. All studies included patients with relapsed and refractory 
disease. Response rates for the 4 studies were independent of high-risk factors or genomic features. 
The predictable and characteristic pattern of response, with rapid reduction in lymphadenopathy, 
frequent and early hematologic improvement, and transient lymphocytosis, is consistent with the 
established anti-homing, anti-adhesion, pro-apoptotic, and anti-proliferative effects of BTK 
inhibition in CLL cells. Of particular note, high response rates have been demonstrated with 
continuing therapy in Studies PCYC-1102-CA, PCYC-1108-CA, and PCYC-1109-CA.6–8  
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
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Approved, Date: 20 October 2022  
With these results, ImbruvicaTM (Ibrutinib capsule 140 mg). has been approved in various regions 
of the world including India in patients with CLL who have received at least one prior therapy or 
CLL with 17p deletion.  
Efficacy in MCL 
Study PCI- 32765CLL1002 was an open-label drug-drug interaction study of 18 men, in which 
ibrutinib was administered alone at a 120 mg dose or in combination with ketoconazole at a 40 mg 
dose.14 Results demonstrated that ketoconazole, a strong CYP3A4 inhibitor, increased ibrutinib 
exposure (Cmax and AUClast) by 29- and 24-fold, respectively. Terminal half-life was not increased. 
Ibrutinib single-dose administration was well-tolerated in Study PCI-32765CLL1002. No drug-
related AEs were reported. No Grade 3 or 4 toxicities or SAEs were reported.14 
Efficacy results from Study PCYC-04753 and Study PCYC-1104-CA demonstrate that ibrutinib 
has activity as a single-agent in treatment of subjects with relapsed or refractory MCL. 
Study PCYC-04753 was a Phase 1, multicentre, multi-cohort, open-label, dose-escalation study, 
in which 56 subjects with relapsed or refractory NHL including CLL and Waldenström’s 
macroglobulinemia were enrolled across 7 dose cohorts.8 Nine of 56 subjects had a diagnosis of 
MCL and were evaluable for response. Seven of them achieved an objective response by the 
Revised Response Criteria for Malignant Lymphoma, including 3 CRs and 4 partial responses 
[PRs]; 1 subject had stable disease and 1 subject had progressive disease. All of the subjects 
responding to treatment achieved response at the time of the first post-baseline response 
assessment (after 2 cycles of treatment). Of the 3 subjects who achieved a CR, 2 subjects had CR 
on initial post-baseline assessment, and 1 subject achieved a PR initially and they had a CR after 
8 cycles (28-days cycle duration) of therapy. Five subjects who entered a long-term follow-up 
study have durations of response ranging from 10.5 to 27.5 months.8 
This is an ongoing multicentre Phase 2 study in subjects with MCL who are relapsed or refractory 
to their previous treatment. Subjects are stratified based on their previous exposure to the 
chemotherapeutic agent bortezomib.7 The objectives include studying the efficacy of ibrutinib 
given as a continuous fixed dose of 560 mg/day. Preliminary results were recently presented on 68 
subjects, of whom 51 were evaluable for efficacy. Overall best response (CR + PR) was 69%—
71% among the bortezomib naive subjects (N = 31) and 65% among bortezomib-exposed subjects 
(N = 20). In some patients, treatment with ibrutinib was associated with a transient increase in 
peripheral lymphocyte count representing a compartmental shift of cells with the CD19+/CD5+ 
phenotype from nodal tissues to peripheral blood.7 
In a single arm ibrutinib monotherapy study conducted in patients with relapsed / refractory MCL 
an ORR of 67.6% a PFS rate of 63% (95% CI 53, 71%) at 6 months and a duration of response of 
17.5 months were observed. In an update on time-dependent outcomes till March 2014, the 
beneficial effects were sustained. The treatment effect seemed fairly consistent throughout the 
analysed subgroups, including region, relapsed or refractory disease, bulky disease, number of 
prior regimens, simplified MIPI score, and prior therapy with bortezomib or lenalidomide. 
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
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The benefit- risk balance in the indication “treatment of adult patients with relapsed or refractory 
MCL” is considered positive, as outstanding activity is shown in terms of high response rate in 
this patient population of previously treated & relapsed or refractory MCL with an unmet clinical 
need, along with the added convenience of oral dosing once daily. With these results, ImbruvicaTM 
(Ibrutinib capsule 140 mg) has been approved in various regions of the world including India in 
patients with MCL who have received at least one prior therapy. 
 
Safety Overview 
Pooled safety data for subjects treated with ibrutinib monotherapy in 9 studies that have completed 
primary analysis as of the cutoff date for this Investigator’s Brochure update (6 April 2015) 
(Studies 04753, 1102, 1112, 1117, 1104, MCL2001, 1106, 1118E, and JPN-101) are summarized 
below. The data presented also include subjects enrolled in Studies 1112 (N=57) and CLL3001 
(N=90) who crossed over from ofatumumab or placebo, respectively, to receive treatment with 
ibrutinib monotherapy after progression and/or positive interim analysis results. Median duration 
on treatment was 8.3 months (range: 0.0 to 32.3 months).  
Treatment-emergent AEs in more than 10% of subjects receiving ibrutinib as monotherapy 
(N=1071) The most frequently reported treatment-emergent AEs were diarrhea, fatigue, nausea, 
cough, anemia, pyrexia, and neutropenia. 
Treatment-emergent AEs assessed as related to ibrutinib by the investigators in more than 5% of 
subjects receiving ibrutinib as monotherapy (N=1071). Adverse events that were considered by 
the investigator to be related to ibrutinib monotherapy were reported in 75.5% of subjects. The 
most frequently reported AEs related to ibrutinib were diarrhea, fatigue, neutropenia, and nausea. 
Treatment-emergent AEs of Grade 3 or 4 in severity in more than 2% of subjects receiving 
ibrutinib as monotherapy (N=1071). Adverse events of Grade 3 or 4 were reported in 49.3% of 
subjects. The most commonly reported Grade 3 or 4 AEs that were hematologic in nature were 
neutropenia, thrombocytopenia, and anemia. Pneumonia, hypertension, and atrial fibrillation were 
the most frequently reported nonhematologic Grade 3 or 4 AEs. 
The incidence of treatment-emergent SAEs reported in more than 1% of subjects receiving 
ibrutinib as monotherapy (N=1071). Serious AEs were reported in 43.2% of subjects. The most 
frequently reported SAEs were pneumonia, atrial fibrillation, febrile neutropenia, and pyrexia. The 
most frequently reported SAEs (any grade) that were considered related to ibrutinib were 
pneumonia, atrial fibrillation, and febrile neutropenia. 
Among the 1071 subjects in the pooled analysis of monotherapy studies, 11.8% discontinued 
ibrutinib therapy due to an AE. The most frequently reported AEs leading to treatment 
discontinuation included infections (ie, pneumonia [1.4%] and sepsis [0.8%]), respiratory failure 
(0.6%), and subdural hematoma (0.5%). Fatal AEs were reported in 9.3% of subjects during study 
treatment or within 30 days of discontinuation of treatment. The most frequently reported causes 
of fatal AEs included pneumonia (1.7%), sepsis (0.7%), progressive disease (MCL [0.7%] in 
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
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subjects from MCL studies, CLL [0.6%] and Richter’s syndrome (0.4%) in subjects from CLL 
studies).  
Upon initiation of treatment, a reversible increase in lymphocyte counts (i.e. ≥ 50% increase from 
baseline and above absolute count 5000/mcL), often associated with reduction of 
lymphadenopathy, has been observed in most subjects (approximately 69% to 75%) with 
CLL/SLL treated with single agent ibrutinib. This effect has also been observed in some patients 
(33%) with MCL treated with single agent ibrutinib. This observed lymphocytosis is a 
pharmacodynamic effect and should not be considered progressive disease in the absence of other 
clinical findings. In both disease types, lymphocytosis typically occurs during the first few weeks 
of ibrutinib therapy (median time 1.1 weeks) and typically resolves within a median of 8.0 weeks 
in subjects with MCL and 18.7 weeks in subjects with CLL/SLL.  
Lymphocytosis appeared to occur in lower incidence and at lesser magnitude in subjects with 
CLL/SLL receiving ibrutinib in combination with chemo-immunotherapy (i.e. 27% of subjects 
receiving ibrutinib + BR in Study 1108) or immunotherapy (i.e. 55% of subjects receiving ibrutinib 
plus ofatumumab in Group 2 of Study 1109).  
There were isolated cases of leukostasis reported in subjects treated with ibrutinib. A high number 
of circulating lymphocytes (> 400000/mcL) may confer increased risk. Subjects should be closely 
monitored. Administer supportive care including hydration and/or cytoreduction as indicated. 
There have been reports of haemorrhagic events in subjects treated with ibrutinib in both 
monotherapy and combination clinical studies. The majority of these haemorrhagic AEs were of 
Grade 1 or 2 in severity; those included contusion, epistaxis, and petechiae. Haemorrhagic events 
of Grade 3 or higher, including central nervous system (CNS) haemorrhage of any grade severity, 
occurred in 3.4% (17/506) of subjects treated in monotherapy studies and in 3.1% (4/130) of 
subjects treated in combination therapy studies; none were reported in the healthy volunteer studies 
(N=100). In the extension study, PCYC-1103-CA, two additional Grade 3 events associated with 
bleeding were reported (‘gastrointestinal haemorrhage’ and ‘haematotympanum’). It is not clear 
whether or not these events are attributable to ibrutinib. Subjects were excluded from participation 
in specific ibrutinib Phase 2 and 3 studies if they required warfarin or other vitamin K antagonists.  
However, it is possible that treatment with ibrutinib could increase the risk of bruising or bleeding. 
Subjects in the current study will be monitored closely for haemorrhagic AEs. Guidance on use of 
antiplatelet agents and anticoagulants is provided in locally approved prescribing information. 
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects treated 
with ibrutinib therapy. In non-randomized clinical trials, infections (including sepsis, bacterial, 
viral, or fungal infections) were observed in subjects with MCL (≥Grade 3; 25.2%) and CLL/SLL 
(≥Grade 3; 37.6%). Some of these infections have been associated with hospitalization and death. 
Although causality has not been established, cases of progressive multifocal leukoencephalopathy 
have occurred in subjects treated with ibrutinib. Treatment-emergent Grade 3 or 4 cytopenias 
(neutropenia, thrombocytopenia, and anaemia) were reported in subjects treated with ibrutinib. 
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Subjects should be monitored for fever and infections and appropriate anti-infective therapy should 
be instituted as indicated. 
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, particularly 
in subjects with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. 
Periodically monitor subjects clinically for atrial fibrillation. Subjects who develop arrhythmic 
symptoms (e.g., palpitations, lightheadedness) or new onset of dyspnea should be evaluated 
clinically, and if indicated, have an ECG performed. For atrial fibrillation which persists, consider 
the risks and benefits of ibrutinib treatment and follow the dose modification guidelines as per 
Attachment 3 in conjunction with local prescribing information 
Other malignant diseases have been observed in subjects who have been treated with ibrutinib, 
including skin cancers, adenocarcinomas, and other hematologic malignancies. It is not clear 
whether or not these events are attributable to ibrutinib. Subjects in the current study will be 
monitored for other malignancies. 
Tumour lysis syndrome has been reported with ibrutinib therapy. Subjects at risk of tumour lysis 
syndrome are those with high tumour burden prior to treatment.  
Diarrhoea is the most frequently reported nonhaematologic AEs with ibrutinib monotherapy and 
combination therapy. Other frequently reported gastrointestinal events include nausea, vomiting, 
and constipation. These events are rarely severe and are generally managed with supportive 
therapies including antidiarrheal and antiemetic. 
Mild to moderate rash has been commonly reported in subjects treated with either single-agent 
ibrutinib or in combination with chemotherapy. Rash occurred at a higher rate in the ibrutinib arm 
than in the ofatumumab arm in Study PCYC-1112-CA.15 Most rashes were mild to moderate in 
severity. One case of Stevens-Johnson Syndrome (SJS) was reported in a subject with CLL. The 
subject received ibrutinib (420 mg/day) and was also receiving various antibiotics and anti-gout 
medication (allopurinol) known to be associated with SJS. Subjects should be monitored closely 
for signs and symptoms suggestive of SJS. 
Overall Rationale 
Post-marketing phase IV clinical trial is useful in identifying new safety issues and trends, which 
were not observed in previously conducted clinical studies. The data obtained from the present 
study will help to understand the safety profile of ibrutinib in a real-world Indian scenario 
compared with that obtained in a controlled clinical environment. The objective of the present 
study is to address the mandatory regulatory requirement regarding conduct of study in Indian 
population to monitor the adverse events with ImbruvicaTM (Ibrutinib capsule 140 mg). The study 
will assess the safety of ImbruvicaTM prescribed as per locally approved Prescribing Information 
in Indian patients of CLL or MCL who have received at least one prior therapy or CLL with 17p 
deletion. 
 
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2. 
OBJECTIVES AND HYPOTHESIS 
2.1. 
Objectives  
The aim of the present study is to assess the safety of ibrutinib in a routine clinical set-up in Indian 
subjects to address the regulatory requirement. 
2.1.1. 
Objectives 
Primary Objective 
The primary objective of this study is to evaluate the safety of ImbruvicaTM (ibrutinib capsule 140 
mg) under actual conditions of use. 
Exploratory Objectives 
To analyse the following outcomes with ibrutinib:  
x Baseline patient and disease characteristics 
x Response assessment and progression criteria as per International Workshop on Chronic 
Lymphocytic Leukaemia (IWCLL) criteria16–18 for CLL and revised response criteria for 
malignant lymphoma19 for MCL. 
x Change in patient reported outcomes as measured by  
o Quality of Life by EORTC QLQ C-30 instrument (European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaires Core 30) 
o Fatigue by FACIT Fatigue instrument (Functional Assessment of Chronic Illness 
Therapy Fatigue) 
 
2.2. 
Hypothesis 
No formal hypothesis testing will be conducted. Data will be summarized using descriptive 
statistics. Continuous variables will be summarized using the number of observations, mean, SD, 
coefficient of variation, median, and range as appropriate. Categorical values will be summarized 
using the number of observations and percentages as appropriate. 
3. 
STUDY DESIGN AND RATIONALE 
This is a prospective open label, single arm, multicentre, phase IV interventional study to describe 
the safety of ImbruvicaTM in Indian subjects. Approximately, 75 subjects, selected by investigators 
and determined to be eligible for ibrutinib treatment as per protocol eligibility criteria will be 
enrolled in the study, after written informed consent is obtained. Subjects will be monitored for 
AEs during treatment of ImbruvicaTM.  
 
 
 
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
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3.1. 
Overview of Study Design 
Relapsed/refractory CLL and MCL patients who have received at least one therapy or CLL patients 
with deletion 17p selected by investigators and determined to be eligible for ibrutinib treatment as 
per protocol eligibility criteria will be enrolled in the study. Each subject will receive ibrutinib 
treatment for a period of 12 months or till disease progression, whichever is earlier. Enrolled 
subjects will be followed up to 12 months from the treatment initiation. During the study period, 
data will be collected at monthly intervals for the first 6 months, (monthly visit ± 7 days; Visit 1 
to 6) . Subsequent visit would be at 9 months ± 7 days [Visit 7]. The End-of-Treatment (EOT) visit 
will be conducted after the completion of 12-months ImbruvicaTM treatment (at Visit 8) or on the 
day at which the patient discontinued the ImbruvicaTM treatment or study. A telephonic follow-up 
will be conducted 30 days after the EOT Visit. 
Screening cum Enrolment Visit (Day 1):  
Indian subjects who are eligible to receive ImbruvicaTM will be considered in the present study. 
Prior to data collection, all subjects [and/or their legally acceptable representative where 
applicable] must sign an informed consent form (ICF) allowing data collection and source data 
verification in accordance with local regulations. Data collected at this visit may include but not 
limited to demographics, medical history, disease related history, concomitant medications, 
patient-reported outcomes (PROs), laboratory investigations, etc. The use of ImbruvicaTM is 
expected to follow dosing and frequency stipulated in the locally approved prescribing 
information. The recommended dose of ImbruvicaTM as per the locally approved Prescribing 
Information (Appendix 1) is 420 mg (three 140 mg capsules) as a single daily dose for CLL and 
560 mg (four 140 mg capsules) as a single daily dose for MCL. 
Treatment Period (Visit 1 to 6 and Visit 7): 
Enrolled subjects will be followed up to 12 months from the treatment initiation. During the study 
period, data will be collected at monthly intervals for the first 6 months, (monthly visit ± 7 days; 
Visit 1 to 6). Subsequent visit would be at 9 months ± 7 days [Visit 7], Data collected at this visit 
may include but not limited to demographics, medical history, disease related history, AEs, disease 
progression assessment, concomitant medications, patient-reported outcomes (PROs), laboratory 
investigations, etc.  
End-of-Treatment (EOT) (Visit 8) 
The End-of-Treatment (EOT) visit will be conducted after the completion of 12-months 
ImbruvicaTM treatment (at Visit 8) or on the day at which the patient discontinued the ImbruvicaTM 
treatment or study.  
The rationale for such schedule is that in the RESONATE Trial, on long term follow up it was 
found that the prevalence rates for infection, diarrhea, and bleeding events were highest for the 
first 6 months and gradually declined thereafter 
Follow up period (End of Study): A telephonic follow-up will be conducted 30 days after the EOT 
Visit. 
The expected frequency and timing of data collection in this phase IV study are summarized in the 
TIME AND EVENTS SCHEDULE presented after the synopsis. 
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only a limited amount of such data.  Commercial stocks of Ibrutinib affixed with additional 
investigational labels (to meet local regulatory requirements) will be used for the subjects enrolled 
in the study. Subjects will procure Ibrutinib from the existing distribution channel (regular supply 
chain) as obtained by routine subjects but the drug will be free of cost for clinical trial subjects as 
per the mentioned duration in the study protocol.  
4. 
SUBJECT POPULATION 
The study population will include Indian subjects with CLL or MCL who have received at least 
one prior therapy or CLL with 17p deletion who are newly initiated on ImbruvicaTM treatment as 
per protocol eligibility criteria. .  
Participating sites will be encouraged to enrol subjects in a consecutive manner when subjects 
come for their regular consultation, in order to minimize bias in patient selection. All eligible 
subjects should be offered enrolment for data collection within the study. 
At each participating site, the participating physician will assess subjects to determine their 
eligibility for data collection within the study based on the selection criteria listed below. If there 
is a question about any of the selection criteria, the participating physician should consult with the 
appropriate sponsor representative before enrolling the patient. 
A subject will be considered to have completed the study if he has completed the end of study 
telephonic follow-up 30 days after EOT visit. Subjects who prematurely discontinue ImbruvicaTM 
for any reason will be considered as completed the study after they have completed the telephonic 
follow-up post-end of treatment visit at discontinuation. 
A subject will be withdrawn from data collection within the study for any of the following reasons: 
x Lost to follow-up 
x Withdrawal of consent  
x Death 
If a patient is lost to follow-up, every reasonable effort should be made by the participating site 
personnel to contact the subject and determine the reason for discontinuation/withdrawal. The 
measures taken to follow up should be documented. 
When a patient withdraws before completing the study, the reason for withdrawal is to be 
documented in the case report form (CRF) and in the source document. Subjects who withdraw 
will not be replaced. 
Starting or stopping therapies during the study period will not impact data collection for this study. 
If treatment with ImbruvicaTM needs to be discontinued at the discretion of the participating 
physician or the patient discontinues ImbruvicaTM before the end of the 12-month follow-up, this 
will not result in automatic withdrawal of the patient from the study. In this scenario, subsequently 
end  of treatment assessments should be documented and EOS will be conducted 30days after 
EOT.  
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Treatment with ImbruvicaTM should be discontinued if: 
x The participating physician believes that for safety reasons (e.g., AEs) it is in the best 
interest of the patient to discontinue ImbruvicaTM. 
x Disease progression as per participating physician’s assessment 
 
4.1. 
Inclusion Criteria 
Each potential patient must satisfy the following criteria to be eligible for data collection in this 
study: 
1. 
Patient of either sex and >18 years of age 
2. 
CLL or MCL patients being newly initiated on ImbruvicaTM treatment (ibrutinib capsule 
140 mg) based on independent clinical judgment of treating physicians as per locally 
approved prescribing information 
3. 
Must give a written informed consent indicating that they understand the purpose and are 
willing to participate in the study and allowing data collection and source data verification 
in accordance with regulatory requirements 
 
4.2. 
Exclusion Criteria 
Potential patients who meet any of the following criteria will not be eligible for this study: 
1. 
Patients who are not eligible to receive ImbruvicaTM as per the locally approved 
prescribing information. 
2. 
Patients participating or planning to participate in any interventional drug trial during 
the course of this study.  
 
5. 
TREATMENT ALLOCATION 
Participating investigator will be trained on the protocol as well as on the locally approved 
prescribing information of ImbruvicaTM by the sponsor designee before the enrolment of first 
patient. The TIME AND EVENTS SCHEDULE summarizes the frequency and timing of safety 
and other measurements applicable to this study. The exploratory assessments of EORTC QLQ-
30, FACIT Fatigue will be scored according to the scores described in Attachment 1: 
 
EORTC OLQ C-30 (Specimen Sample) 
The primary data source for this study will be the medical records of each participating patient. 
Source documentation should be available in subjects’ medical records for all data entered into the 
CRF. 
Screening cum enrolment visit (Day 1) 
The below mentioned procedure and measurements will be performed. 
x Written Informed Consent 
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x Eligibility Criteria 
x Demographic data 
x Diagnosis and medical history 
x Previous and/or current CLL/MCL characteristics 
o Date of initial diagnosis 
o Date of first symptoms 
o Current hospitalization information (reason for admission, date of admission, physical 
examination including vitals) 
o Prior treatment before enrolment in the study, including chemotherapies, observation, 
and other CLL or MCL treatments including transplants since diagnosis till screening 
visit will be documented: 
o Drug name, start/stop dates, dosing regimen, dose modifications, route of 
administration, and indication. 
x Patient-completed PRO instruments (questionnaires and scales)  
o FACIT Fatigue Instrument 
o EORTC QLQ-30 
x AEs  
x Type, dosage and duration of concomitant medication  
 
 
 
 
Observation Visits (Visit 1 to Visit 8) 
The subjects will be followed up at every monthly interval during Visit 1 to Visit 6 for the first 6 
months, followed by seventh visit at month 9 and eighth visit at month 12, and as outlined in the 
TIME AND EVENTS SCHEDULE The below mentioned procedure and measurements will be 
performed  
x Current medical history (symptoms & signs if any, physical examination including vitals) 
x Disease progression assessment  
x Compliance Assessment 
x Patient-completed PRO instruments (questionnaires and scales)  
o FACIT Fatigue Instrument 
o EORTC QLQ-30 
x Type, dosage and duration of concomitant medication 
x AEs for ImbruvicaTM (see Section  
x Investigations (Hematology and coagulation profile); as per TIME AND EVENTS 
SCHEDULE.  
Note: Visit 8 or discontinuation visit will be the EOT Visit. 
A discontinuation visit is the visit at which the participating physician is discontinuing 
ImbruvicaTM or first routine clinic visit after the patient stopped taking ImbruvicaTM on his own. 
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
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At the discontinuation visit, information on date and reason(s) for ImbruvicaTM discontinuation 
will be collected, if available. The data for discontinuation visit will be collected on the EOT 
Visit page in CRF. 
 
Telephonic follow up (End of Study)  
A follow-up will be performed via a telephonic contact by the participating physician 30 days (±7 
days) after last dose of ImbruvicaTM or 30 days (±7 days) after completion of 12 months of 
ImbruvicaTM treatment (whichever is earlier). In this follow-up call, enquiry about any AEs 
observed or concomitant medications taken will be made and recorded in the CRF unless the 
patient has died, or is lost to follow-up, or has withdrawn consent. Since the information on safety 
is obtained via telephone contact, written documentation of the communication must be available 
for review in the source documents. If the patient has died, the date and cause of death will be 
collected and documented in the CRF. Investigations and their results, if any performed within last 
12 weeks will be recorded. 
Unscheduled Visit 
 
During an unscheduled visit, below mentioned procedures and measurements may be performed 
but are not limited to. 
x Current medical history (symptoms & signs if any, physical examination including vitals) 
x Disease progression assessment  
x Compliance Assessment 
x Type, dosage and duration of concomitant medication  
x AEs for ImbruvicaTM  
 
6. 
DOSAGE AND ADMINISTRATION 
Dosing Regimen and Administration 
ImbruvicaTM will be prescribed to the subjects as per locally approved Prescribing Information. 
The recommended dose of ImbruvicaTM is 420 mg (three 140 mg capsules) as a single daily dose 
for CLL and 560 mg (four 140 mg capsules) as a single daily dose for MCL. 
ImbruvicaTM should be administered orally once daily with a glass of water at approximately the 
same time each day. The capsules should be swallowed whole with water and should not be 
opened, broken, or chewed. ImbruvicaTM must not be taken with grapefruit juice. 
ImbruvicaTM should continue until disease progression or no longer tolerated by the patient. 
Refer to the locally approved prescribing informationfor ImbruvicaTM and Attachment 3 regarding 
the updated dose modification guidelines, special warnings, precautions for use, and other 
important information. 
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
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Subjects will have post-trial access to ImbruvicaTM for at least one year or as decided by EC 
whichever is more as per the recommendations of ethics committee as per the recommendations 
of Subject Expert Committee (Oncology & Haematology) made in its 70th meeting held on 23rd 
May 2018 at Central Drugs Standard Control Organization HQ, New Delhi communicated vide 
F.N. 12-10/2017-DC (Pt-Johnson-snd) 
Dosing Schedule 
Enrolled subjects will receive ibrutinib treatment for the duration of 12 months or till EOT visit. 
Each subject will receive a monthly supply (90 capsules for CLL and 120 capsules for MCL) at 
the enrolment visit till month 6. Subsequent refill will be provided at the end of the month or after 
consumption of the dose provided. Sufficient dose for subsequent 3 months will be provided at the 
beginning of month 7 and month 10.   
 
Enrolment 
visit 
(beginnin
g of 
month 1) 
Mont
h 2 
Mont
h 3 
Mont
h 4 
Mont
h 5 
Mont
h 6 
Mont
h 7 
Mont
h 8 
Mont
h 9 
Mont
h 10 
Mont
h 11 
Mont
h 12 
Ibrutini
b 
monthly 
refill 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
The following data will be documented during the study period: 
x Indication for ImbruvicaTM  
x Start/stop dates and reason for initiation/discontinuation of ImbruvicaTM 
x Date and reason for dose reductions. If dosage reduction of ImbruvicaTM is needed, the 
decision will be taken as per participating physician’s discretion and it should be based on 
and consistent with the recommendation given in the locally approved Prescribing 
Information. 
7. 
TREATMENT COMPLIANCE 
The participating physician or designated personnel will check with the subjects for treatment 
compliance at each visit (Visits 1 to 8) will accordingly document in the CRF. 
8. 
CONCOMITANT THERAPY 
The following data, including drug name, start/stop dates, dose, frequency, dose modifications 
route of administration, and indication, will be documented at baseline and during the prospective 
clinical trial.  
x Other therapy administered as part of ImbruvicaTM treatment regimen 
x All concomitant medications 
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Concomitant therapies for AEs or SAEs during the study should be recorded from the onset of the 
event, including the dose, frequency of administration, and duration of use where available in the 
CRF. 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0.20 All haematological AEs 
will be graded and reported according to the IWCLL 2008 criteria for grading of haematological 
toxicities in CLL studies.16 The study will include the following evaluations of safety and 
tolerability according to the time points provided in the TIME AND EVENTS SCHEDULE. 
9. 
STUDY EVALUATIONS 
9.1. 
Efficacy Evaluations  
At each participating site, any physician assessments should be performed by the same physician 
on each occasion for an individual patient, if possible and in accordance with local clinical practice 
only. Response assessment and progression criteria will be recorded as per International Workshop 
on Chronic Lymphocytic Leukemia (IWCLL) criteria16–18 for CLL and revised response criteria 
for malignant lymphoma19 for MCL  
Patient-reported outcomes will be measured by 2 questionnaires. The EORTC QLQ-C30 is a 
general cancer assessment, and the FACIT Fatigue Scale specifically assesses aspects of fatigue. 
Samples of the PRO scales are provided in Attachments 1, and 2. The PRO questionnaires will be 
collected preferably at the beginning of the clinic visits prior to any procedures or physician 
interactions according to the TIME AND EVENTS SCHEDULE.21 
The EORTC QLQ-C30 includes 30 separate items resulting in 5 functional scales (physical 
functioning, role functioning, emotional functioning, cognitive functioning, and social 
functioning), 1 Global Health Status scale, 3 symptom scales (fatigue, nausea and vomiting, and 
pain), and 6 single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial 
difficulties).22 The recall period is 1 week (the past week). The EORTC QLQ-C30 has been widely 
used among cancer patients in general and specifically in CLL patients.23,24 Scale scores range 
from 0 to 100. A change of 10 points is considered clinically meaningful for the functioning scales. 
Administration time is approximately 11 minutes. 
FACIT Fatigue is an instrument for use as a measure of the effect of fatigue in patients with 
cancer and other chronic diseases (http://www.facit.org). Responses to the 13-item FACIT Fatigue 
Scale are reported on a 5-point categorical response scale ranging from 0 (not at all) to 4 (very 
much). Higher scores indicate poorer health status. The FACIT Fatigue Scale has been validated 
in the general population25 as well as for patients with cancer and rheumatoid arthritis. 
Clinical Response and Patient-Reported Outcomes 
Exploratory Endpoints 
x Proportion of participants experiencing clinical response as per assessment criteria 
x Change from baseline in patient-reported outcomes as per EORTC QLQ C-30 and FACIT 
Fatigue  
 
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
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9.2. 
Safety Evaluations 
Any clinically relevant changes occurring during the study will be recorded in the Adverse Event 
section of the CRF. Any clinically significant abnormalities persisting at the end of the study or at 
discontinuation will be followed by the participating physician until resolution or until a clinically 
stable outcome is reached. 
All non-haematological AEs including laboratory AEs and AEs leading to dose reductions or 
discontinuation will be graded and reported according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0.20 All haematological AEs 
will be graded and reported according to the IWCLL 2008 criteria for grading of haematological 
toxicities in CLL studies.16 The study will include the evaluations of safety and tolerability 
according to the time points provided in the TIME AND EVENTS SCHEDULE. 
Safety assessments will be based on medical review of adverse event reports and the results of 
vital sign measurements, physical examinations, clinical laboratory tests, ECOG performance 
status, and other safety evaluations at specified time points as described in the Time and Events 
Schedules  
All AEs, with the exception of progression of CLL/MCL, will be reported from the time a signed 
and dated informed consent form is obtained until 30 days following the end of observation period 
or until the start of a subsequent systemic antineoplastic therapy, if earlier. AEs will be reported 
by the patient (or, when appropriate, by a caregiver, surrogate, or the subject's legally-acceptable 
representative) for the duration of the study. AEs if any reported by the patient through means 
other than physical visit (e.g. telephonically) will also be captured. AEs will be followed by the 
participating physician, Adverse Event Reporting. Non-hematologic AEs and hematologic AEs 
events will be graded according to specifications. It will include the incidence of deaths, SAEs, 
and AEs reported/observed any time during the course of the study, either during any visit or 
through any other mode of communication. Follow-up will be conducted by participating site via 
telephone contact. SAEs reported after 30 days of follow up period or 30 days after early 
discontinuation of ImbruvicaTM should also be reported if considered related to ImbruvicaTM. 
Follow-up for an AE will be required for 30 days after last dose to determine if any new or ongoing 
drug-related AEs or any SAEs regardless of relationship to ImbruvicaTM exist. The sponsor will 
evaluate any safety information that is spontaneously reported by a participating physician beyond 
the time frame specified in the protocol. 
Adverse Events 
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or 
the subject's legally acceptable representative) for the duration of the study. Adverse events will 
be followed by the investigator as specified in Section 12, Adverse Event Reporting. 
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Clinical Laboratory Tests  
Blood samples for hematology and coagulation profile will be collected as per protocol. The 
investigator must review the laboratory results, document this review, and record any clinically 
relevant changes occurring during the study in the adverse event section of the CRF. The laboratory 
reports must be filed with the source documents. 
The following tests will be performed by the local laboratory 
 
x 
Hematology Panel 
-hemoglobin 
-platelet count 
-hematocrit 
[-percent reticulocytes] 
-red blood cell (RBC) count 
-absolute lymphocyte count (ALC) 
-coagulation (PT, INR and aPTT) 
-white blood cell (WBC) count with differential 
Note: A WBC evaluation may include any abnormal cells, which will then be reported by 
the laboratory. A RBC evaluation may include abnormalities in the RBC count, RBC 
parameters, or RBC morphology, which will then be reported by the laboratory. 
In addition, any other abnormal cells in a blood smear will also be reported. 
 
 
Physical examination and Vital Signs  
Physical examination and vital sign parameters will be documented at the participating site. 
Physical examination and vital sign parameters will include blood pressure, pulse rate, respiratory 
rate, body temperature, and weight. 
9.3. 
Sample Collection and Handling 
The sponsor will provide reimbursement for specific investigations to be conducted as listed in 
TIME AND EVENTS SCHEDULE. The sample collection and handling procedures for these 
investigations, conducted if any, must be performed as per the guidelines prescribed by the local 
laboratory practice.  
The actual date of sample collection must be recorded in the CRF or laboratory requisition form.  
 
10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY 
10.1. 
Completion 
The study will be considered completed with the EOS within the study for the last patient 
participating in the study. A subject will be considered to have completed the study if he or she 
has completed the telephonic assessments at month 13.  
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Last completed assessment of subjects who prematurely discontinue study treatment for any reason 
before completion of this phase IV study will be considered for analysis.  
The sponsor reserves the right to close a participating site for data collection or to terminate the 
study at any time for any reason at the sole discretion of the sponsor. A participating site is 
considered closed when all required documents and study specific supplies have been collected 
and a site closure assessment has been performed. 
The participating physician may initiate site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a participating site by the sponsor or participating physician may 
include but are not limited to:  
x Failure of the participating physician to comply with the protocol, requirements of the IRB 
or local health authorities, or the sponsor's procedures, or GCP guidelines; 
x Inadequate recruitment of subjects by the participating physician. 
 
10.2. 
Discontinuation of Study Treatment/Withdrawal from the Study  
Withdrawal From the Study 
A subject will be withdrawn from the study for any of the following reasons: 
x 
Lost to follow-up 
x 
Withdrawal of consent 
x 
[Death] 
If a subject discontinues study drug and withdraws from the study before the end of the study 
duration, [end-of-treatment] [and] [posttreatment] assessments should be obtained.  
If a subject is lost to follow-up, every reasonable effort must be made by the study-site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented. 
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Subjects who withdraw will not be replaced. 
If a subject withdraws from the study before the end of the the study duration, end-of-treatment 
and post treatment assessments should be obtained. 
11. 
STATISTICAL METHODS 
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.  
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11.1. 
Subject Information 
For all subjects who receive at least 1 dose of study drug descriptive statistics will be provided. 
11.2. 
Sample Size Determination 
The primary objective of this study is to estimate the incidence of AEs in Indian subjects under 
actual conditions of use of ImbruvicaTM. A sample size of 75 subjects is as per the 
recommendations of Subject Expert Committee (Oncology & Haematology) made in its 70th 
meeting held on 23rd May 2018 at Central Drugs Standard Control Organization HQ, New Delhi 
communicated vide F.N. 12-10/2017-DC (Pt-Johnson-snd). 
 
11.3. 
Efficacy Analyses  
Statistical analyses will be performed by or under the authority of the sponsor. A general 
description of the planned statistical methods to be used to analyze the data collected in this study 
is presented in the following subsections. Additional details will be provided in the statistical 
analysis plan. 
No formal hypothesis testing will be conducted for this study. Data will be summarized using 
descriptive statistics. Continuous variables will be summarized using descriptive statistics, which 
will include the number of subjects, mean, standard deviation, median, minimum, and maximum. 
Categorical variables will be summarized using frequencies and percentages, as appropriate. 
Exploratory endpoints will be summarized using descriptive statistics.  
11.4. 
Safety Analyses 
Adverse Events 
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse events 
are adverse events with onset during the treatment phase or that are a consequence of a pre-existing 
condition that has worsened since baseline. All reported adverse events will be included in the 
analysis. For each adverse event, the percentage of subjects who experience at least 1 occurrence 
of the given event will be summarized by treatment group.  
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event. 
Clinical Laboratory Tests 
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline and 
for observed values and changes from baseline at each scheduled time point. Frequency tabulations 
of the changes from baseline. Changes from baseline results will be presented in pre- versus 
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posttreatment cross-tabulations (with classes for below, within, and above normal ranges). 
[Frequency tabulations of the abnormalities will be made. A listing of subjects with any laboratory 
results outside the reference ranges will be provided. A listing of subjects with any markedly 
abnormal laboratory results will also be provided. 
Parameters with predefined National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) toxicity grades will be summarized. Change from baseline to the worst 
adverse event grade experienced by the subject during the study will be provided as shift tables. 
 
 Vital Signs 
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, and blood pressure (systolic 
and diastolic values) and changes from baseline will be summarized at each scheduled time point. 
The percentage of subjects with values beyond clinically important limits will be summarized. 
Descriptive statistics will be calculated at baseline and for observed values and changes from 
baseline at each scheduled time point. Frequency tabulations of the abnormalities will be made.  
Physical Examination 
Descriptive statistics of changes from baseline will be summarized at each scheduled time point. 
Physical examination findings will be summarized at each scheduled time point. Descriptive 
statistics will be calculated at baseline and for observed values and changes from baseline at each 
scheduled time point. Frequency tabulations of the abnormalities will be made. 
 
12. 
ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events or serious adverse events. 
Open-ended and nonleading verbal questioning of the subject is the preferred method to inquire 
about adverse event occurrence.  
Solicited Adverse Events  
Solicited adverse events are predefined local and systemic events for which the subject is 
specifically questioned and which are noted by subjects in their diary.  
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Unsolicited Adverse Events 
Unsolicited adverse events are all adverse events for which the subject is specifically not 
questioned in the subject diary. 
12.1. 
Definitions 
12.1.1. 
Adverse Event Definitions and Classifications 
Adverse Event 
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonisation [ICH]) 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1. All Adverse Events, for time of last adverse event recording). 
Serious Adverse Event 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose: 
x 
Results in death 
x 
Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.) 
x 
Requires inpatient hospitalization or prolongation of existing hospitalization 
x 
Results in persistent or significant disability/incapacity 
x 
Is a congenital anomaly/birth defect 
x 
Is a suspected transmission of any infectious agent via a medicinal product 
x 
Is Medically Important* 
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
usually be considered serious. 
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If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must be 
reported as a serious and unexpected suspected adverse reaction even if it is a component of the 
study endpoint (eg, all-cause mortality).  
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For ibrutinib, the expectedness of an adverse event will be 
determined by whether or not it is listed in the prescribing information.   
Adverse Event Associated With the Use of the Drug 
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2, Attribution Definitions. 
12.1.2. 
Attribution Definitions 
Not Related 
An adverse event that is not related to the use of the drug. 
Doubtful 
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely. 
Possible 
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded. 
Probable 
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant drug(s), 
concomitant disease(s). 
Very Likely 
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in 
time is very suggestive (eg, it is confirmed by dechallenge and rechallenge). 
12.1.3. 
Severity Criteria 
An assessment of severity grade for non-haematological AEs will be made using the NCI-
CTCAE Version 4, which includes following descriptors20: 
x Grade 1 Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
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x Grade 2 Moderate: minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental ADL. 
x Grade 3 Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL. 
x Grade 4 Life-threatening: consequences urgent intervention indicated. 
x Grade 5 Death related to AE. 
Hematologic toxicity will be also assessed by the IWCLL 2008 criteria for grading hematologic 
toxicity in CLL studies.16 
For AEs that are not included in the NCI-CTCAE & IWCLL 2008 criteria, an assessment of 
severity grade will be made using the following general categorical descriptors: 
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities. 
Moderate: Sufficient discomfort is present to cause interference with normal activity. 
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities. 
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities). 
12.2. 
Special Reporting Situations 
Safety events of interest on ibrutinib that may require expedited reporting or safety evaluation 
include, but are not limited to: 
x 
Overdose of a sponsor study drug 
x 
Suspected abuse/misuse of the study drug 
x 
Accidental or occupational exposure to the study drug 
x 
Any failure of expected pharmacologic action (ie, lack of effect) of the study drug 
x 
Unexpected therapeutic or clinical benefit from use of the study drug 
x 
Medication error involving a sponsor product (with or without subject/patient exposure to the  
study drug, eg, name confusion) 
x 
Exposure to a sponsor study drug from breastfeeding 
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the CRF. 
12.3. 
Procedures 
In this phase IV clinical  study, ImbruvicaTM is the Janssen product under study. 
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The sponsor will provide appropriate pharmacovigilance training to the participating site 
personnel. The sponsor assumes responsibility for appropriate reporting of (serious) AEs and 
significant safety information originating from the data collected for Janssen medicinal products 
to the regulatory authorities. All collected AEs will be summarized in the final study report. 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product safety issues and/or quality issues are listed on the contact information page(s), 
which is/are provided separately. 
Sponsor’s Contact Details: 
Local Safety Officer 
Janssen Pharmaceuticals India 
Johnson & Johnson Private Limited, India. 
501, Arena Space, 8th Floor, 
Behind Majas Bus Depot, 
Off. J.V. Link Road, Jogeshwari (East), 
Mumbai 400060, India. 
Telephone: +91 22 6664 6629 
Fax: +91 22 6671 8204 
Email: drugsafe@its.jnj.com 
 
12.3.1. 
All Adverse Events 
All adverse events and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated ICF is obtained until completion of the subject's last study-related 
procedure, which may include contact for follow-up of safety. Serious adverse events, including 
those spontaneously reported to the investigator within 30 days after the last dose of study drug, 
must be reported using the Serious Adverse Event Form. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol. 
Progression of CLL/MCL will not be considered as an AE. All events that meet the definition of a 
serious adverse event will be reported as serious adverse events, regardless of whether they are 
protocol-specific assessments. Signs and symptoms of clinical sequelae resulting from disease 
progression/lack of efficacy will be reported if they fulfill the serious adverse event definition as 
per timelines. Disease progression is defined as per iwCLL 2008 criteria for CLL and revised 
response criteria for malignant lymphoma:2007 for MCL.   
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the CRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology. 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions. 
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The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB.  
12.3.2. 
Serious Adverse Events 
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.  
Information regarding serious adverse events will be transmitted to the sponsor using the Serious Adverse Event Form 
and Safety Report Form of the CRF, which must be completed and reviewed by a physician from the study site, and 
transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious adverse event should be 
transmitted electronically or by facsimile (fax). 
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs: 
x 
The event resolves 
x 
The event stabilizes 
x 
The event returns to baseline, if a baseline value/status is available 
x 
The event can be attributed to agents other than the study drug or to factors unrelated to study 
conduct 
x 
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts) 
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious 
adverse event. Any event requiring hospitalization (or prolongation of hospitalization) that occurs 
during the course of a subject's participation in a study must be reported as a serious adverse event, 
except hospitalizations for the following:  
x 
Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such 
as pending placement in long-term care facility) 
x 
Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event. 
x 
For convenience the investigator may choose to hospitalize the subject for the duration of the 
treatment period. 
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x 
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition (refer to Section 
12.1.1, Adverse Event Definitions and Classifications). 
12.3.3. 
Pregnancy  
Based on findings in animals, Ibrutinib may cause foetal harm when administered to pregnant 
women. All initial reports of pregnancy in female subjects or partners of male subjects must be 
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the event 
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered serious adverse events and must be reported using the Serious Adverse Event Form. 
Any subject who becomes pregnant during the study must be promptly withdrawn from the study 
and discontinue further study treatment.  
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported as noted above.  
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.  
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported as noted above.  
12.4. 
Contacting Sponsor Regarding Safety 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document. 
13. 
PRODUCT QUALITY COMPLAINT HANDLING 
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established 
procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting 
of PQC information; all studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures. 
13.1. 
Procedures 
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event. 
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If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be maintained 
for further investigation if requested by the sponsor.  
 
13.2. 
Contacting Sponsor Regarding Product Quality 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.  
14. 
STUDY DRUG INFORMATION 
14.1. 
Physical Description of Study Drug(s) 
IMBRUVICATM each capsule contains 140 mg of ibrutinib. White opaque, size 0, hard gelatin 
capsule marked with “ibr 140 mg” in black ink. Refer to the prescribing information or a list of 
excipients. 
14.2. 
Packaging 
IMBRUVICA TM  capsules are supplied in a white HDPE bottle with a child resistant closure. 
Each HDPE bottle with a polypropylene closure contains 90 or 120 hard capsules. 
Commercial stocks of IMBRUVICATM affixed with additional investigational labels (to meet 
local regulatory requirements) will be provided by the sponsor to clinical trial subject from the 
existing distribution channel as per the mentioned duration in the study protocol.        
14.3. 
Labeling 
Commercial stocks of IMBRUVICA TM  supplied to the subjects will be affixed with additional 
investigational labels ( to meet local regulatory requirements).  
Keep out of the sight and reach of children. 
14.4. 
Drug Accountability 
Study drug must be handled in strict accordance with the protocol. Study drug returned by the 
subject must be available for verification by the sponsor's study site monitor during on-site 
monitoring visits.  
Study drug should be dispensed under the supervision of the investigator or a qualified member of 
the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only to 
subjects participating in the study 
 
15. 
STUDY-SPECIFIC MATERIAL 
The investigator will be provided with the following supplies: 
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x 
Package Insert for imbruvica TM 
x 
NCI-CTCAE Version 4 
x 
Sample ICF 
x 
CRF & CRF completion guidelines 
x 
PRO questionnaires  
x Quality of Life by EORTC QLQ C-30 instrument (European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaires Core 30) 
x Fatigue by FACIT Fatigue instrument (Functional Assessment of Chronic Illness Therapy 
Fatigue) 
16. 
ETHICAL ASPECTS  
16.1. 
Study-Specific Design Considerations 
Potential subjects will be fully informed, prior to data collection, of the risks and requirements of the 
study and, during the study. Subjects will be given any new information that may affect their decision 
to continue participation. They will be told that their consent to participate in the study is voluntary 
and may be withdrawn at any time with no reason given and without penalty or loss of benefits to 
which they would otherwise be entitled. Only subjects who are fully able to understand the risks, 
benefits, and potential adverse events of the study, and provide their consent voluntarily will be 
enrolled.  
16.2. 
Regulatory Ethics Compliance 
16.2.1. 
Investigator Responsibilities 
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible. 
16.2.2. 
Independent Ethics Committee or Institutional Review Board 
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB 
with current and complete copies of the following documents (as required by local regulations):  
x 
Final protocol and, if applicable, amendments 
x 
Sponsor-approved ICF (and any other written materials to be provided to the subjects) 
x 
Latest local prescribing information 
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x 
Information on compensation for study-related injuries or payment to subjects for 
participation in the study. 
x 
Investigator's curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB) 
x 
Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects 
x 
Any other documents that the IEC/IRB requests to fulfill its obligation 
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
subjects, data or study conduct, unless required locally), the ICF, applicable recruiting materials, 
and subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved. 
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate: 
x 
Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct) 
x 
Revision(s) to ICF and any other written materials to be provided to subjects 
x 
Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable 
x 
Latest local prescribing information 
x 
Reports of adverse events that are serious, unlisted/unexpected, and associated with the study 
drug 
x 
New information that may adversely affect the safety of the subjects or the conduct of the 
study 
x 
Report of deaths of subjects under the investigator's care 
x 
Notification if a new investigator is responsible for the study at the site 
x 
Development Safety Update Report and Line Listings, where applicable 
x 
Any other requirements of the IEC/IRB 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s).  
At the end of the study, the investigator will notify the IEC/IRB about the study completion  
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16.2.3. 
Informed Consent  
Each subject must give written consent according to local requirements after the nature of the study 
has been fully explained. The ICF must be signed before performance of any study-related activity. 
The ICF that is used must be approved by both the sponsor and by the reviewing IEC/IRB and be 
in a language that the subject can read and understand. The informed consent should be in 
accordance with principles that originated in the Declaration of Helsinki, current ICH and GCP 
guidelines, applicable regulatory requirements, and sponsor policy. 
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects  the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw consent 
to participate at any time. They will be informed that choosing not to participate will not affect the 
care the subject will receive for the treatment of his or her disease.  
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. After 
this explanation and before entry into the study, consent should be appropriately recorded by means 
of the subject's personally dated signature. After having obtained the consent, a copy of the ICF 
must be given to the subject. 
16.2.4. 
Privacy of Personal Data 
The collection and processing of personal data from subjects enrolled in this study will be limited 
to those data that are necessary to fulfill the objectives of the study. 
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of subjects confidential. 
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original medical 
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and 
regulatory inspection. This consent also addresses the transfer of the data to other entities and to 
other countries. 
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps will 
be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations. 
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17. 
ADMINISTRATIVE REQUIREMENTS 
17.1. 
Protocol Amendments 
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by 
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the subjects, in which case the amendment must be 
promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) involves only logistic or administrative aspects of the study, the IEC/IRB (where 
required) only needs to be notified. 
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor representative 
listed in the Contact Information page(s), which will be provided as a separate document. Except 
in emergency situations, this contact should be made before implementing any departure from the 
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the 
situation and agree on an appropriate course of action. The data recorded in the CRF and source 
documents will reflect any departure from the protocol, and the source documents will describe 
this departure and the circumstances requiring it. 
17.2. 
Regulatory Documentation 
17.2.1. 
Regulatory Approval/Notification 
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities if 
applicable. The study will not be initiated until all local regulatory requirements are met. 
17.2.2. 
Required Prestudy Documentation 
The following documents must be provided to the sponsor before site initiation to the study site: 
x 
Protocol and amendment(s), if any, signed and dated by the principal investigator 
x 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and subject 
compensation programs. This approval must clearly identify the specific protocol by title and 
number and must be signed (or sealed, where appropriate per local regulations) by the 
chairman or authorized designee. 
x 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from 
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the study. 
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x 
Regulatory authority approval or notification, if applicable 
x 
Documentation of investigator qualifications (eg, curriculum vitae) 
x 
Completed investigator financial disclosure form from the principal investigator, where 
required 
x 
Signed and dated clinical trial agreement, which includes the financial agreement 
x 
Any other documentation required by local regulations 
 
17.3. 
Subject Identification, Enrollment, and Screening Logs 
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness. 
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification 
and date of birth. Since this a non-randomized study, the date seen and date of birth will be used.  
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study. 
17.4. 
Source Documentation 
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
subject identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all adverse events and follow-up of adverse events; concomitant medication; 
drug receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable.  
The author of an entry in the source documents should be identifiable. 
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring guidelines 
(or other equivalent document). 
The following data will be recorded directly into the CRF and will be considered source data  
x 
Blood pressure and pulse/heart rate  
x 
Height and weight  
x 
Details of physical examination 
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x 
PRO (Patient Reported Outcomes) 
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and Section 
4.2, Exclusion Criteria that specify a need for documented medical history are as follows: 
x 
Referral letter from treating physician or 
x 
Complete history of medical notes at the site 
x 
Discharge summaries 
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents. 
If the electronic source system is utilized, references made to the CRF in the protocol include the 
electronic source system but information collected through the electronic source system may not 
be limited to that found in the CRF. Data in this system may be considered source documentation. 
17.5. 
Case Report Form Completion 
Case report forms are prepared and provided by the sponsor for each subject in electronic format. 
All CRF entries, corrections, and alterations must be made by the investigator or authorized study-
site personnel. The investigator must verify that all data entries in the CRF are accurate and correct. 
The study data will be transcribed by study-site personnel from the source documents onto an 
electronic CRF, if applicable.  Study-specific data will be transmitted in a secure manner to the 
sponsor  
 
All subjective measurements (e.g., FACIT Fatigue instrument, EORTC-QLQ-C30) will be 
completed by the same individual who made the initial baseline determinations whenever possible  
 
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after 
the initial entry into the CRF, this can be done in either of the following ways: 
x 
Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool). 
x 
Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel. 
17.6. 
Data Quality Assurance/Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor Written 
instructions will be provided for collection, handling, storage, and shipment of samples.  
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The sponsor will review CRF for accuracy and completeness during on-site monitoring visits and 
after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources. 
17.7. 
Record Retention 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and 
all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 
investigator/institution will take measures to prevent accidental or premature destruction of these 
documents. 
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents 
before having obtained written approval from the sponsor. 
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such reports.  
17.8. 
Monitoring 
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the CRF with the source documents 
(eg, hospital/clinic/physician’s office medical records).  
The nature and location of all source documents will be identified to ensure that all sources of 
original data required to complete the CRF are known to the sponsor and study-site personnel and 
are accessible for verification by the sponsor study-site contact. If electronic records are 
maintained at the study site, the method of verification must be discussed with the study-site 
personnel.  
Direct access to source documents (medical records) must be allowed for the purpose of verifying 
that the recorded data are consistent with the original source data. Findings from this review will 
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49 
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be discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the 
relevant study-site personnel will be available, the source documents will be accessible, and a 
suitable environment will be provided for review of study-related documents. The monitor will 
meet with the investigator on a regular basis during the study to provide feedback on the study 
conduct. 
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these 
remote contacts, study-site personnel will be available to provide an update on the progress of the 
study at the site. 
17.9. 
Study Completion/Termination 
17.9.1. 
Study Completion/End of Treatment 
The study is considered completed with the last visit assessment for the last participating patient 
in the study. The final data from the study site will be sent to the sponsor (or designee) after 
completion of the final patient visit assessment at that participating site, in the time frame specified 
in the Clinical Trial Agreement. 
17.9.2. 
Study Termination 
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to: 
x 
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines 
x 
Inadequate recruitment of subjects by the investigator  
17.10. On-Site Audits 
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be respected. 
The investigator and study-site personnel are responsible for being present and available for 
consultation during routinely scheduled study-site audit visits conducted by the sponsor or its 
designees.  
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part 
of a national GCP compliance program or to review the results of this study in support of a 
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
50 
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regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection. 
17.11. Use of Information and Publication 
All information, including but not limited to information regarding ibrutinib or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including research data, generated as a result of this study, are 
considered confidential and remain the sole property of the sponsor. The investigator agrees to 
maintain this information in confidence and use this information only to accomplish this study, 
and will not use it for other purposes without the sponsor's prior written consent. 
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of ibrutinib, and thus may be disclosed as 
required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study. 
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Study subject identifiers will not be 
used in publication of results. Any work created in connection with performance of the study and 
contained in the data that can benefit from copyright protection (except any publication by the 
investigator as provided for below) shall be the property of the sponsor as author and owner of 
copyright in such work. 
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data and 
information without approval from the investigator. The investigator has the right to publish study 
site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow for 
filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will 
not mandate modifications to scientific content and does not have the right to suppress information. 
Secondary results generally should not be published before the primary endpoints of a study have 
been published. Similarly, investigators will recognize the integrity of a multicenter study by not 
submitting for publication data derived from the individual study site until the combined results 
from the completed study have been submitted for publication, within 12 months of the availability 
of the final data (tables, listings, graphs), or the sponsor confirms there will be no multicenter study 
publication. Authorship of publications resulting from this study will be based on the guidelines 
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
51 
Approved, Date: 20 October 2022  
on authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant contribution 
to the design of the study or analysis and interpretation of the data, provided critical review of the 
paper, and given final approval of the final version. 
Registration of Clinical Studies and Disclosure of Results 
The sponsor will register and disclose the existence of and the results of clinical studies as required 
by law.  
 
 
 
x 
REFERENCES 
1.  
Pan Z, Scheerens H, Li S-J, et al. Discovery of Selective Irreversible Inhibitors for Bruton’s Tyrosine Kinase. ChemMedChem. 
2007;2(1):58-61. doi:10.1002/cmdc.200600221. 
2.  
Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious 
in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci. 2010;107(29):13075-13080. 
doi:10.1073/pnas.1004594107. 
3.  
Herman SEM, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic 
lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117(23):6287-6296. doi:10.1182/blood-2011-01-328484. 
4.  
National Cancer Registry Programme, Indian Council of Medical Research. Consolidated Report of Hospital Based Cancer Registries 
2007-2011- An Assessment of Burden and Care of Cancer Pateints. Bengaluru, India.: National Center for Disease Informatics and 
Research; 2013:361. http://www.ncrpindia.org/ALL_NCRP_REPORTS/HBCR_REPORT_2007_2011/index.htm. Accessed January 10, 
2015. 
5.  
Advani RH, Buggy JJ, Sharman JP, et al. Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients 
With Relapsed/Refractory B-Cell Malignancies. J Clin Oncol. 2013;31(1):88-94. doi:10 1200/JCO.2012.42.7906. 
6.  
Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 
2013;369(1):32-42. doi:10.1056/NEJMoa1215637. 
7.  
Wang ML, Rule S, Martin P, et al. Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med. 
2013;369(6):507-516. doi:10.1056/NEJMoa1306220. 
8.  
Jaglowski SM, Jones JA, Flynn JM, et al. A phase Ib/II study evaluating activity and tolerability of BTK inhibitor PCI-32765 and 
ofatumumab in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and related diseases. ASCO Meet 
Abstr. 2012;30(15_suppl):6508. 
9.  
Brown JR, Barrientos JC, Barr PM, et al. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with 
chronic lymphocytic leukemia. Blood. 2015;125(19):2915-2922. doi:10.1182/blood-2014-09-585869. 
10.  
Jaglowski SM, Jones JA, Nagar V, et al. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic 
lymphocytic leukemia: a phase 1b/2 study. Blood. 2015;126(7):842-850. doi:10.1182/blood-2014-12-617522. 
11.  
Gujral S, Agarwal A, Gota V, et al. A clinicopathologic study of mantle cell lymphoma in a single center study in India. Indian J Pathol 
Microbiol. 2008;51(3):315. doi:10.4103/0377-4929.42503. 
12.  
Naresh KN, Agarwal B, Nathwani BN, et al. Use of the World Health Organization (WHO) Classification of Non-Hodgkin’s Lymphoma 
in Mumbai, India: A Review of 200 Consecutive Cases by a Panel of Five Expert Hematopathologists. Leuk Lymphoma. 
2004;45(8):1569-1577. doi:10.1080/10428190410001683679. 
13.  
Nimmagadda RV, Digumarti R, Nair R, et al. Histopathological pattern of lymphomas and clinical presentation and outcomes of diffuse 
large B cell lymphoma: A multicenter registry based study from India. Indian J Med Paediatr Oncol. 2013;34(4):299. doi:10.4103/0971-
5851 125250. 
14.  
de Jong J, Skee D, Murphy J, et al. Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants. Pharmacol Res Perspect. 
2015;3(4). doi:10.1002/prp2.156. 
15.  
Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia. N Engl J Med. 
2014;371(3):213-223. doi:10.1056/NEJMoa1400376. 
16.  
Hallek M, Cheson BD, Catovsky D, et al. 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. 2008;111(12):5446-5456. doi:10.1182/blood-2007-06-093906. 
17.  
Hallek M. Response Assessment in Chronic Lymphocytic Leukemia Treated with Novel Agents Causing an Increase of Peripheral Blood 
Lymphocytes. June 2012. http://www.bloodjournal.org/content/111/12/5446.e-letters?sso-checked=true#response-assessment-in-chronic-
lymphocytic-leukemia-treated-with-novel-agents-causing-an-increase-of-peripheral-blood-lymphocytes. Accessed November 20, 2015. 
18.  
Hallek M. Clarification Of iwCLL Criteria For A Partial Response To Therapy. November 2013. 
http://www.bloodjournal.org/content/111/12/5446 e-letters?sso-checked=true#clarification-of-iwcll-criteria-for-a-partial-response-to-
therapy. Accessed November 20, 2015. 
19.  
Cheson BD, Pfistner B, Juweid ME, et al. Revised Response Criteria for Malignant Lymphoma. J Clin Oncol. 2007;25(5):579-586. 
doi:10.1200/JCO.2006.09.2403. 
20.  
U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Common Terminology Criteria 
for Adverse Events v4.03. June 2010. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. 
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54179060   Imbruvica (Ibrutinib capsule 140 mg)  
 
 
 
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Approved, Date: 20 October 2022  
21.  
Perry S, Kowalski TL, Chang C-H. Quality of life assessment in women with breast cancer: benefits, acceptability and utilization. Health 
Qual Life Outcomes. 2007;5:24. doi:10.1186/1477-7525-5-24. 
22.  
Fayers P, Aaronson N, on behalf of the EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual. European Organisation 
for Research and Treatment of Cancer, Brussels; 2001. 
23.  
Doorduijn J, Buijt I, van der Holt B, Steijaert M, Uyl-de Groot C, Sonneveld P. Self-reported quality of life in elderly patients with 
aggressive non-Hodgkin’s lymphoma treated with CHOP chemotherapy. Eur J Haematol. 2005;75(2):116-123. doi:10 1111/j.1600-
0609 2005.00438.x. 
24.  
Holzner B, Kemmler G, Kopp M, Nguyen-Van-Tam D, Sperner-Unterweger B, Greil R. Quality of life of patients with chronic 
lymphocytic leukemia: results of a longitudinal investigation over 1 yr. Eur J Haematol. 2004;72(6):381-389. doi:10.1111/j.1600-
0609 2004.00233.x. 
25.  
Cella D, Lai J, Chang C-H, Peterman A, Slavin M. Fatigue in cancer patients compared with fatigue in the general United States 
population. Cancer. 2002;94(2):528-538. doi:10.1002/cncr.10245. 
26.  
Fleiss JL, Levin B, Paik MC. Statistical Inference for a Single Proportion. In: Statistical Methods for Rates and Proportions. 3rd ed. 
Wiley Series in Probability and Statistics. Hoboken, New Jersey: John Wiley & Sons, Inc.; 2003:Page No 25. 
27.  
ImbruvicaTM (Ibrutinib 140 Mg Capsules) [Prescribing Information]. India: Johnson & Johnson Private Limited; 2015. 
 
 
 
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
56 
Approved, Date: 20 October 2022  
English (Universal) 
 
 
 
 
 
 
 
 
16 November 
2007 
© Copyright 1987, 1997; FACIT.org. All rights reserved. 
 
 
 
 
 
Page 1 
of 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
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Clinical Protocol 54179060LYM4005 (Amendment-1) 
57 
Approved, Date: 20 October 2022  
Attachment 3: Dose Modifications for Adverse Reactions 
ImbruvicaTM therapy should be withheld for any new onset or worsening Grade 2 cardiac failure, 
Grade ı 3 non hematological toxicities, Grade 3 or greater neutropenia with infection or fever, or 
Grade 4 hematological toxicities.  
 
Once the symptoms of the toxicity have resolved to Grade 1 or baseline (recovery), resume 
IMBRUVICA therapy at the recommended dose as per the tables below. 
 
Table 1: Recommended dose modifications for events of cardiac failure or cardiac arrhythmias: 
Events 
Toxicity 
occurrence 
MCL/MZL dose modification 
after recovery 
Starting Dose 560 mg/day 
CLL/SLL/WM/cGVHD dose 
modification after recovery 
Starting Dose 420 mg/day 
Grade 2 cardiac failure 
First 
Restart at 420 mg daily 
Restart at 280 mg daily 
Second 
Restart at 280 mg daily 
Restart at 140 mg daily 
Third 
Discontinue ImbruvicaTM 
Grade 3 cardiac 
arrhythmias 
First 
Restart at 420 mg daily† 
Restart at 280 mg daily† 
Second 
Discontinue ImbruvicaTM 
Grade 3 or 4 cardiac failure 
Grade 4 cardiac 
arrhythmias 
First 
Discontinue ImbruvicaTM 
† Evaluate the benefit-risk before resuming treatment. 
 
 
Table 2: Recommended dose modifications for non-cardiac events: 
Events 
Toxicity 
occurrence 
MCL/MZL dose modification 
after recovery 
Starting Dose 560 mg/day 
CLL/SLL/WM/cGVHD dose 
modification after recovery 
Starting Dose 420 mg/day 
Grade 3 or 4 non-hematological 
toxicities 
 
Grade 3 or 4 neutropenia with 
infection or fever 
 
Grade 4 hematological toxicities 
First* 
Restart at 560 mg daily 
Restart at 420 mg daily 
Second 
Restart at 420 mg daily 
Restart at 280 mg daily 
Third 
Restart at 280 mg daily 
Restart at 140 mg daily 
Fourth 
Discontinue ImbruvicaTM 
*When resuming treatment, restart at the same or lower dose based on benefit-risk evaluation. If the toxicity 
reoccurs, reduce daily dose by 140 mg. 
 
Summary of updated dosage modification recommendations: 
x 
For patients experiencing Grade 2 cardiac failure, resume ImbruvicaTM treatment at a lower dose (i.e., 
reduce daily dose by 140 mg). 
x 
For patients experiencing Grade 3 cardiac arrhythmias, evaluate the benefit-risk, and if resuming 
ImbruvicaTM treatment, re-start at a lower dose (i.e., reduce daily dose by 140 mg). 
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54179060   Imbruvica (Ibrutinib capsule 140 mg)  
 
 
 
Clinical Protocol 54179060LYM4005 (Amendment-1) 
58 
Approved, Date: 20 October 2022  
x 
For patients experiencing Grade 3 or 4 cardiac failure or Grade 4 cardiac arrhythmias, discontinue 
ImbruvicaTM at first occurrence.   
x 
For patients experiencing Grade 3 or 4 non-cardiac events, when resuming ImbruvicaTM treatment, evaluate 
benefit-risk and re-start at the same or lower dose (i.e., reduce daily dose by 140 mg). 
 
 
 
 
 
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54179060   Imbruvica (Ibrutinib capsule 140 mg)  
 
 
 
Clinical Protocol 54179060LYM4005 (Amendment-1) 
59 
Approved, Date: 20 October 2022  
 
INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed 
regarding the study drug, the conduct of the study, and the obligations of confidentiality. 
Coordinating Investigator (where required): 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Principal (Site) Investigator: 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Telephone Number: 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Sponsor's Responsible Medical Officer: 
 
Name (typed or printed): 
 
Institution: 
Johnson & Johnson Private Limited 
Signature: 
 
Date: 
20 October 2022 
 
 
 
(Day Month Year) 
 
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required. 
 
PPD
PPD
PPD
NCT03190330

SAP_001.pdf: 
1
Approved, Date: 6 February 2023
Johnson & Johnson Private Limited
Statistical Analysis Plan
A prospective, multicenter, open label single arm Phase IV clinical trial to assess safety of 
ImbruvicaTM (Ibrutinib capsules 140 mg) in Indian patients with chronic lymphocytic 
leukemia or mantle cell lymphoma who have received at least one prior therapy or chronic 
lymphocytic leukemia with 17p deletion
Protocol 54179060LYM4005 ; Phase IV
JNJ-54179060 Imbruvica (Ibrutinib capsule 140mg)
Status:
Approved
Date:
6 February 2023
Prepared by:
Johnson & Johnson Private Limited
Document No.: EDMS-RIM-643104，2.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT03190330


JNJ-54179060  (ImbruvicaTM(Ibrutinib))
Statistical Analysis Plan 54179060LYM4005 
2
Approved, Date: 6 February 2023
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 3
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Trial Objectives ................................................................................................................................ 5
1.2.
Trial Design ...................................................................................................................................... 5
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 7
1.4.
Sample Size Justification ................................................................................................................. 7
1.5.
Randomization and Blinding ............................................................................................................ 7
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 8
2.1.
Analysis Sets.................................................................................................................................... 9
2.1.1.
All Enrolled Analysis Set............................................................................................................... 9
2.1.2.
Safety Analysis Set....................................................................................................................... 9
2.2.
Study Day and Relative Day ............................................................................................................ 9
2.3.
Baseline and Endpoint ..................................................................................................................... 9
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW......................................... 9
4.
SUBJECT INFORMATION................................................................................................................ 10
4.1.
Demographics and Baseline Characteristics ................................................................................. 10
4.2.
Disposition Information................................................................................................................... 10
4.3.
Treatment Compliance .................................................................................................................. 11
4.4.
Extent of Exposure......................................................................................................................... 11
4.5.
Protocol Deviations ........................................................................................................................ 11
4.6.
Prior and Concomitant Medications ............................................................................................... 11
4.7.
Medical History............................................................................................................................... 12
5.
EFFICACY/ EXPLORATORY............................................................................................................ 12
5.1.
Patient Reported Outcomes........................................................................................................... 12
5.1.1.
EORTC QLQ-C30 .......................................................................................................................... 12
5.1.2.
FACIT Fatigue................................................................................................................................ 13
5.1.3.
Proportion of Subjects experiencing clinical response as per assessment criteria ...................... 15
5.1.4    Progression-Free Survival .............................................................................................................. 16
6.
SAFETY............................................................................................................................................. 16
6.1.
Adverse Events .............................................................................................................................. 16
6.2.
Clinical Laboratory Tests................................................................................................................ 17
6.3.
Vital Signs and Physical Examination............................................................................................ 18
6.4.
ECOG performance status............................................................................................................. 18
7.
REFERENCES................................................................................................................................... 19
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JNJ-54179060  (ImbruvicaTM(Ibrutinib))
Statistical Analysis Plan 54179060LYM4005 
3
Approved, Date: 6 February 2023
AMENDMENT HISTORY
Version
Effective 
Date
Changes
Rationale 
1.0
23-Jun-2022
Not Applicable 
Initial release 
2.0
06-Feb-2023
1.
General analysis definition 
summary section 2 has been 
updated to add (Table 1A) for 
visit windows.
2.
Clinical Laboratory Tests
(section 6.2) has been updated 
for sensitivity analysis
3.
Vital Sign and Physical 
Examination (section 6.3) has 
been updated to add Table 4 for 
Normal Ranges for Vital Signs
4.
Progression-Free Survival
(section 5.1.4) has been updated 
to add PFS analysis
1.The visit window is applied in 
order to have the new set of 
analysis visits based on the T&E 
schedule available in the 
protocol.
2.Clinical Laboratory data was 
not captured prior to dose 
administration, so baseline 
definition is re-considered, used 
for sensitivity analysis (section 
6.2).
3.Normal Ranges for Vital Signs 
can provide sufficient 
information to describe the 
Abnormality results. 
4.PFS interpretation can provide 
sufficient information to describe 
the assessment criteria
NCT03190330


JNJ-54179060  (ImbruvicaTM(Ibrutinib))
Statistical Analysis Plan 54179060LYM4005 
4
Approved, Date: 6 February 2023
ABBREVIATIONS
ADA
ADR
anti-drug antibody
adverse Drug Reaction
AE
adverse event
ATC
anatomic and therapeutic Class
BMI
body mass index
BSA
BTK
body surface area
Bruton’s Tyrosine Kinase
CI
confidence interval
CL
CR
total systemic clearance
complete response
CRF
case report form
CSR
Clinical Study Report
dell 17p
deletions in the short arm of chromosome 17
DMC
Data Monitoring Committee
ECOG
Eastern Cooperative Oncology Group
ECG
electrocardiogram
eCRF
eDC
EORTC QLQ C-30
EOT
electronic case report form
electronic data capture
European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Core 30
End-Of-Treatment
FDA
FACIT
GCP
Food and Drug Administration
Functional Assessment of Chronic Illness Therapy
Good Clinical Practice
ICH
ICF
International Conference on Harmonization
Informed Consent Form/Document
IRB
Institutional Review Board
IWCLL
MCL
International Workshop on Chronic Lymphocytic Leukaemia
Mantle Cell Lymphoma
MedDRA
NCI-CTCAE
PD
Medical Dictionary for Regulatory Activities
National Cancer Institute Common Terminology Criteria for Adverse Events
preferred term
PI
PR
principal investigator
partial response
PRO
PT
Patient-Reported Outcome
preferred term
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
SD
standard deviation
stable disease
SMQsSLL
SOC
Standardised MedDRA queries Small Lymphocytic Lymphoma
system organ class
TEAE
treatment-emergent adverse event
US NCI
United States National Cancer Institute
WHO
WHO-DD
World Health Organization
World Health Organization Drug Dictionary
NCT03190330


JNJ-54179060  (ImbruvicaTM(Ibrutinib))
Statistical Analysis Plan 54179060LYM4005 
5
Approved, Date: 6 February 2023
1.
INTRODUCTION
Ibrutinib (PCI-32765; JNJ-54179060) is a first in class potent, orally administered, covalently 
binding small molecule inhibitor of Bruton’s tyrosine kinase (BTK) currently under development 
for the treatment of B-cell malignancies.
This study is designed to assess the safety of ImbruvicaTM (ibrutinib capsule 140 mg) prescribed 
as per locally approved prescribing information in Indian patients of chronic lymphocytic leukemia 
(CLL) or mantle cell lymphoma (MCL) who have received at least one prior therapy or CLL with 
17p deletion.
This statistical analysis plan (SAP) for the 54179060LYM4005 describes the statistical analysis 
for subject information, safety data and clinical response.
1.1.
Trial Objectives
Primary Objective
The primary objective of this study is to evaluate the safety of ImbruvicaTM (ibrutinib capsule 140 
mg) under actual conditions of use, and to understand the Incidence of adverse events (AEs) 
(Serious and Non-serious AEs). 
Exploratory Objectives
To analyse the following outcomes with ibrutinib: 

Baseline patient and disease characteristics 

Response assessment and progression criteria as per International Workshop on Chronic 
Lymphocytic Leukaemia (IWCLL) criteria for CLL and revised response criteria for 
malignant lymphoma for MCL. 

Change in patient reported outcomes as measured by 

Quality of Life by EORTC QLQ C-30 instrument (European Organization for Research
and Treatment of Cancer Quality of Life Questionnaires Core 30)

Fatigue by FACIT Fatigue instrument (Functional Assessment of Chronic Illness Therapy 
Fatigue)
1.2.
Trial Design
This is a prospective open label, single arm, multicenter, phase IV interventional study to describe 
the safety of ImbruvicaTM in Indian subjects. Approximately, 75 subjects selected by investigators 
and determined to be eligible for ibrutinib treatment as per protocol eligibility criteria will be 
enrolled in the study.
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The recommended dose of ImbruvicaTM as per the locally approved prescribing information is 420 
mg (three 140 mg capsules) as a single daily dose for CLL and 560 mg (four 140 mg capsules) as 
a single daily dose for MCL.
Screening cum Enrolment Visit (Day 1)
Prior to data collection, all subjects [and/or their legally acceptable representative where 
applicable] must sign an informed consent form (ICF) allowing data collection and source data 
verification in accordance with local regulations. Data collected at this visit may include but not 
limited to demographics, medical history, disease related history, concomitant medications, 
patient-reported outcomes (PROs), laboratory investigations, etc.
Treatment Period (Visits 1 to 6 and Visit 7)
Enrolled subjects will be followed up to 12 months from the treatment initiation. During the study 
period, data will be collected at monthly intervals for the first 6 months, (monthly visit ± 7 days; 
Visits 1 to 6). Subsequent visit would be at 9 months ± 7 days [Visit 7].
End-of-Treatment (EOT) (Visit 8)
The End-of-Treatment (EOT) visit will be conducted after the completion of 12-months 
ImbruvicaTM treatment (at Visit 8) or on the day at which the patient discontinued the ImbruvicaTM
treatment or study. 
The end of the treatment will be the End of Treatment visit within the study for the last participating 
patient.
Follow up period (End of Study)
A telephonic follow-up will be conducted 30 days after the EOT Visit.
The observation period including the Enrolment Visit and telephonic Follow-up will be up to a 
maximum duration of 13 months for each patient. 
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Schematic Overview of the study
The overall duration of the study, including recruitment [and/or follow up], is expected to be 36 
months.
1.3.
Statistical Hypotheses for Trial Objectives
No formal hypothesis testing will be conducted. Data will be summarized using descriptive 
statistics. Continuous variables will be summarized using the number of observations, mean, SD, 
median, and range as appropriate. Categorical values will be summarized using the number of 
observations and percentages as appropriate. Exploratory endpoints will be summarized using 
descriptive statistics.
1.4.
Sample Size Justification
The primary objective of this study is to estimate the incidence of AEs in Indian subjects under 
actual conditions of use of ImbruvicaTM. A sample size of 75 subjects is as per the 
recommendations of Subject Expert Committee (Oncology & Hematology) made in its 70th 
meeting held on 23rd May 2018 at Central Drugs Standard Control Organization HQ, New Delhi 
communicated vide F.N. 12-10/2017-DC (Pt-Johnson-snd).
1.5.
Randomization and Blinding
Randomization and blinding will not be applicable for this study as this is a single arm, open label 
study.
Participating sites will be encouraged to enroll subjects in a consecutive manner when subjects 
come for their regular consultation to minimize bias in patient selection. 
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2.
GENERAL ANALYSIS DEFINITIONS
The below mentioned general principles will be followed throughout the study:

The change from baseline is defined as the post-baseline value minus the baseline value.
Definition of baseline is provided in section 2.3. 

Descriptive statistics will include number of non-missing subject (n), mean, median, standard 
deviation (SD), minimum and maximum values for continuous variables, and for categorical 
variables the frequencies and percentages of subjects will be presented.

For continuous data, mean and median will be rounded to 1 decimal place more than original 
data, SD will be rounded to 2 decimal places more than original data and minimum and 
maximum will be displayed with the same precision as the original data.

For categorical data, percentages will be rounded to 1 decimal place.

If a count is 0, the percentage (0%) should not be displayed.  The 0 count will be displayed, 
but the corresponding percentage should be omitted.

All study data will be included in study data listings. In general, all data will be listed by time 
point within subject.

In general, missing data will not be imputed.

SAS® version 9.4 will be used for all analyses.

Visit Windows for PRO analysis:
To allow for variation in scheduling, the following set of visit windows will be used to assign 
evaluations to a most appropriate visit for analysis (Avisit).
Table 1A:
Visit
Avisit
Start Day
Target Day
End Day
SCR/Enrollment visit/Month 1
Screening
-
1
1
Visit 1/ Month 2 (end of month 1) 
Month 1
2
30
37
Visit 2/Month 3 (end of month 2) 
Month 2
38
60
67
Visit 3/Month 4 (end of month 3)
Month 3
68
90
97
Visit 4/ Month 5 (end of month 4) 
Month 4
98
120
127
Visit 5/ Month 6 (end of month 5) 
Month 5
128
150
157
Visit 6/ Month 7 (end of month 6) 
Month 6
158
180
187
Visit 7/ Month 10 (end of month 9) 
Month 9
188
270
277
Visit 8 (end of month 12/End of 
Treatment)
Month 12
278
360
367
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2.1.
Analysis Sets
2.1.1.
All Enrolled Analysis Set
All enrolled analysis set includes all subjects who had signed the informed consent form (ICF) and 
were enrolled in the study.
2.1.2.
Safety Analysis Set
The safety analysis set includes all subjects who had signed the ICF and received at least one dose 
of ImbruvicaTM.
2.1.3.
Efficacy Analysis Set
The efficacy analysis set will include all subjects who have taken at least 1 dose of study treatment 
and have both baseline and at least 1 post-baseline efficacy assessment.
2.2.
Study Day and Relative Day
Study Day 1 or Day 1 refers to the start of the first study agent administration. All safety 
assessments at all visits will be assigned a day relative to this date.
Study day or relative day for a visit is defined as:

Visit date - (date of Study Day 1) +1, if visit date is ≥date of Day 1

Visit date - Date of Day 1, if visit date <date of Day 1
There is no 'Day 0'.
2.3.
Baseline and Endpoint
Baseline is defined as the last non-missing observation on or prior to the start of the first study 
agent administration.
Primary Endpoint

The number and type of TEAEs reported by the investigator or the patient.
Exploratory Endpoints 

Proportion of subjects experiencing clinical response as per assessment criteria defined in 
section 9.1 of the protocol.

Change from baseline in patient-reported outcomes as per EORTC QLQ C-30 and FACIT 
Fatigue
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
For the study no interim analysis and data monitoring committee (DMC) review is planned.
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4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
Table 1 presents a list of the demographic variables that will be summarized for the safety analysis 
set.
Table 1: Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, standard deviation 
[SD], median and range [minimum and maximum]).
Weight (kg)
Categorical Variables
Sex (male, female, unknown, undifferentiated)
Frequency distribution with the number and percentage 
of subjects in each category.
Race (INDIAN)
Table 2: Baseline Characteristics 
Baseline characteristics
Summary Type
Type of disease
Staging
Number of prior therapies
ECOG status at baseline
Frequency distribution with the number and percentage 
of subjects in each category.
Number of years of diagnosis
EORTC-QLQ-C30 at baseline
FACIT Fatigue
Descriptive statistics (N, mean, standard deviation 
[SD], median and range [minimum and maximum]
4.2.
Disposition Information
Number of enrolled subjects and screen failures will be summarized for all enrolled analysis set.
The summary table and listing for treatment disposition and study disposition will be presented 
based on safety analysis set.
The summary for the treatment disposition will be as follows:

Number of subjects receiving study agent

Number of subjects who completed the study agent

Number of subjects discontinued the study agent

Reasons for discontinuation of study agent
The summary for the study disposition will be as follows:

Number of subjects receiving study agent

Number of subjects completed the study

Number of subjects discontinued from the study

Reasons for study discontinuation
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A listing of subjects will be provided along with the dates, study days and reason for 
discontinuation/ termination for the following categories:

Subjects who discontinued study agent

Subjects who terminated study prematurely
4.3.
Treatment Compliance
Study drug compliance with actual amount taken/expected amount taken X 100% and for 
categories <80%, 80-<120%, ≥120% will be summarized.
4.4.
Extent of Exposure
Summary for the total amount of study drug (ImbruvicaTM) received (mg), total treatment duration 
(month), total amount of study drug prescribed (mg), and the average daily dose (mg/day) will be 
presented. The average daily dose is calculated as (total amount of study drug received) / treatment
duration.
A listing of subject receiving study agent (ImbruvicaTM) along with the start/stop dates, dose 
amount, frequency, indication and study day will be presented.
Additionally, if dosage reduction/adjustment of ImbruvicaTM is needed, the number of percentages 
of subjects will be summarized and then date and reason for dose reductions/adjustment will be 
listed.
4.5.
Protocol Deviations
Listing of subjects with major protocol deviations will be provided.  
Subjects with major and minor protocol deviations related to Covid-19 (if any) will be listed 
separately.
A listing of subjects with inclusion/exclusion deviation will be listed, if applicable.
Note If there are a certain number of patients with COVID-19 infection and/or death due to COVID 
infection during the study, the impact of COVID-19 needs to be assessed. Based on the impact 
assessments, more listings and summary tables (regarding prior and concomitant, AE, efficacy and 
etc..) may be added to the analyses. 
4.6.
Prior and Concomitant Medications
Prior and Concomitant medications will be coded using the latest World Health Organization Drug 
Dictionary (WHO-DD). Prior medications are defined as any therapy used before the day of first 
dose (partial or complete) of study agent. Concomitant medications are defined as any therapy 
used on or after the same day as the first dose of study agent, including those that started before 
and continue on after the first dose of study agent.
The data on prior and concomitant medications will be listed separately for each subject.
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4.7.
Medical History 
Medical History will be summarized and listed for all subjects on all enrolled analysis set.
5.
EFFICACY/EXPLORATORY
5.1.
Exploratory Endpoints
5.1.1.
EORTC QLQ C-30
European Organization for Research and Treatment of Cancer Quality of Life Questionnaires 
Core 30.
 
 
 
 
 
 
 
 
 
 
CCI
CCI
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5.1.2.
FACIT Fatigue
Functional Assessment of Chronic Illness Therapy-Fatigue
The PRO questionnaires will be collected preferably at the beginning of the clinic visits prior to 
any procedures or physician interactions
FACIT Fatigue is an instrument for use as a measure of the effect of fatigue in patients with cancer 
and other chronic diseases. Responses to the 13-item FACIT Fatigue Scale are reported on a              
5-point categorical response scale ranging from 0 (not at all) to 4 (very much). Below is the list of 
items for FACIT-fatigue:
CCI
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Figure 1
5.1.3.
Proportion of subjects experiencing clinical response as per assessment 
criteria
Following are the response categories to be assessed:

Complete Response (CR)

Partial Response (PR)
CCI
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
Stable Disease (SD)

Disease Progressive (PD)
Analysis: The number and percentage of subjects will be provided in the following response 
categories: CR, PR, SD, PD. Data for response assessment will be listed individually for each 
subject at each visit for efficacy analysis set. The proportion of subjects who achieved the best 
response of (CR+PR) and its 95% confidence interval (CI) will be analyzed on efficacy analysis 
set.
5.1.4.
Progression-Free Survival
Progression-Free Survival (PFS) is defined as the duration from the date of first dose of study drug 
to either progressive disease the IWCLL criteria or death, whichever occurs first. For subjects who 
have not progressed and are alive, data will be censored at the Visit 8, or last visit date. The Kaplan-
Meier method will be used for descriptive summaries. Median PFS and its 95% CI will be provided. 
The PFS rates with 95% CI at selected landmark points (6 months and 12 months) will be 
calculated. PFS will be analyzed on both safety and efficacy analysis set.
6.
SAFETY
All safety analyses will be based on the safety analysis set based on actual treatment received, 
unless otherwise specified.
For all continuous safety variables, descriptive statistics will include the N, mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be summarized using 
frequency counts and percentages.
6.1.
Adverse Events
The verbatim terms used in the case report form (CRF) by investigators to identify adverse events 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Any AE
occurring at or after the initial administration of study agent through the day of last dose is 
considered to be treatment emergent. If the event occurs on the day of the initial administration of 
study agent, and either event time or time of administration are missing, then the event will be 
assumed to be treatment emergent. If the event date is recorded as partial or completely missing, 
then the event will be considered to be treatment emergent unless it is known to be prior to the first 
administration of study agent based on partial onset date or resolution date. All reported treatment-
emergent adverse events will be included in the analysis. 
For each adverse event, the percentage of subjects who experience at least 1 occurrence of the 
given event will be summarized by treatment group. 
Summary tables will be provided for:

Overall summary of TEAEs

TEAEs by SOC and PT
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
TEAEs by SOC, PT, and severity (Mild, Moderate and Severe)

TEAEs by SOC, PT, and NCI-CTCAE toxicity grade (for non-hematological AEs (using NCI-
CTCAE Version 4)) TEAEs by SOC, PT, and IWCLL toxicity grade (for hematologic AEs
(using IWCLL 2008 criteria))

TEAEs by SOC, PT, and relationship to study agent (Not Related, Doubtful, Possible, 
Probable, Very Likely or Related [possible, probably, Very Likely] and Non-related)

Serious TEAEs by SOC and PT

Treatment related TEAEs by SOC, PT, and toxicity grade >= 3

Treatment related serious TEAEs by SOC and PT

TEAEs leading to discontinuation of study agent by SOC and PT

AEs leading to death by SOC and PT
In addition to the summary tables, listings will be provided for subjects who had:

Any TEAEs

Serious TEAEs (SAEs)

Severe TEAEs

Treatment related TEAEs

TEAEs leading to discontinuation of study agent

AEs leading to Death
6.2.
Clinical Laboratory Tests
The following summary tables will be presented by type of laboratory test:

Descriptive statistics will be calculated for each laboratory analyte (Hematology and 
Coagulation) for observed values at each scheduled time point.

Parameters with predefined National Cancer Institute Common Terminology Criteria for
Adverse Events (NCI-CTCAE, Version 4) toxicity grades at each scheduled time point of 
measurement

The number and percentage of subjects with NCI-CTCAE grade >= 3 (markedly abnormal) 
for the parameters with predefined NCI-CTCAE toxicity grades at each scheduled time point 
of measurement

Subjects with abnormal laboratory values at all measured time point.

Subjects with any markedly abnormal laboratory results 

Normal reference ranges.
Since there is no conventional baseline visit, the values and abnormalities will be summarized by 
visit without change from baseline analysis. But the sensitivity analysis will be performed with 
baseline defined as Visit 1.
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
Descriptive statistics will be calculated for each laboratory analyte (Hematology and 
Coagulation) at baseline and for observed values and changes from baseline at each scheduled 
time point.

Shift tables (cross-tabulations) summarizing the shift in laboratory values from baseline to the 
worst post baseline measurement experienced by the subject during the study with respect to 
NCI-CTCAE toxicity grades

Shift tables (cross-tabulations) summarizing the shift in laboratory values for non-graded 
parameters from baseline to each scheduled time point of measurement with respect to 
abnormality criteria (low, normal, high).

For all participants, a listing to support the sensitivity analysis table will be provided which 
will include clinical laboratory test results and change from baseline at all measured time 
points.
6.3.
Vital Signs and Physical Examination

Descriptive statistics of temperature, pulse/heart rate, respiratory rate, mean arterial pressure 
and blood pressure (systolic and diastolic values) and changes from baseline will be 
summarized at each scheduled time point

The percentage of subjects with values beyond clinically important limits will be summarized.

Listing of vital sign measurements and the change from baseline will be presented for all 
participants. 

A listing of abnormal vital signs will be presented, including unscheduled visits.
      Table 4: Normal Ranges for Vital Signs
Parameter
Range
Unit
Body temperature
36.1 – 37.2
C
Pulse rate
60 – 100
beats/min
Systolic Blood Pressure
90 – 120
mmHg
Diastolic Blood Pressure
60 – 80
mmHg
Mean Arterial Pressure
70 - 100
mmHg
Respiratory Rate
12 – 20
breaths/min
Physical examination findings will be listed.
6.4.
ECOG Performance Status
Subjects will be listed with its performance status at all the schedule timepoints. Counts and 
percentages of ECOG will be presented at scheduled visits.
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7.
REFERENCES
1.
https://www.eortc.org/app/uploads/sites/2/2018/02/SCmanual.pdf
2. FACIT-F_INDICE.pdf (ser.es)
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