Clinical trial NCT02927925
Conditions: Lymphoma
Sponsor: Janssen Research & Development, LLC
Start date: 2017-02-14; Completion date: 2020-01-07
Enrollment: 32 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the clinical efficacy and safety of daratumumab in relapsed or refractory natural killer/T-cell lymphomas (NKTCL).

Detailed description:

Arms: arm 1: Participants will receive daratumumab 16 milligram per kilogram (mg/kg) by intravenous (IV) infusion once weekly for 8 weeks, then every 2 weeks for 16 weeks, then every 4 weeks thereafter until study drug discontinuation due to progressive disease (PD), consent withdrawal or unacceptable toxicity.
Interventions: intervention 1: Daratumumab
Intervention descriptions: intervention 1: Participants will receive daratumumab 16 mg/kg as intravenous infusion.

Protocol documents:
Prot_000.pdf: 
1
Status: Approved, Date: 24 January 2019
Janssen Research & Development *
Clinical Protocol
An Open Label, Phase 2 Study to Assess the Clinical Efficacy and Safety of Daratumumab 
in Patients With Relapsed or Refractory Natural Killer/T-Cell Lymphoma (NKTCL), 
Nasal Type
Protocol 54767414NKT2001; Phase 2
AMENDMENT 4
JNJ-54767414  Daratumumab
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information
page that accompanies the protocol.
Status:
Approved
Date:
24 January 2019
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-123873150, 7.0
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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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 16
TIME AND EVENTS SCHEDULE .............................................................................................................. 18
TIME AND EVENTS SCHEDULE: PK AND IMMUNOGENICITY (ALL SAMPLES SHOULD BE 
SENT TO THE CENTRAL LABORATORY) ..................................................................................... 21
ABBREVIATIONS ...................................................................................................................................... 22
DEFINITIONS OF TERMS.......................................................................................................................... 23
1.
INTRODUCTION................................................................................................................................ 24
1.1.
CD38 Expression in NKTCL .......................................................................................................... 25
1.2.
Preliminary Findings on NK Cell Reduction Following Daratumumab Treatment ......................... 25
1.3.
Background .................................................................................................................................... 27
1.3.1.
Daratumumab............................................................................................................................. 27
1.3.2.
Nonclinical Studies ..................................................................................................................... 27
1.3.3.
Clinical Studies ........................................................................................................................... 28
1.4.
Overall Rationale for the Study...................................................................................................... 30
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 30
2.1.
Objectives and Endpoints .............................................................................................................. 30
2.1.1.
Objectives ................................................................................................................................... 30
2.1.2.
Endpoints.................................................................................................................................... 31
2.2.
Hypothesis ..................................................................................................................................... 31
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 31
3.1.
Overview of Study Design.............................................................................................................. 31
3.2.
Study Design Rationale.................................................................................................................. 33
4.
SUBJECT POPULATION.................................................................................................................. 33
4.1.
Inclusion Criteria ............................................................................................................................ 34
4.2.
Exclusion Criteria ........................................................................................................................... 35
4.3.
Prohibitions and Restrictions ......................................................................................................... 37
5.
DOSAGE AND ADMINISTRATION .................................................................................................. 37
5.1.
Daratumumab preparation ............................................................................................................. 38
5.2.
Daratumumab Administration ........................................................................................................ 38
5.3.
Guidelines for Prevention of Infusion Reactions............................................................................ 39
5.3.1.
Preinfusion Medication ............................................................................................................... 39
5.3.2.
Postinfusion Medication.............................................................................................................. 39
5.3.3.
Management of Infusion-Related Reactions .............................................................................. 40
5.3.3.1.
Infusion-Related Events of Grade 1 or Grade 2 (mild to moderate)........................................ 40
5.3.3.2.
Infusion-Related Reactions of Grade 3 (severe) or Higher ..................................................... 41
5.3.3.3.
Recurrent Infusion-Related Reactions .................................................................................... 41
6.
TREATMENT COMPLIANCE............................................................................................................ 41
6.1.
Dose Delays and Dose Modification.............................................................................................. 41
6.1.1.
Daratumumab-Related Toxicity Management............................................................................ 41
6.1.2.
Daratumumab Interruption or Missed Doses.............................................................................. 42
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7.
CONCOMITANT THERAPY.............................................................................................................. 42
7.1.
Recommended Therapies.............................................................................................................. 43
7.1.1.
Prophylaxis for Pneumocystis Carinii ......................................................................................... 43
7.1.2.
Prophylaxis for Herpes Zoster Reactivation ............................................................................... 43
7.1.3.
Prevention of Steroid-Induced Gastritis...................................................................................... 43
7.1.4.
Management of Hepatitis B Virus Reactivation .......................................................................... 43
7.2.
Permitted Therapies....................................................................................................................... 43
7.3.
Prohibited Therapies...................................................................................................................... 44
8.
STUDY EVALUATIONS .................................................................................................................... 44
8.1.
Study Procedures........................................................................................................................... 44
8.1.1.
Overview..................................................................................................................................... 44
8.1.2.
Screening Phase ........................................................................................................................ 45
8.1.3.
Treatment Phase ........................................................................................................................ 46
8.1.4.
Posttreatment Phase (Follow-Up) .............................................................................................. 47
8.2.
Efficacy Evaluations....................................................................................................................... 47
8.2.1.
PET-CT Scan.............................................................................................................................. 49
8.2.2.
Radiographic (CT or MRI) Assessments.................................................................................... 49
8.2.3.
Clinical Examination ................................................................................................................... 50
8.2.4.
Bone Marrow Assessment.......................................................................................................... 50
8.2.5.
Tumor Biopsy Assessment......................................................................................................... 50
8.2.6.
Blinded Independent Central Review ......................................................................................... 50
8.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 51
8.3.1.
Evaluations ................................................................................................................................. 51
8.3.2.
Analytical Procedures................................................................................................................. 51
8.3.3.
Pharmacokinetic Parameters ..................................................................................................... 51
8.3.4.
Immunogenicity Assessments .................................................................................................... 51
8.4.
Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 52
8.5.
Biomarkers ..................................................................................................................................... 52
8.6.
Safety Evaluations ......................................................................................................................... 54
8.7.
Sample Collection and Handling.................................................................................................... 58
9.
SUBJECT COMPLETION/WITHDRAWAL FROM THE STUDY...................................................... 58
9.1.
Completion ..................................................................................................................................... 58
9.2.
Discontinuation of Study Treatment/Withdrawal From the Study .................................................. 58
9.3.
Withdrawal From the Use of Samples in Future Research............................................................ 60
10.
STATISTICAL METHODS................................................................................................................. 60
10.1.
Subject Information ........................................................................................................................ 60
10.2.
Sample Size Determination ........................................................................................................... 60
10.3.
Efficacy Analyses ........................................................................................................................... 60
10.3.1.
Primary Efficacy Endpoint........................................................................................................... 60
10.3.2.
Secondary Efficacy Endpoint...................................................................................................... 61
10.4.
Pharmacokinetic Analyses............................................................................................................. 61
10.5.
Immunogenicity Analyses .............................................................................................................. 62
10.6.
Biomarker Analyses ....................................................................................................................... 62
10.7.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 62
10.8.
Safety Analyses ............................................................................................................................. 63
10.9.
Interim Analysis.............................................................................................................................. 64
11.
ADVERSE EVENT REPORTING ...................................................................................................... 64
11.1.
Definitions ...................................................................................................................................... 64
11.1.1.
Adverse Event Definitions and Classifications ........................................................................... 64
11.1.2.
Attribution Definitions.................................................................................................................. 66
11.1.3.
Severity Criteria .......................................................................................................................... 66
11.2.
Special Reporting Situations.......................................................................................................... 67
11.3.
Procedures..................................................................................................................................... 67
11.3.1.
All Adverse Events...................................................................................................................... 67
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11.3.2.
Serious Adverse Events ............................................................................................................. 68
11.3.3.
Pregnancy................................................................................................................................... 69
11.4.
Contacting Sponsor Regarding Safety........................................................................................... 69
12.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 69
12.1.
Procedures..................................................................................................................................... 69
12.2.
Contacting sponsor Regarding Product Quality............................................................................. 70
13.
STUDY DRUG INFORMATION......................................................................................................... 70
13.1.
Physical Description of Study Drug(s) ........................................................................................... 70
13.2.
Packaging ...................................................................................................................................... 70
13.3.
Labeling.......................................................................................................................................... 70
13.4.
Preparation, Handling, and Storage............................................................................................... 70
13.5.
Drug Accountability ........................................................................................................................ 70
14.
STUDY-SPECIFIC MATERIALS....................................................................................................... 71
15.
ETHICAL ASPECTS ......................................................................................................................... 71
15.1.
Study-Specific Design Considerations........................................................................................... 71
15.2.
Regulatory Ethics Compliance....................................................................................................... 72
15.2.1.
Investigator Responsibilities ....................................................................................................... 72
15.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 72
15.2.3.
Informed Consent ....................................................................................................................... 74
15.2.4.
Privacy of Personal Data ............................................................................................................ 75
15.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 75
16.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 76
16.1.
Protocol Amendments.................................................................................................................... 76
16.2.
Regulatory Documentation ............................................................................................................ 76
16.2.1.
Regulatory Approval/Notification ................................................................................................ 76
16.2.2.
Required Prestudy Documentation............................................................................................. 77
16.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 77
16.4.
Source Documentation................................................................................................................... 78
16.5.
Case Report Form Completion ...................................................................................................... 79
16.6.
Data Quality Assurance/Quality Control ........................................................................................ 79
16.7.
Record Retention ........................................................................................................................... 80
16.8.
Monitoring ...................................................................................................................................... 80
16.9.
Study Completion/Termination....................................................................................................... 81
16.9.1.
Study Completion/End of Study.................................................................................................. 81
16.9.2.
Study Termination....................................................................................................................... 81
16.10.
On-Site Audits ................................................................................................................................ 82
16.11.
Use of Information and Publication................................................................................................ 82
REFERENCES............................................................................................................................................ 84
ATTACHMENT ........................................................................................................................................... 86
INVESTIGATOR AGREEMENT ................................................................................................................. 95
LIST OF ATTACHMENTS
Attachment 1:
ECOG Performance Status Scale19 ........................................................................... 86
Attachment 2:
Conversion Table for Glucocorticosteroid Dose......................................................... 87
Attachment 3:
Family of Antihistamine Medications .......................................................................... 88
Attachment 4:
Asthma Guidelines (NHLBI) ....................................................................................... 89
Attachment 5:
Calculated and Measured Creatinine Clearance ....................................................... 91
Attachment 6:
Revised Response Criteria for Response Assessment12........................................... 92
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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Disease Distribution by Region................................................................................................. 24
Table 2:
Daratumumab Infusion Rates ................................................................................................... 38
Table 3: 
Daratumumab-Related Toxicity Management .......................................................................... 42
Table 4: 
Volume of Blood to be Collected From Each Subject (Based on assumption for a 
female subject completing a total of Cycle 7) ........................................................................... 45
FIGURES
Figure 1: 
NK Cells Decreased With Daratumumab Treatment................................................................ 26
Figure 2: 
Schematic Overview Study Treatment Administration ............................................................. 38
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PROTOCOL AMENDMENTS
Protocol Version 
Date
Original Protocol
22 December 2016
Amendment 1
25 January 2017
Amendment 2
Amendment 3
Amendment 4
05 July 2017
30 May 2018
24 January 2019
Amendments below are listed beginning with the most recent amendment.
Amendment 4 (24 January 2019)
The overall reason for the amendment: The overall reason for the amendment is to update the hepatitis B virus 
(HBV) related sections to include a newly identified risk of hepatitis B reactivation associated with the use of 
daratumumab.
Applicable Section(s)
Description of Change(s)
Rationale: The text for identification of HBV reactivation, testing, and management of subjects with the 
potential for HBV reactivation was added or modified in response to identification of a new important risk (HBV 
reactivation).
Time and Events 
Schedule
Added a footnote for HBV serology.
Added a row for HBV DNA test and identified when the HBV DNA test would be 
conducted.
4.2 Exclusion Criteria 
(Criterion #8.1)
Clarified language to exclude subjects who are seropositive for hepatitis B. 
Section 7.1.4 
Management of 
Hepatitis B Virus 
Reactivation
Added a new section providing information for the management of HBV reactivation.
Section 8.1.1 
Overview
Added footnote ‘e’ to ‘Serology (hepatitis B and C)’ in Table 4 mentioning that - For 
subjects with serologic evidence of resolved HBV infection (ie, positive antibodies to 
hepatitis B surface antigen [Anti-HBs] or positive antibodies to hepatitis B core antigen
[Anti-HBc]) at Screening, more samples may need to be collected to perform HBV 
DNA testing during the treatment and during follow up.
Section 8.6 Safety 
evaluations
Mentioned that Hepatitis B Screening would include tests for HBsAg, Anti-HBc, and 
Anti-HBs and added information detailing the conduct of HBV serology and DNA tests.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 3 (30 May 2018)
The overall reason for the amendment: To provide clarification that all the efficacy evaluations will be based on 
blinded independent central review (BICR), to update rules of patient treatment management as per the central review 
process, adjust various pharmacokinetics (PK) and biomarker sampling timepoints, and to adopt daratumumab 
standard protocol language.
Applicable Sections
Description of Changes
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Rationale: To clarify that efficacy evaluations and rules of patient treatment management will be based on BICR
process.
Synopsis Objectives; 
Synopsis Endpoints;
2.1 Objectives and 
Endpoints;
3.1 Overview of Study 
Design;
10.3.1 Primary Efficacy 
Endpoint;
10.3.2 Secondary Efficacy 
Endpoint
Clarified that efficacy assessments will be evaluated based on BICR.
8.1.3 Treatment Phase End-
of-Treatment; 
8.1.4 Posttreatment Phase 
(Follow-up); 
8.2 Efficacy Evaluations; 
8.2.6 Blinded Independent 
Central Review;
9.2 Discontinuation of study 
treatment/withdrawal from the
study
Added the text which specified that the all efficacy evaluations including confirmation 
of progressive disease (PD) was based on BICR. In addition, clarified that 
discontinuation of study treatment due to PD would be based on central review process.
Added new section “8.2.6: Blinded Independent Central Review” and described the 
role of BICR in the study.
Rationale: To update the time frame of study end after the last subject receives the first dose of daratumumab. 
Synopsis Overview of 
Study Design; 
Synopsis Statistical 
Methods; 
3.1 Overview of Study 
Design; 
10.2 Sample Size 
Determination
The word “approximately” was added to the following 2 sentences 
“Following that, additional patients (ie, approximately 35 patients) may be enrolled in 
an expansion phase to confirm the clinical response rate of daratumumab”
“study will end approximately 9 months after the last subject receives the first dose of 
daratumumab”.
Rationale: To clarify and adapt the detailed requirements on various study procedures in Time and Events Schedule.
Time and Events Schedule: 
ECOG, Weight, Height, 
footnote “f”; 
8.6 Safety Evaluations
Added Eastern Cooperative Oncology Group (ECOG) assessment at End-of-Treatment 
(EoT) visit and the footnote “f” was updated with the ECOG collection information.
The ECOG assessment was no longer specified to be done prior to other assessments 
except prior to dosing of daratumumab on Day 1 of each cycle, and therefore, the text 
on the same was deleted from the footnote ‘f’. The same changes were made in 
Section 8.6.
Added assessment of weight and height during Screening Phase and deleted assessment 
of height during Treatment Phase.
Time and Events Schedule:
Circulating plasma 
EBV-DNA quantification 
(central laboratory);
8.5 Biomarkers
Added assessment of circulating plasma Epstein-Barr Virus deoxyribonucleic acid 
(EBV-DNA) quantification (central laboratory) at EoT visit.
Time and Events Schedule: 
Bone marrow biopsy
Added optional assessment of bone marrow biopsy during Screening Phase. In 
addition, clarified that bone marrow assessment is required during Treatment Phase to 
confirm complete response (CR), regardless of whether biopsy was performed during
Screening Phase.
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Time and Events Schedule: 
Tumor biopsy (optional); 
8.2.5 Tumor Biopsy 
Assessment
Added optional assessment of tumor biopsy if in case the lesion is reasonably 
accessible to confirm suspected PD during Screening and Treatment Phases. Added 
footnote “m” for indicating that biopsy was strongly recommended if the tumor lesion 
was accessible to confirm suspected PD.
Added new section “8.2.5 Tumor Biopsy Assessment” which describes the tumor 
biopsy assessments.
Time and Events Schedule 
“Footnotes: g, k, l, n, and o”
Updated footnote “g” for the start timepoint collection of vital signs in case of infusion 
interruption due to infusion-related reactions (IRRs). 
Added a footnote “k” indicating the duration of follow-up in case of treatment 
discontinuation due to PD or any other reason.
Added footnote “l” for clarification of the text indicating blood sample collection in 
case of IRRs which occurred on the same day.
Added footnote “n” for clarity on baseline image data for Positron Emission 
Tomography (PET)/Computer Tomography (CT) or CT or magnetic resonance imaging 
(MRI) scan.
Added footnote “o” for clarity of B-symptoms assessment in every disease evaluation 
assessment.
Time and Events Schedule: 
Whole Blood Collection
Deleted blood collection timepoints of C2D1, C6D1, and added blood collection 
timepoints C3D1, C7D1 to keep biomarker tests consistency with disease evaluation 
schedule.
Rationale: To clarify on disease evaluation method.
8.2.3 Clinical Examination
Added text for collecting any clinical information which can support disease evaluation 
including palpable lesion.
Rationale: To clarify the schedule of PK/Immunogenicity.
Time and Events Schedule: 
PK and Immunogenicity
‘footnotes”
Deleted footnote “b” on time points of blood sampling.
Added a footnote “d” stating that the EOT was within 30 days (+7) of the last dose and 
Follow-Up (FU) weeks 4 and 8 were 4 weeks (±7 days) and 8 weeks (±14 days) from 
the last dose. In addition, PK/Immunogenicity samples were to be collected at these 
timepoints regardless of subject discontinuation.
Time and Events Schedule: 
PK and Immunogenicity 
‘Pharmacokinetic Samples”, 
Immunogenicity Samples
Defined time duration for collection of samples (“Before Infusion” means “within 2 
hours before the start of infusion” and “End of Infusion” means “within 2 hours after 
end of infusion”).
Deleted PK sample collection timepoints at +2, +5, and +24 hours.
Deleted all PK/Immunogenicity sample collection timepoints of Cycle 1 Day 4.
8.3.3. Pharmacokinetics 
Parameters; 
10.4. Pharmacokinetic 
Analyses
PK parameters: Ctrough, Clearance (CL), half-life (t1/2), Volume of distribution (Vd) were 
deleted as they are estimable based on PK sampling schedule. In addition, the definition 
of tmax was added to provide clarity.
Rationale: To clarify the time of primary analysis.
3.1 Overview of Study 
Design
Added cross reference of Time and Events Schedule for Follow-up phase.
Clarification to the time of primary analysis was made by adding the following 
sentence “the primary analysis will be performed at 6 months after the last subject
receives the first dose of daratumumab”.
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Rationale: To clarify the requirement on subject overall status before including in the study.
4.1 Inclusion Criteria
Added life expectancy of ≥ 3 months in inclusion criterion number 5.
Rationale: To clarify that the classification used for efficacy response assessment was “LUGANO” classification.
Throughout the protocol:
The classification of Revised Criteria for Response Assessment was specified as 
“LUGANO Classification”.
Rationale: To update the quantity of blood volumes for pharmacokinetic, biomarker research, and efficacy parameters 
as per the Time and Events Schedule.
8.1.1 Overview; 
15.1 Study Specific Design 
Considerations
Blood volumes were updated for pharmacokinetic/immunogenicity samples and 
circulating plasma EBV-DNA quantification for efficacy evaluation.
Rationale: To clarify the protocol text to avoid confusion and errors.
3.1 Overview of Study 
Design
The phrase “as determined by investigator” was deleted from following sentence:
“After study completion, the sponsor will ensure that subjects who are currently on 
treatment and receiving benefit, will continue to receive daratumumab until PD, 
unacceptable toxicity or other.”
4.1 Inclusion Criteria
Text was added in “Note” of Section 4.1 to clarify that the subjects consented to 
provide the optional research samples had to follow the sample collection schedule 
listed in optional consent form.
5.3.2 Postinfusion 
Medication
Clarity to the days of steroid administration was added by adding following phrase 
“given on Day 2 for 2 days’.
8.1.3 Treatment Phase
Phrase “within-cycle” was added to word “visit” to clarify such visits (eg Cycle 1 
Day15, Cycle 2 Day 22). 
8.1.4 Posttreatment Phase 
(Follow-Up)
Updated text for study physician’s confirmation of PD form during Follow-Up Phase of 
the study.
9.2 Discontinuation of 
StudyTreatment/Withdrawal 
from the Study
Added cross references of Sections 8.1.4 and 15.2.3 for clarity.
10.4 Pharmacokinetic 
Analysis
The definition of pharmacokinetic population was modified by adding a phrase “at 
least”.
Rationale: To modify biomarker terms to define markers and analysis more precisely.
3.2 Study Design Rationale;
8.5 Biomarkers; 
15.1 Study-Specific Design 
Considerations
Replaced certain instances of CD59 with Complement Inhibitory Proteins (CIPs) to 
include assessments of other CIPs such as CD55 and CD46.
Addition of immunofluorescent staining method.
8.5 Biomarkers
Added text regarding additional information needed for archived biopsy samples. In 
addition, text on methodology to be followed in case of re-biopsy of samples was 
added.
Rationale: To revise and place the text in appropriate section as per the global oncology therapeutic area and protocol 
review committee.
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11.3.1 All Adverse Events; 
11.3.2 Serious Adverse 
Events
Moved paragraph explaining the text on “PD is not considered as adverse event (AE) or 
serious adverse event (SAE) during AE reporting period” from Section 11.3.2 to 11.3.1.
Rationale: To adopt the standard daratumumab protocol language
1.3.1 Daratumumab
Updated background information on daratumumab IV infusion.
4.1 Inclusion Criteria
Updated the criteria on contraception of women and value of hemoglobin in mmoL/L.
5. Dosage and 
administration; 
5.2 Daratumumab 
administration; 
5.3.1 Preinfusion 
Medication; 
5.3.3.1 Infusion-Related 
Events of Grade 1 or Grade 
2 (mild to moderate); 
5.3.3.2 Infusion-Related 
Reactions of Grade 3 
(severe) or Higher; 
5.3.2 Postinfusion 
Medication; 
5.3.3 Management of 
Infusion-Related Reactions
5.3.3.3 Recurrent Infusion-
Related Reactions
Adopted the standard daratumumab protocol language on guidelines for prevention of 
infusion reactions. 
Added new Section 5.3.3.3 Recurrent Infusion-Related Reactions as per standard 
daratumumab protocol language.
6.1.1 Daratumumab-Related 
Toxicity Management
Adopted the standard daratumumab protocol language.
7.1.2 Prophylaxis for 
Herpes Zoster Reactivation
Adopted the standard daratumumab protocol language on guidelines for prophylaxis for 
Herpes Zoster Reactivation.
9.2 Discontinuation of 
Study 
Treatment/Withdrawal from 
the Study 
Updated one of the criteria for “Discontinuation of Study Treatment”.
Deleted the following withdrawal reason from the study: “The study investigator, for 
any reason, stops the subject’s participation in the study”
Rationale: To align the protocol text per the current protocol template.
Title page: Sponsorship
Statement
Added “Janssen Pharmaceutical NV” (new operating company) added to the group of 
companies who act as legal entity for Janssen Research & Development in various 
countries.
8.6 Safety Evaluations
In the paragraph related to clinically significant abnormalities, changed "clinically 
stable endpoint" to "clinically stable condition".
Section 16.3 Subject 
Identification, Enrollment, 
and Screening Logs
To identify the subjects by their date of birth added a criterion “as allowed by local 
regulations” in parentheses next to date of birth.
16.11 Use of Information 
and Publications
Added the text “for the study” in the below sentence: "key assessment parameters of 
the study will be used to determine a coordinating investigator for the study."
Rationale: Minor errors were noted
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Throughout the protocol
Minor grammatical, formatting, or spelling changes were made. List of Abbreviations 
and list of references was updated and abbreviations were added to the protocol text.
Amendment 2 (05 July 2017)
The overall reason for the amendment: The overall reason for the amendment is to clarify the mandatory and 
optional biomarker tests and update the blood volume to be collected for biomarker research.
Applicable Section(s)
Description of Change(s)
Rationale: To add a footnote for whole blood collection. 
Time and Events 
Schedule
Added a footnote “j” to specify that refer to the laboratory manual for the detailed 
instructions for the whole blood collection. 
Rationale: To clarify that predose samples will be collected on Cycle 1 Day 1, Cycle 2 Day 1 and Cycle 6 Day 1 
for biomarker research.
Time and Events 
Schedule
In the row for whole blood collection, added “(predose)” in the column for “C1D1 and 
C2D1” and “C6D1”.
Rationale: To update the blood volume to be collected for mandatory biomarker research and efficacy to be 
consistent with the laboratory manual and to update the blood volume and collection time point for exploratory 
genetic biomarker research per current genetic biomarker research plan.
Table 4: Volume of 
Blood to be Collected 
From Each Subject 
(Based on assumption 
for a female subject 
completing a total of 
Cycle 7)
For “Circulating plasma EBV-DNA”, volume per samples was revised from 2 mL to 4 
mL, and approximate total volume of blood was revised from 14 mL to 28 mL.
For “β2-microglobulin”, volume per samples was revised from 5 mL to 2.5 mL, and 
approximate total volume of blood was revised from 5 mL to 2.5 mL.
For “Pharmacodynamic/Biomarker samples”, volume per sample was revised from 9.5 
mL to 12 mL, and approximate total volume of blood was revised from 38 mL to 48 mL.
The total volume per sample for all type of sample was revised from 34.5 mL to 36.5 mL, 
and the approximate total volume of blood for all samples was revised from 235 mL to 
256.5 mL.
8.1.1. Overview
Revised the total blood volume to be collected from a subject who completed a total of 
Cycle 7 from 235 mL to 256.5 mL.
Revised the total blood volume to be collected for efficacy from 19 mL to 30.5 mL.
Revised the total blood volume to be collected for biomarker research from 38 mL to 48 
mL.
Revised the additional blood volume to be collected for exploratory genetic biomarker 
research from 11 mL to 2 mL. Specified that the exploratory genetic biomarker research 
will be collected prior to daratumumab infusion on Cycle 1 Day 1.
15.1. Study-Specific 
Design Considerations
Updated the total blood volume to be collected for each subject during screening, Cycle 
1-6, Cycle 7 and thereafter, and at end-of-treatment visit.
Rationale: To add a footnote to clarify that safety evaluations will be conducted at local laboratory and the blood 
volume may vary among different local laboratories.
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Applicable Section(s)
Description of Change(s)
Table 4: Volume of 
Blood to be Collected 
From Each Subject 
(Based on assumption 
for a female subject 
completing a total of 
Cycle 7)
Added footnote “b” indicating that “safety evaluations will be conducted at local 
laboratory and the blood volume may vary among different local laboratories.”
Rationale: To correct the errors in the text for blood volumes to be collected after Cycle 7.
8.1.1. Overview
Original text:
From Cycle 8 onwards until disease progression, 2 mL blood samples will be taken for 
Hematology, 5 mL for clinical chemistry and 10 mL for PK at Day 1 of each cycle. Only 
Cycle 12 Day 1 predose sample will be assessed for immunogenicity.
Modified text:
From Cycle 8 onwards until disease progression, 2 mL blood samples will be taken for 
Hematology, 3 mL for clinical chemistry, and 4 mL for Circulating plasma EBV‑DNA 
quantification on Day 1 of each cycle; 5 mL blood samples will be taken for PK on Day 1 
every two cycles from Cycle 7, plus on Day 1 of Cycle 12.
Rationale: To modify text to indicate that immunophenotyping will be performed by both flow cytometry and 
mass cytometry/time-of-flight mass spectrometry (CyToF) considering that CyToF is a newly developed method 
that provides opportunity to analyze more cell populations and provide more information, which is complementary 
to flow cytometry.
8.5. Biomarkers
Modified text to indicate that immunophenotyping will be performed by both flow 
cytometry and mass cytometry/time-of-flight mass spectrometry (CyToF).
Rationale: To clarify that DNA sequencing is also performed in optional exploratory biomarker research.
8.5. Biomarkers
Modified text to clarify that DNA sequencing is also performed in optionale exploratory 
biomarker research.
Rationale: To add the scientific rationale of complement protein analysis, and remove other analysis that will not
be conducted in the study.  
8.5. Biomarkers
Original text: 
Plasma samples may be analyzed for proteins associated with disease progression or 
daratumumab response, including complement proteins, soluble CD38 (sCD38), proteins 
indicative of infusion reaction (interleukin [IL]-1, IL-6, TNFα, IFNγ, tryptase), and 
exploratory proteomics. Analyses will determine whether specific proteins are associated 
with daratumumab response.
Modified text:
Since CDC is one of the key mechanisms of action for daratumumab, and normal 
function of complement system in the body is required for CDC activity, plasma samples 
will be analyzed for complement proteins, to study whether specific complement protein 
level is associated with daratumumab response.
Rationale: To clarify that fasting blood glucose will be tested.
8.6. Safety 
Evaluations
In the serum chemistry panel, added “(fasting)” to clarify that fasting blood glucose will 
be tested.
Rationale: To clarify the scope of exploratory genetic analyses.
10.6. Biomarker 
Analyses
Modified text to clarify that Exploratory genetic analyses will be summarized in separate 
technical reports.
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Applicable Section(s)
Description of Change(s)
Rationale: To clarify the timing of interim analysis and to make it consistent with section 10.2 Sample Size 
Determination
Synopsis Statistical 
Methods; 3.1. 
Overview of Study 
Design; 10.9. Interim 
Analysis
Modified text to clarify that an interim analysis will be conducted after approximately 15 
subjects have received at least one dose of study drug and had at least one post-baseline 
disease evaluation.
Rationale: To correct a format error in the Time and Events Schedule.
Time and Events 
Schedule
Moved the row for “β2-microglobulin” from biomarkers section to clinical laboratory 
assessments section.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 1 (25 January 2017)
The overall reason for the amendment: The overall reason for the amendment is to add radiographic (CT/MRI) 
assessments to collect additional radiological data on disease response and clarify the schedules of 
PK/immunogenicity samplings.
Applicable Section(s)
Description of Change(s)
Rationale: Radiographic assessments (CT/MRI) were added to collect additional radiological data on disease 
response.
Time and Events 
Schedule
A row for CT or MRI imaging (neck, chest, abdomen, and pelvis) and a footnote were
added.
4.1. Inclusion Criteria
Revised criterion 4 to specify that each subject must have at least 1 measurable site of 
disease.
8.2. Efficacy 
Evaluation
One section (Section 8.2.1) to specify the definition of measurable disease, assessable 
disease, target lesion, and non-target lesion and 1 section (Section 8.2.3) for radiographic 
(CT/MRI) assessments were added.
Rationale: Clinical examination for skin lesions was added.
8.2.4. Clinical 
Examination
A section to specify the clinical examination for skin lesions was added.
Rationale: Clarified the schedules of PK/Immunogenicity.
Time and Events 
Schedule: PK and 
Immunogenicity; 
Added a “X” in the row for before-infusion pharmacokinetic samples on Cycle 12 Day 1 
to clarified that there will be a predose PK/immunogenicity sampling on Cycle 12 Day 1; 
The visit window was revised as per defined in the main Time and Events Schedule; 
A footnote was added to clarify that for complete study drug administration schedule 
beyond Cycle 3, refer to the main Time and Events Schedule; 
Added a footnote “m” indicating that “If EOT sample is collected within 3-5 weeks after 
the last dose, ie, the window of FU-Wk4 visit, then FU-Wk4 sample does not need to be 
collected.”
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Applicable Section(s)
Description of Change(s)
8.3.4. Immunogenicity 
Assessments
Added a sentence to clarify that daratumumab serum concentration will also be 
determined from all immunogenicity samples.
Rationale: The inclusion criteria regarding contraception and pregnancy were modified to be consistent with the 
current global standard protocol language for Daratumumab.
4.1. Inclusion Criteria
Inclusion criterion 7, 8, 9, 10 and 11 were removed. Two new inclusion criteria (7 and 8) 
regarding contraception and pregnancy were added.
Rationale: Clarified that the biomarker analysis is not restricted in CD38 expression.
4.2. Exclusion Criteria
Deleted “CD38 expression determination” and added “retrospective biomarker
determination” in the exclusion criterion 1.
Rationale: The exclusion criterion for screening 12-lead ECG was revised to be consistent with the current global 
standard protocol language for Daratumumab.
4.2. Exclusion Criteria
Revised the wording of the criterion for screening 12-lead ECG as “Screening 12-lead 
ECG showing a baseline QT interval as corrected (QTc) >470 msec.”
Rationale: Wordings regarding CD59 IHC were revised to clarify that it is not mandatory.
3.2. Study Design 
Rationale; 8.5. 
Biomarker
Revised the wordings regarding CD59 IHC to clarify that it is not a mandatory test and 
will be performed whenever samples are available.
Rationale: Clarified that adverse events will be monitored until 30 days after the last dose of study drug.
11.3.1. All Adverse 
Events
Revised the AE reporting period as “until 30 days after the last dose of study drug, unless 
the subject withdraws consent for study participation, or starts subsequent anticancer 
therapy”.
Rationale: Updated the market authorization status of daratumumab in the US.
1.3.3. Clinical Studies
Added a sentence to specify that FDA has approved daratumumab in combination with 
lenalidomide and dexamethasone or bortezomib and dexamethasone for patients with 
multiple myeloma who has received at least one prior therapy.
Rationale: Clarified that signing the separate informed consent for optional samples will not impact subject 
enrollment.
4.1. Inclusion Criteria
Listed inclusion criterion 15 as a note instead of a separate inclusion criterion.
Rationale: Immunohistochemistry will not be used for bone marrow evaluation.
8.2.5. Bone Marrow 
Assessment
Deleted “IHC staining”.
Rationale: Revised the wording regarding the administration of preinfusion medication to avoid 
misunderstanding.
5.3.1. Preinfusion 
Medication
Deleted “Preinfusion medications for subjects receiving daratumumab will be 
administered as described in the T&E Schedule”.
Rationale: Clarified the procedure of discontinuation of study treatment due to disease progression.
8.1.3. Treating Phase; 
9.2. Discontinuation 
of Study 
Treatment/Withdrawal 
from the Study
Wordings were revised to specify that disease progression will be documented by 
completing a disease progression form; study treatment discontinuation will be recorded 
in IWRS.
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Applicable Section(s)
Description of Change(s)
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
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SYNOPSIS
An Open Label, Phase 2 Study to Assess the Clinical Efficacy and Safety of Daratumumab in Patients 
With Relapsed or Refractory Natural Killer/T-Cell Lymphoma (NKTCL), Nasal Type
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds with high affinity to a unique 
epitope on CD38, a transmembrane glycoprotein. Given the high frequency of CD38 expression in 
NKTCL and the significant daratumumab treatment-related reduction of NK cells in other settings, we are 
conducting a proof of concept Phase 2 study to assess the clinical efficacy and safety of daratumumab in 
relapsed or refractory NKTCL.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Primary Objective
The primary objective of the study is to evaluate the efficacy of daratumumab in subjects with NKTCL by
objective response rate (ORR) including complete response (CR) and partial response (PR) based on a 
blinded independent central review (BICR) per Revised Criteria for Response Assessment of Hodgkin 
and non-Hodgkin Lymphoma: LUGANO classification.
Secondary Objectives
The secondary objectives are:

To evaluate the efficacy of daratumumab in NKTCL by CR rate, progression free survival (PFS), 
duration of response (DoR), time to response based on a BICR, and overall survival (OS). 

To evaluate safety and tolerability

To evaluate pharmacokinetics (PK) and immunogenicity.
Primary Endpoint
ORR based on BICR
Secondary Endpoints

CR rate based on BICR

DoR based on BICR

Time to response based on BICR

PFS based on BICR

OS 

Safety.
Hypothesis
It is hypothesized that treatment with daratumumab results in an ORR of >30% versus a null hypothesis 
of at most 15% in relapsed or refractory NKTCL, nasal type subjects who failed (relapsed or refractory 
after achieving complete or partial remission) at least one line of chemotherapy.
OVERVIEW OF STUDY DESIGN
Up to 32 subjects, age ≥18 years, who have histologically confirmed extranodal NK/T-cell lymphoma, 
nasal type that was refractory to or relapsed after at least 1 line of chemotherapy will be enrolled into the 
study. Following that, additional patients (ie, approximately 35 patients) may be enrolled in an expansion 
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phase to confirm the clinical response rate of daratumumab. All the subjects enrolled into the study will 
be required to provide archival or fresh tumor samples for assessment of CD38 expression. Daratumumab 
(16 mg/kg) will be administered by intravenous (IV) infusion to subjects once every week for 8 weeks;
then once every other week for 16 weeks; thereafter once every 4 weeks until documented progression,
unacceptable toxicity, or study end.
Interim analysis divides the study into 2 stages: Stage 1 and Stage 2. The study will end approximately 
9 months after the last subject receives the first dose of daratumumab. After study completion, the 
sponsor will ensure that subjects, who are currently on treatment and receiving benefit will continue to 
receive daratumumab until PD or unacceptable toxicity or other. Additional samples for pharmacokinetic, 
immunogenicity and biomarker evaluations will be collected during the study. Safety will be measured by 
adverse events (AEs), laboratory test results, electrocardiograms (ECGs), vital signs measurements, 
physical examination findings, and assessment of Eastern Cooperative Oncology Group (ECOG)
performance status score. All toxicities will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03.
STATISTICAL METHODS
The study is a Simon’s 2-stage design with an interim analysis conducted after approximately 15 subjects 
have received at least one dose of study drug and had at least one post-baseline disease evaluation. 
Enrollment may be put on hold pending the decision of interim analysis unless the decision is clear based 
on available data before IA. If the study proceeds to the second stage, the total sample size will be 32 with 
2 stages combined. Following that, additional patients (ie, approximately 35 patients) may be enrolled in 
an expansion phase to confirm the clinical response rate of daratumumab, if supported by emerging data.
An estimate of ORR and CR rate will be presented along with a 2-sided 95% exact confidence interval
(CI). The number and percentage of subjects falling into each response category will be descriptively 
tabulated.
For time to event endpoints (eg, PFS, OS, time to response, DoR), Kaplan-Meier estimates will be 
presented. Median along with corresponding 95% CIs will be obtained from the Kaplan-Meier estimates. 
Analysis of time to response and DoR will be for responders only.
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TIME AND EVENTS SCHEDULE
Phase
Screening
Treatment
Day 1 of each cycle (4-week cycles)
EoT
FUk
Period
Within 21 days of 
Cycle 1 Day 1
Cycle 1 and 2
Cycle 3 to 6
Cycle 7+
Within 30 days 
of last dose
Q8 weeks
Day
-21 to -1
D1
D8
D15
D22
D1
D15
D1
±2 weeks
Study Procedures
Screening/Administrative
Informed consent
Subjects must sign the ICF before any study-specific procedures are performed.
Inclusion/exclusion criteriaa
X
Medical history and demographics
X
FEV1 for subjects with COPD
X
Tumor samplec
X
ECOGf
X
X
X
X
X
8 wks post 
PD
Pregnancy test (serum/urine)b
X
As clinically indicated
X
Study Drug Administration
Daratumumabh
X
X
X
X
X
X
X
Safety Assessments
Physical examination (including neurological 
examination, lymphoma B-symptoms will be 
recorded separately)
X
Symptom and disease directed exam as clinically indicated
Weighte
X
X
X
X
Height
X
Vital signsg
X
X
X
X
X
X
X
X
12-lead ECG
X
C3D1, 
C6D1
X
Lymphoma B-symptomso
X
X
X
X
X
Clinical Laboratory Assessments
Hematologyd
X
X
X
X
X
X
X
X
X
Clinical chemistryd
X
X
X
X
X
Hepatitis Bp and C serology (local laboratory)
X
HBV DNA testingq
X
Every 12 weeks upto 6 months after last dose of daratumumab
ABO, Rh and IAT
X 
(predose)
β2-microglobulin (central laboratory)
X
Pharmacokinetics/ Immunogenicity
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TIME AND EVENTS SCHEDULE
Phase
Screening
Treatment
Day 1 of each cycle (4-week cycles)
EoT
FUk
Period
Within 21 days of 
Cycle 1 Day 1
Cycle 1 and 2
Cycle 3 to 6
Cycle 7+
Within 30 days 
of last dose
Q8 weeks
Day
-21 to -1
D1
D8
D15
D22
D1
D15
D1
±2 weeks
Study Procedures
Daratumumab PK and Immunogenicity
Please see T&E Schedule: PK and Immunogenicity
In addition, any time an IRR is observed during the study, an unscheduled blood sample should be drawn as soon as 
possible after the reaction for potential immune response analysisl
Disease Evaluations: Refer to Section 8.2 for details.
PET-CT scan
Xn
Every 8 weeks (±7 days) for the first 6 months; thereafter, 
every 16 weeks (±7 days)
CT or MRI imaging (neck, chest, abdomen,
and pelvis)i
Xn
Every 8 weeks (±7 days) for the first 6 months; thereafter, 
every 16 weeks (±7 days)
Circulating plasma EBV-DNA quantification
(central laboratory)
X
X
X
X
Bone marrow biopsy
X (optional)
Required to confirm CR, regardless of whether biopsy was 
performed at screening
Tumor biopsy (optional) 
Xm
As clinically indicatedm
Subsequent therapy
X
Other new malignancy
X
Survival
X
Biomarkers 
Whole blood collectionj
C1D1 (predose)
C3D1
(predose)
C7D1
(predose)
X
Ongoing Subject Review
Concomitant therapy
continuous from the time of signing of ICF until 30 days after last dose of study drug;
See Section 7 for detailed instructions.
Adverse events
continuous from the time of signing of ICF until 30 days after last dose of study drug;
See Section 11 for detailed instructions.
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Abbreviations: Anti-HBc= antibodies to hepatitis B core antigen; Anti-HBs= antibodies to hepatitis B surface antigen; C=cycle; COPD=chronic obstructive pulmonary 
disease; CR=complete response; CT=computed tomography; D=day; DNA=deoxyribonucleic acid; EBV=Epstein Barr virus; ECG=electrocardiogram; 
ECOG=Eastern Cooperative Oncology Group; EoT=end-of-treatment; FEV1= forced expiratory volume (in 1 second); FFPE= formalin-fixed, paraffin-embedded; 
FU=follow-up; HBV=hepatitis B virus; HBsAg= hepatitis B surface antigen; IAT=indirect antiglobulin test; ICF=informed consent form; IRR=infusion related 
reaction; MRI=magnetic resonance imaging; PCR=polymerase chain reaction; PD=progressive disease; PET=positron emission tomography; PK=pharmacokinetics; 
Q8 weeks=every 8 weeks; SIPPM=site investigational product procedures manual; Wk=week.
Footnotes:
a.
Diagnosis of NKTCL is performed by the local hospital and the pathology report will be verified by the sponsor before enrolment.
b.
Women of childbearing potential only, within 14 days of C1D1.
c.
Fresh biopsy within 21 days prior to C1D1 or archived sample FFPE sample (block or slides) should be sent to sites prior to C1D1.
d.
For Cycle 1 Day 1, no need to repeat tests if they have been performed within the past 5 days. Testing may be performed up to 2 days before other infusion days. 
Results of hematology tests must be evaluated before each study drug administration. Perform at additional time points, as clinically indicated. To be done by local 
lab. Refer to Section 8.6 for parameters to be tested.
e.
If a subject’s weight changes by more than 10% from baseline, the dose of the study drug will be re-calculated.
f.
ECOG assessment should be obtained prior to dosing of daratumumab on Day 1 of each cycle. ECOG is also required to be collected in every disease evaluation 
assessment date.
g.
Vital signs (blood pressure, temperature, pulse) measured in sitting position. On Cycle 1 Day 1: before the start of daratumumab infusion; at 0.5, 1, 1.5, 2, 3.5 hrs 
after the start of the infusion; at end of infusion; and 0.5,1 hr after end of infusion. If an IRR occurred during the infusion due to which infusion is stopped and later 
the infusion is resumed, the site will follow initial infusion start time point for the vital sign collection. For all other infusions, vital signs will be measured 
immediately before infusion start and at end of daratumumab infusion.
h.
Refer to SIPPM for recommendations on daratumumab infusion rate. Administer pre- and postinfusion medications as per Section 5.3.
i.
May be performed with oral contrast only if the subject is intolerant of IV contrast agents. If other areas of disease are involved, they can be imaged by either CT 
or MRI. All scans will be collected and reviewed centrally. The similar methodology should be used throughout the study.
j.
Refer to the laboratory manual for the detailed instructions for the whole blood collection. 
k.
Follow- up will begin once a subject discontinues study treatment; if subject discontinue due to PD, follow-up will occur at least every 8 weeks (±2 weeks). If 
subject discontinue due to other reasons (not PD), follow-up will occur at least every 8 weeks (±2 weeks), including regular scheduled scan until PD is confirmed, 
and follow-up visit will be continued after PD confirmation.
l.
If more than one IRRs occurs during dose administration, blood sample should be collected only when the first IRR occurs.
m.
Tumor biopsy may be conducted as clinically indicated and is strongly recommended if lesion is reasonably accessible to confirm suspected PD.
n.
If PET/CT or CT or MRI is performed before ICF signed date due to site’s routine practice and if it fulfills the study requirement in the image manual, those image 
data will be considered as baseline image data as long as the image scanned date is within 21 days prior to Cycle 1 Day 1.
o.
B-Symptoms assessment is also required to be collected in every disease evaluation assessment date.
p.
Local testing for HBsAg, Anti-HBs, and Anti-HBc. Refer to Section 8.6.
q.
For subjects with serologic evidence of resolved HBV infection (ie, positive Anti-HBs or positive Anti-HBc) at Screening, HBV DNA testing by PCR must be 
performed locally.  Refer to Section 8.6.
Note: The start of each cycle may occur ±3 days of the scheduled day in order to accommodate the schedule of the site or subject. For Cycles 1-6, there may be ±1 day
window for the scheduled infusion within the cycle. The EoT visit may occur +7 days of scheduled day. After PD is documented, subjects will continue to be 
followed for survival, second primary malignancies, and subsequent anticancer therapy.
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TIME AND EVENTS SCHEDULE: PK AND IMMUNOGENICITY (ALL SAMPLES SHOULD BE SENT TO THE CENTRAL 
LABORATORY)
Treatment Phase
EoTd
Follow-up Phase
Weekly for 8 infusions
Biweekly for 8 infusions
Once every 4 weeks
Cycle
Cycle 1
Cycle 2
Cycle 
3
Cycle 
4
Cycle 
5
Cycle 
6
Cycle 
7
Cycle 
9
Cycle 
11
Cycle 
12
Cycles
13, 15, 
17+
Study Day (Day)
1
8
15
22
1
8
15
22
1
1
1
1
1
1
1
1
1
FU-Wk4d
FU-Wk8d
Visit Window (day)
0
±1
±1
±1
±3
±1
±1
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
+7
±7
±14
Study Drug 
Administrationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetic Samples
Before Infusion
(within 2 hours before 
the start of infusion)
X
X
X
X
X
X
X
X
X
X
X
X
X
Xb
X
Xc
X
End of infusion
(within 2 hours after 
end of infusion)
X
X
X
Immunogenicity Samples (NO additional immunogenicity samples needed and will be taken from PK samples for the planned time points.)
Before Infusion
(within 2 hours before 
the start of infusion)
X
X
X
X
Xc
X
Footnote:
a.
For complete study drug administration schedule beyond Cycle 3, refer to the main Time and Events Schedule.
b.
Samples will be collected at every other dose from Cycle 13+, ie, at Cycle 13, 15, 17, etc.
c.
If EoT sample is collected within 3-5 weeks after the last dose, ie, the window of FU-Wk4 visit, then FU-Wk4 sample does not need to be collected.
d.
The EoT is within 30 days (+7) of the last dose. FU-Wk4 and FU-Wk8 is 4 weeks (±7 days) and 8 weeks (±14 days) from the last dose, respectively.
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ABBREVIATIONS
ADCC
antibody-dependent cell-mediated cytotoxicity
ADCP
antibody dependent cellular phagocytosis
AE
adverse event(s)
ANC
absolute neutrophil count
Anti-HBc
antibodies to hepatitis B core antigen
Anti-HBs
antibodies to hepatitis B surface antigen
BICR
blinded independent central review
CDC
complement dependent cytotoxicity
CI
confidence interval
CIP
Complement Inhibitory Protein
CNS
central nervous system
COPD
chronic obstructive pulmonary disease
CR
complete remission
CT
computed tomography
DNA
deoxyribonucleic acid
DoR
duration of response
DTT
dithiothreitol
EBV
Epstein–Barr virus
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
eDC
electronic data capture
EoT
end-of-treatment
FDA
Food and Drug Association
FDG
18F-fluorodeoxyglucose
FEV1
forced expiratory volume in 1 second
FFPE
formalin-fixed, paraffin-embedded
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HIV
human immunodeficiency virus
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IHC
immunohistochemistry
IRB
Institutional Review Board
IRR
infusion-related reactions
IV
intravenous
IVRS
interactive voice response system
IWRS
interactive web response system
LDi
longest diameter
MedDRA
Medical Dictionary for Regulatory Activities
mAb
monoclonal antibody
MDR
multidrug resistant
MM
multiple myeloma
MRI
magnetic resonance imaging
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
non-Hodgkin’s lymphomas
NKTCL
natural killer/T-cell lymphomas
ORR
objective response rate
OS
overall survival
PD
progressive disease
PCR
polymerase chain reaction
PET
positron emission tomography
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PFS
progression free survival
PI
proteasome inhibitor
PK
pharmacokinetic(s)
PO
orally
PQC
product quality complaint
PRO
patient-reported outcome(s) (paper or electronic as appropriate for this study)
RBC
red blood cell(s)
RhD
Rhesus factor–D antigen
RNA
ribonucleic acid
SAE
serious adverse event(s)
SD
standard deviation
SDI
short diameter
SIPPM
site investigational product procedures manual
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of normal
WHO
World Health Organization
DEFINITIONS OF TERMS
Clinical outcome
assessment
Includes Clinician Reported Outcomes 
Cmax
Maximum observed concentration
tmax
The actual sampling time to reach maximum observed concentration
AUC
Area under the concentration – time curve
SMILE regimen
chemotherapeutic combination regimen of Steroid=dexamethasone, Methotrexate, 
Ifosfamide, L-asparaginase, and Etoposide
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1.
INTRODUCTION
Natural killer/T-cell lymphomas (NKTCL) are a rare, Epstein–Barr virus (EBV)-associated and 
distinct subtype of peripheral T-cell lymphoma (PTCL), which are predominantly extranodal and 
mostly of the nasal type.22 The disease is more common in Asia and Central/South America, and 
accounts for around 3-16% of all the non-Hodgkin’s lymphomas (NHL) in China, Korea, 
Taiwan, and Japan (refer to Table 1 for detailed prevalence).20,23 The outcome of patients with 
NKTCL is very poor. According to a report from the International T-cell Lymphoma Project, the 
5-year overall survival (OS) rate for all patients with NKTCL was 32%, and the median OS was 
about 8 months.1,9,23
Table 1: 
Disease Distribution by Region
Country or area
NKTCL% of PTCL
NKTCL% of NHL
Europe
4.3
0.2-0.4
North America
5.1
0.3-0.5
China
48
16
Taiwan
23
3
Korea
28.7
6
Japan
10.4
3
PTCL: Peripheral T-cell Lymphoma.
Randomized studies comparing different regimens have not been conducted, to date, because 
NKTCL are rare malignancies. Therefore, standard therapy has not been established for patients 
with this disease. Localized NKTCL is radiosensitive; however, radiotherapy alone is inadequate 
because of a high systemic failure rate. It responds poorly to the anthracycline-based regimens 
used in other lymphomas because NKTCL cells are associated with a high expression of 
P-glycoprotein leading to multidrug resistance. Current data indicate that regimens employing 
non–multidrug resistant (MDR)-dependent drugs together with radiotherapy give good local 
disease control with around 70-90% of patients achieving complete remission (CR).22
For patients relapsing after radiotherapy or combined radiotherapy and anthracycline-containing
chemotherapy, it is found that the use of an L-asparaginase–containing regimen may offer 
benefit. Asparaginase can hydrolyze and exhaust serum asparagines in NKTCL cells, and this 
drug is not influenced by P-glycoprotein. L-asparaginase–containing regimens that incorporate 
non–MDR dependent drugs demonstrated activity in the treatment of advanced-stage and
relapsed/refractory NKTCL. Clinical trials on L-asparaginase in the treatment of NKTCL are 
limited to non-randomized studies. In a Phase 2 study of the SMILE regimen (combination 
chemotherapeutic regimen with L-asparaginase, methotrexate, ifosfamide, etoposide, and 
dexamethasone), 38 patients were treated. The objective response rate (ORR) and complete 
response rate after 2 cycles of SMILE chemotherapy were 79% and 45%, respectively. The 
1-year overall survival rate was 55%.26
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However, more than 20% of patients with NKTCL are primarily resistant to asparaginase-based 
treatment and around 50% of patients with advanced disease relapse after the treatment with 
asparaginase.24,26 Viewing the high failure rate of the available treatments and the limited choices 
of the therapies, new treatments are needed to improve the outcomes of patients with advanced-
stage NKTCL.
1.1.
CD38 Expression in NKTCL
CD38 expression was analyzed by Janssen in 8 cases of relapsed/refractory NKTCL, as it is the 
targeted population in this proposed study. It was found that all relapsed/refractory cases were 
positive for CD38 expression. Five cases (62.5%) showing relatively high expression (defined as 
tumor with more than 50% cells CD38 positive).
In a separate study, clinical data of 94 patients with NKTCL had been reviewed in Sun Yat-sen 
University.25 All the tumors expressed CD38, among which 47 samples (50%) are strong 
positive (defined by author’s laboratory). This study also analyzed the prognostic value of CD38 
expression for NKTCL. In the Cox regression model, CD38 turned out to be an independent 
prognostic factor for poor outcome, suggesting that CD38 may be a new prognostic biomarker 
and a novel therapy target for NKTCL. Combining Janssen’s in-house data and published data at 
Sun Yat-sen University, CD38 expression was detected in all NKTCL patients in the target 
population for this study, which supports further investigation of daratumumab to treat NKTCL.
1.2.
Preliminary Findings on NK Cell Reduction Following Daratumumab 
Treatment
Preliminary evidence of decreases in absolute counts and percentages of total NK cells
(CD16+CD56+) and activated (CD16+CD56dim) NK cells was observed in blood and bone 
marrow collected from multiple myeloma (MM) patients in the single-agent daratumumab 
studies, GEN501 and MMY2002.7,14 Figure 1 presents decrease in NK cells with daratumumab 
treatment.
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Figure 1: 
NK Cells Decreased With Daratumumab Treatment
Similar to single agent studies, total NK cells were also reduced in the peripheral blood and bone
marrow of all patient cohorts receiving combination treatment regimens in the GEN503 and 
MMY1001
studies.3,17
These data indicate that NK cells may be
sensitive to 
daratumumab-mediated lysis.
Daratumumab induces tumor cell lysis through immune effector functions such as complement 
dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody 
dependent cellular phagocytosis (ADCP) as well as apoptosis in cells that express CD38. 
Daratumumab induced >20% apoptosis in 11 out of 16 cell lines in the presence of a 
cross-linking agent. In tumor cell killing assays, daratumumab induced >25% ADCC in 7 out of 
16 cell lines and >30% CDC in 6 out of 16 cell lines. While no linear correlation was observed 
between CD38 expression and the extent of ADCC and CDC, tumor cell lysis >10% was 
observed only in cell lines with >50,000 CD38 receptors/cell. Although some preclinical data 
suggest that a threshold of CD38 expression may be required for daratumumab-induced CDC 
and ADCC, selection of patients suitable for daratumumab therapy based on CD38 expression 
was not considered justified yet in the reported clinical studies. In MM trials, a large overlap in
baseline CD38 expression was observed between responders and nonresponders. Some subjects 
continued to maintain a good clinical response to daratumumab with the reduction in CD38 
expression levels in the MM cells. Correlation between CD38 expression level and the disease 
response to daratumumab needs to be further investigated. Therefore, the role of CD38 
expression in predicting NKTCL tumor response to daratumumab treatment will be explored in 
this study.
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For the most comprehensive nonclinical and clinical information regarding daratumumab, refer 
to the latest version of the Investigator's Brochure (IB).18 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.
1.3.
Background
1.3.1.
Daratumumab
Daratumumab for Intravenous Infusion
In the US, intravenously administered daratumumab (Daratumumab IV) is indicated for use as 
follows: in combination with bortezomib, melphalan and prednisone for the treatment of patients 
with newly diagnosed MM who are ineligible for autologous stem cell transplant; in combination 
with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of 
patients with MM who have received at least one prior therapy; in combination with 
pomalidomide and dexamethasone for the treatment of patients with MM who have received at 
least two prior therapies including lenalidomide and a proteasome inhibitor; as monotherapy, for 
the treatment of patients with MM who have received at least three prior lines of therapy 
including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double
refractory to a PI and an immunomodulatory agent.14
In the EU, Daratumumab IV is indicated for use as monotherapy for the treatment of adult 
patients with relapsed and refractory MM, whose prior therapy included a PI and an 
immunomodulatory agent and who have demonstrated PD on the last therapy. And in 
combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the 
treatment of adult patients with MM who have received at least one prior therapy.15
For the most comprehensive nonclinical and clinical information regarding daratumumab, refer 
to the latest version of the IB (IB Daratumumab).18 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.
1.3.2.
Nonclinical Studies
Pharmacologic Profile
An extensive series of experiments were performed to assess the pharmacology and mechanism 
of action of daratumumab. The pharmacology studies focused on scientifically relevant primary 
and secondary pharmacodynamic aspects including binding properties, CDC, ADCC, ADCP, 
apoptosis, agonistic activity, inhibition of CD38 enzymatic activity, reactivity with normal 
human tissues and species cross-reactivity. For more details on the design and key findings of all 
pharmacology studies, please refer Appendix 1 in the IB.18
Based upon the pharmacology studies, daratumumab is believed to induce CDC, ADCC, ADCP, 
direct apoptosis after cross-linking, and to modulate CD38 enzymatic activity. In mouse 
xenograft models, daratumumab reduced tumor growth in both preventive and therapeutic 
settings. Daratumumab had no effect on proliferation of human peripheral blood mononuclear 
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cells (PBMCs), and cytokine release was similar to other marketed therapeutic antibodies. 
Hence, daratumumab can recruit multiple effector mechanisms to facilitate the lysis of malignant 
cells in vitro and in vivo. These observations suggest a strong potential for the treatment of 
CD38-expressing malignancies.
Positive Indirect Coombs Tests in Subjects Treated with Daratumumab
In Phase 1/2 clinical studies (Study GEN501 and MMY2002), in which the safety and efficacy of 
daratumumab were evaluated, it was observed that blood plasma of subjects who had received 
daratumumab tested positive on routine antibody screens in the blood bank (indirect Coombs 
testing).7,16 This is likely due to low-level of expression of CD38 on the surface of
erythrocytes.5,27 The binding of daratumumab to CD38 on red blood cells triggers a positive 
readout on indirect Coombs testing, and as a result, interferes with the ability to detect red cell 
alloantibodies.
Flow cytometry analyses of erythrocytes indicated that erythrocytes express a low level of CD38 
(301-634 CD38 molecules per cell). In preclinical studies, plasma spiked with daratumumab 
induced concentration-dependent agglutination of erythrocytes in an indirect Coombs test.20
Additional studies to evaluate various mitigation strategies such as neutralization of 
daratumumab using soluble CD38, anti-idiotype antibody, or pretreatment of reagent or donor 
red blood cells (RBCs) with dithiothreitol (DTT) to circumvent the positive readout on indirect 
Coombs testing were conducted. These methods successfully mitigated the interference of 
daratumumab with indirect Coombs test and allowed for identification of alloantibodies in the 
serum containing daratumumab.11, 22
1.3.3.
Clinical Studies
No clinical studies with daratumumab have been conducted in NKTCL. As of June 2015, 
9 clinical studies in MM and 1 clinical study of daratumumab in NHL (diffuse large B-cell 
lymphoma, mantle cell lymphoma, follicular lymphoma) are ongoing. More than 1,300 subjects 
with MM and 29 subjects with NHL have been enrolled in the clinical studies of daratumumab. 
Daratumumab was approved by the US Food and Drug Administration
(FDA)
in 
November 2015 for the treatment of patients with MM who have received at least 3 prior lines of 
therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are 
double-refractory to a PI and an immunomodulatory agent. In November 2016, US FDA 
approved daratumumab in combination with lenalidomide and dexamethasone or bortezomib and 
dexamethasone for patients with multiple myeloma who has received at least one prior therapy. 
Additionally, in May 2016, the European Commission granted conditional approval to 
daratumumab administered as monotherapy in adult patients with relapsed and refractory MM, 
whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory agent and 
who had demonstrated progressive disease (PD) while on the last therapy. A dose of 16 mg/kg is 
the recommended dose for global clinical trials in MM and NHL.
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Human Pharmacokinetics
The PK of daratumumab following intravenous (IV) administration was evaluated in subjects 
with relapsed and refractory MM at dose levels from 0.1 mg/kg to 24 mg/kg, and included the 
recommended 16 mg/kg dose and regimen. The population PK analysis included 223 subjects 
with MM receiving daratumumab in 2 clinical trials, GEN501 and MMY2002 (150 subjects 
received 16 mg/kg) 7,16 Over the dose range from 1 to 24 mg/kg, increases in area under the 
concentration-time curve (AUC) were more than dose-proportional. Clearance decreased with 
increasing dose and repeated dosing, indicating target-mediated PK. Following the recommended 
schedule and dose of 16 mg/kg, the mean [standard deviation (SD)] serum Cmax value was 
915 (410) µg/mL at the end of weekly dosing, approximately 2.9-fold higher than following the 
first infusion. The mean (SD) predose (trough) serum concentration at the end of weekly dosing 
was 573 (332) µg/mL. Based on the population PK analysis, daratumumab steady state is 
achieved approximately 5 months into the every-4-week dosing period (by the 21st infusion), 
and the mean (SD) ratio of Cmax at steady-state to Cmax after the first dose was 1.6 (0.5). The 
mean (SD) linear clearance and mean (SD) central volume of distribution are estimated to be 
171.4 (95.3) mL/day and 4.7 (1.3) L, respectively. The mean (SD) estimated terminal half-life
associated with linear clearance was approximately 18 (9) days. Population PK analyses 
indicated that the central volume of distribution and clearance of daratumumab increase with 
increasing body weight, supporting the body weight-based dosing regimen. Population PK 
analyses also showed that age (31 to 84 years) and gender do not have clinically important 
effects on the PK of daratumumab.
Based on data from Study GEN501 and MMY2002, no subjects were positive for antibodies to 
daratumumab 7,16 Anti-daratumumab antibody production after long-term treatment will be 
investigated.
Safety and tolerability
In general, daratumumab is tolerated well. Maximum tolerated dose has not been reached 
following IV infusion up to 24 mg/kg. No dose dependent toxicity was identified. 
In the daratumumab monotherapy studies MMY2002, GEN501, and MMY1002, , Among the 
156 subjects treated with 16 mg/kg daratumumab as monotherapy , the most frequently reported 
AEs were fatigue (39%); nausea and anemia (27% each); back pain (23%); neutropenia (22%); 
pyrexia and cough (21% each), and thrombocytopenia and upper respiratory tract infection (20% 
each).2,7,16 The most frequently reported Grade 3 or 4 AEs in 16 mg/kg group were anemia 
(17%),
thrombocytopenia (14%), neutropenia (12%), lymphopenia (6%), leukopenia, 
pneumonia, and hypertension (5% each). Across all dose groups, the most frequently reported 
SAEs were pneumonia (5%), pyrexia and general physical health deterioration (3% each). The 
incidence and types of SAEs in the 16 mg/kg group were similar to the total population of 
subjects who received daratumumab monotherapy. 
Infusion-related reactions (IRRs) were reported in approximately half (75/156 subjects; 48%) of 
all subjects treated with 16 mg/kg daratumumab monotherapy. Of the subjects who experienced 
an IRR, 95% experienced an IRR at the first infusion; 5% (8/156) had an IRR in more than 
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1 infusion. The most common IRRs in the 16 mg/kg group were nasal congestion (11%), cough 
(8%), chills (7%), allergic rhinitis, and throat irritation (6% each), dyspnea, nausea, and vomiting 
(5% each). Bronchospasm was reported in 4 subjects (2.6%), and laryngeal edema was reported 
in 1 subject (0.6%). Grade 3 IRRs were reported in 3% of subject; no Grade 4 or 5 IRRs were 
reported. No subject in the 16 mg/kg group discontinued treatment due to an IRR. The types and 
incidence of IRRs across all dose groups were similar to what was reported in the 16 mg/kg 
group. In the 16 mg/kg group, the median duration of the first infusion was 7 hours, which 
decreased to 4.6 hours at the second infusion, and to 3.4 hours in subsequent infusions. 
Across all dose groups, 15 subjects (6%) died within 30 days of last dose of study drug 
(14 subjects in the 16 mg/kg group and 1 subject in the 8 mg/kg group). Twelve deaths were due 
to PD and 3 deaths were due to AEs considered not related to daratumumab. In the 16 mg/kg 
group, 11 subjects (7%) died due to PD, and 3 subjects (2%) died due to AEs, all of which were 
considered not related to daratumumab treatment. Adverse events (AEs) leading to death 
included cardiorespiratory arrest in the setting of H1N1 influenza, general physical health 
deterioration secondary to aspiration pneumonia, and pneumonia. None of the fatal AEs were 
considered related to daratumumab.
1.4.
Overall Rationale for the Study
This Phase 2 study is set up due to the high frequency of CD38 expression in NKTCL and the 
significant daratumumab treatment-related reduction of NK cells. It will be conducted to assess 
the clinical efficacy and safety of daratumumab in relapsed or refractory NKTCL. The role of 
CD38 expression in predicting tumor response to treatment with daratumumab will be explored.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objective
The primary objective of the study is to evaluate the efficacy of daratumumab in subjects with 
NKTCL by ORR including complete response (CR) and partial response (PR) based on a blinded 
independent central review (BICR) per Revised Criteria for Response Assessment of Hodgkin 
and non-Hodgkin Lymphoma: LUGANO classifcation.12
Secondary Objectives
The secondary objectives are:

To evaluate the efficacy of daratumumab in NKTCL by CR rate, progression free survival 
(PFS), duration of response (DoR), time to response based on a BICR, and OS 

To evaluate safety and tolerability

To evaluate PK and immunogenicity.
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Exploratory Objectives
The exploratory objectives are:

To explore the role of CD38 expression in predicting response to daratumumab treatment

To explore the role of circulating plasma EBV-DNA in monitoring tumor response to 
daratumumab treatment

To explore the role of biomarkers in predicting tumor response to daratumumab treatment,
such as CD59, blood NK cell counts, etc.

To 
explore 
the 
PK/pharmacodynamic 
relationship 
of 
daratumumab, 
such 
as 
exposure-response relationship for efficacy/safety endpoints and/or disease-related or 
mechanism-based biomarkers.
2.1.2.
Endpoints
Primary Endpoint
Objective response rate (ORR) is defined as the proportion of subjects who achieve CR or PR 
per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin lymphoma: 
LUGANO classification based on BICR.12
Secondary Endpoints

CR rate, PFS, DoR, Time to response based on BICR, OS

Safety: AEs, vital sign measurements, ECG, physical examination findings, and clinical 
laboratory tests.
Exploratory Endpoints

CD38 expression

Plasma circulating EBV-DNA quantification.
Refer to Section 8, Study Evaluations for evaluations related to endpoints.
2.2.
Hypothesis
It is hypothesized that treatment with daratumumab results in an ORR of >30% versus a null 
hypothesis of at most 15% in relapsed or refractory NKTCL, nasal type subjects failed (relapsed 
or refractory after achieving complete or partial remission) at least one line of chemotherapy.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is an open label, single arm, multicenter, Phase 2 study to evaluate the efficacy and safety of 
daratumumab monotherapy in subjects with relapsed and refractory extranodal NKTCL, nasal 
type. The study is a Simon’s 2-stage design with up to 32 subjects to be enrolled. Following that, 
additional patients (ie, approximately 35 patients) may be enrolled in an expansion phase.
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Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase. 
The Screening Phase will be up to 21 days prior to Cycle 1, Day 1. Prior to enrollment, diagnosis 
of NKTCL must be verified by the sponsor from the local pathology report. Before enrollment to 
the study, sites will be required to provide archival or fresh tumor samples for assessment of 
CD38 expression. Fresh biopsy samples are preferred if available. Otherwise, archived 
formalin-fixed, paraffin-embedded (FFPE) blocks/slides are also acceptable. 
The Treatment Phase will extend from Cycle 1, Day 1 until study drug discontinuation. After the 
first dose, disease evaluations will occur every 8 weeks for the first 6 months and thereafter,
every 16 weeks. Subjects will be monitored for safety and assessed for PK and immunogenicity 
according to the scheduled assessments in the Time and Events (T&E) schedules (T&E Schedule
and T&E Schedule: PK and Immunogenicity). Subjects will be treated until PD, unacceptable 
toxicity, or other reasons as listed in the protocol. End-of-Treatment (EoT) Visit is to occur 
within 30 days (+7-day window) after the last dose of all study treatments.
The Follow-up Phase will begin once a subject discontinues study treatment, and will continue 
until death, lost to follow up, consent withdrawal for study participation, or end of study, 
whichever occurs first. The follow-up schedule is presented in the T&E Schedule.
The study is a Simon’s 2-stage design with an interim analysis conducted after approximately 
15 subjects have received at least one dose of study drug and had at least one post-baseline 
disease evaluation. The purpose of the interim analysis is to evaluate efficacy and safety data in 
stage 1 and facilitate the early preparation for the next step of development. The totality of 
efficacy (ORR), safety, and biomarker data will be analyzed at the interim. Enrollment may be 
put on hold pending the decision of interim analysis unless the decision is clear based on 
available data before the interim analysis. The futility criteria are defined in Section 10.9. The 
study may be terminated if the futility criteria are met and supported by totality of data. In 
addition, at interim, the association between daratumumab activity and CD38 expression level 
will be explored. A population enrichment strategy may be applied after the interim analysis if 
such a strategy is supported by emerging data. The primary analysis will be performed at 
approximately 6 months after the last subject receives the first dose of daratumumab.
The end of study is defined as approximately 9 months after the last subject receives the first 
dose of daratumumab. After study completion, the sponsor will ensure that subjects who are 
currently on treatment and receiving benefit, will continue to receive daratumumab until PD, 
unacceptable toxicity or other. 
Assessment of tumor response and PD will be based on BICR in accordance with the Revised 
Criteria for Response Assessment - LUGANO Classification.12
Subjects will be monitored for safety during the Screening and Treatment Phases and up to 
30 days after the last dose of study drug. Adverse events (AE), including laboratory AEs, will be 
graded and summarized using National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE), version 4.03. Measures to prevent infusion-related reactions will 
include preinfusion medication with methylprednisolone, acetaminophen (or paracetamol), and 
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an antihistamine before each daratumumab infusion. Blood samples will be drawn for 
assessment of PK, immunogenicity, and biomarkers.
Additional patients (ie, approximately 35 patients) may be enrolled in an expansion phase to 
confirm the clinical response rate of daratumumab if supported by emerging data.
3.2.
Study Design Rationale
Daratumumab Dose Rationale
An established dose regimen of 16 mg/kg (weekly for 8 weeks, then every 2 weeks for 16 weeks, 
then every 4 weeks thereafter), administered via IV until PD or unacceptable toxicity, was 
selected based on an acceptable safety profile, clinical activity, and pharmacokinetics consistent 
with saturation of the target (CD38). 
Rationale for Pharmacokinetics and Immunogenicity
Data obtained from the current study will provide information about the pharmacokinetic profile 
of daratumumab in subjects with NKTCL.
Immunogenicity to daratumumab is possible. Therefore, samples to determine the presence of 
antibodies to daratumumab (immunogenicity) will be collected from all subjects. The 
pharmacokinetic assessments collected at all immunogenicity time points will be used to 
interpret the immunogenicity data. The information from these samples and data from other 
studies will be used to determine the immunogenicity of daratumumab.
Biomarker Collection
Biomarkers collected in this study will evaluate tumor CD38 levels as a predictive marker of
response. Exploratory analysis of Complement Inhibitory Proteins (CIPs, such as CD59, CD55 
and CD46) expression from previous studies has indicated that high expression of CIPs might be 
predictive of lower or lack of response to daratumumab. Therefore, samples collected in this 
study might evaluate both CD38 and CIPs expression levels by immunohistochemistry (IHC) or 
immunofluorescent staining. CD38 IHC is a mandatory test, and CIPs staining will be performed 
whenever samples are available. Specific immune cell subtypes (NK cells, T cells, and B cells)
and their subtypes will be analyzed to evaluate the effects of daratumumab on immune cells. 
This will provide information on potential prognostic markers in NKTCL to better understand 
this disease, as well as potential markers that predict response to daratumumab.
4.
SUBJECT POPULATION
Adult subjects age 18 and older with extranodal NK/T-cell lymphoma, nasal type, are eligible for 
the study.
Screening for eligible subjects will be performed within 21 days before Cycle 1, Day 1, before 
administration of the study drug.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
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investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed.
For a discussion of the statistical considerations of subject selection, refer to Section 10.2, 
Sample Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
At least 18 years of age
2.
Documented as histologically confirmed extranodal NK/T-cell lymphoma, nasal type
according to the World Health Organization (WHO) classification,10,13,20 and the 
pathology report will be verified by the Sponsor.
3.
Criterion modified per Amendment 1:
3.1
Failed (relapsed or refractory after achieving complete or partial remission) at least 1
line of chemotherapy, and who, according to treating physician or investigator, is not 
candidate to receive other treatment modalities.
4.
Criterion modified per Amendment 1:
4.1
At least 1 measurable site of disease (see Section 8.2.1), which should be positive 
18F-fluorodeoxyglucose (FDG) uptake in nodal or extranodal sites on positron 
emission tomography (PET) scan. 
5.
ECOG performance status score of 0, 1 or 2. (refer Attachment 1) and life expectancy 
≥ 3 months.
6.
Subject must have pretreatment clinical laboratory values meeting the following 
criteria during the Screening Phase:
a.
hemoglobin ≥7.5 g/dL (≥4.65 mmol/L) without transfusion support 
within 7 days;
b. absolute neutrophil count (ANC) ≥0.75x109/L (ie, ≥750/µL) without 
growth factor support within 7 days;
c.
platelet count ≥50x109/L without transfusion support within 7 days;
d. aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN);
e.
alanine aminotransferase (ALT) ≤2.5 x ULN;
f.
total bilirubin ≤1.5 x ULN, except in subjects with congenital 
bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin 
≤1.5 x ULN required);
g. calculated creatinine clearance of ≥30 mL/min (refer Attachment 5: 
Calculation of Creatinine Clearance using Cockcroft-Gault formula);
7.
Criterion modified per Amendment 1:
7.1
Women of childbearing potential must commit to either abstain continuously from 
heterosexual sexual intercourse or to use 2 methods of reliable birth control 
simultaneously. This includes one highly effective form of contraception (tubal 
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ligation, intrauterine device, hormonal [birth control pills, injections, hormonal 
patches, vaginal rings or implants] or partner's vasectomy) and one additional 
effective contraceptive method (male latex or synthetic condom, diaphragm, or 
cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable 
contraception is indicated even where there has been a history of infertility, unless due 
to hysterectomy.
8.
Criterion modified per Amendment 1:
8.1 
A man who is sexually active with a woman of childbearing potential and has not had 
a vasectomy must agree to use a barrier method of birth control eg, either condom 
with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, 
and all men must also not donate sperm during the study and for 3 months after
receiving the final dose of study drug.
9.
Criterion removed per Amendment 1
10.
Criterion removed per Amendment 1
11.
Criterion removed per Amendment 1
12.
A woman of childbearing potential must have a negative serum/urine pregnancy test 
(highly sensitive serum [-human chorionic gonadotropin]) within 14 days prior to the 
first study agent administration.
13.
Subject must be willing and able to adhere to the prohibitions and restrictions 
specified in this protocol, as referenced in the ICF
14.
Each subject must sign an ICF indicating that he or she understands the purpose of 
and procedures required for the study and is willing to participate in the study.
Note: Each subject must sign a separate informed consent form if he or she agrees to provide 
optional samples for research. If subject agreed to provide optional samples for research study, 
subject should follow the sample collection schedule that is listed in the optional consent form.
Refusal to give consent for the optional research samples does not exclude a subject from 
participation in the study.
4.2.
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from participating in the study:
1.
Criterion modified per Amendment 1:
1.1
No fresh or archived FFPE tumor samples for retrospective biomarker determination
2.
Received daratumumab or other anti-CD38 therapies previously
3.
Chemotherapy or radiotherapy
within 3
weeks before the first study agent 
administration, or corticosteroids as part of disease treatment within 2 weeks before the 
first study agent administration, with the exception of an emergency use of 
corticosteroids such as in the management of severe lymphoma symptoms or life-
threatening allergic reaction.
4.
Previous allogenic stem cell transplant; or autologous stem cell transplant within 
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12 weeks before the first administration of the study drug
5.
History of active malignancy (other than NKTCL) within 2 years before the first study 
drug administration (exceptions are adequately treated squamous and basal cell 
carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive 
lesion that in the opinion of the investigator, with concurrence with the sponsor's study 
responsible physician, is considered cured with minimal risk of recurrence within 2 
years)
6.
Clinical symptoms of central nervous system (CNS) involvement
7.
Subject has either of the following:
a.
Known chronic obstructive pulmonary disease (COPD) with a Forced 
Expiratory Volume in 1 second (FEV1) <50% of predicted normal. Note that 
FEV1 testing is required for patients suspected of having COPD and subjects 
must be excluded if FEV1 <50% of predicted
b.
Known moderate or severe persistent asthma within the past 2 years (refer
Attachment 4: National Heart, Lung, and Blood Institute (NHLBI) table of 
asthma severity), or uncontrolled asthma of any classification. (Note: subjects 
who currently have controlled intermittent asthma or controlled mild persistent 
asthma are allowed to participate in the study)
8
8.1
Criterion modified per Amendment 4:
Seropositive for hepatitis B or hepatitis C. 
Note: Seropositive for hepatitis B (defined by a positive test for hepatitis B surface 
antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg 
negative but positive for antibodies to hepatitis B core antigen [Anti-HBc] and/or 
antibodies to hepatitis B surface antigen [Anti-HBs]) must be screened using real-time 
polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. 
Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic 
findings suggestive of HBV vaccination (Anti-HBs positivity as the only serologic 
marker) AND a known history of prior HBV vaccination, do not need to be tested for 
HBV DNA by PCR.
If Hepatitis C antibody is positive, RNA PCR needs to be performed and confirmed 
negative prior to the first study agent administration.
9.
Seropositive for human immunodeficiency virus (HIV)
10.
Unresolved or unstable, serious toxicity from prior administration of another
investigational drug and/or of prior cancer treatment.
11.
Subject has any concurrent medical condition or psychiatric condition or disease (eg, 
active infection, diabetes mellitus, acute diffuse infiltrative pulmonary disease) that is 
likely to interfere with study procedures or results, or that in the opinion of the 
investigator would constitute a hazard for participating in this study.
12.
Criterion modified per Amendment 1:
12.1
Subject has clinically significant cardiac disease, including:
a.
Myocardial infarction within 6 months before the first study agent 
administration, or unstable or uncontrolled disease/condition related to or 
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affecting cardiac function (eg, unstable angina, congestive heart failure, New 
York Heart Association Class III-IV)
b.
Uncontrolled cardiac arrhythmia (Common Terminology Criteria for Adverse 
Events [CTCAE] [most recent version] Grade 3 or higher) or clinically 
significant ECG abnormalities
c.
Screening 12-lead ECG showing a baseline QT interval as corrected (QTc) 
>470 msec.
13.
Known allergies, hypersensitivity, corticosteroids, monoclonal antibodies or human 
proteins, or their excipients (refer to respective package inserts or IB), or known 
sensitivity to mammalian-derived products18
14.
Known or suspected of not being able to comply with the study protocol (eg, because of 
alcoholism, drug dependency, or psychological disorder) or the subject has any 
condition for which, in the opinion of the investigator, participation would not be in the 
best interest of the subject (eg, compromise their well-being) or that could prevent, 
limit, or confound the protocol-specified assessments
15.
Invasive investigational medical device within 4 weeks before the screening period or is 
currently enrolled in an interventional investigational study
16.
Vaccination with live attenuated vaccines within 4 weeks of first study agent 
administration.
17.
Pregnant or lactating
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study drug is given such 
that he or she no longer meets all eligibility criteria, then the subject should be excluded from 
participation in the study. Section 8.1.2, Screening Phase, describes options for retesting. 
Section 16.4, Source Documentation, describes the required documentation to support meeting 
the enrollment criteria.
4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:

Subjects agree to follow the contraceptive requirements as noted in the inclusion criteria.
5.
DOSAGE AND ADMINISTRATION
Daratumumab is to be administered as described in Figure 2. Each cycle is of 28 days. The first 
visit of a cycle should be 4 weeks after the start of the previous cycle. The start of each cycle 
may occur ±3 days of the scheduled day in order to accommodate the schedule of the site or 
subject. The start of each cycle should be scheduled relative to Cycle 1 Day 1 and should not 
change if within-cycle visits have shifted within the allowed window. In Cycles 1 through 6, 
daratumumab infusions may be given within ± 1 day of the scheduled day in order to 
accommodate the schedule of the site or subject.
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A schematic of study treatment administration is provided in Figure 2.
Figure 2: 
Schematic Overview Study Treatment Administration
5.1.
Daratumumab preparation
The infusion solution will be prepared on the day of the planned infusion. Detailed instructions
for preparation and administration of daratumumab will be supplied in the Site Investigational
Product Procedures Manual (SIPPM) or equivalent document.
5.2.
Daratumumab Administration
Daratumumab will be administered as an IV infusion. Each subject’s dose will be calculated 
based on the subject’s weight at Cycle 1 Day 1 rounded to the nearest kilogram. There is no cap 
on the absolute dose allowed, as long as the dose does not exceed 16 mg/kg. The dose of 
daratumumab will remain constant throughout the study, unless the subject’s weight changes 
more than 10% from Cycle 1 Day 1. Subjects will receive preinfusion medications and 
postinfusion medications as outlined in Section 5.3.
The dilution volumes, initial infusion rates, and increment for the first, second, and subsequent 
doses are provided in Table 2. The first infusion, with a volume of 1,000 mL, takes 
approximately 8 hours; the second and subsequent infusions, with volumes of 500 mL, take 
approximately 4 hours. The maximum infusion rate for all infusions is 200 mL/hour. The 
sponsor may modify the infusion rates or the preinfusion medications prospectively based upon 
the information collected to date from this and other studies. Additional details for administration 
times and rates, as well as preinfusion medications, will be provided in the administration 
guidelines (study site investigational product and procedures manual).
Table 2:
Daratumumab Infusion Rates
Dilution 
Volume
Initial Infusion 
Rate (first hour)
Incremental Increases
in Infusion Rate
Maximum 
Infusion Rate
First infusion
1,000 mL
50 mL/hour
50 mL/hour 
every hour
200 mL/hour
Second infusiona
500 mL
50 mL/hour
50 mL/hour 
every hour
200 mL/hour
Subsequent infusionsb
500 mL
100 mL/hour
50 mL/hour 
every hour
200 mL/hour
a
Modified rates should only be used if the first infusion of daratumumab was well-tolerated as defined by an absence of 
> Grade 1 infusion-related reactions during the first 3 hours.
b
Modified rates should only be used if the first 2 infusions of daratumumab were well-tolerated as defined by an absence of 
> Grade 1 infusion-related reactions during a final infusion rate of ≥100 mL/hr.
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As noted in the T&E Schedule, vital signs should be monitored extensively on Cycle 1 Day 1 
before, during, and after the first infusion of daratumumab. For all other infusions, vital signs 
should be measured before the start of the infusion and at the end of the infusion. If a subject 
experiences any significant medical event, then the investigator should assess whether the
subject should stay overnight for observation. If the subject has not experienced a significant 
medical event but is hospitalized overnight only for observation, then the hospitalization should 
not be reported as an SAE. In instances of daratumumab-related toxicity management, schedule 
adjustments for daratumumab administration are outlined in Table 3.
5.3.
Guidelines for Prevention of Infusion Reactions
5.3.1.
Preinfusion Medication
In an effort to prevent infusion related reactions, all subject will receive the following 
medications 1 to 3 hours prior to each study drug administration (1 hour prior to study drug 
administration is preferred):

An antipyretic: Paracetamol (acetaminophen) 650-1,000 mg IV or per oral (PO)

An antihistamine: diphenhydramine 25-50 mg IV or PO, or equivalent but avoid IV use of 
promethazine (see Attachment 3 for Family of antihistamine medications that may be used)

A corticosteroid: Methylprednisolone 100 mg IV for the first 2 infusions, 60 mg IV for all 
subsequent infusions, administered approximately 1 hour prior to daratumumab infusion. If 
methylprednisolone is not available, an equivalent intermediate-acting or a long-acting 
corticosteroid may substitute (refer Attachment 2 for Conversion Table). 

Leukotriene inhibitor (optional) on Cycle 1 Day 1: montelukast 10 mg PO, or equivalent and 
can be administered up to 24 hours before infusion as per investigator discretion.
If necessary, all PO preinfusion medications may be administered outside of the clinic on the day 
of the infusion, provided they are taken within 1-3 hours before the infusion. If the preinfusion
medication is provided via IV, it should be administrated within 1-3 hours prior to daratumumab 
infusion.
5.3.2.
Postinfusion Medication
For the prevention of delayed IRRs, all subjects will receive long- or intermediate-acting 
corticosteroid PO (20 mg methylprednisolone or equivalent in accordance with local standards) 
on the 2 days following the first 3 daratumumab infusions (beginning the day after the infusion
date). In the absence of infusion-related AEs after the first 3 infusions, postinfusion 
corticosteroids should be administered per investigator discretion.
For subjects with higher risk of respiratory complications (ie, subjects who have COPD with an
FEV1 <80% at screening or developed FEV1 <80% during the study without any medical 
history or subjects with mild asthma), the following postinfusion medications are recommended:

Antihistamine (diphenhydramine or equivalent) on the 2 days following all daratumumab 
infusions (beginning the day after the infusion)

Leukotriene inhibitor (montelukast or equivalent)
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
Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol

Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2 adrenergic 
receptor agonists for subjects with asthma; long-acting bronchodilators such as tiotropium or 
salmeterol ± inhaled corticosteroids for subjects with COPD).
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights after a
daratumumab administration. If subjects are hospitalized, then their FEV1 should be documented 
before discharge. If these subjects are not hospitalized, then a follow-up telephone call should be 
made to monitor their condition within 48 hours after all infusions. If the subject has not 
experienced a significant medical event but is hospitalized overnight only for observation, then 
the hospitalization should not be reported as an
SAE. Investigators may prescribe 
bronchodilators, H1-antihistamines, and corticosteroids that are deemed necessary to provide 
adequate supportive care in the event a bronchospasm occurs after subjects are released from the 
hospital/clinic. If an at-risk subject is taking postinfusion medications and experiences no major 
IRRs, then these medications may be stopped after 4 full doses, at the investigator’s discretion.
Any postinfusion medication will be administered after the infusion has completed.
5.3.3.
Management of Infusion-Related Reactions
Subjects should be carefully observed during daratumumab infusions. Trained study staff at the 
clinic should be prepared to intervene in case of any IRRs occurring, and resources necessary for 
resuscitation (eg, agents such as epinephrine and aerosolized bronchodilator, also medical 
equipment such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be available
at the bedside. Attention to staffing should be considered when multiple subjects will be dosed at 
the same time.
If an IRR develops, then daratumumab administration should be temporarily interrupted. Please 
see the investigational product preparation instructions (IPPI) for further details. Subjects who 
experience AEs during daratumumab administration must be treated for their symptoms. 
Subjects should be treated with acetaminophen, antihistamine, or corticosteroids, as needed. 
Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea, subjects may 
require antihistamines, oxygen, corticosteroids, or bronchodilators. For hypotension, subjects 
may require vasopressors. In the event of a life-threatening IRR (which may include pulmonary 
or cardiac events) or anaphylactic reaction, daratumumab should be discontinued and no 
additional daratumumab should be administered to the subject.
5.3.3.1.
Infusion-Related Events of Grade 1 or Grade 2 (mild to moderate)
If the investigator assesses a Grade 1-2 IRR adverse event to be related to administration of study 
drug, then the daratumumab administration should be paused. When the subject's condition is 
stable, daratumumab administration may be restarted at the investigator's discretion. 
If the subject experiences a Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher 
event of bronchospasm that does not respond to systemic therapy and does not resolve within 
6 hours from onset, then the subject must be withdrawn from daratumumab treatment.
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5.3.3.2.
Infusion-Related Reactions of Grade 3 (severe) or Higher
For IRR adverse events (other than laryngeal edema or bronchospasm) that are Grade 3, the 
daratumumab administration must be stopped and the subject must be observed carefully until 
resolution of the adverse event or until the intensity of the event decreases to Grade 1, at which 
point the daratumumab administration may be restarted at the investigator’s discretion. If the 
intensity of the adverse event returns to Grade 3 after restart of the daratumumab administration, 
then the subject must be withdrawn from daratumumab treatment.
For IRR adverse events that are Grade 4, the daratumumab administration must be stopped and 
the subject withdrawn from daratumumab treatment.
5.3.3.3.
Recurrent Infusion-Related Reactions 
If a Grade 3 IRR (or Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher event of 
bronchospasm) recurs during or within 24 hours after a subsequent daratumumab administration, 
the daratumumab treatment must be discontinued. 
6.
TREATMENT COMPLIANCE
6.1.
Dose Delays and Dose Modification
Dose modification of daratumumab is not permitted, but dose delay is the primary method for 
managing daratumumab-related toxicities.
6.1.1.
Daratumumab-Related Toxicity Management
Refer to Section 5.3 for details on management of IRRs. The study treatment must be held if any 
of the following criteria below are met, to allow for recovery from toxicity, regardless of 
relationship to daratumumab. The criteria for a dose delay are:
1.
Grade 4 hematologic toxicity, except for grade 4 lymphopenia
2.
Grade 3 thrombocytopenia with bleeding
3.
Febrile neutropenia
4.
Neutropenia with infection, of any grade
5.
Grade 3 or higher non-hematologic toxicities with the following exceptions:
a.
Grade 3 nausea that responds to antiemetic treatment within 7 days
b.
Grade 3 vomiting that responds to antiemetic treatment within 7 days
c.
Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days
d.
Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab
e.
Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab.
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Administration of daratumumab may be restarted upon recovery from toxicity to Grade 2 or 
better or baseline, with the exception that Grade 2 laryngeal edema or Grade 2 bronchospasm 
must be fully recovered.
If a daratumumab administration does not commence within the prespecified window (Table 3) 
of the scheduled administration date, then the dose will be considered a missed dose. 
Administration may resume at the next planned dosing date. A missed dose will not be made up.
Table 3: 
Daratumumab-Related Toxicity Management
Cycles
Frequency
Dose Held
Dosing Restart*
1 and 2
Weekly
(Q1W)
>3 days
next planned weekly dosing date
3 to 6
Biweekly
(Q2W)
>7 days
next planned biweekly dosing date
7+
Every 4 weeks
(Q4W)
>14 days
next planned every 4 weeks dosing date
*Dosing on Day 1 of a cycle must not be skipped.
Cycles may be delayed up to 4 weeks (Cycle 1 to Cycle 6) or up to 6 weeks (Cycle 7 and 
beyond). If a dose is delayed on Day 1 of a cycle, then the dates of all the subsequent doses 
should be adjusted accordingly to maintain the 28-day cycle duration. However, if a within-cycle 
dose is delayed, then the dates of the subsequent doses should not be adjusted.
Any AE deemed to be related to daratumumab that requires a dose hold of more than 4 weeks 
(Cycle 1 to Cycle 6) or more than 6 weeks (Cycle 7 and beyond) will result in permanent 
discontinuation of daratumumab. If a dose delay occurs, then PK and pharmacodynamic
assessments should be performed on the actual administration day of daratumumab, not on the 
original scheduled administration day.
6.1.2.
Daratumumab Interruption or Missed Doses
A daratumumab dose that is held for more than the permitted time (Table 3) from the 
per-protocol administration date for any reason other than toxicities suspected to be related to 
daratumumab should be brought to the attention of the sponsor at the earliest possible time. 
Subjects whose dose was delayed for more than 4 weeks (Cycle 1 to Cycle 6) or 6 weeks 
(Cycle 7 and beyond) should have study treatment discontinued, unless, upon consultation with 
the sponsor and the review of safety and efficacy, continuation is agreed upon.
7.
CONCOMITANT THERAPY
All prior oncologic therapies, including those since diagnosis, must be recorded at screening.
Throughout the study, investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care except for those listed in Section 7.3. The 
sponsor must be notified in advance (or as soon as possible thereafter) of any instances in which 
prohibited therapies are administered.
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Routine systemic use of concomitant medications will be collected in the electronic case report 
form (eCRF) and recorded in the source documents beginning with signing of the ICF to 30 days 
after the last dose of the last study treatment or until the start of subsequent anticancer treatment, 
if earlier. Concomitant medications to manage AEs and SAEs will be recorded as per 
Section 7.1.
Modification of an effective preexisting therapy should not be made for the explicit purpose of 
entering a subject into the study.
7.1.
Recommended Therapies
In addition to the mandatory preinfusion medications outlined in Section 5.3.1, the following 
therapies are recommended.
7.1.1.
Prophylaxis for Pneumocystis Carinii
Pneumocystis carinii pneumonia (PCP) prophylaxis should be considered, as per institutional 
guidelines.
7.1.2.
Prophylaxis for Herpes Zoster Reactivation
Prophylaxis for herpes zoster reactivation is recommended during the Treatment Phase as per 
institutional guidelines and continue for 3 months following treatment. Initiate antiviral 
prophylaxis to prevent herpes zoster reactivation within 1 week after starting study treatment and 
continue for 3 months following study treatment. Acceptable antiviral therapy includes acyclovir 
(eg 400 mg given orally 3 times a day, or 800 mg given orally 2 times a day or per institutional 
standards), famcyclovir (eg, 125 mg given orally, twice a day or per institutional standards), or 
valacyclovir (eg, 500 mg given orally, twice a day or per institutional standards), initiated within 
1 week after the start of study drug.
7.1.3.
Prevention of Steroid-Induced Gastritis
Steroids may induce gastritis. Medications to prevent gastritis are permitted per institutional 
guidelines, for example proton pump inhibitors (omeprazole or equivalent) or sucralfate, or H2 
blockers (ranitidine or equivalent).
7.1.4.
Management of Hepatitis B Virus Reactivation
Primary antiviral prophylaxis is permitted as per local standard of care. Per protocol, HBV DNA 
testing by PCR is mandatory for subjects at risk for HBV reactivation (see Section 8.6).
For subjects who are diagnosed with HBV reactivation while on treatment, study treatment 
should be interrupted until the infection is adequately controlled. If the benefits outweigh the 
risks, study treatment may be resumed with concomitant antiviral prophylaxis as per local 
standard of care. Consult a liver disease specialist as clinically indicated.
7.2.
Permitted Therapies
Subjects are to receive full supportive care during the study. The following medications and 
supportive therapies are examples of support therapies that may be used during the study:
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
Antivirals

Colony stimulating factors and erythropoietin except during Cycle 1, and transfusion of 
platelets and red blood cells.

Loperamide is recommended for the treatment of diarrhea, starting at the time of the first 
watery stool. The loperamide dose and regimen is according to institutional guidelines.
Prophylactic loperamide is not recommended.

It is important to prevent constipation (eg, adequate hydration, high-fiber diet, and stool 
softeners if needed)

Prophylactic antiemetics, with the exception of corticosteroids.
7.3.
Prohibited Therapies
Use of the treatments listed below is prohibited during the study:

Prophylactic use of hematopoietic growth factors during Cycle 1

Other agents that target CD38

Concurrent radiation therapy is prohibited while on study.

Administration of commercially available agents with activity against or under investigation 
for NKTCL, including systemic corticosteroids (≥20 mg/day of prednisone or its equivalent 
per day for more than 7 days during study, unless reviewed/approved by the study 
responsible physician) (other than those given for IRRs as described in Section 5.3.2) is 
prohibited.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
8.
STUDY EVALUATIONS
8.1.
Study Procedures
8.1.1.
Overview
The T&E Schedule summarizes the frequency and timing of assessments of safety and efficacy, 
PK, immunogenicity, and biomarker, measurements applicable to this study.
Blood collections for PK assessments should be kept as close to the specified time as possible. 
Other measurements may be done earlier than specified time points if needed. Actual dates and 
times of assessments will be recorded in the source documentation. Additional serum or urine 
pregnancy tests may be performed, as determined necessary by the investigator or required by 
local regulation, to establish the absence of pregnancy at any time during the subject's 
participation in the study.
The number of blood samples and volume of blood that will be required from each subject for 
the various study procedures is outlined in the Laboratory Manual. The number of samples and 
the blood volume will vary depending on the number of cycles of the study drug that the subject 
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receives as well as which part the subject is enrolled. This includes laboratory assessments 
associated with safety, efficacy, and pharmacokinetic evaluations, as well as scientific research 
samples. Unscheduled blood samples may be required for safety issues of individual subjects.
The total blood volume to be collected from a subject who completed a total of Cycle 7 is 
approximately 
240.5 mL 
(78
mL 
for 
safety, 
34.5 mL 
for 
efficacy, 
80 mL 
for
PK/immunogenicity, and 48 mL for biomarker research). If a subject agrees to participate in the 
exploratory genetic biomarker research, about 2 mL of additional blood samples will be collected
prior to daratumumab infusion at Cycle 1 Day 1.
Table 4: 
Volume of Blood to be Collected From Each Subject (Based on assumption for a female subject 
completing a total of Cycle 7)
Type of Sample
Volume per 
Sample (mL)
No. of Samples 
per Subject
Approximate 
Total Volume of 
Blood (mL)a
Safetyb (including screening and posttreatment 
assessments
- Hematology
2
19
38
- Serum chemistryc
3
9
27
Serology (hepatitis B and C)e
3
1
3
Serum -hCG pregnancy tests
5
2
10
Efficacy
Circulating plasma EBV‑DNA quantification 
4
8
32
β2-microglobulin
2.5
1
2.5
Pharmacokinetic/Immunogenicity samples
5
16
80
Pharmacodynamic/Biomarker samples
12
4
48
Approximate Totald
36.5
60
240.5
a. Calculated as number of samples multiplied by amount of blood per sample.
b. Safety evaluations will be conducted at local laboratory and the blood volume may vary among different local
laboratories.
c. Serum chemistry includes serology (hepatitis B and C) and serum -hCG pregnancy tests.
d. Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples.
e. For subjects with serologic evidence of resolved HBV infection (ie, positive Anti-HBs or positive Anti-HBc) at 
Screening, more samples may need to be collected to perform HBV DNA testing during the treatment and 
during follow up. Refer to Section 8.6.
Note: An indwelling intravenous cannula may be used for blood sample collection. [If a mandarin (obturator) is 
used, blood loss due to discard is not expected.]
From Cycle 8 onwards until PD, 2 mL blood samples will be taken for Hematology, 3 mL for 
clinical chemistry, and 4 mL for Circulating plasma EBV‑DNA quantification on Day 1 of each 
cycle; 5 mL blood samples will be taken for PK on Day 1 every two cycles from Cycle 7, plus 
5 mL PK and immunogenicity sample on Day 1 of Cycle 12.
8.1.2.
Screening Phase
All subjects must sign an ICF prior to the conduct of any study-related procedures in the 
screening phase. The Screening Phase begins when the first screening assessment is conducted 
(that was not performed as part of the subject’s standard of care, typically signing of the ICF). 
During this phase, eligibility criteria will be reviewed as specified in the T&E Schedule. 
Screening procedures will be performed within 21 days before first dose.
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Pathological confirmation of Diagnosis
Diagnosis of NKTCL is performed by the local hospital and the pathology report will be verified 
by the sponsor. This diagnosis report must include immunophenotype of NK/T‒cells. Subject 
must be documented as histologically confirmed extranodal NKTCL, nasal type according to the 
WHO classification.10,12,20 The report containing this information must be sent to sponsor for 
confirmation of the diagnosis prior to enrollment.
Determination of CD38 expression
Before enrollment to the study, subjects will be required to provide tumor samples (fresh biopsy 
is preferred. When not available, archived FFPE samples are acceptable) for assessment of CD38 
expression. An investigational IHC assay will be used by the central laboratory to determine 
CD38 expression levels. The role of CD38 expression in predicting tumor response to the 
treatment of daratumumab will be analyzed retrospectively in the study. Only subjects who agree 
to provide the required tumor samples and that the sample are available are considered for 
participation in the study. 
8.1.3.
Treatment Phase
The Treatment Phase will begin at first intake of study drug and will continue until study drug 
discontinuation due to PD, consent withdrawal or unacceptable toxicity. Details of the 
procedures performed during the Treatment Phase are outlined in the T&E Schedule. A window 
of ±3 days is allowed for visits to the clinic. The start of each cycle should be scheduled relative 
to Cycle 1 Day 1 and should not change if within-cycle visits (eg Cycle 1 Day 15; Cycle 2 Day 
22) have shifted within the allowed window.
Subjects will be closely monitored for AEs, laboratory abnormalities, and clinical response. 
Clinical evaluations and laboratory studies may be repeated more frequently, if clinically 
indicated. If PD is diagnosed, then the subject will discontinue study treatment, complete the 
EoT Visit, and enter the Follow-up Phase.
End-of-Treatment
Unless a subject withdraws consent for study participation or is lost to follow up, an EoT Visit is 
to occur within 30 days (+7 days’ window) after the last dose of all study treatments. Every 
effort should be made to conduct the EoT Visit before the subject starts subsequent treatment eg, 
anticancer therapy. If a subject is unable to return to the site for the EoT Visit, then the subject 
should be contacted to collect information on AEs and concomitant medications that occur up to 
30 days after the last dose of study treatment.
Subjects will be discontinued from study treatment if they have objective radiological PD based 
on real time BICR according to LUGANO Classification.12 Following centrally confirmed
radiological PD, site will document the PD by completing and faxing a PD form to the sponsor 
and the study responsible physician will provide written confirmation based on the central 
confirmed radiological PD that study treatment may be discontinued and recorded in interactive 
web response system (IWRS) before the subject can enter the Follow-up Phase.
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For subjects who have PD as evidenced by unambiguous clinical information (eg. pathologically 
demonstrated as PD) without confirmation by BICR, they may be discontinued from study 
treatment at the investigator’s discretion. Before such subjects discontinue study treatment, sites 
will document PD by completing and faxing a PD form to the sponsor as soon as possible and 
within 48 hours of PD assessment. The study responsible physician will provide written 
confirmation that treatment should be discontinued. After written confirmation from the sponsor, 
study treatment may be discontinued and recorded in IWRS before the subject can enter the 
Follow-up Phase.
Subjects should be discontinued from study treatment if they have objective radiological PD by 
BICR, however, subjects may be allowed to continue study treatment if PD was documented 
only by local evaluation and the investigator believes, and sponsor study physician concurs, that 
the subject could continue to receive benefit and will not experience serious toxicity, and there is 
no available better alternative treatment that could benefit the subject. These subjects will 
continue study procedure as per T&E Schedule. If subsequent PD is confirmed either by 
centrally diagnosis or clinical judgement per investigator discretion, the subject must be 
discontinued from the study treatment, a subsequent PD form is required for study physician to 
provide the written confirmation for subject discontinued the study treatment. 
8.1.4.
Posttreatment Phase (Follow-Up)
The Follow-up Phase will begin once a subject discontinues study treatment, the date of 
discontinuation of study treatment is based on the study physician’s written confirmation date in 
the PD form. Subjects who discontinue before PD (for other reasons such as an AE) must 
continue to have their regularly scheduled scans according to the T&E Schedule until centrally 
confirmed PD, death, the start of a new anticancer therapy, withdrawal of consent, lost to 
follow-up, or the end of the study. After PD is centrally evidenced with study physician’s 
confirmation of PD form, follow-up will occur at least every 8 weeks (±2 weeks). Subsequent 
anticancer therapy, second primary malignancies, and survival status will be recorded.
If the follow-up information is obtained via telephone contact, written documentation of the 
communication must be available for review in the source documents. If the subject has died, the 
date and cause of death will be collected and documented in the eCRF. 
Investigators may recontact the subject to obtain long-term follow-up information regarding the 
subject's safety or survival status as noted in the informed consent form (refer to Section 15.2.3, 
Informed Consent).
8.2.
Efficacy Evaluations
Disease evaluations will be performed at Screening, every 8 weeks (±7 days) for the first 
6 months and thereafter, every 16 weeks (±7 days) until PD, withdrawal of consent from study 
participation, or the end of study.
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Radiological and PET-CT scans should be performed and collected according to instructions 
from the independent imaging laboratory. A BICR will be performed to review all the imaging 
data and clinical information per pre-defined independent central review charter.
The central reviewers will assess disease status based on the Revised Criteria for Response 
Assessment: LUGANO classification, provided in Attachment 6.12 Similar methodology should 
be used for disease assessment at screening and throughout the course of the study. The 
treatment discontinuation due to PD should be based upon the real time reading results 
conducted by the central readers. On the basis of clinical information, if PD is confirmed, then 
for all such subjects, as soon as PD is confirmed by local assessment, the sponsor should be 
informed immediately.
In order to maximally reduce potential bias between different readers, rigorous methodology will 
be employed and thus, ensure robustness of the primary endpoint assessment of ORR which is 
based on BICR. All radiological scans and collected clinical information will be sent to a sponsor 
appointed Clinical Research Organization (CRO) for a real time BICR. All treatment decisions 
will be based on such timely central review result. Subjects who are determined to have 
progressed according to LUGANO classification by the investigator will have scans centrally 
reviewed for confirmation of objective disease progression. If PD is not confirmed after central 
review, daratumumab treatment should be continued until centrally documented PD. This 
procedure may not be followed if the clinical information of subject (eg, Pathologically 
demonstrated PD) is sufficient enough to demonstrate PD, for such cases, PD confirmation from 
sponsor study physician is also required.
Definition of Measurable Disease, Assessable Disease, Target Lesion, and Non-Target Lesion
Measurable sites of disease are defined as lymph nodes, lymph node masses, or extranodal sites 
of lymphoma. A measurable node must have a longest diameter (LDi) greater than 1.5 cm. A 
measurable extranodal lesion should be greater than 1.0 cm in any axis. The measurable site of 
disease should be clearly measurable in 2 perpendicular dimensions (LDi and short diameter
[SDI]). Measurement must be determined by local imaging evaluation. All other sites of disease 
are considered assessable, but not measurable. Assessable disease includes objective evidence of 
disease that is identified by radiological imaging, physical examination, or other procedures as
necessary, but is not measurable as defined above. Examples of assessable disease include bone 
lesions; mucosal lesions in the gastrointestinal tract; effusions; pleural, peritoneal, or bowel wall 
thickening; disease limited to bone marrow; and groups of lymph nodes that are not measurable 
but are thought to represent lymphoma. Note: Lesions to be used as measurable disease for the 
purpose of response assessment must either a) not reside in a field that has been subjected to 
prior radiotherapy, or b) have demonstrated clear evidence of radiographic progression since the 
completion of prior radiotherapy and prior to study enrollment.
Up to 6 measurable sites of disease with FDG uptake positive (5-point scale 4 or 5) might be 
identified as target lesions and will be followed during the course of study treatment. Eligible 
subjects must have at least 1 measurable target lesion. Target lesions should be chosen such that 
they are representative of the subject’s disease (this includes splenic and extranodal disease). If 
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there are lymph nodes or lymph node masses in the mediastinum or retroperitoneum larger than 
1.5 cm in 2 perpendicular dimensions, at least 1 lymph node mass from each region should 
always be included. In addition, selection of target lesions should be from as disparate regions of 
the body as possible. Skin lesions will be considered as target lesion only if there are no other 
measurable lesions available elsewhere. All the other measurable/assessible diseases are 
considered as non-target lesions.
8.2.1.
PET-CT Scan
During the study, disease response will be assessed using whole-body 18F-FDG PET-computed 
tomography (CT) scans (skull base to the upper 1 third of the thighs). PET-CT scans are reported 
using a fixed display and color table scaled to the standardized uptake value (SUV) to assist with 
consistency of reporting. Contrast enhancement is preferred for the CT portion in order to obtain 
diagnostic CT imaging. When follow-up PET-CT is performed, it is recommended to use the 
same scanner with the same reconstruction algorithm as in the initial scan. 
Positive uptake is defined as any focal or diffuse area of increased activity, in a location 
incompatible with normal anatomy or normal variant. For response assessment, the lesions 
should be scored according to the Deauville Score (DS) using a 5-point scale with the following 
criteria:10
1.
No uptake
2.
Uptake ≤mediastinum
3.
Uptake > mediastinum but ≤ liver
4.
Uptake moderately higher than liver
5.
Uptake markedly higher than liver and/or new lesion
X.  (New) areas of uptake unlikely to be related to lymphoma.
Additional scan or biopsy may be considered for suspicious PD at the investigator’s discretion 
(eg, in case that EBV-DNA persistently detectable or rising from a previous unquantifiable level 
after apparent remission, uncertain etiology of new lesions, etc).
8.2.2.
Radiographic (CT or MRI) Assessments
During the study, disease response will be assessed using CT scans with IV contrast of the neck, 
chest, abdomen, and pelvis and any other location where disease was present at Screening. 
Subjects who are intolerant of IV CT contrast agents will have CT scans performed with oral 
contrast.
Hybrid PET-CT scanners may be used to acquire the required CT images only if CT produced by 
the scanner is of diagnostic quality, adheres to specified scan parameters, and includes contrast. 
Non-diagnostic CT images acquired for attenuation purposes during PET-CT are NOT 
acceptable as the only CT scan for the timepoint. Diagnostic CT images with contrast and 
adequate slice thickness with a standalone CT scanner is required if PET-CT is unable to acquire 
diagnostic CT images.
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Evaluation of other sites of disease by radiological imaging, physical examination, or other
procedures as necessary (to be performed throughout the study using the same method of
assessment used to assess disease at baseline), and review of hematology and clinical chemistry
results may also occur at the site level.
Magnetic resonance imaging (MRI) may be used to evaluate sites of disease that cannot be 
adequately imaged using CT (in cases where MRI is desirable, the MRI must be obtained at 
baseline and at all subsequent response evaluations). For all other sites of disease, MRI studies 
do not replace the required neck, chest, abdomen, and pelvic CT scans. Brain MRI and lumbar 
puncture are required only if clinically indicated.
8.2.3.
Clinical Examination
Clinically detected lesions will only be considered measurable when they are superficial (eg, skin 
lesions). In the case of skin lesions, documentation by color photography, including 
ruler/calipers to measure the size of the lesion in millimeters (mm), is required. Any clinical 
information which can support disease evaluation should be collected (eg, palpable lesion). 
8.2.4.
Bone Marrow Assessment
A bone marrow biopsy is required for documentation of a CR; a confirmatory bone marrow 
biopsy should be done preferably within 30 days of the initial documentation of CR. Bone 
marrow evaluation must include morphological examination and ISH for Epstein–Barr 
virus-encoded ribonucleic acid (EBV-encoded RNA; EBER), if warranted, to confirm the 
presence or absence (CR) of lymphoma.
8.2.5.
Tumor Biopsy Assessment
Lymphoma lesion biopsy may be conducted in a clinically indicated way. It is strongly 
recommended if lesion is reasonably accessible to confirm suspected PD. Tumor biopsy 
evaluation must include morphological examination and ISH for EBV-encoded RNA; EBER. 
Such pathological data from site will also be used for central oncology review.
8.2.6.
Blinded Independent Central Review 
An independent review of all scans and clinical information used in the assessment of tumors
will be conducted according to the Revised Criteria for Response Assessment: LUGANO 
classification.12 All imaging assessments including unscheduled visit scans will be collected on 
an ongoing basis and sent to a sponsor appointed CRO for central analysis. The central review 
process will be clearly defined in a BICR charter in advance of the start of the study.
The treatment discontinuation due to PD will be based upon the results of the real time central 
review. This procedure may not be followed if the clinical information of subject (eg,
Pathologically demonstrated PD) is sufficient enough to demonstrate PD, for such cases, PD 
confirmation from sponsor study physician is also required.
The efficacy analysis for this study will be based on the BICR data.
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8.3.
Pharmacokinetics and Immunogenicity
For all subjects, serum samples will be evaluated for the PK of daratumumab, as well as the 
generation of anti-daratumumab
antibodies, according to
T&E Schedule: PK and 
Immunogenicity. Serum collected for PK and immunogenicity analyses may additionally be used 
to evaluate safety or efficacy aspects that address concerns arising during or after the study 
period. Genetic analyses will not be performed on these serum samples. Subject confidentiality 
will be maintained.
8.3.1.
Evaluations
At specified time points, venous blood samples (5 mL per sample) will be collected to determine 
serum concentration of daratumumab and each serum sample will be divided into 3 aliquots 
(1 aliquot for PK analysis, 1 aliquot for antibodies to daratumumab analysis [when appropriate], 
and 1 aliquot as a backup). Samples collected for determining serum concentrations of 
daratumumab in this study may be retained to address questions about drug characteristics that 
may arise at a later time point.
The exact dates and times of blood sampling must be recorded. Additional information about the 
collection, handling, and shipment of biological samples can be found in the Laboratory Manual.
Collected samples must be stored under the specified and controlled conditions for the 
temperatures indicated in the laboratory manual.
8.3.2.
Analytical Procedures
Pharmacokinetics and Immunogenicity
Serum samples will be analyzed to determine concentrations of daratumumab or for the detection 
and characterization of antibodies to daratumumab using validated, immunoassay methods by or 
under the supervision of the sponsor. 
8.3.3.
Pharmacokinetic Parameters
The PK parameters are defined as:

Cmax
Maximum observed concentration

tmax
The actual sampling time to reach maximum observed concentration

AUC
Area under the concentration – time curve
All parameters will be estimated using the actual sampling times by non-compartmental analysis 
methods.
8.3.4.
Immunogenicity Assessments
Anti-daratumumab antibodies will be evaluated in serum samples collected from all subjects 
according to the T&E Schedule. Daratumumab serum concentration will also be determined 
from all immunogenicity samples to ensure proper interpretation of the immunogenicity results.
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Serum samples will be screened for antibodies binding to daratumumab and the titer of 
confirmed positive samples will be reported. Other immunogenicity analyses (eg, assessment of 
neutralizing capabilities) may be performed to further characterize the immune responses that are 
generated.
When both serum concentration and immunogenicity analyses are specified, they are performed 
on aliquots from the same blood draw and no additional sampling is required. Procedures for 
sample collection, preparation, identification, storage, and shipment will be provided in the 
Laboratory Manual or equivalent document.
A blood sample should be drawn, if possible, for determination of antibodies to daratumumab 
any time an infusion reaction is observed or reported during the study. Daratumumab serum 
concentration will also be determined from the same infusion reaction sample for the purpose of 
interpreting immunogenicity data. These samples will be stored and evaluated if deemed 
necessary. If the infusion reaction results in treatment discontinuation, then subjects should 
undergo all scheduled safety and efficacy evaluations. Samples collected for the analysis of 
daratumumab immunogenicity/serum concentration may additionally be used to evaluate safety 
or efficacy aspects that address concerns arising during or after the study period or for the 
evaluation of relevant biomarkers by the sponsor or sponsor’s designee.
8.4.
Pharmacokinetic/Pharmacodynamic Evaluations
If sufficient data are available, then other PK/pharmacodynamic modeling may be performed, 
including exploring the relationship between serum concentrations of daratumumab and 
endpoints of clinical efficacy and safety. Disease-related or mechanism-based biomarkers will be 
also explored, such as plasma EBV-DNA, blood NK cell counts, and tissue CD38 expression. If 
these analyses are performed, then the details and results will be presented in a separate report.
8.5.
Biomarkers
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and may 
be deferred or not performed if, during or at the end of the study, it becomes clear that the 
analysis will have no scientific value, or if there are not enough samples or not enough 
responders to allow for adequate biomarker evaluation. In the event the study is terminated early 
or shows poor clinical efficacy, completion of biomarker assessments is based on justification 
and intended utility of the data. Samples for biomarker evaluations will be collected as specified 
in the T&E Schedule.
Circulating plasma EBV-DNA quantification
Circulating plasma EBV-DNA quantification will be monitored monthly as a biomarker of tumor 
load at the central laboratory. Circulating plasma EBV-DNA quantification will also be
monitored at EoT visit.
Determination of CD38 and CIPs Expression
Before enrollment to the study, subjects will be required to provide tumor samples for 
assessment of CD38 expression based on central testing using investigational IHC methodology 
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under development (Section 8.1.2). Fresh biopsy samples are preferred, and if not available, 
archived FFPE blocks/slides are acceptable. Fresh tumor samples should be from core needle 
biopsy but not fine needle aspirates and should be done within 21 days of Cycle 1 Day 1; 
archived sample (slides or tumor block) can be acquired more than 21 days prior to Cycle 1 
Day 1. If archived samples are provided instead of fresh biopsy, additional information should be 
provided, including but not limited to date of biopsy/resection, site/organ of biopsy, collection 
method, pathology report and diagnostic, treatment received after biopsy. If possible, it is also 
recommended to provide the following information: type of fixative used, time of execution to 
fix, fixation time. If FFPE sections are provided instead of block, date of section should be 
provided.
In addition to evaluating CD38 expression, fresh or archived biopsy samples may be evaluated in 
all subjects to identify markers predictive of response to daratumumab or prognostic markers for 
disease progression. Paraffin-embedded, formalin-fixed tumor tissue may also be subjected to 
DNA (eg, somatic mutations) and RNA analysis (eg, GEP, qRT-PCR, or RNA-seq) to determine
if specific mutations or transcriptomic profiles (translocations, deletions, inversions, genes 
involved CD38 signaling pathways, or others) are associated with daratumumab response. 
Comparison of CD38 IHC results may be made to transcriptomic data. In addition to CD38, CIPs
expression might be measured by IHC or immunofluorescent staining in a designated laboratory 
as an exploratory biomarker whenever samples are available. CD59, CD55 and CD46 are
complement inhibitory proteins and can contribute to resistance to CDC, which may be 
important for daratumumab response.
If re-biopsy is needed for any clinical reasons, such as to confirm diagnosis or study pathology of 
new lesion, it is encouraged that FFPE slides/block to be submitted to determine CD38 and CIP 
expression. Correlation of biomarker expression and treatment response in the site will be 
studied, and the change of biomarker expression at new sites compared to the original site will 
also be analyzed. The information will be used to advance the understanding of daratumumab 
response and resistance mechanism in NKTCL patients. 
Immunophenotyping.
Previous daratumumab clinical studies in MM have demonstrated that baseline immune profiles 
of subjects may be predictive of response to daratumumab, and that specific immune 
subpopulations increase (CD8+ T cells) or decrease (NK cells) with daratumumab treatment. 
Therefore, whole blood samples will be utilized for immunophenotyping, (performed by flow 
cytometry and mass cytometry/time-of-flight mass spectrometry [CyTOF]) which includes 
analysis of NK, T cells, and B cells as well as other potential immune cell subpopulations. NK 
cells are known to express CD38, and early clinical data indicates rapid decreases in absolute 
counts of circulating NK cells upon daratumumab dosing. It is not known how critical NK cells 
are for the clinical efficacy of daratumumab but based on the rapid and sustained decreased 
absolute counts observed across all subjects, NK cells (CD45+CD3-CD16+CD56+) can be used 
as a pharmacodynamic biomarker for daratumumab. In addition, preliminary data from clinical 
studies in MM indicate that the immune fitness of subjects at baseline may preclude response to 
daratumumab. 
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To investigate whether an immune fitness signature can be developed utilizing either flow 
cytometry or genomic profiling, whole blood samples may also be subject to DNA sequencing, 
RNA profiling or methylation assessment to identify potential predictive marker for 
daratumumab response and genomic alterations related to NKTCL disease mechanism, to
evaluate novel technologies for immune profiling in whole blood, and to compare these 
methodologies to standard flow cytometry. 
Since CDC is one of the key mechanisms of action for daratumumab, and normal function of 
complement system in the body is required for CDC activity, plasma samples will be analyzed 
for complement proteins, to study whether specific complement protein level is associated with 
daratumumab response.
Additional Collections
If it is determined at any time before study completion that additional material is needed from a 
formalin-fixed, paraffin-embedded (FFPE) tumor sample for the successful completion of the 
protocol-specified analyses, the sponsor may request that additional material be retrieved from 
existing samples. Also, based on emerging scientific evidence, the sponsor may request 
additional material from previously collected tumor samples during or after study completion for 
a retrospective analysis. In this case, such analyses would be specific to research related to the 
study drug(s) or diseases being investigated.
8.6.
Safety Evaluations
Safety will be measured by AEs, laboratory test results, ECGs, vital signs measurements, 
physical examination findings, and assessment of ECOG performance status score. All toxicities 
will be graded according to the NCI-CTCAE version 4.03. Any clinically relevant changes 
occurring during the study must be recorded on the AE section of the eCRF. Any clinically 
significant abnormalities persisting at the end of the study/early withdrawal will be followed by 
the investigator until resolution or until a clinically stable condition is reached.
Based on the previous human experience with daratumumab, in vitro studies, and animal 
toxicological findings, IRRs/allergic reactions, infection, hemolysis, and thrombocytopenia will 
be closely monitored. As a biologic agent, immunogenicity also will be monitored. Any of the 
safety monitoring assessments may be performed more frequently, and AEs should be evaluated 
by the investigator according to the standard practice, if clinically indicated.
Any clinically relevant changes occurring during the study must be recorded on the AE section 
of the eCRF. Any clinically significant abnormalities persisting at the end of the study/early 
withdrawal will be followed by the investigator until resolution or until a clinically stable 
endpoint is reached. Safety assessments will be based on medical review of AE reports and the 
results of vital sign measurements, electrocardiograms (ECGs), physical examinations, clinical 
laboratory tests, ECOG performance status, and other safety evaluations at specified time points 
as described in the T&E Schedule.
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Adverse Events
Adverse events (AEs; with the exception of progression of NKTCL) will be reported by the 
subject (or, when appropriate, by a caregiver or surrogate) for the duration of the study. Adverse 
events (AEs) will be followed by the investigator as specified in Section 11, AE Reporting.
Clinical Laboratory Tests
Blood samples for serum hematology and chemistry will be collected. The investigator must 
review the laboratory results, document this review, and record any clinically relevant changes 
occurring during the study in the AE section of the eCRF. The laboratory reports must be filed 
with the source documents.
The following tests will be performed by the local laboratory unless otherwise noted:

Hematology Panel
-hemoglobin
-platelet count
-white blood cell (WBC) count
-Absolute neutrophil count (ANC) and 
Lymphocytes

Serum Chemistry Panel
-sodium
-aspartate aminotransferase (AST)
-potassium
-alanine aminotransferase (ALT)
-calcium
-lactic acid dehydrogenase (LDH)
-creatinine
-total bilirubin
-direct bilirubin (for subjects with congenital bilirubinemia, such as 
Gilbert syndrome)
-blood glucose (fasting) -alkaline phosphatase

Serum or Urine Pregnancy Testing (for women of childbearing potential only and as 
clinically indicated)

Hepatitis B Screening (local laboratory)
-HBsAg
-Anti-HBc
-Anti-HBs
HBV Serology
All subjects will be tested locally for HBsAg, Anti-HBs, and Anti-HBc at Screening. 
Additionally, subjects ongoing in the Treatment Phase who are within 6 months of starting study
treatment when Protocol Amendment 4 is implemented will be required to have HBV serology 
performed locally upon signing the updated ICF. Hepatitis B Virus serology is not required at 
Screening or for subjects ongoing in the Treatment Phase who are within 6 months of starting 
study treatment if this was performed as part of standard of care within 3 months prior to first 
dose.
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HBV DNA Tests
Subjects who are positive for Anti-HBc or Anti-HBs will undergo testing for HBV DNA by 
PCR. Subjects with serologic findings suggestive of HBV vaccination (Anti-HBs positivity as 
the only serologic marker) and a known history of prior HBV vaccination do not need to be 
tested for HBV DNA by PCR. During and following study treatment, subjects who have history 
of HBV infection will be closely monitored for clinical and laboratory signs of reactivation of 
HBV as specified in the Time and Events Schedule.  Where required by local law, the results of 
HBV testing may be reported to the local health authorities.

Hepatitis C Screening (local laboratory)

Hepatitis C antibody
If Hepatitis C antibody is positive, RNA PCR needs to be performed and confirmed negative 
prior to first study agent administration.
Daratumumab Interference Indirect Antiglobulin Testing (IAT) results
Blood group, Rh type, and IAT should be done before the first dose of daratumumab. Subject 
RBC phenotyping (standard or extended) is an alternative option to the IAT test, if locally 
required. Either method must be completed prior to first daratumumab infusion.
Daratumumab interferes with the indirect antiglobulin test (IAT), which is a routine pre-
transfusion test performed to identify a patient’s antibodies to minor antigens so that suitable 
donor blood can be given for transfusion. Daratumumab does not interfere with ABO/ Rhesus 
factor–D antigen (RhD) grouping/typing. 
CD38 is expressed at very low levels on erythrocytes. Preliminary data indicate that 
daratumumab binds to the CD38 on erythrocytes, which results in a positive IAT (also known as 
indirect Coombs test) and will make complete blood typing difficult while subjects are receiving 
treatment. This effect occurs during daratumumab treatment and for up to 6 months after 
treatment ends. Despite daratumumab binding to CD38 on erythrocytes, no indication of 
clinically significant hemolysis was observed. Eleven of 78 subjects in Study GEN501 had blood 
transfusions during treatment with daratumumab.16 The preliminary data indicate that transfusion 
of these subjects treated with daratumumab was not adversely affected. In alternate situations, 
blood banks can eliminate the daratumumab interference with IAT by treating reagent RBCs 
with dithiothreitol.11
Subjects will receive a patient identification wallet card for the study that includes the blood 
profile (ABO, Rh, and IAT or phenotyping) determined before the first infusion of daratumumab 
along with information on the IAT interference for healthcare providers/blood banks. Subjects 
are to carry this card throughout the treatment period and for at least 6 months after treatment 
ends. 
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Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving 
daratumumab include:
1.
Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping) or 
genotypically matched units
2.
Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using DTT-treated reagent RBCs.
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is 
needed emergently as per local blood bank practice. 
For additional details, refer to the 
daratumumab IB.
β2-microglobulin
Baseline β2-microglobulin will be measured in serum to assess lymphoma tumor burden as well 
as disease prognosis.
Pulmonary Function Test
Subjects with known or suspected COPD must have a FEV1 test during screening. Refer to 
Section 5.3 (Guidelines for Prevention of Infusion Reactions) for details on subjects with higher 
risk of respiratory complications.
Electrocardiogram (ECG)
Electrocardiogram (ECGs) will be performed as specified in the T&E Schedule. During the 
collection of ECGs, subjects should be in a quiet setting without distractions (eg, television, cell 
phones). Subjects should rest in a supine position for at least 5 minutes before ECG collection 
and should refrain from talking or moving arms or legs. If blood sampling or vital sign 
measurement is scheduled for the same time point as ECG recording, then the procedures should 
be performed in the following order: ECG(s), vital signs, blood draw.
Vital Signs 
Vital signs (pulse, temperature, and blood pressure) will be performed as specified in T&E 
Schedule. It is recommended that blood pressure (sitting) and pulse measurements be preceded 
by at least 5 minutes of rest in a quiet setting without distractions (eg, television, cell phones). 
All measurements will be recorded in the source documents. Blood pressure and pulse/heart rate 
measurements will be assessed with a completely automated device. Manual techniques will be 
used only if an automated device is not available.
Physical Examination and ECOG Performance Status
A complete physical examination (including neurological examination) should be performed 
during the Screening Phase. Thereafter, only a symptom and disease directed physical 
examination is required. Height will be measured at screening only; weight will be measured 
regularly as specified in the T&E Schedule. Abnormalities will be recorded in the appropriate 
sections of the eCRF. Eastern Cooperative Oncology Group (ECOG) Performance Status (refer
Attachment 1) will be used to evaluate the impact of the disease status on the activities of daily 
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living. When scheduled, ECOG assessments should be obtained prior to dosing of daratumumab 
on Day 1 of each cycle.
8.7.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. If blood samples are collected via an indwelling cannula, an appropriate 
amount (1 mL) of serosanguineous fluid slightly greater than the dead space volume of the lock 
will be removed from the cannula and discarded before each blood sample is taken. After blood 
sample collection, the cannula will be flushed with 0.9% sodium chloride, United States 
Pharmacopeia (or equivalent)/sodium heparin of 10 U/mL and charged with a volume equal to 
the dead space volume of the lock. If a mandarin (obturator) is used, blood loss due to discard is 
not expected.
Refer to the T&E Schedule for the timing and frequency of all sample collections. Instructions 
for the collection, handling, storage, and shipment of samples are found in the laboratory manual
that will be provided. Collection, handling, storage, and shipment of samples must be under the 
specified, and where applicable, controlled temperature conditions as indicated in the laboratory 
manual.
9.
SUBJECT COMPLETION/WITHDRAWAL FROM THE STUDY
9.1.
Completion
A subject will be considered to have completed the study if he or she has completed all 
protocol-specified procedures before the end of the study, has died before the end of the study, 
has not been lost to follow up, has not withdrawn consent for study participation before the end 
of the study, or has transitioned to commercial drug product.
9.2.
Discontinuation of Study Treatment/Withdrawal From the Study
Discontinuation of Study Treatment
If a subject's study treatment must be discontinued, it will not result in automatic withdrawal of 
the subject from the study. The EoT Visits and Follow-up visit assessments should continue as 
specified in the T&E Schedule.
A subject's study treatment (daratumumab) should be discontinued if:

The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the 
best interest of the subject to discontinue study treatment

The subject becomes pregnant 

The subject withdraws consent for administration of study drug

The subject initiates treatment with a prohibited medication

The subject received concurrent (non-protocol) treatment for NKTCL

The subject experiences unacceptable toxicity, including IRRs described in Section 5.3
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
The subject’s dose of daratumumab is held for more than 4 weeks in Cycles 1-6 or for more 
than 6 weeks in Cycle 7 and beyond (unless sponsor approves continuation)

The subject experiences PD (see below and Attachment 6). Relapse from CR is not 
considered as disease progression.

Daratumumab becomes commercially available (or when daratumumab can be accessed 
from another source) for this disease. At this time, the subject will be transitioned from 
study drug to commercial product and will be withdrawn from the study. In these 
circumstances, the sponsor and investigator will support transition of the subject to ensure 
that treatment continues and remains uninterrupted.

A subject who experiences a second primary malignancy that cannot be treated by surgery
or radiotherapy alone must be withdrawn from the study. However, a subject who develops 
a malignancy that can be cured surgically or with definitive radiotherapy may continue to 
receive the assigned study treatment and should continue to be followed for subsequent 
progression of NKTCL.
Subjects should be discontinued from study treatment if they have objective radiological PD
based on real time BICR according to LUGANO Classification. Following centrally confirmed 
radiological PD subjects will be discontinued from study treatment and enter the Follow-up
phase.
For subjects who have PD as evidenced by unambiguous clinical information (eg. pathologically 
demonstrated as PD), before such subjects discontinue study treatment due to PD, sites will 
document PD by completing and faxing a PD form to the sponsor as soon as possible and within 
48 hours of PD assessment; EoT steps will be performed. The study responsible physician will 
confirm that treatment should be discontinued. After confirmation from the sponsor, study 
treatment may be discontinued and the subject can enter into Follow-up phase. If a subject 
discontinues study treatment for any reason other than PD, then disease assessments should be 
obtained as specified in the T&E Schedule.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death

Sponsor terminates the study.
If a subject is considered 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 eCRF and in the source document (refer Section 8.1.4 and Section 15.2.3 for 
details on collection of long-term survival status). Study drug assigned to the withdrawn subject 
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may not be assigned to another subject. Subjects who withdraw will not be replaced. If a subject 
withdraws from the study before the EoT, assessments should be obtained.
9.3.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 15.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will 
be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the main ICF.
10.
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.
10.1.
Subject Information
The primary analysis population is the safety population, which will include all treated subjects. 
The pharmacokinetic analyses will be performed on the pharmacokinetic evaluable population. 
Continuous variables will be summarized using descriptive statistics such as mean, SD, and 
range. Categorical variables will be summarized using frequency tables. For time-to-event 
variables, the Kaplan-Meier method will be used for descriptive summaries.
10.2.
Sample Size Determination
The study is designed to evaluate the effect of daratumumab on ORR utilizing Simon’s 2-stage 
design. The null hypothesis is that ORR is at most 15%, and the alternative hypothesis is that 
ORR is at least 30%. With a 1-sided α of 10%, and a power of 78%, a total of 32 subjects are to
be enrolled into the study. The stage 1 analysis is to be performed when approximately 
15 subjects are enrolled in the study and have sufficient data for response evaluation. The futility 
criterion of ORR is defined as when at most 1 out of 15 subjects have achieved CR/PR after 
stage 1 according to Simon’s 2-stage design. Future enrollment into stage 2 may be terminated if 
it is determined during the first stage that the treatment group is considered as ineffective or not 
well-tolerated. If study proceeds to second stage with a total of 32 subjects with 2 stages 
combined, the null hypothesis is to be rejected if 8 or more responses are observed.
To achieve 1-sided α of 2.5% and a power of 80%, additional patients (ie, approximately 35 
patients) may be enrolled in an expansion phase to confirm the clinical response rate of 
daratumumab if supported by emerging data.
10.3.
Efficacy Analyses
10.3.1.
Primary Efficacy Endpoint
Objective response rate (ORR) is defined as the proportion of subjects who achieve CR or PR 
per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin lymphoma: 
LUGANO classification12 based on BICR. An estimate of the primary efficacy endpoint ORR 
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will be presented along with a 2-sided 95% exact CI. The number and percentage of subjects 
falling into each response category will be descriptively tabulated.
10.3.2.
Secondary Efficacy Endpoint
Complete response (CR) rate is defined as the proportion of subjects who achieve CR based on
BICR and will be analyzed similarly as the primary efficacy endpoint.
Progression-free survival (PFS) is defined as the duration from the date of the first daratumumab 
dose to the date of progression/relapse based on BICR or death, whichever comes first. For those 
subjects who are still alive without progression/relapse, PFS will be censored at the last adequate 
tumor assessment.
Duration of response (DoR) will be duration from the date of the initial documentation of a 
response to the date of first documented evidence of PD based on BICR (PD; or relapse for 
subjects who experience CR) or death. For those subjects who are still without 
progression/relapse, DoR will be censored at the last adequate tumor assessment. 
Time to response is defined as the duration from the date of the first dose of daratumumab to the 
earliest date that a response (CR/PR based on BICR) is first documented. For nonresponders, it 
will be censored at the date of PD/relapse or the date of the last adequate disease assessment, 
whichever comes first. 
Overall survival (OS) is defined as the duration from the date of the first daratumumab dose to 
the date of death. For those subjects who are still alive without progression/relapse, OS will be 
censored at the last date known to be alive.
For time to event endpoints (eg, PFS, OS, time to response, DoR), Kaplan-Meier estimates will 
be presented. Median along with corresponding 95% CIs will be obtained from the Kaplan-Meier 
estimates. Analysis for time to response and DoR will be for responders only.
10.4.
Pharmacokinetic Analyses
Pharmacokinetic (PK): PK analyses will be performed on the PK-evaluable population, defined 
as subjects who have received at least 1 dose of daratumumab and at least 1 postinfusion sample. 
All serum concentrations below the lowest quantifiable concentration in a sample or missing data 
will be labeled as such in the concentration database. Concentrations below the lowest 
quantifiable concentration in a sample will be treated as zero in the summary statistics. All 
subjects and samples excluded from the analysis will be clearly documented in the clinical study 
report.
Descriptive statistics will be used to summarize daratumumab serum concentrations at each 
sampling time point and PK parameters of daratumumab (Cmax, tmax, AUC) following the 1st
infusion. Mean serum daratumumab concentration time profiles will be plotted after the first 
dose of study drug, and composite serum concentration time profiles may also be plotted.
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If sufficient data are available, then population pharmacokinetic analysis of serum concentration 
time data of daratumumab may be performed using nonlinear mixed-effects modeling and may 
include data from other studies. If the population pharmacokinetic analysis is conducted, then 
details will be given in a population pharmacokinetic analysis plan and the results of the analysis 
will be presented in a separate report.
The relationship between derived PK parameters and covariates, such as actual dose, body 
weight, and selected laboratory parameters, may be evaluated graphically. Further exploratory 
analyses of PK data may be performed and reported separately.
10.5.
Immunogenicity Analyses
The incidence of antibodies to daratumumab (immunogenicity) will be summarized for all 
subjects who receive a dose of daratumumab and have appropriate samples for detection of 
antibodies to daratumumab. A listing of subjects whose sample(s) are positive will also be 
presented. Daratumumab concentrations will be summarized at all immunogenicity time points.
The maximum titers of antibodies to daratumumab will be summarized for subjects who are 
positive for antibodies to daratumumab.
The impact of antibodies to daratumumab on drug exposure and efficacy/safety will be analyzed 
if there are positive samples.
10.6.
Biomarker Analyses
All biomarker measurements will be listed, tabulated, and where appropriate, plotted. Results of 
biomarker and pharmacodynamic analyses may be presented in a separate report. Planned 
analyses are based on the availability of clinically valid assays and may be deferred if emerging 
study data show no likelihood of providing useful scientific information.
Associations between baseline levels and changes from baseline in select markers and clinical 
response 
(CD38 
expression, 
EBV-DNA 
quantification 
and 
other 
biomarkers 
PK/pharmacodynamic modeling) will be explored. Exploratory genetic analyses will be 
summarized in separate technical reports.
Results will be presented in a separate report.
10.7.
Pharmacokinetic/Pharmacodynamic Analyses
If sufficient data are available, then other pharmacokinetic/pharmacodynamic modeling may be 
performed, including exploring the relationship between serum concentrations of daratumumab 
and endpoints of clinical efficacy and safety. Disease-related or mechanism-based biomarkers 
will be also explored, such as plasma EBV-DNA, blood NK cell counts, and tissue CD38 
expression. If performed, details and results of the analysis will be presented in a separate report.
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10.8.
Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). All reported AEs with onset during the 
Treatment Phase (ie, treatment-emergent AEs, and AEs that have worsened since baseline) will 
be included in the analysis. For each AE, 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 AE, or who experience a severe or an
SAE.
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. Changes from 
baseline results will be presented in pre- versus 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 NCI-CTCAE version 4.03 toxicity grades will be summarized. 
Change from baseline to the worst toxicity grade experienced by the subject during the study will 
be provided as shift tables. Worst toxicity grade during treatment will be presented, according to 
NCI-CTCAE (version 4.03). Clinical relevant changes (ie, causing a treatment intervention or 
need for concomitant therapy) will be also recorded on the AE eCRF. All other lab abnormalities 
need not be recorded as AEs.
Electrocardiogram (ECG)
Electrocardiogram data will be summarized by ECG parameter. 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.
Vital Signs
Descriptive statistics of temperature 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.
Physical Examination
Descriptive statistics of changes from baseline will be summarized at each scheduled time point.
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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.
10.9.
Interim Analysis
The study is designed with an interim analysis performed at the end of stage 1 when 
approximately 15 subjects have received at least one dose of study drug and had at least one 
post-baseline disease evaluation. Enrollment may be put on hold pending the decision of interim 
analysis unless the decision is clear based on available data before the interim analysis. The 
purpose of the interim analysis is to evaluate efficacy and safety data in stage 1 and facilitate the 
early preparation for the next step of development. The totality of efficacy (ORR), safety, and 
biomarker data will be analyzed at interim. The futility criterion of ORR is defined as at most 1 
out of 15 subjects have achieved CR/PR after stage 1. This futility boundary is considered 
non-binding. Study may be terminated if the futility criteria are met or supported by the totality 
of data including biomarker and safety data. 
In addition, at interim, the association between daratumumab activity and CD38 expression level 
will be explored. If a strong association between daratumumab activity and CD38 expression 
level is confirmed by emerging data or a low response rate is observed from stage 1 data due to 
low CD38 expression levels, then an enrichment strategy may be applied for stage 2 to mitigate 
the risk of low responses possibly attributed to low CD38 expression. The final analysis may be 
adjusted accordingly (eg, primary analysis would be based on enriched population) if an 
enrichment strategy is applied in stage 2.
11.
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.
11.1.
Definitions
11.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE 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])
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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 AEs starting with the signing of the ICF (refer to Section 11.3.1, All 
AEs, for time of last AE recording).
Serious Adverse Event
An SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use is any untoward medical occurrence that at any dose:

Results in death

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.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

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 1 of the other outcomes listed in the definition above.
These should usually be considered serious.
If a serious and unexpected AE 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, PD).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For daratumumab, the expectedness of an AE will be 
determined by whether or not it is listed in the IB.18
Adverse Event Associated With the Use of the Drug
An AE is considered associated with the use of the drug if the attribution is possible, probable, or 
very likely by the definitions listed in Section 11.1.2, Attribution Definitions.
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11.1.2.
Attribution Definitions
Not Related
An AE that is not related to the use of the drug.
Doubtful
An AE 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 AE 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 AE 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 AE 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).
11.1.3.
Severity 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).
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11.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Accidental or occupational exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)

Exposure to a sponsor study drug from breastfeeding.
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the SAE page of the eCRF.
11.3.
Procedures
11.3.1.
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from 
the time a signed and dated ICF is obtained until 30 days after the last dose of study drug, unless 
the subject withdraws consent for study participation, or starts subsequent anticancer therapy.
For subjects who have received additional treatment with therapeutic intent for NKTCL during 
the AE reporting period, only AEs that are considered to be possibly, probably, or definitely 
related to study drug must be reported (unless the subject has been withdrawn from the study). 
Serious adverse events (SAEs), including those spontaneously reported to the investigator within 
30 days after the last dose of study drug, must be reported using the SAE Form. The sponsor will 
evaluate any safety information that is spontaneously reported by an investigator beyond the time 
frame specified in the protocol.
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be 
recorded using medical terminology in the source document and the eCRF. 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 eCRF their opinion concerning the relationship of 
the AE to study therapy. All measures required for AE management must be recorded in the 
source document and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of AEs 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). 
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For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind.
Progression of the disease under study is not considered an AE (or SAE), even if it results in 
death during the AE reporting period. If a clinical sign or symptom or a laboratory test 
abnormality is observed in a subject with PD, but is not related to PD under study, then the usual 
AE reporting requirements apply.
11.3.2.
Serious Adverse Events
All SAEs 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 SAEs will be transmitted to the sponsor using the SAE Form, which must 
be completed and signed by a physician from the study site, and transmitted to the sponsor 
within 24 hours. The initial and follow-up reports of an SAE should be made by facsimile (fax).
All SAEs 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:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

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 an SAE. 
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 an SAE, except hospitalizations 
for the following:
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
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as 
pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). 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 SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.

For convenience the investigator may choose to hospitalize the subject for the duration of 
the treatment period.
11.3.3.
Pregnancy
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 SAEs 
and must be reported using the SAE Form. Any subject who becomes pregnant during the study 
must promptly 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.
11.4.
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.
12.
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.
12.1.
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 SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 11.3.2, SAEs). A sample of 
the suspected product should be maintained for further investigation if requested by the sponsor.
12.2.
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.
13.
STUDY DRUG INFORMATION
13.1.
Physical Description of Study Drug(s)
The daratumumab supplied for this study is a colorless to yellow liquid and sterile concentrate of 
20 mg/mL as a liquid vial. It will be manufactured and provided under the responsibility of the 
sponsor. Refer to the IB for a list of excipients.
13.2.
Packaging
Daratumumab is supplied in glass vials containing daratumumab at a concentration of 
20 mg/mL.
13.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. Each 
vial will contain a study-specific label with a unique identification number.
13.4.
Preparation, Handling, and Storage
Daratumumab product must be stored in the original carton in a refrigerator at controlled 
temperatures ranging from 2°C to 8°C. Study drug must not be utilized after the expiry date 
printed on the label. The daratumumab product must be protected from light and must not be 
frozen. Daratumumab does not contain preservatives; therefore, any unused portion remaining in 
the vial must be discarded.
Refer to the pharmacy manual/study site investigational product and procedures manual for 
additional guidance on study drug preparation, handling, and storage.
13.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The administration of study drug to the subject must be 
documented on the drug accountability form. All study drug will be stored and disposed of 
according to the sponsor's instructions. Study-site personnel must not combine contents of the 
study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug must be available for verification by the sponsor's 
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study site monitor during on-site monitoring visits. The return to the sponsor of unused study 
drug will be documented on the drug return form. When the study site is an authorized 
destruction unit and study drug supplies are destroyed on-site, this must also be documented on 
the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
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. Returned study drug must not be dispensed again, even to 
the same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.
14.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

IB18, Study protocol

Daratumumab manual/study site investigational product and procedures manual

Laboratory manual

NCI-CTCAE version 4.03

eDC Manual

IWRS Manual (if any)

Sample ICF

Investigator File

Subject identification wallet card.
15.
ETHICAL ASPECTS
15.1.
Study-Specific Design Considerations
The primary safety profile of daratumumab is consistent with IRRs; see Section 5.3 for 
prevention details. Based on the mode of action of daratumumab, a potential risk could be 
infection; therefore the protocol requires the review of hematological laboratory results prior to 
daratumumab infusion. CD38 is distributed in erythrocytes and platelets. A significant reduction 
of platelets was reported in an animal study. In a human clinical study (Study GEN501), 
thrombocytopenia was also reported. However, safety laboratory monitoring did not show a 
clinically meaningful reduction of platelets. Anemia was also reported in Study GEN501. Free 
hemoglobin was mildly elevated, but other parameters did not support hemolysis. No bleeding 
events were observed. Routine safety laboratory measurement of RBCs and platelets will be 
closely monitored in this study.
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The archived biopsy samples were originally taken prior to the clinical study as part of the
subject’s NKTCL disease clinical work-up or management. The archived biopsy tissue is then 
sent to the central laboratory biomarker status determination such as CD38 and CIPs. Therefore, 
there is no risk related to tissue biopsy for this study for subjects with archived tissue. For 
subjects undergoing re-biopsy for this study, the risks are included in the Janssen ICF, under the 
“Fresh Tissue Biopsy Risk” section.
Further, in the Simon’s 2-stage design of the clinical study protocol, a futility analysis will be
performed to evaluate efficacy and safety data at interim. If the futility criteria are met, the study
may be terminated and further subject exposure will be limited. 
Potential subjects will be fully informed 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 AEs of the study, and provide their consent voluntarily will be enrolled.
The total blood volume to be collected is estimated about 15.5 mL for screening tests, 158 mL
from Cycle 1-6, 26 mL at Cycle 7 and thereafter, 31 mL at the end-of treatment visit and 10 mL
for follow-up visit. The total blood volume to be collected is considered to be within the normal 
range allowed for this subject population in a cancer clinical study and reasonable over the time 
frame of the study.
15.2.
Regulatory Ethics Compliance
15.2.1.
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.
15.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
Independent Ethics Committee (IEC)/ Institutional Review Board (IRB) with current and 
complete copies of the following documents (as required by local regulations):

Final protocol and, if applicable, amendments

sponsor-approved ICF (and any other written materials to be provided to the subjects)
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
IB (or equivalent information) and amendments/addenda18

sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

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:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the IB and amendments/addenda18

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of AEs that are serious, unlisted/unexpected, and associated with the study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB.
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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 least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
15.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any study-
related activity. The ICF(s) that is/are 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. Subjects will be told 
that alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow up if needed and that their records 
may be accessed by health authorities and authorized sponsor personnel without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the ICF the subject is authorizing such access, which includes permission to obtain 
information about his or her survival status. It also denotes that the subject agrees to allow his or 
her study physician to recontact the subject for the purpose of obtaining consent for additional 
safety evaluations, and subsequent disease-related treatments, if needed.
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.
Subjects will be asked for consent to provide optional samples for research. After informed 
consent for the study is appropriately obtained, the subject will be asked to sign and personally 
date a separate ICF indicating agreement to participate in the optional research component. 
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Refusal to participate in the optional research will not result in ineligibility for the study. A copy 
of this signed ICF will be given to the subject.
If the subject is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) and 
should personally date and sign the ICF after the oral consent of the subject is obtained.
When prior consent of the subject is not possible, enrollment procedures should be described in 
the protocol with documented approval/favorable opinion by the IEC/IRB to protect the rights, 
safety, and well-being of the subject and to ensure compliance with applicable regulatory 
requirements. The subject must be informed about the study as soon as possible and give consent 
to continue.
15.2.4.
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.
Exploratory biomarker, PK/pharmacodynamic, and immunogenicity research is not conducted 
under standards appropriate for the return of data to subjects. In addition, the sponsor cannot 
make decisions as to the significance of any findings resulting from exploratory research. 
Therefore, exploratory research data will not be returned to subjects or investigators, unless 
required by law or local regulations. Privacy and confidentiality of data generated in the future 
on stored samples will be protected by the same standards applicable to all other clinical data.
15.2.5.
Long-Term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand daratumumab, to 
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understand NKTCL, to understand differential drug responders, and to develop tests/assays 
related to daratumumab and NKTCL. The research may begin at any time during the study or the 
post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 9.3, Withdrawal From the Use of Samples in Future 
Research.
16.
ADMINISTRATIVE REQUIREMENTS
16.1.
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 eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
16.2.
Regulatory Documentation
16.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
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16.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

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 if 
applicable, 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.

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.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations.
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable.
16.3.
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 
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and date of birth (as allowed by local regulations). In cases where the subject is not enrolled into 
the study, the date seen and date of birth (as allowed by local regulations) 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.
16.4.
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 AEs and follow-up of AEs; 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 eCRF and will be considered source data:

Race

History of smoking, all nicotine use, eg, cigarettes (including e-cigarettes or the equivalent 
of e-cigarettes), cigars, chewing tobacco, patch, gum

Blood pressure and pulse/heart rate 

Height and weight 

Details of physical examination

Investigator-completed scales and assessments.
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:

Subject must be documented as histologically confirmed extranodal NK/T-cell lymphoma, 
nasal type according to the World Health Organization (WHO) classification.10,13,21

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries.
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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.
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 
the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If the electronic source system is utilized, references made to 
the eCRF 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 eCRF. Data in this system 
may be considered source documentation.
16.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format. 
All eCRF 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 eCRF are accurate 
and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
electronic eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the 
sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documents. Data must be entered into 
eCRF in English. The eCRF must be completed as soon as possible after a subject visit and the 
forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible.
If necessary, queries will be generated in the electronic data capture (eDC) tool. If corrections to 
an eCRF are needed after the initial entry into the eCRF, this can be done in either of the 
following ways:

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).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
16.6.
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, and direct 
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transmission of clinical laboratory data from a central laboratory into the sponsor's data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study.
The sponsor will review eCRF 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.
16.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
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.
16.8.
Monitoring
The sponsor will use a combination of monitoring techniques central, remote, or on-site 
monitoring to monitor this study.
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 
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monitor will compare the data entered into the eCRF with the source documents 
(eg, hospital/clinic/physician’s office medical records). 
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 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.
Central monitoring will take place for data identified by the sponsor as requiring central review.
16.9.
Study Completion/Termination
16.9.1.
Study Completion/End of Study
The study is considered completed with the last scheduled study assessment shown in the 
T&E Schedule for the last subject participating in the study. The final data from the study site 
will be sent to the sponsor (or designee) after completion of the final subject assessment at that 
study site, in the time frame specified in the Clinical Trial Agreement.
16.9.2.
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:

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

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development.
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16.10. 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 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
16.11. Use of Information and Publication
All information, including but not limited to information regarding daratumumab 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 pharmacogenomic, or exploratory biomarker 
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 daratumumab, 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 for the study. Results of
pharmacogenomic, or exploratory biomarker analyses performed after the Clinical Study Report 
has been issued will be reported in a separate report and will not require a revision of the Clinical 
Study Report. 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 
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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. For multicenter study designs and substudy approaches, 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 8 weeks 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 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.
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REFERENCES
1.
A Study Comparing Daratumumab, Lenalidomide, and Dexamethasone With Lenalidomide and 
Dexamethasone in Relapsed or Refractory Multiple Myeloma.
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2.
A Study of Daratumumab in Japanese Participants With Relapsed or Refractory Multiple Myeloma.
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3.
A Study of Combination of Daratumumab and Velcade (Bortezomib) Melphalan-Prednisone (DVMP) 
Compared to Velcade Melphalan-Prednisone (VMP) in Participants With Previously Untreated Multiple 
Myeloma.
https://clinicaltrials.gov/ct2/show/NCT02195479. Accessed 29 April 2016.
4.
A Study of JNJ-54767414 (HuMax CD38) (Anti-CD38 Monoclonal Antibody) in Combination With 
Backbone Treatments for the Treatment of Patients With Multiple Myeloma.
https://clinicaltrials.gov/ct2/show/NCT01998971. Accessed 23 February 2016.
5.
Addition of Daratumumab to Combination of Bortezomib and Dexamethasone in Participants With Relapsed 
or Refractory Multiple Myeloma.
https://clinicaltrials.gov/ct2/show/NCT02136134. Accessed 29 April 2016.
6.
Albeniz I, Demir Ö, Türker-Şener L, Yalçıntepe L, Nurten R, Bermek E. Erythrocyte CD38 as a prognostic 
marker in cancer. Hematology. 2007;12:409–414.
7.
An Efficacy and Safety Study of Daratumumab in Patients With Multiple Myeloma Who Have Received at 
Least 3 Prior Lines of Therapy (Including a Proteasome Inhibitor [PI] and Immunomodulatory Drug [IMiD]) 
or Are Double Refractory to a PI and an IMiD.
https://clinicaltrials.gov/ct2/show/NCT01985126. Accessed 16 February 2016.
8.
Artz AS1, Somerfield MR, Feld JJ, et al. American Society of Clinical Oncology provisional clinical opinion: 
chronic hepatitis B virus infection screening in patients receiving cytotoxic chemotherapy for treatment of 
malignant diseases. J Clin Oncol. 2010;28(19):3199-3202.
9.
Au WY, Weisenburger DD, Intragumtornchai T, et al. Clinical differences between nasal and extranasal 
natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma 
Project. Blood. 2009;113(17):3931-3937.
10.
Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of 
lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J 
Clin Oncol. 2014;32(27):3048-3058.
11.
Chapuy, C, Nicholson R, Aguad MD, et al. Resolving the daratumumab interference with blood compatibility 
testing. Transfusion. 2015; 55:1545-1554.
12.
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response 
assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 
2014;32(27):3059-3067.
13.
Chinese Society of Hematology, Chinese Medical Association; Committee of Malignant Lymphoma, Chinese 
Anti-cancer Association; Chinese Society of Hepatology, Chinese Medical Association. Consensus on the 
management of lymphoma in patients with hepatitis B virus infection. Zhonghua Gan Zang Bing Za Zhi. 
2013;21(11):815-820.
14.
DARZALEX (daratumumab) injection [package insert]. Horsham, PA Janssen Biotech, Inc. May 2018.
15.
DARZALEX (daratumumab) DARZALEX 20 mg/mL concentrate for solution for infusion [Summary Product 
Characteristics]. 
Beerse, 
Belgium, 
Janssen 
Cilag 
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NV, 
Aug 
2017.
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Product_Information/human/004077/WC50
0207296.pdf
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Daratumumab (HuMax®-CD38) Safety Study in Multiple Myeloma.
https://clinicaltrials.gov/ct2/show/NCT00574288. Accessed 16 February 2016.
NCT02927925


JNJ-54767414 Daratumumab
Clinical Protocol 54767414NKT2001 Amendment 4
85
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17.
Daratumumab in Combination With Lenalidomide and Dexamethasone in Relapsed and Relapsed-refractory 
Multiple Myeloma.
https://clinicaltrials.gov/ct2/show/NCT01615029. Accessed 16 February 2016.
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Investigator’s Brochure: JNJ-54767414 (daratumumab), edition 14. Janssen Research & Development, LLC 
(05 October 2017).
19.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;5:649–655.
20.
Oostendorp M, van Bueren J, Doshi P, et al. When blood transfusion medicine becomes complicated due to 
interference by monoclonal antibody therapy. Transfusion. 2015;55:1555-1562.Park S, Ko YH. Peripheral T
cell lymphoma in Asia. Int J Hematol. 2014;99:227–239.
21.
Pearlman BL and N Traub. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus 
Infection: A Cure and So Much More. Clin Infect Dis. 2011:52 (7): 889-900.
22.
Tse E, Kwong YL.How I treat NK/T-cell lymphomas. Blood. 2013;121(25):4997-5005.
23.
Vose J, Armitage J, Weisenburger D. International T-Cell Lymphoma Project. International peripheral T-cell 
and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 
2008;26(25):4124-4130.
24.
Wang L, Wang ZH, Chen XQ, et al. First-line combination of gemcitabine, oxaliplatin, and L-asparaginase 
(GELOX) followed by involved-field radiation therapy for patients with stage IE/IIE extranodal natural 
killer/T-cell lymphoma. Cancer. 2013;119(2):348-355.
25.
Wang L. CD38 expression predicts poor prognosis and might be a potential therapy target in extranodal NK/T 
cell lymphoma, nasal type. Ann Hematol. 2015;94(8):1381-1388.
26.
Yamaguchi M, Kwong YL, Kim WS, et al. Phase II study of SMILE chemotherapy for newly diagnosed stage 
IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: The NK-Cell Tumor 
Study Group study. J Clin Oncol. 2011;29:4410–4416.
27.
Zocchi E, Franco L, Guida L, et al. A Single Protein Immunologically Identified as CD38 Displays NAD+ 
Glycohydrolase, ADP-Ribosyl Cyclase and Cyclic ADP-Ribose Hydrolase Activities at the Outer Surface of 
Human ErythrocytesOriginal Research Article. Biochem Biophys Res Commun. 1993;196(3):1459–1465.
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ATTACHMENT
Attachment 1: ECOG Performance Status Scale19
Grade
ECOG Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more 
than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
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Attachment 2: Conversion Table for Glucocorticosteroid Dose
Glucocorticoid
Approximate Equivalent Dose (mg)
Half-life (Biologic) hours
Intermediate-Acting
Methylprednisolone
4
18-36
Prednisolone
5
18-36
Prednisone
5
18-36
Triamcinolone
4
18-36
Long-Acting
Betamethasone
0.6 – 0.75
36-54
Dexamethasone
0.75
36-54
Generic Name
Oral or Intravenous
Dose (mg)
Dexamethasone
0.75
Methylprednisolone
4
Prednisolone
5
Prednisone
5
Betamethasone
0.6
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Attachment 3: Family of Antihistamine Medications
The following antihistamines may be used for daratumumab preinfusion medication (including, but not 
limited to):

Diphenhydramine

Cetirizine

Fexofenadine

Loratadine

Clemastine

Dexchlorpheniramine

Promethazine*
*The IV formulation of promethazine should be avoided.
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Attachment 4: Asthma Guidelines (NHLBI)
Components of
Severity
ClassificationofAsthma Severity
Intermittent
Persistent
Mild
Moderate
Severe
0-4
yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
Impairment
Normal 
FEV1/FVC :
8-19 yr 85%
20-39 yr 80%
40-59 yr 75%
60-80 yr 70%
Symptoms
≤2 days/week
≥2 days/week but not daily
Daily
Throughout the day
Nighttime awakenings
0
≤2x/month
1-2x/
month
3-4x/month
3-4x/
month
> 1x/week but not 
nightly
> 1x/
month
Often 7x/week
SABA use for 
symptom control (not 
prevention
of EIB)
≤2 days/week
≤2 days/week but not daily
>2 days/ 
week but
not daily,
and
not more 
than 1x on
d
Daily
Several time per day
Interference with 
normal activity
None
Minor limitation
Some limitation
Extremely limited
Lung function
FEV1
FEV1/FVC
N/A
Normal FEV1 
between 
exacerbations
> 80%
> 85%
Normal FEV1 
between 
exacerbations
> 80%
Normal
N/A
> 80%
> 80%
> 80% 
Normal
N/A
60-80%
75-80%
60-80% 
Reduced 5%
N/A
< 60%
< 75%
< 60% 
Reduced 5%
Risk
Exacerbations 
requiring oral 
systemic 
corticosteroids
0-1/year
≥2 exacerbations in 6
months requiringoral 
steroids or >4 wheezing 
episodes/1 year lasting >1 
day and risk factors for 
persistent asthma
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2 exacerbations in 6
months requiring oral 
steroids or >4 wheezing 
episodes/1 year lasting >1 
day and risk factors for 
persistent asthma
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2 exacerbations in
6 months requiring oral 
steroids or >4 wheezing 
episodes/1 year lasting >1
day and risk factors for 
persistent asthma
≥ 2/year
Relative annual
risk may be 
related to 
FEV1.
≥ 2/year
Relative 
annual risk
may be
related
to FEV1.
Consider severity and interval since last exacerbation. Frequency and severity may fluctuate over time for patients in any severity category.
Recommended Step
for
Initiating Treatment
Step 1
Step 2
Step 3 and consider 
short course of oral 
steroids
Step 3: 
medium dose 
ICS and 
consider
short course 
of oral 
steroids
Step 3 and 
consider short 
course of oral 
steroids
Step 3 and consider 
short course of oral 
steroids
Step 3: medium
dose ICS OR
Step 4 and
consider short
course of oral
steroids
Step 4 or 5 
and consider 
short course
of oral
steroids
In 2-6 weeks, evaluate level of asthma control that is achieved.
0-4 years: If no clear benefit is observed in 4-6 weeks, stop treatment and consider alternate diagnosis or adjusting therapy. 5-11 and 12+ years: adjust therapy accordingly.
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Components of 
Control
Classification of Asthma Control
Well Controlled
Not Well Controlled
Very Poorly Controlled
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs 12 + yrs
0-4 yrs
5-11 yrs 12 + yrs
Symptoms
≤ 2 days/week but not 
more than once on each 
day
≤ 2 days/
week
> 2 days/week or 
multiple times on 
≤2 days/week
> 2 days/
week
Throughout the day
Impairment
Nighttime 
awakenings
≤ 1x/month
≤ 2x/month
> 1x/month
≥ 2x/month
1-3x/week
> 1x/week
≥ 2x/week
≥ 4x/week
Interference with 
normal activity
None
Some limitation
Extremely limited
SABA use for symptom 
control (not prevention of
EIB)
≤2 days/week
> 2 days/week
Several times per day
Lung function
FEV1 or peak flow
FEV1/FVC
N/A
> 80%
> 80%
> 80%
N/A
60-80%
75-80%
60-80%
N/A
< 60%
< 75%
< 60%
Validated questionnaires
ATAQ
ACQ
ACT
0
≤ 0.75
≥ 20
1-2
≥ 1.5
16-19
3-4
N/A
≤ 15
Risk
Exacerbations requiring oral 
systemic corticosteroids
0-1/year
≥2/year
Consider severity and interval since last exacerbation
Reduction in lung growth/ 
Progressive loss of lung function
Evaluation requires long-term follow-up
Recommended Action for
Treatment
• Maintain current step
• Regular follow-up every 1-
6 months
• Consider step down if well 
controlled for at least 3 months
Step up 1 
step
Step up at 
least 1 step
• Step up 1 
step
• Reevaluate
in 2-6 
weeks
• For side 
effects, 
consider 
alternative 
treatment 
options
• Consider short course of 
oral steroids
• Step up 1-2 steps
• Consider short 
course of oral 
steroids
• Step up 1-2 
steps
• Reevaluate in
2 weeks
• For side
effects, 
consider 
alternative 
treatment 
options
• Before step up:
Review adherence to medication, inhaler 
technique, and environmental control. If 
alternative treatment was used, discontinue 
it and use preferred treatment for that step.
• Reevaluate the level of asthma control 
in 2-6 weeks to achieve control.
0-4 years: If no clear benefit is observed in
4-6 weeks, consider alternative diagnoses or 
adjusting therapy.
5-11 years: Adjust therapy accordingly.
• For side effects, consider alternative 
treatment options.
• Before step up:
Review adherence to medication, inhaler 
technique, and environmental control. If 
alternative treatment was used, discontinue 
it and use preferred treatment for that step.
• Reevaluate the level of asthma control 
in 2-6 weeks to achieve control.
0-4 years: If no clear benefit is observed in
4-6 weeks, consider alternative diagnoses or 
adjusting therapy.
5-11 years: Adjust therapy accordingly.
• For side effects, consider alternative 
treatment options.
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Attachment 5: Calculated and Measured Creatinine Clearance
Cockcroft-Gault formula:
To calculate the subject’s creatinine clearance (CrCl), use the following Cockcroft-Gault formula:
CrCl = (140 - age [in years]) x weight (kg)
(x 0.85 for females)
(72 x serum creatinine [mg/dL])
If the serum creatinine is obtained using the International System of Units (SI) (ie, mmol/L), use the 
following formula to convert SI units to conventional (mg/dL) units (Manual of Laboratory & Diagnostic 
Tests, 2004):
•
Serum creatinine (mmol/L) divided by 88.4 = serum creatinine (mg/dL)
Formula to measure creatinine clearance:
CrCl = UCr x Uvol
PCr x Tmin
Corrected CrCl = CrCl x 1.73
BSA
Notes: UCr, Urine creatinine concentration; Uvol, Urine volume from 24 hrs collection; PCr, plasma 
creatinine concentration; Tmin, collection time in minutes (24 hrs x 60 min); BSA, body surface area.
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Attachment 6: Revised Response Criteria for Response Assessment12
Response and Site
PET-CT–Based Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response (all of the following)
Lymph nodes and extralymphatic sites
Score 1, 2, or 3* with or without a residual mass on 5PS†
It is recognized that in Waldeyer’s ring or extranodal 
sites with high physiologic uptake or with activation 
within spleen or marrow (eg, with chemotherapy or 
myeloid colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response may be 
inferred if uptake at sites of initial involvement is no 
greater than surrounding normal tissue even if the tissue 
has high physiologic uptake
Target nodes/nodal masses must regress to ≤1.5 cm in LDi;
No extralymphatic sites of disease
Nonmeasured lesions
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow
Normal by morphology; if inderterminate, IHC negative
Partial
Partial metabolic response
Partial remission (all of the following)
Lymph nodes and extralymphatic sites
Score 4 or 5† with reduced uptake compared with 
baseline and residual mass(es) of any size
≥50% decrease in SPD of up to 6 target measurable nodes and 
extranodal sites from baseline;
When a lesion is too small to measure on CT, assign 5mm×5mm 
as the default value;
When no longer visible, 0×0mm;
For a node > 5mm× 5mm, but smaller than normal, use actual 
measurement for calculation
Nonmeasured lesions
Not applicable
Absent/normal, regressed, but no increase
Organ enlargement
Not applicable
Spleen must have regressed by >50% in length beyond normal
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake 
compatible with reactive changes from chemotherapy 
allowed). If there are persistent focal changes in the 
marrow in the context of a nodal response, consideration 
should be given to further evaluation with MRI or biopsy 
or an interval scan
Not applicable
No response or stable disease
No metabolic response
Stable disease
Target nodes/nodal masses, extranodal 
lesions
Score 4 or 5 with no significant change in FDG uptake 
from baseline
<50% decrease from baseline in SPD of up to 6 dominant, 
measurable nodes and extranodal sites; no criteria for 
progressive disease are met
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Response and Site
PET-CT–Based Response
CT-Based Response
Nonmeasured lesions
Not applicable
No increase consistent with progression
Organ enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive disease
Progressive metabolic response
Progressive disease requires at least 1 of the following
Target nodes/nodal masses, extranodal 
lesions
Score 4 or 5 with an increase in intensity of uptake from 
virtually determined nadir
PPD progression:
An individual target (nodal or extranodal) must be abnormal 
with:
Node >1.5 cm in LDi or extranodal lesion>1.0 cm in any axis;
Increase by≥50% from PPD nadir and
An increase in LDi or SDi from nadir:
≥0.5 cm for lesions≤2 cm
≥1.0 cm for lesions>2 cm
In the setting of splenomegaly, the splenic length must
increase by>50% of the extent of its prior increase
beyond baseline (eg, a 15-cm spleen must increase to
>16 cm). If no prior splenomegaly, must increase by at
least 2 cm from baseline
New or recurrent splenomegaly
Nonmeasured lesions
None
New or clear progression of preexisting nonmeasured lesions
New lesions
New FDG-avid foci consistent with lymphoma rather 
than another etiology (eg, infection, inflammation). If 
uncertain regarding etiology of new lesions, biopsy or 
interval scan may be considered.
Regrowth of previously resolved lesions
A new node  >1.5 cm in LDi;
A new extranodal site >1.0 cm in any axis; if  <1.0 cm in
any axis, its presence must be unequivocal and must be 
attributable to lymphoma;
Assessable disease of any size unequivocally attributable to 
lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
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Response and Site
PET-CT–Based Response
CT-Based Response
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; LDi, longest transverse diameter of a lesion;
MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, short diameter, the widest 
part of the lesion perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions.
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving PET where 
de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant lesions: Up to six of 
the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two diameters. Nodes should preferably be from disparate regions 
of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (eg, liver, spleen, kidneys, 
lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly 
assessable disease should be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that 
do not meet the requirements for measurability but are still considered abnormal, as well as truly assessable disease, which is any site of suspected disease that would 
be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions 
that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the 
mediastinum with complete metabolic response, but should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of 
chemotherapy or myeloid growth factors).
†PET 5PS: 1, no uptake above background; 2, uptake≤mediastinum; 3, uptake>mediastinum but≤liver; 4, uptake moderately> liver; 5, uptake markedly higher than 
liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma.
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INVESTIGATOR AGREEMENT
PPD
NCT02927925

SAP_001.pdf: 
1
Approved, Date: 19 November 2019
Janssen Research & Development *
Statistical Analysis Plan
An Open Label, Phase 2 Study to Assess the Clinical Efficacy and Safety of Daratumumab 
in Patients With Relapsed or Refractory Natural Killer/ T-Cell Lymphoma (NKTCL), 
Nasal Type
Protocol 54767414NKT2001
JNJ 54767414  (Daratumumab)
Author(s):
Date:
29 April 2020
Status:
Approved
Date:
19 November 2019
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-ERI-200918055
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.
PPD
NCT02927925


JNJ 54767414  (Daratumumab)
Statistical Analysis Plan 54767414NKT2001
2
Approved, Date: 19 November 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 4
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Trial Objectives ................................................................................................................................ 5
1.2.
Trial Design ...................................................................................................................................... 5
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 5
1.4.
Sample Size Justification ................................................................................................................. 6
1.5.
Randomization and Blinding ............................................................................................................ 6
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 6
2.1.
Visit Windows................................................................................................................................... 6
2.2.
Pooling Algorithm for Analysis Centers............................................................................................ 6
2.3.
Study Treatment and Study Drug .................................................................................................... 7
2.4.
Study Treatment Dosing Date.......................................................................................................... 7
2.5.
Treatment Cycle............................................................................................................................... 7
2.6.
Baseline Measurement .................................................................................................................... 7
2.7.
Imputation of Partial Dates............................................................................................................... 7
2.7.1.
Missing/Partial Adverse Event Onset Date................................................................................... 7
2.7.2.
Missing/Partial Adverse Event End Date...................................................................................... 8
2.7.3.
Partial Concomitant Medication Start/End Date ........................................................................... 8
2.7.4.
Partial Initial Disease Diagnosis Date........................................................................................... 8
2.7.5.
Partial Subsequent Anticancer Therapy Start Date...................................................................... 9
2.8.
Analysis Sets.................................................................................................................................... 9
2.8.1.
Efficacy Analysis Set(s) ................................................................................................................ 9
2.8.2.
Safety Analysis Set....................................................................................................................... 9
2.8.3.
Pharmacokinetics Analysis Set .................................................................................................... 9
2.8.4.
Pharmacodynamics Analysis Set ............................................................................................... 10
2.9.
Definition of Subgroups.................................................................................................................. 10
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 10
4.
SUBJECT INFORMATION................................................................................................................ 10
4.1.
Demographics and Baseline Characteristics ................................................................................. 10
4.2.
Disposition Information................................................................................................................... 11
4.3.
Treatment Compliance................................................................................................................... 11
4.4.
Extent of Exposure......................................................................................................................... 11
4.5.
Protocol Deviations ........................................................................................................................ 12
4.6.
Prior Medications ........................................................................................................................... 12
4.7.
Concomitant Medications............................................................................................................... 12
4.8.
Subsequent Anticancer Therapy.................................................................................................... 12
5.
EFFICACY ......................................................................................................................................... 12
5.1.
Analysis Specifications................................................................................................................... 12
5.1.1.
Level of Significance................................................................................................................... 12
5.1.2.
Data Handling Rules................................................................................................................... 12
5.2.
Primary Efficacy Endpoint(s).......................................................................................................... 12
5.2.1.
Definition..................................................................................................................................... 12
5.2.2.
Analysis Methods........................................................................................................................ 13
5.3.
Secondary Endpoints..................................................................................................................... 13
5.3.1.
Definition..................................................................................................................................... 13
5.3.2.
Analysis Methods........................................................................................................................ 13
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6.
SAFETY............................................................................................................................................. 14
6.1.
Adverse Events .............................................................................................................................. 14
6.2.
Deaths............................................................................................................................................ 14
6.2.1.
All Deaths ................................................................................................................................... 14
6.3.
Clinical Laboratory Tests................................................................................................................ 14
6.4.
Electrocardiogram.......................................................................................................................... 15
6.5.
Vital Signs ...................................................................................................................................... 15
7.
PHARMACOKINETICS/PHARMACODYNAMICS/IMMUNOGENICITY .......................................... 15
7.1.
Pharmacokinetics Analyses ........................................................................................................... 15
7.2.
Pharmacokinetics/ Pharmacodynamics Analyses ......................................................................... 15
7.3.
Immunogenicity Analyses .............................................................................................................. 16
8.
BIOMARKER ANALYSES ................................................................................................................ 16
9.
HEALTH ECONOMICS ..................................................................................................................... 16
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AMENDMENT HISTORY
ABBREVIATIONS
AE
adverse event
TEAE
Treatment-emergent adverse event
CI
confidence interval
CRF
case report form
CSR
Clinical Study Report
ECG
Electrocardiogram
eCRF
electronic case report form
ORR
Overall response rate
CR
Complete response
PR
Partial response
PFS
Progression free survival
OS
Overall survival
DoR
Duration of response
MedDRA
Medical Dictionary for Regulatory Activities
PD
Pharmacodynamic
PK
pharmacokinetic(s)
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for all planned analysis.
1.1.
Trial Objectives
Primary Objectives
The primary objective of the study is to evaluate the efficacy of daratumumab in subjects with 
NKTCL by ORR including complete response (CR) and partial response (PR) based on a blinded 
independent central review (BICR) per Revised Criteria for Response Assessment of Hodgkin and 
non-Hodgkin Lymphoma: LUGANO classification.
Secondary Objectives

To evaluate the efficacy of daratumumab in NKTCL by CR rate, progression free survival 
(PFS), duration of response (DoR), time to response based on a BICR, and OS 

To evaluate safety and tolerability

To evaluate PK and immunogenicity
1.2.
Trial Design
This is an open-label, single arm, multicenter, phase 2 study to evaluate the efficacy and safety of 
daratumumab monotherapy in subjects with relapsed and refractory extranodal NKTCL, nasal 
type. Each cycle will consist of 28 days. 
The study is designed as Simon’s 2-stage with an interim analysis conducted after approximately 
15 subjects who have received at least one dose of study drug and had at least one post-baseline 
disease evaluation. The purpose of the interim analysis is to evaluate efficacy and safety data in 
stage 1 and facilitate the early preparation for the next step of development. The totality of efficacy 
(ORR), safety, and biomarker data will be analyzed at the interim. Enrollment may be put on hold 
pending the decision of interim analysis unless the decision is clear based on available data before 
IA. The study may be terminated if the futility criteria are met and supported by totality of data. 
In addition, at interim, the association between daratumumab activity and CD38 expression level 
will be explored. A population enrichment strategy may be applied after the interim analysis if 
such a strategy is supported by emerging data. If the study proceeds to the second stage, the total 
sample size will be 32 with 2 stages combined. Following that, additional patients (ie, up to 35 
patients) may be enrolled in an expansion phase to confirm the clinical response rate of 
daratumumab, if supported by emerging data.
1.3.
Statistical Hypotheses for Trial Objectives
It is hypothesized that treatment with daratumumab results in an ORR of >30% versus a null 
hypothesis of at most 15% in relapsed or refractory NKTCL, nasal type subjects who failed 
(relapsed or refractory after achieving complete or partial remission) at least one line of 
chemotherapy.
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1.4.
Sample Size Justification
The study is designed to evaluate the effect of daratumumab on ORR utilizing Simon’s 2-stage 
design. The null hypothesis is that ORR is at most 15%, and the alternative hypothesis is that ORR 
is at least 30%. With a 1-sided alpha of 10%, and a power of 78%, a total of 32 subjects are to be 
enrolled into the study. The stage 1 analysis is to be performed when approximately 15 subjects 
are enrolled in the study and have sufficient data for response evaluation. The futility criterion of 
ORR is defined as when at most 1 out of 15 subjects have achieved CR/ PR after stage 1 according 
to Simon’s 2-stage design. Future enrollment into stage 2 may be terminated if it is determined 
during the first stage that the treatment group is considered as ineffective or not well tolerated. If 
study proceeds to second stage with a total of 32 subjects with 2 stages combined, the null 
hypothesis is to be rejected if 8 or more responders are observed.
To achieve 1-sided alpha of 2.5% and a power of 80%, additional patients (ie, up to 35 patients) 
may be enrolled in an expansion phase to confirm the clinical response rate of daratumumab if 
supported by emerging data.
1.5.
Randomization and Blinding
Not applicable.
2.
GENERAL ANALYSIS DEFINITIONS
Unless specifically stated, the summary will be analyzed and presented by total subjects combined.
The analyses for continuous variables will be summarized by descriptive statistics (mean, standard 
deviation, median, and range). Categorical variables will be presented with frequency, percentage, 
or 95% CI if appropriate. Time to event variables will be summarized by descriptive Kaplan-Meier 
statistics, or 95% CI if appropriate.
2.1.
Visit Windows
Any analysis that uses time-to-event data will be based on the exact determination of time from 
first dose of Dara to the date of the event. For the calculation of time-to-event and duration-of-
event variables, the difference between the start date and the end date plus 1 day will be used.
For analyses of data by cycle, if data are collected by date (ie, AE onset), the corresponding study 
evaluations will be assigned to actual sequential cycles, which are derived from the study treatment 
administration data. The start date of a particular cycle is defined as the date of the first Dara, and 
the end date of a cycle is the start date of the next cycle minus 1. For the last cycle, the end date is 
defined as the end of treatment visit date or the minimum of last study treatment date plus 30 days 
or subsequent anticancer therapy minus 1 day, if the end of treatment visit date is not available.  
In general, if data (e.g., laboratory and vital sign, etc.) are collected by cycle, the nominal cycle 
will be used to summarize data.
2.2.
Pooling Algorithm for Analysis Centers
All data will be pooled together regardless of analysis centers.
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2.3.
Study Treatment and Study Drug  
In this study, Study treatment/Study drug refers daratumumab.
2.4.
Study Treatment Dosing Date
Study treatment dosing date is the date on which a subject actually received study treatment
(partial or complete) and will be recorded in the study treatment administration dataset. The first 
study treatment date is defined as the earliest date of non-zero dose of daratumumab. The last 
study treatment date is defined as the latest date of non-zero dose of the daratumumab.
2.5.
Treatment Cycle
A subject is considered as treated in a cycle if he/she receives any non-zero dose of daratumumab in 
that cycle.
2.6.
Baseline Measurement
Baseline measurement is defined as the closest non-missing measurement taken on or prior to the 
date of first study agent administration (including time if available). If the first study treatment 
date is missing, the corresponding visit date should be used. 
2.7.
Imputation of Partial Dates
Unless specified otherwise, no data imputation will be applied for missing safety and efficacy
evaluations. For analysis and reporting purpose, missing or partial dates in adverse event (AE onset 
date; AE end date), concomitant therapies (start date; end date), prior therapy (start date; end date), 
initial disease diagnosis date and start date of subsequent anticancer therapy will be imputed. 
2.7.1.
Missing/Partial Adverse Event Onset Date
If the onset date of an adverse event is missing partially, the following imputation rules will be 
used.

When month and year are present and the day is missing,
–
If the onset month and year are the same as the month and year of first study 
treatment, the day of first study treatment or the day-component of the AE end 
date (possibly imputed) is imputed, whichever is earlier
–
If the onset month and year are not the same as the month and year of first study 
treatment, then the first day of the month is imputed

When only a year is present or no components of the onset date are present, 
–
If the onset year is the same as the year of first study treatment. If AE end date is 
available and is prior to first study treatment, the day and month of AE end date 
are imputed. Otherwise, the day and month of first study treatment are imputed
–
If the onset year is different from the year of first study treatment, the 1st of 
January is imputed

If the onset date is completely missing, the date of first study treatment is imputed as the 
onset date.
No imputation will be done for partial or missing AE onset time. 
If AE onset date needs imputation, but the AE onset time is available, the AE onset time will be 
dropped in the imputed AE onset date/time variable.
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2.7.2.
Missing/Partial Adverse Event End Date
If the end date of an adverse event is missing partially, the following imputation rules will be used.

If month and year are present and the day of the month is missing, the last day of the 
month is imputed. 

If only a year is present, the 31st of December is used. 

If the imputed date is later than the date of death (if available), the date of death will be 
used as the imputed date instead.
No imputation will be done for partial or missing AE end time. 
If AE end date needs imputation, but the AE end time is available, the AE end time will be dropped 
in the imputed AE end date/time variable.
2.7.3.
Partial Concomitant Medication Start/End Date
In case of partially missing concomitant medication start/end dates, the following imputation rules 
will be applied. If the date is completely missing, no imputation will be performed.

If only the day is missing, the 15th day of the month will be used

If both the day and month are missing, the 30th of June will be used
If the medication was taken prior to study start, and the imputed start date is after first treatment 
date, further adjust the imputed start date as the day prior to first dosing date; if the medication 
was taken after study start, and the imputed start date is prior to first dosing date, further adjust the 
imputed start date as first dosing date. 
After applying above adjusting method, if it results in medication start date that is after medication 
end date, the medication start date needs re-adjustment as follows:
If medication start date was imputed then adjust as follows: 

Impute the same month and year as mediation end date if the non-imputed date parts are 
the same 

Impute the first day of the month as medication start day
If medication end date was imputed then re-adjust medication end date to be the same as the 
medication start date if the corresponding non-imputed date parts match the medication start date. 
Also adjust the imputed medication end date so that it is on or after first dosing date.
2.7.4.
Partial Initial Disease Diagnosis Date
For partially missing initial diagnosis dates, the following imputation rules will be applied. If the 
date is completely missing, no imputation will be performed.

If only the day is missing:
•
If month and year of start of 1st line of prior therapy are the same year and month of 
diagnosis, and day of start of 1st line of prior therapy is available, impute day with 
day of start of 1st line of prior therapy;
•
Otherwise, impute day with 15.
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
If both the day and month are missing:
•
If year of diagnosis is the same as year of start of 1st line of prior therapy, and month 
information is available for start of the 1st line of prior therapy;
–
Impute month with month of start of 1st line of prior therapy;
–
If day of start of 1st line of prior therapy is available, impute diagnosis day with 
day of start of 1st line of prior therapy; otherwise, impute diagnosis day with 15.
•
Otherwise, impute with June 30.
2.7.5.
Partial Subsequent Anticancer Therapy Start Date
If year or month of subsequent anticancer therapy start date is missing or no components of the 
start date are present, no imputation will be performed.
If only the day-component is missing, the following steps apply: 

If the month and year of the start date are the same as the month and year of last dosing 
date, the day of last dosing date or the day-component of the stop date of subsequent 
anticancer therapy is imputed, whichever is earlier. 

If the start month and year are not the same as the month and year of last dosing date, the 
first day of the month is imputed.
If after the above imputation are applied, the imputed start date is after the non-imputed end date 
then re-adjust the start to be the same as the end date.
No imputation will be applied for missing or partial subsequent anticancer therapy end date. 
2.8.
Analysis Sets
2.8.1.
Efficacy Analysis Set(s)
The all treated analysis set will consist of all subjects who receive at least 1 dose of daratumumab. 
This analysis set will be used for efficacy analysis unless otherwise stated.
The response evaluable analysis set will consist of all subjects who satisfy all of the following:
–
Received at least 1 dose of study drug;
–
Had a baseline and at least 1 post-treatment disease evaluation.
Response evaluable analysis set will be used for the efficacy analyses at interim analysis.
2.8.2.
Safety Analysis Set
The all treated population will be used for safety analysis unless otherwise stated.
2.8.3.
Pharmacokinetics Analysis Set
The PK analysis population will consist of all subjects who received at least 1 dose of 
daratumumab and have at least 1 sample collected during treatment to determine the concentration. 
This analysis wet will be used for PK analysis.
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2.8.4.
Pharmacodynamics Analysis Set
The PD analysis population will consist of all subjects who received at least 1 dose of 
daratumumab and have at least 1 sample collected to determine PD biomarker response. This 
analysis set will be used for PD analysis.
2.9.
Definition of Subgroups
No specific subgroup analysis will be performed.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
The study is designed with an interim analysis performed at the end of stage 1 when approximately 
15 subjects have received at least one dose of study drug and had at least one post-baseline disease 
evaluation. Enrollment may be put on hold pending the decision of interim analysis unless the 
decision is clear based on available data before the interim analysis. The purpose of the interim 
analysis is to evaluate efficacy and safety data in stage 1 and facilitate the early preparation for the 
next step of development. The totality of efficacy (ORR), safety, and biomarker data will be 
analyzed at interim. The futility criterion of ORR is defined as at most 1 out of 15 subjects have 
achieved CR/PR after stage 1. This futility boundary is considered non-binding. Study may be 
terminated if the futility criteria are met or supported by the totality of data including biomarker 
and safety data.
In addition, at interim, the association between daratumumab activity and CD38 expression level 
will be explored. If a strong association between daratumumab activity and CD38 expression level 
is confirmed by emerging data or a low response rate is observed from stage 1 data due to low 
CD38 expression levels, then an enrichment strategy may be applied for stage 2 to mitigate the 
risk of low responses possibly attributed to low CD38 expression. The final analysis may be 
adjusted accordingly (e.g., primary analysis would be based on enriched population) if an 
enrichment strategy is applied in stage 2.
4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
Unless specified otherwise, all demographic and baseline characteristics variables will be 
summarized for the all treated analysis set. 
The distribution of subject enrollment will be presented according to region and country. Subjects 
who did not meet study inclusion/exclusion criteria will be listed by subject ID, and specific criteria 
not met. 
Subject demographic and baseline characteristic variables: age (< 65 years, 65 to < 75 years, and 
≥75 years), sex, ethnicity, race, weight (kg), height (cm), and ECOG performance status will be 
summarized. A listing of subject demographic and baseline characteristics will be provided as 
well.  
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Baseline disease diagnosis including CD38 expression, ß2-microglobulin, and months since initial 
diagnosis will be summarized. A listing of disease diagnosis will be provided as well.
Medical history collected at baseline or screening visit will be summarized by system-organ class 
and preferred term. 
4.2.
Disposition Information
An overview of subject disposition will be provided. The overview includes a summary of total 
number of subjects who are treated. For all treated subjects (defined as subjects who have received 
at least 1 administration of daratumumab), the number and percentage of subjects who 
discontinued study treatment including reason for discontinuation as indicated by the investigators
will be summarized. The similar summaries will be presented for all treated subjects who 
discontinued from study participation. 
A listing of subjects who discontinued study treatment or study participation including reasons for 
discontinuation will be provided. 
4.3.
Treatment Compliance
Compliance will be analyzed as part of exposure. Please refer to 4.4
4.4.
Extent of Exposure
Extent of exposure to study treatment will be summarized and presented based on all treated 
population. 
The number and percentage of subjects treated within each cycle will be summarized. The 
maximum number of treatment cycles received for each subject will be summarized by frequency 
and descriptive statistics.  
Duration of study treatment, defined as the number of days from the date of the first administration 
of study treatment to the date of the last administration of study treatment, will be summarized. 
The number of daratumumab infusions will be summarized for all treated subjects.
Daratumumab dose intensity, which is defined as the sum of total dose administered (mg/kg) in 
all cycles divided by the number of treatment cycles, will be summarized. Additionally, the 
daratumumab dose intensity will be summarized for cycles with high-intensity (Cycles 1-2) or 
low-intensity (Cycles 3-6 and Cycles 7+).
The relative dose intensity (%) defined as the ratio of total actually received dose and total planned 
dose will be calculated and summarized using descriptive statistics.  
The number of subjects with cycle delays or dose modifications (dose delays or dose skipping) 
including reasons (AE or other) for cycle delays or dose modifications, will be reported. 
A listing of subjects with daratumumab infusions will be provided. 
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4.5.
Protocol Deviations
A listing of subjects with major protocol deviations including subject ID, type of deviation, and 
reasons for deviation will be provided. 
4.6.
Prior Medications
A summary of prior therapies (systemic therapy, radiotherapy, or cancer-related surgery/
procedure) will be provided. Specifically, the number of prior lines of therapy will be calculated 
and summarized by the following categories: 1, 2, or ≥ 3 through frequency and descriptive 
statistics. Additionally, the prior systemic therapy will be summarized by therapeutic class, 
pharmacologic class and drug name. 
4.7.
Concomitant Medications
Concomitant medications collected in the CRF page during the study will be summarized by 
therapeutic class, pharmacologic class, and drug name. A similar summary will be provided for 
pre-infusion medication and post-infusion medication, respectively. A listing will be provided for 
pre-infusion medication and post-infusion medication, respectively.
4.8.
Subsequent Anticancer Therapy
The total number of subjects who received subsequent anticancer therapy will be reported. A 
summary of subsequent anticancer therapy will be presented by therapeutic class, pharmacologic 
class and drug name.
5.
EFFICACY
5.1.
Analysis Specifications
The analysis of efficacy will be based on BICR for all treated population. Sensitivity analysis will 
be performed based on investigators’ assessment.
5.1.1.
Level of Significance
Not applicable.
5.1.2.
Data Handling Rules
No data imputation will be performed for missing efficacy endpoint values.
5.2.
Primary Efficacy Endpoint(s)
Study will evaluate evidence of clinical responses with primary efficacy endpoint of objective 
response rate.
5.2.1.
Definition
Objective response rate (ORR) is defined as the proportion of subjects who achieve CR or PR per 
Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin lymphoma: LUGANO 
classification based on BICR.
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5.2.2.
Analysis Methods
An estimate of the ORR will be presented along with a two-sided 95% exact confidence interval. 
The number and percentage of subjects in the following response categories will be presented: 
complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), not 
evaluable (NE), overall response (CR+PR) and Clinical benefit rate (CR+PR+SD).
5.3.
Secondary Endpoints
Secondary endpoints include complete response (CR) rate, progression-free survival (PFS), 
duration of objective response (DOR), time to response, and overall survival (OS).
5.3.1.
Definition
Complete response (CR) rate is defined as the proportion of subjects who achieve CR based on 
BICR and will be analyzed similarly as the primary endpoint ORR.
Progression-free survival (PFS) is defined as the duration from the date of the first daratumumab
dose to the date of progression/relapse based on BICR or death, whichever comes first. For those 
subjects who are still alive without progression/relapse, PFS will be censored at the last adequate 
tumor assessment. Subjects who are progression-free and alive or have unknown status will be 
censored at last tumor assessment. Subjects with no post baseline disease assessment will be 
censored on Day 1. Subjects who started a subsequent anti-cancer therapy in the absence of 
progression will be censored at the last disease assessment before the start of subsequent therapy.
Subjects whose diseases have not progressed and who are still alive at the end of the study or 
clinical cutoff will be censored at the last adequate disease assessment. 
Duration of response (DoR) will be duration from the date of the initial documentation of a
response to the date of first documented evidence of progressive disease based on BICR (PD; or 
relapse for subjects who experience CR) or death and calculated only for responders. For those 
subjects who are still without progression/relapse, DoR will be censored at the last adequate tumor 
assessment.
Time to response (TTR) is defined as the duration from the date of the first dose of daratumumab 
to the earliest date that a response (CR/PR based on BICR) is first documented. Descriptive 
analysis will be performed for responders including median, mean, standard deviation, and range. 
Overall survival (OS) is defined as the duration from the date of the first daratumumab dose to the 
date of death. Subjects who withdraw consent from the study or are lost to follow-up will be censored 
at the time of withdrawal or lost to follow-up. For those subjects who are still alive at the time of 
analysis, OS will be censored at the last date known to be alive.
5.3.2.
Analysis Methods
Descriptive analysis will be performed for secondary endpoints. The Kaplan-Meier method will 
be used to estimate the distribution of PFS, OS and DoR. The number of events, subjects censored, 
the estimate of medians, and 95% confidence interval for medians will be presented. Plots of PFS, 
OS and DoR using Kaplan-Meier method will be presented. For CR rate, point estimate as well as 
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exact 95% CI will be provided. For TTR, mean, standard deviation, and range will be provided for 
responders.
6.
SAFETY
Unless specifically stated, the observations that occurred during treatment period (i.e., within 30 
days from the last study drug dosing) will be used for safety analyses. All observations will be 
presented in listings.
6.1.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the most current version of the Medical Dictionary for Regulatory Activities (MedDRA). 
Toxicities will be graded for severity according to CTCAE, Version 4.03. All reported adverse 
events with onset during the treatment period (ie, treatment-emergent adverse events, and adverse 
events that have worsened since baseline, and within 30 days from the last dose) will be included 
in the analysis and reported using descriptive statistics and frequency tabulations.  
The incidence of TEAEs will be summarized overall, by MedDRA system organ class (SOC) and 
preferred term, by toxicity grade, and by relationship to study treatment administration.
Specifically, the following will be summarized or listed:

All adverse events

Grade 3 or higher adverse events

Serious adverse events

Adverse events leading to discontinuation of treatment

Treatment-emergent infusion related reactions

Adverse events leading to treatment cycle delays or dose modifications

Adverse events leading to death
6.2.
Deaths
6.2.1.
All Deaths
A summary of all deaths and cause of death will be summarized for all treated population. The 
primary cause of death collected on CRF page will be reported. Similar summaries will be 
presented for subjects who died within 30 days of last study treatment. 
A listing of death information will be provided.
6.3.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be 
calculated for each laboratory analyte at baseline and for observed values and changes from 
baseline at each scheduled time point. Changes from baseline results will be presented in pre-
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versus post-treatment 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.
NCI-CTCAE version 4.03 will be used to derive toxicity grades for clinical laboratory tests when 
applicable. Shift tables from baseline to worst value on study (from treatment start to 30 days after 
last dose or the End of Treatment visit date, whichever is later) will also be provided. The worst 
toxicity grade during the study will be tabulated.
6.4.
Electrocardiogram
Electrocardiogram data will be summarized by ECG parameter. 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.
6.5.
Vital Signs
Descriptive statistics of temperature, pulse, 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.
7.
PHARMACOKINETICS/PHARMACODYNAMICS/IMMUNOGENICITY
7.1.
Pharmacokinetics Analyses
Pharmacokinetic (PK): PK analyses will be performed on the PK-evaluable population, defined as 
subjects who have received at least 1 dose of daratumumab and at least 1 post-infusion sample.
All serum concentrations below the lowest quantifiable concentration in a sample or missing data
will be labeled as such in the concentration database. Concentrations below the lowest quantifiable 
concentration in a sample will be treated as zero in the summary statistics. All subjects and samples 
excluded from the analysis will be clearly documented in the clinical study report.
Descriptive statistics will be used to summarize daratumumab serum concentrations at each
sampling time point and PK parameters of daratumumab (Cmax, tmax, AUC) following the 1st
infusion. In addition, above PK parameters following the first infusion, if available, may be 
summarized by response status. Mean serum daratumumab concentration time profiles will be 
plotted after the first dose of study drug. Composite serum concentration time profiles and Cycle 
3 Day 1 pre-dose serum concentrations stratified by response status may also be plotted. Further 
exploratory analyses of PK data may be performed.
7.2.
Pharmacokinetics/ Pharmacodynamics Analyses
If sufficient data are available, then the relationship between serum concentrations of 
daratumumab and endpoints of clinical efficacy and safety may be analyzed graphically. 
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7.3.
Immunogenicity Analyses
The incidence of antibodies to daratumumab (immunogenicity) will be summarized for all subjects 
who received at least 1 administration of daratumumab and have at least 1 during-treatment-sample 
collected to assess the generation of antibodies to daratumumab. A listing of subjects whose 
sample(s) are positive will also be presented. Daratumumab concentrations will be summarized at 
all immunogenicity time points. The maximum titers of antibodies to daratumumab will be 
summarized for subjects who are positive for antibodies to daratumumab. The impact of antibodies 
to daratumumab on drug exposure and efficacy/safety may be analyzed if there are positive 
samples. 
8.
BIOMARKER ANALYSES
Biomarker analyses will be focused on CD38 expression and EBV-DNA at baseline, over time 
performance of total natural killer cells and EBV-DNA. The relationship of biomarkers with 
efficacy outcome, e.g. disease response, may also be explored. The corresponding summaries and 
figures will be provided. 
If data are available, disease-related or mechanism-based biomarkers will be also explored. Details 
and results of the analysis will be presented in a separate report.
9.
HEALTH ECONOMICS
Not applicable.
NCT02927925