An Open Label, Phase 2 Study to Evaluate Efficacy and Safety of Daratumumab in Relapsed or Refractory Mantle Cell Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular Lymphoma
Phase: PHASE2
Conditions: Lymphoma, Mantle-Cell, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Follicular
Sponsor: Janssen Research & Development, LLC

1
Status: Approved,  Date: 19 January 2016
Janssen Research & Development *
Clinical Protocol
An Open Label, Phase 2 Study to Evaluate Efficacy and Safety of Daratumumab in Relapsed or 
Refractory Mantle Cell Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular 
Lymphoma
Protocol 54767414LYM2001; Phase 2
Amendment-1
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, Inc; Janssen Infectious Diseases BVBA; 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.
EudraCT NUMBER: 2014-005299-26
Status:
Approved
Date:
19 January 2016
Prepared by:
Janssen Research & Development, LLC 
EDMS number:
EDMS-ERI-96525113, version 4.0
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 IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 14
ABBREVIATIONS ...................................................................................................................................... 24
1.
INTRODUCTION................................................................................................................................ 26
1.1.
Background .................................................................................................................................... 26
1.1.1.
Diffuse Large B-cell Lymphoma (DLBCL) .................................................................................. 26
1.1.2.
Follicular Lymphoma (FL)........................................................................................................... 26
1.1.3.
Mantle Cell Lymphoma (MCL).................................................................................................... 27
1.2.
Daratumumab ................................................................................................................................ 28
1.2.1.
Nonclinical Studies ..................................................................................................................... 28
1.2.1.1.
Toxicology................................................................................................................................ 29
1.2.2.
Clinical Studies ........................................................................................................................... 29
1.2.2.1.
Clinical Pharmacokinetics........................................................................................................ 29
1.2.2.2.
Preliminary Efficacy................................................................................................................. 30
1.2.2.3.
Safety and Tolerability............................................................................................................. 30
1.3.
Overall Rationale for the Study...................................................................................................... 31
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 32
2.1.
Objectives ...................................................................................................................................... 32
2.2.
Hypothesis ..................................................................................................................................... 33
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 33
3.1.
Overview of Study Design.............................................................................................................. 33
3.2.
Study Design Rationale.................................................................................................................. 36
4.
SUBJECT POPULATION.................................................................................................................. 38
4.1.
Inclusion Criteria ............................................................................................................................ 38
4.2.
Exclusion Criteria ........................................................................................................................... 40
4.3.
Prohibitions and Restrictions ......................................................................................................... 43
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 43
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 43
6.1.
Daratumumab Preparation............................................................................................................. 43
6.2.
Daratumumab Administration ........................................................................................................ 44
6.3.
Guidelines for Prevention of Infusion Reactions............................................................................ 44
6.3.1.
Preinfusion Medication ............................................................................................................... 44
6.3.2.
Postinfusion Medication.............................................................................................................. 44
6.3.3.
Management of Infusion-related Reactions................................................................................ 45
6.3.3.1.
Infusion-Related Events of Grade 1 or Grade 2...................................................................... 46
6.3.3.2.
Infusion-Related Reactions of Grade 3 or Higher ................................................................... 46
6.4.
Dose Delays and Dose Modification.............................................................................................. 46
6.4.1.
Daratumumab-Related Toxicity Management............................................................................ 46
6.4.2.
Daratumumab Interruption or Missed Doses.............................................................................. 47
7.
TREATMENT COMPLIANCE............................................................................................................ 48
8.
CONCOMITANT THERAPY.............................................................................................................. 48
8.1.
Recommended Therapies.............................................................................................................. 48
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8.1.1.
Therapy for Tumor Lysis Syndrome ........................................................................................... 48
8.1.2.
Prophylaxis for Pneumocystis Carinii ......................................................................................... 48
8.1.3.
Prophylaxis for Herpes Zoster Reactivation ............................................................................... 49
8.2.
Permitted Therapies....................................................................................................................... 49
8.3.
Prohibited Therapies...................................................................................................................... 49
9.
STUDY EVALUATIONS .................................................................................................................... 49
9.1.
Study Procedures........................................................................................................................... 49
9.1.1.
Overview..................................................................................................................................... 49
9.1.2.
Screening Phase ........................................................................................................................ 50
9.1.3.
Treatment Phase ........................................................................................................................ 51
9.1.4.
Follow-up Phase......................................................................................................................... 51
9.2.
Efficacy........................................................................................................................................... 52
9.2.1.
Evaluations ................................................................................................................................. 52
9.2.1.1.
Definition of Measurable and Assessable Disease ................................................................. 52
9.2.1.2.
Radiographic (CT/MRI) Assessments ..................................................................................... 53
9.2.1.3.
Positron Emission Tomography (PET Scan)........................................................................... 53
9.2.1.4.
Bone Marrow Assessment....................................................................................................... 54
9.2.1.5.
Endoscopy............................................................................................................................... 54
9.2.2.
Endpoints.................................................................................................................................... 54
9.2.2.1.
Primary Endpoint ..................................................................................................................... 54
9.2.2.2.
Major Secondary Endpoints .................................................................................................... 54
9.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 55
9.3.1.
Evaluations ................................................................................................................................. 55
9.3.2.
Analytical Procedures................................................................................................................. 55
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 55
9.3.4.
Immunogenicity Assessments (Antibodies to Daratumumab).................................................... 55
9.4.
Biomarkers ..................................................................................................................................... 56
9.5.
Safety Evaluations ......................................................................................................................... 57
9.6.
Sample Collection and Handling.................................................................................................... 60
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 60
10.1.
Completion ..................................................................................................................................... 60
10.2.
Discontinuation of Study Treatment............................................................................................... 60
10.3.
Withdrawal From the Study............................................................................................................ 61
11.
STATISTICAL METHODS................................................................................................................. 62
11.1.
Subject Information ........................................................................................................................ 62
11.2.
Sample Size Determination ........................................................................................................... 62
11.3.
Efficacy Analyses ........................................................................................................................... 64
11.3.1.
Primary Efficacy Endpoint........................................................................................................... 64
11.3.2.
Secondary Efficacy Endpoints.................................................................................................... 64
11.4.
Pharmacokinetic Analyses............................................................................................................. 65
11.5.
Immunogenicity Analyses .............................................................................................................. 65
11.6.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 65
11.7.
Biomarker Analyses ....................................................................................................................... 65
11.8.
Safety Analyses ............................................................................................................................. 66
11.9.
Interim Analysis.............................................................................................................................. 67
12.
ADVERSE EVENT REPORTING ...................................................................................................... 67
12.1.
Definitions ...................................................................................................................................... 67
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 67
12.1.2.
Attribution Definitions.................................................................................................................. 69
12.1.3.
Severity Criteria .......................................................................................................................... 69
12.2.
Special Reporting Situations.......................................................................................................... 70
12.3.
Procedures..................................................................................................................................... 70
12.3.1.
All Adverse Events...................................................................................................................... 70
12.3.2.
Serious Adverse Events ............................................................................................................. 71
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12.3.3.
Pregnancy................................................................................................................................... 72
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 72
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 73
13.1.
Procedures..................................................................................................................................... 73
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 73
14.
STUDY DRUG INFORMATION......................................................................................................... 73
14.1.
Physical Description of Study Drug................................................................................................ 73
14.2.
Packaging ...................................................................................................................................... 73
14.3.
Labeling.......................................................................................................................................... 73
14.4.
Preparation, Handling, and Storage............................................................................................... 73
14.5.
Drug Accountability ........................................................................................................................ 74
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 74
16.
ETHICAL ASPECTS ......................................................................................................................... 75
16.1.
Study-Specific Design Considerations........................................................................................... 75
16.1.1.
CD38 IHC Assay......................................................................................................................... 75
16.2.
Regulatory Ethics Compliance....................................................................................................... 76
16.2.1.
Investigator Responsibilities ....................................................................................................... 76
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 76
16.2.3.
Informed Consent ....................................................................................................................... 78
16.2.4.
Privacy of Personal Data ............................................................................................................ 78
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 79
16.2.6.
Country Selection ....................................................................................................................... 79
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 80
17.1.
Protocol Amendments.................................................................................................................... 80
17.2.
Regulatory Documentation ............................................................................................................ 80
17.2.1.
Regulatory Approval/Notification ................................................................................................ 80
17.2.2.
Required Prestudy Documentation............................................................................................. 80
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 81
17.4.
Source Documentation................................................................................................................... 81
17.5.
Case Report Form Completion ...................................................................................................... 82
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 83
17.7.
Record Retention ........................................................................................................................... 83
17.8.
Monitoring ...................................................................................................................................... 84
17.9.
Study Completion/Termination....................................................................................................... 84
17.9.1.
Study Completion ....................................................................................................................... 84
17.9.2.
Study Termination....................................................................................................................... 84
17.10.
On-Site Audits ................................................................................................................................ 85
17.11.
Use of Information and Publication................................................................................................ 85
REFERENCES............................................................................................................................................ 87
ATTACHMENT 1:
REVISED RESPONSE CRITERIA FOR RESPONSE ASSESSMENT 
(CHESON 2014) ................................................................................................................................ 89
ATTACHMENT 2: ECOG PERFORMANCE STATUS SCALE ................................................................. 92
ATTACHMENT 3:
CALCULATED CREATININE CLEARANCE ........................................................... 93
ATTACHMENT 4:
ASTHMA GUIDELINES ............................................................................................ 94
ATTACHMENT 5:
CONVERSION TABLE FOR GLUCOCORTICOSTEROID DOSE........................... 96
INVESTIGATOR AGREEMENT ................................................................................................................. 97
LAST PAGE................................................................................................................................................ 97
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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Time And Events Schedule Overview ...................................................................................... 20
Table 2:
Time And Events Schedule, Dose Administration .................................................................... 23
Table 3:
Number of Subjects Enrolled .................................................................................................... 34
Table 4:
Daratumumab-Related Toxicity Management .......................................................................... 47
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 35
Figure 2:
Schematic Overview Study Treatment Administration ............................................................. 43
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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
12 January 2015
Amendment 1
19 January 2016
Amendments below are listed beginning with the most recent amendment.
Amendment-1 (19 January 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: To optimize candidate screening potential, elaborate on Indirect 
Antiglobulin (Coombs) Testing (IAT) during the Screening Phase due to the risk of daratumumab interference with
IAT, as well as make updates throughout the protocol to align with the other daratumumab protocols.
Applicable Section(s)
Description of Change(s)
Rationale: Changes were made to the subject inclusion criteria to increase candidate screening without 
compromising study objectives.
Synopsis; Subject 
Population,
4.1 Inclusion Criteria 
#2, MCL
The MCL prior line restriction of 2 to 5 lines of prior therapy was changed to at least 2 
prior lines of therapy, with no upper limit.
Synopsis, Overview
of Study Design, 
Biomarkers 
evaluation; Table 1
Time and Events 
Schedule, Tumor 
sample; 3.1 Overview 
of Study Design;
4.1 Inclusion Criteria 
#4; 9.1.2 Screening 
Phase; 9.5 
Biomarkers
To ease sample collection for the CD38 assay plus paired sample. Subjects must have 
available archival or fresh tumor tissue or both for CD38 assay.  
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Applicable Section(s)
Description of Change(s)
Synopsis, Primary 
Objective, 
Hypothesis, and 
Overview of Study 
Design; 1.3 Overall 
Rationale for the 
Study; 2.1 Objectives, 
Primary Objective; 
2.2 Hypothesis; 3.1 
Overview of Study 
Design; Figure 1; 
Table 3; 3.2 Study 
Design Rationale, 1);
4.1 Inclusion Criteria 
#4; 9.1.2 Screening 
Phase;
11.2 Sample size 
determination; 11.3.1 
Primary Efficacy 
Endpoint; 11.9 
Interim analysis
Stage 2 will allow for enrollment of subjects with all levels of CD38 expression. Changed 
CD38 expression level for subset of Stage 2 to <50% throughout. Removed CD38 positive 
subjects from text throughout.
Synopsis, Subject 
Population; 4.1
Inclusion Criteria #2, 
MCL
Changed “ibrutinib” to “Bruton’s tyrosine kinase (BTK) inhibitor”
4.2 Exclusion Criteria 
#3
Subject history of malignancy was reduced to be less strict from 5 years before screening 
period to 3 years. The minimal risk of recurrence was reduced from 3 years to 2 years.
4.2 Exclusion Criteria 
#5
Subjects with a history of Hepatitis C should not be excluded if the viral load becomes 
negative with modern therapy.
4.2 Exclusion Criteria 
#10
Added emergent use of steroids at screening stage (100 mg prednisone per day or 
equivalent for up to 7 days).
Rationale: Due to risk of daratumumab interference with IAT testing, text was removed from Prohibitions and 
Restrictions and added to Sec 9.5 Safety Evaluations to be consistent to other daratumumab protocols.
4.3 Prohibitions 
and Restrictions
Removed the text pertaining to daratumumab interference with indirect antiglobulin testing
(IAT) from here as this information is provided in Section 9.5 Safety Evaluations.
9.5 Safety
Evaluations
Updated text on daratumumab interference with indirect antiglobulin testing (IAT) to align 
with other daratumumab protocols.
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Applicable Section(s)
Description of Change(s)
Rationale: To clarify the timing of daratumumab PK and Immunogenicity sample collections and PK parameters.
Time and Events 
Schedule 
Overview
9.3.2 Analytical 
Procedures
Modified Laboratory Assessments for Daratumumab PK sampling in End-of-Treatment and 
Follow-up Phase: Added 1 week window for PK collections
Text removed:  All  samples collected and received up to the time of the primary study 
endpoint analysis (first bioanalysis) are planned to be analyzed for immunogenicity (when 
applicable) and serum daratumumab concentration as indicated by Table 1. The final 
bioanalysis is planned to include all serum daratumumab concentration (pharmacokinetics) 
and immunogenicity samples that become available after the previous analysis. Adjustments 
to bioanalysis timing may be made if it is later determined that the timing for data needed to 
facilitate crucial decision-making differs from these two planned efforts.  However, data from 
each round of bioanalysis will be considered final and samples will not be reanalyzed in any 
subsequent efforts.
9.3.3 
Pharmacokinetic 
Parameters; 11.4 
Pharmacokinetic 
Analyses
Removal of PK parameters to be tested CL, V.  Definitions for Cmin and Cmax for added.
9.4
Pharmacokinetic/
Pharmacodynamic 
Evaluations
Removal of section as text is duplicated in Sec 11.6.
11.5 
Immunogenicity
Analyses
Text added “In addition, subjects who are positive for antibodies to daratumumab will also be 
listed.”
Rationale: Miscellaneous updates made to clarify or add consistency.
Synopsis, Overview 
of Study Design and 
Efficacy Evaluations; 
Table 1 Time and 
Events Schedule; 3.1 
Overview of Study 
Design; 9.2.1 
Evaluations; 10.2 
Discontinuation of
Study Treatment
Disease evaluations were restated in weeks not cycle times.  The follow text regarding the 
timing of disease evaluations was added.  After first dose, disease evaluations will occur 
every 8 weeks for the first 3 evaluations, then every 16 weeks for the next two 
evaluations and then every 24 weeks thereafter.
Synopsis, Overview 
of Study Design; 3.1 
Overview of Study 
Design; 9.1.4 Follow-
up Phase
Clarification made for end of cohort. The end of the study cohort for each NHL subtype is 
defined as 18 months after the last subject in the particular NHL subtype receives the first 
dose of daratumumab.
Table 1; 6 Dosage 
and Administration
Clarification to give a 1 day window within-cycle (Cycles 1-6) to accommodate site or 
subject logistics.
6. 3.2 Postinfusion 
Medication 
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 salbumatol salmeterol ± inhaled corticosteroids for subjects with COPD).
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Applicable Section(s)
Description of Change(s)
6.4.1 Daratumumab-
Related Toxicity 
Management; 
Footnote added to 
Table 4
Edits made to clarify dose delays and adjustments. Text added: “If a dose is delayed on 
Day 1of a cycle, then the dates of all the subsequent doses should be adjusted. However, if 
a within-cycle dose is delayed, then the dates of the subsequent doses should not be 
adjusted.”
9.1.1 Overview; 16.1
Study Specific-
Design 
Considerations
Clarifications made to total estimated blood volumes.
9.2.1.3 PET Scan
Clarification made to add “per investigator discretion” and remove “and relapse from CR”.
Attachment 1: 
Revised Response 
Criteria for Response 
Assessment
Clarified site for no response or stable disease of  “Target nodes/nodal masses, extranodal 
lesions” to be consistent with the Revised Response Criteria for Response Assessment
9.5 Safety 
Evaluations 
9.5 Safety 
Evaluations, Vital 
Signs
Blood type, RhD tests added
Text was removed that was contradictory to the eCRF. Only vital signs associated with an 
AE will be entered in the eCRF;
Synopsis, Overview 
of Study Design; 4.1 
Inclusion Criteria #4; 
9.1.2 Screening 
Phase; 9.4
Biomarkers 
Clarified that the CD38 IHC test is “investigational and under development”.
7. Treatment 
Compliance
Added “and postinfusion” medications for clarity.  A subject diary may be used to 
document any pre- and post- infusion medications taken at home.
Rationale:  Clarification made to the Follow-up Phase.
Table 1, Time and 
Events Schedule
During Follow-up Phase, 8 weeks post PD collection of ECOG was removed as it is not 
necessary.
Table 1, Time and 
Events Schedule; 
9.1.4 Follow-up 
Phase
Added window of +/- 2 weeks for Follow-up Phase and changed 4 months to 16 weeks.
Rationale: To increase the strength of our primary endpoint analysis.
Synopsis, Statistical 
Methods; 11.3.1 
Primary Efficacy 
Endpoint
For each NHL subtype, an estimate of the ORR was changed from 90% to 95% for the 
two-sided exact confidence interval.
Rationale:  Hypokalemia increases the risk of QT elongation in ECG.
4.3 Prohibitions and 
Restrictions
Added: 2. Subjects with persistent hypokalemia (eg, serum potassium <3.5 mM after 
proper treatment) need to be monitored for the potential of QTc prolongation.
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Applicable Section(s)
Description of Change(s)
Rationale:  To align language to be consistent with other daratumumab protocols, IB, and new template text.
1.2 Daratumumab
Revised text: For the most comprehensive nonclinical and clinical information regarding 
daratumumab, refer to the latest version of the Investigator's Brochure (Daratumumab IB). 
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.
4. Subject Population
4.1 Inclusion Criteria, 
#6 g)
If there is a question about the inclusion or exclusion criteria below, the investigator 
should must consult with the appropriate sponsor representative and resolve any issues
before enrolling a subject in the study. Waivers are not allowed.
Changed calculated creatinine clearance of ≥30 mL/min.
4.1 Inclusion Criteria, 
#9, 4.2 Exclusion 
Criteria #11
Changed text that men should not donate sperm for 3 months after receiving study drug. 
Women should not become pregnant within 3 months after last dose of daratumumab, or 
man should not father a child within 3 months after last dose of daratumumab.
Synopsis, Subject 
Population; 4.1 
Inclusion Criteria #2, 
DLBCL
Clarified text to subjects with relapsed or refractory disease who have not received 
HDT and ASCT and are ineligible for HDT/ASCT due to comorbidities
4.2 Exclusion 
Criteria, #7c)
4.2 Exclusion 
Criteria, NOTE
Modify the language of “screening 12-lead ECG showing a baseline QT interval as 
corrected by Fridericia’s formula (QTcF) >470 msec ” as “screening 12-lead ECG 
showing a baseline QT interval as corrected QTc>470 msec”
Revised 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. See 
Section 17.4, Source Documentation, describes the required documentation to support 
meeting the enrollment criteria.
4.3 Prohibitions and 
Restrictions
New text: 1. Subjects agree to follow the contraceptive requirements as noted in the 
inclusion criteria.
6.4.1 Daratumumab-
Related Toxicity 
Management
Changed Grade 3 or higher neutropenia with infection to “any grade”
8.3 Prohibited 
Therapies
The maximum dose of  prednisone allowed was increased to ≥20 mg/day of prednisone 
or its equivalent per day for more than 7 days during study, unless 
reviewed/approved by medical monitor).(>10 mg  prednisone per day or equivalent for 
over 7 days) 
12.3.3 Pregnancy
Any subject who becomes pregnant during the study must promptly discontinue further 
study treatment. If a subject becomes pregnant during the study, a determination 
regarding study drug discontinuation must be made by the investigator in 
consultation with the sponsor.
17.5 Case Report 
Form Completion
Text regarding corrections to eCRFs updated.
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Applicable Section(s)
Description of Change(s)
Rationale:  Optional endoscopy at baseline added as CRs must be confirmed with endoscopy if the lymphoma 
originated from or involved the GI tract at diagnosis.  
Table 1 Time and 
Events Schedule 
Overview; 9.2.1.5 
Endoscopy (new)
Endoscopy added.  New section added: CRs must be confirmed with endoscopy 
examination if the lymphoma originated from or involved the GI tract at diagnosis.  
Rationale: To reflect current practice, updated management of infusion-related reactions section to indicate that the 
infusion will be paused (not interrupted or slowed down) if an infusion-related reaction occurs.
6.3.3 Management 
of Infusion-
Related Reactions
If an infusion-related reaction develops, then the infusion should be paused temporarily 
interrupted or slowed down.
Rationale:  Removal of the term “legally acceptable representative” to address IRB concerns that for those adults 
who lack capacity to consent should be excluded.
4.1 Inclusion Criteria 
#10, 9.5 Safety 
Evaluations (Adverse 
Events); 10.2 
Discontinuation of 
Study 
Treatment;15.2.3 
Informed Consent; 
16.2.4 Privacy of 
Personal Data
Removal of “legally acceptable representative” throughout the protocol.
Rationale: Beta 2 microglobulin (β2M) was added because it is an important lymphoma biomarker for tumor 
burden as well as prognosis. 
Table 1 Time and 
Events Schedule 
Overview; 9.5 Safety 
Evaluations; 11.3.1 
Primary Efficacy 
Endpoint
Beta 2 microglobulin was added to the Time and Events Schedule and safety analyses.  
Statistical methods for beta 2 microglobulin were added. 
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Applicable Section(s)
Description of Change(s)
Rationale: Update tumor lysis syndrome text added to align with other daratumumab protocols and provide 
additional detailed information for tumor lysis syndrome diagnosis and management.
8.1.1 Therapy for 
Tumor Lysis 
Syndrome 
Subjects should be monitored for symptoms of tumor lysis syndrome. Management of 
tumor lysis syndrome, including dehydration and abnormal laboratory test results such as 
hyperkalemia, hyperuricemia, and hypocalcemia, are highly recommended. It is also 
recommended that high-risk subjects, ie, those with a high tumor burden, be treated 
prophylactically in accordance with local standards (eg, rehydration; diuretics; allopurinol 
300 mg daily and medication to increase urate excretion).
Text updated: 
The symptoms for tumor lysis syndrome should be monitored. Subjects with more than 1 
of the factors listed below are considered to be at increased risk of tumor lysis syndrome 
and should be considered for hydration and treatment with a uric acid-lowering agent as 
well as for frequent monitoring of tumor lysis associated signs and symptoms, including 
blood chemistry. Uric acid-lowering agents may include xanthine oxidase inhibitor 
allopurinol or Uloric® [Adenuic™, febuxostat] with or without rasburicase per the drug 
product package inserts.
1. Serum creatinine ≥1.5 x ULN or calculated creatinine clearance <60 mL/min 
2. Uric acid ≥450 µmol/L or 7.5 mg/dL 
3. Bulky disease (eg, lymph node >10 cm or massive splenomegaly)
4. Elevated LDH >2 x ULN 
Rationale:  Since this study is in relapsed/refractory setting, chest x rays are not necessary for all subjects, unless 
clinically indicated.
Table 1 Time and 
Events Schedule 
Overview; 9.1.2 
Screening Phase
Chest x rays were removed from the Time and Events Schedule. 
Rationale:  Updated text reflects most recent screening data in clinical study.
3.2 Study Design 
Rationale
This subset of subjects may represent about up to 50%, 30% and 60% 30% of population 
with MCL, DLBCL and FL, respectively. If a low overall response rate is observed in this 
subset of subjects, it is highly unlikely that there exists a practical subset of subjects based 
on CD38 expression level in which a clinically meaningful overall response rate can be 
observed.
Rationale:  Since the study may include subjects that have taken BTK inhibitors, a washout period for BTK 
inhibitors was added.
4.2 Exclusion                  h) for the MCL cohort, BTK inhibitors within 1 week or 5 half-lives, whichever is longer
Criteria #2, h) new
Rationale:  Subject wallet (study) cards were corrected.
12.3.1 All Adverse 
Events;
15 Study-Specific 
Materials
Removed “Blood antigen profile” and replaced with Blood type, Rh, and IAT or 
phenotyping result collected before first daratumumab dose
Rationale:  Additional risk benefit language added for the investigational CD38 IHC Assay.
16.1.1 CD38 IHC 
Assay (New Section 
added)
New risk benefit language for the investigational CD38 IHC assay to included false 
positives and false-negative results.
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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 Evaluate Efficacy and Safety of Daratumumab in Relapsed or 
Refractory Mantle Cell Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular Lymphoma
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds with high affinity to a unique 
epitope on CD38, a transmembrane glycoprotein. It is a targeted immunotherapy directed towards tumor 
cells that express high levels of CD38, such as plasma cells from patients with multiple myeloma. CD38 
is also expressed in subtypes of non-Hodgkin’s lymphoma (NHL), warranting further investigation of 
daratumumab in NHL.
OBJECTIVES AND HYPOTHESIS
Primary Objective
The study will evaluate daratumumab separately in three relapsed or refractory NHL subtypes: mantle cell 
lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), and follicular lymphoma (FL). There are 
two main objectives:

To assess overall response rate (ORR, including complete response [CR] and partial response [PR]), 
of daratumumab in subjects with NHL. 

To evaluate association between ORR and CD38 expression level in order to determine a threshold 
for CD38 expression level in each NHL subtype, above which daratumumab activity is enhanced.
Secondary Objectives
For each subtype of NHL, the secondary objectives are:

To assess the duration of response (DoR), progression-free survival (PFS), and overall survival (OS)

To assess time to response

To assess and correlate the CD38 expression level with DoR, PFS, and OS 

To assess pharmacokinetics of daratumumab 

To assess immunogenicity of daratumumab 

To assess the safety profile of daratumumab
Exploratory Objectives

To explore biomarkers, in addition to CD38 expression level, predictive of response to daratumumab 
Hypothesis
For each subtype of NHL, analyses will be conducted on the overall population and on the CD38 enriched 
population (only subjects with CD38 expression level above a threshold to be determined via statistical 
inference). There is one hypothesis for each population. Daratumumab is considered active per subtype if 
at least one of the null hypotheses is rejected:
For MCL

For the overall population, ORR is at least 35% (versus a null hypothesis of at most 20%)

For the enriched population, ORR is at least 40% (versus a null hypothesis of at most 20%)
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For DLBCL 

For the overall population, ORR is at least 30% (versus a null hypothesis of at most 15%)

For the enriched population, ORR is at least 40% (versus a null hypothesis of at most 15%)
For FL

For the overall population, ORR is at least 50% (versus a null of at most 30%)

For the enriched population ORR is at least 60% (versus a null of at most 30%).
OVERVIEW OF STUDY DESIGN
This is an open-label, multicenter, Phase 2 study in subjects at least 18 years of age with tumors in MCL, 
DLBCL, or FL. Approximately 210 subjects may be enrolled, with up to 100 subjects planned for MCL 
and up to 55 subjects each for DLBCL and FL.
This study will be conducted and analyzed separately for each subtype of NHL. A biomarker adaptive 
threshold design is implemented that enables testing of the overall population and the establishment of a 
biomarker-defined enriched population simultaneously. Two stages are planned.
Stage 1 of the study is designed to provide a preliminary assessment of activity at an early stage. Since 
CD38 expression level may be associated with daratumumab activity, Stage 1 will enroll subjects who 
have tumors where at least 50% of the cells are CD38 positive as determined by the CD38 test currently 
under development. This requirement seeks to mitigate the possibility that a low response rate observed in 
Stage 1 might be due to low levels of CD38 expression. The selection of the 50% cutoff is based on the
existing CD38 expression level data in these NHL subtypes as well as practical considerations.
At the end of Stage 1, which is expected to be 6 months after the last subject is enrolled in each NHL 
subtype, or earlier if emerging data allows, an interim analysis will be conducted. The purpose of the 
interim analysis is to evaluate efficacy and safety data in Stage 1. The efficacy assessment will be focused 
on ORR. If the futility criteria as defined in the protocol are met, an NHL subtype may be terminated. 
Alternatively, if the futility criteria are not met and if supported by the totality of the Stage 1 data, Stage 2 
for that NHL subtype may be opened for accrual. If the required number of responses (eg, 5 responders 
out of 20 enrolled subjects in MCL) is observed prior to completion of enrollment in Stage 1, Stage 2 may 
be opened immediately upon completion of enrollment to Stage 1, if supported by the totality of data.
Stage 2, if opened, is designed to further evaluate safety and efficacy as well as to determine a threshold 
for CD38 expression that is associated with enhanced daratumumab activity. Therefore, Stage 2 will allow 
for enrollment of subjects with all levels of CD38 expression.  However, to mitigate the possibility that a 
low response may be observed due to low levels of CD38 expression in enrolled subjects, the number of 
Stage 2 subjects with CD38 expression level <50% will be capped within each NHL subtype.
The target number of subjects in each stage by CD38 expression level is shown in the table below.
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Type of NHL
Number of Subjects
Stage 1
CD38 expression 
level b
≥50%
Stage 2 (optional)
Overall
CD38 expression level a
<50%
CD38 expression 
level b
≥50%
Total
MCL
20
≤30
≥50
100
DLBCL
15
≤20
≥20
55
FL
15
≤20
≥20
55
a.
These subjects have tumors where <50% of the cells are positive for CD38 by immunohistochemistry.
b.
These subjects have tumors where ≥50% of the cells are positive for CD38 by immunohistochemistry.
Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase. The 
Screening Phase will be up to 28 days prior to Cycle 1, Day 1. Prior to enrollment, subjects are required 
to provide tumor tissue to determine CD38 expression level by immunohistochemistry (IHC) at a central 
laboratory. An additional fresh biopsy should be obtained whenever possible even if an archival sample is 
provided. The Treatment Phase will extend from Cycle 1, Day 1 until study drug discontinuation. After 
first dose, disease evaluations will occur every 8 weeks for the first 3 evaluations, then every 16 weeks for 
the next two evaluations and then every 24 weeks thereafter. Subjects will be treated until disease 
progression, unacceptable toxicity, or other reasons as listed in the protocol. 
The Follow-up Phase will begin once a subject discontinues study drug, and will continue until death, loss 
to follow up, consent withdrawal for study participation, or end of study, whichever occurs first.
An interim analysis for futility will be conducted in each NHL subtype no later than 6 months from when 
the last subject is enrolled in Stage 1 in that NHL subtype. If Stage 2 is expanded for a particular NHL 
subtype, the primary analysis will be performed at 6 months after the last subject is enrolled in Stage 2.
The end of the cohort for each NHL subtype is defined as 18 months after the last subject in the particular 
NHL subtype receives the first dose of daratumumab. After each NHL subtype completes the study, the 
sponsor will ensure that subjects, who are currently on treatment and receiving benefit, as determined by 
the investigator, will continue to receive daratumumab. The end of the study is defined as the completion 
of all three NHL subtypes.
Assessment of tumor response and disease progression will be conducted by investigators in accordance 
with the Cheson 2014 response criteria. Safety evaluations will include AE monitoring, physical 
examinations, electrocardiogram (ECG) monitoring, clinical laboratory parameters (hematology and 
chemistry), vital sign measurements, and Eastern Cooperative Oncology Group (ECOG) performance 
status. Measures to prevent infusion-related reactions will include preinfusion medication with 
methylprednisolone, acetaminophen (or paracetamol), and an antihistamine before each daratumumab 
infusion. Blood samples will be drawn for assessment of pharmacokinetics, immunogenicity, biomarkers 
and pharmacodynamics parameters.
SUBJECT POPULATION
Key eligibility criteria include the following: subjects who are 18 years of age, have histologically 
confirmed diagnosis of MCL, DLBCL, or FL and measurable disease, centrally determined expression 
levels of CD38, and an ECOG performance status score of 0 or 1. Key criteria for each NHL subtype:
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MCL:

pathologically verified diagnosis of MCL based on local pathology report, AND

relapsed or refractory disease after at least 2 prior lines of therapy, including at least one cycle of a 
Bruton’s tyrosine kinase  (BTK) inhibitor therapy and documented PD during or after BTK inhibitor 
treatment or subjects who could not tolerate BTK inhibitor (ie, discontinued BTK inhibitor due to 
adverse events [AEs])
DLBCL:

pathologically confirmed diagnosis of non-transformed DLBCL, AND

relapsed or refractory disease; for those subjects who have not received HDT/ASCT and are not 
eligible for HDT/ASCT due to comorbidities 
FL:

pathologically confirmed diagnosis of FL of Grade 1, 2, or 3a according to World Health 
Organization criteria without pathological evidence of transformation, AND

relapsed disease after at least two prior systemic therapies including one anti-CD20 containing 
combination regimen
DOSAGE AND ADMINISTRATION
Daratumumab (16 mg/kg) will be administered by 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.
EFFICACY EVALUATIONS/ENDPOINTS
After the first dose, disease evaluations will be performed every 8 weeks (±7 days) in the first 6 months
(Week 9 ±7 days, Week 17 ±7 days, Week 25 ±7 days, followed by every 16 weeks ±7 days [Weeks 41 
and 57], and thereafter every 24 weeks [±14 days] until PD). These assessments will be conducted until 
disease progression, withdrawal of consent from study participation, or the end of study. 
The determination of disease status will be assessed by the investigator based on the Revised Criteria for 
Response Assessment (Cheson 2014). Identical methodology should be used for disease assessment at 
screening and throughout the course of the study.
Radiological and PET scans should be performed and collected according to instructions from the 
independent imaging laboratory. A central review of the response assessments may be performed if 
deemed necessary.
The major efficacy endpoint, ORR, is defined as the proportion of subjects who achieve CR or PR. 
Secondary efficacy endpoints are:

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 (or relapse for subjects who experience CR). For 
those subjects who are still without progression/relapse, DoR will be censored at the last adequate 
tumor assessment.

PFS is defined as the duration from the date of the first daratumumab dose to the date of 
progression/relapse 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.
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
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.

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) is first documented. For non-responders, it will be censored at 
the date of progressive disease/relapse or the date of the last adequate disease assessment, whichever 
comes first.
PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS
For all subjects, pharmacokinetic samples to determine serum concentration of daratumumab will be 
obtained according to Time and Events Schedule. At specified timepoints, venous blood samples (5 mL 
per sample) will be collected to determine serum concentration of daratumumab and the serum will be 
divided into 3 aliquots (1 aliquot for pharmacokinetic analysis, 1 aliquot for antibodies to daratumumab 
analysis [when appropriate], and 1 aliquot as a backup). 
BIOMARKER EVALUATIONS 
During screening, subjects will be required to provide archived tumor samples for assessment of CD38 
expression based on the CD38 investigational IHC test performed at the central laboratory. An additional 
fresh biopsy should be obtained whenever possible even if an archival sample is provided. Fresh tumor 
samples can be either lymph node excision or core needle biopsy; fine needle aspirates are not acceptable. 
In addition to evaluating CD38 expression, archived biopsy samples and/or fresh may be evaluated 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, Gene Expression  Profiling [GEP], quantitative RT-PCR, or RNA-seq) to
determine if specific mutations or transcriptomic profiles (translocations, deletions, inversions, genes 
involved in B-cell signaling pathways, 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, CD59 expression will be measured by IHC in a designated laboratory as an exploratory 
biomarker. CD59 is a complement inhibitory protein and can contribute to resistance to complement-
dependent cytotoxicity, which may be important for daratumumab response.
Whole blood samples will be utilized for immunophenotyping, (performed by flow cytometry or mass 
cytometry/time-of-flight mass spectrometry [CyTOF]) which includes analysis of natural killer cells, T 
cells, and B cells as well as other potential immune cell subpopulations. 
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 
(IL-1, IL-6, TNFα, IFNγ, tryptase), and exploratory proteomics.
SAFETY EVALUATIONS
Safety will be measured by AEs, laboratory test results, ECGs, vital sign measurements, physical 
examination findings, and assessment of ECOG performance status score.
STATISTICAL METHODS
For each NHL subtype, an estimate of the ORR will be presented along with a two-sided 95% exact 
confidence interval. In addition, the biomarker adaptive threshold method of Jiang (2007)16 will be 
utilized to select a threshold for CD38 expression level. The threshold is used to define an enriched 
subpopulation above which the daratumumab activity is enhanced. The number and percentage of 
subjects falling into each response category will be descriptively tabulated. Duration of response will be 
provided descriptively using the Kaplan-Meier method for responders only. 
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Progression-free survival and OS will be analyzed using the Kaplan-Meier method, and the comparison 
between the above- and below-threshold subpopulations will be made using log-rank test and Cox 
regression.
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Table 1:
Time And Events Schedule Overview
Notes
Screening 
Phase
Treatment Phase 
EOT
FU 
Phase
within 28 
days before 
Cycle 1 Day 1
Day 1 of each cycle (4-week cycles)
within 30
days of 
last dose
Q16 
weeks 
+/- 2 
weeks
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.
Procedures
Informed consent
ICF must be signed before any study-related procedures are 
performed and may be more than 28 days prior to C1D1.
X
Eligibility criteria
X
Demography/ 
Medical History
X
FEV1 test
Subjects with COPD 
X
Tumor sample
If a fresh biopsy (lymph node excision or core needle biopsy) 
is taken, then it should be done within 28 days of C1D1.  
Archived sample (slides or tumor block) can be acquired more 
than 28 days prior to C1D1. 
For subjects with MCL a copy of the pathology report must be 
sent to the sponsor. CD38 assessment by IHC performed 
centrally; enrollment only after defined CD38 criteria are met.
X
ECOG
Obtain prior to any other study procedures planned for the 
same day.
X
C1D1, C3D1, D5D1, C7D1, thereafter every 12 wks
16 wks
post PD
12-lead ECG
Acceptable for screening if performed as part of SOC within 
42 days before Cycle 1 Day 1
X
C3D1, C6D1
X
Physical 
examination
Height at screening only
X
symptom and disease directed exam as clinically 
indicated
Vital signs, weight
X
Please see Table 2 for details.
Lymphoma B 
symptoms
Review and record (fevers, night sweats, weight loss)
X
X
X
Blood type and 
Indirect 
Antiglobulin Test 
(IAT)
ABO, Rh, and IAT
predose C1D1
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Notes
Screening 
Phase
Treatment Phase 
EOT
FU 
Phase
within 28 
days before 
Cycle 1 Day 1
Day 1 of each cycle (4-week cycles)
within 30
days of 
last dose
Q16 
weeks 
+/- 2 
weeks
Laboratory Assessments
Pregnancy test
serum or urine, women of childbearing potential only, within 
14 days of C1D1
X
As clinically indicated
X
Hematology
X
Please see Table 2 for details.
X
Serum chemistry
X
Please see Table 2 for details.
X
β2-microglobulin
X
Biomarker sample
Whole blood samples for plasma and PBMC biomarker 
assessments and for immunophenotyping
C1D1, C2D1, and C6D1 predose
X
Daratumumab PK 
On dara infusion days, 1 sample is to be collected before 
(window -2 hrs) and 1 sample immediately after (window +2 
hrs) end of infusion. Samples to be sent to central laboratory.
C1D1, C3D1, C5D1, C7D1, C11D1, C15D1
4 wks (+/- 1 wk) and 
8 wks (+/- 1 wk) after 
last daratumumab 
dose
Daratumumab 
immunogenicity
No additional sample needed for planned timepoints; will be 
taken from PK sample. 
C1D1 predose 
If an infusion reaction occurs, obtain unscheduled 
blood sample as soon as possible.
4 wks  (+/- 1 wk) and 
8 wks (+/- 1 wk) after 
last daratumumab 
dose
Disease Evaluations: Every effort should be made to conduct disease evaluations as per schedule. Refer to Section 9.2 for details on efficacy evaluations.
CT or MRI 
imaging (neck, 
chest, abdomen, 
and pelvis) 
Acceptable for screening if performed as part of SOC within 
42 days before Cycle 1 Day 1. 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 stored at a 
central lab.
X
Week 9 ±7 days, Week 17 ±7 days, Week 25 ±7 days (8 weeks since 
previous image)
Week 41±7 days and Week 57 ±7 days (16 weeks since previous image)
Thereafter every 24 wks (±14 days) until PD (24 weeks since previous image)
The same methodology should be used throughout the study.
FDG-PET scan
(skull base to the 
proximal femur)
Acceptable for screening if performed as part of SOC within 
42 days before Cycle 1 Day 1. All scans will be collected and 
stored at a central lab
optional
if positive PET at screening, at the time of maximal 
tumor reduction (eg, CR or 2 consecutive CT scans 
showing no further tumor reduction) 
Bone marrow 
aspirate/biopsy
Acceptable for screening if performed as part of SOC within 
42 days before Cycle 1 Day 1. 
optional
required to confirm CR (all lymphoma subtypes), 
regardless of whether aspirate/biopsy was 
performed at screening
Endoscopy
Only subjects with diagnosis of lymphoma with GI 
involvement
optional
CRs must be confirmed with endoscopy if the 
lymphoma originated from or involved the GI tract 
at diagnosis.
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Notes
Screening 
Phase
Treatment Phase 
EOT
FU 
Phase
within 28 
days before 
Cycle 1 Day 1
Day 1 of each cycle (4-week cycles)
within 30
days of 
last dose
Q16 
weeks 
+/- 2 
weeks
Subsequent 
therapy
X
Other new
malignancy
X
Survival
X
Ongoing Subject Review
Adverse Events
See Section 12 for detailed instructions.
continuous from the time of signing of ICF until 30 days after last dose of last study drug
Concomitant 
Medications
See Section 8 for detailed instructions.
continuous from the time of signing of ICF until 30 days after last dose of last study drug
Abbreviations: AE=adverse event; C=cycle; COPD=chronic obstructive pulmonary disease; CR=complete response; CT=computed tomography; ECOG=Eastern 
Cooperative Oncology Group; D=day; Dara=daratumumab; ECG=electrocardiogram; EOT= End-of-Treatment; FEV= Forced Expiratory Volume (in 1 second); 
FU=follow-up; IAT=indirect antiglobulin test; ICF=informed consent form; IHC=immunohistochemistry; MCL=mantle cell lymphoma; MRI=magnetic resonance imaging; 
PBMC= peripheral blood mononuclear cell ; PET=positron emission tomography; PK=pharmacokinetics; PD= disease progression; Q16 weeks=every 16 weeks;
SAE=serious adverse event; SIPPM=site investigational product procedures manual; SOC=standard of care;  Wk=week
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Table 2:
Time And Events Schedule, Dose Administration
Notes
Cycle 1 and Cycle 2
Cycle 3-Cycle 6
Cycle 7 and after
EOT
D1
D8
D15
D22
D1
D15
D1
Hematology
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 timepoints, as clinically 
indicated. To be done by local lab. Refer to Section 9.5 for 
parameters to be tested.
X
X
X
X
X
X
X
X
Clinical 
Chemistry
X
X
X
X
Weight
If a subject’s weight changes by more than 10% from 
baseline, the dose study treatment will be re-calculated
X
X
X
Vital Signs
Vital signs (blood pressure, temperature, pulse) measured in 
sitting position. On Cycle 1 Day 1: immediately before the 
start of dara 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. For all other infusions, vital signs will be measured 
immediately before infusion start and at end of dara infusion.
X
X
X
X
X
X
X
Study Drug Administration
Daratumumab
Refer to SIPPM for recommendations on daratumumab 
infusion rate. Administer pre- and postinfusion medications as 
per Section 6.
X
X
X
X
X
X
X
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ABBREVIATIONS
ADCC
antibody-dependent cell-mediated cytotoxicity
ADCP
antibody-dependent cellular phagocytosis
AE
adverse event
ALT
alanine aminotransferase
ASCT
autologous stem cell transplantation
AST
aspartate aminotransferase
BTK
Bruton’s tyrosine kinase
CDC
complement-dependent cytotoxicity
CHOP
cyclophosphamide, doxorubicin, vincristine, and prednisone
Cmax
maximum observed concentration
Cmin
minimum observed concentration
COPD
chronic obstructive pulmonary disease
CR
complete response
CrCl
creatinine clearance
CT
computed tomography
DLBCL
diffuse large B cell lymphoma
DoR
duration of response
eCRF
electronic case report form
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eDC
electronic data capture
EU
European Union
FDA
Food and Drug Administration
FdG
fluoro-deoxyglucose
FEV
forced expiratory volume
FL
follicular lymphoma
GCP
Good Clinical Practice
hyper-CVAD
hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone
IAT
indirect antiglobulin test (also known as indirect Coombs test)
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
Ig
immunoglobulin
IHC
immunohistochemistry
IRB
Institutional Review Board
IRR
infusion-related reaction
IV
intravenous
MCL
mantle cell lymphoma
MR
minimal response
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
non-Hodgkin’s lymphoma
NK
natural killer
ORR
overall response rate
OS
overall survival
PD
disease progression
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetics
PQC
Product Quality Complaint
PR
partial response
RBC
red blood cell
R-CHOP
rituximab + CHOP
R-DHAP
rituximab, dexamethasone, high-dose cytarabine, and cisplatin
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R-Hyper-
CVAD
rituximab + hyper-CVAD
R-ICE
rituximab, ifosfamide, carboplatin, and etoposide
SAE
serious adverse event
SIPPM
Site Investigational Product Procedures Manual (or equivalent document)
ULN
upper limit of normal
VGPR
very good partial response
VR-CAP
bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone
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1.
INTRODUCTION
1.1.
Background
The non-Hodgkin’s lymphomas (NHLs) are a diverse group of blood cancers that originate from 
lymphocytes. They can occur at any age and are often manifested by enlarged lymph nodes, 
fever, and weight loss. There are many different types of NHLs. Clinically, there are aggressive 
and indolent types of NHL. These NHLs can be formed from either B-cells (>90%) or T-cells 
(<10%) or rarely natural killer (NK) T cells. Prognosis and treatment depend on the stage and 
type of disease.
1.1.1.
Diffuse Large B-cell Lymphoma (DLBCL)
The most common histological subtype of NHL is Diffuse Large B-Cell Lymphoma (DLBCL) 
which accounts for approximately 30% to 58% of all new cases diagnosed annually worldwide 
(Tilly 2010)25. Standard chemotherapy treatment consists of cyclophosphamide, doxorubicin, 
vincristine, and prednisone (CHOP) and rituximab. A randomized study of CHOP versus 
rituximab-CHOP (R-CHOP) was performed in 398 newly diagnosed DLBCL patients, 60 to 
80 years of age (Coiffier 2002)4. The rate of complete response (CR) was significantly higher in 
the group that received R-CHOP compared with the group that received CHOP alone (76% vs. 
63%; p=0.005). With a median follow-up of 2 years, event-free survival (EFS) was 57% in the 
R-CHOP group and 38% in the CHOP group. Results from the 10-year analysis confirmed the 
benefit of the addition of rituximab to CHOP (10-year progression-free survival [PFS]: 36.5% 
vs. 20% for R-CHOP and CHOP, respectively; 10-year OS: 43.5% vs. 27.6%, respectively) 
(Coiffier 2010)6. Despite high response rates with an anthracycline-containing regimen such as 
R-CHOP, approximately one-third of patients with DLBCL have refractory disease or will 
relapse. A variety of combination cytotoxic chemotherapy regimens are used in the relapsed / 
refractory setting. Two commonly used regimens are R-ICE (rituximab, ifosfamide, carboplatin, 
and etoposide) and R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin). 
The CORAL study (Collaborative Trial in Relapsed Aggressive Lymphoma, Gisselbrecht 
2010)11 compared the R-ICE and R-DHAP regimens in relapsed patients with DLBCL followed 
by high-dose chemotherapy-autologous stem cell transplantation (HD-ASCT) after an induction 
response. The study showed similar 3-year EFS and OS rates for the 2 induction regimens;
however, subjects previously treated with rituximab had an OS of 40% compared with 66% for 
subjects with no prior rituximab treatment. Subjects whose disease progressed less than 
12 months after diagnosis compared with more than 12 months also had significantly lower 
response rates (46% vs. 88%, respectively; p<0.001), indicating a poor prognosis for those 
patients who relapse early following rituximab-containing first-line therapy. Although subjects 
who underwent ASCT had longer PFS (3-year PFS=39%) compared with subjects who did not 
receive ASCT (14%; p<0.001), only 50% of subjects were able to undergo ASCT. Therefore, 
given the limited options for salvage therapy in the relapsed/refractory setting, additional 
therapies are urgently needed to improve outcomes in relapsed/refractory DLBCL.
1.1.2.
Follicular Lymphoma (FL)
Follicular lymphoma (FL) is the second most common NHL and comprises approximately 20% 
to 33% of all NHL cases (Anderson 1998)1. Follicular lymphoma is characterized by an indolent 
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clinical course, typical morphology, and the presence of a chromosomal translocation, 
t(14;18)(q32;q21) or variant in 85% of patients (Relander 2010)24. This translocation results in 
the overexpression of BCL2 protein, a member of a family of proteins that inhibits apoptosis 
(Freedman 2012)10. Transformation of FL to an aggressive lymphoma, most commonly the 
clonally related DLBCL, occurs at a rate of 3% per year and is associated with substantial 
morbidity and mortality (Relander 2010)24, including rapid progression of lymphadenopathy, 
extranodal disease, B symptoms (fever, drenching night sweats, and weight loss 10%), and 
elevated serum lactate dehydrogenase (LDH) (Freedman 2012)10. In patients with early-stage FL 
(Stage I or II), radiation therapy is associated with 10-year progression-free survival (PFS) rates 
of 45% to 60%, and is considered to represent a curative treatment in this otherwise incurable 
disease with conventional modalities (Jacobson 2012)15. Advanced-stage FL (Stage III or IV) is 
incurable with conventional chemotherapy, even if combined with radiotherapy (Relander 
2010)24. Historically, median survival has ranged from 6 to 10 years. Responsiveness to therapy 
and duration of response (DoR) both decline with repeated treatments when relapsed,
particularly after documented transformation of FL to a more aggressive histology lymphoma, 
with death generally resulting from the disease (Montoto 2007)18. Idelalisib (Zydelig) was 
recently approved by the FDA to treat relapsed FL in patients who have received at least two 
prior systemic therapies, which defines a population with unmet medical needs. The safety and 
efficacy of Zydelig in patients with FL was evaluated in a single-arm, multicenter clinical trial 
which included 72 patients with follicular B-cell non-Hodgkin lymphoma who had relapsed 
within 6 months following rituximab and an alkylating agent and had received at least 2 prior 
treatments. The results showed that overall response rate (ORR) was 54% (CR 8% and partial 
response (PR) 46%). The median DoR range was between 1-15 months.
1.1.3.
Mantle Cell Lymphoma (MCL)
Mantle cell lymphoma (MCL) is an incurable subtype of NHL that was recognized as a unique 
clinicopathologic entity in the 1990s (Harris 1994)12. It is often said to incorporate the worst 
aspects of both the aggressive and indolent lymphomas. The disease progresses quickly, like the 
aggressive lymphomas, but it is incurable, like the indolent lymphomas. The unique 
characterization at the molecular level is the overexpression of the cell cycle regulator protein 
cyclin D1. This is due to the chromosomal translocation t(11;14)(q13;q32), which puts the cyclin 
D1 gene, B-cell leukemia/lymphoma-1 (bcl-1), under the control of the immunoglobulin heavy 
chain enhancer with subsequent overexpression of cyclin D1 (Harris 1994; Van Den Berghe 
1979; Williams 1992)12,26,27. Current initial therapy for the treatment of MCL includes CHOP or 
hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating 
with methotrexate and cytarabine (Hyper-CVAD), often in combination with rituximab (R-
CHOP or R-Hyper-CVAD). The FDA also approved in October 2014 the use of bortezomib, 
rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) as frontline treatment for 
patients with MCL. The use of R-CHOP in previously untreated patients resulted in an ORR of 
96%, including CR of 48% (Howard 2002)14. Once the disease has progressed after first-line 
therapy, the prognosis for patients with MCL is dismal. Although the treatment of patients with 
relapsed or refractory MCL requires the use of aggressive therapies, there is currently no 
consensus regarding a standardized approach for treating this population. In the 
relapsed/refractory setting, temsirolimus (Torisel®) was approved in the European Union (EU), 
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bortezomib was approved by the FDA (ORR 31% and median DoR 9.3 months, n=155) for 
treatment of MCL patients who have received at least 1 prior therapy, and lenalidomide was 
approved  by the FDA (ORR 26%, and median DoR 16.6 months, n=134) for treatment of MCL 
patients whose disease has relapsed or progressed after two prior therapies, one of which 
included bortezomib. Patients treated with temsirolimus (175/75-mg) had significantly longer 
PFS than those treated with investigator choice (median PFS 4.8 vs. 1.9 months; hazard 
ratio=0.44; p=0.0009). The ORR in the temsirolimus (175/75-mg) group was 22% (CR 2%). 
Median OS was 12.8 months, which was not significantly different from that of the investigator 
choice group (9.7 months) (Hess 2009)13. Ibrutinib (Imbruvica) is a BTK inhibitor approved 
(FDA 2013 and EU 2014) as a single agent for treatment of patients with MCL who have at least 
one prior therapy. The study from a single-arm open-label trial of 111 MCL showed that ORR 
was 65.9% (CR17.1% and PR48.6%). The median DoR was 17.5 months. The median time to 
response was 1.9 months. However, there are still about 35% of patients who either do not
respond to ibrutinib or cannot tolerate ibrutinib due to treatment related toxicity.
1.2.
Daratumumab
Daratumumab is a fully human IgG1monoclonal antibody that binds with high affinity to a 
unique epitope on CD38, a transmembrane glycoprotein. It is a targeted immunotherapy directed 
towards tumor cells that express high levels of CD38 in a variety of hematological malignancies 
including multiple myeloma, lymphoma, and leukemia.
Daratumumab induces lysis of CD38-expressing tumor cells, by a wide spectrum of mechanisms 
including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated 
cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP), through activation 
of complement proteins, NK cells,
and macrophages, respectively (de Weers 2011, 
Overdijk 2013)7,22.
For the most comprehensive nonclinical and clinical information regarding daratumumab, refer 
to the latest version of the Investigator's Brochure (Daratumumab IB). 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.
1.2.1.
Nonclinical Studies
Preliminary pharmacodynamic studies suggest that daratumumab utilizes multiple effector cell 
functions, resulting in immune mediated killing of CD38-expressing tumor cells. In ex vivo 
experiments utilizing human bone marrow stromal cells co-cultured with primary CD38-
expressing multiple myeloma cells, CDC occurs rapidly and demonstrates maximal myeloma 
cell killing by daratumumab within 1 hour of antibody-mediated activation of the complement 
proteins (de Weers 2011)7. Daratumumab-induced ADCC is slower in its action, with maximal 
ADCC by daratumumab observed at 4 hours in vitro (de Weers 2011)7. Daratumumab has also 
been shown to induce ADCP in the presence of macrophages within 4 hours in vitro (Overdijk 
2013)22. Further, in vitro studies indicated that daratumumab inhibited the cyclase activity of 
CD38 and stimulated the CD38 hydrolase activity (Study No. GMB 3003-013).
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Studies on proliferation of and release of cytokines in human blood cells have indicated that 
daratumumab does not exert target-specific agonistic activity. The cytokine release observed is 
mainly caused by the Fc-portion of IgG1 and comparable to that of approved therapeutic 
antibodies already in clinical use. Specific binding of daratumumab was detected in multiple 
tissues of both human and chimpanzee origin. 
1.2.1.1.
Toxicology
Toxicology data have been derived from studies with daratumumab in chimpanzees and with a 
surrogate anti-CD38 antibody in cynomolgus monkeys. The primary toxicities identified in 
chimpanzees were infusion-related reactions during the first, but not subsequent, daratumumab 
infusions and thrombocytopenia. Anemia was observed in cynomolgus monkeys. The binding 
affinity of daratumumab is significantly higher for chimpanzee platelets than for human platelets, 
suggesting that thrombocytopenia may be less pronounced in humans. The effect on platelets and 
red blood cells was reversible.
Depletion of specific lymphocyte phenotypic cell populations, as expected, based on the intended 
pharmacological effect of daratumumab, was observed in both chimpanzees and cynomolgus 
monkeys. No genotoxicity, chronic toxicity, carcinogenicity, or reproductive toxicity testing has 
been conducted.
1.2.2.
Clinical Studies
No clinical studies with daratumumab have been conducted in NHL. Preliminary data from 
5 ongoing clinical studies on multiple myeloma are summarized below. For further details and 
the most up-to-date information, please refer to the Daratumumab IB.
As of 31 July 2014, approximately 300 subjects with multiple myeloma have been treated across 
5 ongoing clinical studies of daratumumab: Studies GEN501, GEN503, 54767414MMY1001, 
54767414MMY1002, and 54767414MMY2002 (hereafter referred to as MMY1001, MMY1002, 
and MMY2002, respectively). Single-agent daratumumab has been administered to 232 subjects 
in Studies GEN501, MMY1002, and MMY2002; 41 subjects have been treated with 
daratumumab in combination with lenalidomide and dexamethasone in Study GEN503, and 25 
subjects have been treated with daratumumab in combination with VELCADE-containing 
regimens (VELCADE-dexamethasone [VD], VELCADE-thalidomide-dexamethasone [VTD], 
VELCADE-melphalan-prednisone [VMP]) and pomalidomide-dexamethasone [Pom-dex] in 
Study MMY1001. In addition, as of the clinical cutoff date, 16 subjects have been randomized in 
Study 54767414MMY3003 (MMY3003), a Phase 3 study comparing daratumumab, 
lenalidomide, and dexamethasone to lenalidomide and dexamethasone in subjects with relapsed 
or refractory multiple myeloma. 
1.2.2.1.
Clinical Pharmacokinetics
Pharmacokinetic (PK) data are available from Study GEN501 Part 1. The doses ranged from 
0.005 to 24 mg/kg. The PK profile was consistent with target mediated disposition (TMD) with 
rapid target-related clearance at low doses and slower clearance at higher doses. Following long-
term treatment, clearance may decrease as the tumor burden decreases. The preliminary PK data 
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in Studies GEN501 Part 2 and MMY2002 are consistent with the PK profile obtained in 
GEN501 Part 1. Preliminary PK data from Study GEN503 show that following both the first 
dose and multiple repeated doses, the PK profile of daratumumab in combination with 
lenalidomide and dexamethasone is similar to what was observed in Study GEN501 following 
the same dose and schedule. The data suggest that lenalidomide and dexamethasone do not affect 
the PK profile of daratumumab. 
1.2.2.2.
Preliminary Efficacy
Preliminary efficacy data for Study GEN501 Parts 1 and 2 were presented at the 2013 and 2014 
American Society of Clinical Oncology (ASCO) Annual Meetings, respectively. As the study is 
still ongoing, and data reconciliation activities are underway, the data should be considered 
preliminary. Among 12 subjects treated with daratumumab in Part 1 at doses ≥ 4mg/kg, 5 partial 
responders (PRs) and 3 minimal responders (MRs) were observed. Seven (7) of these subjects 
had a 50 to 100% concomitant reduction in bone marrow plasma cells. Among 29 subjects 
treated with 8 mg/kg daratumumab in Part 2, 3 subjects (10%) had a PR; the response rate was 
10%. Among 20 subjects treated with 16 mg/kg, 2 subjects (10%) had a CR, 1 subject (5%) had 
a very good partial response (VGPR), and 4 subjects (20%) had a PR; the response rate was 
35%. 
1.2.2.3.
Safety and Tolerability
In general, daratumumab is tolerated well. Maximum tolerated dose (MTD) has not been reached 
following intravenous (IV) infusions up to 24 mg/kg monotherapy and 16 mg/kg in combination 
studies. The most frequently reported adverse events (AEs) across the daratumumab program 
have been infusion-related reactions (IRRs) following single agent therapy. Among all subjects 
treated in ongoing studies (monotherapy and combination therapy), IRRs have been reported in 
49% of subjects; among 151 subjects treated with 16 mg/kg daratumumab monotherapy in 
Studies GEN501 and MMY2002, the percentage of subjects with a reported IRR was identical 
(49%) to what was observed across all treated subjects. The most frequently reported AEs 
(reported in ≥5% of subjects) reported as IRRs were rhinitis allergic (8%), cough (7%), and nasal 
congestion (6%). Among subjects treated with 16 mg/kg daratumumab monotherapy, the most 
commonly reported IRRs were nasal congestion (8%), cough (7%), and rhinitis allergic and 
throat irritation (5% each). Grade 3 or higher IRRs were reported in 5% of subjects treated with 
16 mg/kg daratumumab as monotherapy, with bronchospasm and hypertension being the most 
frequently reported Grade 3 or higher IRRs (1% each). 
Across all ongoing studies, bronchospasm was reported in 10 subjects. Early in daratumumab 
development, in Study GEN501, 2 cases of bronchospasm were reported 24-48 hours following 
the second full-dose infusion of daratumumab. With the exception of those 2 cases, which had a 
delayed onset, all other reported bronchospasm events occurred following the first dose. All of 
the events occurring during the infusion period resolved quickly after standard treatments were 
administered. The daratumumab infusion was restarted, and no new onset of bronchospasm 
occurred. Most of the subjects who experienced bronchospasm had underlying respiratory 
diseases (asthma, chronic obstructive pulmonary disease [COPD], and others). 
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Among the 151 subjects treated with 16 mg/kg daratumumab as monotherapy in 
Studies GEN501 and MMY2002, the most frequently reported AEs (reported in >10% of 
subjects) other than IRR were fatigue (29%); anemia (23%); nausea (19%); back pain (18%); 
cough (17%); thrombocytopenia (16%); decreased appetite (13%); pyrexia, dyspnea, upper 
respiratory tract infection (12% each); nasal congestion and neutropenia (11% each).  Grade 3 
and higher AEs were reported in 48% of subjects treated with 16 mg/kg monotherapy 
daratumumab. The most frequently reported Grade 3 or higher AEs were anemia (13%) and 
thrombocytopenia (9%). All other Grade 3 and higher AEs were reported in <5% of subjects. No 
deaths due to daratumumab-related AEs have been reported in any ongoing study.
1.3.
Overall Rationale for the Study
The CD38 target in NHL has been intensively studied in both preclinical models as well primary 
tumors. Quantitative flow cytometry analysis of 16 NHL cell lines showed that CD38 expression 
levels varied among cell lines, but the majority (81%, n=13/16) had >1000 CD38 receptors per 
cell (Doshi 2014)8. Of 80 MCL subjects studied, CD38 expression was found in 32 (94%) of 
34 subjects with tumors in peripheral lymphadenopathy, and 16 (48%) of 33 subjects with 
tumors without lymphadenopathy (Orchard 2003)21. In another study with 17 typical MCL 
subjects, the median CD38 expression was 89% in tumor by flow cytometry analysis (Espinet 
2014)9. A panel of 99 primary DLBCL tumors was screened for CD38 staining using an 
established immunohistochemistry (IHC) method. Staining score and intensity were defined by 
semi-quantitative parameters. Forty-seven percent of tumors had CD38 expression (any grade). 
About 30% of tumors had CD38 expression in over 50% of cells at any grade, and about 20% of 
tumors had CD38 expression in over 50% of cells at a staining score of 2+ or 3+. In another 
DLBCL study, CD38 expression after ibrutinib treatment was sequentially monitored (n=23) by 
flow cytometry in every cycle for up to 6 cycles. The results showed that subjects with high 
CD38 level maintained CD38 expression during therapy (unpublished data). By using the 
established IHC methodology described above, a panel of 20 primary FL tumors was studied. 
Seventy-five percent of tumors had CD38 expression at any grade. About 30% of tumors had 
CD38 expression in over 50% of cells at any grade, and about 21% of tumors had CD38 
expression in over 50% of cells with a staining score of 2+ or 3+. These data suggest that a 
significant portion of NHL express CD38. Based on these observations, it is hypothesized that 
daratumumab may show clinical activity in NHL subjects whose tumors express CD38. 
Daratumumab induces tumor cell lysis through immune effector functions such as CDC, ADCC, 
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. These data suggest that a threshold of CD38 expression is required for 
daratumumab-induced CDC and ADCC although the specific threshold for CD38 expression 
required for clinical response needs to be established in a clinical study. Furthermore, emerging 
data from a clinical study of daratumumab in multiple myeloma reveal a trend for correlation 
between CD38 expression and clinical response (Nijhof 2014)19; however, other factors, possibly 
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disease-related, may also influence daratumumab activity. Since MCL, DLBCL, and FL are 
distinct diseases, it is conceivable that different threshold levels of CD38 expression may be 
required for robust daratumumab activity in each of the NHL subtypes.
In an in vivo mouse xenograft model established with Burkitt’s lymphoma line NAMALWA, 
treatment with daratumumab in combination with CHOP resulted in significant tumor growth 
inhibition (47%, p < 0.001) compared to the control group on day 26. In a DLBCL in vivo mouse 
xenograft model established with SU-DHL-6 line, treatment with daratumumab either alone or in 
combination with CHOP also caused significant tumor growth inhibition (55% and 63%, 
respectively, p<0.01). In a human tumor xenograft model (tumor from a subject with DLBCL) in 
which 80% of tumor cells had CD38 expression at a score of 3+ measured by IHC, treatment 
with daratumumab in combination with CHOP or R-CHOP induced complete tumor regression.
The tumors did not regrow even after as few as 3 doses of daratumumab. At the end of study 
(day 60), the mice in the combination treatment groups were still tumor free compared to 
daratumumab alone, CHOP alone or R-CHOP alone. These data suggest that daratumumab 
significantly inhibits tumor growth or induces long-term tumor regression in xenograft tumor
models that express CD38 (Doshi 2014)8.
Given these compelling preclinical data as well as the molecular epidemiological survey, this 
proof-of-concept Phase 2 study was designed to assess the overall response rate and safety of 
daratumumab in relapsed or refractory MCL, DLBCL, and FL where there are significant unmet 
medical needs. 
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The study will evaluate daratumumab separately in three relapsed or refractory NHL subtypes:
MCL, DLBCL, and FL. There are two main objectives:

To assess overall response rate (ORR, including CR and PR), of daratumumab in subjects 
with NHL. 

To evaluate association between ORR and CD38 expression level in order to determine a 
threshold for CD38 expression level in each NHL subtype, above which daratumumab 
activity is enhanced. 
Secondary Objectives
For each subtype of NHL, the secondary objectives are:

To assess the DoR, PFS and OS

To assess time to response

To assess and correlate the CD38 expression level with DoR, PFS and OS 

To assess pharmacokinetics of daratumumab 
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
To assess immunogenicity of daratumumab 

To assess the safety profile of daratumumab
Exploratory Objective

To explore biomarkers, in addition to CD38 expression level, predictive of response to 
daratumumab
2.2.
Hypothesis
For each subtype of NHL, analyses will be conducted on the overall population and on the CD38 
enriched population (only subjects with CD38 expression level above a threshold to be 
determined via statistical inference). There is one hypothesis for each population. Daratumumab 
is considered active per subtype if at least one of the null hypotheses is rejected:
For MCL

For the overall population, ORR is at least 35% (versus a null hypothesis of at most 20%)

For the enriched population, ORR is at least 40% (versus a null hypothesis of at most 20%)
For DLBCL 

For the overall population, ORR is at least 30% (versus a null hypothesis of at most 15%)

For the enriched population, ORR is at least 40% (versus a null hypothesis of at most 15%)
For FL

For the overall population, ORR is at least 50% (versus a null of at most 30%)

For the enriched population ORR is at least 60% (versus a null of at most 30%).
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is an open-label, multicenter, Phase 2 study in subjects at least 18 years of age with MCL, 
DLBCL, or FL. Approximately 210 subjects may be enrolled, with up to 100 subjects planned 
for MCL and up to 55 subjects each for DLBCL and FL.
This study will be conducted and analyzed separately for each subtype of NHL. A biomarker 
adaptive threshold design (Jiang, 2007)16 is implemented that enables testing of the overall 
population and the establishment of a biomarker-defined enriched population simultaneously. 
Two stages are planned.
Stage 1 of the study is designed to provide a preliminary assessment of activity at an early stage. 
Since CD38 expression level may be associated with daratumumab activity, Stage 1 will enroll 
subjects who have tumors where at least 50% of the cells are CD38 positive. This requirement 
seeks to mitigate the possibility that a low response rate observed in Stage 1 might be due to low 
levels of CD38 expression. The selection of the 50% cutoff is based on the existing CD38 
expression level data in these NHL subtypes as well as practical considerations.
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At the end of Stage 1, which is expected to be 6 months after the last subject is enrolled in each 
NHL subtype, or earlier if emerging data allows, an interim analysis will be conducted. The 
purpose of the interim analysis is to evaluate efficacy and safety data in Stage 1. The efficacy
assessment will be focused on ORR. The futility criteria for each NHL subtype are defined in 
Section 11.9 and provided in Figure 1. If the futility criteria are met, an NHL subtype may be 
terminated. Alternatively, if the futility criteria are not met and if supported by the totality of the 
Stage 1 data, Stage 2 for that NHL subtype may be opened for accrual. If the required number of 
responses (eg, 5 responders out of 20 enrolled subjects in MCL as shown in Figure 1), is 
observed prior to completion of enrollment in Stage 1, Stage 2 may be opened immediately upon 
completion of enrollment to Stage 1, if supported by the totality of data.
Stage 2, if opened, is designed to further evaluate safety and efficacy as well as to determine a 
threshold for CD38 expression that is associated with enhanced daratumumab activity. Supported 
by the preliminary activity observed in Stage 1, Stage 2 will enroll any subject in each NHL 
subtype. To mitigate the possibility that a low response may be observed due to low levels of 
CD38 expression in enrolled subjects, the number of Stage 2 subjects with CD38 expression 
level <50% will be capped within each NHL subtype. 
The target number of subjects in each stage by CD38 expression level is shown in Table 3.
Table 3:
Number of Subjects Enrolled
Type of 
NHL
Number of Subjects
Stage 1
CD38 expression 
level b
≥50%
Stage 2 (optional)
Overall
CD38 expression 
level a
<50%
CD38 expression 
level b
≥50%
Total
MCL
20
≤30
≥50
100
DLBCL
15
≤20
≥20
55
FL
15
≤20
≥20
55
DLBCL=diffuse large B cell lymphoma ; FL=follicular lymphoma; MCL= mantle cell lymphoma
a.
These subjects have tumors where <50% of the cells are positive for CD38 by immunohistochemistry.
b.
These subjects have tumors where ≥50% of the cells are positive for CD38 by immunohistochemistry.
A diagram of the study design is provided in Figure 1.
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Figure 1:
Schematic Overview of the Study
DLBCL=diffuse large B cell lymphoma; FL=follicular lymphoma; MCL= mantle cell lymphoma; POC=proof-of-
concept
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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 28 days prior to Cycle 1, Day 1. Prior to enrollment, subjects 
are 
required to 
provide tumor tissue 
to
determine CD38 
expression 
level by 
immunohistochemistry (IHC) at a central laboratory. An additional fresh biopsy should be 
obtained whenever possible even if an archival sample is provided. The Treatment Phase will 
extend from Cycle 1, Day 1 until study drug discontinuation. Subjects will be treated until 
disease progression, unacceptable toxicity, or other reasons as listed in Section 10.2. After first 
dose, disease evaluations will occur every 8 weeks for the first 3 evaluations, then every 16 
weeks for the next two evaluations and then every 24 weeks thereafter.
The Follow-up Phase will begin once a subject discontinues study drug, and will continue until 
death, loss to follow up, consent withdrawal for study participation, or end of study, whichever 
occurs first.
An interim analysis for futility will be conducted in each NHL subtype no later than 6 months
from when the last subject is enrolled in Stage 1 in that NHL subtype. If Stage 2 is expanded for 
a particular NHL subtype, the primary analysis will be performed at 6 months after the last 
subject is enrolled in Stage 2.
The end of the cohort for each NHL subtype is defined as 18 months after the last subject in the
particular NHL subtype receives the first dose of daratumumab. After each NHL subtype
completes the study, the sponsor will ensure that subjects who are currently on treatment and 
receiving benefit, as determined by the investigator, will continue to receive daratumumab. The 
end of the study is defined as the completion of all three NHL subtypes.
Assessment of tumor response and disease progression will be conducted by investigators in 
accordance with the Cheson 20143 response criteria (see Attachment 1). Safety evaluations will 
include AE monitoring, physical examinations, electrocardiogram (ECG) monitoring, clinical 
laboratory parameters (hematology and chemistry), vital sign measurements, and Eastern 
Cooperative Oncology Group (ECOG) performance status. Measures to prevent IRRs will 
include preinfusion medication with methylprednisolone, acetaminophen (or paracetamol), and 
an antihistamine before each daratumumab infusion. Blood samples will be drawn for 
assessment of pharmacokinetics, immunogenicity, biomarkers and pharmacodynamics 
parameters.
3.2.
Study Design Rationale
Rationale for Design, Dose, and Primary Endpoint
A biomarker adaptive threshold design (Jiang, 2007)16 is implemented which combines the 
evaluation of the ORR of daratumumab in all subjects with the establishment and validation of a 
threshold for CD38 expression level, which will be used to define an enriched subpopulation. In 
addition, an early interim futility analysis is to be performed within each NHL subtype.
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The study is designed to address two questions for each NHL subtype:
1)
if daratumumab is sufficiently active in the overall population of all subjects, and
2)
if a threshold value for CD38 expression at baseline can be defined, above which 
daratumumab produces robust clinical activity
Furthermore, within each NHL type, an early interim analysis is incorporated. The purpose of 
Stage 1 is to assess the preliminary activity of daratumumab in each NHL subtype, thus 
providing the opportunity for an early futility check. 
It is hypothesized that an unknown threshold of CD38 expression may exist for enhanced
daratumumab activity. As such, an a priori cutoff for CD38 expression level should be selected
for Stage 1 subjects in order to mitigate the possibility that a low response rate observed in 
Stage 1 could be attributed to low CD38 expression levels in the enrolled subjects, thus 
improving the reliability of the interim futility decision. It is therefore required that Stage 1 
subjects, for all three NHL subtypes, should have a CD38 expression level of at least 50% at 
baseline. The selection of this 50% expression level, while relatively subjective, is based on the 
following considerations. 
1)
This subset of subjects is presumably more likely to respond to daratumumab treatment than 
those subjects with a majority of tumor cells not expressing CD38.
2)
This subset of subjects may represent up to 50%, 30% and 60% of the population with 
MCL, DLBCL and FL, respectively. If a low ORR is observed in this subset of subjects, it is 
highly unlikely that there exists a practical subset of subjects based on CD38 expression 
level in which a clinically meaningful ORR can be observed.
An established dose regimen of 16 mg/kg weekly for 8 weeks, 16 mg/kg every 2 weeks for 16 
weeks, and then 16 mg/kg every 4 weeks until disease progression was selected because it
maximally saturates the target (ie, CD38) using the principles of target mediated drug disposition 
tested in the multiple myeloma setting with manageable toxicity profile. 
The primary efficacy endpoint of ORR (CR+PR) will be assessed according to the Cheson 20143
response criteria. Additional endpoints will include response duration and overall survival (and 
others). Durable and objective response rates have been accepted by regulatory authorities as 
reasonably likely to predict clinical benefit. 
Rationale for Pharmacokinetic, Immunogenicity, and Biomarker Evaluations
Data obtained from the current study will provide information about the pharmacokinetic profile 
of daratumumab in subjects with NHL.
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 during the Follow-up Phase will be used to interpret the 
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immunogenicity data. The information from these samples and data from other studies will be 
used to determine the immunogenicity of daratumumab. 
Biomarkers collected in this study will evaluate tumor CD38 levels as a predictive marker of 
response. Exploratory analysis of CD59 expression from previous studies has indicated that high 
expression of CD59 might be predictive of lower or lack of response to daratumumab. Therefore, 
samples collected in this study will evaluate both CD38 and CD59 expression levels by IHC. 
Specific immune cell subtypes (NK cells, T cells, and B cells) will be analyzed to evaluate the 
effects of daratumumab on immune cells. This will provide information on potential prognostic 
markers in NHL to better understand these diseases, as well as potential markers that predict 
response to daratumumab.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 28 days before Cycle 1 Day 1.
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 
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 11.2, 
Sample Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1.
Subject must be at least 18 years of age (and satisfying the legal age of consent in the 
jurisdiction in which the study is taking place).
2.
Criterion modified as per Amendment-1
2.1  Diagnosis and prior treatment for each NHL subtype as defined below:
MCL:

pathologically verified diagnosis of MCL based on local pathology report (please 
refer to Section 9.1.2), AND

relapsed or refractory disease after at least 2 prior lines of therapy, including at least 
1 cycle of BTK inhibitor therapy and documented PD during or after BTK inhibitor
treatment or subjects who could not tolerate BTK inhibitor (ie, discontinued BTK 
inhibitor due to AEs)
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DLBCL:

pathologically confirmed diagnosis of non-transformed DLBCL, AND

relapsed or refractory disease; for those subjects who have not received 
HDT/ASCT are not eligible for HDT/ASCT due to comorbidities 
FL:

pathologically confirmed diagnosis of FL of Grade 1, 2, or 3a according to World 
Health 
Organization 
(WHO) 
criteria 
without 
pathological 
evidence 
of 
transformation, AND

relapsed disease after at least two prior systemic therapies including one anti-CD20 
containing combination regimen
3.
At least 1 measurable site of disease as described in Section 9.2.1.1.
4.
Criterion modified as per Amendment-1
4.1  Subjects must have available archival or fresh tumor tissue or both to submit to a 
central laboratory for CD38 assay. Expression of CD38
is measured
by 
immunohistochemistry on fresh or archived tumor sample by central assessment using a 
CD38 investigational IHC assay under development:

Stage 1: subjects whose tumors are ≥50% positive for CD38

Stage 2: subject has <50% CD38+ or > 50% CD38+ depending on the distribution 
of CD 38 expression of enrolled subjects during Stage 2 (see Table 3). The sponsor 
will advise on which eligibility criterion is permitted during the enrollment period. 
5.
Subject must have an ECOG performance status score of 0 or 1 (refer to Attachment 2)
6.
Subject must have pretreatment clinical laboratory values meeting the following criteria 
during the Screening Phase:
a) hemoglobin 7.5 g/dL (mmol/L) without transfusion support within 7 days 
before the lab test;
b) absolute neutrophil count (ANC) 0.75 x 109/L (ie, ≥750/ µL);
c) platelet count 50 x 109/L without transfusion support within 7 days of test;
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) Criterion modified as per Amendment-1
g1) creatinine determined by serum creatinine levels ≤1.5 x ULN or a calculated 
creatinine clearance of ≥30 mL/min (see Attachment 3 for Cockcroft-Gault 
formula)
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7.
Criterion modified as per Amendment-1
7.1  Women of childbearing potential must be practicing a highly effective method of 
birth control consistent with local regulations regarding the use of birth control 
methods for subjects participating in clinical studies: eg, established use of oral, 
injected or implanted hormonal methods of contraception; placement of an intrauterine
device (IUD) or intrauterine system (IUS); barrier methods: condom with spermicidal 
foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/suppository; male partner sterilization (the 
vasectomized partner should be the sole partner for that subject); true abstinence (when 
this is in line with the preferred and usual lifestyle of the subject) during and after the 
study (3 months after the last dose of any component of the treatment regimen).
Reliable contraception is indicated even where there has been a history of infertility, 
unless due to hysterectomy or bilateral oophorectomy. During the study and for 3 
months after receiving the last dose of daratumumab, a woman must agree not to 
donate eggs (ova, oocytes) for the purposes of assisted reproduction.
8.
Criterion modified as per Amendment-1
8.1  A woman of childbearing potential must have a negative serum or urine pregnancy 
test within 14 days before commencing treatment. Females of reproductive potential 
must commit either to abstain continuously from heterosexual sexual intercourse or to 
use 2 methods of reliable birth control simultaneously.
9.
Criterion modified as per Amendment-1
9.1  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 last dose of any component of the treatment regimen. The exception to this 
restriction is that if the subject’s female partner is surgically sterile, a second method of 
birth control is not required.
10.
Criterion modified as per Amendment-1
10.1  Each subject must sign an informed consent form (ICF) indicating that he or she 
understands the purpose of and procedures required for the study and is willing to 
participate in the study. Subject must be willing and able to adhere to the prohibitions 
and restrictions specified in this protocol, as referenced in the ICF.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. 
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1.
Known central nervous system lymphoma.
2.
Prior anti-tumor therapy including (all times measured prior to start of study drug):
a) nitrosoureas within 6 weeks
b) chemotherapy within 3 weeks 
c) therapeutic antibodies within 4 weeks
d) radio- or toxin-immunoconjugates within 10 weeks
e) radiation therapy within 2 weeks
f)
investigational agents within 3 weeks, unless antibody this should be within 4 
weeks
g) Daratumumab or other anti-CD38 therapies
Criterion modified as per Amendment-1
h) for the MCL cohort, BTK inhibitors within 1 week or 5 half-lives, whichever is 
longer
3.
Criterion modified as per Amendment-1
3.1  Subject has a history of malignancy (other than NHL) within 3 years before the 
screening period (exceptions are squamous and basal cell carcinomas of the skin and 
carcinoma in situ of the cervix, non-muscle invasive bladder cancer (papillary 
neoplasms of low malignant potential and primary non-invasive tumors), or malignancy 
that in the opinion of the investigator, with concurrence with the sponsor's medical 
monitor, is considered cured with minimal risk of recurrence within 2 years).
4.
a)
Subject has known COPD with a Forced Expiratory Volume in 1 second (FEV1) 
< 50% predicted normal. Note that FEV1 testing is required for patients suspected 
of having COPD and subjects must be excluded if FEV1 <50%
b)
Subject has known moderate or severe persistent asthma within 2 years (see 
Attachment 4: NHLBI table of asthma severity), or currently has uncontrolled 
asthma of any classification. (Note that subjects who currently have controlled 
intermittent asthma or controlled mild persistent asthma are allowed in the study).
5.
Criterion modified as per Amendment-1
5.1  Subject is known to be seropositive for human immunodeficiency virus (HIV), 
known to have hepatitis B surface antigen positivity, or known to have a history of 
hepatitis C (except for those with Sustained Virologic Response [SVR]). SVR is defined 
as aviremia 24 weeks after completion of antiviral therapy for chronic hepatitis C virus 
(HCV) infection (Pearlman 2011).23
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6.
Subject has any concurrent medical or psychiatric condition or disease (eg, autoimmune 
disease, active systemic disease, myelodysplasia) that is likely to interfere with the 
study procedures or results, or that in the opinion of the investigator, would constitute a 
hazard for participating in this study.
7.
Subject has clinically significant cardiac disease, including:
a) myocardial infarction within 1 year before the screening period, or an unstable or 
uncontrolled disease/condition related to or affecting cardiac function (eg, unstable 
angina, congestive heart failure, New York Heart Association Class III-IV)
b) Criterion modified as per Amendment-1
b1) uncontrolled cardiac arrhythmia (NCI CTCAE Version 4 Grade ≥3) or clinically 
significant ECG abnormalities
c) Criterion modified as per Amendment-1
c1) screening 12-lead ECG showing a baseline QT interval as corrected QTc 
>470 msec 
8.
Subject has known allergies, hypersensitivity, or intolerance to monoclonal antibodies or 
human proteins, or their excipients (refer to respective package inserts or Investigator's 
Brochure).
9.
Vaccination with live attenuated vaccines within 4 weeks of first study agent 
administration
10.
Criterion modified as per Amendment-1
10.1 Subject is known or suspected of not being able to comply with the study protocol 
(eg, because of alcoholism, drug dependency, or psychological disorder). 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 the well-being) or that could prevent, 
limit, or confound the protocol-specified assessments. Subject is taking any prohibited 
therapies, as per Section 8.3, during screening with the exception of an emergency use 
of a short course of corticosteroids (equivalent of prednisone 100 mg/day for a 
maximum 7 days) before enrollment.
11.
Criterion modified as per Amendment-1
11.1 Subject is a woman who is pregnant, or breast-feeding, or planning to become 
pregnant while enrolled in this study or within 3 months after the last dose of 
daratumumab. Or, subject is a man who plans to father a child while enrolled in this 
study or within 3 months after the last dose of daratumumab.
12.
Subject has used an invasive investigational medical device within 4 weeks before the 
screening period or is currently enrolled in an interventional investigational study.
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. See Section 17.4, Source Documentation, describes the required 
documentation to support meeting the enrollment criteria.
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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. For restrictions related 
to concomitant medications, please refer to Section 8.3.
1. Subjects agree to follow the contraceptive requirements as noted in the inclusion criteria.
2. Subjects with persistent hypokalemia (eg, serum potassium <3.5 mM after proper 
treatment) need to be monitored for the potential of QTc prolongation.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
After determination of eligibility, subjects will be enrolled to the study. No randomization will 
be used in this study.
Blinding
As this is an open study, blinding procedures are not applicable.
6.
DOSAGE AND ADMINISTRATION
Daratumumab is to be administered as described in Figure 2. Each cycle is 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 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.
A schematic of study treatment administration is provided in Figure 2.
Figure 2:
Schematic Overview Study Treatment Administration
6.1.
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.
DARATUMUMAB 
16 mg/kg IV
Cycles 1-2
Cycle 7+
D15
D1
D1
D15
Follow-up
D22
D8
Cycles 3-6
D1
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6.2.
Daratumumab Administration
Daratumumab (16 mg/kg) will be administered by 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. After the end of the study, the
sponsor will ensure that subjects benefiting from treatment with daratumumab will be able to 
continue treatment.
Each subject’s dose will be calculated based on the subject’s weight at baseline rounded to the 
nearest kilogram at screening. There is no cap on the absolute dose allowed, as long as the dose 
does not exceed 16 mg/kg. If a subject’s weight changes by more than 10% from baseline, the 
dose of daratumumab will be re-calculated. For recommendations on daratumumab infusion rate, 
please refer to the SIPPM. Subjects will receive preinfusion medications and postinfusion 
medications as outlined in Section 6.3. 
Every effort should be made to keep subjects on the planned dosing schedule. Time windows for 
daratumumab administration are outlined in Table 1. In instances of daratumumab-related 
toxicity management, time windows for daratumumab administration are outlines in Table 4.
As noted in Table 2, 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 immediately before the start of 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. 
6.3.
Guidelines for Prevention of Infusion Reactions
6.3.1.
Preinfusion Medication 
On daratumumab infusion days, subjects will receive the following medications prior to infusion:

Acetaminophen (paracetamol) 650-1000 mg IV approximately 1 hour prior to daratumumab 
infusion or orally (PO)

An antihistamine (diphenhydramine or equivalent) 25-50 mg IV approximately 1 hour prior 
to daratumumab infusion or PO

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 [see Attachment 5 for conversion table]. IV administration is 
preferred, but oral steroids may be substituted if IV administration is not available.
If necessary, all PO preinfusion medications may be administered outside of the clinic on the day 
of the infusion, provided they are taken within 3 hours prior to the infusion.
6.3.2.
Postinfusion Medication
For the prevention of delayed IRRs, all subjects will receive corticosteroid orally (20 mg 
methylprednisolone or equivalent in accordance with local standards) on the 2 days following the 
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first 3 daratumumab infusions (beginning the day after the infusion). 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 a FEV1 <80%
or subjects with 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)

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 an 
infusion. If subjects are hospitalized, then their FEV1 should be measured 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 a serious adverse event. Investigators may prescribe bronchodilators, 
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.
6.3.3.
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 infusion reactions 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 infusion-related reaction develops, then the infusion should be paused. Subjects who 
experience adverse events during the infusion must be treated according to the investigator’s 
judgment and best clinical practice. The following guidelines may apply:

Subjects should be treated with acetaminophen
(paracetamol), antihistamine, or 
corticosteroids. 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 infusion-related reaction (which may include pulmonary or 
cardiac events), or anaphylactic reaction, daratumumab should be discontinued and no 
additional daratumumab should be administered to the subject. Aggressive symptomatic 
treatment should be applied. 
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If an infusion is paused or the infusion rate is decreased, then a longer-than-anticipated infusion 
time may occur. Overnight stays at the hospital because of slow infusion times should not be 
reported as a serious adverse event. However, if the underlying cause of the delayed infusion 
time is an adverse event or serious adverse event, then that should be reported as such.
6.3.3.1.
Infusion-Related Events of Grade 1 or Grade 2
If the investigator assesses an adverse event to be related to the daratumumab infusion, then the 
infusion should be paused. When the subject’s condition is stable, the infusion may be restarted 
at the investigator’s discretion. Upon restart, the infusion rate should be half of that used before 
the interruption. Subsequently, the infusion rate may be increased 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 the onset, then the subject must be withdrawn from treatment.
6.3.3.2.
Infusion-Related Reactions of Grade 3 or Higher
For infusion-related adverse events that are Grade 4, the infusion should be stopped and 
treatment with daratumumab will be discontinued for that subject.
For infusion-related adverse events that are Grade 3, the daratumumab infusion must be stopped, 
and the subject must be observed carefully until the resolution of the adverse event or until the 
intensity of the event decreases to Grade 1, at which point the infusion may be restarted at the 
investigator’s discretion. Upon restart, the infusion rate should be half of that used before the 
interruption. Subsequently, the infusion rate may be increased at the investigator’s discretion.
If the intensity of the adverse event returns to Grade 3 after restart of the infusion, then the 
procedure described in this section may be repeated at the investigator’s discretion. Should the 
intensity of the adverse event increase to Grade 3 for a third time, then treatment with 
daratumumab will be discontinued for that subject.
6.4.
Dose Delays and Dose Modification
Dose modification of daratumumab is not permitted, but dose delay is the primary method for 
managing daratumumab-related toxicities. 
6.4.1.
Daratumumab-Related Toxicity Management
Refer to Section 6.3 for details on management of IRRs. If any of the following criteria are met, 
the daratumumab infusion must be held to allow for recovery from toxicity. The criteria for a 
dose delay are:
1)
Grade 4 hematologic toxicity 
2)
Grade 3 thrombocytopenia with bleeding
3)
Febrile neutropenia 
4)
Neutropenia with infection, of any grade 
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5)
Grade 3 or higher nonhematologic 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
If a daratumumab administration does not commence within the prespecified window (Table 4) 
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 4:
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)
>1 week
next planned biweekly dosing date
7+
Every 4 weeks 
(Q4W)
>2 weeks
next planned every 4 weeks dosing date
*Dosing on Day 1 of a cycle must not be skipped. 
Doses of daratumumab 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. However, if a within-cycle dose is delayed, then the dates 
of the subsequent doses should not be adjusted.  
Any adverse event 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 pharmacokinetic and 
pharmacodynamic assessments should be performed on the actual administration day of 
daratumumab, not on the original scheduled administration day.
6.4.2.
Daratumumab Interruption or Missed Doses
A daratumumab dose that is held for more than the permitted time (Table 4) 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.
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7.
TREATMENT COMPLIANCE
Daratumumab will be administered by qualified site staff, and the details of each administration 
will be recorded in the electronic case report form (eCRF). A subject diary may be used to 
document any pre- and post- infusion medications taken at home. Additional details are provided 
in the SIPPM or equivalent document.
8.
CONCOMITANT THERAPY
Throughout the study, investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care except for those listed in Section 8.3. The 
sponsor must be notified in advance (or as soon as possible thereafter) of any instances in which 
prohibited therapies are administered.
Routine systemic use of the following concomitant medications will be collected in the 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: 
growth factors, transfusions, anti-infectives (antibacterials, antivirals, and antimycotics), steroids, 
anti-arrhythmics and other cardiac supportive therapy, anti-epileptics, centrally acting psychiatric 
medication, antihistamines and other medications targeting postinfusion systemic reactions, and 
any anticancer therapy (including radiation). Concomitant medications to manage AEs and SAEs 
will be recorded as per Section 12.3.1.
8.1.
Recommended Therapies
In addition to the mandatory preinfusion medications outlined in Section 6.3.1, the following 
therapies are recommended.
8.1.1.
Therapy for Tumor Lysis Syndrome
The symptoms for tumor lysis syndrome should be monitored. Subjects with more than 1 of the 
factors listed below are considered to be at increased risk of tumor lysis syndrome and should be 
considered for hydration and treatment with a uric acid-lowering agent as well as for frequent 
monitoring of tumor lysis associated signs and symptoms, including blood chemistry. Uric acid-
lowering agents may include xanthine oxidase inhibitor allopurinol or Uloric® [Adenuic™, 
febuxostat] with or without rasburicase per the drug product package inserts.
1.
Serum creatinine ≥1.5 x ULN or calculated creatinine clearance <60 mL/min 
2.
Uric acid ≥450 µmol/L or 7.5 mg/dL 
3.
Bulky disease (eg, lymph node >10 cm or massive splenomegaly)
4.
Elevated LDH >2 x ULN 
8.1.2.
Prophylaxis for Pneumocystis Carinii
Pneumocystis carinii pneumonia (PCP) prophylaxis should be considered, as per institutional 
guidelines.
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8.1.3.
Prophylaxis for Herpes Zoster Reactivation
Prophylaxis for herpes zoster reactivation may be used at the discretion of the investigator.
8.2.
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:

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.
8.3.
Prohibited Therapies
During Cycle 1, the prophylactic use of hematopoietic growth factors is prohibited. 
Vaccination with live attenuated vaccines is prohibited. Concurrent radiation therapy is 
prohibited while on study.
Concomitant administration of any other antineoplastic therapy for the intention of treating NHL 
not defined in the study protocol is prohibited, including medications that target CD38.
Concomitant administration of investigational agents is prohibited. Administration of 
commercially available agents with activity against or under investigation for NHL, including 
systemic corticosteroids (≥20 mg/day of prednisone or its equivalent per day for more than 
7 days during study, unless reviewed/approved by medical monitor) (other than those given for 
IRRs as described in Section 6.3.2) is prohibited. 
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule (Table 1) summarizes the frequency and timing of efficacy, 
pharmacokinetic, immunogenicity, biomarker, and safety measurements applicable to this study.
Blood collections for pharmacokinetic assessments should be kept as close to the specified time 
as possible. Other measurements may be done earlier than specified timepoints if needed. Actual 
dates and times of assessments will be recorded in the source documentation.
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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 total blood volume to be collected is estimated at about 20 mL (about 1.5 tablespoons) for 
screening tests, 215 mL (about 1 cup) for Cycles 1-7, 20 mL (about 1.5 tablespoons) at 
subsequent cycles, and 36 mL (about 2 tablespoons) at the End-of-Treatment Visit and the post
treatment visits. This includes laboratory assessments associated with, safety, efficacy, and 
pharmacokinetic evaluations, as well as scientific research samples. Repeat or unscheduled 
samples may be taken for safety reasons or for technical issues with the samples.
9.1.2.
Screening Phase
The signed ICF must be obtained before any study-specific procedures are performed. 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 the 
Screening Phase, eligibility criteria will be reviewed and a complete clinical evaluation will be 
performed as specified in Table 1. Screening procedures will be performed within 28 days before 
Cycle 1 Day 1; however, results of tests (such as radiologic tests; ECG; or bone marrow 
aspirate/biopsy) performed up to 6 weeks (42 days) before Cycle 1 Day 1 as routine standard of 
care for the subject’s disease can be used. 
Pathological Confirmation of Diagnosis
Diagnosis of MCL must be verified by the sponsor from the local pathology report. This 
diagnosis report must include expression of either cyclin D1 in association with other relevant 
markers (eg, CD20 and CD5) or evidence of t(11;14) as assessed by cytogenetics, fluorescent in 
situ hybridization, or polymerase chain reaction. The report containing this information must be 
sent to sponsor for confirmation of the diagnosis prior to enrollment.
If possible, local pathology report for diagnosis of FL will be collected. The report should
include expression of B-cell lymphoma 2 (Bcl-2) in association with other relevant markers (eg, 
CD10 and CD19) or evidence of t(14;18) as assessed by cytogenetics, fluorescent in situ 
hybridization, or polymerase chain reaction. 
If possible, local pathology report for diagnosis of DLBCL will also be collected. The report 
should include: a) histologic documentation of no significant follicular or low grade component; 
b) evidence of positive B-cell lineage, and c) documentation of a sufficient large cell component 
or increased Ki67-defined proliferative rate.
Determination of CD38 Expression
Before enrollment to the study, subjects will be required to provide tumor samples for 
assessment of CD38 expression. Subjects are strongly encouraged to provide both fresh and 
archival tumor tissue for this study. Where feasible, a fresh lymph node biopsy (excision or core 
needle biopsy) should be collected. An investigational IHC assay currently under development 
will be used by the central laboratory to determine CD38 expression levels. Only subjects who 
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fulfill the eligibility criteria, including tumors with ≥50% cells CD38 positive for Stage 1 and 
tumors <50% cells CD38 positive or ≥50% cells CD38 positive for Stage 2, will be considered 
for participation in the study. An ICF for CD38 screening only may be obtained separately from 
the full study ICF.
9.1.3.
Treatment Phase
Details of the procedures performed during the Treatment Phase are outlined in the Table 1. The 
start of each cycle should be scheduled relative to Cycle 1 Day 1 and should not change if visits 
have shifted within the allowed window. Subjects will be closely monitored for adverse events, 
laboratory abnormalities, and clinical response. Clinical evaluations and laboratory studies may 
be repeated more frequently, if clinically indicated. If disease progression is diagnosed, then the 
subject will discontinue study treatment, complete the End-of-Treatment Visit, and enter the 
Follow-up Phase.
End-of-Treatment Visits
Unless a subject withdraws consent for study participation or is lost to follow up, an End-of-
Treatment Visit is to occur within 30 days (+7 day window) after the last dose of all study 
treatments. Every effort should be made to conduct the End-of-Treatment Visit before the subject 
starts subsequent treatment. If a subject is unable to return to the site for the End-of-Treatment 
Visit, then the subject should be contacted to collect information on adverse events and 
concomitant medications that occur up to 30 days after the last dose of study treatment.
Additional information on reporting of adverse events is presented in Section 12.
9.1.4.
Follow-up Phase
The Follow-up Phase will begin once a subject discontinues study treatment. Subjects who 
discontinue before disease progression (for other reasons such as an AE) must continue to have 
their regularly scheduled scans according to the Table 1 until confirmed PD, death, the start of a 
new anticancer therapy, withdrawal of consent, lost to follow up, or the end of the study for that 
NHL subtype. After disease progression is documented, follow-up will occur at least every 
16 weeks (±2 weeks). Subsequent anticancer therapy, second primary malignancies, and survival 
status will be recorded.
If the 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. 
The end of the cohort for each NHL subtype is defined as 18 months after the last subject in the 
particular NHL subtype receives the first dose of daratumumab. After completion of an NHL 
subtype, the sponsor will ensure that subjects who are currently on treatment and receiving 
benefit, as determined by the investigator, will continue to receive daratumumab. The end of the 
study is defined as the completion of all three NHL subtypes.
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9.2.
Efficacy
9.2.1.
Evaluations
After the first dose, disease evaluations will be performed every 8 weeks (±7 days) in the first 6 
months (Weeks 9, 17, 25), followed by every 16 weeks (±7 days) for the next 6 months (Weeks 
41 and 57), and thereafter every 24 weeks (±14 days). These assessments will be conducted until 
disease progression, withdrawal of consent from study participation, or the end of study. 
The determination of disease status will be assessed by the investigator based on the Revised 
Criteria for Response Assessment (Cheson 2014)3, provided in Attachment 1. Identical 
methodology should be used for disease assessment at screening and throughout the course of the 
study.
Radiological and PET scans should be performed and collected according to instructions from 
the independent imaging laboratory. A central review of the response assessments may be 
performed if deemed necessary.
For all subjects, as soon as disease progression is confirmed by local assessment, the sponsor 
should be informed immediately.
9.2.1.1.
Definition of Measurable and Assessable Disease
Eligible subjects must have at least 1 measurable site of disease. Measurable sites of disease are 
defined as lymph nodes, lymph node masses, or extranodal sites of lymphoma. Each measurable 
site of disease must be greater than 1.5 cm in the long axis regardless of short axis measurement 
or greater than 1.0 cm in the short axis regardless of long axis measurement, and clearly 
measurable in 2 perpendicular dimensions. Measurement must be determined by local imaging 
evaluation. All other sites of disease are considered assessable, but not measurable. 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, clearly measurable in 2 perpendicular dimensions, will be 
followed for each subject. Measurable sites of disease should be chosen such that they are 
representative of the subject’s disease (this includes splenic and extranodal disease). If 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 measurable lesions should be from as disparate regions of the 
body as possible.
All other sites of disease will be considered assessable. 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 
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not measurable but are thought to represent lymphoma. In addition, if more than 6 sites of 
disease are measurable, these other sites of measurable disease may be included as assessable 
disease.
9.2.1.2.
Radiographic (CT/MRI) Assessments
During the study, disease response will be assessed using CT scans with IV contrast of the neck 
(only if neck lymph nodes are involved, in which case full neck views must be obtained), 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.
A separate CT scan and PET scan are preferred but, if the only available modality is 
combined/dual PET/CT scanner, then the CT portion of a PET/CT may be used in lieu of a 
dedicated CT.
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 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.
9.2.1.3.
Positron Emission Tomography (PET Scan)
FDG-PET is important for the complete assessment of response and progression in subjects with 
FL. Whole body FDG-PET scans (skull base to the proximal femur) should be done at screening, 
per investigator discretion. For subjects who are PET-positive at baseline, PET scans will be 
done at the time of maximal tumor reduction (eg, CR or 2 consecutive CT scans showing no 
further tumor reduction).
Assessment of PET results is based on published criteria (Juweid 2007)17. Visual assessment is 
considered adequate for determining whether a PET scan is positive, and use of the standardized 
uptake value is not necessary. A positive scan is defined as focal or diffuse FDG uptake above 
background in a location incompatible with normal anatomy or physiology, without a specific 
standardized uptake value cutoff. Other causes of false-positive scans should be ruled out. 
Exceptions include mild and diffusely increased FDG uptake at the site of moderate- or large-
sized masses with an intensity that is lower than or equal to the mediastinal blood pool, hepatic 
or splenic nodules 1.5 cm with FDG uptake lower than the surrounding liver/spleen uptake, and 
diffusely increased bone marrow uptake within weeks after treatment.
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9.2.1.4.
Bone Marrow Assessment
An optional bone marrow biopsy, with or without aspirate, at Screening to document bone 
marrow involvement with lymphoma may be obtained at the investigator’s discretion. A bone 
marrow biopsy obtained as routine standard of care may be used instead if taken up to 42 days 
before first dose of study drug. If bone marrow aspirate is obtained, determination of bone 
marrow involvement may be confirmed by flow cytometry. However, 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 either flow cytometry or immunohistochemistry (IHC), 
if warranted, to confirm the presence or absence (complete remission) of lymphoma. If bone 
marrow involvement can be confirmed with morphology, IHC need not be done if this is not part 
of a study-site standard practice.
9.2.1.5.
Endoscopy
CRs must be confirmed with endoscopy examination if the lymphoma originated from or 
involved the GI tract at diagnosis.  
9.2.2.
Endpoints 
9.2.2.1.
Primary Endpoint
Overall response rate is defined as the proportion of subjects who achieve CR or PR. 
9.2.2.2.
Major Secondary Endpoints
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 (or relapse for subjects who experience 
CR). For those subjects who are still without progression/relapse, DoR will be censored at the 
last adequate tumor assessment.
PFS is defined as the duration from the date of the first daratumumab dose to the date of 
progression/relapse 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.
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.
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) is first documented. For non-responders, it will be censored 
at the date of progressive disease/relapse or the date of the last adequate disease assessment, 
whichever comes first.
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9.3.
Pharmacokinetics and Immunogenicity
9.3.1.
Evaluations
For all subjects, pharmacokinetic samples to determine serum concentration of daratumumab 
will be obtained according to Table 1. At specified timepoints, venous blood samples (5 mL per 
sample) will be collected to determine serum concentration of daratumumab and the serum will 
be divided into 3 aliquots (1 aliquot for pharmacokinetic 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 timepoint. 
The exact dates and times of blood sampling must be recorded. Refer to the Laboratory Manual 
or equivalent document for sample collection requirements. Collected samples must be stored
under the specified and controlled conditions for the temperatures indicated in the laboratory 
manual.
9.3.2.
Analytical Procedures
Serum samples will be analyzed to determine concentrations of daratumumab or generation of 
antibodies to daratumumab using validated immunoassay methods by or under the supervision of 
the sponsor’s bioanalytical facility. 
For the immunogenicity assessments, serum samples will be screened for antibodies binding to 
daratumumab and serum titer will also be determined from confirmed positive samples. Other 
immunogenicity analyses (eg, assessment of neutralizing capabilities) may be performed to 
further characterize the immune responses that are generated.
9.3.3.
Pharmacokinetic Parameters
The pharmacokinetic parameters are defined as:
Cmax
Maximum observed concentration
Cmin
Minimum observed concentration
Pharmacokinetic samples to determine serum concentration of daratumumab will be obtained 
from all subjects. Pharmacokinetic endpoints include:

Minimum observed concentration (Cmin)

Maximum observed concentration (Cmax)
If sufficient data are available, then other pharmacokinetic parameters may be calculated.
9.3.4.
Immunogenicity Assessments (Antibodies to Daratumumab)
Serum from venous blood samples collected from all subjects will be assessed for the generation 
of antibodies to daratumumab (immunogenicity) according to Table 1. Daratumumab 
concentration is also evaluated at all immunogenicity time points to ensure appropriate 
interpretation of immunogenicity data. When both serum concentration and immunogenicity 
analyses are specified, they are performed on aliquots from the same blood draw and no 
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additional sampling is required. Procedures for sample collection, preparation, identification, 
storage, and shipment will be provided in the Laboratory Manual or equivalent document.  
Additionally, blood samples should also be collected at the final visit from subjects who are 
discontinued from treatment. Subjects who discontinue treatment will also be asked to return for 
immunogenicity evaluation during the Follow-up Phase. 
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.
9.4.
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 Table 1.
Determination of CD38 and CD59 Expression:
During screening, subjects will be required to provide tumor samples for assessment of CD38 
expression based on central testing using investigational IHC methodology under development
(Section 9.1.2). An additional fresh biopsy should be obtained whenever possible even if an 
archival sample is provided. Fresh tumor samples can be either lymph node excision or core 
needle biopsy; fine needle aspirates are not acceptable.
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 in B-cell signaling pathways, 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, CD59 expression will be measured by IHC in a designated laboratory as an 
exploratory biomarker. CD59 is a complement inhibitory protein and can contribute to resistance 
to CDC, which may be important for daratumumab response.
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Companion Diagnostic:
The tumor sample will be collected, tested for CD38 expression by investigational IHC test 
under development, and stored in order to potentially develop a companion diagnostic in parallel 
to the clinical study. Additional biopsy material may be requested if the initial sample is 
determined to be insufficient for all evaluations.
Immunophenotyping:
Previous daratumumab clinical studies in multiple myeloma 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 or 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 multiple myeloma indicate that the immune fitness of 
subjects at baseline may preclude response to daratumumab. 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 RNA profiling (RNA-seq, gene expression profiling) or 
methylation assessment to evaluate novel technologies for immune profiling in whole blood, and 
to compare these methodologies to standard flow cytometry.  These assessments will be 
evaluated for association with clinical response. 
Plasma samples may be analyzed for proteins associated with disease progression or 
daratumumab response, including complement proteins, sCD38, proteins indicative of infusion 
reaction (IL-1, IL-6, TNFα, IFNγ, tryptase), and exploratory proteomics. Analyses will 
determine whether specific proteins are associated with daratumumab response.
9.5.
Safety Evaluations
Safety will be measured by adverse events, 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. Any clinically 
relevant changes occurring during the study must be recorded on the Adverse Event 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.
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 
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safety monitoring assessments may be performed more frequently, and adverse events should be 
evaluated by the investigator according to the standard practice, if clinically indicated.
Adverse Events
Adverse events (with the exception of progression of NHL) will be reported by the subject (or, 
when appropriate, by a caregiver, or surrogate) for the duration of the study. Adverse events will 
be followed by the investigator as specified in Section 12, Adverse Event Reporting.
Clinical Laboratory Tests 
Blood samples for serum chemistry and hematology 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 adverse event section of the eCRF. The laboratory reports must 
be filed with the source documents.
The tests below will be performed by the local laboratory unless otherwise noted.

Hematology Panel
-hemoglobin
-white blood cell (WBC) count with absolute 
neutrophils and lymphocytes
-platelet count

Serum Chemistry Panel
-sodium
-aspartate aminotransferase (AST)
-potassium
-alanine aminotransferase (ALT)
-calcium
-alkaline phosphatase
-creatinine
-lactic acid dehydrogenase (LDH)
-albumin
-uric acid
-total protein
-total bilirubin
-direct bilirubin (for subjects with congenital 
bilirubinemia, such as Gilbert syndrome)
Pregnancy Testing
For women of childbearing potential only: serum or urine pregnancy test at screening and as 
clinically indicated.
Blood Type, Rh, and Indirect Antiglobulin Testing (IAT)
Blood Type, Rh, 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 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/RhD typing.  CD38 is expressed at very 
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low levels on erythrocytes.  Daratumumab binds to the CD38 on erythrocytes, which results in a 
positive IAT (Indirect Coombs Test).   This positive result masks the detection of antibodies to 
minor antigens and may prevent or delay blood banks from issuing donor blood for transfusion.  
This effect occurs during daratumumab treatment and for up to 6 months after treatment ends.  
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.  Blood banks can eliminate the daratumumab interference with IAT by treating reagent 
RBCs with dithiothreitol (DTT) (Chapuy 2015)2.
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving 
daratumumab include:
a) Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping) or 
genotypically matched units
b) 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.
Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically significant 
hemolysis has been observed in daratumumab studies. For additional details, refer to the 
Daratumumab IB.
β2-microglobulin
Baseline Beta-2 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 6.3.2 for details on subjects with higher risk of respiratory complications.
Electrocardiogram (ECG)
ECGs will be performed as specified in Table 1. 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.
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Vital Signs 
Vital signs (pulse, temperature, and blood pressure) will be performed as specified in Table 1
and Table 2. 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.
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 Table 2. Abnormalities will be recorded in the appropriate sections of 
the eCRF. ECOG performance status (Attachment 2) will be used to evaluate the impact of the 
disease status on the activities of daily living. When scheduled, ECOG assessments should be 
obtained prior to any other study procedures planned for the same day.
9.6.
Sample Collection and Handling
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 Table 1 for the timing and frequency of all sample collections.
For samples collected for the central laboratory, sample dates and times must be recorded on the 
laboratory requisition form. Further 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.
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the study if he or she has finished all protocol-
specified procedures before the end of the study, has not been lost to follow up, or has not 
withdrawn consent for study participation before the end of the study.
10.2.
Discontinuation of Study Treatment
If a subject's study treatment must be discontinued before the end of the treatment regimen, this 
will not result in automatic withdrawal of the subject from the study. After treatment 
discontinuation, the subject will move into the Follow-up Phase. The End-of-Treatment Visit and 
Follow-up visit assessments should continue as specified in Table 1. If study treatment is 
discontinued for a reason other than disease progression, then disease evaluations will continue 
to be performed as specified in Table 1.
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A subject's study treatment should be discontinued if:

The investigator believes that for safety reasons (eg, adverse event) 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 treatment

The subject initiates treatment with a prohibited medication

The subject received concurrent (non-protocol) treatment for NHL

The subject experiences unacceptable toxicity, including IRRs described in Section 6.3.3

The subject’s dose of daratumumab is held for more than 4 weeks (Cycle 1 to Cycle 6) or 6 
weeks (Cycle 7 and beyond) should have study treatment discontinued, unless, after 
consultation with the sponsor and review of safety and efficacy, continuation is agreed upon

The subject experiences disease progression (please see below). Relapse from CR is not 
considered as disease progression
A subject who experiences a second primary malignancy that cannot be treated by surgery alone 
must be withdrawn from the study. However, a subject who develops a malignancy that can be 
cured surgically may continue to receive the assigned study treatment and should continue to be 
followed for subsequent progression of lymphoma. 
The primary reason for discontinuation of study treatment is to be recorded in the eCRF.
10.3.
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 for study participation

Death

The study investigator or sponsor, for any reason, stops the study or stops the subject’s 
participation in the study
Before 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. Study treatment assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced. If a 
subject withdraws from the study, assessments outlined in the End-of-Treatment Visit should be 
obtained.
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Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for future research (refer to
Section 16.2.5). 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.
11.
STATISTICAL METHODS
Efficacy and safety analyses will be performed separately for each of the three NHL subtypes
(MCL, DLBCL, FL). In addition, safety data across the NHL subtypes may be combined 
together for analysis at the end of the study when appropriate.
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.
11.1.
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, standard 
deviation, 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.
11.2.
Sample Size Determination
Within each subtype of NHL, a biomarker adaptive threshold design (Jiang 2007)16 is to be
utilized, which allows identification of a biomarker threshold based on data analysis in parallel 
with the statistical testing of the ORR for proof-of-concept. That is, the proof-of-concept could 
be established either in the overall population or in the subpopulation of subjects as identified by 
the biomarker (CD38 expression level) threshold. In order to provide an early futility check 
within each NHL subtype, a two-stage procedure is also incorporated, which will be detailed 
later.
Given that there are two potential pathways for proof-of-concept and the inherent multiple 
testing issues associated with the selection of the biomarker threshold, per the recommendation 
by Jiang (2007)16, the powering for MCL will be based on the overall population with an overall 
alpha of 0.04, which preserves the power of the overall test while providing a reasonable power 
against a strong subset effect at the same time with the remaining alpha of 0.01. Since further 
randomized Phase 2 proof-of-concept studies in combination with other agents are likely 
required for DLBCL and FL, an alpha of 0.05 is used for the overall population in these two 
subtypes.
In Stage 1, a total of 50 subjects will be enrolled for all 3 NHL types combined. In Stage 2, a 
maximum of 160 subjects may be enrolled if all three tumor types are expanded, bringing the 
maximal sample size to 210 with all tumor types combined.
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For MCL, the null hypothesis is that the ORR is at most 20%, and the alternative hypothesis is 
that the ORR is at least 35% for all subjects, or at least 40% for those subjects whose CD38 
expression level is above a to-be-determined level. These are based on the fact that some recent 
approvals in previously treated MCL were based on an ORR of approximately 31% for 
bortezomib and 26% for lenalidomide. Up to 100 MCL subjects with positive CD38 expression 
may be enrolled. Seventy (70) of those must have tumors with 50% or more cells positive for
CD38 expression at baseline in order to rule out that any lack of activity is mostly due to low 
CD38 expression level in the enrolled subjects.
For DLBCL, the null hypothesis is that the ORR is at most 15%, and the alternative hypothesis is 
that the ORR is at least 30% for all subjects, or at least 40% for those subjects whose CD38 
expression level is above a to-be-determined level. These were based on the clinical observation 
that relapsed DLBCL subjects who are not eligible for HDT/ASCT have a very poor prognosis 
and no established therapeutic options. 
For FL, the null hypothesis is that the ORR is at most 30%, and the alternative hypothesis is that 
the ORR is at least 50% for all subjects, or at least 60% for those subjects whose CD38 
expression level is above a to-be-determined level. These are based on the published ORRs of 
idelalisib (54%, which was the basis of an accelerated approval is the U.S.) and rituximab 
monotherapy (49%, Coiffier 2011)5.
For both DLBCL and FL, 55 subjects may be enrolled. Thirty-five (35) of those must have 
tumors with 50% or more cells positive for CD38 expression at baseline in order to rule out that 
any lack of activity is mostly due to low CD38 expression level in the enrolled subjects. 
The trial will be carried out in two stages within each NHL subtype, as in a Simon’s two-stage 
design. Each NHL subtype, independent of the other subtypes, may be discontinued after Stage 1 
due to futility. To exclude the possibility that an observed low response rate is due to low CD38 
expression level at baseline, the trial will enroll sufficient number of subjects with tumors where
≥50% of cells are CD38 positive in both stages. The detailed procedure will proceed as follows. 
For MCL, Stage 1 will accrue 20 subjects with tumors where ≥50% of cells are CD38 positive. If 
the futility criteria are met (at most 4 responses overall), no further expansion is planned. 
Otherwise, an additional 80 subjects will be enrolled to Stage 2; at least 50 of these subjects will 
have tumors where ≥50% of cells are CD38 positive. The sample size will provide 
approximately 85% power to reject the null hypothesis for the overall population with a one-
sided significance level of 0.04.
For DLBCL, Stage 1 will accrue 15 subjects with tumors where ≥50% of cells are CD38 
positive. If the futility criteria are met (at most 3 responses overall), no further expansion is 
planned. Otherwise, an additional 40 subjects will be enrolled to Stage 2; at least 20 of these 
subjects will have tumors where ≥50% of cells are CD38 positive. The sample size will provide 
approximately 80% power to reject the null hypothesis for the overall population with a one-
sided significance level of 0.05.
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For FL, Stage 1 will accrue 15 subjects with tumors where ≥50% of cells are CD38 positive. If 
the futility criteria are met (at most 6 responses overall), no further expansion is planned. 
Otherwise, an additional 40 subjects will be enrolled to Stage 2; at least 20 of these subjects will 
have tumors where ≥50% of cells are CD38 positive. The sample size will provide 
approximately 80% power to reject the null hypothesis for the overall population with a one-
sided significance level of 0.05.
At the end of the study, all available data for each particular NHL subtype will be analyzed to 
determine a CD38 expression threshold for that subtype, which will be used to define an 
enriched population, via statistical inference.
11.3.
Efficacy Analyses
11.3.1.
Primary Efficacy Endpoint
For each NHL subtype, an estimate of the ORR will be presented along with a two-sided 95%
exact confidence interval. In addition, the biomarker adaptive threshold method of Jiang (2007)16
will be utilized to select a threshold for CD38 expression level. The threshold is used to define an 
enriched subpopulation above which the daratumumab activity is enhanced. The number and 
percentage of subjects falling into each response category will be descriptively tabulated. 
For each NHL subtype, a test for the null hypothesis in all subjects is to be combined with the 
establishment and validation of a CD38 expression threshold level, which is to be used to 
identify a sensitive subpopulation, using the biomarker adaptive threshold method (Jiang 
2007).16 Specifically, for a threshold value of c, a log-likelihood ratio statistic, S(c), will be 
obtained is used to test the null hypothesis in the subset of subjects with CD38 expression level 
above c. Then a maximally selected test statistic will be defined as 
T=max{S(0)+R,maxc>0[S(c)]} 
Here, R is specified to be a constant 2.2, which is equal to the difference between the 95th and 
80th percentiles from the chi-squared distribution with 1 degree of freedom and provides an 
optimal ability to detect a subset effect without compromising the overall effect power. Due to 
the inherent multiple testing issue and the complexity in constructing the test statistic, a bootstrap 
resampling method will be used to perform the test at an overall level of 0.05 for each NHL 
subtype. Similarly, the confidence intervals for the CD38 threshold value will also be obtained 
for each NHL subtype via bootstrapping.
The correlation between ORR and baseline tumor burden related variables (eg, beta-2 
microglobulin) will be explored, as appropriate.
11.3.2.
Secondary Efficacy Endpoints
Duration of response will be provided descriptively using the Kaplan-Meier method for 
responders only. 
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Progression-free survival and OS will be analyzed using the Kaplan-Meier method, and the 
comparison between the above- and below-threshold subpopulations will be made using log-rank 
test and Cox regression.
11.4.
Pharmacokinetic Analyses
Pharmacokinetic analyses will be performed on the pharmacokinetic-evaluable population, 
defined as subjects who have received at least 1 dose of daratumumab and have at least one 
postinfusion sample.
All serum concentrations below the lowest quantifiable concentration in a sample or missing data 
will be labeled as such in the concentration data listings. 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 timepoint and pharmacokinetic parameters of daratumumab. Cmin is defined as the 
concentration observed immediately before infusion and Cmax is defined as the concentration 
observed at the end of infusion, as presented in the summary of serum concentration by sampling 
time point. Other pharmacokinetic parameters may also be summarized. 
If sufficient data are available, then population pharmacokinetic analysis of serum concentration 
time data of daratumumab may be performed 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.
11.5.
Immunogenicity Analyses
The incidence of antibodies to daratumumab will be summarized for all subjects who receive at 
least one dose of daratumumab and have appropriate samples for detection of antibodies to 
daratumumab. In addition, subjects who are positive for antibodies to daratumumab will also be 
listed.
11.6.
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. If performed, details and results of the analysis will be 
presented in a separate report.
11.7.
Biomarker Analyses
Biomarker studies are designed to identify markers predictive of response (or resistance) to 
daratumumab, as well as to gain deeper understanding of NHL. Analyses will be stratified by 
clinical covariates or molecular subgroups using the appropriate statistical methods (eg, 
parametric or non-parametric, univariate or multivariate, analysis of variance [ANOVA], or 
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survival analysis, depending on the endpoint). Correlation of baseline expression levels or 
changes in expression levels with clinical parameters will identify responsive (or resistant) 
subgroups in addition to immune cells, genes and pathways attenuated following treatment with 
daratumumab. 
Natural killer cells, as a potential pharmacodynamic measure, will be listed, tabulated, and where 
appropriate, plotted. Subjects may be grouped by NHL subtype, dose, or clinical response. Data 
from CD38 testing by investigational IHC assay underdevelopment will be used for enrollment 
purposes, as well as correlated to overall clinical response to establish a potential threshold of 
CD38 expression that can be used for future subject selection.  As this is an open-label study 
without a control treatment, statistical analyses will be done to aid in the understanding of the 
results. 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
11.8.
Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). The severity assessment for 
an adverse event or serious adverse event should be completed using the NCI CTCAE Version 4. 
All reported adverse events with onset during the Treatment Phase (ie, treatment-emergent 
adverse events, and adverse events that have worsened since baseline) will be included in the 
analysis. For each adverse event, the percentage of subjects who experience at least 1 occurrence 
of the given event will be summarized by treatment group.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline 
and for observed values and changes from baseline at each scheduled time point. Changes from 
baseline results will be presented in pre- 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.
Parameters with predefined NCI CTCAE 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). Clinically relevant changes (i.e. causing a treatment intervention or need for 
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concomitant therapy) will be also recorded on the adverse event eCRF. All other lab 
abnormalities need not be recorded as adverse events.
Electrocardiogram (ECG)
Electrocardiogram data will be summarized and listed.
Vital Signs
Descriptive statistics of temperature and blood pressure (systolic and diastolic) values and 
changes from baseline will be summarized.
11.9.
Interim Analysis
Within each NHL subtype, an interim analysis will be performed. The main purpose of the 
interim analysis is futility assessment based on ORR. In case of low ORR taking into 
consideration of CD38 expression level, an individual NHL subtype may be terminated for 
futility. The detailed futility stopping guideline is as follows.
1)
For MCL, if at least 5 out of 20 subjects have achieved CR or PR after Stage 1, then Stage 2 
may be initiated. For DLBCL, if at least 4 out of 15 subjects have achieved CR or PR after 
Stage 1, then Stage 2 may be initiated. For FL, if at least 7 out of 15 subjects have achieved 
CR or PR after Stage 1, then Stage 2 may be initiated.
2)
For MCL, if at most 4 out of 20 subjects have achieved CR or PR after Stage 1, consider 
terminating MCL for futility. For DLBCL, if at most 3 out of 15 subjects have achieved CR 
or PR after Stage 1, consider terminating DLBCL for futility. For FL, if at most 6 out of 15 
subjects have achieved CR or PR after Stage 1, consider terminating FL for futility.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
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related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonization [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

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 one of the other outcomes listed in the 
definition above. These should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study treatment and the event (eg, death from anaphylaxis), the event 
must be reported as a serious and unexpected suspected adverse reaction even if it is a 
component of the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product Reference Safety Information. For daratumumab, the expectedness of an 
adverse event will be determined by whether or not it is listed within the Reference Safety 
Information included in the Investigator's Brochure. 
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Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
The severity assessment for an adverse event or serious adverse event should be completed using 
the NCI CTCAE Version 4. Any adverse event or serious adverse event not listed in the 
NCI CTCAE Version 4 will be graded according to investigator clinical judgment by using the 
standard grades as follows:
Grade 1 (Mild): Awareness of symptoms that are easily tolerated, causing minimal discomfort 
and not interfering with everyday activities.
Grade 2 (Moderate): Sufficient discomfort is present to cause interference with normal activity.
Grade 3 (Severe): Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities.
Grade 4: Life-threatening of disabling adverse event
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Grade 5: Death related to the adverse event
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study drug. No MTD has been reached for daratumumab. However, if 
the dose exceeds the maximum tested dose of 24 mg/kg, then it will be considered as 
overdose in this study

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 exposure to the 
sponsor study drug, eg, name confusion)

Exposure to a sponsor study drug from breast-feeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the adverse event page of the 
eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until 30 days after the last dose of 
study treatment, unless the subject withdraws consent for study participation, or starts subsequent 
anticancer therapy. For subjects who have received subsequent treatment with therapeutic intent 
for lymphoma during the adverse event reporting period, only adverse events that are considered 
to be possibly, probably, or definitely related to daratumumab need to be reported. Serious 
adverse events, including those spontaneously reported to the investigator within 30 days after 
the last dose of study treatment, must be reported using the Serious Adverse Event Form. The 
sponsor will evaluate any safety information that is spontaneously reported by an investigator 
beyond the time frame specified in the protocol.
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition (refer to 
Section 12.1.1). Death should not be recorded as an adverse event or serious adverse event, but 
as the outcome of an adverse event. The adverse event that resulted in the death should be 
reported as a serious adverse event. All events that meet the definition of a serious adverse event 
will be reported as serious adverse events, regardless of whether they are protocol-specific 
assessments.
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All adverse events, regardless of seriousness, severity, or presumed relationship to study 
treatment, 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 adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all serious adverse events that are unlisted (unexpected) and associated 
with the use of the study drug. The investigator (or sponsor where required) must report these 
events to the appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
that approved the protocol unless otherwise required and documented by the IEC/IRB. 
Subjects (or their designees, if appropriate) will 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

Subject name

Blood type, Rh, and IAT or phenotyping result collected before first daratumumab dose (as 
described in Section 9.5)
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, 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 a serious 
adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:
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
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 a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

If the subject has not experienced a significant medical event but is hospitalized overnight 
only for observation following infusion of daratumumab, then the hospitalization should not 
be reported as a serious adverse event.

Hospitalizations not intended to treat an acute illness or adverse event (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 serious adverse events. Any adverse event that results in a prolongation of 
the originally planned hospitalization is to be reported as a new serious adverse event.
12.3.3.
Pregnancy
All initial reports of pregnancy 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, stillbirth, and congenital 
anomaly) are considered serious adverse events and must be reported using the Serious Adverse 
Event Form. If a subject becomes pregnant during the study, a determination regarding study
drug discontinuation must be made by the investigator in consultation with the sponsor.
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported by the study-site personnel within 24 hours of their 
knowledge of the event using the appropriate pregnancy notification form.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
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13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug
The daratumumab supplied for this study is a colorless to yellow liquid and sterile concentrate of 
20 mg/mL in a vial. It will be manufactured and provided under the responsibility of the sponsor.
Refer to the Investigator's Brochure for a list of excipients.
14.2.
Packaging
Daratumumab is supplied in glass vials containing daratumumab at a concentration of 
20 mg/mL.
14.3.
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.
14.4.
Preparation, Handling, and Storage
All study drug vials must be stored in the original carton in a refrigerator ranging from 2°C to 
8°C and must not be utilized after the expiry date printed on the label. The product must be 
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protected from light and must not be frozen. Daratumumab does not contain preservatives; 
therefore any unused portion remaining in the vial must be discarded.
Daratumumab will be diluted in a sterile, pyrogen-free physiological saline solution (0.9% NaCl) 
prior to IV administration. Refer to the Investigational Product Procedures Manual or equivalent 
document for details regarding dose preparation, storage, and handling of diluted solutions.
14.5.
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 study drug administered 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 
study-site monitor during on-site monitoring visits. The return to the sponsor of unused study 
drug, or used returned study drug for destruction, 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. 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.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator Brochure for daratumumab

Site Investigational Product Procedures Manual

Laboratory manual

eCRF completion guidelines

Sample ICF

Subject wallet card indicating blood type, Rh, and IAT or phenotyping result before first 
daratumumab dose 
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16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
The primary safety profile of daratumumab is consistent with IRRs; see Section 6.3 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.
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 adverse events of the study, and provide their consent voluntarily will be enrolled.  
The total blood volume to be collected is estimated at about 20 mL (about 1.5 tablespoons) for 
screening tests, 215 mL (about 1 cup) for Cycles 1-7, 20 mL (about 1.5 tablespoons) at 
subsequent cycles, and 36 mL (about 2 tablespoons) at the End-of-Treatment Visit and the post 
treatment visits (see Section 9.1.1). This includes laboratory assessments associated with, safety, 
efficacy, and pharmacokinetic evaluations, as well as scientific research samples. These blood 
volumes are not burdensome and fall within the normal range of a single blood donation.
16.1.1.
CD38 IHC Assay 
The archived biopsy samples were originally taken prior to the clinical study as part of the 
subject’s non-Hodgkin’s lymphoma disease clinical work-up or management. The archived biopsy 
tissue is then sent to the central laboratory for CD38 status determination. 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.
The risks to MCL, DLBCL, FL subjects whose tumors are tested by the Dako CD38 IHC 
pharmDx involves potential misclassification with respect to CD38 expression status. 

False-negative assay result- if the test returns a false-negative result at patient screening, 
the patient would be excluded from the clinical study. Patients with relapsed or refractory 
MCL, DLBCL, or FL would be treated as per the local practice or entered into another 
clinical study. Since the efficacy of daratumumab is yet to be proven in these patient 
populations, the impact of a false-negative result is believed to be minimal.
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
False-positive assay result- if the test returns a false-positive result during patient 
screening, the outcome is that the subject would be entered in the clinical study and 
treated with daratumumab. Considering the absence of approved SOC treatment in the 
US for relapsed or refractory MCL, DLBCL, or FL, the overall risk to the subject with a 
false-positive result is expected to be low.
Further, in the Simon 2-stage design of the clinical study protocol, a futility analysis will be 
performed to evaluate efficacy and safety data at the end of Stage 1. If the futility criteria are 
met, an NHL subtype may be terminated and further subject exposure, inclusive of those who 
might have had false-positive test results, will be limited. Similarly, the number of Stage 2 
subjects with CD38 expression level <50% will be capped within each NHL subtype, including 
those who might have had false-positive test results, to mitigate the possibility that a low 
response may be observed due to low levels of CD38 expression.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements. Good Clinical Practice is an international ethical and scientific 
quality standard for designing, conducting, recording, and reporting studies that involve the 
participation of human subjects. Compliance with this standard provides public assurance that 
the rights, safety, and well-being of study subjects are protected, consistent with the principles 
that originated in the Declaration of Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

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)
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
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 Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events 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
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). Furthermore, where required, progress reports/written summaries of the study
status will be submitted to the IRB/IEC annually, or more frequently if requested.
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). 
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16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. An ICF for CD38 screening may be obtained separately from the 
full study ICF. 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, including permission to obtain 
information about his or her survival status, and agrees to allow his or her study physician to 
recontact the subject for the purpose of obtaining consent for additional safety evaluations, if 
needed, and subsequent disease-related treatments, or to obtain information about his or her 
survival status.
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 either the subject's personally dated signature. After having obtained the consent, a 
copy of the ICF must 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 is not available, 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.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study. These data must be 
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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/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.
16.2.5.
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 
understand lymphoma, to understand differential drug responders, and to develop tests/assays 
related to daratumumab and lymphoma.  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 10.3, Withdrawal From the Study).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 16, Study-Specific Design 
Considerations.
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17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB/IEC (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.
17.2.
Regulatory Documentation
17.2.1.
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.
17.2.2.
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 
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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
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification 
and date of birth. In cases where the subject is not enrolled into the study, the date seen and date 
of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care, must be available for the 
following: subject identification, eligibility, and study identification; study discussion and date of 
signed informed consent; dates of visits; results of safety and efficacy parameters as required by 
the protocol; record of all adverse events and follow-up of adverse events; concomitant 
medication; drug receipt/dispensing/return records; study treatment administration information; 
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and date of study completion and reason for early discontinuation of study treatment or 
withdrawal from the study, if applicable. 
In addition, 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 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:

Referral letter from treating physician 

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
17.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format. 
All data relating to the study must be recorded in CRF. All CRF entries, corrections, and 
alterations must be made by the investigator or authorized study-site personnel. The investigator 
must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
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 
eCRFs 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. The investigator must verify that all data entries in the eCRFs are accurate and correct.
All eCRF entries, corrections, and alterations must be made by the investigator or other 
authorized study-site personnel. If necessary, queries will be generated in the electronic Data 
Capture (eDC) tool. If corrections to a CRF are needed after the initial entry into the CRF, this 
can be done in either of the following ways:

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).
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
Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor, and direct 
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 eCRFs for accuracy and completeness during on-
site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
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.
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17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study-site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the eCRFs with the hospital or clinic records (source 
documents, eg, hospital/clinic/physician’s office medical records). The nature and location of all 
source documents will be identified to ensure that all sources of original data required to 
complete the eCRF are known to the sponsor and study-site personnel and are accessible for 
verification by the sponsor study-site contact. If electronic records are maintained at the study 
site, the method of verification must be discussed with the study-site personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRFs and source documents 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 documentation 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.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed for each NHL subtype approximately 18 months after the last 
subject receives the first dose of daratumumab in that NHL subtype. The end of the study is 
defined as the completion of all three subtypes. The final data from the study site will be sent to 
the sponsor (or designee) after completion of the final subject at that study site, in the time frame 
specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

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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17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and 
available for consultation during routinely scheduled study-site audit visits conducted by the 
sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding 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 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 eCRF 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. Results of 
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. The results 
of each NHL subtype may be published separately from the others. Similarly, investigators will 
recognize the integrity of a multicenter study by not submitting for publication data derived from 
the individual study site until the combined results from the completed study have been 
submitted for publication, within 12 months of the availability of the final data (tables, listings, 
graphs), or the sponsor confirms there will be no multicenter study publication. Authorship of 
publications resulting from this study will be based on the guidelines 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.
Anderson JR, Armitage JO, Weisenburger DD for the Non-Hodgkin’s Lymphoma Classification Project. 
Epidemiology of the non-Hodgkin’s lymphomas: distributions of the major subtypes differ by geographic 
locations. Ann Oncol. 1998;9(7):717-720.
2.
Chapuy, C, Nicholson R, Aguad MD, et al. Resolving the daratumumab interference with blood compatibility 
testing. Transfusion. 2015; 55:1545-1554.
3.
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;32:3059-
3067.
4.
Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in 
elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-242.
5.
Coiffier B, Osmanov EA, Hong X, et al. Bortezomib plus rituximab versus rituximab alone in patients with 
relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial. Lancet 
Oncol. 2011; 12:773-784.
6.
Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the 
first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a 
study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 2010;116:2040-2045.
7.
de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal 
antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186:1840-
1848.
8.
Doshi P Sasser  AK, Axel A, et al. Daratumumab treatment in combination with CHOP or R-CHOP results in 
the inhibition or regression of tumors in preclinical modes of NHL - Presented at EHA 2014.
9.
Espinet B, Ferrer A, Bellosillo B, et al. Distinction between Asymptomatic Monoclonal B-cell Lymphocytosis 
with Cyclin D1 Overexpression and Mantle Cell Lymphoma: From Molecular Profiling to Flow Cytometry. 
Clin Cancer Res. 2014;20:1007-1019.
10.
Freedman A. Follicular lymphoma: 2012 update on diagnosis and management. Am J Hematol. 
2012;87(10):988 995.
11.
Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large 
B cell lymphoma in the Rituximab era. J Clin Oncol. 2010;28:4184-4190.
12.
Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a 
proposal from the International Lymphoma Study Group. Blood. 1994;84(5):1361-1392.
13.
Hess G, Herbrecht R, Romaguera J, et al. Phase III Study to evaluate temsirolimus compared with 
investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 
2009;27:3822-3829.
14.
Howard OM, Gribben JG, Neuberg DS, et al. Rituximab and CHOP induction therapy for newly diagnosed 
mantle-cell lymphoma: Molecular complete responses are not predictive of progression-free survival. J Clin 
Oncol. 2002;20:1288–1294.
15.
Jacobson CA, Freedman AS. Early stage follicular lymphoma, current management and controversies. Curr 
Opin Oncol. 2012;24(5):475-479.
16.
Jiang W, Freidlin B, Simon R. Biomarker-Adaptive Threshold Design: A Procedure for Evaluating Treatment 
With Possible Biomarker-Defined Subset Effect. J Natl Cancer Inst 2007; 99:1036-1043.
17.
Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for response assessment of 
lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. 
J Clin Oncol. 2007;25(5):571-578.
18.
Montoto S, Davies AJ, Matthews J, et al. Risk and clinical implications of transformation of follicular 
lymphoma to diffuse large B-cell lymphoma. J Clin Oncol. 2007;25(17):2426-2433.
NCT02413489

JNJ-54767414 Daratumumab
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19.
Nijhof IS, Lokhorst HM, Kessel B, et al. Combination of the anti-CD28 monoclonal antibody daratumumab 
and all-trans retinoic acid. Presented at Hematologic Malignancies: Translating discoveries to novel therapies. 
AACR, Sept 30-23, 2014, Philadelphia, PA.
20.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;5(6):649-655.
21.
Orchard J, Garand R, Davis Z, et al. A subset of t (11;14) lymphoma with mantle cell features displays mutated 
IgVH genes and includes patients with good prognosis, nonnodal disease. Blood. 2003; 101:4975-4981.
22.
Overdijk MB, Verploegen S, Bogels M, et al. Phagocytosis is a potent mechanism of action for the therapeutic 
human monoclonal antibody daratumumab in lymphoma and multiple myeloma. Submitted to Blood. 
13 May 2013.
23.
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.
24.
Relander T, Johnson NA, Farinha P, et al. Prognostic factors in follicular lymphoma. J Clin Oncol. 
2010;28(17):2902-2913.
25.
Tilly H and Dreyling M. Diffuse large B-cell non-Hodgkin’s lymphoma: ESMO clinical practice guidelines for 
diagnosis, treatment and follow-up. Annals of Oncology. 2010;21(Suppl 5): v172-v174.
26.
Van Den Berghe H, Parloir C, David G, Michaux JL, Sokal G. A new characteristic karyotypic anomaly in 
lymphoproliferative disorders. Cancer. 1979; 44 (1):188-195.
27.
Williams ME, Swerdlow SH, Rosenberg CL, Arnold A. Characterization of chromosome 11 translocation 
breakpoints at the bcl-1 and PRAD1 loci in centrocytic lymphoma. Cancer Res. 1992;52(19 Suppl):5541s-
5544s.
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ATTACHMENT 1:
REVISED RESPONSE CRITERIA FOR RESPONSE 
ASSESSMENT (CHESON 2014)
Refer to full manuscript (Cheson 2014)3 for details.
Response
Site
PET-CT-Based Response
CT-Based Response
Complete
Lymph 
nodes 
and 
extralymphatic 
sites
Complete metabolic response
Complete radiologic response 
(all of the following)
Score 1, 2, or 3a with or without a residual 
mass on 5PS2
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
Non 
measured 
lesion
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 
determinate, IHC negative
Partial
Lymph 
nodes 
and 
extralymphatic
sites
Partial metabolic response
Partial remission (all of the 
following)
Score 4 or 5b with reduced uptake compared 
with baseline and residual mass(es) of any 
size
At 
interim, 
these 
findings 
suggest 
responding disease
At end of treatment, these findings indicate 
residual disease
≥ 50% decrease in SPD of up to 
6 target measurable nodes and 
extranodal sites
When a lesion is too small to 
measure on CT, assign 5 mm × 
5 mm as the default value
When no longer visible, 0 × 
0 mm
For a node > 5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation
Nonmeasured 
lesion
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
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Response
Site
PET-CT-Based Response
CT-Based Response
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
Target 
nodes/nodal 
masses, 
extranodal 
lesions
No metabolic response
Stable disease
Score 4 or 5 with no significant change in 
FDG uptake from baseline at interim or end 
of treatment
< 50% decrease from baseline 
in SPD of up to 6 dominant, 
measurable 
nodes 
and 
extranodal sites; no criteria for 
progressive disease are met
Non measured 
lesion
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
Individual target 
nodes/nodal 
masses
Progressive metabolic disease
Progressive disease requires at 
least 1 of the following
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or
PPD progression:
Extranodal 
lesions
New 
FDG-avid 
foci 
consistent 
with 
lymphoma at interim or end-of-treatment 
assessment
An individual node/lesion must 
be abnormal with:
LDi > 1.5 cm and
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
Non measured 
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 any 
axis
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 
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Response
Site
PET-CT-Based Response
CT-Based Response
attributable to lymphoma
Assessable disease of any size 
unequivocally attributable to 
lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
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, shortest axis 
perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions. 
a: 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). 
b: 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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ATTACHMENT 2: ECOG PERFORMANCE STATUS SCALE
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 selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5
Dead
Reference:  Oken 198220
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ATTACHMENT 3:
CALCULATED 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, micromol/L), 
use the following formula to convert SI units to conventional (mg/dL) units (Manual of 
Laboratory & Diagnostic Tests, 2004):
•
serum creatinine (micromol/L) divided by 88.4 = serum creatinine (mg/dL).
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ATTACHMENT 4:
ASTHMA GUIDELINES
Components of
Severity
Classification of Asthma 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
any day
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 
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.
≥ 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 
week
s
• For side 
effects, 
consider 
alternativ
e 
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:
CONVERSION TABLE FOR GLUCOCORTICOSTEROID DOSE
Generic Name
Oral or Intravenous
Dose (mg)
Dexamethasone
0.75
Methylprednisolone
4
Prednisolone
5
Prednisone
5
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INVESTIGATOR AGREEMENT
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