Conditions: Carcinoma, Non-Small-Cell Lung
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 100
Healthy volunteers: no

Brief summary:
The purpose of the study is to compare the overall response rate (ORR) in non-small cell lung cancer (NSCLC) participants treated with daratumumab in combination with atezolizumab versus atezolizumab alone.

Detailed description:
This randomized (study medication assigned to participants by chance), multicenter study will provide study treatment (atezolizumab alone or atezolizumab+daratumumab) to participants with previously treated advanced or metastatic NSCLC to assess the anti-tumor activity and safety. Participants who receive atezolizumab treatment with confirmed disease progression based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be eligible to crossover to treatment (atezolizumab + daratumumab) if they meet crossover eligibility criteria. It is expected that 100 participants will enroll in the study including 6 participants in the safety run in phase. Data Monitoring Committee (DMC) will review ongoing data, and may formulate recommendations on study conduct, including expansion of enrollment of some PD-L1 subgroups, resulting in greater than 96 participants. The participants in the safety run in phase will be administered the combination of daratumumab and atezolizumab to determine the safety and tolerability that will be evaluated by the Safety Evaluation Team (SET) for dose limiting toxicity before the random assignment of participants in a 1:1 ratio in 2 treatment arms. The study consists of 3 phases: Screening Phase (up to 28 days), Treatment Phase and Post-Treatment Follow-up Phase which will continue until death, lost to follow-up, withdrawal of consent, or the End of the Study \[the study end is approximately 6 to 12 months after that last participant is enrolled\]. Participants will undergo tumor assessments (RECIST 1.1), immunogenicity, pharmacokinetics, biomarkers and safety evaluations (adverse events, laboratory tests, electrocardiogram \[ECGs\], vital sign measurements, physical examinations, Eastern Cooperative Oncology Group \[ECOG\] performance status score) over the time.

Arms:
arm 1: Participants in Treatment Arm A will receive Atezolizumab 1,200 milligram (mg) intravenously (IV) on Day 1 of every 21-day cycle. Participants with confirmed disease progression based on RECIST 1.1 may cross over to Arm B and receive daratumumab and atezolizumab, provided crossover eligibility criteria are met. arm 2: Participants will receive daratumumab 16 milligram per kilogram \[mg/kg\] (Safety Run-in and Treatment Arm B) Intravenously (IV) weekly for 3 cycles (Day 1, 8 and 15), and Day 1 of every 21-day cycle thereafter. Atezolizumab will be administered at 1200 mg IV on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter. Participants will continue to receive study treatment until confirmed disease progression, unacceptable toxicity, or any other treatment discontinuation criteria are met.

Interventions: intervention 1: Atezolizumab intervention 2: Daratumumab
Intervention descriptions: intervention 1: Participants will receive atezolizumab 1200 mg intravenously. intervention 2: Participants will receive daratumumab 16 mg/kg intravenously.

Protocol document:
Prot_001.pdf: 
Status: Approved, Date: 4 October 2018
Janssen Research & Development *
Clinical Protocol
A Phase 1b/2, Open-Label, Randomized Study of Daratumumab Administered in 
Combination with Atezolizumab Compared with Atezolizumab Alone in Subjects with 
Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer
Protocol 54767414LUC2001; Phase 1b/2
AMENDMENT 7
DARZALEX®
JNJ-54767414  (daratumumab)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the Sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen 
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “Sponsor” is used throughout 
the protocol to represent these various legal entities; the Sponsor is identified on the Contact Information 
page that accompanies the protocol.
Daratumumab and atezolizumab are being investigated in Phase 1, 2 and 3 clinical studies.
Daratumumab and atezolizumab are approved for marketing in 2 indications each.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER:  2016-002579-83
Status:
Approved
Date:
4 October 2018
Prepared by:
Janssen Research & Development, LLC  
EDMS number:
EDMS-ERI-123755712, 14.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 32
ABBREVIATIONS ...................................................................................................................................... 39
1.
INTRODUCTION................................................................................................................................ 41
1.1.
Background .................................................................................................................................... 41
1.2.
Clinical Experience with Atezolizumab .......................................................................................... 44
1.3.
Clinical Experience with Daratumumab ......................................................................................... 47
1.3.1.
Daratumumab IV......................................................................................................................... 48
1.4.
Overall Rationale for the Study...................................................................................................... 49
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 50
2.1.
Objectives and Endpoints .............................................................................................................. 50
2.1.1.
Objectives ................................................................................................................................... 50
2.1.2.
Endpoints.................................................................................................................................... 51
2.2.
Hypothesis ..................................................................................................................................... 51
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 52
3.1.
Overview of Study Design.............................................................................................................. 52
3.2.
Study Conduct After DMC Recommendations .............................................................................. 55
3.3.
Safety Evaluation ........................................................................................................................... 55
3.4.
Study Design Rationale.................................................................................................................. 57
4.
SUBJECT POPULATION.................................................................................................................. 59
4.1.
Inclusion Criteria ............................................................................................................................ 60
4.2.
Exclusion Criteria ........................................................................................................................... 62
4.3.
Inclusion and Exclusion Criteria for Crossover .............................................................................. 65
4.3.1.
Inclusion Criteria for Crossover .................................................................................................. 65
4.3.2.
Exclusion Criteria for Crossover ................................................................................................. 67
4.4.
Prohibitions and Restrictions ......................................................................................................... 68
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 69
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 69
6.1.
Daratumumab ................................................................................................................................ 69
6.1.1.
Daratumumab IV Preparation..................................................................................................... 69
6.1.2.
Daratumumab Treatment Schedule and Administration ............................................................ 69
6.1.3.
Guidelines for Prevention of Daratumumab Infusion Reactions................................................. 71
6.1.3.1.
Predose Medications ............................................................................................................... 71
6.1.3.2.
Postadministration Medications............................................................................................... 71
6.1.4.
Dose Delay and Modification...................................................................................................... 72
6.1.5.
Toxicity Management.................................................................................................................. 72
6.2.
Atezolizumab.................................................................................................................................. 73
6.2.1.
Management of Atezolizumab-Specific Adverse Events............................................................ 74
6.2.1.1.
Pulmonary Events ................................................................................................................... 75
6.2.1.2.
Hepatic Events ........................................................................................................................ 75
6.2.1.3.
Gastrointestinal Events............................................................................................................ 75
6.2.1.4.
Endocrine Events .................................................................................................................... 75
6.2.1.5.
Ocular Events .......................................................................................................................... 76
6.2.1.6.
Immune-Related Myocarditis................................................................................................... 76
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6.2.1.7.
Pancreatic Events.................................................................................................................... 76
6.2.1.8.
Dermatologic Events ............................................................................................................... 77
6.2.1.9.
Neurologic Disorders ............................................................................................................... 77
6.2.1.10.
Immune-Related Meningoencephalitis .................................................................................... 77
6.2.1.11.
Immune-related Nephritis ........................................................................................................ 77
6.2.1.12.
Systemic Immune Activation ................................................................................................... 78
6.3.
Management of Infusion-related Reactions ................................................................................... 78
6.3.1.
Infusion-related Reactions.......................................................................................................... 78
6.3.2.
Atezolizumab .............................................................................................................................. 79
7.
TREATMENT COMPLIANCE............................................................................................................ 79
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 80
8.1.
Permitted Therapies....................................................................................................................... 81
8.2.
Prohibited Therapies...................................................................................................................... 82
9.
STUDY EVALUATIONS .................................................................................................................... 82
9.1.
Study Procedures........................................................................................................................... 82
9.1.1.
Overview..................................................................................................................................... 82
9.1.2.
Optional Prescreening Phase..................................................................................................... 83
9.1.3.
Screening Phase ........................................................................................................................ 83
9.1.4.
Open-Label Treatment Phase .................................................................................................... 83
9.1.5.
Follow-Up Phase ........................................................................................................................ 84
9.2.
Procedures for Subjects Continuing on Study with Atezolizumab Monotherapy (per 
Amendment 6)................................................................................................................................ 85
9.3.
Guidance for Subjects Continuing on Study with Atezolizumab Monotherapy (per 
Amendment 7)................................................................................................................................ 85
9.4.
Efficacy Evaluations....................................................................................................................... 86
9.4.1.
Disease Assessments ................................................................................................................ 86
9.4.2.
Treatment After Initial Disease Progression............................................................................... 87
9.5.
Pharmacokinetics and Immunogenicity ......................................................................................... 88
9.5.1.
Evaluations ................................................................................................................................. 88
9.5.2.
Analytical Procedures................................................................................................................. 89
9.5.3.
Pharmacokinetic Parameters ..................................................................................................... 89
9.5.4.
Immunogenicity Assessments .................................................................................................... 89
9.6.
Biomarker Assessments ................................................................................................................ 90
9.6.1.
Tumor Tissue Samples............................................................................................................... 90
9.6.2.
Biomarker Assays in Blood Samples.......................................................................................... 92
9.7.
Safety Evaluations ......................................................................................................................... 92
9.8.
Sample Collection and Handling.................................................................................................... 95
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 96
10.1.
Completion ..................................................................................................................................... 96
10.2.
Discontinuation of Study Treatment/Withdrawal from the Study ................................................... 96
10.3.
Withdrawal From the Use of Research Samples........................................................................... 97
11.
STATISTICAL METHODS................................................................................................................. 98
11.1.
Subject Information ........................................................................................................................ 98
11.2.
Sample Size Determination ........................................................................................................... 98
11.3.
Efficacy Analyses ........................................................................................................................... 98
11.4.
Pharmacokinetic Analyses............................................................................................................. 99
11.5.
Immunogenicity Analyses .............................................................................................................. 99
11.6.
Biomarker Analyses ..................................................................................................................... 100
11.7.
Pharmacokinetic/Pharmacodynamic Analyses............................................................................ 100
11.8.
Safety Analyses ........................................................................................................................... 100
11.9.
Data Monitoring Committee ......................................................................................................... 101
12.
ADVERSE EVENT REPORTING .................................................................................................... 101
12.1.
Definitions .................................................................................................................................... 102
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12.1.1.
Adverse Event Definitions and Classifications ......................................................................... 102
12.1.2.
Attribution Definitions................................................................................................................ 103
12.1.3.
Severity Criteria ........................................................................................................................ 104
12.2.
Special Reporting Situations........................................................................................................ 104
12.3.
Procedures................................................................................................................................... 104
12.3.1.
All Adverse Events.................................................................................................................... 104
12.3.2.
Serious Adverse Events ........................................................................................................... 106
12.4.
Safety Reporting for Atezolizumab Monotherapy Subjects (per Amendment 6) ......................... 107
12.5.
Safety Reporting for Atezolizumab Monotherapy Subjects (per Amendment 7) ......................... 107
12.6.
Pregnancy .................................................................................................................................... 108
12.7.
Contacting Sponsor Regarding Safety......................................................................................... 108
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 108
13.1.
Procedures................................................................................................................................... 108
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 108
14.
STUDY DRUG INFORMATION....................................................................................................... 109
14.1.
Physical Description of Study Drug(s) ......................................................................................... 109
14.2.
Packaging .................................................................................................................................... 109
14.3.
Labeling........................................................................................................................................ 109
14.4.
Preparation, Handling, and Storage............................................................................................. 109
14.5.
Drug Accountability ...................................................................................................................... 109
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 110
16.
ETHICAL ASPECTS ....................................................................................................................... 110
16.1.
Study-Specific Design Considerations......................................................................................... 110
16.2.
Regulatory Ethics Compliance..................................................................................................... 111
16.2.1.
Investigator Responsibilities ..................................................................................................... 111
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 111
16.2.3.
Informed Consent ..................................................................................................................... 113
16.2.4.
Privacy of Personal Data .......................................................................................................... 114
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 114
16.2.6.
Country Selection ..................................................................................................................... 115
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 115
17.1.
Protocol Amendments.................................................................................................................. 115
17.2.
Regulatory Documentation .......................................................................................................... 115
17.2.1.
Regulatory Approval/Notification .............................................................................................. 115
17.2.2.
Required Prestudy Documentation........................................................................................... 115
17.3.
Subject Identification, Enrollment, Prescreening, and Screening Logs ....................................... 117
17.4.
Source Documentation................................................................................................................. 117
17.5.
Case Report Form Completion .................................................................................................... 118
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 118
17.7.
Record Retention ......................................................................................................................... 119
17.8.
Monitoring .................................................................................................................................... 119
17.9.
Study Completion/Termination..................................................................................................... 120
17.9.1.
Study Completion/End of Study................................................................................................ 120
17.9.2.
Study Termination..................................................................................................................... 120
17.10.
On-Site Audits .............................................................................................................................. 121
17.11.
Use of Information and Publication.............................................................................................. 121
REFERENCES.......................................................................................................................................... 123
INVESTIGATOR AGREEMENT ............................................................................................................... 147
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LIST OF ATTACHMENTS
Attachment 1:
Antihistamine Medications........................................................................................ 126
Attachment 2:
Conversion Table for Glucocorticosteroid Dose....................................................... 127
Attachment 3:
ECOG Performance Status Scale ............................................................................ 128
Attachment 4:
Anticipated Events.................................................................................................... 129
Attachment 5:
Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference ............ 131
Attachment 6:
Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)............ 133
Attachment 7:
Management Guidelines for Atezolizumab............................................................... 134
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Time and Events Schedule – Safety Run-in, Randomized Arms ............................................. 35
Table 2: 
Tumor and Immune Cell PD-L1 Expression and Scoring......................................................... 44
Table 3:
Patients with NSCLC in Study PCD4989g:  Confirmed Objective Response Rate by 
Tumor PD-L1 Expression and Best Overall Response Rate (per RECIST, Version 1.1) ........ 45
Table 4:
Patients with NSCLC in Study GO28754: ORR, PFS, and OS by Tumor PD-L1 
Expression and Number of Prior Lines of Therapy................................................................... 46
Table 5:
Overall Survival in Study GO28915 (OAK)............................................................................... 47
Table 6:
Criteria for Dose-limiting Toxicity.............................................................................................. 56
Table 7:
Daratumumab Infusion Rates ................................................................................................... 70
Table 8:
Pre- and Postinfusion Methylprednisolone Doses (or equivalent) for Dara-IV......................... 71
Table 9:
Daratumumab-related Toxicity Management ........................................................................... 72
Table 10:
Management Guidelines for Daratumumab Infusion-related Reactions................................... 78
Table 11:
Management Guidelines for Atezolizumab Infusion-related Reactions.................................... 79
Table 12:
Imaging and Treatment after First Radiologic Evidence of Progressive Disease .................... 88
Table 13:
Management Guidelines for Pulmonary Events, Including Pneumonitis................................ 135
Table 14:
Management Guidelines for Hepatic Events .......................................................................... 136
Table 15:
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis)............................. 137
Table 16:
Management Guidelines for Endocrine Events ...................................................................... 138
Table 17:
Management Guidelines for Ocular Events............................................................................ 140
Table 18:
Management Guidelines for Pancreatic Events, Including Pancreatitis................................. 141
Table 19:
Management Guidelines for Immune-Related Myocarditis..................................................... 142
Table 20:
Management Guidelines for Dermatologic Events ................................................................. 143
Table 21:
Management Guidelines for Neurologic Disorders, Including Meningoencephalitis .............. 144
Table 22:
Diagnostic Criteria and Management for Systemic Immune Activation.................................. 145
Table 23:
Management Guidelines for Immune-Related Nephritis......................................................... 146
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 54
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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
25 July 2016
Amendment 1
1 September 2016
Amendment 2
22 March 2017
Amendment 3
24 August 2017
Amendment 4
26 February 2018
Amendment 5
19 April 2018
Amendment 6
14 August 2018
Amendment 7
4 October 2018
Amendments below are listed beginning with the most recent amendment.
Amendment 7 (4 October 2018)
The overall reason for the amendment:
This amendment provides guidance for the end-of-study data collection and permits subjects who are deriving 
clinical benefit from atezolizumab monotherapy to continue to receive treatment according to local regulatory 
approval and standard of care guidelines.50,51
Applicable Section(s)
Description of Change(s)
Rationale: Pursuant to the recommendations from the Data Monitoring Committee (DMC; [third planned review on 
23 May 2018]), who determined that there was no increased benefit with combination daratumumab and 
atezolizumab therapy, treatment with daratumumab was discontinued and active subjects were allowed to continue 
on atezolizumab monotherapy (Amendment 6). For active subjects who are deriving clinical benefit, but do not have 
access to commercial atezolizumab, the Sponsor will continue to supply atezolizumab. The administration of 
atezolizumab will occur under the supervision of treating investigators in accordance with local regulatory approvals 
and standard of care guidelines.50,51 With the clinical database now locked and subjects receiving only atezolizumab 
monotherapy, data from efficacy and safety evaluations performed according to local regulatory approvals and 
standard of care guidelines50,51 will no longer be collected with the exception of serious adverse events that are to be 
reported and entered in the Sponsor safety repository.
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Applicable Section(s)
Description of Change(s)
Synopsis (Overview 
of Study Design, 
Dosage and 
Administration, 
Efficacy Evaluations, 
and Safety 
Evaluations
subsections);
Table 1: Time and 
Events Schedule;
3.1 Overview of 
Study Design;
3.2 Study Conduct 
After DMC 
Recommendations;
6.2 Atezolizumab;
6.2.1 Management of 
Atezolizumab-specific 
Adverse Events
7 Treatment 
Compliance;
9.1.5 Follow-up 
Phase;
9.3 Guidance for 
Subjects Continuing 
on Study with 
Atezolizumab 
Monotherapy (per 
Amendment 7) (new
section);
9.4 Efficacy 
Evaluations;
9.7 Safety 
Evaluations;
9.8 Sample Collection 
and Handling;
12.5 Safety Reporting 
for Atezolizumab 
Monotherapy Subjects 
(per Amendment 7)
(new section);
14.5 Drug 
Accountability;
17.5 Case Report 
Form Completion;
17.9.1 Study 
Completion/End of 
Study;
References.
Clarified that, as of the implementation of Amendment 7, subjects who are deriving 
clinical benefit from atezolizumab monotherapy, but do not have access to commercial 
atezolizumab, may continue treatment according to local regulatory approvals and standard 
of care guidelines.50,51
Clarified that, as of the implementation of Amendment 7, data from efficacy and safety 
evaluations performed according to local regulatory approvals and standard of care 
guidelines50,51 will no longer be collected with the exception of serious adverse events that 
are to be reported and entered in the Sponsor safety repository.
Rationale: Minor grammatical, formatting, or spelling changes were made for consistency with the other changes in 
this amendment, including updating the abbreviations list
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
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Amendment 6 (14 August 2018)
The overall reason for the amendment:
As of 25 May 2018, the Sponsor notified the sites to terminate further enrollment into this study, 
54767414LUC2001 (CALLISTO), in which the combination of daratumumab and atezolizumab is being studied in
subjects with non-small cell lung cancer. At the third planned DMC review on 23 May 2018, the DMC reviewed the 
subject data (n=88, 44 per arm) for this study. The DMC determined that there was no observed benefit within the 
combination treatment arm, daratumumab plus atezolizumab, over atezolizumab alone, and recommended stopping 
enrollment of the study. In addition, the DMC recommended discontinuation of daratumumab treatment to all active 
subjects receiving combination therapy (subjects randomized to the combination Arm B, as well as subjects 
randomized to Arm A who crossed over into Arm B). Although no unexpected imbalances in on-treatment toxicities 
were observed, the DMC noted a clear difference in the number of deaths between the atezolizumab monotherapy 
and combination arm. Therefore, enrollment is discontinued in this study, treatment with the combination of 
daratumumab and atezolizumab will be discontinued, and ongoing subjects will be given the option to continue on 
atezolizumab monotherapy until the subject meets one or more of the treatment discontinuation criteria in 
Section 10.2.
In addition, since the subcutaneous administration of daratumumab (Phase 1b Dara-SC cohort) was never 
implemented, this is removed from the protocol.
Guidelines on managing immune-related nephritis are added based on recent information on this risk with 
atezolizumab.
Applicable Section(s)
Description of Change(s)
Rationale: Enrollment is discontinued in this study, treatment with the combination of daratumumab and 
atezolizumab is discontinued, and ongoing subjects will be given the option to continue on atezolizumab 
monotherapy. Note that to preserve the history of the protocol design, certain sections have not been changed (eg, 
objectives).
Synopsis;
Time and Events Schedule Tables 2 
through 7 (removed);
1.4 Overall Rationale for the Study; 
3.1 Overview of Study Design;
3.2 Study Conduct After DMC 
Recommendations (new);
3.4 Study Design Rationale;
4 Subject Population; 4.3 Inclusion and 
Exclusion Criteria for Crossover;
5 Treatment Allocation and Blinding;
9.1.1 Overview;
9.2 Procedures for Subjects Continuing 
on Study with Atezolizumab 
Monotherapy (per Amendment 6) (new);
9.3 Efficacy Evaluations;
9.3.1 Disease Assessments, Table 19;
9.5 Biomarker Assessments;
9.6 Safety Evaluations;
10.2 Discontinuation from Study 
Treatment/Withdrawal from the Study;
12.4 Safety Reporting for Atezolizumab 
Monotherapy Subjects (per 
Amendment 6) (new);
14 Study Drug Information;
17.8 Monitoring;
17.9.1 Study Completion/End of Study
Time and Events Schedules for biomarkers, pharmacokinetics, 
immunogenicity, and crossover (Tables 2-7) were removed because 
of the discontinuation of daratumumab combination treatment.
Described the rationale for terminating enrollment into the study and 
clarified the assessments that will be performed for subjects that 
remain in the study.
New Sections 3.2 and 9.2 were added to define study conduct 
changes.
Removed rationale for crossover and noted that crossover will no 
longer be performed.
Specified that those subjects who crossed over to Arm B should be 
carefully evaluated for potential benefit for atezolizumab 
monotherapy.
Clarified that any treatment beyond disease progression requires prior 
discussion with and approval by the Sponsor’s Study Responsible 
Physician; subjects with documented disease progression should 
discontinue study therapy. Table 19 (Imaging and Treatment after 
First Radiologic Evidence of Progressive Disease) and Section 10.2 
are revised accordingly. Clarified that subjects who had crossed over 
to Arm B should be carefully evaluated to determine whether they 
will benefit from treatment with atezolizumab monotherapy.
The blood type, Rh, and Indirect Antiglobulin Test (IAT) no longer 
needs to be performed in those who have discontinued daratumumab.
Safety reporting will be limited for the atezolizumab monotherapy 
subjects.
Daratumumab study drug information is removed.
Study monitoring will be limited.
The study completion/end of study definition is revised.
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Applicable Section(s)
Description of Change(s)
Rationale: The subcutaneous administration for daratumumab (Dara-SC) was added in Amendment 5; however, 
this was not implemented due to daratumumab administration being discontinued in this study.
Synopsis (Objectives, Endpoints, 
Overview of Study Design, Dosage and 
Administration, Pharmacokinetic and 
Immunogenicity Evaluations);
Table 1: Time and Events Schedule-
Safety Run-in, Randomized Arms (and 
Phase 1b Dara-SC Cohort); 
1.3.2 Daratumumab for Subcutaneous 
Administration (removed);
2.1.1 Objectives;
2.1.2 Endpoints;
3.1 Overview of Study Design, 
Figure 1 Schematic Overview of the 
Study;
3.4 Study Design Rationale (rationale 
for Dara-SC removed; Figures 2-4 
removed);
4.1 Inclusion Criterion 5;
4.2 Exclusion Criteria (1, 6);
5 Treatment Allocation and Blinding;
6 Dosage and Administration;
6.1.2 Dara-SC Preparation;
6.1.3 Daratumumab Treatment Schedule 
and Administration;
6.1.4 Guidelines for Prevention of 
Daratumumab Infusion Reactions;
6.1.4.1 Predose Medications;
6.1.4.2 Postadministration Medications;
6.2 Atezolizumab;
6.3 Management of Injection-site and
Infusion-Related Reactions;
6.3.1 Local Injection-site Reactions 
(removed);
9.4 Pharmacokinetics and 
Immunogenicity;
11.2 Sample Size Determination;
11.3 Efficacy Analyses; 
11.5 Immunogenicity Analyses; 
11.9 Data Monitoring Committee; 
14 Study Drug Information;
16.1 Study-Specific Design 
Considerations
Removed all text, figures, and assessments in tables regarding the 
Phase 1b Dara-SC cohort, including objectives and endpoints, dosing, 
pharmacokinetics, and immunogenicity assessments (including 
assessment of anti-rHuPH20 antibodies), and the rationale for Dara-
SC administration
Removed Phase 1b Dara-SC Cohort assessments in Table 1.
Removed Inclusion and Exclusion criteria specific for this cohort.
Removed Dara-SC drug administration information.
Removed statistical analyses for this cohort.
Removed description of Dara-SC study drug.
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Applicable Section(s)
Description of Change(s)
Rationale: Added information of immune-related nephritis, which was recently added as an important identified 
risk with atezolizumab.
6.2.1.11 Immune-Related Nephritis;
Attachment 7 Table 30 Management 
Guidelines for Immune-Related 
Nephritis (new)
Information on immune-related nephritis and management guidelines 
have been added.
Rationale: Minor grammatical, formatting, or spelling changes were made for consistency with the other changes 
in this amendment, including updating the abbreviations list.
Throughout the protocol
Amendment 5 (19 April 2018)
The overall reason for the amendment:
 
 
 
 
 
 
 
Applicable Section(s)
Description of Change(s)
Rationale:
 
Synopsis;
Time and Events Schedules –
Tables 1, 2, 4 (new
pharmacokinetic table), 5, 7; 
1.3.2 Daratumumab for 
Subcutaneous Administration 
(new); 
2.1.1 Objectives; 
2.1.2 Endpoints;
3.1 Overview of Study
Design;
3.3 Study Design Rationale
 
 
A new primary objective and endpoint is added for the new cohort.
Safety criteria are specified for evaluating the first 6 subjects and for expansion 
of enrollment based on Data Monitoring Committee (DMC) evaluation.
 
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JNJ-54767414  (daratumumab)
Clinical Protocol 54767414LUC2001; Amendment 7
11
Approved, Date: 4 October 2018
Applicable Section(s)
Description of Change(s)
4.1 Inclusion Criteria; 4.2 
Exclusion Criteria;
Tumor cell PD-L1 score as determined by an IHC assay performed by the 
central laboratory on tissue obtained after the last line of therapy:
-
Subjects with a tumor cell PD-L1 score of TC0 who are anti-PD-1 or 
anti-PD-L1 treatment naïve will be eligible for screening
-
Subjects who have disease progression on or after anti-PD-1 or anti-
PD-L1 therapy and with any tumor cell PD-L1 score (TC0-3), will be 
eligible for screening.
Randomized phase
Subjects with a tumor cell PD-L1 score of TC1-3 who are anti-PD-1 or 
anti-PD-L1 treatment naïve will be eligible for screening
Exclusion Criterion 1 is modified:
 
Exclusion Criterion 6 is modified:
 
5 Treatment Allocation and 
Blinding;
6.1 Daratumumab;
6.1.1 Daratumumab IV
Preparation;
6.1.2 Daratumumab 
Subcutaneous Preparation
(new); 
6.1.3 Daratumumab 
Treatment Schedule and 
Administration;
6.1.4 Guidelines for 
Prevention of Daratumumab 
Infusion Reactions; 
6.2 Atezolizumab;
6.3 Management of 
Injection-site and Infusion-
Related Reactions;
6.3.1 Local Injection-site 
Reactions (new); 
11.2 Sample Size 
Determination;
11.3 Efficacy Analyses;
11.9 Data Monitoring 
Committee;
14 Study Drug Information
Added: 
 
 
 
 
 
 
 
 
 
 
 
16.1 Study-Specific Design 
Considerations
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JNJ-54767414  (daratumumab)
Clinical Protocol 54767414LUC2001; Amendment 7
12
Approved, Date: 4 October 2018
Applicable Section(s)
Description of Change(s)
Synopsis;
Section 2.1 Objectives and 
Endpoints;
2.1.1 Objectives;
2.1.2 Endpoints;
3.3 Study Design Rationale;
9.3 Pharmacokinetics and 
Immunogenicity;
11.5 Immunogenicity 
Analyses
 
 
Rationale: An optional Prescreening informed consent will be offered for the purpose of testing archival tumor 
tissue to assess PD-L1 status using the SP142 assay to help determine the likelihood of eligibility for participation 
in this study. However, final eligibility for study participation will be based on PD-L1 staining on the fresh 
biopsy required during the Screening Phase.
Time and Events Schedules -
Tables 1 and 2; 
4 Subject Population; 9.1.2 
Optional Prescreening Phase;
17.3 Subject Identification, 
Enrollment, Prescreening,
and Screening Logs 
The optional Prescreening Phase for archival testing to assess PD-L1 status is 
specified.
Add “Prescreening” to the heading for 17.3.
Rationale: To obtain longer-term kinetics of immunological biomarkers, biomarker sample collection at Cycle 4 
is added.
Time and Events Schedules -  
Table 2 and 6
Cycle 4 Day 1 predose whole blood biomarker samples are added.
Rationale: Updated the incidence of IRRs for atezolizumab.
1.4 Overall Rationale for the 
Study
IRRs occur in only approximately 1% of patients treated with atezolizumab
Rationale: Minor errors were noted
Throughout the protocol
Revisions and modifications were made throughout the protocol to increase 
clarity and consistency, to update the protocol based on revisions made during 
this amendment, or to correct omissions and errors. Minor grammatical, 
formatting, or spelling changes were made.
NCT03023423


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414LUC2001; Amendment 7
13
Approved, Date: 4 October 2018
Amendment 4 (26 Feb 2018)
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: The overall reason for the amendment is to expand the Screening 
period for the informed consent and for PD-L1 testing, and to specify the PD-L1 score inclusion criterion. During 
its review of the study data at the initial interim analysis (40 evaluable subjects), the DMC determined that the 
study had enrolled a sufficient number of subjects with a PD-L1 score of TC0 and recommended continued 
enrollment only in subjects in the TC1-3 subgroups.
In addition, the safety management guidelines for atezolizumab have been updated based on the current 
Investigator’s Brochure.
Note: where actual changes are shown in this amendment table, new text is in bold font and text that is removed 
is struck out.
Applicable Section(s)
Description of Change(s)
Rationale: To expand the Screening period for PD-L1 testing to prevent unnecessary Screening testing for 
subjects who do not qualify for the study; and to clarify the PD-L1 score criterion.
Table 1 Time and
Events Schedule;
4 Subject Population;
Table 2 Biomarker
Assessments – Safety 
Run-in and 
Randomized Arms
3.1 Overview of Study 
Design, Figure 1;
5 Treatment Allocation
and Blinding
Table 2 Biomarker
Assessments – Safety 
Run-in and 
Randomized Arms
footnote b, footnote c;
Table 6 Biomarker 
Assessments  
Crossover, footnote c, 
footnote d;
9.4 Biomarker 
Assessments; 9.4.1 
Tumor Tissue Samples
Expanded the Screening period for the informed consent and for PD-L1 testing to 
-56 to -1 days.
In Table 2, added reference to the expanded period of -56 to -1 d for Screening PD-L1 
testing.
Revised Figure 1 Schematic Overview of the Study to add the expanded Screening 
period for PD-L1 testing.
Clarified that pursuant with DMC recommendations, only subjects with a PD-L1 score 
of TC1-3 will be eligible to enroll in the study, therefore, all subjects will have PD-L1 
expression status of “other”, and will only be stratified by histology (squamous vs. 
non-squamous), and number of previous lines of therapy (1 or >1). 
Specified that the collection of a fresh tumor biopsy is mandatory at Cycle 3 and at 
progression.
Cycle 3 biopsy may be collected within 7 days prior to or up to 21 days after the Cycle 
3 Day 1 dose, but must be prior to the Cycle 4 Day 1 dose. In addition, this biopsy must 
be performed following the first radiologic tumor assessment.
The corresponding footnote in Table 5 (crossover) was also revised and a note was 
added to Section 9.4.1.
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JNJ-54767414  (daratumumab)
Clinical Protocol 54767414LUC2001; Amendment 7
14
Approved, Date: 4 October 2018
4 Study Population; 
9.1.2 Screening Phase
4.1 Inclusion Criteria
Explanation added for enrolling subjects with TC1-3 PD-L1 score: During its review 
of the study data at the initial interim analysis (40 evaluable subjects), the DMC 
determined that the study had enrolled a sufficient number of subjects with a PD-L1 
score of TC0 and recommended continued enrollment only in subjects in the TC1-3 
subgroups.
New text added for PD-L1 screening: The signing of the informed consent and 
collection of tumor specimen for PD-L1 testing may occur up to 56 days before the 
first administration of study drug. All other screening procedures must be performed 
only after PD-L1 results are available, and within 28 days before the first 
administration of study drug. For subjects who do not meet Inclusion Criterion 5, no 
further Screening procedures should be performed.
Criterion 5 is revised: Known Tumor cell PD-L1 score of TC1-3 and immune cell 
PD-L1 score of IC0-3 tumor status as determined by an IHC assay performed by the 
central laboratory on tissue obtained after the last line of therapy at Screening.
4.4 Prohibitions and 
Restrictions
New requirement is added: 3. Express understanding of the requirement for on-
treatment biopsies during the study (ie, Cycle 3, after progression, crossover)
11.9. Data Monitoring 
Committee
Revised: The DMC will review the totality of data after approximately 40, 60, and 90 
subjects have been enrolled, and will formulate recommendations on study conduct, 
including but not limited to future subject enrollment (see Section 11.3). The DMC 
may request additional ad-hoc reviews as data accumulate to monitor safety or 
efficacy in certain PD-L1 subgroups.
Rationale: Updates the safety management guidelines for atezolizumab based on the current Investigator’s 
Brochure. Added anticipated events based on the current  
6.2 Atezolizumab;
6.2.1 Management of 
Atezolizumab-Specific 
Adverse Events;
6.3.2 Atezolizumab;
Attachment 7: 
Management 
Guidelines for 
Atezolizumab;
8.2 Prohibited 
Medications
Discontinuation of atezolizumab may not have an immediate therapeutic effect and, in 
severe cases, immune-mediated toxicities may require acute management with topical 
corticosteroids, systemic corticosteroids, mycophenolate, or TNF-inhibitors. or 
other immunosuppressive agents.
Sections 6.2.1.1 – 6.2.1.7 have been revised, including a new section on immune-
mediated myocarditis. Sections 6.2.1.8 Dermatologic Events and 6.2.1.9 Neurologic 
Events have not changed. A new section on immune-related meningoencephalitis
(6.2.1.10) has been added. 
Management of atezolizumab infusion-related reactions text has been revised:
No premedication is indicated for the administration of atezolizumab in Cycle 1. 
Subjects who experience an IRR with Cycle 1 of atezolizumab may receive 
premedication with antihistamines or antipyretics/analgesics (eg, acetaminophen) for 
subsequent infusions. Metamizole (dipyrone) is prohibited in treating atezolizumab 
associated infusion-related reactions, due to its potential for causing 
agranulocytosis. Table 11 provides management guidelines for atezolizumab IRRs in 
Cycle 1. For subsequent cycles, infusion-related reactions should be managed 
according to institutional guidelines. Footnote a has been added to Table 16.
The tables in Attachment 7 have also been revised, including a new table for immune-
mediated myocarditis.
Dipyrone is added to the list of prohibited medications.
Attachment 4 
Anticipated Events
Endocrinopathies (diabetes mellitus, pancreatitis, adrenal insufficiency, or 
hyperthyroidism, hypophysitis)
Events suggestive of hypersensitivity, cytokine release, influenza-like illness, systemic 
inflammatory response syndrome, systemic immune activation, infusion reactions 
syndrome, immune-mediated myocarditis, vasculitis, severe cutaneous adverse 
reactions autoimmune hemolytic anemia
NCT03023423


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414LUC2001; Amendment 7
15
Approved, Date: 4 October 2018
Rationale: To modify planned statistical analysis as a result of DMC recommendation.
Synopsis; 
11.2 Sample Size 
Determination 
The following text is revised: Assuming that the ORR for atezolizumab monotherapy is 
approximately 20%, and the addition of daratumumab would improve ORR by 20% to 
40%, 90 subjects need to be randomized with a 1:1 ratio in order to achieve 80% power 
to detect this difference with a one-sided alpha of 0.10. The statistical power of 80% 
is to reject the null hypothesis that there is no difference in ORR between the two 
treatment arms. In the event that benefit from the combination is not observed across 
the total overall study population, target enrollment of subgroups, based on tumor PD-
L1 expression level, may be adjusted, based on DMC recommendations.  
(see Section 11.3). provides guidelines for the DMC to use when recommending 
sample size adjustments. As such, approximately 50 additional subjects in the 
TC2/TC3 subgroups may be enrolled to evaluate the treatment effect. If the ORR 
is 25% for atezolizumab monotherapy and 50% for the atezolizumab + 
daratumumab combination in the TC2/TC3 subgroup, the lower bound of the 
90% CI for the difference in ORR would exclude 0 (ie, a positive signal in favor of 
the combination).
Synopsis;
11.3 Efficacy Analyses
Number and percent of subjects in each response category will be tabulated, along with 
those for subjects who achieve overall response (CR or PR) and who achieve disease 
control (ie, CBR: CR, PR, or SD with duration of at least 16 weeks). Treatment 
comparison will be made via a likelihood ratio test. Odds ratio and its 95% confidence 
interval will be provided as a measure of treatment effect. Descriptive summaries 
(mean, standard deviation, median, and range) will be provided for time to response 
among those subjects who have CR or PR.
For time-to-event endpoints (PFS, OS, and duration of response), Kaplan-Meier 
estimates of the survival functions will be presented. For PFS and OS, treatment 
comparison will be made via a log-rank test. Cox’s regression will be performed to 
obtain the hazard ratio estimate and the corresponding 95% CI, which will be used as a 
measure for treatment effect.
Rationale: Revisions to the text in the RECIST and irRECIST criteria are made for consistency with current 
guidelines.
Attachment 6 Immune-
related Response 
Evaluation Criteria in 
Solid Tumors 
(irRECIST)
Text for new, non- measurable lesions, non-target lesions, and progressive disease (PD) 
are revised.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
NCT03023423


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414LUC2001; Amendment 7
16
Approved, Date: 4 October 2018
Amendment 3 (24 August 2017)
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: The overall reason for the amendment is to allow for the enrollment of 
subjects in certain PD-L1 subgroups to collect sufficient data to confirm clinical benefit.
Applicable Section(s)
Description of Change(s)
Rationale: To allow the Sponsor, based on the recommendation of the Data Monitoring Committee (DMC), to 
modify enrollment of subjects in certain PD-L1 subgroups in order to collect sufficient data to confirm clinical 
benefit.
Synopsis, Overview Of 
Study Design;
3.1. Overview of Study 
Design
Added language related to enrollment of subjects in specific PDL-1 subgroups.
…including the expansion of enrollment of some PD-L1 subgroups, resulting in 
greater than 96 subjects.
1.2. Clinical 
Experience with 
Atezolizumab
Added information for an immunohistochemistry (IHC) assay that has been used that 
measures specific PD-L1 expression signals in tumor infiltrating immune cells (ICs) and 
tumor cells (TCs). Deleted previous information about a prototype IHC assay.
Added reference: Peters 2017.
Added reference: Ventana 2016a.
Added reference: Ventana 2016b.
Added Table 7 for Tumor and Immune Cell PD-L1 Expression and Scoring.
Cross references to tables are updated throughout the protocol.
3.3. Study Design 
Rationale, Rationale 
for Biomarker 
Evaluations
Added information that based on interim or final analyses, the DMC may recommend 
modification to enrollment of subjects to the study based on PD-L1 expression in 
accordance with the product label of the Ventana SP-142 assay. For additional details, 
refer to Section 11.3.
11.2. Sample Size 
Determination
Added information that in the event that benefit from the combination is not observed 
across the total study population, target enrollment of subgroups, based on tumor PD-L1 
expression level, may be adjusted (see Section11.3). Table 17 provides guidelines for the 
DMC to use when recommending sample size adjustments.
Added Table 17 for Target Enrollment based on PD-L1 Expression.
11.3. Efficacy 
Analyses
Added information that the primary endpoint will be evaluated after approximately 
90 subjects have been enrolled. The DMC will perform additional interim analyses after 
approximately 40 subjects and 60 subjects have had at least 1 disease assessment, 
respectively. These analyses will include an evaluation of efficacy as a function of PD-L1 
expression. Based on these results, the DMC may recommend restricting enrollment of 
subjects in PD-L1 subgroups in whom clinical benefit is not demonstrated or expanding 
enrollment by a maximum of 100 subjects in PD-L1 subgroups without adequate 
enrollment (see Section 11.2) in accordance with the product label of the Ventana SP-142 
assay. Study sites will be notified in writing of any changes to enrollment based on DMC 
recommendations.
NCT03023423


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414LUC2001; Amendment 7
17
Approved, Date: 4 October 2018
Rationale: Included an internal Janssen Data Monitoring Committee (DMC), independent of the study team, in this 
study to review efficacy and safety data.
Synopsis, Overview Of 
Study Design;
3.1. Overview of Study 
Design
11.9. Data Monitoring 
Committee
Added information about the DMC’s role in this study.
Added a new section for information about the structure of the DMC. The DMC will 
review the safety and efficacy data after approximately 40, 60, and 90 subjects have been 
enrolled, and will formulate recommendations on study conduct (see Section 11.3). The 
DMC may request additional ad-hoc reviews as data accumulate.
Rationale: Clarification that subjects must have progressed on or after prior platinum-based therapy to be eligible 
for this study. Clarified stage for NSCLC subjects.
4.1. Inclusion Criteria, 
Criterion 3
Each potential subject must have histologically or cytologically confirmed advanced or 
metastatic NSCLC (Stage IIIb or greater IV).
Clarifications were added to indicate that subjects must have received at least 2 cycles of 
standard platinum-based therapy for Stage IIIb or greater IV NSCLC and had disease 
progression on or after therapy.
Added a note to clarify that “Subjects who have received fewer than 2 cycles of 
platinum-based therapy due to intolerance to (history of hypersensitivity or allergic 
reactions and other adverse events which prevent continuation of platinum-based agent), 
therapy are eligible for study participation, provided there is documentation of 
disease progression.
Rationale: Clarification of ECG timepoints for subject monitoring.
Table 1 Time and 
Events Schedule –
12-lead ECG
The C1D1 12-lead ECG may be omitted if the Screening ECG was performed ≤7 days 
earlier. ECGs should be performed and interpreted locally. During the treatment period, a 
single 12-lead ECG will be performed pre-dose on D1 of Cycles 1-4 and then pre-dose, 
D1 of every third cycle (Cycle 4, 7, 10, 13, etc.). Record new or worsened clinically 
significant abnormalities on the AE CRF.
Rationale: Clarification of imaging timepoint calculations using C1D1 as the first on study assessment and for 
subsequent assessment timing.
Table 1 Time and 
Events Schedule –
Tumor assessment
Added text that “Imaging timepoints should be calculated from the date of C1D1.”
Rationale: Clarification. Instructions for laboratory assessments were updated.
Table 1 Time and 
Events Schedule –
Laboratory 
Assessments 
-
Refer to Inclusion Criterion 6 for specific laboratory values that must be met 
prior to first dose of study drug administration.
-
C1D1 laboratory assessments (hematology, chemistry) may be omitted if 
Screening tests were was performed ≤ 7 days prior to the first administration of 
study drug and the results meet eligibility criteria. After Cycle 1, predose 
laboratory tests can be conducted up to 72 hours prior to dosing. Laboratory test 
results must be reviewed by the investigator or qualified designee and found to be 
acceptable prior to administration of each dose of study drug.
NCT03023423


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414LUC2001; Amendment 7
18
Approved, Date: 4 October 2018
Rationale: Blood typing is not required for subjects in Arm A in the main study. Only subjects on combination 
therapy are required to have blood typing performed.
Table 1 Time and 
Events Schedule –
Blood group and type 
assessment and indirect 
antiglobulin (IAT).  
ABO, Rh, IAT
Assessment for blood typing was moved from Screening to C1D1.
“Up to” was deleted.
Current text reads” C1D1 predose; run-in and Arm B only”
Rationale: Updates were made to text for Indirect Antiglobulin Test (IAT).standard text to align with current 
template language for daratumumab studies. Clarified the heading row for IAT assessments. References for 
daratumumab interference with blood compatibility testing were updated.
Table 1 Time and 
Events Schedule –
Blood group and type 
assessment and indirect 
antiglobulin (IAT).  
ABO, Rh, IAT;
9.5. Safety 
Evaluations, Indirect 
Antiglobulin Test 
(IAT) results
Assessment Heading Row
Blood group and type assessment typing and indirect antiglobulin (IAT).  ABO, Rh, 
IAT
Blood Type, Rh, and Indirect Antiglobulin Test (IAT) should be done before the first 
dose of daratumumab. Subject red blood cell (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.
Blood banks can eliminate the daratumumab interference with IAT by treating reagent 
RBCs with dithiothreitol (DTT) (Chapuy 2015, 2016). 10,9
Added reference: Chapuy 2016.
Rationale: Clarification that the Ventana label will be used for the PD-L1 assay.
Table 2 Biomarker
Assessments
footnote a
Footnote a
The Screening assessment of PD-L1 status will be assessed by a central laboratory 
using the done according to the Ventana Medical Systems, Inc. PD-L1 (SP142) assay in 
accordance with the assay instructions by the central laboratory.
Rationale: Inclusion of atezolizumab as an approved targeting antibody for PD-L1.
1.1. Background
Three Two PD-1 or PD-L1 targeting antibodies, (nivolumab, and pembrolizumab, and 
atezolizumab) have been approved for use in previously treated NSCLC.
Rationale: Correction. Four studies are cited in the protocol.
1.2. Clinical 
Experience with 
Atezolizumab
The single-agent safety and efficacy data is summarized below from 4 3 clinical studies:
Rationale: Clarification that laboratory values must meet specified criteria for subjects to be eligible for the study. 
For added clarity, added a link from the Inclusion Criteria to Time and Events Schedule.
4.1. Inclusion Criteria, 
Criterion 6
The following lLaboratory values results that meet the following criteria obtained 
within 14 days prior to first administration of study drug (see Table 1):
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JNJ-54767414  (daratumumab)
Clinical Protocol 54767414LUC2001; Amendment 7
19
Approved, Date: 4 October 2018
Rationale: For clarity and emphasis of information, moved the “Note” at the end of the exclusion criteria to the 
front of the inclusion criteria for each section.
4.1. Inclusion Criteria
4.3. Inclusion and 
Exclusion Criteria for 
Crossover
Investigators should ensure that all study enrollment criteria have been met...describes the 
required documentation to support meeting the enrollment criteria. (Moved from 
Section 4.2).
Investigators should ensure that all crossover eligibility criteria enrollment criteria have 
been met… must be discussed with and approved by the Sponsor on a case-by-case basis. 
(Moved from Section 4.3.2).
Rationale: All concomitant medications administered for adverse event/infusion-related reactions (AE/iRRs)
should be recorded for subject monitoring.
8. Prestudy And 
Concomitant Therapy
The use of concomitant medications used to treat Grade 2 or higher adverse events or any
infusion-related reactions will be collected in the CRF and recorded in the source 
documents beginning with the signing of the ICF until PD.
Rationale: The use of steroids should be permitted to premedicate a subject for whom CT scans with contrast are 
contraindicated as the subject will be receiving steroids for pre/post infusion medications.
8.2. Prohibited 
Therapies
Deleted text which does not apply to this study.

Use of corticosteroids to premedicate subjects for whom CT scans with contrast are 
contraindicated (ie, subjects with contrast allergy or impaired renal clearance); in 
such subjects, non-contrast CT scans of the chest and non-contrast CT scans or 
MRIs of the abdomen and pelvis should be performed.
Rationale: Clarification of screening procedure timelines.
9.1.2. Screening Phase
The Screening Phase begins with the signing of the ICF which The signed ICF must 
be obtained before any study-specific procedures are performed (except for tumor 
imaging assessments that were performed as part of the subject’s routine standard 
of care). The Screening Phase may be extended by a maximum of 14 days in 
situations in which screening procedures require repetition or PD-L1 results are not 
available, after consultation with the Sponsor. However, all screening procedures, 
including standard of care tumor imaging assessments, must be performed within 
28 days of first administration of study drug. The Screening Phase begins when the 
first protocol specified Screening assessment is performed (typically signing of  the ICF).
Rationale: To comply with Janssen protocol template standards, the Company Sponsorship Statement was updated. 
Updated abbreviations list.
Title Page
Abbreviations
Added text in bold:
Janssen Pharmaceutica NV;
DMC Data Monitoring Committee
ECPI European Commission Package Insert
USPI United States Package Insert
Rationale: Clarification that RECIST 1.1 is the response criteria, so it is not necessary to repeat wording “response 
criteria”.
Synopsis, Primary 
Endpoint
2.1.2. Endpoints, 
Primary Endpoint

The primary endpoint is ORR: the proportion of subjects with a partial response 
(PR) or complete response (CR) as defined by RECIST 1.1 response criteria
NCT03023423


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414LUC2001; Amendment 7
20
Approved, Date: 4 October 2018
Rationale: Reference to the Atezolizumab Investigator’s Brochure was previously cited in this section.
1.2. Clinical 
Experience with 
Atezolizumab
Deleted redundant text in this section.
Refer to the Atezolizumab Investigator’s Brochure for details on clinical activity in 
NSCLC patients treated to date.
Rationale: Numbering from previous amendment was corrected.
4.2. Exclusion Criteria
15.1 14.1 Administration of a live, attenuated vaccine within 4 weeks before first 
administration of study drug.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
NCT03023423


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414LUC2001; Amendment 7
21
Approved, Date: 4 October 2018
Amendment 2 (22 March 2017)
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: The overall reason for the amendment is to allow subjects in Arm A 
(atezolizumab monotherapy) to cross over to Arm B (atezolizumab + daratumumab combination therapy) after 
confirmed disease progression. Combination therapy of daratumumab and atezolizumab may provide clinical 
benefit in NSCLC subjects who had disease progression on atezolizumab monotherapy. The combination of 
daratumumab with atezolizumab may lead to an improvement in clinical responses in NSCLC by enhancing the 
anti-tumor T cell responses facilitated by checkpoint inhibition. Therefore, subjects in Arm A with confirmed 
disease progression based on RECIST 1.1 may cross over to Arm B, provided all crossover eligibility criteria are 
met.
Applicable Section(s)
Description of Change(s)
Rationale: Changes are made throughout the protocol for procedures related to Arm A subjects who crossover to 
also receive daratumumab (Arm B).
Synopsis, Exploratory 
Objectives, Exploratory 
Endpoints, Overview of Study 
Design; 
Time and Events Schedules;
2. Objectives, Exploratory 
Objectives, 2.1.2 Exploratory 
Endpoints; 3.1 Overview of 
Study Design, Figure 1; 3.3 
Study Design Rationale, 
Rationale for Crossover; 4.3 
Inclusion and Exclusion Criteria 
for Crossover; 9.1.1 Overview; 
9.1.3 Open-Label Treatment 
Phase; 9.2 Efficacy Evaluations; 
9.2.1 Disease Assessments; 9.2.2 
Treatment After Initial Disease 
Progression; 9.3.1 Evaluations; 
9.4.1 Tumor Tissue Samples; 9.5 
Safety Evaluations;
10.2 Discontinuation of Study 
Treatment/Withdrawal from the 
Study; 11.3 Efficacy Analyses
An exploratory objective and an exploratory endpoint are added to explore 
the benefit of daratumumab and atezolizumab treatment in subjects who had 
confirmed disease progression on previous atezolizumab monotherapy.
Time and Events Schedule Tables 1 to 3 are revised to be specific for the 
Safety Run-in and Randomized cohorts. New Time and Events Schedules 
(Tables 4 to 6) are added for the crossover cohort. Cross references to the 
new tables are updated throughout the protocol.
For subjects in Arm A who cross over to Arm B after confirmed disease 
progression, the last scan performed prior to the first crossover dose of study 
drug will be the crossover baseline scan.
New eligibility criteria are added for crossover subjects.
Certain clinical laboratory tests will not need to be performed in crossover, 
except as clinically indicated: Coagulation, calcium, urinalysis, thyroid 
panel, and serology.
Exploratory analyses for overall survival may be performed to adjust for the 
effect of crossover.
NCT03023423


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414LUC2001; Amendment 7
22
Approved, Date: 4 October 2018
Rationale: To better align with RECIST 1.1, the Immune-Related Response Evaluation Criteria in Solid Tumors
(irRECIST) is being used instead of irRC
Abbreviations; 
Synopsis Exploratory Objectives; 
Exploratory Endpoints; 
2.1.1 Exploratory Objectives; 
2.1.2 Exploratory Endpoints; 
9.2 Efficacy Evaluations; 
Attachment 5;
Attachment 6
Reference to irRC is replaced with irRECIST.
Changes to Attachment 5:
Minimum Size of Measurable Lesions
≥10 mm in longest diameter (LD) by CT scan of which slice is thickness 
no greater than 5 mm and 2X the slice thickness for extranodal lesions
≥15 mm in short axis diameter (SAD) for nodal lesions by CT scan of 
which slice is thickness no greater than 5 mm.
Lymph Nodes
Lymph nodes are considered pathologically enlarged if >10 mm in SAD. 
To be measurable, nodal lesions must be ≥15 mm in SAD by CT scan of 
which slice is thickness no greater than 5 mm.
Cystic Lesions
Non-cystic lesions are preferable.
If noncystic lesions are present in the same patient, they are preferred 
for selection as target lesions.
Definition of Complete Response (CR)
CR requires:

The disappearance of all extranodal lesions. 

All lymph nodes must be non-pathological in size (<10 mm SAD).

Normalization of tumor marker level.
the regression of all nodal lesions to <10 mm SAD and the normalization of 
tumor marker level.
Definition of Progressive Disease (PD)
Added this sentence: Furthermore, the appearance of 1 or more new 
lesions or unequivocal progression of a non-target lesion is also 
considered as PD.
Overall Response
One overall response table integrates target, non-target and new lesions for 
subjects with measurable disease; and another table integrates non-target 
and new lesions for the assessment of subjects without measurable disease.
Confirmation of response – removed this sentence:  In these trials, 
subsequent confirmation of PR with one interim timepoint of SD is 
acceptable.
Definitions of PR and SD are also added to this attachment.
Changes to Attachment 6 (IRRC replaced with irRECIST):
Removed (ie, ≥5 mm) in the first 2 rows for both New, measurable lesions 
and New, nonmeasurable lesions.
For CR and PR: removed “in 2 consecutive observations not less than 4 
weeks apart.”
PD – added text: At least 20% increase in the sum of the diameters for target
lesions and/or unequivocal progression of non-target lesions, compared 
with nadir (at any single time point including baseline). The sum must 
also demonstrate an absolute increase of at least 5 mm.
In both Attachment 5 and 6: replaced the word extranodal with non-nodal 
and index with target (lesion).
Added references: Henze 2016 and Nishino 2013.
Rationale: Tumor imaging is clarified for Screening
Table 1 Time and Events 
Schedule – Safety Run-in and 
Randomized Arms;
Table 4 Time and Events 
Schedule – Crossover
CT or MRI of head, chest, abdomen, and pelvis are required. Include neck 
if clinically indicated and any other known site of active disease.
(and known sites of active disease)
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Rationale: Dosing for the Safety Run-in, Arm A, and Arm B is clarified.
Synopsis, Dosage and 
Administration;
3.1 Overview of Study Design; 
6 Dosage and Administration, 
6.1 Daratumumab, 
6.2 Atezolizumab
Dosing instructions are clarified for each cohort, including that 
daratumumab should always be administered before atezolizumab.
For Arm A, atezolizumab will be administered at 1,200 mg IV on Day 1 of 
every 21-day cycle.
For the Safety Run-in cohort and Arm B, daratumumab will be administered 
intravenously (IV) at 16 mg/kg weekly on Days 1, 8, and 15, for the first 3 
cycles, then on Day 1 of each 21-day cycle thereafter. Atezolizumab will be 
administered at 1,200 mg IV on Day 2 of Cycle 1 and on Day 1 of every 21-
day cycle thereafter.
Clarifications are added for subjects who have crossed over:
Subjects will continue on the assigned study treatment (atezolizumab alone 
or atezolizumab+daratumumab) until treatment discontinuation due to 
disease progression, unacceptable toxicity, or other protocol-defined 
treatment discontinuation criteria (see Section 10.2); or until subjects in 
Arm A crossover. Subjects in Arm B, who experience unacceptable toxicity 
directly attributable to one agent and who are experiencing clinical benefit 
(ie, stable disease or better) may stay on the other agent until treatment 
discontinuation criteria are met, after discussion with the Sponsor. Subjects 
who have crossed over and experience unacceptable toxicity directly 
attributable to atezolizumab and who are experiencing clinical benefit 
(ie, stable disease or better) may stay on daratumumab until treatment 
discontinuation criteria are met, after discussion with the Sponsor.
Rationale: Enrollment and dosing procedures for the Safety Run-in phase are clarified
3.1 Overview of Study Design
After Cycle 1, subjects in the Safety Run-in cohort may continue to receive 
additional cycles of daratumumab + atezolizumab while enrollment into the 
Safety Run-in cohort is ongoing and after the study has proceeded to the 
randomization phase until they meet the protocol-specified treatment 
discontinuation criteria.
Enrollment into the Safety Run-in cohort will continue until ≥2 subjects 
experience a DLT, at which time new subject enrollment will stop until after 
the SET convenes and makes recommendations regarding conduct of the 
study. While the SET is reviewing the DLT data, remaining subjects in the 
Safety Run-in cohort who have not experienced a DLT may continue to 
receive additional cycles of daratumumab + atezolizumab after consultation 
with the Sponsor.
Rationale: Clarifications to the Inclusion and Exclusion criteria
Inclusion Criterion 3
Clarified stage for NSCLC subjects:
Subjects must have received at least 2 cycles of standard platinum-based 
therapy for Stage IIIb or IV NSCLC
Inclusion Criterion 8
Revised contraception wording to align with current daratumumab standard 
wording regarding using 2 methods of reliable birth control simultaneously: 
1 highly effective method and 1 additional effective method.
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Exclusion Criterion 2
Revised: Other investigational agent or participation in another clinical study 
with therapeutic intent within 28 days or 5 half-lives of the investigational 
agent (whichever is longer) to enrollment prior to first administration of 
study drug.
Added: Whole brain radiation within 28 days or other radiotherapy within 
14 days prior to first administration of study drug.
The text on corticosteroid use is revised with additional detail:
Use of systemic corticosteroids >10 mg/day prednisone equivalent within 
14 days ≤2 weeks before prior to first administration of study drug Cycle 
1 Day 1. Acute use of >10 mg/day prednisone equivalent may be allowed 
with Sponsor approval. Note: Steroids that are topical, inhaled, nasal 
(spray), or ophthalmic solution are permitted.
Exclusion Criterion 3
The following text is added regarding CNS metastases and corticosteroid 
treatment:
Active or untreated CNS metastases as determined by computed tomography 
(CT) or magnetic resonance imaging (MRI) evaluation.  during Screening 
and prior radiographic assessments. Subjects with a history CNS 
metastases must have completed treatment for the CNS metastases (see 
Exclusion Criterion 2.1 for guidelines regarding timing of radiation 
therapy), be neurologically stable, and must have discontinued
corticosteroids prior to first administration of study drug.
Leptomeningeal disease or spinal cord compression not definitively treated 
with surgery or radiation, or requiring corticosteroid treatment at first 
administration of study drug.
For uncontrolled tumor-related pain, it is clarified for symptomatic lesions 
amenable to palliative radiotherapy and asymptomatic metastatic lesions 
whose further growth would likely cause functional deficits or intractable 
pain should be treated prior to Screening, not randomization.
Exclusion Criterion 5
Revised: Malignancies other than NSCLC within 2 years prior to 
randomization first administration of study drug, with the exception of 
carcinoma in situ of the cervix or breast, basal or squamous-cell skin cancer, 
or other malignancy that in the opinion of the investigator and Sponsor’s
Study Responsible Physician is considered cured with a minimal risk of 
recurrence within 5 years.
Exclusion Criterion 7
To exclude subjects with a history of any type of pulmonary fibrosis to 
reduce the risk of immune mediated pulmonary events (ie, pneumonitis), the 
word idiopathic is removed: History of idiopathic pulmonary fibrosis.
Exclusion Criterion 8
Revised: Known chronic obstructive pulmonary disease (COPD) with a 
forced expiratory volume in 1 second (FEV1) <50% of predicted normal. 
Note that spirometry FEV1 testing is required during the Screening period
for subjects suspected of having COPD and subjects must be excluded if 
FEV1 <50% of predicted normal.
Exclusion Criterion 10;
Section 9.5 Safety Evaluations
This exclusion is revised to align with current Janssen text, make other 
clarifications, and to specify when polymerase chain reaction testing should 
be done.
The clinical laboratory test table is revised to add RNA PCR testing as 
needed.
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Exclusion Criterion 11
Revised: Severe infections (including active tuberculosis) within 1 week 
prior to first administration of study drug, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe 
pneumonia.
Exclusion Criteria 12 and 13
To align with current text used in daratumumab protocols, revised text for 
cardiac-related exclusion is added (Exclusion Criterion 12). The revised text 
related to the former Exclusion Criterion 13 is included in Exclusion 
Criterion 12; therefore, the existing Exclusion Criterion 13 is removed. 
Exclusion Criterion 15 
Revised: Administration of a live, attenuated vaccine within 4 weeks before 
first administration of study drug.
Exclusion Criterion 20 (new)
Major surgery (eg, requiring general anesthesia) exclusion is added, per 
standard daratumumab wording.
Rationale: The end of study definition is revised to better align with current expectations for this study.
17.9.1 Study Completion/End of 
Study Definition
The end of the study is anticipated to be approximately 6 to 12 months after 
the last patient has been enrolled (last patient in) and the study may be 
extended to allow for further treatment and follow-up of subjects.
Rationale: Additional changes have been made to improve the clarity of the protocol.
Table 1 Time and Events 
Schedule – Safety Run-in and 
Randomized Arms
Table 4 Time and Events 
Schedule – Crossover
6.1.2 Daratumumab Treatment 
Schedule and Administration
6.1.3.2 Postinfusion Medication
Vital signs assessments are clarified to describe difference between Arm A 
and the other arms:
Measured at Screening and on study drug dosing days. Safety Run-in and 
Arm B only: C1D1: measure vital signs immediately before the start of the 
infusion; at 0.5, 1, 1.5, 2 and 3.5 hours after the start of the infusion; at the 
end of the infusion; and 0.5 and 1 hr after the end of the infusion. For all 
subsequent other Safety Run-in and Arm B infusions (daratumumab + 
atezolizumab) infusions, measure immediately before the infusion start, at 
the end of the infusion, and as clinically indicated. Arm A only: vital signs 
should be assessed at Screening, within 24 hours of the start of each 
infusion and at the end of each infusion.
For all other subsequent daratumumab and atezolizumab infusions, measure 
immediately before the infusion start, at the end of the infusion, and as 
clinically indicated.
As noted in Table 1 and Table 5 (Time and Events Schedules), vital signs 
for subjects in the Safety Run-in and Arm B cohorts should be monitored 
frequently on Cycle 1 Day 1 before, during, and after the first infusion of 
daratumumab. For all other subsequent infusions, vital signs should be 
measured before the start of infusion and at the end of the infusion.
This text is removed as it is clarified in Table 1 and Table 4:
Vital signs (temperature, blood pressure, and pulse rate) should be measured 
<24 hours prior to each planned dose of daratumumab, every 15 (±5) 
minutes during the first 2 hours of each infusion, every 60 (±10) minutes 
thereafter for the remainder of the infusion, and at the end of infusion.
Table 1 Time and Events 
Schedule – Safety Run-in and 
Randomized Arms
Clarified that the D8 and D15 hematology and chemistry assessments are for 
Cycle 1 and 2 only for Arm A and for Cycles 1-3 for the Safety Run-in and 
Arm B cohorts.
Clarified that prior medications will be collected in addition to concomitant 
medications.
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Table 1 Time and Events 
Schedule – Safety Run-in and 
Randomized Arms;
Table 4 Time and Events 
Schedule – Crossover
Clarified the timing of study procedures relative to dosing: For every cycle, 
study procedures may occur ±3 days of the scheduled Day 1 dose, but prior 
to study drug administration, in order to accommodate the schedule of the 
site or subject. For Cycles 1 to 3, Day 8 and Day 15, study procedures may 
be done ±1 day of the scheduled dose, but prior to daratumumab 
administration.
There should be at least 21 days between Day 1 of every dosing cycle 
(except for daratumumab in Cycle 1-3).
For the Laboratory Assessments, added clarification on the timing of 
predose testing: After Cycle 1, predose laboratory tests can be conducted up 
to 72 hours prior to dosing. Laboratory test results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to 
administration of each dose of study drug.
Time and Events schedules for 
biomarker assessments (Table 2 
[new footnotes c, d, e] and Table 5 
[new]); 6.2.1.9 Systemic Immune 
Activation; 9.4 Biomarker 
Assessments; 9.4.1 Tumor Tissue 
Samples
For the Diagnostic Archival Tissue or Fresh Biopsy, 
 
For Cycle 3, biopsy may be collected at Cycle 3 Day 1 ±7 days but must be done 
following the first tumor assessment.
If a biopsy sample(s) is collected at any time during the study for other reasons, 
a portion should be retained for biomarker analysis.
In Section 9.4, this text is also revised: All biomarker assessments will be 
performed centrally. Tumor biopsies and blood samples will be taken from all 
study subjects in both treatment groups as outlined in the Time and Events 
Schedule for Biomarkers (Table 2 and Table 5). In this study, mandatory 
archival or fresh tumor specimens from subjects at Screening will be evaluated 
for expression of PD-L1+, CD38+, and other markers indicative of cell 
populations of interest 
 
 
Published results suggest that the expression of 
PD-L1 in tumors correlates with response to antiPD-L1 therapy (Horn 2015; 
Spira 2015).23,45 Evaluation of CD38+ expression will be performed to determine 
if elevated expression of CD38+ correlates with responses to daratumumab 
therapy. Fresh biopsies at Cycle 3 and at progressive disease are required, if 
clinically feasible, to evaluate biomarkers related to the clinical benefit of 
atezolizumab + daratumumab. Additionally, if a biopsy is taken at any other 
time while a subject is on study, a sample is also requested for biomarker 
analysis. Evaluation of biopsies collected at Cycle 3 by IHC and IF may be 
evaluated for include PD-L1 and CD38 expression in addition to other 
markers and cell populations 
 
to identify changes in these inflammatory populations 
in response to treatment. Collection of a tumor biopsy, at the time of 
radiographic progression will be evaluated for immune infiltrate, PD-L1, and 
CD38 expression by IHC CD8+ T cells and regulatory T cell (CD3+/Foxp3+) 
infiltration will be evaluated by IHC and is required in order to distinguish 
pseudoprogression/tumor-immune infiltration from true progression.
In Section 9.4.1, the following text is added: For subjects enrolled in the 
crossover arm, if a biopsy was taken at the time of disease progression while 
enrolled in Arm A of this protocol, a new biopsy is not required at Cycle 1X Day 
1 predose.
New footnotes are added to Table 2:
c. Cycle 3 biopsy may be collected at Cycle 3 Day 1 ±7 days but must be done 
following the first radiologic tumor assessment.
d. If biopsy sample(s) is collected at any time during the study for other reasons, 
a portion should be retained for biomarker analysis.
e. A serum sample for selected cytokines should be drawn within 6 hours of 
suspected cytokine-release syndrome, and submitted to the central laboratory. 
The Sponsor will closely monitor and evaluate the collection of cytokine 
samples and will notify the participating centers of any change to the collection 
requirements.
The serum sample for cytokines is also specified in Section 6.2.1.9.
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Time and Events schedules for 
pharmacokinetic and 
immunogenicity assessments 
(Table 3 and Table 6[new]); 
9.3.2 Analytical Procedures
Cycle 1 Day 1 predose pharmacokinetic sample for atezolizumab will be for 
all arms (Safety Run-in, Arm A, Arm B, and crossover). The Cycle 1 Day 2 
predose sample is removed.
The every 8 Cycles after Cycle 8 (Day 1) samples are removed and replaced 
with Cycle 12 and Cycle 16 samples.
Revised footnote a: Daratumumab should always be administered prior to 
atezolizumab. In subjects receiving both agents, predose PK and 
immunogenicity samples for daratumumab and atezolizumab should always 
be obtained up to 2 hours before the start of the daratumumab infusion, even 
in Cycle 1 when atezolizumab is administered one day later on Day 2. End 
of infusion samples are to be taken within 2 hours after the end of the 
infusion of the respective drug.
Predose sample to be taken up to 2 hours before the start of the infusion; end 
of infusion sample to be taken within 2 hours after the end of the infusion.
New footnote b (Table 3): If an Arm A subject crosses over to combination 
treatment, follow-up samples will not be obtained until after all dosing is 
complete (Table 6). 
In Section 9.3.2, this sentence is revised: Serum samples will be analyzed to 
determine concentrations of daratumumab, concentrations of atezolizumab, 
or the generation of antibodies to daratumumab or atezolizumab using 
validated immunoassay methods by or under the supervision of the 
Sponsor’s bio-analytical facility.
Time and Events schedules for 
biomarker assessments (Table 2 
and new Table 5); Time and 
Events schedules for 
pharmacokinetic and 
immunogenicity assessments 
(Table 3, footnote a, and new 
Table 6)
It specified that if a dose delay occurs, then samples should be taken on the 
actual day of drug administration, not on the originally scheduled 
administration day.
Title page; 1 Introduction
Current approvals for atezolizumab and daratumumab are updated.
1.2 Clinical Experience with 
Atezolizumab
Recently published results are summarized for Study GO28915 (OAK):  A 
randomized, Phase 3, open-label study assessing the clinical benefit of 
atezolizumab as a single agent versus docetaxel in PD-L1 unselected 
patients with locally advanced or metastatic NSCLC that has progressed 
during or following treatment with a platinum-containing regimen
6.1.2 Daratumumab Treatment 
Schedule and Administration
This sentence is removed since the additional details specified are not 
included in the SIPPM: Additional details for administration times and rates, 
as well as preinfusion medications, will be provided in the Site 
Investigational Product Procedures Manual (SIPPM).
6.1.5 Toxicity Management; 
6.2 Atezolizumab
Added that a delay in daratumumab dosing will result in a subsequent delay 
in atezolizumab dosing. Revised Table 12 to align with the dosing in this 
study.
Added that if atezolizumab administration does not commence within the 
prespecified dosing window (±3 days), 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.
6.2.1.8 Neurologic Disorders
Revised this sentence: Myasthenia gravis, Guillain-Barré syndrome, and 
meningoencephalitis have been observed with single agent atezolizumab.
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6.3.2 Atezolizumab, Table 14
In Table 14, Management Guidelines for Atezolizumab Infusion-related 
Reactions, for Grade 2 treatment examples are added:
Administer aggressive symptomatic treatment (eg, oral or IV 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen).
Table 2 (biomarker assessments), 
footnote a; 
9.1.2 Screening Procedures
This is added to Table 2 footnote a: using the Ventana Medical Systems, 
Inc. PD-L1 (SP142) kit.
This sentence is revised: Subjects will be stratified based on PD-L1 status 
(IC0 and TC0 vs. others), based on central laboratory assessment (using 
the Ventana Medical Systems, Inc. PD-L1 (SP142)IHC kit) and histology 
(squamous vs. non-squamous) based on central laboratory assessment, as 
well as number of previous lines of therapy (1 or >1).
9.2 Efficacy Evaluations
This sentence is added at the end of the paragraph: Subjects who have 
disease progression and continue to receive study treatment should 
continue to undergo disease evaluations including tumor assessments.
9.2.2 Treatment After Initial 
Disease Progression
In Table 15 (Imaging and Treatment after First Radiologic Evidence of 
Progressive Disease), it is clarified to continue regularly scheduled imaging 
assessments for subjects who continue treatment and that repeat imaging is 
by RECIST 1.1. Also, it is clarified that for clinically unstable subjects 
whose repeat tumor imaging does not show PD, to continue regularly 
scheduled assessments per investigator’s discretion and there should be 
consultation with the Sponsor to restart study treatment if the condition has 
improved or is clinically stable. The format of the table is revised to merge 
the additional imaging and treatment columns together.
10.2 Discontinuation of Study 
Treatment/Withdrawal from the 
Study
For discontinuation of treatment this bullet is revised:
The subject experiences confirmed disease progression (per RECIST 1.1). 
However, subjects in either Arm A or Arm B may continue treatment in 
the setting of clinical benefit with Sponsor approval. Subjects in Arm A 
with confirmed disease progression may cross over to Arm B, provided 
crossover eligibility criteria are met (see Section 3.1 and Section 4.3).
10.3 Withdrawal From the Use of 
Research Samples
This is revised because there is no separate informed consent: The collected 
samples will be retained and used in accordance with the subject's original
separate informed consent for optional research samples.
References
Henze, Nishino, and Rittmeyer are added.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made, including 
changing Medical Monitor and Study Responsible Physician to Sponsor.
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Amendment 1 (1 September 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: The overall reason for the amendment is to update toxicity and adverse
event management in response to Health Authority request, to remove the patient-reported outcomes assessments 
(PRO), and to add timepoints for biomarker sample collection.
Applicable Section(s)
Description of Change(s)
Rationale:  The patient-reported outcome assessments were deemed by the Sponsor to be not needed for this 
Phase1b/2 study.
Synopsis Objectives; Synopsis 
Endpoints; Table 1 Time and
Events Schedule; Abbreviations; 
2.1.1 Objectives; 2.1.2 
Endpoints; 3.1 Overview of 
Study Design; 3.3 Study Design 
Rationale; 9.1.1 Overview; 
9.5 Patient-reported Outcomes; 
11.8 Patient-reported Outcomes 
Analyses; 15 Study-specific 
Materials; 18 References; 
Attachment 7; Attachment 8; 
Attachment 9
The PRO assessments measured by the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire- Core 30 (EORTC-QLQ-
C30), lung cancer symptom module (EORTC QLQ-LC13), and the European 
Quality of Life 5 Dimensions Questionnaire (EQ-5D-5L) have been removed.
Rationale: Clarification for pregnancy testing to be done only at Screening
Table 1 Time and Events 
Schedule; 
4.1 Inclusion Criteria
Clarified that pregnancy testing is not needed for Day 1, Cycles 1 to 3 (removed 
X in Table 1). Text specifying pregnancy testing for Day 1, Cycle 1 removed 
from Inclusion Criterion 7.
Rationale: Additional timepoints are added to further explore the effect of daratumumab and atezolizumab on the 
biomarkers in this study.
Table 2 Biomarker Assessments
Biomarker sample collection for Flow/immunophenotyping, PBMC/CyTOF, 
and plasma-based biomarkers is added at the following timepoints:

Cycle 1, Day 8 and Day 15

Cycle 2, Day 8 and Day 15
Rationale: Text added to clarify specific timepoints for predose and post-infusion PK/Immunogenicity collection 
for atezolizumab Cycle 1, Days 1 and 2.
Table 3 Pharmacokinetics and 
Immunogenicity
Pharmacokinetic sample collection for atezolizumab is added/clarified at the 
following timepoints:

Cycle 1, Day 1

Cycle 1, Day 2
Rationale: Chemistry and hematology sample collection during Cycles 1 and 2 is aligned for both Arms.
Table 1 Time and Events 
Schedule
The chemistry and hematology sample collection and study visits for Arm A are 
aligned with Arm B to be weekly during Cycles 1 and 2.
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Applicable Section(s)
Description of Change(s)
Rationale: Clarifying text and definition added to Inclusion Criteria 3 and 6 per Health Authority request
4.1 Inclusion Criteria
Text added to Inclusion Criterion 3 to define intolerance to prior platinum-based 
therapy. 
Text added to Inclusion Criterion 6 to specify that, in the case of documented 
bone metastases, the parameter of 5x ULN applies only to alkaline 
phosphatase and does not include AST or ALT 
Rationale: Clarification that subjects who had received prior treatment with vaccines are eligible for study 
participation.
Section 4.2 Exclusion Criteria
Text in Exclusion Criterion 1 prohibiting the inclusion of subjects receiving 
prior vaccines was deleted.
Rationale: Correction of text regarding post-infusion corticosteroids to align with the product information for 
daratumumab
6.1.3.2 Postinfusion Medication 
Text outlining that post-infusion corticosteroids may be omitted in subsequent 
infusions if no IRR is observed has been deleted.
Rationale: Guidelines for daratumumab dose modification clarified per Health Authority request.
6.1.5 Toxicity Management
Text modified to note that for all other adverse events, with cited exceptions 
outlined in the protocol, daratumumab should be withheld for Grade 3 or higher 
toxicities.
Rationale: Text specifying toxicity grade at which administration of daratumumab may be restarted modified per 
Health Authority request
6.1.5 Toxicity Management
Text modified to note that administration of daratumumab may be restarted
upon recovery from toxicity to Grade 1 or baseline.
Rationale: Text added outlining the risk of herpes zoster reactivation and recommendations for antiviral 
prophylaxis per Health Authority request
6.1.5 Toxicity Management
Text outlining the risk of herpes zoster reactivation observed with daratumumab 
administration and recommendations for antiviral prophylaxis have been added.
Rationale: Clarification of text to indicate that in cases involving non-adverse event-related atezolizumab treatment 
discontinuation of 105 consecutive days, drug can be restarted in subjects deriving clinical benefit with the 
approval of the Sponsor
6.2 Atezolizumab
Text added to specify that restarting of atezolizumab after treatment 
discontinuation of 105 consecutive days is limited to subjects whose holds are 
not caused by adverse events, with the approval of the Sponsor.
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Applicable Section(s)
Description of Change(s)
Rationale: Guidelines for treatment interruption or discontinuation and management of specific adverse events for 
atezolizumab expanded and clarified per Health Authority request.
6.2.1 Management of 
Atezolizumab-Specific Adverse 
Events; References;
New Attachment 7

Text added specifying that non-immune-mediated adverse events 
associated with atezolizumab administration should be managed according 
to standard medical practice.

Text previously allowing for continuation of atezolizumab treatment in 
patients meeting criteria for permanent discontinuation has been deleted.

Specific guidelines for immune-mediated events are provided in new 
Attachment 7.

Text added to specify that atezolizumab should be held in the event of 
Grade ≥3 infections. In addition, for all other non-immune mediated 
adverse events, with cited exceptions outlined in the protocol, 
atezolizumab is to be withheld for Grade ≥3 toxicity. Administration of 
atezolizumab to be restarted upon recovery from toxicity to Grade 1 or 
baseline.

Text referring adverse event management back to the atezolizumab 
Investigator’s Brochure deleted and directed to new Attachment 7 in all 
subsections of Section 6.2.1. 

Text added to specify that atezolizumab should be withheld and
appropriate supportive care, including corticosteroid therapy, initiated in 
the event of systemic immune activation.

New references in Table 20 added to Reference List.
Rationale: Clarification of discontinuation timepoints for daratumumab and atezolizumab
10.2 Discontinuation of Study 
Treatment/Withdrawal from the 
Study

Bullet updated to indicate that subject’s study treatment must be 
discontinued if the subject missed more than 2 consecutive planned doses 
due to daratumumab-related adverse events.

New bullet added to indicate that subject’s study treatment must be 
discontinued if the subject missed more than 105 consecutive treatment 
days due to atezolizumab-related adverse events.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
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SYNOPSIS
A Phase 1b/2, Open-Label, Randomized Study of Daratumumab Administered in Combination with 
Atezolizumab Compared with Atezolizumab Alone in Subjects with Previously Treated Advanced or 
Metastatic Non-Small Cell Lung Cancer
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Primary Objective

To compare the overall response rate (ORR) in subjects treated with daratumumab in combination 
with atezolizumab versus atezolizumab alone
Secondary Objectives

To assess the safety of the combination of daratumumab and atezolizumab

To compare the duration of response (DoR) in subjects treated with daratumumab in combination 
with atezolizumab versus atezolizumab alone 

To compare the clinical benefit rate (CBR) in subjects treated with daratumumab in combination 
with atezolizumab versus atezolizumab alone

To compare progression-free survival (PFS) in subjects treated with daratumumab in combination 
with atezolizumab versus atezolizumab alone

To compare overall survival (OS) in subjects treated with daratumumab in combination with 
atezolizumab versus atezolizumab alone 

To evaluate the pharmacokinetic and immunogenicity profile of daratumumab when given in 
combination with atezolizumab

To evaluate the pharmacokinetic and immunogenicity profile of atezolizumab when given in 
combination with daratumumab
Exploratory Objectives

To compare ORR evaluated by the Immune-Related Response Evaluation Criteria in Solid Tumors
(irRECIST)

To explore biomarkers predictive of response to therapy

To evaluate potential pharmacodynamic biomarkers in response to therapy

To explore the relationships between pharmacokinetics, pharmacodynamics, adverse event profiles, 
and clinical activity of daratumumab given in combination with atezolizumab in subjects with 
previously treated advanced or metastatic NSCLC

To explore the benefit of daratumumab and atezolizumab treatment in subjects who had confirmed 
disease progression on atezolizumab monotherapy.
Primary Endpoint

The primary endpoint is ORR: the proportion of subjects with a partial response (PR) or complete 
response (CR) as defined by RECIST 1.1
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Secondary Endpoints

Incidence of adverse events

DoR: the duration from the date of the initial documentation of a response to the date of the first 
objectively documented evidence of recurrence or progressive disease or death, whichever status is 
recorded first.

CBR: the proportion of subjects who achieve disease control (CR, PR, or SD with duration of at least 
16 weeks).

PFS: the duration from the date of randomization to the date of objectively documented progression 
or death due to any cause, whichever status is recorded first.

OS: the duration from the date of randomization to the date of death due to any cause.

Serum daratumumab concentration (Cmin, Cmax) and incidence of anti-daratumumab antibodies

Serum atezolizumab concentration (Cmin, Cmax) and incidence of anti-atezolizumab antibodies
Exploratory Endpoints

ORRi: the proportion of subjects with a partial response (PR) or complete response (CR) evaluated 
by irRECIST

ORR, DoR, CBR, incidence of adverse events, daratumumab and atezolizumab serum concentration 
and incidence of anti-daratumumab antibodies and anti-atezolizumab antibodies
Refer to Section 9, Study Evaluations for related evaluations.
Hypothesis
The primary hypothesis is that daratumumab in combination with atezolizumab will significantly improve 
ORR compared to atezolizumab alone in subjects with NSCLC.
OVERVIEW OF STUDY DESIGN
This is a randomized, open-label, parallel-group, multicenter Phase 1b/2 study assessing the anti-tumor 
activity and safety of daratumumab in combination with atezolizumab compared with atezolizumab alone 
in subjects with previously treated advanced or metastatic NSCLC. Approximately 96 subjects will be 
enrolled in this study, including 6 subjects in a safety run-in cohort followed by 90 subjects randomly 
assigned in a 1:1 ratio to 2 treatment arms. The subjects in the safety run-in cohort will be administered 
the combination of daratumumab and atezolizumab and will be evaluated by the Safety Evaluation Team 
(SET) for dose-limiting toxicity.
An internal Janssen Data Monitoring Committee (DMC), independent of the study team, will be
established to review the efficacy and safety data in the randomization phase. The DMC will review the 
totality of data after approximately 40, 60, and 90 subjects have been enrolled, including activity within 
distinct PD-L1 expression subgroups. Based on
these findings, the DMC may formulate 
recommendations on study conduct, including the expansion of enrollment of some PD-L1 subgroups, 
resulting in greater than 96 subjects. The DMC may request additional ad-hoc reviews as data 
accumulate.
Beginning with the implementation of Amendment 7, the Sponsor will continue to supply atezolizumab to 
active subjects who are deriving clinical benefit from atezolizumab monotherapy, but do not have access 
to commercial atezolizumab. The administration of atezolizumab will occur under the supervision of 
treating investigators in accordance with local regulatory approvals and standard of care guidelines.50,51
Data from efficacy and safety evaluations performed according to local regulatory approvals and standard 
of care guidelines50,51 will no longer be collected with the exception of serious adverse events that are to 
be reported and entered in the Sponsor safety repository.
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SUBJECT POPULATION
Subjects 18 years and older with advanced or metastatic NSCLC who had at least 2 cycles of standard 
platinum-based therapy with disease progression or intolerance to therapy are eligible.
DOSAGE AND ADMINISTRATION
For Arm A, atezolizumab will be administered at 1,200 mg IV on Day 1 of every 21-day cycle. For the 
Safety Run-in cohort and Arm B, daratumumab will be administered intravenously (IV) at 16 mg/kg 
weekly on Days 1, 8, and 15, for the first 3 cycles, then on Day 1 of each 21-day cycle thereafter. 
Atezolizumab will be administered at 1200 mg IV on Day 2 of Cycle 1 and on Day 1 of every 21-day 
cycle thereafter. Subjects will continue to receive study treatment until confirmed disease progression, 
unacceptable toxicity, or any other treatment discontinuation criteria are met.
Beginning with the implementation of Amendment 7, subjects who are deriving clinical benefit from 
atezolizumab monotherapy, but do not have access to commercial atezolizumab, may continue treatment 
under the supervision of the treating investigator in accordance with local regulatory approvals and 
standard of care guidelines.50,51
EFFICACY EVALUATIONS
Subjects will undergo tumor assessments until radiographic disease progression per RECIST 1.1, or 
withdrawal of consent, study termination by Sponsor, or death, whichever occurs first. For subjects who 
discontinue treatment for reasons other than progression (eg, adverse event), disease assessments will 
continue to be performed until disease progression or a new cancer therapy is initiated, or another study 
withdrawal criterion is met.
Beginning with the implementation of Amendment 7, efficacy evaluations will be performed by the 
investigator according to local regulatory approvals and standard of care guidelines.50,51 These data will 
no longer be collected by the Sponsor.
SAFETY EVALUATIONS
Safety assessments include the incidence and severity of adverse events, laboratory test results, ECGs, 
vital sign measurements, physical examination findings, and ECOG performance status score.
Beginning with the implementation of Amendment 7, safety evaluations will be performed by the 
investigator according to local regulatory approvals and standard of care guidelines.50,51 These data will 
no longer be collected by the Sponsor with the exception of serious adverse events that are to be reported 
and entered in the Sponsor safety repository.
STATISTICAL METHODS
The primary analysis population for the efficacy endpoint will be the intent-to-treat population in the 
randomized phase of the study. Assuming that the ORR for atezolizumab monotherapy is approximately 
20%, and the addition of daratumumab would improve ORR by 20% to 40%, 90 subjects need to be 
randomized with a 1:1 ratio in order to achieve 80% power to detect this difference with a one-sided alpha 
of 0.10.
Number and percent of subjects in each response category will be tabulated, along with those for subjects 
who achieve overall response (CR or PR) and who achieve disease control (ie, CBR: CR, PR, or SD that 
lasts at least 16 weeks). Odds ratio and its 95% confidence interval will be provided as a measure of
treatment effect. Descriptive summaries (mean, standard deviation, median, and range) will be provided 
for time to response among those subjects who have CR or PR. The primary hypothesis is that 
daratumumab in combination with atezolizumab will significantly improve ORR compared to 
atezolizumab alone in subjects with NSCLC.
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Table 1:
Time and Events Schedule – Safety Run-in, Randomized Arms
Beginning with the implementation of Amendment 7, subjects who continue to derive benefit from atezolizumab treatment, may continue to receive atezolizumab under the 
supervision of treating investigators in accordance with local regulatory approvals and standard of care guidelines.50,51 Data from efficacy and safety evaluations performed 
according to local regulatory approvals and standard of care guidelines50,51 will no longer be collected with the exception of serious adverse events that are to be reported 
and entered in the Sponsor safety repository.
Assessments
Prescreening
(optional)
Screening
Treatment Period (21-day cycles)
EOT
(30 +7d 
after 
last 
dose)
Follow-up 
Period
Arm
Cycles 1-3
Cycle 4 
and 
beyond
Pre-PD
Post-PD 
Survival 
Day
Any time 
prior to start 
of Screening
-56 to -1
-28 to -1
D1
(±3)
D2
D8
(±1)
D15 
(±1)
D1
(±3)
q12 
weeks
(±1 wk)
Procedures    
For every cycle, study procedures may occur ±3 days of the scheduled Day 1 dose, but prior to study drug administration (except for those routinely needed after administration), in order 
to accommodate the schedule of the site or subject. For Cycles 1 to 3, Day 8 and Day 15, study procedures may be done ±1 day of the scheduled dose, but prior to daratumumab 
administration. Day 2 visit is only required for Safety Run-in and Arm B subjects during Cycle 1 only. 
Prescreening Informed Consent
X
Archival tumor tissue (Section 9.1.2)
X
Informed Consent
X
Eligibility Criteria
X
Demographics
X
Medical and cancer history
X
4
Tumor tissue specimen for PD-L1 testing 
(central lab)
X
X – Cycle 3 and at time of radiographic progression 
Vital signs (pulse, blood pressure, and 
temperature) and Weight
Measured at Screening and on study drug 
dosing days.a
X
Arm A
X
X
Safety 
Run-in, 
Arm B
X
C1 
only
X
X
X
X
Physical exam, height
Complete physical exam at Screening; height
only measured at Screening. During the 
treatment period, perform a limited, 
symptom-directed examination as clinically 
indicated. Record new or worsened clinically 
significant abnormalities on the AE CRF.
X
        ------------------------ X ----------------------
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Table 1:
Time and Events Schedule – Safety Run-in, Randomized Arms
Beginning with the implementation of Amendment 7, subjects who continue to derive benefit from atezolizumab treatment, may continue to receive atezolizumab under the 
supervision of treating investigators in accordance with local regulatory approvals and standard of care guidelines.50,51 Data from efficacy and safety evaluations performed 
according to local regulatory approvals and standard of care guidelines50,51 will no longer be collected with the exception of serious adverse events that are to be reported 
and entered in the Sponsor safety repository.
Assessments
Prescreening
(optional)
Screening
Treatment Period (21-day cycles)
EOT
(30 +7d 
after 
last 
dose)
Follow-up 
Period
Arm
Cycles 1-3
Cycle 4 
and 
beyond
Pre-PD
Post-PD 
Survival 
Day
Any time 
prior to start 
of Screening
-56 to -1
-28 to -1
D1
(±3)
D2
D8
(±1)
D15 
(±1)
D1
(±3)
q12 
weeks
(±1 wk)
ECOG performance status
X
X
X
X
12-lead ECG
The C1D1 12-lead ECG may be omitted if 
the Screening ECG was performed ≤7 days 
earlier. ECGs should be performed and 
interpreted locally. During the treatment 
period, a single 12-lead ECG will be 
performed predose on D1 of Cycles 1-4 and 
then predose, D1 of every third cycle 
(Cycle 7, 10, 13, etc.). Record new or 
worsened clinically significant abnormalities 
on the AE CRF.
X
X
X
X
FEV-1   
Only for subjects with known or suspected 
COPD; FEV1 <50% of predicted normal is 
excluded.
X
Tumor assessment
CT or MRI imaging of all disease sites 
documented at Screening should be 
performed using the same methodology 
throughout the study. Tumor assessments 
will be performed per RECIST 1.1. For 
subjects who discontinue treatment for 
reasons other than progression (eg, adverse 
event), tumor assessments will continue to 
be performed until documented disease 
progression or a new cancer therapy is 
initiated.
CT or MRI of 
head, chest, 
abdomen, and 
pelvis are 
required. 
Include neck if 
clinically 
indicated and 
any other 
known site of 
active disease.
X
CT or MRI of chest and abdomen 
(and known sites of active disease) 
Every 6 weeks (±1 week) for the first 12 months of treatment and 
every 9 weeks (±1 week) thereafter regardless of treatment delays. 
Same frequency for all subjects.
Imaging timepoints should be calculated from the date of C1D1.
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Table 1:
Time and Events Schedule – Safety Run-in, Randomized Arms
Beginning with the implementation of Amendment 7, subjects who continue to derive benefit from atezolizumab treatment, may continue to receive atezolizumab under the 
supervision of treating investigators in accordance with local regulatory approvals and standard of care guidelines.50,51 Data from efficacy and safety evaluations performed 
according to local regulatory approvals and standard of care guidelines50,51 will no longer be collected with the exception of serious adverse events that are to be reported 
and entered in the Sponsor safety repository.
Assessments
Prescreening
(optional)
Screening
Treatment Period (21-day cycles)
EOT
(30 +7d 
after 
last 
dose)
Follow-up 
Period
Arm
Cycles 1-3
Cycle 4 
and 
beyond
Pre-PD
Post-PD 
Survival 
Day
Any time 
prior to start 
of Screening
-56 to -1
-28 to -1
D1
(±3)
D2
D8
(±1)
D15 
(±1)
D1
(±3)
q12 
weeks
(±1 wk)
Laboratory Assessments:
-
Refer to Inclusion Criterion 6 for specific laboratory values that must be met prior to first dose of study drug administration.
-
C1D1 laboratory assessments (hematology, chemistry) may be omitted if Screening tests were performed ≤ 7 days prior to the first administration of study drug and the results meet 
eligibility criteria. After Cycle 1, predose laboratory tests can be conducted up to 72 hours prior to dosing. Laboratory test results must be reviewed by the investigator or qualified 
designee and found to be acceptable prior to administration of each dose of study drug.
Hematology (see Section 9.7; performed by 
local lab)
X
X
X
X
X
X
Arm A: Cycle 
1 & 2 only; 
Safety
Run-in, Arm B
Chemistry (see Section 9.7; performed by local 
lab); see below for amylase, lipase
X
X
X
X
X
X
Arm A: Cycle 
1 & 2 only; 
Safety
Run-in, Arm B
HBV/HCV Serology (see Section 9.7; 
performed by local lab)
X
Coagulation (see Section 9.7; performed by 
local lab)
X
Thyroid function (see Section 9.7; performed 
by local lab)
Amylase, lipase (see Section 9.7; performed by 
local lab)
Screening, C4D1, every third cycle thereafter 
(ie, C7, C10, C13, etc.) and EOT
X
X
X
Urinalysis – dipstick
X
Pregnancy test – serum at Screening within 
14 days prior to first study drug administration; 
serum or urine thereafter if clinically indicated
X
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JNJ-54767414  (daratumumab)
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Approved, Date: 4 October 2018
Table 1:
Time and Events Schedule – Safety Run-in, Randomized Arms
Beginning with the implementation of Amendment 7, subjects who continue to derive benefit from atezolizumab treatment, may continue to receive atezolizumab under the 
supervision of treating investigators in accordance with local regulatory approvals and standard of care guidelines.50,51 Data from efficacy and safety evaluations performed 
according to local regulatory approvals and standard of care guidelines50,51 will no longer be collected with the exception of serious adverse events that are to be reported 
and entered in the Sponsor safety repository.
Assessments
Prescreening
(optional)
Screening
Treatment Period (21-day cycles)
EOT
(30 +7d 
after 
last 
dose)
Follow-up 
Period
Arm
Cycles 1-3
Cycle 4 
and 
beyond
Pre-PD
Post-PD 
Survival 
Day
Any time 
prior to start 
of Screening
-56 to -1
-28 to -1
D1
(±3)
D2
D8
(±1)
D15 
(±1)
D1
(±3)
q12 
weeks
(±1 wk)
Blood group and type assessment and indirect 
antiglobulin (IAT).  ABO, Rh, IAT
A wallet card with subject blood type and 
IAT will be provided 
C1D1 
predose; 
Run-in,
Arm B
Study Drug Administration
For subjects in the Safety Run-in and Arm B, the daratumumab infusion should precede the atezolizumab infusion on Day 1 of each cycle, starting with Cycle 2. Only one agent will be 
infused at a time. See the SIPPM for additional details. There should be at least 21 days between Day 1 of every dosing cycle (except for daratumumab in Cycles 1-3).
Atezolizumab
Arm A
X
X
Run-in, 
Arm B
C2/
C3
C1 
only
X
Daratumumab IV
(daratumumab will no longer be administered 
per Amendment 6)
Run-in, 
Arm B
X
X
X
X
Ongoing Subject Review
Adverse events b
Continuous from ICF through 30 days (or 90 days for SAEs) after the last dose of study drug or start of subsequent 
anticancer therapy, if earlier (see Section 12.3.1)
Prior and Concomitant Medications
Continuous 30 days prior to 1st administration of study drug through 30 days after last dose of study drug
Survival and subsequent anti-cancer therapy
X
AE=adverse event, C=cycle, CRF=case report form, COPD=chronic obstructive pulmonary disease, CT=computed tomography, D or d=day, ECOG= Eastern Cooperative Oncology Group Performance 
Status, EOT=end of treatment, FEV-1=forced expiratory volume; maximal amount of air forcefully exhaled in 1 sec., HBV=hepatitis B virus, HCV=hepatitis C virus, IAT=indirect antiglobulin test, 
ICF=informed consent form, MRI=magnetic resonance imaging, PD=progressive disease, PD-L1=programmed death-ligand 1, Ph=phase, q=every, SIPPM=Site Investigational Product Procedures 
Manual
a.
Safety Run-in and Arm B only: C1D1: measure vital signs immediately before the start of the infusion; at 0.5, 1, 1.5, 2 and 3.5 hrs after the start of the infusion; at the end of the 
infusion; and 0.5 and 1 hr after the end of the infusion. For all subsequent Safety Run-in and Arm B administrations (daratumumab + atezolizumab), measure immediately before the 
administration start, at the end of the atezolizumab infusion, and as clinically indicated. Arm A only: vital signs should be assessed at Screening, within 24 hrs of the start of each 
infusion and at the end of each infusion.
b.
Beginning with the implementation of Amendment 7, only serious adverse events will be reported and entered in the Sponsor safety repository for subjects who continue to be 
treated according to local regulatory approval and standard of care guidelines.50,51
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ABBREVIATIONS
ADCC
antibody dependent cell-mediated cytotoxicity
AE
adverse event
ALK
anaplastic lymphoma kinase
Breg
regulatory B cell
CBC
complete blood count
CBR
clinical benefit rate
CDC
complement-dependent cytotoxicity
COPD
chronic obstructive pulmonary disease
CR, sCR
complete response; stringent complete response
CRF
case report form(s) (paper or electronic as appropriate for this study)
CT
computed tomography
CyTOF
cytometry time of flight
DCF
data clarification form
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group Performance Status
UCPI
European Commission Package Insert
EGFR
epidermal-growth factor receptor
EOT
end of treatment
EOTX
end of treatment for crossover
FEV-1
forced expiratory volume; maximal amount of air forcefully exhaled in 1 sec.
FFPE
formalin-fixed, paraffin-embedded
GCP
Good Clinical Practice
HBc
hepatitis B core antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IAT
indirect antiglobulin test
IC
tumor-infiltrating immune cells
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IF
immunofluorescence
Ig
immunoglobulin
IHC
immunohistochemistry
IMiD
immunomodulatory agent
INR
International Normalized Ratio
IRB
institutional review board
IRR
infusion-related reaction
irRECIST
Immune-Related Response Evaluation Criteria in Solid Tumors
IV
intravenous
IWRS
interactive web response system
LDH
lactate dehydrogenase
mAb
monoclonal antibody
MDSC
myeloid-derived suppressor cell
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NGS
next-generation sequencing
NSCLC
non-small cell lung cancer
ORR
overall response rate
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OS
overall survival
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
progressive disease
PD-1
programmed death-1
PD-L1
programmed death-ligand 1
PFS
progression-free survival
PI
proteasome inhibitor
PK
pharmacokinetic(s)
PQC
product quality complaint
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
SD
stable disease
SET
safety evaluation team
SIPPM
Site Investigational Product Procedures Manual
SUSAR
suspected unexpected serious adverse reaction
SVR
sustained virologic response
TC
tumor cell
Treg
regulatory T cell
ULN
upper limit of normal
USPI
United States Package Insert
VGPR
very good partial response
β-hCG
β-human chorionic gonadotropin
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1.
INTRODUCTION
This is an open-label, randomized, Phase 1b/2 study of the combination of 2 monoclonal 
antibodies, TECENTRIQ® (atezolizumab) and DARZALEX® (daratumumab) in subjects with 
previously treated advanced or metastatic non-small cell lung cancer (NSCLC). Both 
atezolizumab and daratumumab are investigational medicinal products (IMPs) in this study.
Atezolizumab is a humanized immunoglobulin G (IgG) 1 monoclonal antibody (mAb) that was 
engineered to target cells expressing programmed death ligand-1 (PD-L1) and inhibits its 
interaction with its receptor, programmed death-1 (PD-1). Atezolizumab also blocks the binding 
of PD-L1 to B7.1, an interaction that is reported to provide additional inhibitory signals to T cells 
(Butte 2007).7 Atezolizumab is approved by the US FDA for treatment of patients with urothelial 
carcinoma that has relapsed from or has become resistant to treatment with platinum-based 
agents (see the Product Information for atezolizumab for the specific indication). Atezolizumab 
is also currently approved for patients with metastatic NSCLC who have disease progression 
during or following platinum-containing therapy. It is currently being studied as a therapy for 
other solid tumors and hematologic malignancies in humans.
Daratumumab is a human immunoglobulin G1 kappa (IgG1ĸ) monoclonal antibody (mAb) that 
binds CD38-expressing cells with high affinity. Daratumumab is approved by the US FDA for 
the treatment of patients with multiple myeloma who have received at least 3 lines of therapy 
including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are 
double-refractory to a PI and an IMiD; and in combination with lenalidomide and 
dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple 
myeloma who have received at least one prior therapy. It is also approved in the European 
Union for the treatment of adults with relapsed and refractory multiple myeloma (see the Product 
Information for daratumumab for the specific indication). It is also being studied as a therapy for 
other hematologic malignancies including non-Hodgkin lymphoma and amyloidosis.
For the most comprehensive nonclinical and clinical information regarding atezolizumab and 
daratumumab, refer to the latest versions of the respective Investigator's Brochures.
The term "Sponsor" used throughout this document refers to the entities listed in the Contact 
Information page, which will be provided as a separate document.
1.1.
Background
Non-small Cell Lung Cancer Background
Lung cancer is the leading cause of cancer deaths globally (WHO 2015).56 In the United States
(US), lung cancer is the second most commonly diagnosed cancer with over 200,000 people 
diagnosed annually. It is the leading cause of cancer-related deaths, with almost 160,000 people 
estimated to succumb to the disease each year (Am Cancer Society 2014).1 Similar data from
Europe estimate that there were 313,000 new cases of lung cancer and 268,000 deaths in 2012
(GLOBOCAN 2012).16 Approximately 80% to 85% of the newly diagnosed cases of lung cancer 
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are NSCLC (adenocarcinoma, squamous carcinoma, and large-cell carcinoma) and 15% to 20% 
are small-cell lung carcinoma (Molina 2008; Howlader 2011).30, 24
Treatment of Advanced or Metastatic Non-Small Cell Lung Cancer
Patients with Stage I, II, or III NSCLC are generally treated with curative intent using surgery or 
radiation therapy, sometimes combined with concurrent or adjuvant chemotherapy 
(Goldstraw 2007).17 In contrast, systemic therapy is generally appropriate for patients with 
Stage IIIB or Stage IV disease at presentation. Systemic therapy is also used for patients who 
have relapsed with advanced disease after definitive treatment. 
The choice of treatment for a patient with advanced NSCLC depends on the histologic subtype 
and the presence or absence of characteristic molecular abnormalities, as well as the patient’s
age, functional status, comorbidities, and prior therapy. Initial systemic therapy (chemotherapy 
or targeted agents) may delay disease progression and prolong survival in patients with advanced 
NSCLC; however, almost all patients eventually develop progressive disease (PD).
Therapy should be individualized based on molecular and histologic features of the tumor.  
Whenever possible, patients should have tumor tissue assessed for the presence of a driver 
mutation that stimulates tumor growth. These mutations define subsets of patients likely to 
respond to specific inhibitors that target the protein produced by the relevant mutation
(NCCN Guidelines).32 Patients with a known driver mutation in the epidermal growth factor 
receptor (EGFR) are managed initially with an EGFR tyrosine kinase inhibitor (Moran and 
Sequist 2012, and Gridelli 2012).31,18 Those with an anaplastic lymphoma kinase (ALK) fusion 
oncogene in their tumor are treated initially with an ALK inhibitor, such as crizotinib 
(Kwak 2010, Camidge 2012, Shaw 2012).26,8,44
Chemotherapy is the primary treatment for patients with advanced NSCLC whose tumor does 
not have an activating mutation of EGFR or the ALK fusion oncogene. Current American Society 
of Clinical Oncology (ASCO) guidelines suggest that 2-drug cytotoxic combinations should be 
administered for no more than 6 cycles (Azzoli 2009)3 for treatment of NSCLC. There is no 
single optimal chemotherapy combination (Schiller 2002, Scagliotti 2002, Ohe 2007).43,42,34
However, randomized studies suggest that cisplatin-based regimens are slightly more effective 
than carboplatin-based combinations or nonplatinum regimens (Ardizzoni 2007).2
Most patients with advanced NSCLC eventually develop PD. Based on results of Phase 3 
studies, docetaxel and pemetrexed are approved for second-line chemotherapy after progression 
on an earlier chemotherapy regimen. In this setting, treatment with these agents results in few 
objective responses, which, generally, are of short duration, and results in limited improvement 
in PFS and OS. The choice of agent is influenced by the chemotherapy regimen used in the 
initial treatment setting. For patients whose tumor contains a driver mutation, those who were 
initially treated with cytotoxic chemotherapy should be treated with the appropriate targeted 
therapy.
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Among the innovative treatment approaches currently undergoing evaluation in clinical studies, 
immunotherapies with immune checkpoint-inhibitors, including those targeting PD-L1 or PD-1,
appear to be the most promising (Ruiz 2014).40 Several anti-PD-1 antibodies have demonstrated 
promising clinical activity with prolonged responses in various tumor types, including NSCLC. 
Three PD-1 or PD-L1 targeting antibodies (nivolumab, pembrolizumab, and atezolizumab) have 
been approved for use in previously treated NSCLC. Nivolumab was approved on the basis of an 
overall survival benefit versus docetaxel (hazard ratio [HR] 0.59 and 0.73 in squamous and 
non-squamous, respectively) independent of PD-L1 expression status; pembrolizumab was 
approved for use on the basis of an overall response rate of 41% in NSCLC patient expressing 
PD-L1 on >50% of their tumor cells.
Pharmacologic Profile
Atezolizumab
Blockade of PD-L1 or PD-1 with mAbs results in potent and often rapid anti-tumor effects in 
multiple murine tumor models (Iwai 2002; Strome 2003).25,48 These data suggest that 
tumor-specific T cells may be present in the tumor microenvironment in an inactive or repressed 
state, and that inhibition of the PD-L1/PD-1 pathway reinvigorates tumor-specific T-cell 
responses. Reports from Phase 1 oncology studies of molecules targeting either PD-L1 or PD-1 
have demonstrated activity in patients with advanced stage and metastatic disease that is 
refractory to standard therapy (Brahmer 2015; Topalian 2012).6,50
Daratumumab
Daratumumab is a targeted immunotherapy directed toward cells that express high levels of 
CD38, such as plasma cells from patients with multiple myeloma. Once binding to CD38 occurs, 
daratumumab 
induces 
cell 
death 
through 
diverse 
immune-mediated 
mechanisms
(complement-dependent cytotoxicity [CDC], antibody-dependent cell-mediated cytotoxicity 
[ADCC], antibody dependent cellular phagocytosis [ADCP]), and induction of apoptosis 
(de Weers 2011; Overdijk 2015).12,36
Translational biomarker studies of Phase 1 and Phase 2 multiple myeloma daratumumab patient 
samples (GEN501 and MMY2002, respectively) reveal
immunomodulatory effects of 
daratumumab (Krejcik 2016).27
Daratumumab leads
to the elimination of highly 
immunosuppressive subsets of CD38+ T-regulatory cells (Tregs), CD38+ myeloid derived 
suppressor cells (MDSCs), and CD38+ B regulatory cells (Bregs). It has also been shown that 
daratumumab may modulate the enzymatic activity of CD38 and may lead to a reduction in 
immunosuppressive adenosine levels (Horenstein
2013).22 This shift away from an 
immunosuppressive environment may lead to the generation of protective immune responses. 
Elimination of these highly immunosuppressive cell subsets in parallel with increases in the
absolute number of activated T cells may potentiate the activity of an anti-PD-L1 antibody in 
NSCLC and other PD-L1 expressing malignancies.
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1.2.
Clinical Experience with Atezolizumab
Atezolizumab is currently being tested in multiple Phase 1, 2, and 3 studies, both as monotherapy 
and in combination with several anti-cancer therapies (see the Atezolizumab Investigator’s
Brochure). The single-agent safety and efficacy data is summarized below from 4 clinical studies:

Study PCD4989g: A Phase 1 study of atezolizumab monotherapy assessing the PK and 
safety in locally advanced or metastatic solid tumors or hematologic malignancies

Study GO28753 (POPLAR): A randomized, Phase 2, open-label study assessing the clinical 
benefit of atezolizumab as a single agent versus docetaxel in PD-L1 unselected patients with 
locally advanced or metastatic NSCLC that has progressed during or following treatment 
with a platinum-containing regimen

Study GO28754 (BIRCH): A Phase 2, single-arm trial of atezolizumab as first-line or 
subsequent therapy for locally advanced or metastatic PD-L1-selected NSCLC

Study GO28915 (OAK): A randomized, Phase 3, open-label study assessing the clinical 
benefit of atezolizumab as a single agent versus docetaxel in PD-L1 unselected patients with 
locally advanced or metastatic NSCLC that has progressed during or following treatment 
with a platinum-containing regimen.
The PCD4989g, POPLAR, BIRCH, and OAK trials used an immunohistochemistry (IHC) assay 
to measure PD-L1 protein expression in tumor infiltrating immune cells (ICs) and tumor cells 
(TCs) (Ferenbacher 2016, Peters 2017, Rittmeyer 2017, Herbst 2016).15,37,39,20 This IHC assay 
has been approved as a complementary diagnostic PD-L1 IHC assay for use with atezolizumab 
in NSCLC by the US FDA (Ventana 2016a [USPI])53 and the European Commission
(Ventana 2016b [ECPI])54.
PD-L1 staining categories in ICs are defined as IC0, IC1, IC2, and IC3 and are defined in TCs as 
TC0, TC1, TC2, and TC3 according to Table 2. 
Table 2: 
Tumor and Immune Cell PD-L1 Expression and Scoring
Percentage PD-L1 Expression at any Intensity
Score
Immune Cells
   <1% Immune Cells in the tumor area
IC0
   ≥1% and <5% Immune cells in the tumor area
IC1
   ≥5% and <10% Immune cells in the tumor area
IC2
   ≥10% Immune cells in the tumor area
IC3
Tumor Cells
   <1% Tumor cells
TC0
   ≥1% and <5% Tumor cells
TC1
   ≥5% and <50% Tumor cells
TC2
   ≥50% Tumor cells
TC3
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Single-Agent Clinical Activity in Patients with NSCLC in Study PCD4989g
Preliminary results suggest that PD-L1 expression in tumor tissue is likely to be associated with 
response to atezolizumab. Table 3 summarizes the overall response rate (ORR) by PD-L1 tumor 
expression in NSCLC patients in the Phase 1 study (PCD4989g), in which atezolizumab 
monotherapy is administered to patients with locally advanced or metastatic solid tumors or 
hematologic malignancies. As of the clinical cutoff date, 8 of 20 patients have continued to 
respond after 7+ to 27+ weeks. The median duration of response (DoR) is 17 months. The most 
frequently reported adverse events (occurring in 10% of patients) included fatigue, decreased 
appetite, nausea, pyrexia, constipation, and cough.
Table 3:
Patients with NSCLC in Study PCD4989g:  Confirmed Objective Response 
Rate by Tumor PD-L1 Expression and Best Overall Response Rate (per 
RECIST, Version 1.1)
PD-L1 IHC Expression
Category
ORR 
(n 88)
PR
SD
TC3 or IC3
50% (11 of 22)
95% CI: 28.2%71.8%
50% (11 of 22)
18.2% (4 of 22)
TC3 or IC2/3
31.6% (12 of 38)
95% CI: 17.5%48.6%
31.6% (12 of 38)
28.9% (11 of 38)
TC0/1/2 and IC0/1/2
12.1% (7 of 58)
95% CI: 5.7%22.5%
12.1% (7 of 58)
36.2% (21 of 58)
TC0/1/2 and IC0/1
14.3% (6 of 42)
95% CI: 6.4%27.7%
14.3% (6 of 42)
33.3% (14 of 42)
ICtumor-infiltrating immune cell; IHCimmunohistochemistry; NSCLCnonsmall cell lung cancer; 
ORR objective response rate; PD-L1programmed deathligand 1; PRpartial response; 
RECISTResponse Evaluation Criteria in Solid Tumors; SDstable disease; TCtumor cell.
Notes:  This table is based on a data cutoff date of 21 April 2014 of patients with NSCLC dosed by 
21 October 2013.  Objective response is per RECIST 1.1.
Single-Agent Clinical Activity in Patients with Advanced or Metastatic NSCLC in 
Study GO28753 (POPLAR)
GO28753 (POPLAR) is a randomized Phase 2 study in advanced or metastatic NSCLC patients 
who failed prior platinum therapy (Ferenbacher 2016).15 Two hundred eighty-seven (287)
patients were enrolled and randomly allocated to atezolizumab or docetaxel in a 1:1 ratio. At a 
minimum follow-up of 13 months (60% of patients had died), atezolizumab significantly 
improved overall survival compared with docetaxel (12.6 vs 9.7 months; HR 0.73 [95% CI 0.53, 
0.99], p=0.04). The overall survival benefit from atezolizumab increased with increasing PD-L1 
expression on tumor cells, tumor infiltrating immune cells, or both. 
The most frequently observed adverse events in the POPLAR study (occurring in 20% of 
atezolizumab-treated patients) included fatigue, nausea, diarrhea, constipation, cough, dyspnea, 
and decreased appetite.
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Single-Agent Clinical Activity in Patients with Locally Advanced or Metastatic NSCLC in 
Study GO28754 (BIRCH) 
GO28754 (BIRCH) is a single-arm Phase 2 study in locally advanced or metastatic PD-L1 
expressing NSCLC (Besse 2015).5 Six-hundred and sixty seven (667) patients with PD-L1 
positive tumors (TC2/3 or IC2/3) were enrolled and treated with atezolizumab monotherapy. 
Table 4 summarizes the efficacy findings including ORR, progression-free survival (PFS) and 
overall survival (OS) by number of prior lines of therapy and PD-L1 expression status.
Table 4:
Patients with NSCLC in Study GO28754: ORR, PFS, and OS by Tumor PD-L1 Expression 
and Number of Prior Lines of Therapy
First-line
Second-line
Third-line+
TC3 or IC3
TC2/3 or IC2/3
TC3 or IC3
TC2/3 or IC2/3
TC3 or IC3
TC2/3 or IC2/3
N
65
139
122
267
115
253
ORR %
26 
19 
24 
17 
27 
17 
6-mo PFS %
48
46 
34 
29 
39 
31 
6-mo OS %
79 
82 
80 
76 
75 
71 
The safety profile of atezolizumab monotherapy in the BIRCH study was consistent with the 
other studies in this population. Thirty-eight percent (38%) of patients had a Grade 3 or 4 
adverse event (AE); 11% had a treatment-related Grade 3 or 4 AE. The most common related 
AEs were fatigue (18%) and nausea (10%). Six percent (6%) of patients discontinued study 
treatment due to an AE (eg, pneumonitis, 0.6%; pneumonia, 0.5%).
Single-Agent Clinical Activity in Patients with Locally Advanced or Metastatic NSCLC in 
Study GO28915 (OAK) 
GO28915 is an ongoing, randomized, open-label Phase 3 study in advanced or metastatic 
NSCLC patients who failed prior platinum therapy, in which 1,225 patients were enrolled and 
were randomly allocated to atezolizumab or docetaxel in a 1:1 ratio (Rittmeyer 2016)39. The 
primary analysis population consists of the first 850 randomized patients. Atezolizumab 
significantly improved OS compared with docetaxel; the results of GO28915 with a median 
follow-up of 21 months are presented in Table 5. Of the 850 patients, 16% were classified as 
having high PD-L1 expression, defined as having PD-L1 expression on ≥50% of TC or ≥10% of 
IC. In an exploratory efficacy subgroup analysis of OS based on PD-L1 expression, the hazard 
ratio was 0.41 (95% CI: 0.27,0.64) in the high PD-L1 expression subgroup and 
0.82 (95% CI: 0.68, 0.98) in patients who did not have high PD-L1 expression.
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Table 5:
Overall Survival in Study GO28915 (OAK)
Atezolizumab
n=425
Docetaxel
n=425
Overall Survival
    Deaths %
271 (64%)
298 (70%)
   Median, months (95% CI)
13.8 (11.8, 15.7)
9.6 (8.6, 11.2)
    Hazard ratioa
         p-valueb
0.73 (0.62, 0.87)
0.0003
CI=confidence interval
a.
Stratified by PD-L1 expression in tumor infiltrating immune cells, the number of prior 
chemotherapy regimens, and histology.
b. Based on the stratified log-rank test.  
Safety data in Study GO28915 are consistent with previously reported safety data from the 
atezolizumab Phase 2 study in patients with previously treated NSCLC (POPLAR). The 
percentage of Grade 3 or 4 adverse events in the atezolizumab and docetaxel were 37% and 54%, 
respectively, with fewer treatment-related adverse events with atezolizumab compared with 
docetaxel. Among the 609 patients treated with atezolizumab in this study, the following were
the most common atezolizumab-related adverse events of any grade (event, percentage of 
patients with the event): fatigue (14%), nausea (9%), decreased appetite (9%), and asthenia (8%). 
Immune-mediated adverse events reported with atezolizumab included pneumonitis (any grade: 
6 patients, 1%; Grade 3: 4 patients, <1%); hepatitis (Grade 3, 2 patients <1%); and colitis 
(Grade 2, 2 patients <1%). Adverse events leading to treatment discontinuation occurred in 
46 (8%) of 609 patients with atezolizumab and in 108 (19%) of 578 patients with docetaxel. 
There were no deaths related to atezolizumab and 1 related to docetaxel (respiratory tract 
infection).
Given the mechanism of action of atezolizumab, events associated with inflammation or 
immune-mediated adverse events have been closely monitored during the atezolizumab clinical 
program. These include immune-mediated dermatologic, hepatic, endocrine, gastrointestinal, and 
respiratory events.
Refer to the atezolizumab Investigator’s Brochure for details on 
immune-mediated adverse events and other adverse events that were observed in patients treated 
with atezolizumab.
1.3.
Clinical Experience with Daratumumab
This is the first clinical study of daratumumab in NSCLC. Current clinical information is based 
on studies of patients with multiple myeloma.
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1.3.1.
Daratumumab IV
Human Pharmacokinetics and Immunogenicity  
Daratumumab clearance decreases with increasing dose and repeated dosing, indicating 
target-mediated pharmacokinetics. Following the approved multiple myeloma schedule and dose 
of 16 mg/kg, the mean serum maximum observed concentration (Cmax) at the end of 8 weeks of 
weekly dosing was 915 µg/mL, approximately 2.9-fold higher than following the first infusion. 
The mean predose (trough) serum concentration at the end of weekly dosing was 573 µg/mL. 
Based on the population pharmacokinetic (PK) analysis, daratumumab steady state is achieved 
approximately 5 months into the every-4-week dosing period (by the 21st infusion), and the 
mean ratio of Cmax at steady-state to Cmax after the first dose was 1.6. The mean estimated 
terminal half-life associated with linear clearance was approximately 18 days.
Of the 199 total subjects in Studies GEN501 and MMY2002 that were evaluable for 
immunogenicity, none were positive for anti-daratumumab antibodies.
Efficacy/Safety Studies
The US FDA and European Commission (EC) have approved daratumumab for the treatment of 
patients with multiple myeloma who have received at least 3 prior lines of therapy including a 
PI and an IMiD or who are double-refractory to a PI and an IMiD. These approvals were based 
on data from the pivotal study MMY2002 and key supportive study GEN501.
Integration of data from Study MMY2002 and Part 2 of Study GEN501 resulted in an ORR of 
31% with duration of response of 7.6 months. Median time to first response is slightly less than 
1 month, corresponding to the first disease assessment. The response at the dose of 16 mg/kg was 
consistent across all subgroups, regardless of the number of prior lines of therapy, refractory 
status, or geographic region. The rate of very good partial response (VGPR) or better induced by 
single-agent daratumumab was 11% across Study MMY2002 and Study GEN501. Following 
treatment with daratumumab, 3 stringent complete responses (sCRs), 2 complete responses 
(CRs), and 12 VGPRs were observed across both studies. The CR/sCR rate was 3%.
The integrated safety analysis of these studies (MMY2002 and GEN501) included 156 subjects 
who received at least one dose of daratumumab 16 mg/kg monotherapy. The most frequently 
reported treatment-emergent AEs were fatigue, nausea, anemia, neutropenia, back pain, cough, 
and thrombocytopenia. Infusion-related reactions were reported for 51% of subjects. Grade 3 
infusion-related reactions were reported for 4% of subjects; no Grade 4 infusion-related reaction
(IRR) was reported. Most of the IRRs (91%) occurred with the first infusion; they were managed 
well with preinfusion and postinfusion medications, and no IRR resulted in discontinuation of 
treatment.
Refer to the Daratumumab Investigator’s Brochure for details on the clinical experience in 
patients treated with daratumumab.
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1.4.
Overall Rationale for the Study
This Phase 1b/2 Study will inform future clinical development of daratumumab and 
atezolizumab in NSCLC patients. Despite recent improvements in treatment, the prognosis for 
patients with advanced NSCLC remains dismal, with a median OS of approximately 12.3 months 
(Sandler 2006).41 Patients who receive second-line treatment for their disease have an even more 
limited prognosis, with a median survival duration of approximately 8
to 9 months 
(Stinchcombe 2008).47
Inhibition of PD-L1 signaling has been shown to produce durable responses in some patients, 
and expression of PD-L1 by TCs in several tumor types (including NSCLC) correlates with 
response to therapy (Topalian 2012)50 and improved OS (Ferenbacher 2016; Herbst 2016).15,20
Data from the Phase 1a Study PCD4989g evaluating single-agent atezolizumab in several tumor 
types, including NSCLC, suggest that PD-L1 expression in TCs and ICs as determined by IHC 
correlates with response to atezolizumab. An ORR of 31.6% was observed in patients with high
levels of PD-L1 staining in TCs or ICs (TC3 or IC2/3 group) compared with an ORR of 14.3% 
in patients with low or no PD-L1 staining in TCs and ICs (TC0/1/2 and IC0/1 group).
Additionally, data from the GO28754 (BIRCH) study provide evidence that response rates are 
generally consistent in both treatment naive and previously treated patients with varying degrees 
of PD-L1 expression status. Despite these encouraging data, it is clear that the majority of 
patients in these studies do not respond to PD-L1 inhibition. Therefore, new therapeutic 
approaches are needed.
Expansion of Tregs and MDSCs in the lung tumor microenvironment is part of the mechanism 
by which cancer cells escape from host immune surveillance and may limit response to 
checkpoint inhibitors (Peterson 2006; Dasanu 2012; Srivastava 2012).38,11,46 Daratumumab is a 
first-in-class human monoclonal CD38 targeting antibody that induces deep clinical responses in 
multiple myeloma. Flow cytometry analysis revealed a previously unknown immunomodulatory 
role of daratumumab, by way of induction of T cell expansion through the reduction of immune 
suppressive cell populations CD38+ MDSC, CD38+ Treg, and CD38+ Breg cells. Therefore, the 
combination of daratumumab with atezolizumab may lead to an improvement in clinical 
responses in NSCLC by enhancing the anti-tumor T cell responses facilitated by checkpoint 
inhibition.
 
 
 
 
Overlapping toxicities of daratumumab and atezolizumab are not expected.
While 
infusion-related reactions (IRRs) are observed in approximately half of patients treated with 
daratumumab, IRRs occur in only approximately 1% of patients treated with atezolizumab. 
As of 25 May 2018, the Sponsor terminated further enrollment into this study after the third 
planned Data Monitoring Committee (DMC) review on 23 May 2018. At that time
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(n=88, 44 subjects per arm), the DMC determined that there was no observed benefit within the 
combination treatment arm, daratumumab plus atezolizumab, over atezolizumab alone, and 
recommended stopping enrollment of the study. In addition, the DMC recommended 
discontinuation of daratumumab treatment to all active subjects receiving combination therapy 
(subjects randomized to the combination Arm B, as well as subjects randomized to Arm A who 
crossed over into Arm B). Although no unexpected imbalances in on-treatment toxicities were 
observed, the DMC noted a numerical increase in the number of deaths in the combination arm. 
Therefore, enrollment is discontinued in this study, treatment with daratumumab will be 
discontinued, and ongoing subjects will be given the option to continue on atezolizumab 
monotherapy until the subject meets one or more of the treatment discontinuation criteria in 
Section 10.2. Additionally, Phase 1b expansion to explore the subcutaneous formulation as 
outlined in Amendment 5 will not be implemented.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objective

To compare the overall response rate (ORR) in subjects treated with daratumumab in
combination with atezolizumab versus atezolizumab alone.
Secondary Objectives

To assess the safety of the combination of daratumumab and atezolizumab

To compare the duration of response (DoR) in subjects treated with daratumumab in 
combination with atezolizumab versus atezolizumab alone 

To compare the clinical benefit rate (CBR) in subjects treated with daratumumab in 
combination with atezolizumab versus atezolizumab alone

To compare progression-free survival (PFS) in subjects treated with daratumumab in 
combination with atezolizumab versus atezolizumab alone

To compare overall survival (OS) in subjects treated with daratumumab in combination with 
atezolizumab versus atezolizumab alone 

To evaluate the pharmacokinetic and immunogenicity profile of daratumumab when given 
in combination with atezolizumab

To evaluate the pharmacokinetic and immunogenicity profile of atezolizumab when given in 
combination with daratumumab.
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Exploratory Objectives

To compare ORR evaluated by the Immune-Related Response Evaluation Criteria in Solid 
Tumors (irRECIST)

To explore biomarkers predictive of response to therapy

To evaluate potential pharmacodynamic biomarkers in response to therapy

To explore the relationships between pharmacokinetics, pharmacodynamics, adverse event 
profiles, and clinical activity of daratumumab given in combination with atezolizumab in 
subjects with previously treated advanced or metastatic NSCLC

To explore the benefit of daratumumab and atezolizumab treatment in subjects who had
confirmed disease progression on atezolizumab monotherapy.
2.1.2.
Endpoints
Primary Endpoint

The primary endpoint is ORR: the proportion of subjects with a partial response (PR) or 
complete response (CR) as defined by RECIST 1.1
Secondary Endpoints

Incidence of adverse events

DoR: the duration from the date of the initial documentation of a response to the date of the 
first objectively documented evidence of recurrence or progressive disease or death, 
whichever status is recorded first.

CBR: the proportion of subjects who achieve disease control (CR, PR, or SD with duration 
of at least 16 weeks).

PFS: the duration from the date of randomization to the date of objectively documented 
progression or death due to any cause, whichever status is recorded first.

OS: the duration from the date of randomization to the date of death due to any cause.

Serum daratumumab concentration (Cmin, Cmax) and incidence of anti-daratumumab 
antibodies

Serum atezolizumab concentration (Cmin, Cmax) and incidence of anti-atezolizumab 
antibodies
Exploratory Endpoints

ORRi: the proportion of subjects with a partial response (PR) or complete response (CR) 
evaluated by irRECIST

ORR, DoR, CBR, incidence of adverse events, daratumumab and atezolizumab serum 
concentration and incidence of anti-daratumumab antibodies and anti-atezolizumab
antibodies
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
2.2.
Hypothesis
The primary hypothesis is that daratumumab in combination with atezolizumab will significantly 
improve ORR compared to atezolizumab alone in subjects with NSCLC.
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3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, open-label, parallel-group, multicenter Phase 1b/2 study assessing the 
anti-tumor activity and safety of daratumumab in combination with atezolizumab compared with
atezolizumab alone in subjects with previously treated advanced or metastatic NSCLC. 
Approximately 96 subjects will be enrolled in this study, including 6 subjects in a safety run-in 
cohort followed by 90 subjects randomly assigned in a 1:1 ratio to 2 treatment arms. In addition 
to safety and efficacy, pharmacokinetics, and biomarkers will also be assessed.
An internal Janssen Data Monitoring Committee (DMC), independent of the study team, will be 
established to review the efficacy and safety data in the randomization phase. The DMC will 
review the totality of data after approximately 40, 60, and 90 subjects have been enrolled, 
including activity within distinct PD-L1 expression subgroups. Based on these findings, the 
DMC may formulate recommendations on study conduct, including the expansion of enrollment 
of some PD-L1 subgroups, resulting in greater than 96 subjects. The DMC may request 
additional ad hoc reviews as data accumulate.
Beginning with the implementation of Amendment 7, the Sponsor will continue to supply 
atezolizumab to active subjects who are deriving clinical benefit from atezolizumab 
monotherapy, but do not have access to commercial atezolizumab. The administration of 
atezolizumab will occur under the supervision of treating investigators in accordance with local 
regulatory approvals and standard of care guidelines.50,51 Data from efficacy and safety 
evaluations performed according to local regulatory approvals and standard of care 
guidelines50,51 will no longer be collected with the exception of serious adverse events that are to 
be reported and entered in the Sponsor safety repository.
Safety Run-in Phase
A 6-subject Safety Run-in cohort will be evaluated by the Safety Evaluation Team (SET; see 
Section 3.2) to determine the safety and tolerability of atezolizumab administered in combination 
with daratumumab before proceeding with the randomized phase of the study.

Enrollment into the safety run-in will be staggered, with at least 48 hours between initiation 
of daratumumab + atezolizumab combination therapy (Cycle 1 Day 1) of individual 
subjects.

Daratumumab will be administered intravenously (IV) at 16 mg/kg weekly on Days 1, 8, 
and 15, for the first 3 cycles, then on Day 1 of each 21-day cycle thereafter. Atezolizumab 
will be administered at 1,200 mg IV on Day 2 of Cycle 1 and on Day 1 of every 21-day 
cycle thereafter.

After Cycle 1, subjects in the Safety Run-in cohort may continue to receive additional cycles 
of daratumumab + atezolizumab while enrollment into the Safety Run-in cohort is ongoing 
and after the study has proceeded to the randomization phase until they meet 
protocol-specified discontinuation criteria.

If <2 of the first 6 subjects experience a dose-limiting toxicity (DLT; see Section 3.2) during 
the first treatment cycle (ie, 21 days), the selected doses and dose regimens for 
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daratumumab + atezolizumab combination therapy will be considered tolerable in subjects 
with advanced or metastatic NSCLC, and the study will proceed to the randomized phase 
after the SET provides approval.

If 2 subjects experience a DLT, new subject enrollment into the Safety Run-in cohort will 
stop until after the SET convenes to review DLT data from those subjects and makes 
recommendations regarding the conduct of the study. The SET may consider the exploration 
of alternate doses and dose regimens. While the SET is reviewing the DLT data, remaining 
subjects in the Safety Run-in cohort who have not experienced a DLT may continue to 
receive additional cycles of daratumumab + atezolizumab after consultation with the 
Sponsor.
Randomized Phase
Approximately 90 subjects were to have been stratified based on PD-L1 expression status 
(IC0 and TC0 vs. others), histology (squamous vs. non-squamous), and number of previous lines 
of therapy (1 or >1), and then assigned randomly in a 1:1 ratio into 2 treatment arms as follows:
Arm A: atezolizumab
Arm B: atezolizumab + daratumumab IV
Treatment
Note: subjects will only be eligible to receive atezolizumab monotherapy (per Amendment 6), 
see Section 3.2.
For Arm A, atezolizumab will be administered at 1,200 mg IV on Day 1 of every 21-day cycle.
Subjects in Arm A who experience confirmed disease progression based on RECIST 1.1 will be 
eligible to crossover to Arm B provided crossover eligibility criteria are met.
For Arm B, daratumumab will be administered intravenously (IV) at 16 mg/kg weekly on 
Days 1, 8, and 15, for the first 3 cycles, then on Day 1 of each 21-day cycle thereafter. 
Atezolizumab will be administered at 1,200 mg IV on Day 2 of Cycle 1 only and then on Day 1 
of every 21-day cycle thereafter. Measures to prevent infusion-related reactions will include 
preinfusion medication (see Section 6.3). Subjects will be monitored closely for immune-
mediated adverse events including pneumonitis, enterocolitis, hepatitis, dermatitis, neuropathies,
and endocrinopathies.
Study visits for subjects receiving daratumumab (Safety Run-in and Arm B) will occur weekly 
during the first 3 cycles and every 3 weeks for all cycles thereafter. Study visits for subjects 
randomized to Arm A (atezolizumab alone) will occur weekly during the first 2 cycles and every 
3 weeks thereafter. Subjects will continue on the assigned study treatment (atezolizumab alone or 
atezolizumab + daratumumab) until treatment discontinuation due to disease progression, 
unacceptable 
toxicity,
or 
other 
protocol-defined 
treatment 
discontinuation
criteria 
(see Section 10.2); or until subjects in Arm A crossover. Subjects in Arm B, who experience
unacceptable toxicity directly attributable to one agent and who are experiencing clinical benefit 
(ie, stable disease or better) may stay on the other agent until treatment discontinuation criteria 
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are met, after discussion with the Sponsor. Subjects who have crossed over and experience 
unacceptable toxicity directly attributable to atezolizumab and who are experiencing clinical 
benefit (ie, stable disease or better) may stay on daratumumab until treatment discontinuation 
criteria are met, after discussion with the Sponsor.
Follow-up
The Follow-up phase will begin after the End-of-Treatment visit, 30 (+7) days after the 
discontinuation of the study drugs. Subjects will be followed for survival every 12 weeks after 
confirmed disease progression or start of new anticancer therapy. For subjects who discontinue
treatment for reasons other than progression (eg, adverse event), disease assessments will 
continue to be performed until disease progression or a new cancer therapy is initiated
(or another study withdrawal criterion is met, see Section 10.2).
The timing of assessments is provided in the Time and Events Schedule (Table 1). A diagram of 
the study design is provided in Figure 1.
Figure 1:
Schematic Overview of the Study
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3.2.
Study Conduct After DMC Recommendations
As of 25 May 2018, the Sponsor terminated further enrollment into this study. Ongoing 
treatment with daratumumab will be discontinued in all active subjects receiving combination 
therapy (subjects randomized to the combination Arm B, as well as subjects randomized to Arm 
A who have crossed over into Arm B). Crossover to Arm B is also no longer permitted. Ongoing 
subjects will be given the option to continue on atezolizumab monotherapy until the subject 
meets one or more of the treatment discontinuation criteria in Section 10.2. For subjects 
remaining on the study, protocol procedures and the atezolizumab dosing schedule will continue 
according to Section 9.2 and the Time and Events Schedule (Table 1) until locking of the clinical 
database. All procedures outlined in previous versions of this protocol pertaining to patients 
randomized to treatment other than atezolizumab monotherapy (in Table 2 through Table 7, 
which were removed beginning with the implementation of Amendment 6) will no longer be 
performed. For safety reporting changes, see Section 12.4. Upon clinical database closure, only 
serious adverse events will be reported and entered in the Sponsor safety repository for subjects 
who continue to be treated according to local regulatory approval and standard of care 
guidelines.50,51
The changes to study conduct and status implemented in Amendment 7 were also pursuant to 
these recommendation from the DMC.  
A clinical study report (CSR) will be prepared based on the interim analysis data reviewed by the 
DMC at the third DMC review (prior to discontinuation of enrollment and daratumumab dosing).
3.3.
Safety Evaluation
Dose-Limiting Toxicity (DLT)
Toxicities will be graded for severity according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03. During the 6-subject 
Safety Run-in phase, the DLT evaluation period is 21 days starting from the day of the first dose 
of study drug. Only toxicities that occur during the DLT evaluation period will be considered for 
DLT assessment. Subjects who are not evaluable for DLT can be replaced. A DLT evaluable 
subject (DLT evaluable analysis set) is:

Any subject who has a DLT regardless of dose received or 

A subject who did not have a DLT but received at least 75% of the planned dose during the 
DLT evaluation period.
Dose-limiting toxicity is defined as any of the events listed in Table 6. Toxicities with a clear 
alternative explanation (eg, due to disease progression) or transient toxicities (≤72 hours) and 
abnormal laboratory values without associated clinically significant signs or symptoms based on 
investigator determination can be deemed a non-DLT.
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Table 6:
Criteria for Dose-limiting Toxicity
DLT criteria for Non-hematologic Toxicitya
AST or ALT
Grade 3 persisting ≥14 days after treatment with corticosteroids, Grade 4, or 
any case meeting Hy’s Law criteriab
Laboratory abnormality
Grade 3 persisting ≥7 days despite BSCc or Grade 4
Any otherd
Grade 3 persisting ≥7 days despite BSCc or Grade 4; except Grade ≥3 
asymptomatic or mildly symptomatic rash that can be adequately managed 
with supportive care or resolves to become asymptomatic or Grade ≤2 within 
7 days of supportive therapy.
Infusion-related reaction
Grade 4 infusion-related reaction that occurs during or within 24 hours after 
the infusion of atezolizumab or daratumumab.
Ocular toxicity
Grade 2 or higher episcleritis, uveitis, or iritis
DLT criteria for Hematologic Toxicitya
Neutropenia
Grade 3 persisting >7 days despite BSCc, febrile neutropenia, or any Grade 4
Thrombocytopenia
Grade 3 with bleeding or Grade 3 persisting >7 days despite BSCc, or any 
Grade 4
Any other
Grade 3 persisting ≥7 days despite BSCc or Grade 4
ALT=alanine aminotransferase, AST=aspartate aminotransferase, ALP=alkaline phosphatase
a.
Toxicity graded according to the NCI-CTCAE, Version 4.03.
b.
Hy’s Law criteria, defined as ALT or AST value ≥3 x upper limit of normal (ULN), total bilirubin ≥2 x ULN, and ALP ≤2 x 
ULN; with no alternative etiology.
c.
Best supportive care (BSC) if available, according to institutional standards.
d.
With the exception of alopecia and Grade 3 fatigue in a subject with Grade 1 or Grade 2 fatigue at baseline.
Safety Evaluation Team (SET)
Ongoing safety evaluation during the safety run-in phase of this open-label study will be 
overseen by the SET. The SET established by the Sponsor will monitor all available treatment-
emergent data on an ongoing basis throughout study conduct for the purpose of ensuring the 
continued safety of subjects enrolled in this study. The SET will also be responsible for 
reviewing the safety data during the safety run-in phase and making a formal determination of 
whether the study will proceed to the 90-subject randomized phase based on the DLT rules set 
forth above.
The SET will be chaired by the Sponsor’s Study Responsible Physician. Membership will 
include a Sponsor clinical scientist, statistician, clinical pharmacologist, along with additional 
Sponsor staff, as appropriate. Additionally, the investigators who have enrolled the 6 safety run-
in subjects will participate. The team will meet approximately monthly during the safety run-in 
phase and as necessary during the conduct of the remainder of the study. Documentation of 
meeting outcomes will be maintained by the Sponsor in the Study Master File. Decisions with 
the potential to affect subject safety (eg, unfavorable change in benefit/risk assessment) will be 
promptly communicated to investigators and regulatory authorities as appropriate.
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3.4.
Study Design Rationale
Rationale for Study Design
Clinical study experience with the use of atezolizumab monotherapy in NSCLC has established 
its safety and tolerability in the population under study. Targeting CD38+ immunosuppressive 
cells with daratumumab may synergistically combine with PD-L1 blockade to increase the 
activity of effector T cells and lead to improved clinical responses in NSCLC.
Adequate steps have been taken to ensure the validity of data in an open-label study design. This 
includes performing tumor assessments at the same frequency in both arms, adhering to 
protocol-defined schedules, and determining the strategy for the final analysis of the primary 
endpoint prior to study start, including predefined methods for handling missing data and 
censoring rules.
Randomization will be used to minimize bias in the assignment of subjects to treatment groups. 
To further minimize imbalance across treatment arms and to allow for balanced enrollment in 
important subgroup analyses, subjects will initially be stratified based on centrally determined 
PD-L1 expression status (TC0 and IC0 vs. others; see Section 1.2), histology (squamous vs. 
non-squamous), and number of prior therapies (1 vs >1). 
Rationale for Daratumumab IV Dose Selection
The dose used in this study (16 mg/kg) is the approved dose of daratumumab for the treatment of 
subjects with relapsed and refractory multiple myeloma. This dose selection was based on an 
acceptable safety profile, maximal clinical activity, and pharmacokinetics consistent with 
saturation of the target. This dose and similar schedules have been shown to be tolerable in 
several combination studies.
Based on these data, the initial dose and schedule for NSCLC subjects in combination with 
atezolizumab is 16 mg/kg weekly for 3 cycles (Day 1, 8 and 15), and Day 1 of every 21-day 
cycle thereafter. This is a slight modification of the approved multiple myeloma schedule 
(weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks thereafter) to match dosing
frequency of atezolizumab for patient convenience. A similar daratumumab schedule was 
previously used and shown to be safe and efficacious in the Phase 3 MMY3004 study (weekly 
during Cycles 1, 2 and 3), every 3 weeks until the end of Cycle 8 (ie, the end of 
bortezomib/dexamethasone treatment per the bortezomib label), and then alone every 4 weeks 
(ie, daratumumab only from Cycles 9 onward).
Rationale for Atezolizumab Dose Selection
The fixed dose of 1200 mg (equivalent to an average body weight-based dose of 15 mg/kg) was 
selected on the basis of nonclinical studies and available clinical data from Study PCD4989g as 
described below and has been used in subsequent studies evaluating atezolizumab as a 
monotherapy in NSCLC, including GO28753 and GO287504 (as described in Section 1.2).
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The target exposure for atezolizumab was projected on the basis of nonclinical tissue distribution 
data in tumor-bearing mice, target-receptor occupancy in the tumor, the observed atezolizumab 
interim pharmacokinetics in humans, and other factors. The target trough concentration (Ctrough) 
was projected to be 6 g/mL on the basis of several assumptions, including the following: 
1) 95% tumor-receptor saturation is needed for efficacy and 2) the tumor-interstitial 
concentration to plasma ratio is 0.30 based on tissue distribution data in tumor-bearing mice.
The atezolizumab dose is also informed by available clinical activity, safety, pharmacokinetics, 
and immunogenicity data. Anti-tumor activity has been observed across doses from 1 mg/kg to 
20 mg/kg. The maximum tolerated dose (MTD) of atezolizumab was not reached, and no DLTs 
have been observed at any dose in Study PCD4989g. Currently available pharmacokinetic and 
anti-drug antibody data suggest that the 15-mg/kg atezolizumab every 3-week regimen 
(or fixed-dose equivalent) for Phase 2 and Phase 3 studies would be sufficient to both maintain 
Ctrough 6 g/mL and further safeguard against both interpatient variability and the potential 
effect of anti-drug antibodies that could lead to subtherapeutic levels of atezolizumab relative to 
the 10-mg/kg atezolizumab every 3 week regimen (or fixed-dose equivalent). From inspection of 
available observed Ctrough data, moving further to the 20-mg/kg atezolizumab every 3-week
regimen does not appear to be warranted to maintain targeted Ctrough levels relative to the 
proposed 15-mg/kg atezolizumab every 3 week level. 
Simulations (Bai 2012)4 do not suggest any clinically meaningful differences in exposure 
following a fixed dose or a dose adjusted for weight. Therefore, a fixed dose of 1200 mg has 
been selected (equivalent to an average body weightbased dose of 15 mg/kg). Selection of an 
every-21-day dosing interval is supported by this preliminary pharmacokinetics evaluation.
Rationale for ORR as the Primary Endpoint
Objective response is generally accepted as a convincing measure of anti-tumor activity for the 
reason that spontaneous regression fulfilling criteria for at least partial response is uncommon. 
Furthermore, durable and objective response rates have been accepted by regulatory authorities 
as reasonably likely to predict clinical benefit.
Rationale for Pharmacokinetics and Immunogenicity Assessments
The demographic characteristics of the NSCLC population differ significantly from previously 
studied daratumumab subject populations and may affect the pharmacokinetic profile. Therefore, 
samples will be obtained from all subjects for assessment of minimum and maximum observed 
concentrations (Cmin and Cmax). Data may also be used for a population pharmacokinetic analysis 
to estimate additional pharmacokinetic parameters and provide information about the 
determinants of inter-subject variability in this population.
Immunogenicity to atezolizumab and daratumumab is possible, and the incidence of anti-drug 
antibody generation in subjects with NSCLC may be different from previously studied 
populations because these subjects are expected to be less immune compromised. Therefore, 
samples to determine the presence of antibodies to atezolizumab
and
daratumumab
(immunogenicity) will be collected during treatment and after the last dose in the study.
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Rationale for Biomarker Evaluations
Biomarker samples will be collected to evaluate biomarkers of biologic activity of 
atezolizumab+daratumumab in subjects with NSCLC. Published results suggest that the 
expression of PD-L1 in tumors correlates with response to antiPD-L1 therapy 
(Horn 2015; Spira 2015).23,45 Mandatory tumor specimens from subjects at Screening will be 
evaluated and used to initially stratify patients by PD-L1 status to minimize imbalance between 
the treatment groups. In addition, based on interim or final analyses, the DMC may recommend
modification to enrollment of subjects to the study based on PD-L1 expression in accordance 
with the product label of the Ventana SP-142 assay. For additional details, refer to Section 11.3. 
Tumor specimens from subjects at Screening, on-treatment, and at progression will be 
retrospectively evaluated for CD38+ expression,
 
Evaluation of CD38+ expression will be performed to determine if 
elevated CD38+ expression at Screening and decreases with daratumumab treatment correlate 
with responses to combined therapy. Circulating immune cells and CD38+ immunosuppressive 
cells will be evaluated by flow cytometry as potential pharmacodynamic and response 
biomarkers.
4.
SUBJECT POPULATION
Subjects 18 years and older with advanced or metastatic NSCLC who had at least 2 cycles of 
standard platinum-based therapy with disease progression or intolerance to therapy will be 
eligible for this study.
An optional Prescreening informed consent will be offered for the purpose of testing archival 
tumor tissue to assess PD-L1 status using the SP142 assay (Section 9.1.2) to help determine the
likelihood of eligibility for participation in this study. However, final eligibility for study 
participation will be based on PD-L1 staining on the fresh biopsy required during the Screening 
Phase, unless the archival tumor sample used in the Prescreening Phase was obtained after 
completion of the most recent line of therapy with no intervening therapies, and is less than 1
year old. The signing of the main study informed consent and collection of tumor specimen for 
PD-L1 testing may occur up to 56 days before the first administration of study drug. All other 
screening procedures must be performed only after PD-L1 results are available, and within 28 
days before the first administration of study drug. For subjects who do not meet Inclusion 
Criterion 5, no further Screening procedures should be performed. For subjects in the 
randomized phase, treatment should start within 72 hours after randomization.
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.
During its review of the study data at the initial interim analysis (40 evaluable subjects), the 
DMC determined that the study had enrolled a sufficient number of subjects with a PD-L1 score 
of TC0 and recommended continued enrollment only in subjects in the TC1-3 subgroups. After
this DMC recommendation, the sites were notified that only subjects with a PD-L1 score of 
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TC1-3 will be eligible to enroll in the study, and the protocol was amended to reflect this 
DMC recommendation (Section 4.1).
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination.
After the third data review by the DMC, this study is closed to further enrollment.
4.1.
Inclusion Criteria
Investigators should ensure that all study enrollment criteria have been met at Screening. If a 
subject's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study drug is given such 
that he or she no longer meets all eligibility criteria, then the subject should be excluded from 
participation in the study. Section 9.1.3, Screening Phase, describes options for retesting. 
Section 17.4, Source Documentation, describes the required documentation to support meeting 
the enrollment criteria.
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
≥18 years of age
2.
ECOG performance status of 0 or 1.
3.
Criterion modified per Amendment 2.
3.1 Criterion modified per Amendment 3. 
3.2 Have histologically or cytologically confirmed advanced or metastatic NSCLC (Stage IIIb or 
greater).
-  Subjects must have received at least 2 cycles of standard platinum-based therapy for Stage IIIb or 
greater NSCLC and had disease progression on or after therapy.
Note: Subjects who have received fewer than 2 cycles of platinum-based therapy due to intolerance 
(history of hypersensitivity or allergic reactions and other adverse events which prevent continuation 
of platinum-based agent), are eligible for study participation, provided there is documentation of 
disease progression.
-
Subjects who received prior treatment with vaccines or investigational agents, are eligible for 
study participation. 
-
Subjects with known genetic alterations of ALK, EGFR, and ROS1 are not eligible for study 
participation.
4.
Criterion modified per Amendment 2.
4.1 Measurable disease, as defined by RECIST 1.1.
5.
5.1 Criterion modified per Amendment 4.
5.2 Criterion modified per Amendment 5
5.3 Criterion modified per Amendment 6
Tumor cell PD-L1 score as determined by an IHC assay performed by the central laboratory on 
tissue obtained after the last line of therapy:
Randomized phase of the study
Subjects with a tumor cell PD-L1 score of TC1-3 who are anti-PD-1 or anti-PD-L1 treatment 
naïve will be eligible for screening.
6. 
Criterion modified per Amendment 2.
6.1 Criterion modified per Amendment 3.
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6.2 Laboratory values that meet the following criteria within 14 days prior to first administration of 
study drug (see Table 1):

ANC >1.5 × 109/L (without growth factor support 1 week before 1st administration)

Platelets >100 × 109/L

Hemoglobin >9 g/dL 

Transfusion is acceptable to meet the hemoglobin and platelet criteria if stable for 1 week 
prior to first administration of study drug 

Calculated creatinine clearance >50 mL/min per Cockroft-Gault formula

INR or aPTT ≤1.5 x ULN

Applies only to subjects who are not receiving therapeutic anticoagulation; subjects 
receiving therapeutic anticoagulation should be on a stable dose for at least 4 weeks.

AST, ALT, and alkaline phosphatase: 

2.5 ULN, if no liver metastases 

5 ULN with documented liver metastases

5 ULN alkaline phosphatase (not AST or ALT) with documented bone metastases

Total bilirubin ≤2.0 x ULN, except in subjects with congenital bilirubinemia, such as Gilbert 
syndrome (direct bilirubin ≤2.0 x ULN)

Serum ionized calcium ≤1.5 mmol/L or serum calcium ≤12 mg/dL or corrected serum calcium 
<ULN)
7.
A woman of childbearing potential must have a negative highly sensitive serum (-human chorionic 
gonadotropin [-hCG]) at Screening within 14 days prior to study drug administration.
8.
Criterion modified per Amendment 2.
8.1 Contraceptive use by men or women should be consistent with local regulations regarding the 
use of contraceptive methods for subject participating in clinical studies.
Before enrollment, a woman must be either:
a. Not of childbearing potential defined as:

postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the 
postmenopausal range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy, however in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient.

permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal 
occlusion/ligation procedures, and bilateral oophorectomy.
b. Of childbearing potential and

practicing 2 methods of reliable birth control simultaneously: 1 highly effective method of 
contraception (failure rate of <1% per year when used consistently and correctly) and 1 
additional effective method.
Examples of highly effective contraceptives include:
- user-independent methods:
implantable progestogen-only hormone contraception associated with inhibition of 
ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); 
vasectomized partner; sexual abstinence (sexual abstinence is considered a highly 
effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study drug. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the subject.)
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- user-dependent methods:
combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only 
hormone contraception associated with inhibition of ovulation: oral and injectable
Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
subjects participating in clinical studies. Hormonal contraception may be susceptible to 
interaction with the study drug, which may reduce the efficacy of the contraceptive method.
Examples of additional effective contraceptive methods include:
-
male latex or synthetic condom, diaphragm, or cervical cap

agrees to remain on the 2 contraception methods (1 highly effective and 1 additional reliable 
method) throughout the study and for at least 3 months after last dose of daratumumab or 
5 months after the last dose of atezolizumab. In addition, during the study and for 3 months 
after receiving the last dose of daratumumab or 5 months after the last dose of atezolizumab, a 
woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
Note: If the childbearing potential changes after start of the study or the risk of pregnancy changes 
(eg, a woman who is not heterosexually active becomes active) a woman must begin a highly 
effective method of contraception and 1 additional reliable method, as described throughout the 
inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
9.
During the study and for a minimum of approximately 3 months after the last dose of daratumumab 
or 5 months after the last dose of atezolizumab, in addition to the highly effective method of 
contraception, a man

who is sexually active with a woman of childbearing potential must agree to use a barrier 
method of contraception (eg, condom with spermicidal foam/gel/film/cream/suppository)

who is sexually active with a woman who is pregnant must use a condom

must agree not to donate sperm.
10. Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
11. 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.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
Criterion modified per Amendment 5.
1.1 Criterion modified per Amendment 6.
1.2 Received any of the following prescribed medications or therapies in the past: 

Randomized Phase: Anti-CD38 therapy (including daratumumab), CD137 agonists, and 
immune checkpoint inhibitors including but not limited to anti-CTLA-4, anti-PD-1, and 
anti-PD-L1 therapies
2.
Criterion modified per Amendment 2.
2.1Received any of the following prescribed medications or therapies within the specified period:

Approved anti-cancer therapy, including chemotherapy, within 3 weeks prior to first 
administration of study drug. 
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
Other investigational agent or participation in another clinical study with therapeutic intent 
within 28 days or 5 half-lives of the investigational agent (whichever is longer) prior to first 
administration of study drug.

Whole brain radiation within 28 days or other radiotherapy within 14 days prior to first 
administration of study drug.

Use of systemic corticosteroids >10 mg/day prednisone equivalent within 14 days prior to first 
administration of study drug. Acute use of >10 mg/day prednisone equivalent may be allowed 
with Sponsor approval. Note: Steroids that are topical, inhaled, nasal (spray), or ophthalmic 
solution are permitted.
3.
Criterion modified per Amendment 2.
3.1Has any of the following conditions:

Active or untreated CNS metastases as determined by computed tomography (CT) or magnetic 
resonance imaging (MRI) evaluation. Subjects with a history of CNS metastases must have 
completed treatment for the CNS metastases (see Exclusion Criterion 2.1 for guidelines 
regarding timing of radiation therapy), be neurologically stable, and must have discontinued
corticosteroids for the treatment of the CNS metastases prior to first administration of study 
drug.

Leptomeningeal disease or spinal cord compression not definitively treated with surgery or 
radiation, or requiring corticosteroid treatment at first administration of study drug.

Uncontrolled tumor-related pain:

Symptomatic lesions amenable to palliative radiotherapy (eg, bone metastases, or 
metastases causing nerve impingement) should be treated prior to Screening.

Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (eg, epidural metastasis that is not currently associated with 
spinal cord compression) should be considered for loco-regional therapy, if appropriate, 
prior to Screening.
4.
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures 
(once monthly or more frequently); indwelling catheters are allowed.
5.
Criterion modified per Amendment 2.
5.1 Malignancies other than NSCLC within 2 years prior to first administration of study drug, with 
the exception of carcinoma in situ of the cervix or breast, basal or squamous-cell skin cancer, or 
other malignancy that in the opinion of the investigator and Sponsor is considered cured with a 
minimal risk of recurrence within 5 years.
6.
Criterion modified per Amendment 2.
6.1 Criterion modified per Amendment 5.
6.2 Criterion modified per Amendment 6.
6.3 History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel 
disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, 
Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.

Subjects with a history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone may be eligible (with Sponsor approval).

Subjects with controlled Type I diabetes mellitus on a stable dose of insulin regimen are 
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eligible.

Subjects with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic 
manifestations only (eg, subjects with psoriatic arthritis would be excluded) are permitted 
provided that they meet the following conditions: 

Rash must cover less than 10% of body surface area (BSA)

Disease is well controlled at baseline and only requiring low potency topical steroids

No acute exacerbations of underlying condition within the last 12 months (not requiring 
PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, high potency or oral steroids)
7.
Criterion modified per Amendment 2.
7.1 History of pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced 
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan; 
history of radiation pneumonitis in the radiation field (fibrosis) is permitted.
8.
Criterion modified per Amendment 2.
8.1 Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 
1 second (FEV1) <50% of predicted normal. Note that spirometry is required during the screening 
period for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of 
predicted normal.
9.
Known to be seropositive for human immunodeficiency virus (HIV).
10. Criterion modified per Amendment 2.
10.1 Active hepatitis B, defined by a positive test for hepatitis B surface antigen (HBsAg) or prior 
history of hepatitis B, defined by presence of antibodies to hepatitis B core antigen [anti-HBc], 
regardless of hepatitis B surface antibody [anti-HBs] status; active hepatitis C or prior history of 
hepatitis C (anti-HCV positive), except in the setting of a sustained virologic response (SVR), 
defined as aviremia 12 weeks after completion of antiviral therapy.

If hepatitis C virus (HCV) antibodies are detected, an HCV RNA test for viral load by 
polymerase chain reaction (PCR) should be performed at least 12 weeks after completion of 
antiviral therapy to rule out active infection.
11. Severe infections (including active tuberculosis) within 1 week prior to first administration of study 
drug, including but not limited to hospitalization for complications of infection, bacteremia, or 
severe pneumonia.
12. Criterion modified per Amendment 2.
12.1 Clinically significant cardiac disease, including:

Myocardial infarction within 6 months before first administration of study drug, or unstable or 
uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, 
congestive heart failure, New York Heart Association Class III-IV)

Uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities.

Screening 12-lead ECG showing a baseline corrected QT interval (QTc) >470 msec.
13. Criterion deleted per Amendment 2.
14. Prior allogeneic bone marrow transplantation or solid organ transplant.
15. Criterion modified per Amendment 2.
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15.1 Administration of a live, attenuated vaccine within 4 weeks before first administration of study 
drug.
16. Women who are pregnant, lactating, or intending to become pregnant during the study or within at 
least 3 months after last dose of daratumumab or 5 months after the last dose of atezolizumab; men 
who intend to father a child during the study or within at least 3 months after the last dose of 
daratumumab or 5 months after the last dose of atezolizumab.
17. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized 
antibodies or fusion proteins.
18. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or 
any component of the daratumumab or atezolizumab formulation.
19. Any other concurrent medical or psychiatric condition, diseases, metabolic dysfunction, physical 
examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or 
condition that contraindicates the use of an investigational drug or that may affect the interpretation 
of the results or render the subject at high risk from treatment complications.
20. Major surgery (eg, requiring general anesthesia) within 2 weeks before Screening, not fully 
recovered from surgery, or surgery planned during the time the subject is expected to participate in 
the study or within 2 weeks after the last dose of study treatment. Note: Subjects with planned 
surgical procedures to be conducted under local anesthesia may participate after consultation with 
the Sponsor. Kyphoplasty or vertebroplasty are not considered major surgery.
4.3.
Inclusion and Exclusion Criteria for Crossover 
Crossover will no longer be performed in this study; therefore, this section is no longer 
applicable.
Subject Population 
The inclusion and exclusion criteria listed in this section apply only to those subjects crossing 
over from Arm A to Arm B. Subjects who satisfy all of the criteria below are eligible to 
crossover from Arm A to Arm B at the investigator’s discretion. If there is a question about the 
inclusion or exclusion criteria below, then the investigator must consult with the appropriate 
Sponsor representative and resolve any issues before enrolling a subject in the crossover arm. 
Note that subjects must complete the End of Treatment Visit prior to screening for crossover.
Investigators should ensure that all crossover eligibility criteria have been met at the time of 
screening for crossover. If a subject's status changes, then the subject should be excluded from 
crossing over. Subjects who fail to meet the inclusion and exclusion criteria for crossover may be 
rescreened if their condition changes. Rescreening must be discussed with and approved by the 
Sponsor on a case-by-case basis.
4.3.1.
Inclusion Criteria for Crossover 
In order to be eligible to cross over from Arm A to Arm B, subjects must meet the following
criteria:
1X. Subjects must have been randomized to Arm A of the study and had radiographic disease progression 
according to RECIST 1.1 (disease progression confirmed by principal investigator and reported to the 
Sponsor).
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2X. Subjects must have ECOG performance status of 0 or 1.
3X. Subjects must have a mandatory biopsy at the time of disease progression according to RECIST 1.1 
prior to crossing over. If not clinically feasible, discussion with Sponsor is required. 
4X. The first dose of atezolizumab in the crossover arm should be within 42 days of last dose but no less 
than 21 days from the last dose prior to crossing over.
5X. The following laboratory results obtained within 28 days prior to first administration of study drug
after crossing over:

ANC >1.5 × 109/L (without growth factor support 1 week before first administration of study 
drug after crossing over)

Platelets >100 × 109/L

Hemoglobin >9 g/dL 

Transfusion is acceptable to meet the hemoglobin and platelet criteria if stable for 1 week 
prior to administration of study drug

AST, ALT, and alkaline phosphatase: 

2.5 ULN, if no liver metastases 

5 ULN with documented liver metastases

5 ULN alkaline phosphatase (not AST or ALT) with documented bone metastases

Total bilirubin ≤2.0 x ULN, except in subjects with congenital bilirubinemia, such as Gilbert 
syndrome (direct bilirubin ≤2.0 x ULN)
6X. Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for subject participating in clinical studies.
Before crossing over, a woman must be either:
c.
Not of childbearing potential defined as: 

postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the 
postmenopausal range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy, however in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient.

permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal 
occlusion/ligation procedures, and bilateral oophorectomy.
d.
Of childbearing potential and

practicing 2 methods of reliable birth control simultaneously: 1 highly effective method of 
contraception (failure rate of <1% per year when used consistently and correctly) and 1 
additional effective method.
Examples of highly effective contraceptives include:
- user-independent methods:
implantable progestogen-only hormone contraception associated with inhibition of 
ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); 
vasectomized partner; sexual abstinence (sexual abstinence is considered a highly 
effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study drug. The reliability of sexual abstinence 
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needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the subject.)
- user-dependent methods:
combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only 
hormone contraception associated with inhibition of ovulation: oral and injectable
Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
subjects participating in clinical studies. Hormonal contraception may be susceptible to 
interaction with the study drug, which may reduce the efficacy of the contraceptive method.
Examples of additional effective contraceptive methods include:
-
male latex or synthetic condom, diaphragm, or cervical cap

agrees to remain on the 2 contraception methods (1 highly effective and 1 additional reliable 
method) throughout the study and for at least 3 months after last dose of daratumumab or 
5 months after the last dose of atezolizumab. In addition, during the study and for 3 months 
after receiving the last dose of daratumumab or 5 months after the last dose of atezolizumab, a 
woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
Note: If the childbearing potential changes after start of the study or the risk of pregnancy changes (eg, a 
woman who is not heterosexually active becomes active) a woman must begin a highly effective method 
of contraception and 1 additional reliable method, as described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
7X. During the study and for a minimum of approximately 3 months after the last dose of daratumumab 
or 5 months after the last dose of atezolizumab, in addition to the highly effective method of 
contraception, a man

who is sexually active with a woman of childbearing potential must agree to use a barrier 
method of contraception (eg, condom with spermicidal foam/gel/film/cream/suppository)

who is sexually active with a woman who is pregnant must use a condom

must agree not to donate sperm.
8X. Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
4.3.2.
Exclusion Criteria for Crossover
Subjects who meet any of the following criteria prior to crossing over to Arm B will be excluded 
from participating in the study: 
1X. Received any subsequent anti-cancer therapies from the time between the last dose of atezolizumab 
prior to the first administration of study drug after crossing over
2X. Whole brain radiation within 28 days or other radiotherapy within 14 days prior to first 
administration of study drug after crossing over.
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3X. Has any of the following conditions:

Active or untreated CNS metastases as determined by computed tomography (CT) or magnetic 
resonance imaging (MRI). 

Leptomeningeal disease or spinal cord compression not definitively treated with surgery or 
radiation, or requiring corticosteroid treatment at first administration of study drug after 
crossing over.

Uncontrolled tumor-related pain
Prior to crossing over, symptomatic lesions amenable to palliative radiotherapy (eg, bone metastases 
or metastases causing nerve impingement) should be treated, and treatment must be completed at 
least 14 days prior to the first administration of crossover study drug. Imaging assessments obtained 
after completion of radiotherapy will be used to determine crossover eligibility and must show 
evidence of measureable disease according to RECIST 1.1.
4X. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures 
(once monthly or more frequently); indwelling catheters are allowed.
5X. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second 
(FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of 
having COPD and subjects must be excluded if FEV1 <50% of predicted normal.
6X. Severe infections (including active tuberculosis) within 1 week prior to first administration of study 
drug after crossing over, including but not limited to hospitalization for complications of infection, 
bacteremia, or severe pneumonia
7X. Clinically significant cardiac disease, including:

Unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable 
angina, congestive heart failure, New York Heart Association Class III-IV)

Uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities.

QTc >470 msec.
8X. Women who are pregnant, lactating, or intending to become pregnant during the study or within at 
least 3 months after last dose of daratumumab or 5 months after the last dose of atezolizumab; men 
who intend to father a child during the study or within at least 3 months after the last dose of 
daratumumab or 5 months after the last dose of atezolizumab.
9X. Any other concurrent medical or psychiatric condition, diseases, metabolic dysfunction, physical 
examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or 
condition that contraindicates the use of an investigational drug or that may affect the interpretation 
of the results or render the subject at high risk from treatment complications.
4.4.
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:
1.
Refer to Section 8 Concomitant Therapy for details regarding prohibited and restricted therapy 
during the study.
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2.
Agree to follow the contraceptive requirements as noted in the inclusion criteria.
3.
Express understanding of the requirement for on-treatment biopsies during the study (ie, 
Cycle 3, after progression, crossover)
5.
TREATMENT ALLOCATION AND BLINDING
Procedures for Randomization and Stratification
Following the safety run-in, central randomization will be implemented in this study. Subjects 
were stratified by PD-L1 status (TC0 and IC0 vs other), histology (squamous vs. non-squamous), 
and number of prior therapies received (1 vs. >1) and assigned randomly 1:1 using permuted 
blocks to 1 of 2 treatment groups based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the Sponsor. Pursuant to DMC 
recommendations after the first interim analysis of study data, enrollment was closed to subjects 
with PD-L1 score of TC0 (Section 4) as of 16 Jan 2018. Therefore, subjects will be stratified by 
histology (squamous vs. non-squamous), and number of prior therapies received (1 vs. >1).
The interactive web response system (IWRS) will assign a unique treatment code, which will 
dictate the treatment assignment and matching study drug kit for the subject. The requestor must 
use his or her own user identification and personal identification number when contacting the 
IWRS and will then give the relevant subject details to uniquely identify the subject.
As of 25 May 2018, this study was closed to further enrollment.
6.
DOSAGE AND ADMINISTRATION
Daratumumab will no longer be administered.
6.1.
Daratumumab
Daratumumab will be administered to subjects as described in the Time and Events Schedule 
(Table 1). Daratumumab should always be administered prior to atezolizumab (Safety Run-in 
and Arm B). Subjects will continue to receive daratumumab until disease progression, 
unacceptable toxicity, or other reasons as listed in Section 10.2.
6.1.1.
Daratumumab IV Preparation
Infusion solution will be prepared as a 1,000-mL (first dose) or 500-mL (second and subsequent 
doses) dilution of daratumumab in sterile, pyrogen-free 0.9% NaCl. Preparation of infusion bags 
should be done on the day of the planned infusion. Daratumumab must be administered as an 
IV infusion given through a well-functioning IV catheter by using an infusion pump. The study 
drug must be filtered by using an inline filter (0.2 μM) during the infusion. Manuals with 
detailed descriptions for preparation and administration of daratumumab will be supplied to each 
pharmacy and site.
6.1.2.
Daratumumab Treatment Schedule and Administration
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Daratumumab will be administered on Days 1, 8, and 15, for the first 3 cycles, then on Day 1 of 
each 21-day cycle thereafter until one or more treatment discontinuation criteria are met 
(eg, disease progression or unacceptable toxicity).
Daratumumab will be administered IV at 16 mg/kg. Each subject’s dose will be calculated based 
on the subject’s weight at Cycle 1 Day 1 rounded to the nearest kilogram. The dose of 
daratumumab will remain constant throughout the study, unless the subject’s weight changes 
more than 10% from Cycle 1 Day 1. All infusions will be planned as outpatient visits. Subjects 
will receive preinfusion medications and postinfusion medications as outlined in Section 6.1.3.
The dilution volumes, initial infusion rates, and increment of infusion rates for the first, second, 
and subsequent doses in the absence of an infusion-related reaction >Grade 1 are provided in 
Table 7. The first infusion, with a volume of 1,000 mL, takes approximately 8 hours; the second 
and subsequent infusions, with volumes of 500 mL, take approximately 4 hours. The maximum 
infusion rate for all infusions is 200 mL/hour. The Sponsor may modify the infusion rates or the 
preinfusion medications prospectively based upon the information collected to date from this and 
other studies. 
Table 7:
Daratumumab Infusion Rates
Dilution 
Volume
Initial Infusion 
Rate (first hour)
Incremental Increases 
in Infusion Ratea
Maximum 
Infusion Rate
First infusion
1000 mL
50 mL/hour
50 mL/hour 
every hour
200 mL/hour
Second infusionb
500 mL
50 mL/hour
50 mL/hour 
every hour
200 mL/hour
Subsequent infusionsc
500 mL
100 mL/hour
50 mL/hour 
every hour
200. mL/hour
a.
Consider titration of the infusion rate only in the absence of infusion reactions.
b.
Dilution volume of 500 mL should be used only if there were no Grade 1 (mild) or greater infusion reactions during the 
first 3 hours of the first infusion. Otherwise, continue to use a dilution volume of 1000 mL.
c.
Use a modified initial rate for subsequent infusions (ie, third infusion onwards) only if there were no Grade 1 (mild) or 
greater infusion reactions during a final infusion rate of ≥100 mL/hr in the first two infusions. Otherwise, continue to use 
instructions for the second infusion.
As noted in Table 1 (Time and Events Schedule), vital signs for subjects in the Safety Run-in and 
Arm B cohorts should be monitored frequently on Cycle 1 Day 1 before, during, and after the 
first infusion of daratumumab. For all subsequent infusions, vital signs should be measured 
before the start of infusion and at the end of the infusion. If the subject experiences any 
significant medical event, then the investigator should assess whether the subject should stay 
overnight for observation. If the subject has not experienced a significant medical event but is 
hospitalized overnight only for observation, then the hospitalization should not be reported as a 
serious adverse event.
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6.1.3.
Guidelines for Prevention of Daratumumab Infusion Reactions
6.1.3.1.
Predose Medications
Predose medications for subjects receiving daratumumab will be administered on dosing days 
(see the Time and Events Schedule Table 1). Subjects will receive the medications 
approximately 1 hour prior to daratumumab administration; premedication up to 3 hours before 
the dose of daratumumab is permitted.
If necessary, all oral (PO) preinfusion medications may be administered outside of the clinic on 
the day of the infusion, provided they are taken within 3 hours before the infusion.
In addition to the medications specified below, a leukotriene inhibitor (optional; montelukast 
10 mg PO or equivalent) can be administered up to 24 hours before infusion as per investigator 
discretion. Substitutions for methylprednisolone are allowed, please refer to Attachment 2.
Predose Medications

Paracetamol (acetaminophen) 650-1000 mg IV or orally (PO).

An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent). Avoid the use of IV 
promethazine (see Attachment 1 for a list of antihistamines that may be used). 

Methylprednisolone 100 mg IV or PO or equivalent. Following the second infusion of 
daratumumab, the dose of corticosteroid may be reduced (IV methylprednisolone 60 mg or 
equivalent) (Table 8).
Table 8:
Pre- and Postinfusion Methylprednisolone Doses (or equivalent) for Dara-IV
Cycle/Day
Methylprednisolone
Predose 
Postdose
1st and 2nd day following 
Dara-IV infusion day
C1D1
100 mg
20 mg
C1D8
100 mg
20 mg
C1D15 +
60 mg
20 mg
6.1.3.2.
Postadministration Medications
Postadministration medication should be given to reduce the risk of delayed infusion reactions in
all subjects. For subjects with a history of COPD, consider administering medications such as 
short- and long-acting bronchodilators and inhaled corticosteroids. Following the first 
4 infusions, if the subject experiences no major infusion reactions, these additional inhaled 
medications may be discontinued. Refer to Section 6.3 for additional details on the management 
of infusion reactions.
Postinfusion Medications

Oral corticosteroid (20 mg methylprednisolone or equivalent) on the first and second day
following the day of all infusions (Table 8).
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6.1.4.
Dose Delay and Modification
Dose modification of daratumumab is not permitted. Dose delay is the primary method for 
managing daratumumab-related toxicities.
6.1.5.
Toxicity Management
Cycle Delays
On the first day of each new treatment cycle and before each daratumumab dose, the subject will 
be evaluated by the treating physician for possible toxicities that may have occurred after the 
previous dose(s). Toxicities are to be assessed according to NCI-CTCAE, Version 4.03. Dose 
delays will be made based on the toxicity experienced during the previous infusion or newly 
encountered on Day 1 of a new cycle. 
The study treatment must be held if any of the following criteria below are met, to allow for 
recovery from toxicity, regardless of relationship to daratumumab.
The criteria for a dose delay are:

Grade 4 hematologic toxicity, except for Grade 4 lymphopenia

Grade 3 or higher thrombocytopenia with bleeding

Febrile neutropenia

Neutropenia with infection, of any grade

For all other adverse events, daratumumab should be withheld for Grade 3 or higher 
toxicities with the following exceptions: 

Grade 3 nausea that responds to antiemetic treatment within 7 days

Grade 3 vomiting that responds to antiemetic treatment within 7 days

Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days

Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab

Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab
Administration of daratumumab may be restarted upon recovery from toxicity to Grade 1 or 
baseline, with the exception of Grade 2 laryngeal edema, Grade 2 bronchospasm or febrile 
neutropenia, which must be fully recovered. If daratumumab administration does not commence 
within the prespecified window (Table 9) 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. A delay in daratumumab dosing will result in a subsequent 
delay in atezolizumab dosing.
Table 9:
Daratumumab-related Toxicity Management
Cycles
Frequency
Dose Held
Dosing Re-start
Cycle 1, 2, 3
Weekly (q1wk)
>3 days
Next planned weekly dosing date
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Cycle 4 and beyond
Every 3 weeks (q3wks)
>7 days
Next planned every 3-week dosing date
If 2 consecutive planned doses of daratumumab are missed due to any adverse event, then 
consultation with the Sponsor is required before dosing may be continued. 
For subjects whose dose is held for more than 28 days for any drug related adverse event or who 
miss ≥3 consecutive planned doses of daratumumab due to any adverse event, then the treatment 
should be permanently discontinued.
If a dose is delayed beyond 5 days in Cycles 2 to 20, then the dates of all subsequent doses must 
be adjusted accordingly. If a dose delay occurs, then pharmacokinetic and biomarker assessments 
should be performed on the actual daratumumab administration day, not on the originally 
scheduled administration day.
Herpes Zoster Virus Reactivation
In monotherapy studies, herpes zoster was reported in 3% of patients. Accordingly, prophylaxis 
for herpes zoster virus reactivation is recommended (Section 8.1).
6.2.
Atezolizumab
Beginning with the implementation of Amendment 7, subjects who are deriving clinical benefit 
from atezolizumab monotherapy, but do not have access to commercial atezolizumab, may 
continue treatment under the supervision of the treating investigator in accordance with local 
regulatory approvals and standard of care guidelines.50,51 Prior to the administration of 
atezolizumab, investigators will be required to submit documentation of subject response and 
clinical status to the Sponsor, either electronically or via facsimile.
For subjects in Arm A, atezolizumab will be administered at 1,200 mg IV on Day 1 of every 
21-day cycle. For subjects in the Safety Run-in and Arm B, atezolizumab will be administered 
on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter. Atezolizumab should always 
be administered after daratumumab. A delay in daratumumab dosing will result in a subsequent 
delay in atezolizumab dosing. All study subjects should continue to be treated until one or more 
treatment discontinuation criteria are met (Section 10.2).
Refer to the SIPPM for detailed instructions on drug preparation, storage, and administration.
Dose modifications to atezolizumab are not permitted. Guidelines for treatment interruption or 
discontinuation and the management of specific adverse events are provided below.
Subjects may temporarily suspend study treatment for up to 105 days beyond the last dose if they 
experience an adverse event that requires a dose to be withheld. If atezolizumab is withheld 
because of adverse events for 105 days, then the subject will be discontinued from 
atezolizumab treatment and will be followed for safety and efficacy as specified in Section 9.1.5.
If, in the judgment of the investigator, the subject is likely to derive clinical benefit from 
atezolizumab after a hold of 105 consecutive days that is not adverse event-related, study drug 
may be restarted with the approval of the Sponsor. 
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If a subject must be tapered off steroids used to treat adverse events, atezolizumab may be 
withheld for additional time beyond 105 days from the last dose until steroids are discontinued or 
reduced to prednisone dose (or dose equivalent) 10 mg/day. The acceptable length of 
interruption will depend on agreement between the investigator and the Sponsor.
Dose interruptions for reason(s) other than adverse events, such as surgical procedures, may be 
allowed with Sponsor approval. The acceptable length of interruption will depend on agreement 
between the investigator and the Sponsor.
If atezolizumab administration does not commence within the prespecified dosing window, 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.
6.2.1.
Management of Atezolizumab-Specific Adverse Events
Beginning with the implementation of Amendment 7, toxicities associated or possibly associated 
with atezolizumab treatment, including non-immune mediated adverse events, should be 
managed according to local regulatory approvals and standard of care guidelines.50,51 Additional 
tests, such as autoimmune serology or biopsies, should be used to determine a possible 
immunogenic etiology.
Although most immune-mediated adverse events observed with immunomodulatory agents have 
been mild and self-limiting, such events should be recognized early and treated promptly to 
avoid potential major complications. Discontinuation of atezolizumab may not have an 
immediate therapeutic effect and, in severe cases, immune-mediated toxicities may require acute 
management with topical corticosteroids, systemic corticosteroids, or other immunosuppressive 
agents.
The investigator should consider the benefit-risk balance a given subject may be experiencing 
prior to further administration of atezolizumab. Atezolizumab should be permanently 
discontinued in subjects with life-threatening, immune-mediated adverse events. Specific 
guidelines for immune-mediated events are provided in Attachment 7. 
For all other non-immune mediated adverse events, including infections, atezolizumab should be 
withheld for Grade 3 or higher toxicity with the following exceptions:

Grade 3 nausea that responds to antiemetic treatment within 7 days

Grade 3 vomiting that responds to antiemetic treatment within 7 days

Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days

Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last 
administration of atezolizumab

Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last 
administration of atezolizumab
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Administration of atezolizumab may be restarted upon recovery from toxicity to Grade 1 or 
baseline.
6.2.1.1.
Pulmonary Events
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab. Subjects will be assessed for pulmonary signs and 
symptoms throughout the study and will also have CT scans of the chest performed at every 
tumor assessment.
All pulmonary events should be thoroughly evaluated, as follows, for other commonly reported 
etiologies such as pneumonia/infection, lymphangitic carcinomatosis, pulmonary embolism, 
heart failure, chronic obstructive pulmonary disease, or pulmonary hypertension. For specific 
management guidelines, please see Attachment 7.
6.2.1.2.
Hepatic Events
Immune-mediated hepatitis has been associated with the administration of atezolizumab. Eligible 
subjects must have adequate liver function, as manifested by measurements of total bilirubin and 
hepatic transaminases, and liver function will be monitored throughout study treatment.
While in this study, subjects who present with right upper-quadrant abdominal pain or 
unexplained nausea or vomiting should have liver function tests (LFTs) performed immediately 
and reviewed before administration of the next dose of study drug.
If LFTs increase, concurrent medications, viral hepatitis, and toxic or neoplastic etiologies 
should be considered and addressed, as appropriate.
For specific management guidelines, please see Attachment 7.
6.2.1.3.
Gastrointestinal Events
Immune-mediated colitis has been associated with the administration of atezolizumab.
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies. If the event is of significant duration or magnitude or is associated with signs of 
systemic inflammation or acute phase reactants (eg, increased C-reactive protein [CRP], platelet 
count, or bandemia), the following are recommended:

Perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy with 3 to 
5 specimens for standard paraffin block to check for inflammation and lymphocytic 
infiltrates for confirmation of the diagnosis of colitis.
For specific management guidelines, please see Attachment 7.
6.2.1.4.
Endocrine Events
Thyroid disorders, type 1 diabetes mellitus, adrenal insufficiency, and pituitary disorders have 
been associated with the administration of atezolizumab.
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Subjects with unexplained symptoms such as fatigue, myalgias, impotence, constipation, or 
mental status changes, should be investigated for the presence of thyroid, pituitary, or adrenal 
endocrinopathies. An endocrinologist should be consulted if an endocrinopathy is suspected. 
Thyroid stimulating hormne (TSH), triiodthyronine 3 (T3), and free thyroxine (T4) levels should 
be obtained to determine whether thyroid abnormalities are present. Pituitary hormone levels and 
function tests (eg, TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, 
testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels and ACTH stimulation test) 
and MRI of the brain (with detailed pituitary sections) may help to differentiate primary adrenal 
insufficiency from primary pituitary insufficiency.
For specific management guidelines, please see Attachment 7.
6.2.1.5.
Ocular Events
An ophthalmologist should evaluate visual complaints (eg, uveitis, retinal events). 
For specific management guidelines, please see Attachment 7.
6.2.1.6.
Immune-Related Myocarditis
Immune-related myocarditis has been associated with the administration of atezolizumab. 
Immune-related myocarditis should be suspected in any subject presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope. Immune-related myocarditis 
needs to be distinguished from myocarditis resulting from infection (commonly viral, eg, in a 
subject who reports a recent history of gastrointestinal illness), ischemic events, underlying 
arrhythmias, exacerbation of pre-existing cardiac conditions, or progression of malignancy.
All subjects with possible myocarditis should be evaluated urgently by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines. A cardiologist should be consulted. An endomyocardial 
biopsy may be considered to enable a definitive diagnosis and appropriate treatment, if clinically 
indicated. Subjects with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Attachment 7.
6.2.1.7.
Pancreatic Events
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab. The differential 
diagnosis of acute abdominal pain should include pancreatitis. Appropriate work-up should 
include an evaluation for ductal obstruction, as well as serum amylase and lipase tests.
For specific management guidelines, please see Attachment 7.
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6.2.1.8.
Dermatologic Events
Treatment-emergent rash has been associated with atezolizumab. The majority of cases of rash 
were mild in severity and self-limited, with or without pruritus. A dermatologist should evaluate 
persistent or severe rash or pruritus. A biopsy should be considered unless contraindicated.
For specific management guidelines, please see Attachment 7.
6.2.1.9.
Neurologic Disorders
Myasthenia gravis, Guillain-Barré syndrome, and meningoencephalitis have been observed with 
single agent atezolizumab. Subjects may present with signs and symptoms of sensory or motor 
neuropathy. Diagnostic work-up is essential for an accurate characterization to differentiate 
between alternate etiologies.
For specific management guidelines, please see Attachment 7.
6.2.1.10.
Immune-Related Meningoencephalitis
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab. Immune-related meningoencephalitis should be suspected in any subject
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness. Encephalopathy from metabolic or electrolyte imbalances
needs to be distinguished from potential meningoencephalitis resulting from infection (bacterial, 
viral, or fungal) or progression of malignancy, or secondary to a paraneoplastic process. All 
subjects being considered for meningoencephalitis should be evaluated urgently with a CT scan 
and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema. If deemed safe 
by the treating physician, a lumbar puncture should be performed and a neurologist should be 
consulted. For specific management guidelines, please see Attachment 7.
6.2.1.11.
Immune-related Nephritis
Immune-related nephritis is an identified risk associated with the administration of atezolizumab. 
Immune-related nephritis is a relatively rare complication of checkpoint inhibitor therapy with 
the most common reported underlying pathology being acute tubulo-interstitial nephritis (ATIN). 
The most common presentation is asymptomatic increase in creatinine levels. In the absence of 
alternative etiologies (eg, prerenal and postrenal causes, and concomitant medications), 
immune-related nephritis is defined as renal dysfunction requiring steroids treatment and/or 
confirmed by biopsy. For specific management guidelines, please see Attachment 7.
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6.2.1.12.
Systemic Immune Activation
Systemic immune activation is a rare condition characterized by an excessive immune response. 
Given the mechanism of action of atezolizumab, systemic immune activation is considered a 
potential risk when given in combination with other immunomodulating agents. Systemic 
immune activation should be included in the differential diagnosis for subjects who, in the 
absence of an alternate etiology, develop a sepsis-like syndrome after administration of 
atezolizumab, and the initial evaluation should include the following:
Complete blood count (CBC) with peripheral smear
Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, and D-dimer
Ferritin
Triglycerides
AST, ALT, total bilirubin
Lactate dehydrogenase (LDH)
Complete neurologic and abdominal examination (assess for hepatosplenomegaly)
Serum sample for cytokine analysis
If systemic immune activation is still suspected after the initial evaluation, atezolizumab should 
be withheld with the provision of appropriate supportive medical care, including corticosteroid 
therapy. The Sponsor should be contacted for additional recommendations.
For specific management guidelines, please see Attachment 7.
6.3.
Management of Infusion-related Reactions
6.3.1.
Infusion-related Reactions
Subjects should be observed carefully during infusions. Trained study staff at the clinic should 
be prepared to intervene in case of an IRR, and resources necessary for resuscitation must be 
available. Attention to staffing should be considered when multiple subjects will be dosed at the 
same time.
For infusion reactions of any grade/severity, immediately interrupt the daratumumab infusion 
and manage symptoms. Management of infusion reactions may require reduction in the rate of 
infusion, or discontinuation of daratumumab (see Table 10).
Table 10:
Management Guidelines for Daratumumab Infusion-related Reactions
Severity
Management
Grade 1-2 
(mild to 
moderate)
Once reaction symptoms resolve, resume the infusion at no more than half the rate at 
which the reaction occurred. If the subject does not experience any further reaction 
symptoms, then infusion rate escalation may resume at increments and intervals as
clinically appropriate up to the maximum rate of 200 mL/hr (see Table 7).
Grade 3 
(severe)
Once reaction symptoms resolve, consider restarting the infusion at no more than half 
the rate at which the reaction occurred. If the subject does not experience additional 
symptoms, then resume infusion rate escalation at increments and intervals as outlined 
in Table 7. Repeat the procedure above in the event of recurrence of Grade 3 
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6.3.2.
Atezolizumab
No premedication is indicated for the administration of atezolizumab in Cycle 1. Subjects who 
experience an IRR with Cycle 1 of atezolizumab may receive premedication with antihistamines 
or antipyretics/analgesics (eg, acetaminophen) for subsequent infusions. Metamizole (dipyrone) 
is prohibited in treating atezolizumab associated IRRs, due to its potential for causing 
agranulocytosis. Table 11 provides management guidelines for atezolizumab IRRs in Cycle 1.
For subsequent cycles, infusion-related reactions should be managed according to institutional 
guidelines.
Table 11:
Management Guidelines for Atezolizumab Infusion-related Reactions
Severity
Management
Grade 1 

Reduce infusion rate to half the rate being given at the time of event onset.

After the event has resolved, the investigator should wait for 30 minutes while 
delivering the infusion at the reduced rate.

If tolerated, the infusion rate may then be increased to the original rate.
Grade 2

Interrupt atezolizumab infusion.

Administer aggressive symptomatic treatment (eg, oral or IV antihistamine, anti-
pyretic, glucocorticoids, epinephrine, bronchodilators, oxygen).

Restart only after the symptoms have adequately resolved to baseline grade.

The infusion rate at restart should be half of the infusion rate that was in progress at the 
time of the onset of the IRR.

At next cycle, administer oral premedication with antihistamine and anti-pyretic and 
monitor closely for IRR. 
Grades 34

Stop infusion.

Proper medical management which may include oral or IV antihistamine, anti-pyretic, 
glucocorticoids, epinephrine, bronchodilators, and oxygen

Discontinue atezolizumab.a

Contact the Sponsor if atezolizumab is discontinued. 
IRR infusion-related reaction; IV intravenous.
a. Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Study Responsible Physician.
7.
TREATMENT COMPLIANCE
Study drugs (daratumumab and atezolizumab) will be administered by qualified site staff, and 
the details of each administration will be recorded in the case report form (CRF). Additional 
details are provided in the SIPPM.
Beginning with the implementation of Amendment 7, subjects who are deriving clinical benefit 
from atezolizumab monotherapy, but do not have access to commercial atezolizumab, may 
continue treatment under the supervision of treating investigators in accordance with local 
regulatory approvals and standard of care guidelines.50,51 Study drug accountability must 
continue to be monitored and documented by the study site.
symptoms. Permanently discontinue daratumumab if the subject experiences a ≥Grade 
3 infusion-related symptom at the subsequent infusion.
Grade 4 
(life threatening)
Permanently discontinue daratumumab treatment.
IRRinfusion-related reaction; IVintravenous.
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8.
PRESTUDY AND 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 8.2. The 
Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in which 
prohibited therapies are administered.
All prior treatments for malignancies, including those since diagnosis, must be recorded at 
Screening.
Routine systemic use of the following concomitant medications will be collected in the CRF and 
recorded in the source documents beginning with signing of the ICF to PD or until the start of 
subsequent anticancer treatment, if earlier: growth factors, transfusions, anti-infectives 
(antibacterials, antivirals, and antimycotics), corticosteroids, anti-arrhythmics and other cardiac 
supportive therapy, anti-epileptics, centrally acting psychiatric medication, anti-histamines and 
other medications targeting postinfusion systemic reactions, bisphosphonates, and any anticancer 
therapy (including radiation).
The use of concomitant medications used to treat adverse events or infusion-related reactions 
will be collected in the CRF and recorded in the source documents beginning with the signing of 
the ICF until PD.
Prestudy therapies administered up to 30 days before first dose of study drug must be recorded at 
Screening. Concomitant therapies must be recorded throughout the study beginning with start of 
the first dose of study drug until the end of treatment assessment. Concomitant therapies should 
also be recorded beyond 30 days after the last dose of study drug only in conjunction with
serious adverse events that meet the criteria outlined in Section 12.3.2, Serious Adverse Events.
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8.1.
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:

Antivirals (antiviral prophylaxis should be considered for the prevention of herpes zoster 
virus reactivation)

Granulocyte colony stimulating factors and transfusion of platelets 

Oral contraceptives

Hormone-replacement therapy

Palliative radiotherapy (eg, treatment of known bony metastases) provided it does not 
interfere with the assessment of tumor target lesions (eg, the lesion being irradiated is not 
the only site of disease, as that would render the subject not evaluable for response by tumor 
assessments according to RECIST 1.1). It is not a requirement to withhold atezolizumab 
during palliative radiotherapy; discuss with the Sponsor

Mineralocorticoids (eg, fludrocortisone) 

Corticosteroids are allowed for the treatment of immune-related adverse events, infusion-
related reactions, and as pre-infusion or pre-injection medication for daratumumab. Acute 
use of systemic corticosteroids >10 mg/day prednisone equivalent, or acute use of higher 
equivalent doses may be allowed with Sponsor approval.
Other symptoms may be managed according to institutional guidelines provided prohibited 
therapies are not administered (see Section 8.2).
Premedication with antihistamines may be administered for any atezolizumab infusions 
after Cycle 1.
In general, investigators should manage subject
care with supportive therapies as 
clinically indicated per local standards.  Subjects who experience infusion-associated symptoms 
may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, or famotidine 
or another H2 receptor antagonist per standard practice (for sites outside the United States, 
equivalent medications may be substituted per local practice). Serious infusion-associated events 
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen 
saturation, or respiratory distress should be managed with supportive therapies as 
clinically indicated (eg, supplemental oxygen and 2-adrenergic agonists). 
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8.2.
Prohibited Therapies
Use of the treatments listed below is prohibited during the study:

Other agents that target CD38, PD-1 or its ligand, PD-L1.

Any concomitant therapy intended for the treatment of cancer, including NSCLC, whether 
health authorityapproved or experimental, is prohibited for various time periods prior to 
starting study treatment, depending on the anti-cancer agent (see Section 4.2), and during 
study treatment until disease progression is documented and subject has discontinued study 
treatment. This includes but is not limited to chemotherapy, hormonal therapy, 
immunotherapy, radiotherapy, investigational agents, or herbal therapy (unless otherwise 
noted).

Denosumab; subjects who are receiving denosumab prior to enrollment must be willing and 
eligible to receive a bisphosphonate instead while in the study. 

Dipyrone (metamizole)

Any live, attenuated vaccine (eg, FluMist) within 4 weeks prior to administration of study 
drug or during treatment or within 5 months following the last atezolizumab dose.
The Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule (Table 1) summarize the frequency and timing of assessments
applicable to this study.
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. Repeat or unscheduled samples may be taken for 
safety reasons or for technical issues with the samples.
As of Amendment 6, subject screening and enrollment has been terminated, combination 
treatment will be discontinued, and subjects will be given the option to receive atezolizumab 
monotherapy, following the treatment procedures for Arm A (Section 6.2). Limited data 
collection will subsequently be performed, see Section 9.2.
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9.1.2.
Optional Prescreening Phase
The optional Prescreening Phase, which will include a separate informed consent, will allow 
for the collection of archival formalin-fixed paraffin-embedded (FFPE) tumor tissue to be 
submitted for PD-L1 determination using the SP142 assay, before the formal screening process 
for the full study. Given the inter-assay differences in PD-L1 determination, these results can 
help determine the likelihood of eligibility for study participation, prior to signing of informed 
consent for study participation (Hirsch 2016)21. Unless the archival tumor sample used in the 
Prescreening Phase was obtained after completion of the most recent line of therapy with no 
intervening therapies and is less than 1 year old, the subject will be required to have a fresh 
biopsy performed during the Screening Phase (Section 9.6.1 Tumor Tissue Samples), which will 
be used to formally determine study eligibility based on tumor cell PD-L1 status. Archival 
PD-L1 staining may not correlate with PD-L1 staining using a fresh tumor specimen.
9.1.3.
Screening Phase
The Screening Phase begins with the signing of the ICF, which must be obtained before any 
study-specific procedures are performed (except for tumor imaging assessments that were 
performed as part of the subject’s routine standard of care). The screening for PD-L1 status may
occur within 56 days prior to first administration of study drug. Tumor samples must meet the 
same requirements as outlined in Section 9.6.1. All other screening procedures must be 
performed only after PD-L1 results are available, and within 28 days before the first 
administration of study drug. For subjects who do not meet Inclusion Criterion 5, no further 
Screening procedures should be performed. The Screening Phase may be extended by a 
maximum of 14 days in situations in which screening procedures require repetition or PD-L1 
results are not available, after consultation with the Sponsor. However, screening procedures, 
including standard of care tumor imaging assessments, must be performed within 28 days of first 
administration of study drug. During the Screening Phase, eligibility criteria will be reviewed 
and a complete clinical evaluation will be performed as specified in the Time and Events 
Schedule (Table 1). Subjects were initially stratified based on PD-L1 status (IC0 and TC0 vs. 
others), based on central laboratory assessment (using the Ventana Medical Systems, Inc. PD-L1 
[SP142] assay), and histology (squamous vs. non-squamous), as well as number of previous lines 
of therapy (1 or >1), see Section 5 for the current stratification procedures. Screening procedures 
will be performed within 28 days before enrollment. Subjects may be retested for laboratory 
values that do not meet eligibility criteria within the 28-day Screening Phase.
If a subject does not meet all inclusion and exclusion criteria (is a screen failure) but at some 
point in the future is expected to meet the subject eligibility criteria, the subject may be 
rescreened on 1 occasion. Subjects who are rescreened will be assigned a new subject number, 
undergo the informed consent process, and then restart a new Screening Phase.
9.1.4.
Open-Label Treatment Phase
Details of the procedures performed during the Treatment Phase are outlined in the Time and 
Events Schedule (Table 1). Subjects in the randomized phase should start study treatment within
72 hours after randomization. A window of ±1 day for Cycles 1 to 3 for subjects receiving 
daratumumab and ±3 days for all other drug administration visits is allowed for drug 
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administration visits to the clinic. Clinical evaluations and laboratory studies may be repeated 
more frequently than outlined in the Time and Events Schedule, if clinically indicated. If 
treatment is discontinued, the subject will complete the End-of-Treatment assessment, and enter 
the Follow-up Phase.
End of Treatment
Unless a subject withdraws consent for study participation or is lost to follow up, an 
End-of-Treatment Visit is to occur at 30 days after the last dose of study treatment. A delay of 
this visit to up to 7 days is permitted. 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 Grade 2 or higher adverse events and concomitant medications used to treat 
Grade 2 or higher adverse events, any immune-related AE, or any infusion-related reactions until 
disease progression. Additional information on reporting of AEs is presented in Section 12.
9.1.5.
Follow-Up Phase
The posttreatment Follow-up Phase will begin once the subject completes the End-of-Treatment 
evaluation. Reasons for discontinuation of study treatment are listed in Section 10.2. Subjects 
who discontinue treatment before disease progression must continue to have disease evaluations 
as described in Table 1 and Section 9.4 (every 6 weeks [±1 week] for the first 12 months of after 
the start of treatment and every 9 weeks [±1 week] thereafter regardless of treatment delays).
After disease progression is confirmed, follow-up for survival status and subsequent anti-cancer 
therapy will be obtained at least every 12 weeks after the last dose of study drug, until the subject 
has died, is lost to follow-up, or has withdrawn consent. If the information on survival status 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 on the CRF.
The end of the study is anticipated to be 24 months after the last subject has been enrolled 
(last patient in) or when the last subject has the last assessment in this study (eg, last survival 
follow-up for the last subject), whichever occurs first.
Investigators may recontact the subject to obtain long-term follow-up information regarding the 
subject's safety or survival status as noted in the informed consent form (refer to Section 16.2.3, 
Informed Consent).
Subjects will be instructed that study drug will not be made available to them after they have 
completed/discontinued study drug and that they should return to their primary physician to 
determine standard of care.
Beginning with the implementation of Amendment 7, data from safety evaluations performed 
according to local regulatory approvals and standard of care guidelines50,51 will no longer be 
collected with the exception of serious adverse events that are to be reported and entered in the 
Sponsor safety repository.
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9.2.
Procedures for Subjects Continuing on Study with Atezolizumab 
Monotherapy (per Amendment 6)
Subjects who had received combination therapy will have the opportunity to receive 
atezolizumab monotherapy, per the schedule in Table 1 and Section 6.2, and will complete 
adverse event follow up as defined in Section 12.4.
Subjects remaining in the study on atezolizumab monotherapy will no longer require 
pharmacokinetic, immunogenicity, or biomarker assessments. Therefore, only the Table 1
assessments will be performed for these subjects (assessments in Table 2 through Table 7
included in previous versions of this protocol will no longer be followed and were removed). 
Treatment-related information, such as exposure data, adverse events, and disease assessments,
will continue to be collected and treatment with atezolizumab will continue until the criteria in 
Section 10.2 is met. As no new subjects will be initiating therapy, treatment beyond initial 
radiographic progression will no longer be allowed without prior consultation with the Sponsor’s 
Study Responsible Physician.  
Safety Assessments
Safety reporting for those continuing on atezolizumab monotherapy is described in Section 12.4.
Laboratory and other safety assessments will continue as in Table 1 and in Section 9.7.
Disease Evaluations
Disease evaluations, including assessment of response, will be conducted by the site, as 
described in Table 1 and Section 9.4.
9.3.
Guidance for Subjects Continuing on Study with Atezolizumab 
Monotherapy (per Amendment 7)
The third planned DMC review (23 May 2018) determined that the addition of daratumumab to 
atezolizumab did not result in additional clinical benefit. As a result, further treatment with 
daratumumab was discontinued (with implementation of Amendment 6) and data collection will 
cease after locking of the clinical database (with implementation of Amendment 7). For those 
subjects who are deriving clinical benefit from atezolizumab monotherapy, but do not have 
access to commercial atezolizumab, treatment may continue under the supervision of treating 
investigators in accordance with local regulatory approvals and standard of care guidelines.50,51
Prior to the administration of atezolizumab, investigators will be required to submit 
documentation of subject response and clinical status to the Sponsor, either electronically or via 
facsimile.
Data from these safety and efficacy evaluations will no longer be collected with the exception of 
serious adverse events that are to be reported and entered in the Sponsor safety repository. Study 
drug accountability must continue to be monitored and documented by the study site.
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9.4.
Efficacy Evaluations
Beginning with the implementation of Amendment 7, efficacy evaluations will be performed by 
the investigator according to local regulatory approvals and standard of care guidelines.50,51
These data will no longer be collected by the Sponsor.
Efficacy evaluations will be performed at shown in the Time and Events Schedule (Table 1), per 
RECIST 1.1 (Attachment 5) and irRECIST (Attachment 6). Results will be evaluated by the 
investigator and recorded in the CRF. Subjects will undergo tumor assessments until 
radiographic disease progression, or withdrawal of consent, study termination by Sponsor, or 
death, whichever occurs first. For subjects who discontinue treatment for reasons other than 
progression (eg, adverse event), disease assessments may be discontinued. Subjects who have 
documented disease progression should discontinue study therapy.
9.4.1.
Disease Assessments
Screening Tumor Assessments 
Screening tumor assessments will include CT scans (with IV contrast unless contraindicated) or 
MRIs of the chest, abdomen, head, and pelvis. For subjects with known bone lesions, CT, or 
MRI scan of the affected area of bone will be required at Screening. Additionally, CT scans of 
the neck should also be performed at Screening if clinically indicated. Subjects who are 
intolerant to IV contrast agents or in whom IV contrast is contraindicated may have CT scans 
performed with oral contrast; the reason for not using IV contrast must be noted in the source 
documents. At the investigator’s discretion, other methods of assessment of measurable disease 
(eg, physical examination) as per RECIST 1.1 may be used. 
Magnetic resonance imaging may be used to evaluate sites of disease that cannot be adequately 
imaged using CT or if IV and oral contrast for CT scan are contraindicated. In any case where an 
MRI is performed, it must be the imaging technique used to assess disease at Screening and at all 
subsequent response evaluations.
Tumor assessments performed as standard of care prior to obtaining informed consent and within 
28 days of Cycle 1, Day 1 may be used rather than repeating tests. All known sites of active 
disease must be documented at Screening.
Subsequent Tumor Assessments
At each subsequent tumor evaluation, chest and abdomen CT scans or MRIs, in addition to any 
other known sites of active disease, will be performed. The same radiographic procedure used to 
assess disease sites at Screening should be used throughout the study (eg, the same contrast 
protocol for CT scans). Response will be assessed by the investigator using RECIST 1.1; 
irRECIST will also be used for exploratory purposes.  
Deterioration of health status requiring discontinuation of study treatment without objective 
evidence of progressive disease should be reported as “clinical disease progression”. Every effort 
should be made to document objective progression via radiographic confirmation.
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Subjects in Arm A who crossed over to Arm B after confirmed disease progression should be 
carefully evaluated to determine whether they will benefit from treatment with atezolizumab 
monotherapy.
9.4.2.
Treatment After Initial Disease Progression
Anti-tumor response patterns seen with immunotherapeutic agents may extend beyond the 
typical time course of responses seen with cytotoxic agents. Therefore, the investigator may 
decide to continue a treatment with study drug beyond tumor progression determined on the 
basis of the RECIST 1.1 criteria. Any treatment beyond disease progression requires prior 
discussion with and approval by the Sponsor’s Study Responsible Physician.
Once the specific criteria of RECIST 1.1 defined disease progression are met, a repeat efficacy 
evaluation should be performed at the next per protocol scheduled assessment timepoint or 
earlier, if clinically necessary, but no sooner than 4 weeks from the previous assessment, in order 
to confirm disease progression. This allowance to continue treatment despite initial radiologic 
progression takes into account the observation that some subjects can have a transient tumor flare 
in the first few months after the start of immunotherapy but develop subsequent disease 
response. Subjects should continue study treatment at the discretion of the treating physician
while waiting for confirmation of disease progression if they are clinically stable as defined by 
the following criteria:

Absence of clinical signs and symptoms indicating disease progression

Clinical disease progression not requiring immediate therapeutic intervention

No decline in ECOG performance status

Absence of progressive tumor at critical anatomical sites (eg, cord compression) requiring 
urgent alternative medical intervention
Subjects that are deemed clinically unstable are not required to have imaging assessments and 
can be taken off study treatment.
Table 12 provides guidelines to continue or discontinue study drug based on the initial and 
subsequent assessments of the tumor and the clinical status.
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Table 12:
Imaging and Treatment after First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Additional Imaging and Treatment 
Additional Imaging and Treatment
1st radiologic evidence 
of PD by RECIST 1.1 
Any treatment beyond first disease progression 
requires prior discussion with and approval by 
the Sponsor’s Study Responsible Physician. If 
continued treatment is approved by Sponsor’s 
Study Responsible Physician, imaging should be 
repeated ≥4 weeks later (or the next protocol 
specified timepoint) to confirm PD.
Repeat imaging at ≥4 weeks to 
confirm PD per investigator’s 
discretion only and subject should 
discontinue study treatment
Repeat tumor imaging 
confirms PD by 
RECIST 1.1
No additional imaging required if the subject 
discontinues study treatment. 
No additional imaging required and 
subject should discontinue study 
treatment
Regularly scheduled imaging should be 
performed if the subject continues on study 
treatment (exception to continue study 
treatment is possible upon consultation with 
Sponsor).
Repeat tumor imaging 
does not show PD by 
RECIST 1.1
Regularly scheduled imaging should be 
performed while the subject continues on study 
treatment.
Continue regularly scheduled 
imaging assessments, per 
investigator’s discretion. 
Subject may restart study treatment if 
condition has improved or clinically 
stable per investigator’s discretion, 
upon consultation with Sponsor.
9.5.
Pharmacokinetics and Immunogenicity
Pharmacokinetics/immunogenicity samples will no longer be collected in this study, therefore 
this section is no longer applicable.
Serum samples from venous blood collections will be used to evaluate the pharmacokinetics and 
immunogenicity (generation of anti-drug antibodies) of atezolizumab and daratumumab. Serum 
collected for pharmacokinetic and immunogenicity analyses may additionally be used to evaluate 
safety and efficacy questions, drug characteristics, or certain biomarkers for future research. 
Genetic analyses will not be performed on these serum samples. Subject confidentiality will be 
maintained.
9.5.1.
Evaluations
Samples will be collected for measurement of serum concentrations of atezolizumab and 
daratumumab and the assessment of anti-atezolizumab and anti-daratumumab antibodies
(immunogenicity). Serum samples should be collected at the final visit from subjects who are 
discontinued from treatment or withdrawn from the study. Subjects who discontinue treatment 
will also be asked to return for immunogenicity evaluation during the Follow-up Phase. These
samples will be tested by the Sponsor or Sponsor’s designee.
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The exact dates and times of blood sampling must be recorded. Refer to the Laboratory Manual 
for sample collection requirements. Collected samples must be stored under the specified and 
controlled conditions for the temperatures indicated in the Laboratory Manual. Additional 
information about the collection, handling, and shipment of biological samples can be found in 
the Laboratory Manual.
9.5.2.
Analytical Procedures
Serum samples will be analyzed to determine concentrations of daratumumab, concentrations of 
atezolizumab, or the generation of antibodies to daratumumab and atezolizumab using validated 
immunoassay methods.
All samples collected for detection of anti-atezolizumab and daratumumab antibodies will also 
be evaluated for serum concentration to enable interpretation of the antibody data. For the 
atezolizumab and daratumumab immunogenicity assessments, serum samples will be screened 
for antibodies binding to atezolizumab or 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.
Neutralizing antibody assessments may also be performed to further characterize immune 
responses that are generated.
9.5.3.
Pharmacokinetic Parameters
The PK parameters are defined as:
Cmax = Maximum observed concentration
Cmin = Minimum observed concentration
For both atezolizumab and daratumumab, the PK evaluations include Cmin and Cmax. If sufficient 
data are available, other PK parameters may be calculated. The Cmin and Cmax will be 
summarized by descriptive statistical method for Arm A and Arm B. If there are sufficient data, 
then a population PK analysis of serum concentration-time data of daratumumab and
atezolizumab may be performed and may include data from other clinical studies. If performed, 
details will be provided in a population-PK analysis plan and the results of the analysis will be 
presented in a separate report.
9.5.4.
Immunogenicity Assessments
When both serum concentration and immunogenicity analyses are specified, they will be 
performed on aliquots from the same blood draw and no additional sampling is required. 
No unscheduled samples need to be collected for IRRs associated with the first administration of 
daratumumab. Daratumumab serum concentration will also be determined from the 
daratumumab IRR sample for interpreting immunogenicity data. If the IRR results in treatment 
discontinuation, then subjects should undergo all scheduled safety and efficacy evaluations. 
Procedures for sample collection, preparation, identification, storage, and shipment will be 
provided in the Laboratory Manual or equivalent document.
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Subjects who discontinue treatment or withdraw from the study before confirmation of PD 
should have samples collected at the time of early discontinuation. Subjects who discontinue 
treatment will also be asked to return for immunogenicity evaluation during the Follow-up 
Phase.
9.6.
Biomarker Assessments
Biomarker samples will no longer be collected in this study.
In this study, mandatory archival or fresh tumor specimens from subjects at Screening will be
evaluated for expression of PD-L1+, CD38+, 
 
 
 
Published results suggest that the expression of PD-L1 in tumors correlates with response to 
anti-PD-L1 therapy (Horn 2015; Spira 2015).23,45 Evaluation of CD38+ expression will be 
performed to determine if elevated expression of CD38+ correlates with responses to 
daratumumab therapy.
Fresh biopsies at Cycle 3 and at progressive disease are mandatory, if clinically feasible, to 
evaluate biomarkers related to the clinical benefit of atezolizumab + daratumumab. Additionally, 
if a biopsy is taken at any other time while a subject is on study, a sample is also requested for 
biomarker analysis. Evaluation of biopsies by IHC and IF may include PD-L1 and CD38 
expression in addition to other markers and cell populations 
 
to identify changes in inflammatory populations in response to 
treatment. Collection of a tumor biopsy, at the time of radiographic progression will be evaluated 
for immune infiltrate, PD-L1, and CD38 expression by IHC and is required in order to 
distinguish pseudoprogression/tumor-immune infiltration from true progression. Anti-tumor 
immune responses such as those potentially associated with atezolizumab + daratumumab may 
result in objective responses that are preceded by initial apparent radiological progression as a 
result of robust tumor-immune infiltration with a concomitant increase in tumor size in 8 to 10%
of patients treated with PD-1 inhibitors (Dronca 2016).13 DNA or RNA extraction may be 
performed to enable next-generation sequencing (NGS) to identify biomarkers associated with 
disease progression or acquired resistance to atezolizumab + daratumumab and to increase 
understanding of disease pathobiology.
Evaluation of blood biomarkers may provide evidence for biomarkers of biologic activity of 
atezolizumab + daratumumab in subjects with NSCLC. Flow cytometry will be performed to 
immunophenotype 
 
 
 
response to treatment. These samples may be used to evaluate specific subsets of immune cells 
 by CyTOF. 
Proteomic analysis may also be used to evaluate potential biomarkers of response and resistance.
9.6.1.
Tumor Tissue Samples
As of 25 May 2018, scheduled tumor biopsies are no longer required. However, if a subject has 
an unscheduled tumor biopsy, tissue samples may be submitted as per protocol.  
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Archival and freshly collected tumor tissue samples for screening
Tumor tissue should be of good quality based on total and viable tumor content (sites will be 
informed if the quality of the submitted specimen is inadequate to determine tumor PD-L1 
status). An archival tumor specimen can be submitted if available. Archival tumor biopsies are 
acceptable at baseline as long as the biopsy was collected after completion of the most recent 
prior therapy and is less than one year old. If an archival specimen is not available, the subject
may still be eligible, with the assumption that the subject is willing to consent to and undergo a 
pretreatment biopsy or resection of the tumor. For subjects enrolled in the crossover arm, if a 
biopsy was taken at the time of disease progression while enrolled in Arm A of this protocol, a 
new biopsy is not required at Cycle 1X Day 1 predose.
For freshly collected biopsy specimens, acceptable samples include:

Core needle biopsy sample collection for deep tumor tissue: At least 3 cores, embedded 
into a single paraffin block, should be submitted for evaluation.

Excisional, incisional, punch, or forceps biopsy sample collection for cutaneous, 
subcutaneous, or mucosal lesions 

Fine-needle aspiration, brushing, cell pellets (eg, from pleural effusion), and lavage 
samples are not acceptable.
For archival samples, the remaining tumor tissue block for all subjects enrolled will be returned 
to the site upon request or 18 months after final closure of the study database, whichever is 
sooner. Tissue samples from subjects who are deemed ineligible to enroll in the study will be 
returned promptly after eligibility determination.
Tumor samples at Cycle 3 and at the time of confirmed radiographic progression
Subjects in all treatment arms will undergo a tumor biopsy to obtain a mandatory tumor sample, 
unless not clinically feasible, at Cycle 3, Cycle 3X, and at the time of radiographic disease 
progression.
Note: The Cycle 3 biopsy may be collected within 7 days prior to or up to 21 days after the 
Cycle 3 Day 1 dose but must be done prior to Cycle 4 Day 1. In addition, this biopsy must be 
performed following the first radiologic tumor assessment.
Acceptable samples include:

Core needle biopsy sample collection for deep tumor tissue; at least three cores, embedded 
into a single paraffin block, should be submitted for evaluation.

Excisional, incisional, punch, or forceps biopsy sample collection for cutaneous, 
subcutaneous, or mucosal lesions
Tumor tissue resection
The status of immune-related, tumor typerelated, and other exploratory biomarkers (including,
but not limited to, T-cell markers and non-inherited biomarkers identified through NGS on 
extracted DNA or RNA) in tumor tissue samples may be evaluated.
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9.6.2.
Biomarker Assays in Blood Samples
Blood samples will be obtained for biomarker evaluation (including but not limited to 
biomarkers that are related to NSCLC or tumor immune biology) from all eligible subjects. 
Samples will be processed to obtain plasma and serum for the determination of changes in blood-
based biomarkers. Whole blood samples may be processed to obtain their derivatives (eg, RNA 
and DNA) and evaluated for immune-related, tumor typerelated, and other exploratory 
biomarkers (eg, alterations in gene expression or clonal T-cell expansion). Also, based on 
emerging scientific evidence, the Sponsor may request additional blood samples for biomarker 
evaluation. In this case, such analyses will be limited to research related to the study drug(s) or 
diseases being investigated.
Stopping Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the 
end of the study, it becomes clear that the analysis will not have sufficient scientific value for
biomarker evaluation, or if there are not enough samples or 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.
Additional Collections
If it is determined at any time before study completion that additional material is needed from a 
FFPE tumor sample for the successful completion of the protocol-specified analyses, the Sponsor
may request that additional material be retrieved from existing samples. Also, based on emerging 
scientific evidence, the Sponsor may request additional material from previously collected tumor 
samples during or after study completion for a retrospective analysis. In this case, such analyses 
would be specific to research related to the study drug(s) or diseases being investigated.
9.7.
Safety Evaluations
Beginning with the implementation of Amendment 7, safety evaluations will be performed by 
the investigator according to local regulatory approvals and standard of care guidelines.50,51
These data will no longer be collected by the Sponsor with the exception of serious adverse 
events that are to be reported and entered in the Sponsor safety repository.
Safety will be assessed by the incidence and severity of adverse events, laboratory test results, 
ECGs, vital sign measurements, physical examination findings, ECOG performance status score,
and other evaluations as described in the Time and Events Schedule (Table 1). Toxicities will be 
graded according to the NCI-CTCAE Version 4.03. Any clinically relevant changes occurring 
during the study must be recorded on the Adverse Event section of the CRF. 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, 
infusion-related 
reactions/allergic 
reactions, 
hemolysis, 
and 
thrombocytopenia will be closely monitored. As daratumumab and atezolizumab are both
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biologic agents, immunogenicity also will be monitored. Any of the safety monitoring 
assessments may be performed more frequently, and adverse events should be evaluated by the 
investigator according to the standard practice, if clinically indicated.
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally acceptable representative) for the duration of the study. Adverse events 
will be followed by the investigator as specified in Section 12, Adverse Event Reporting.
Clinical Laboratory Tests 
Blood samples for clinical laboratory evaluation 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 CRF. The laboratory reports must be filed 
with the source documents. The following tests will be performed by the local laboratory, unless 
otherwise specified:
Hematology
Hemoglobin
White blood cell (WBC)
Absolute neutrophil count (ANC)
Absolute lymphocyte count (ALC)
Platelet count
Coagulationa
Prothrombin time/International Normalized Ratio
Activated partial thromboplastin time
Chemistry
Sodium
Total bilirubinb
Potassium
Alkaline phosphatase
Creatinine
Lactic acid dehydrogenase (LDH)
Aspartate aminotransferase (AST)
Calciuma
Alanine aminotransferase (ALT)
Amylase, lipase
Urinalysisa
Standard Urine Dipstick
Other Tests
Thyroid panela
Thyroid stimulating hormone (TSH)
Triiodothyronine (T3; total or free)
Free thyroxine (T4)
Serology (hepatitis B, hepatitis C) and HCV Viral 
Load: a
Hepatitis B: HBsAg, anti-HBc
Hepatitis C: anti-HCV; HCV RNA PCR, if 
necessary
Pregnancy Test (for women of childbearing potential only)
serum (<5 IU/mL) -hCG at Screening; serum or 
urine thereafter as clinically indicated
a. Not performed for subjects who crossover from Arm A to Arm B, except as clinically indicated.
b. Direct bilirubin if Gilbert disease.
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Indirect Antiglobulin Test (IAT) results
This test no longer needs to be performed since daratumumab treatment is discontinued.
Blood Type, Rh, and Indirect Antiglobulin Test (IAT) should be done before the first dose of 
daratumumab. Subject red blood cell (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 pretransfusion test performed to 
identify a subject’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 
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, 2016).10,9
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 Investigator’s Brochure.
Pulmonary Function Test
Subjects with known or suspected COPD must have a FEV1 test during Screening. Refer to 
Section 6.2.1.1 of the protocol for details on subjects with higher risk of respiratory 
complications.
Electrocardiogram: 
A 12-lead ECG will be performed at Screening and at End-of-Treatment.
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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, the procedures 
should be performed in the following order: ECG(s), vital signs, blood draw.
Clinically significant abnormalities will be recorded as adverse events in the appropriate CRF.
Vital Signs
Temperature, pulse/heart rate, blood pressure will be performed as specified in the Time and 
Events Schedule (Table 1). Clinically significant abnormalities will be recorded as adverse 
events in the appropriate CRF.
Blood pressure and pulse/heart rate measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. Blood 
pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of rest in a 
quiet setting without distractions (eg, television, cell phones).
Physical Examination and ECOG performance status
A complete physical examination should be performed during the Screening Phase and at 
crossover eligibility assessment. Thereafter, only a symptom directed physical examination is 
required. Height will be measured at Screening only; weight will be measured regularly at 
Screening and preinfusion, as specified in Time and Events schedule. Abnormalities will be 
recorded in the appropriate section of the CRF. ECOG performance status will be used to 
evaluate the effect of the disease status on the activities of daily living (Attachment 3). When 
scheduled, ECOG assessments should be obtained prior to any other study procedures planned 
for the same day.
9.8.
Sample Collection and Handling
Beginning with the implementation of Amendment 7, samples will no longer be collected in this 
study.
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form. Refer to the Time and Events Schedule for the timing and frequency of all 
sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
Laboratory Manual. Collection, handling, storage, and shipment of samples must be under the 
specified, and where applicable, controlled temperature conditions as indicated in the Laboratory 
Manual.
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10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed study treatment if he or she has completed all 
planned administrations of the study drug(s) in the assigned treatment arm. 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 died before the end of the study, has not been lost to follow up, 
and has not withdrawn consent for study participation before the end of the study.
10.2.
Discontinuation of Study Treatment/Withdrawal from the Study
Discontinuation of Study Treatment
A subject will not be automatically withdrawn from the study if he or she has to discontinue 
treatment. The End-of-Treatment Visit and Follow-up visit assessments should continue as 
specified in the Time and Events Schedules.
A subject's study treatment must be discontinued if:

The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it 
is in the best interest of the subject to discontinue study treatment

The subject becomes pregnant

The subject (or the subject’s legally acceptable representative) withdraws consent for 
administration of study treatment

The subject experiences unacceptable toxicity, including IRRs described in Section 6.3

The subject missed more than 2 consecutive planned doses due to daratumumab-related AEs

The subject missed more than 105 consecutive treatment days due to atezolizumab-related 
AEs

The subject experiences confirmed disease progression (per RECIST 1.1), see Table 12.

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 NSCLC.
The primary reason for discontinuation of study treatment is to be recorded in the CRF.
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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 to study participation

Pregnancy

Second primary malignancy (see Discontinuation of Study Treatment for additional details)

Death

The study investigator, for any reason, stops the subject's participation in the study

Sponsor terminated the study
Before a subject is lost to follow-up, every reasonable effort must be made by the study-site 
personnel to contact the subject and determine the reason for discontinuation/withdrawal. The 
measures taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced. If a 
subject discontinues from treatment, end-of-treatment assessments should be obtained.
10.3.
Withdrawal From the Use of Research Samples
A subject who withdraws from the study will have the following options regarding the optional
research samples:

The collected samples will be retained and used in accordance with the subject's original 
informed consent for optional research samples.

The subject may withdraw consent for optional research samples, in which case the samples
will be destroyed and no further testing will take place. To initiate the sample destruction 
process, the investigator must notify the Sponsor study site contact of withdrawal of consent 
for the optional research samples and to request sample destruction. The Sponsor study site 
contact will, in turn, contact the biomarker representative to execute sample destruction. If 
requested, the investigator will receive written confirmation from the Sponsor that the 
samples have been destroyed.
Withdrawal From the Optional Research Samples While Remaining in the Main Study
The subject may withdraw consent for optional research samples while remaining in the study. In 
such a case, the optional research samples will be destroyed. The sample destruction process will 
proceed as described above.
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Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will 
be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the main ICF and in the separate ICF for optional research 
samples.
11.
STATISTICAL METHODS
Statistical analysis will be done by the Sponsor or under the authority of the Sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.
11.1.
Subject Information
The primary analysis population for the efficacy endpoint will be the intent-to-treat population in 
the randomized phase of the study. The subjects in the safety run-in cohort will also be included 
in the efficacy analyses and listed separately. Safety will be evaluated for all subjects who have 
received at least 1 dose of study drug (atezolizumab or daratumumab). The pharmacokinetic 
analyses will be performed on the population described in Section 11.4.
11.2.
Sample Size Determination
Assuming that the ORR for atezolizumab monotherapy is approximately 20%, and the addition 
of daratumumab would improve ORR by 20% to 40%, 90 subjects need to be randomized with a 
1:1 ratio in order to achieve 80% power to detect this difference with a one-sided alpha of 0.10.
In the event that benefit from the combination is not observed across the overall study 
population, targeted enrollment of subgroups, based on tumor PD-L1 expression level, may be 
implemented, based on DMC recommendations (see Section 11.3). As such, approximately 
50 additional subjects in the TC2/TC3 subgroups may be enrolled to preliminarily evaluate the
treatment effect. If the ORR is 25% for atezolizumab monotherapy and 50% for the 
atezolizumab + daratumumab combination in the TC2/TC3 subgroup, the lower bound of the 
90% CI for the difference in ORR would exclude 0 (ie, a positive signal in favor of the 
combination).
11.3.
Efficacy Analyses
The primary endpoint will be evaluated after approximately 90 subjects have been enrolled. The 
DMC will perform additional interim analyses after approximately 40 subjects and 60 subjects 
have had at least 1 disease assessment, respectively. These analyses will include an evaluation of 
efficacy as a function of PD-L1 expression. Based on these results, the DMC may recommend 
restricting enrollment of subjects in PD-L1 subgroups in whom clinical benefit is not 
demonstrated or expanding enrollment by a maximum of 100 subjects in PD-L1 subgroups 
without adequate enrollment (see Section 11.2) in accordance with the product label of the 
Ventana SP-142 assay. Study sites will be notified in writing of any changes to enrollment based 
on DMC recommendations.
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Number and percent of subjects in each response category will be tabulated, along with those for 
subjects who achieve overall response (CR or PR) and who achieve disease control (ie, CBR: 
CR, PR, or SD with duration of at least 16 weeks). Odds ratio and its 95% confidence interval 
will be provided as a measure of treatment effect. Descriptive summaries (mean, standard 
deviation, median, and range) will be provided for time to response among those subjects who 
have CR or PR.
For time-to-event endpoints (PFS, OS, and duration of response), Kaplan-Meier estimates of the 
survival functions will be presented. For PFS and OS, Cox’s regression will be performed to 
obtain the hazard ratio estimate and the corresponding 95% CI, which will be used as a measure 
for treatment effect. Additional Cox’s regression may be performed to include appropriate 
baseline prognostic variables. Furthermore, exploratory analyses for OS may be performed to 
adjust for the effect of crossover. Analysis of duration of response will be performed 
descriptively among those subjects who achieve CR or PR.
11.4.
Pharmacokinetic Analyses
Pharmacokinetic analyses will be performed on the PK-evaluable population, defined as subjects 
who have received at least 1 dose of daratumumab or atezolizumab and have at least 
1 postinfusion sample.
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. Concentrations below the lowest quantifiable concentration 
will be treated as zero in the summary statistics. The number of subjects and samples excluded 
from the analysis will be clearly documented.
Descriptive statistics will be used to summarize daratumumab and atezolizumab serum 
concentrations at each sampling time point. Cmin is defined as the minimal concentration 
observed immediately before infusion and Cmax is defined as the maximum concentration 
observed at the end of infusion, as presented in the summary of serum concentration by sampling 
time point and route of administration. Other PK parameters, if available, may also be 
summarized. 
If sufficient data are available, population-PK analysis of serum concentration-time data of 
daratumumab or atezolizumab may be performed and may be combined with data from other 
studies. If the population-PK analysis is conducted, details will be given in a population-PK 
analysis plan and the results of the analysis will be presented in a separate report.
11.5.
Immunogenicity Analyses
The incidence of anti-atezolizumab and daratumumab antibodies will be summarized for all 
subjects who receive at least 1 dose of atezolizumab and daratumumab and have appropriate 
samples for detection of antibodies to atezolizumab and daratumumab (ie, subjects with at least 
1 sample obtained after their first dose). In addition, subjects who are positive for antibodies to 
atezolizumab or daratumumab will be listed.
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Other immunogenicity analyses may be performed to further characterize the immune responses 
that are generated.
11.6.
Biomarker Analyses
Biomarker studies are designed to identify markers predictive of response (or resistance) to
daratumumab and atezolizumab. 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, or survival analysis, depending on the endpoint). 
Correlation of baseline expression levels or changes in expression levels with response to time-
to-event endpoints will identify responsive (or resistant) subgroups in addition to genes and 
pathways attenuated following treatment with daratumumab and atezolizumab. 
Any pharmacodynamic measures will be listed, tabulated, and where appropriate, plotted. 
Subjects may be grouped by cohort, dose schedule, or clinical response. As this is an open-label 
study with an observation control arm, 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.
11.7.
Pharmacokinetic/Pharmacodynamic Analyses
If sufficient data are available, then other PK/pharmacodynamic modeling may be performed, 
including exploring the relationship between serum concentrations of atezolizumab and 
daratumumab and endpoints of clinical efficacy and safety. If performed, details and results of 
the analysis will be presented in a separate report.
11.8.
Safety Analyses
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse 
events are AEs with onset during the treatment phase or that are a consequence of a pre-existing 
condition that has worsened since baseline. All reported adverse events will be included in the 
analysis. For each adverse event, the percentage of subjects who experience at least 1 occurrence 
of the given event will be summarized by treatment group. In addition, comparisons between 
treatment groups will be provided if appropriate.
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.
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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 timepoint. Changes from 
baseline results will be presented in pre- versus posttreatment cross-tabulations (with classes for 
below, within, and above normal ranges). 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 adverse event grade experienced by the subject during the study will be 
provided as shift tables.
Electrocardiogram
Electrocardiogram data will be summarized based on categories of normal, abnormal either 
clinically significant or not clinically significant and listed.
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, and blood pressure (systolic and diastolic)
values and changes from baseline will be summarized at each scheduled timepoint. The 
percentage of subjects with values beyond clinically important limits will be summarized.
11.9.
Data Monitoring Committee
An internal Janssen DMC, independent of the study team, will be established to review the 
efficacy and safety data in the randomization phase. The DMC will consist of a minimum of 
3 members with at least 1 clinician and a statistician, 1 of whom will chair the committee. The 
DMC will review the totality of data after approximately 40, 60, and 90 subjects have been 
enrolled, and will formulate recommendations on study conduct, including but not limited to 
future subject enrollment (see Section 11.3). The DMC may request additional ad-hoc reviews as 
data accumulate to monitor safety or efficacy in certain PD-L1 subgroups. Additional details will 
be specified in a separate DMC charter.
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.
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Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events or serious adverse events. 
Open-ended and nonleading verbal questioning of the subject is the preferred method to inquire 
about adverse event occurrence.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The Sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

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 
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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 drug and the event (eg, death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For atezolizumab and daratumumab, the 
expectedness of an adverse event will be determined by whether or not it is listed within the 
Reference Safety Information in the Investigator's Brochures.
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2, Attribution Definitions.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
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12.1.3.
Severity Criteria
The severity assessment for an adverse event or serious adverse event should be completed using 
the NCI-CTCAE Version 4.03 Any adverse event or serious adverse event not listed in the 
NCI- CTCAE Version 4.03 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 or disabling adverse event
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

Suspected abuse/misuse of a Sponsor study drug

Accidental or occupational exposure to a Sponsor study drug

Medication error involving a Sponsor product (with or without subject/patient exposure to 
the Sponsor study drug, eg, name confusion)

Exposure to a Sponsor study drug from breastfeeding
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the CRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations will be reported from the time a signed and 
dated ICF is obtained until 30 days after the last dose of study drug (or 90 days for serious 
adverse events), or until start of subsequent anticancer therapy or the subject withdraws consent 
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for study participation, if earlier, which may include contact for follow-up of safety. For subjects 
who have received subsequent treatment with therapeutic intent for NSCLC during the adverse 
event reporting period, only adverse events that are considered to be possibly, probably, or 
definitely related to atezolizumab or daratumumab need to be reported. Serious adverse events,
including those spontaneously reported to the investigator, 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. Anticipated events will be recorded and reported as described in Attachment 4.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the CRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to Sponsor
instructions.
The Sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The Sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). For 
anticipated events reported as individual serious adverse events the Sponsor will make a 
determination of relatedness in addition to and independent of the investigator’s assessment. The 
Sponsor will periodically evaluate the accumulating data and, when there is sufficient evidence 
and the Sponsor has determined there is a reasonable possibility that the drug caused a serious 
anticipated event, they will submit a safety report in narrative format to the investigators (and the 
head of the institute).
The investigator (or Sponsor where required) must report SUSARs to the appropriate 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol 
unless otherwise required and documented by the IEC/IRB.
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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

Blood type and IAT (as described in Section 9.7).
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:

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)
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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 atezolizumab or 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 CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not 
be considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.
12.4.
Safety Reporting for Atezolizumab Monotherapy Subjects (per 
Amendment 6)
Following implementation of Amendment 6, all adverse events and special reporting situations 
(with the exception of Grade 1 to 2 events and non-immune-mediated events) will be reported 
from the time a signed and dated ICF is obtained until 30 days after the last dose of study drug 
(or 90 days for serious adverse events), or until withdrawal of consent for study participation.
For subjects who have received subsequent treatment with therapeutic intent for NSCLC during 
the adverse event reporting period, only adverse events that are considered to be possibly, 
probably, or definitely related to atezolizumab need to be reported; all other Grade 1 to 2 AEs, 
including laboratory abnormalities, do not need to be recorded in the CRF, but should be 
recorded in the source documentation.
Beyond 90 days after the last dose of study drug, SAEs, considered possibly, probably, or 
definitely related to study drug will continue to be collected and reported into the Sponsor’s 
global safety database, using the SAE Form (paper form) faxed to Sponsor’s Local Operational 
Company/Local Safety Officer. These should be reported until the subject discontinues the study 
(per the definitions in Section 10.2). SAEs (see Section 12.3.2) should include information on 
study agent administration and concomitant medications and other treatments associated with the
SAE.
12.5.
Safety Reporting for Atezolizumab Monotherapy Subjects (per 
Amendment 7)
Beginning with the implementation of Amendment 7, data from safety evaluations performed 
according to local regulatory approvals and standard of care guidelines50,51 will no longer be 
collected with the exception of serious adverse events that are to be reported and entered in the 
Sponsor safety repository.
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12.6.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the Sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious 
adverse events and must be reported using the Serious Adverse Event Form. Any subject who 
becomes pregnant during the study must be promptly withdrawn from the study and discontinue 
further study treatment.
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported as noted above.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.7.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the Sponsor, and are mandated by regulatory agencies worldwide. The Sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the Sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the Sponsor by the study-site personnel within 24 hours 
after being made aware of the event.
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.
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14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
Atezolizumab is a colorless to yellow liquid and sterile concentrate of 60 mg/mL in a vial for IV 
administration. Refer to the respective Investigator's Brochures for a list of excipients.
14.2.
Packaging
Atezolizumab is supplied in glass vials containing atezolizumab at a concentration of 60 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
Atezolizumab
Atezolizumab must be stored in the original carton in a refrigerator at controlled temperatures 
ranging from 2°C to 8°C.
Study drug must not be utilized after the expiry date printed on the label. The drug product must be
protected from light and must not be frozen. Atezolizumab do not contain preservatives; therefore,
any unused portion remaining in the vial must be discarded. 
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 monitoring visits. The return to the Sponsor of unused study drug will 
be documented on the drug return form. When the study site is an authorized destruction unit and 
study drug supplies are destroyed on-site, this must also be documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes, and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes.
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be administered
only to subjects participating in the study. Returned study drug must not be dispensed again, 
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even to the same subject. Study drug may not be relabeled or reassigned for use by other 
subjects. The investigator agrees neither to dispense the study drug from, nor store it at, any site 
other than the study sites agreed upon with the Sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator Brochures for daratumumab and atezolizumab

Site Investigational Product Procedures Manual and IPPI

Laboratory manual

IWRS manual

CRF completion guidelines

Sample ICF

Subject wallet card indicating blood type and IAT

Other manuals and guidance documents as needed.
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
This is the first clinical evaluation of daratumumab in combination with atezolizumab in NSCLC 
subjects; hence, the benefits and risks in the NSCLC population are unknown. However, as 
described in Section 1, clinical studies in NSCLC have demonstrated that atezolizumab and 
daratumumab have manageable safety profiles with monitoring and rapid intervention for 
immune-related AEs and infusion reactions. Subjects will be closely monitored throughout the 
study, as discussed throughout this protocol, for both safety and clinical benefit. Subjects in both 
arms will receive atezolizumab, which has been studied in clinical trials of NSCLC subjects
(see Section 1.2 for an overview of the efficacy and safety results). As discussed in Section 1.4, 
based on the known data regarding the response to atezolizumab in NSCLC and the mechanism 
of action of both study drugs, there is adequate justification, including significant unmet clinical 
need, for evaluating these drugs in combination for the treatment of NSCLC in subjects who are 
eligible for this study.
Additionally, all subjects will undergo periodic CT or MRI scans to monitor the underlying 
disease. The frequency of such scans (as well as radiation exposure) is similar to standard 
practice for patients outside of clinical trials and the overall risk is low. Subjects will have a pre-
and posttreatment biopsy. In general, these procedures are routinely performed during a subject’s 
diagnostic workup and follow-up care. Although biopsy collection is associated with risk, the 
complication rate for these procedures is low. The data obtained from these biopsies will 
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generate valuable scientific data on the pharmacodynamic effect of the combination of these 
study drugs in NSCLC subjects.
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 informed 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 blood volume collection for a subject is estimated at approximately 35 mL/month. This blood 
volume is not burdensome and falls within the normal range of a single blood donation.
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 Brochures 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 
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must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required.
At the end of the study, the investigator (or Sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
16.2.3.
Informed Consent
Each subject or a legally acceptable representative must give written consent according to local 
requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) that is/are used must be approved 
by both the Sponsor and by the reviewing IEC/IRB and be in a language that the subject can read 
and understand. The informed consent should be in accordance with principles that originated in 
the Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory 
requirements, and Sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects or their legally acceptable representatives 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 or legally acceptable 
representative is authorizing such access, which includes permission to obtain information about 
his or her survival status. It also denotes that the subject agrees to allow his or her study 
physician to recontact the subject for the purpose of obtaining consent for additional safety 
evaluations, and subsequent disease-related treatments, if needed.
The subject or legally acceptable representative 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 or his or her legally acceptable 
representative's personally dated signature. After having obtained the consent, a copy of the ICF
must be given to the subject.
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
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all written information) and should personally date and sign the ICF after the oral consent of the 
subject or legally acceptable representative is obtained.
When prior consent of the subject is not possible and the subject's legally acceptable 
representative 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 or legally acceptable representative 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 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 or his or her legally acceptable representative
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 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 and 
atezolizumab, to understand NSCLC, to understand differential drug responders, and to develop 
tests/assays related to daratumumab, atezolizumab, and NSCLC. The research may begin at any 
time during the study or the post-study storage period.
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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 Use of Samples in Future 
Research).
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 16.1, Study-Specific Design 
Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the Sponsor will modify this protocol without a formal amendment 
by the Sponsor. All protocol amendments must be issued by the Sponsor, and signed and dated 
by the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
Sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IEC/IRB (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate Sponsor
representative listed in the Contact Information page(s), which will be provided as a separate
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the Sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the CRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
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:
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
Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the Sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable.
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17.3.
Subject Identification, Enrollment, Prescreening, 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 or randomized 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 drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
The 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 or

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.
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 
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the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the Sponsor. If the electronic source system is utilized, references made to 
the CRF in the protocol include the electronic source system but information collected through 
the electronic source system may not be limited to that found in the CRF. Data in this system 
may be considered source documentation.
17.5.
Case Report Form Completion
Beginning with the implementation of Amendment 7, data collection through the electronic data 
capture (eDC) will no longer be performed.
eDC will be used for this study. Case report forms (CRF) are provided for each subject in 
electronic format. Study site personnel must log in eDC via a secure manner (personal 
password). The individual password must keep confidential for personal use.  
The study data will be transcribed by study-site personnel from the source documents onto an 
CRF according to CRF completion guideline provided by the Sponsor. Data must be entered into
CRFs in English. The CRF 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. Worksheets may be 
used for the capture of some data to facilitate completion of the CRF. Any such worksheets will 
become part of the subject's source documentation. 
All subjective measurements (eg, pain scale information or other questionnaires) shall be 
completed by the same individual who made the initial baseline determinations whenever 
possible. The investigator must verify that all data entries in the CRFs are accurate and correct.
All CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool. The investigator or 
study-site personnel must address the queries and update the CRF if applicable.
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after 
the initial entry into the CRF, this can be done in either of the following ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or Sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
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.
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Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The Sponsor will review CRF for accuracy and completeness during on-
site monitoring visits and after transmission to the Sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the Sponsor. It is the responsibility of the Sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The Sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the Sponsor.
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The Sponsor will use a combination of monitoring techniques central, remote, or on-site 
monitoring to monitor this study.
The Sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
postinitiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the CRF with the source documents
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
CRF are known to the Sponsor and study-site personnel and are accessible for verification by the 
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Sponsor study-site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this 
review will be discussed with the study-site personnel. The Sponsor expects that, during 
monitoring visits, the relevant study-site personnel will be available, the source documents will 
be accessible, and a suitable environment will be provided for review of study-related 
documents. The monitor will meet with the investigator on a regular basis during the study to 
provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site. Central monitoring will take place for data identified by the Sponsor as 
requiring central review.
Once Amendment 6 is implemented at a site, monitoring will be limited to on-site monitoring 
visits and remote contacts for the verification and follow-up of SAEs reported to the Sponsor.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
Study completion will occur when the last subject has discontinued study treatment 
(atezolizumab monotherapy), completed the End of Treatment assessments, and safety follow-up 
has completed (ie, last required data collection for the last subject has been captured in the CRF). 
A CSR will be prepared based on interim analysis data reviewed by the DMC at the third 
planned DMC review on 23 May 2018 (prior to discontinuation of enrollment and daratumumab
dosing).
The final data from the study site will be sent to the Sponsor (or designee) after completion of 
the final subject assessment at that study site, in the time frame specified in the Clinical Trial 
Agreement.
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.
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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.
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 atezolizumab and 
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 atezolizumab and daratumumab, and 
thus may be disclosed as required to other clinical investigators or regulatory agencies. To permit 
the information derived from the clinical studies to be used, the investigator is obligated to 
provide the Sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the Sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. 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 
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not be used in publication of results. Any work created in connection with performance of the 
study and contained in the data that can benefit from copyright protection (except any 
publication by the investigator as provided for below) shall be the property of the Sponsor as 
author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the Sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the Sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the Sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the Sponsor will review these issues with the investigator. The Sponsor
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 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.
American Cancer Society; Cancer Facts and Figures 2014. Available at: http://www.cancer.org/acs/groups/ 
content/@research/documents/webcontent/acspc-042151.pdf. Accessed 03 March 2015.
2.
Ardizzoni A, Boni L, Tiseo M, et al. Cisplatin versus carboplatin-based chemotherapy in first-lin treatment of 
advanced non-small cell lung cancer: an individual patient data meta-analysis. J Natl Cancer Inst. 
2007;99:847857.
3.
Azzoli CG, Baker Jr S, Temin S, et al. American Society of Clinical Oncology Clinical Practice Guideline 
update on chemotherapy for Stage IV nonsmall-cell lung cancer. J Clin Oncol. 2009;27:6251-6266.
4.
Bai S, Jorga K, Xin Y, et al. A guide to rational dosing of monoclonal antibodies. Clin Pharmacokinet.
2012;51:119-135.
5.
Besse B, Johnson M, Janne PA, et al. A Phase II, single-arm trial (BIRCH) of atezolizumab as first-line or 
subsequent therapy for locally advanced or metastatic PD-L1-selected non-small cell lung cancer (NSCLC). 
Eur J Cancer. 2015. 51(suppl. 3):S717-718.
6.
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell 
lung cancer. N Engl J Med. 2015;373(2):123-135.
7.
Butte MJ, Keir ME, Phamduy TB. Programmed death-1 ligand 1 interacts specifically with the B7-1 
costimulatory molecule to inhibit T cell responses. Immunity. 2007;27:111122.
8.
Camidge DR, Bang Y, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-
small cell lung cancer: updated results from a Phase 1 study. Lancet Oncol. 2012;13:1011-1019.
9.
Chapuy CI, Aguad MD, Nicholoson RT, et al. International validation of a dithiothreitol (DTT)-based method 
to resolve the daratumumab interference with blood compatibility testing. Transfusion. 2016; 56(12): 
2964-2972.
10.
Chapuy CI, Nicholoson RT, Aguad MD et al. Resolving the daratumumab interference with blood 
compatibility testing. Transfusion. 2015; 55:1545-1554.
11.
Dasanu CA, Sethi N, Ahmed N. Immune alterations and emerging immunotherapeutic approaches in lung 
cancer. Expert Opin Biol Ther. 2012;12:923-937.
12.
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 Immunology. 
2011;186(3):1840-1848.
13.
Dronca RS, Liu X, Harrington SM, et al. T cell Bim levels reflect responses to anti–PD-1 cancer therapy. JCI 
Insight. 2016;1(6):e86014.
14.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.
15.
Ferenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated 
non-small-cell lung cancer (POPLAR): a multicenter open-label, phase 2 randomised controlled trial. Lancet. 
2016;387:1837-1846.
16.
Globocan 2012. Cancer Fact Sheets: Lung Cancer. Cancer Today. Available at: http://gco.iarc.fr/today/fact-
sheets-cancers?cancer=11&type=0&sex=0. Accessed 01 July 2016.
17.
Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision 
of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant 
tumours. J Thorac Onc. 2007;2(8):706-714.
18.
Gridelli C, Ciardello CG, Feld R, et al. First-Line Erlotinib Followed by Second-Line Cisplatin-Gemcitabine 
Chemotherapy in Advanced Non–Small-Cell Lung Cancer: The TORCH Randomized Trial. J Clin Oncol. 
2012;30:3002-3011.
19.
Henze J, Maintz D, Persigehl T. RECIST 1.1, irRECIST 1.1, and mRECIST: How to Do. Curr Radiol Rep. 
2016;4:48.
NCT03023423


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414LUC2001; Amendment 7
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Approved, Date: 4 October 2018
20.
Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, 
advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. 
Lancet. 2016:387(10027):1540-1550.
21.
Hirsch FR, McElhinny A, Stanforth D, et al. PD-L1 Immunohistochemistry Assays for Lung Cancer: Results 
from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project. J Thor Onc. 2016;12(2):208-222.
22.
Horenstein, AL, Chillemi A, Zaccarello G, et al. A CD38/CD203a/CD73 ectoenzymatic pathway independent 
of CD39 drives a novel adenosinergic loop in human T lymphocytes. Oncoimmunology. 2013;2:e26246.
23.
Horn L, Spigel DR, Gettinger SN, et al. Clinical activity, safety and predictive biomarkers of the engineered 
antibody MPDL3280A (anti-PDL1) in non-small cell lung cancer (NSCLC): update from a phase Ia study. J 
Clin Oncology. 2015;33:abstract 8029.
24.
Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2011, National Cancer 
Institute. Bethesda, MD. Available at: http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 
2011 SEER data submission, posted to the SEER web site, 2012. Accessed: 28 January 2016.
25.
Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune 
system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA. 2002;99:12293-12297.
26.
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. 
N Engl J Med. 2010;363:1693-1703.
27.
Krejcik J, Casneuf T, Nijhof I, et al.  Daratumumab depletes CD38+ immune-regulatory cells, promotes T-cell 
expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016 (pre-publish online 24 May 2016).
28.
Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release 
syndrome. Blood. 2014;124:188195.
29.
Maude SL, Barrett D, Teachey DT, et al. Managing cytokine release syndrome associated with novel T cell-
engaging therapies. Cancer J. 2014;20:119122.
30.
Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, 
treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584-594.
31.
Moran T, Sequist LV. Timing of epidermal growth factor receptor tyrosine kinase inhibitor therapy in patients 
with lung cancer with EGFR mutations. J Clin Oncol. 2012;30:3330-3336.
32.
NCCN Guidelines. Non-small cell lung cancer. Version 4.2016. Available at: 
https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed 08 June 2016.
33.
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a common language 
for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. 
Clin Cancer Res. 2013; 19(14):3936-3943.
34.
Ohe Y, Ohashi Y, Kubota K, et al. Randomized phase III study of cisplatin plus irinotecan versus carboplatin 
plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung 
cancer: Four-arm cooperative study in Japan. Ann Oncol. 2007; 18:317-323.
35.
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.
36.
Overdijk MB, Verploegen S, Bögels M, et al. Antibody-mediated phagocytosis contributes to the anti-tumor 
activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 
2015;7(2):311-321.
37.
Peters S, Gettinger S, Johnson ML, et al. Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy 
for Patients With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer (BIRCH). J 
Clin Oncol. 2017; 35(24): 2781-2789.
38.
Petersen RP, Campa MJ, Sperlazza J, et al. Tumor infiltrating Foxp3+ regulatory T-cells are associated with 
recurrence in pathologic stage I NSCLC patients. Cancer. 2006;107:2866-2872.
39.
Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated 
non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. The Lancet. 
2017; 389:255-265.
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40.
Ruiz R, Hunis B, Raez LE. Immunotherapeutic agents in non-small-cell lung cancer finally coming to the front 
lines. Curr Oncol Rep. 2014;16(9):400.
41.
Sandler A, Gray R, Perry MC, et al. Paclitaxel–carboplatin alone or with bevacizumab for non–small-cell lung 
cancer. N Engl J Med. 2006;355:25422550.
42.
Scagliotti GV, De Marinis F, Rinaldi M, et al. Phase III randomized trial comparing three platinum-based 
doublets in advanced non-small-cell lung cancer. J Clin Oncol. 2002;20:42854291.
43.
Schiller JH, Harrington D, Belani CP, et al. Eastern Cooperative Oncology Group. Comparison of four 
chemotherapy regimens for advanced non–small-cell lung cancer. N Engl J Med. 2002;346:9298.
44.
Shaw AT, Kim DW, Nakagawa K, et al. Phase III study of crizotinib versus pemetrexed or docetaxel in 
patients with advanced ALK-positive non-small cell lung cancer (NSCLC). European Society of Medical 
Oncology Meeting 2012:abstract LBA1 PR.
45.
Spira AI, Park K, Mazières J, et al., Efficacy, safety and predictive biomarker results from a randomized phase 
II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR). J Clin Oncol. 2015;33:abstract 
8010.
46.
Srivastava MK, Andersson Å, Zhu L, et al. Myeloid suppressor cells and immune modulation in lung cancer. 
Immunotherapy. 2012;4:291-304.
47.
Stinchcombe TE, Socinski MA, Lee CB, et al.  Considerations for second-line therapy of non-small cell lung 
cancer. Oncologist. 2008;13:128136.
48.
Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous 
cell carcinoma. Cancer Res. 2003;63:6501−6505.
49.
Teachey DT, Rheingold SR, Maude SL, et al. Cytokine release syndrome after blinatumomab treatment related 
to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 
2013;121:51545157.
50.
TECENTRIQ (atezolizumab) [Summary of Product Characteristics]. Roche.
51.
TECENTRIQ (atezolizumab) [United States Package Insert]. Roche.
52.
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of antiPD-1 antibody in 
cancer. N Engl J Med. 2012;366:24432454.
53.
VENTANA PD-L1 (SP142) Assay. 2016a. [package insert, reference 740-4859]. Tucson, AZ, USA: Ventana 
Medical Systems, Inc.
54.
VENTANA PD-L1 (SP142) IHC Assay. 2016b. [package insert, reference 790-4860]. Tucson, AZ, USA: 
Ventana Medical Systems, Inc. and Mannheim, Germany: Roche Diagnostics GmbH.
55.
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: 
immune-related response criteria. Clin Cancer Res. 2009;15(23):7412-7420.
56.
World Health Organization (WHO) Cancer Fact Sheet. 2015. Available at: 
http://www.who.int/mediacentre/factsheets /fs297/en/. Accessed 01 July 2016.
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Attachment 1: Antihistamine Medications
The following antihistamines may be used for daratumumab preinfusion medication:

Diphenhydramine

Cetirizine

Fexofenadine

Loratadine

Clemastine

Dexchlorpheniramine.
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Attachment 2: Conversion Table for Glucocorticosteroid Dose
Glucocorticoid
Approximate Equivalent Dose (mg)
Half-life (Biologic) hours
Intermediate-Acting
Methylprednisolone
4
18-36
Prednisolone
5
18-36
Prednisone
5
18-36
Triamcinolone
4
18-36
Long-Acting
Betamethasone
0.6 – 0.75
36-54
Dexamethasone
0.75
36-54
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Attachment 3: 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
Source:  Oken 198235
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Attachment 4: Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a 
consequence of the underlying disease or condition under investigation (disease related) or 
background regimen.
For the purposes of this study, the following events will be considered anticipated events:

The clinical manifestations from primary tumors, regional spread, metastasis, and paraneoplastic 
syndromes will be considered as anticipated events. These events include local respiratory events 
(such as cough, dyspnea, hemoptysis, wheezing, chest pain, pneumonia, bronchitis, plural 
effusion); metastasis to nervous system events (such as bone pain, spinal cord depression, headache, 
seizures, meningismus, ataxia, altered mental status) and hepatic events; paraneoplastic syndromes 
(hypercalcemia, syndrome of inappropriate antidiuretic hormone production, Cushing syndrome).

Given the mechanism of action of atezolizumab, events associated with immune-mediated adverse 
events will also be considered as anticipated events, including:

Pneumonitis

Colitis

Endocrinopathies (diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, 
hypophysitis)

Hepatitis 

Transaminitis Grade ≥2 (AST or ALT > 3xULN and bilirubin > 2xULN, or AST/ALT 
> 10xULN) 

Systemic lupus erythematosus

Neurologic: 
Guillain-Barré 
syndrome, 
myasthenia 
gravis/myasthenic 
syndrome, 
meningoencephalitis 

Nephritis

Events suggestive of hypersensitivity, cytokine release, influenza-like illness, systemic 
inflammatory response syndrome, systemic immune activation, infusion reactions syndrome, 
immune-mediated myocarditis, vasculitis, severe cutaneous adverse reactions autoimmune 
hemolytic anemia.
Because this is the first study of daratumumab in NSCLC subjects and with the combination of 
atezolizumab and daratumumab, other adverse events cannot be anticipated.
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Reporting of Anticipated Events
All adverse events will be recorded in the CRF regardless of whether considered to be 
anticipated events and will be reported to the Sponsor as described in Section 12.3.1, All 
Adverse Events. Any anticipated event that meets serious adverse event criteria will be reported 
to the Sponsor as described in Section 12.3.2, Serious Adverse Events. These anticipated events 
are exempt from expedited reporting as individual single cases to Health Authorities. However,
if based on an aggregate review, it is determined that an anticipated event is possibly related to 
study drug, the Sponsor will report these events in an expedited manner.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and 
threshold to trigger an aggregate analysis of anticipated events will be provided in a separate 
Anticipated Events Safety Monitoring Plan (ASMP).
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Attachment 5: Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference 
RECIST version 1.1
Measurable Tumor Burden
A maximum of 5 target lesions in total (and up to 2 per organ) can be identified at 
baseline and measured through the course of therapy.
Minimum Size of
Measurable Lesions
≥10 mm in longest diameter (LD) by CT scan of which slice is thickness no 
greater than 5 mm
≥15 mm in short axis (SA) for nodal lesions by CT scan of which slice is thickness 
no greater than 5 mm
≥10 mm in LD for clinical lesions (must be measured using electronic 
calipers)
≥20 mm in LD for chest X-ray (if clearly defined and surrounded by aerated 
lung); CT is preferable
Ultrasound (US) cannot be used to measure lesions
Lymph Nodes
Lymph nodes are considered pathologically enlarged if >10 mm in SA. 
To be measurable, nodal lesions must be ≥15 mm in SA by CT scan of which slice 
is thickness no greater than 5 mm. 
Nodal lesions with SA >10 mm and <15 mm are non- measurable.
The sum of the diameters (LD for non-nodal target lesions, SA for nodal
lesions) is followed through the course of therapy.
Bone Lesions
A lytic or mixed lytic-blastic bone lesion with a soft tissue component assessed on
CT/MRI can be measurable if the minimum size criteria are met.
Blastic bone lesions and bone lesions assessed on bone scan, positron emission
therapy (PET) or plain films are non-measurable.
Cystic Lesions
Lesions that meet the criteria for radiographically defined simple cysts are not
malignant.
Cystic lesions thought to be metastases can be measurable if they meet the
minimum size criteria. 
If noncystic lesions are present in the same patient, they are preferred for selection 
as target lesions.
Lesions with Prior Local 
Treatment
Lesions in previously irradiated areas (or areas treated with local therapy) are not
measurable unless the lesion has progressed since therapy.
Too Small To Measure
If a target lesion becomes too small to measure, a default value of 5 mm is
assigned. If the lesion disappears, the measurement is recorded as 0 mm.
Lesions which split or 
Coalesce
If non-nodal target lesions fragment, the LDs of the fragmented portions are added 
to calculate the sum.
If target lesions coalesce and cannot be distinguished, the LD of the coalesced
lesion is added to the sum.
Definition of Complete 
Response (CR)
CR requires:

The disappearance of all lesions. 

All lymph nodes must be non-pathological in size (<10 mm SA).

Normalization of tumor marker level.
Definition of Partial Response 
(PR)
≥30% decrease in the sum of the diameters of all target lesions compared with
baseline, in absence of new lesions or unequivocal progression of non-target 
lesions
Definition of Stable Disease 
(SD)
<30% decrease in sum of diameters of all target lesions compared with baseline
and  <20% increase compared with nadir, in the absence of new lesions or 
unequivocal progression of nontarget lesions
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Definition of Progressive 
Disease (PD)
PD is assessed if the sum of the diameters has increased by ≥20% and ≥5 mm from 
nadir (including baseline if it is the smallest sum).
Patients with measurable disease: for "unequivocal progression" based on 
nontarget disease, there must be an overall level of substantial worsening that 
merits discontinuation of therapy (if target disease is SD/PR).
Patients without measurable disease: for "unequivocal progression" of non-target 
disease, the increase in overall tumor burden must be comparable to the increase
required for PD of measurable disease. Furthermore, the
appearance of 1 or more new lesions or unequivocal progression of a 
nontarget lesion is also considered as PD.
Assessment of New Lesions
New lesions should be unequivocal and not attributable to differences in scanning 
technique or findings which may not be tumor (ie, 'new' bone lesions may be 
healing or flare of pre-existing lesions). If one is equivocal, repeat scans are 
needed to confirm. If confirmed, PD is assessed at the date of the initial scan. 
Lesions identified in anatomic locations not scanned at baseline are considered 
new. New lesions on US should be confirmed on CT/MRI.
FDG-PET
New lesions can be assessed using FDG-PET: (-) PET at baseline and (+) PET at 
follow-up is PD based on a new lesion. No PET at baseline and (+) PET at follow-
up is PD if the new lesion is confirmed on CT. If a subsequent CT confirms the 
new lesion, the date of the PD is the date of the initial PET scan. No PET at 
baseline and (+) PET at follow-up corresponding to pre-existing lesion on CT that 
is not progressing; not PD.
Recurrence of lesions
For a patient with SD/PR, a lesion which disappears and then reappears will 
continue to be measured and added to the sum. Response will depend upon the 
status of the other lesions. For a patient with CR, reappearance of a lesion would 
be considered PD.
Overall Response
One overall response table integrates target, nontarget, and new lesions for subjects 
with measurable disease; and another table integrates nontarget and new lesions for 
subjects without measurable disease.
Confirmation of Response
In nonrandomized trials where response is the primary endpoint, confirmation of 
PR and CR is required to ensure responses identified are not the result of 
measurement error. In these trials, subsequent confirmation of PR with one interim 
time point of SD is acceptable. In randomized trials, confirmation of response is 
not required.
CR=complete response, CT=computed tomography, FDG-PET=fluorodeoxyglucose positron emission therapy
LD=longest diameter, PD=progressive disease, PR=partial response, SA=short axis, SD=stable disease, 
US=ultrasound
Source: Eisenhauer 2009 14
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Attachment 6: Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)
RECIST 1.1
irRECIST
New, measurable 
lesions
Always represent progressive disease (PD)
Incorporated into tumor burden
New, non-
measurable 
lesions
If unequivocal, represent PD; if equivocal, 
does not represent PD (but precludes 
complete response) and should be followed 
for unequivocal progression at a later 
timepoint
Same as RECIST 1.1.
Non-target lesions
Changes contribute to defining best overall
response (BOR) of CR, PR, SD, and PD
Same as RECIST 1.1.
Response Category
CR
Disappearance of all lesions
Same as RECIST 1.1.
PR
≥30% decrease in the sum of the diameters
of all target lesions compared with baseline,
in absence of new lesions or unequivocal
progression of non-target lesions
Same as RECIST 1.1.
SD
<30% decrease in sum of diameters of all
target lesions compared with baseline and   
<20% increase compared with nadir, in 
the absence of new lesions or unequivocal 
progression of nontarget lesions
Same as RECIST 1.1.
PD
At least 20% increase in the sum of the 
diameters
for
target
lesions 
and/or 
unequivocal 
progression
of 
nontarget
lesions, compared with nadir (at any single 
time point including baseline). The sum 
must also demonstrate an absolute increase 
of at least 5 mm.
Same as RECIST 1.1, with the following 
exceptions:
1. Increases are observed in 2 consecutive 
observations at least 4 weeks apart.
2. New target lesions (maximum of 
5 new target lesions; maximum of 2 per 
organ) are included in calculating tumor 
burden
Handling of 
lymph nodes
Lymph nodes are considered pathologically 
enlarged
if >10 mm in SA. To be
measurable, nodal lesions must be ≥15 mm
in SA. Nodal lesions with SA >10 mm and 
<15 mm are non- measurable. The sum of
the diameters (LD for non-nodal target 
lesions, SA for nodal lesions) is followed 
through the course of therapy.
Same as RECIST 1.1.
BOR=best overall response, CR=complete response, LD=longest diameter, PD=progressive disease, PR=partial 
response, SA=short axis, SD=stable disease
Sources: Henze 201619, Nishino 201333
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Attachment 7: Management Guidelines for Atezolizumab
Management guidelines for toxicities associated or possibly associated with atezolizumab are 
provided as follows:

Pulmonary events, please see Table 13

Hepatic events, please see Table 14

Gastrointestinal events, please see Table 15

Endocrine events, please see Table 16

Ocular events, please see Table 17

Pancreatic events, please see Table 18

Immune-mediated myocarditis, please see Table 19

Dermatologic events, please see Table 20

Neurologic disorders and meningoencelphalitis, please see Table 21

Systemic immune activation events, please see Table 22

Immune-related Nephritis, please see Table 23.
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Table 13:
Management Guidelines for Pulmonary Events, Including Pneumonitis
Event
Management
Pulmonary event,
Grade 1
Continue atezolizumab and monitor closely.
Re-evaluate on serial imaging.
Consider subject referral to pulmonary specialist.
Pulmonary event,
Grade 2
Withhold atezolizumab for up to 12 weeks after event onset.a
Refer subject to pulmonary and infectious disease specialists and consider
bronchoscopy or BAL.
Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.
If event resolves to Grade 1 or better, resume atezolizumab.b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Sponsor.c
Pulmonary event,
Grade 3
or Grade 4
Permanently discontinue atezolizumab and contact the Sponsor.c
Bronchoscopy or BAL is recommended.
Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.
If event does not improve within 48 hours after initiating corticosteroids,
consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
BAL=bronchoscopic alveolar lavage; IVIG=intravenous immunoglobulin
a. Atezolizumab may be withheld for a longer period of time (ie, >12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length of 
the extended period of time must be agreed upon by the investigator and the Sponsor.
b. If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.
c. Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered 
from the immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the Sponsor.
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Table 14:
Management Guidelines for Hepatic Events
Event
Management
Hepatic event,
Grade 1
Continue atezolizumab.
Monitor LFTs until values resolve to within normal limits.
Hepatic event,
Grade 2
All events:
Monitor LFTs more frequently until return to baseline values.
Events of 5 days’ duration:
Withhold atezolizumab for up to 12 weeks after event onset.a
Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.
If event resolves to Grade 1 or better, resume atezolizumab.b  
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Hepatic event,
Grade 3 or 4
Permanently discontinue atezolizumab and contact the Sponsor.c
Consider subject referral to gastrointestinal specialist for evaluation and
liver biopsy to establish etiology of hepatic injury.
Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.
If event does not improve within 48 hours after initiating corticosteroids,
consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
LFTliver function tests.
a. Atezolizumab may be withheld for a longer period of time (ie, > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length
of the extended period of time must be agreed upon by the investigator and the Sponsor.
b. If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral prednisone or
equivalent before atezolizumab can be resumed.
c. Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered
from the immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been
documented by both the investigator (or an appropriate delegate) and the Sponsor.
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Table 15:
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis)
Event
Management
Diarrhea or
colitis, Grade 1
Continue atezolizumab.
Initiate symptomatic treatment.
Endoscopy is recommended if symptoms persist for 7 days.
Monitor closely.
Diarrhea or
colitis, Grade 2
Withhold atezolizumab for up to 12 weeks after event onset. a
Initiate symptomatic treatment.
Subject referral to GI specialist is recommended.
For recurrent events or events that persist 5 days, initiate treatment with
12 mg/kg/day oral prednisone or equivalent.
If event resolves to Grade 1 or better, resume atezolizumab. b  
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor. c
Diarrhea or
colitis, Grade 3
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer subject to gastrointestinal specialist for evaluation and confirmatory
biopsy.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and
convert to 12 mg/kg/day oral prednisone or equivalent upon improvement.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
c
Diarrhea or colitis, 
Grade 4
Permanently discontinue atezolizumab and contact the Sponsor.c
Refer subject to gastrointestinal specialist for evaluation and confirmation 
biopsy.
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement.
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.
a. Atezolizumab may be withheld for a longer period of time (ie, >12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length
of the extended period of time must be agreed upon by the investigator and the Sponsor.
b. If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.
c. Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered 
from the immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the Sponsor.
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Table 16:
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism
Continue atezolizumab.
Initiate treatment with thyroid replacement hormone.
Monitor TSH weekly.
Symptomatic 
hypothyroidism
Withhold atezolizumab.
Initiate treatment with thyroid replacement hormone.
Monitor TSH weekly.
Consider subject referral to endocrinologist.
Resume atezolizumab when symptoms are controlled and thyroid function is 
improving.
Asymptomatic 
hyperthyroidism
TSH ≥0.1 mU/L and <0.5 mU/L:
Continue atezolizumab.
Monitor TSH every 4 weeks.
TSH <0.1 mU/L:
Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism
Withhold atezolizumab.
Initiate treatment with anti-thyroid drug such as methimazole or carbimazole as 
needed.
Consider subject referral to endocrinologist.
Resume atezolizumab when symptoms are controlled and thyroid function is 
improving.
Permanently discontinue atezolizumab and contact the Sponsor for life-threatening 
immune-related hyperthyroidism.a
Symptomatic adrenal 
insufficiency,
Grade 2-4
Withhold atezolizumab for up to 12 weeks after event onset. b
Refer subject to endocrinologist.
Perform appropriate imaging.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and
convert to 12 mg/kg/day oral prednisone or equivalent upon improvement.
If event resolves to Grade 1 or better, resume atezolizumab. c
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor. a
Hyperglycemia, 
Grade 1 or 2
Continue atezolizumab.
Initiate treatment with insulin if needed.
Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4
Withhold atezolizumab.
Initiate treatment with insulin.
Monitor for glucose control.
Resume atezolizumab when symptoms resolve and glucose levels are stable.
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Hypophysitis
pan-hypopituitarism),
Grade 2-3
Withhold atezolizumab for up to 12 weeks after event onset. b
Refer subject to endocrinologist.
Perform brain MRI (pituitary protocol).
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement.
If event resolves to Grade 1 or better, resume atezolizumab. c  
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor.a 
For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis
pan-hypopituitarism),
Grade 4
Permanently discontinue atezolizumab and contact the Sponsor.a
Refer subject to endocrinologist.
Perform brain MRI (pituitary protocol).
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement.b
Initiate hormone replacement therapy if clinically indicated.
TSH=thyroid-stimulating hormone
a. Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered 
from the immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the Sponsor.
b. Atezolizumab may be withheld for a longer period of time (ie, >12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length
of the extended period of time must be agreed upon by the investigator and the Sponsor.
c. If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.
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Table 17:
Management Guidelines for Ocular Events
Event
Management
Ocular event,
Grade 1
Continue atezolizumab.
Subject referral to ophthalmologist is strongly recommended.
Initiate treatment with topical corticosteroid eye drops and topical
immunosuppressive therapy.
If symptoms persist, treat as a Grade 2 event.
Ocular event,
Grade 2
Withhold atezolizumab for up to 12 weeks after event onset.b
Subject referral to ophthalmologist is strongly recommended.
Initiate treatment with topical corticosteroid eye drops and topical
immunosuppressive therapy.
If event resolves to Grade 1 or better, resume atezolizumab.a
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor.c
Ocular event,
Grade 3 or 4
Permanently discontinue atezolizumab and contact the Sponsor.c
Refer subject to ophthalmologist.
Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.
If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
a. If corticosteroids have been initiated, they must be tapered over ≥1 month to≤10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
b. Atezolizumab may be withheld for a longer period of time (ie, >12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length
of the extended period of time must be agreed upon by the investigator and the Sponsor.
c. Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered 
from the immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the Sponsor.
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Table 18:
Management Guidelines for Pancreatic Events, Including Pancreatitis
Event
Management
Amylase and/or lipase
elevation, Grade 2
Continue atezolizumab.
Monitor amylase and lipase weekly.
For prolonged elevation (eg, 3 weeks), consider treatment with
10 mg/day oral prednisone or equivalent.
Amylase and/or lipase
elevation, Grade 3 or 4
Withhold atezolizumab for up to 12 weeks after event onset.a
Refer subject to gastrointestinal specialist.
Monitor amylase and lipase every other day.
If no improvement, consider treatment with 12 mg/kg/day oral
prednisone or equivalent.
If event resolves to Grade 1 or better, resume atezolizumab.b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Sponsor.c
For recurrent events, permanently discontinue atezolizumab and contact 
the Sponsor.C
Immune-related
pancreatitis, Grade 2 or
3
Withhold atezolizumab for up to 12 weeks after event onset.a
Refer subject to gastrointestinal specialist.
Initiate treatment with 12 mg/kg/day intravenous methylprednisolone or
equivalent and convert to 12 mg/kg/day oral prednisone or equivalent
upon improvement.
If event resolves to Grade 1 or better, resume atezolizumab.b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Sponsor.c
For recurrent events, permanently discontinue atezolizumab and contact 
the Sponsor.c
Immune-related
pancreatitis, Grade 4
Permanently discontinue atezolizumab and contact the Sponsor.c
Refer subject to gastrointestinal specialist.
Initiate treatment with 12 mg/kg/day intravenous methylprednisolone or
equivalent and convert to 12 mg/kg/day oral prednisone or equivalent
upon improvement.
If event does not improve within 48 hours after initiating corticosteroids,
consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over
1 month.
a. Atezolizumab may be withheld for a longer period of time (ie, >12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length
of the extended period of time must be agreed upon by the investigator and the Sponsor.
b. If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.
c. Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered 
from the immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the Sponsor.
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Table 19:
Management Guidelines for Immune-Related Myocarditis
Event
Management
Immune-related
myocarditis, Grade 1
Refer subject to cardiologist
Initiate treatment as per institutional guidelines.
Immune-related
myocarditis, Grade 2
Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Sponsor.
Refer subject to cardiologist
Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.
Consider treatment with 1-2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement.a
If event resolves to Grade 1 or better, resume atezolizumab.b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Sponsor.c
Immune-related
myocarditis, Grade 3-4
Permanently discontinue atezolizumab and contact Sponsor.c
Refer subject to cardiologist
Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement.a,b
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better taper corticosteroids over 1
  ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device
a.
Atezolizumab may be withheld for a longer period of time (ie, >12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable 
length of the extended period of time must be agreed upon by the investigator and the Sponsor.
b.
If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.
c.
Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully 
recovered from the immune-related event. Subjects can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Sponsor.
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Table 20:
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic event,
Grade 1
Continue atezolizumab.
Consider treatment with topical corticosteroids and/or other symptomatic
therapy (eg, antihistamines).
Dermatologic event,
Grade 2
Continue atezolizumab.
Consider subject referral to dermatologist.
Initiate treatment with topical corticosteroids.
Consider treatment with higher-potency topical corticosteroids if event does
not improve
Dermatologic event,
Grade 3
Withhold atezolizumab for up to 12 weeks after event onset .a
Refer subject to dermatologist.
Initiate treatment with 10 mg/day oral prednisone or equivalent, increasing 
dose to 1-2 mg/kg/day if event does not improve within 48-72 hours.
If event resolves to Grade 1 or better, resume atezolizumab.b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact Sponsor. 
Dermatologic event,
Grade 4
Permanently discontinue atezolizumab and contact the Sponsor.c
a. Atezolizumab may be withheld for a longer period of time (ie, >12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length
of the extended period of time must be agreed upon by the investigator and the Sponsor.
b. If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.
c. Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered 
from the immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the Sponsor.
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Table 21:
Management Guidelines for Neurologic Disorders, Including Meningoencephalitis
Event
Management
Immune-related
neuropathy, Grade 1
Continue atezolizumab.
Investigate etiology.
Immune-related
neuropathy, Grade 2
Withhold atezolizumab for up to 12 weeks after event onset .a
Investigate etiology.
Initiate treatment as per institutional guidelines.
If event resolves to Grade 1 or better, resume atezolizumab.b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Immune-related
neuropathy, Grade 3 or
4
Permanently discontinue atezolizumab and contact the Sponsor.c
Initiate treatment as per institutional guidelines.
Myasthenia gravis and
Guillain-Barré
syndrome (any grade)
Permanently discontinue atezolizumab and contact the Sponsor.c
Refer subject to neurologist.
Initiate treatment as per institutional guidelines.
Consider initiation of 12 mg/kg/day oral or IV prednisone or equivalent.
Immune-related
meningoencephalitis, all
grades
Permanently discontinue atezolizumab and contact the Sponsor. C
Refer subject to neurologist.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or
equivalent and convert to 12 mg/kg/day oral prednisone or equivalent
upon improvement.
If event does not improve within 48 hours after initiating corticosteroids,
consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
IV=intravenous
a. Atezolizumab may be withheld for a longer period of time (ie, >12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length
of the extended period of time must be agreed upon by the investigator and the Sponsor.
b. If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.
c. Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered 
from the immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the Sponsor.
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Table 22:
Diagnostic Criteria and Management for Systemic Immune Activation
Systemic Immune Activation
Systemic immune activation criteria apply only when alternate etiologies have been excluded
Major Criteria
Minor Criteria

Fever 38.5C (on more than one occasion)

Ferritin 3000 ng/mL

Cytopenias:
Grade 2 in two or more lineages

2 age-adjusted SD elevation soluble IL-2 receptor

Severe multi-organ dysfunction

Decreased fibrinogen

Splenomegaly

Hemophagocytosis
BM, spleen or LN

Elevated GGT or LFTs (AST/ALT/tBili)

Elevated triglycerides

Elevated LDH

Decreased natural killer-cell activity
Number of 
Criteria
Management
Consistent with 
systemic immune 
activation
4 major criteria
Consider tocilizumab (4 mg/kg IV) and Solumedrol(methylprednisolone)
(1g IV QD).
Contact the Sponsor for additional recommendations.
Consider HLH-94 protocol if no clinical improvement.
Probable systemic 
immune 
activation
3 major criteria
OR
2 major criteria
AND
3 minor criteria
Depending on clinical severity, subject can be treated as per “Consistent 
with systemic immune activation” or “Possible systemic immune 
activation” case definition.
Contact the Sponsor for additional recommendations
Possible systemic 
immune 
activation
1 major criteria
AND
4 minor criteria
Consider Solumedrol(1g IV QD)
Contact the Sponsor for additional recommendations.
As per “Consistent with systemic immune activation” recommendations if 
no improvement or clinically worsening
BM bone marrow; GGT gamma-glutamyl transpeptidase; IL-2 interleukin-2; IV intravenous; LFT liver 
function test; LN= lymph node; QD once daily; tBili total bilirubin.
Notes: Criteria adapted from a Delphi Survey of 26 experts regarding helpful criteria in the positive diagnosis of 
Hemophagocytic Syndrome in adult subjects (Hejblum G. et al PLoS One [Public Library of Science]
April 2014; Volume 9, Issue 4). Standard-of-care for systemic immune activation has not been established. Case 
reports and recommendations have been published for cytokine release syndrome (Lee 2014, Maude 2014, 
Teachey 2013),28, 29, 49 and based on etiologic similarities, these practices have been incorporated into the above 
treatment recommendations.
These recommendations do not replace clinical judgment and are intended as suggested guidance.
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Table 23:
Management Guidelines for Immune-Related Nephritis
Event
Management
Immune-related
nephritis, Grade 2
Withhold atezolizumab and contact Sponsor.
Refer subject to renal specialist
Initiate treatment as per institutional guidelines and consider renal biopsy 
and supportive measures.
Corticosteroids and/or additional immunosuppressive agents should be 
administered as clinically indicated.
Immune-related
nephritis, Grade 3-4
Permanently discontinue atezolizumab and contact Sponsor.
Refer subject to renal specialist
Initiate treatment as per institutional guidelines and and consider renal 
biopsy and supportive measures.
Corticosteroids and/or additional immunosuppressive agents should be 
administered as clinically indicated.
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INVESTIGATOR AGREEMENT
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SAP_000.pdf: 
1
Approved, Date: 19 September 2018
Janssen Research & Development 
Statistical Analysis Plan 
A Phase 1b/2, Open-Label, Randomized Study of Daratumumab Administered in 
Combination with Atezolizumab Compared with Atezolizumab Alone in Subjects with 
Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer
Protocol 54767414LUC2001
Phase 1b/2
DARZALEX®
JNJ-54767414 daratumumab    
Status:
Approved
Date:
19 September 2018
Prepared by:
Janssen Research & Development, LLC
Document No.:
EDMS-ERI-171019418
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Trial Objectives ................................................................................................................................ 6
1.2.
Trial Design ...................................................................................................................................... 6
1.3.
Statistical Hypothesis for the Primary Objective .............................................................................. 8
1.4.
Sample Size Determination ............................................................................................................. 8
1.5.
Randomization and Blinding ............................................................................................................ 9
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 9
2.1.
Baseline, Relative Day..................................................................................................................... 9
2.2.
Pooling Algorithm for Analysis Centers............................................................................................ 9
2.3.
Analysis Sets.................................................................................................................................... 9
2.3.1.
Intent-To-Treat Analysis Set......................................................................................................... 9
2.3.2.
Safety Analysis Set....................................................................................................................... 9
2.3.3.
Response-evaluable Analysis Set .............................................................................................. 10
2.3.4.
DLT Analysis Set ........................................................................................................................ 10
2.3.5.
Safety Run-in Analysis Set ......................................................................................................... 10
2.3.6.
Immunogenicity-evaluable Analysis Set..................................................................................... 10
2.3.7.
Pharmacokinetics-evaluable Analysis Set.................................................................................. 10
2.4.
Definition of Subgroups.................................................................................................................. 10
2.5.
Imputation of Missing Data ............................................................................................................ 10
2.6.
Other General Definitions............................................................................................................... 11
2.6.1.
Treatment Groups....................................................................................................................... 11
2.6.2.
Month and Year .......................................................................................................................... 11
2.6.3.
Years since Initial NSCLC Diagnosis ......................................................................................... 11
2.6.4.
Total Dose Received .................................................................................................................. 11
2.6.5.
Duration of Treatment................................................................................................................. 11
2.6.6.
Maximum number of Treatment Cycles...................................................................................... 11
2.6.7.
Relative Dose Intensity............................................................................................................... 11
2.6.8.
End of Follow-up and Duration of Follow-up .............................................................................. 11
2.6.9.
Relationship of Adverse Events to Study Medication................................................................. 12
2.6.10.
Treatment Emergent Adverse Events ........................................................................................ 12
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 12
4.
SUBJECT INFORMATION................................................................................................................ 12
4.1.
Demographics and Baseline Disease Characteristics................................................................... 12
4.2.
Disposition Information................................................................................................................... 13
4.3.
Treatment Compliance................................................................................................................... 13
4.4.
Extent of Exposure......................................................................................................................... 13
4.5.
Protocol Deviations ........................................................................................................................ 13
4.6.
Prior and Concomitant Medications ............................................................................................... 14
4.7.
Subsequent Anti-cancer Treatments ............................................................................................. 14
5.
EFFICACY ......................................................................................................................................... 14
5.1.
Analysis Specifications................................................................................................................... 14
5.1.1.
Level of Significance................................................................................................................... 14
5.1.2.
Data Handling Rules................................................................................................................... 14
5.2.
Primary Efficacy Endpoint.............................................................................................................. 14
5.3.
Major Secondary Efficacy Endpoints ............................................................................................. 15
5.3.1.
Duration of Response................................................................................................................. 15
5.3.2.
Clinical Benefit Rate ................................................................................................................... 15
5.3.3.
Progression Free Survival .......................................................................................................... 16
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5.3.4.
Overall Survival........................................................................................................................... 16
6.
SAFETY............................................................................................................................................. 17
6.1.
Adverse Events .............................................................................................................................. 17
6.1.1.
Treatment Emergent Adverse Events ........................................................................................ 17
6.1.2.
Adverse Events of Clinical Interest............................................................................................. 18
6.1.2.1.
Infusion Related Reactions...................................................................................................... 18
6.1.2.2.
Dose Limiting Toxicity.............................................................................................................. 18
6.1.2.3.
Immune-mediated Adverse Event ........................................................................................... 18
6.2.
Deaths............................................................................................................................................ 18
6.3.
Clinical Laboratory Tests................................................................................................................ 18
6.4.
Vital Signs and Physical Examination Findings ............................................................................. 18
6.5.
Electrocardiogram.......................................................................................................................... 19
6.6.
Other Safety Parameters ............................................................................................................... 19
6.6.1.
ECOG Performance Status ........................................................................................................ 19
7.
PHARMACOKINETICS/IMMUNOGENICITY/PHARMACODYNAMICS .......................................... 19
7.1.
Pharmacokinetics........................................................................................................................... 19
7.2.
Immunogenicity.............................................................................................................................. 19
8.
BIOMARKER..................................................................................................................................... 19
9.
HEALTH ECONOMICS ..................................................................................................................... 20
REFERENCES............................................................................................................................................ 21
Attachment 1: Criteria For Dose Limiting Toxicity (Protocol Table 6) ................................................ 22
Figures
Figure 1:
Schematic Overview of the Study Design................................................................................... 8
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ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
CBR
clinical benefit rate
BSC
best supportive care
CMH
Cochran–Mantel–Haenszel
COPD
chronic obstructive pulmonary disease
CR
complete response
CRF
case report form
CSR
clinical study report
CT
computed tomography
sCR
stringent complete response
CRF
case report form (electronic)
DLT
dose-limiting toxicity
DoR
duration of response
DPS
data presentation specifications
ECG
electrocardiogram
ECOG
eastern cooperative oncology group
FEV1
forced expiratory volume in the first second
FFPE
formalin-fixed, paraffin-embedded
GCP
good clinical practice
HIV
human immunodeficiency virus
ICF
informed consent form
INR
International Normalized Ratio
IRR
infusion-related reaction
ITT
intent-to-treat
IWRS
interactive web response system
LD
longest diamete
MedDRA
medical dictionary for regulatory activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI-CTCAE
national cancer institute common terminology criteria for adverse events
NGS
next-generation sequencing
NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
overall survival
PD
progressive disease
PD-1
programmed death-1
PD-L1
programmed death-ligand 1
PFS
progression-free survival
PI
proteasome inhibitor
PK
pharmacokinetic(s)
PR
partial response
PT
preferred term
PrT
prothrombin time
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PTT
partial thromboplastin time
RECIST
response evaluation criteria in solid tumors 
SAD
short axis diameter
SAE
serious adverse event
SD
stable disease
SET
study evaluation team
SIPPM
site investigational product procedures manual
SOC
system organ class
SPD
sum of the products of the two largest perpendicular diameters
STD
Standard deviation
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
VGPR
very good partial response
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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of the analysis population(s), derived 
variables and statistical methods for Study 54767414 LUC2001.
1.1.
Trial Objectives
Primary Objective
The primary objective of this study is to compare the overall response rate (ORR) in subjects 
treated with daratumumab in combination with atezolizumab versus atezolizumab alone.
Secondary Objectives

To assess the safety of the combination of daratumumab and atezolizumab

To compare the duration of response (DoR) in subjects treated with daratumumab in
combination with atezolizumab versus atezolizumab alone

To compare the clinical benefit rate (CBR) in subjects treated with daratumumab in
combination with atezolizumab versus atezolizumab alone

To compare progression-free survival (PFS) in subjects treated with daratumumab in
combination with atezolizumab versus atezolizumab alone

To compare overall survival (OS) in subjects treated with daratumumab in combination with      
atezolizumab versus atezolizumab alone

To evaluate the pharmacokinetic and immunogenicity profile of daratumumab when given      
in combination with atezolizumab

To evaluate the pharmacokinetic and immunogenicity profile of atezolizumab when given in      
combination with daratumumab
Exploratory Objectives

To compare ORR evaluated by the Immune-Related Response Evaluation Criteria in Solid 
Tumors (irRECIST)

To explore biomarkers predictive of response to therapy

To evaluate potential pharmacodynamic biomarkers in response to therapy

To explore the relationships between pharmacokinetics, pharmacodynamics, adverse event
profiles, and clinical activity of daratumumab given in combination with atezolizumab in
subjects with previously treated advanced or metastatic NSCLC

To explore the benefit of daratumumab and atezolizumab treatment in subjects who had 
confirmed disease progression on atezolizumab monotherapy
1.2.
Trial Design
The study begins with a 6-subject safety run-in cohort to be evaluated by the Study Evaluation 
Team (SET). After evaluation, if SET has determined that the combination therapy of 
daratumumab and atezolizumab are safe and tolerable, the study will proceed to the 
randomization phase in which 90 subjects are randomized into the two treatment arms
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stratified by PD-L1 expression status (IC0 and TC0 vs. others), histology (squamous vs. non-
squamous), and number of previous lines of therapy received (1 or >1): 
Arm A: atezolizumab; Arm B: atezolizumab + daratumumab.
Subjects in Arm A (treated with atezolizumab monotherapy) who have confirmed disease 
progression based on RECIST 1.1 may cross over to Arm B and receive daratumumab and 
atezolizumab after crossover eligibility criteria are met.
An internal Janssen Data Monitoring Committee (DMC), independent of the study team, will be 
established to review the efficacy and safety data in the randomization phase. The DMC will 
review the totality of data after approximately 40, 60, and 90 subjects have been enrolled, 
including activity within distinct PD-L1 expression subgroups. Based on these findings, the 
DMC may formulate recommendations on study conduct, including the expansion of enrollment 
of some PD-L1 subgroups, resulting in greater than 96 subjects. The DMC may request 
additional ad-hoc reviews as data accumulate.
For subjects in Arm A, Atezolizumab will be administered at 1200 mg IV on Day 1 of every 
21-day cycle. For subjects in the safety run-in cohort and in Arm B, Daratumumab will be
administered intravenously (IV) at 16 mg/kg weekly on Days 1, 8, and 15, for the first 3 cycles,
then on Day 1 of each 21-day cycle thereafter. Atezolizumab for these subjects will be
administered at 1200 mg IV on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle 
thereafter. Pre-infusion medication is administered before first infusion of study medication to 
prevent infusion-related reactions. Post-infusion medication is administered to reduce the risk
of delayed infusion reactions in all subjects.
The combination therapy and the monotherapy will continue until treatment discontinuation due 
to disease progression, unacceptable toxicity, or other protocol-defined treatment discontinuation    
criteria. Subjects enter the Follow-up phase after the End-of-Treatment visit, or 30 (+7) days 
after the discontinuation of the study drugs. Subjects will be followed for survival every 12 
weeks after confirmed disease progression or start of new anticancer therapy. 
The end of the study is anticipated to be 6 to 12 months after the last subject has been enrolled
(last subject in) or when the last subject has the last assessment in this study (eg, last survival
follow- up for the last subject), whichever occurs first, and the study may be extended to allow 
for further treatment and follow-up of subjects.
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Figure 1:
Schematic Overview of the Study Design
        
1.3.
Statistical Hypothesis for the Primary Objective
The primary hypothesis is that the combination therapy of atezolizumab with daratumumab will 
significantly improve ORR compared to atezolizumab monotherapy in subjects with NSCLC.
1.4.
Sample Size Determination
A 6-subject safety run-in cohort will be evaluated by the Safety Evaluation Team to determine 
the safety and tolerability of atezolizumab administered in combination with daratumumab 
before proceeding with the randomized phase of the study.
For the randomization part, assuming that the ORR for atezolizumab monotherapy is 
approximately 20%, and the addition of daratumumab would improve ORR by 20% to 40%, 90
subjects need to be randomized with a 1:1 ratio in order to achieve 80% power to detect this 
difference with a one-sided alpha of 0.10. If benefit from the combination is not observed across 
the overall study population, targeted enrollment of subgroups, based on tumor PD-L1 
expression level, may be implemented, based on DMC recommendations. As such, 
approximately 50 additional subjects in the TC2/TC3 subgroups may be enrolled to preliminarily 
evaluate the treatment effect. If the ORR is 25% for atezolizumab monotherapy and 50% for the 
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atezolizumab + daratumumab combination in the TC2/TC3 subgroup, the lower bound of the 
90% CI for the difference in ORR would exclude 0 (i.e., a positive signal in favor of the 
combination).
1.5.
Randomization and Blinding
Central randomization will be implemented following the  safety run-in evaluation. Subjects will 
be randomly assigned to 1 of 2 treatment arms based on a computer-generated randomization 
schedule prepared before the study by or under the supervision of the sponsor. The 
randomization will be balanced by using randomly permuted blocks and will be stratified by 
centrally determined PD-L1 expression status (TC0 and IC0 vs. others), histology (squamous vs. 
non- squamous), and number of prior therapies (1 vs >1). 
2.
GENERAL ANALYSIS DEFINITIONS
All tabular summaries will be presented by treatment group. Categorical data will be summarized 
by the number and percentage of subjects falling within each category. Continuous variables will 
be summarized by descriptive statistics including N, mean, standard deviation, median, 
minimum, and maximum.   
2.1.
Baseline, Relative Day 
Baseline value is defined as the last non-missing value obtained prior to the first dosing date/time 
of study medication. 
Day 1 is the first dosing date of study medication. Study Day is defined as assessment date – first 
dose date + 1 for any assessment done on or after first dose date; otherwise, study day is defined 
as assessment date – first dose date. 
Unless specified otherwise, data to be analyzed or presented over time will be presented by visit 
and time point (as appropriate) that are recorded in the eCRF. 
2.2.
Pooling Algorithm for Analysis Centers
Data from all study centers will be pooled for analyses. 
2.3.
Analysis Sets
2.3.1.
Intent-To-Treat Analysis Set
Intent-to-Treat (ITT) analysis set includes all subjects who have entered the randomization phase 
of the study. Subject information, demographics, baseline disease characteristics, and efficacy 
summaries will be based on this analysis set.
2.3.2.
Safety Analysis Set
Safety analysis set includes all subjects who have received at least 1 administration of any study 
medication. This analysis set will be used for all exposure and safety analyses. 
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2.3.3.
Response-evaluable Analysis Set
Response-evaluable analysis set includes all randomized subjects who have received at least 1 
administration of study medication and have at least 1 adequate post baseline disease assessment. 
Response related endpoints will also be analyzed based on this analysis set as appropriate. 
2.3.4.
DLT Analysis Set
Dose-limiting Toxicity (DLT) analysis set includes any subject in the safety run-in phase who 
has a DLT regardless of dose received or who did not have a DLT but received at least 75% of 
the planned dose during the DLT evaluation period, which is 21 days starting from the day of the 
first dose of study drug.
Criteria for DLT are listed in Attachment 1. This analysis set will be used to summarize the dose-
limiting toxicity. 
2.3.5.
Safety Run-in Analysis Set
Safety run-in analysis set includes all subjects in the safety run-in phase who have received at 
least 1 administration of study medication. 
2.3.6.
Immunogenicity-evaluable Analysis Set
The immunogenicity-evaluable analysis set includes all subjects who receive at least 1 dose of 
atezolizumab or daratumumab and have appropriate samples for detection of antibodies to 
atezolizumab or daratumumab. This analysis set will be used for immunogenicity related 
analyses. 
2.3.7.
Pharmacokinetics-evaluable Analysis Set
Pharmacokinetics-evaluable analysis set includes all subjects who have received at least 1 dose
of daratumumab or atezolizumab and have at least 1 post-infusion sample collected.   This 
analysis set will be used for PK analyses. 
2.4.
Definition of Subgroups 
The following subgroups are to be performed for exploratory efficacy and/or safety analyses. 
Additional subgroup analyses may be planned if deemed necessary. 
Subgroup
Definition
Analysis Type
Sex
Male, Female
Efficacy, Safety
Age
< 65, 65 
Efficacy, Safety
Race
White, Other
Efficacy, Safety
PD-L1 expression status
Negative (IC0 and TC0), High (TC3 
and IC any), Low (others), based on SP-
142 assay
Efficacy
2.5.
Imputation of Missing Data
Data imputation will be limited and detailed rules will be specified in DPS.  
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2.6.
Other General Definitions
2.6.1.
Treatment Groups
The treatment groups are atezolizumab (Arm A) and atezolizumab + daratumumab (Arm B).
2.6.2.
Month and Year
One year equals to 365.25 days. One month equals to 365.25/12 days.
2.6.3.
Years since Initial NSCLC Diagnosis
This is calculated as date of first dose – date of initial NSCLC diagnosis + 1, divided by 365.25.
2.6.4.
Total Dose Received 
For Daratumumab, total dose (mg/kg) is the sum of the administered doses per kilogram at each 
visit, which is calculated as the total dose (mg) recorded on the eCRF divided by body weight 
(kg) at that visit. For Atezolizumab, total dose (mg) is the sum of the administered doses at each 
visit, which is calculated as the total dose (mg) recorded on the eCRF.
2.6.5.
Duration of Treatment
Duration of treatment in months is derived as last non-zero Daratumumab/Atezolizumab dosing 
date – first non-zero Daratumumab/Atezolizumab dosing date + 1, divided by 365.25/12.
2.6.6.
Maximum number of Treatment Cycles
A subject is considered as treated in a cycle if he/she receives any nonzero dose of 
Daratumumab/Atezolizumab in that cycle. The maximum number of treatment cycle for each 
subject is the largest cycle number in which a subject receives any nonzero dose of 
Daratumumab/Atezolizumab.
2.6.7.
Relative Dose Intensity
For Daratumumab, the relative dose intensity (%) is the ratio of total dose received (mg/kg) and 
total planned dose (mg/kg), calculated as the planned dose times the number of administered 
infusions. For Atezolizumab, the relative dose intensity (%) is the ratio of total dose received 
(mg) and total planned dose (mg), calculated as the planned dose times the number of 
administered infusions.
2.6.8.
End of Follow-up and Duration of Follow-up
The end of follow-up is the date of death for subjects who died. For those who still alive, the end 
of follow-up is defined as the maximum date of the following study evaluations:  labs 
(hematology, chemistry, serology, coagulation, thyroid function ), adverse events, vital signs,
ECOG performance status, study drug administration, 12-lead ECG, disposition, pre-infusion 
medications, post-infusion medications, concomitant medications, Subsequent anti-cancer 
treatment, tumor assessment, clinical events/disease response per investigator and date of last
known to be alive.
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Duration of follow-up (in months) equals the end of follow-up minus the first dose date plus 1,
divided by 365.25/12.
2.6.9.
Relationship of Adverse Events to Study Medication
For each adverse event, its relationship to study medication is determined by investigator and 
recorded on the eCRF. An adverse event is considered as related to study medication if the 
relationship is possible, probable or very likely.
2.6.10.
Treatment Emergent Adverse Events
Treatment emergent adverse events (TEAEs) are defined as any AE with onset date and time on 
or after that of the first dose through 30 days after the last study drug administration, or the day 
prior to start of subsequent therapy, whichever is earlier; or any AE that is considered related to 
(very likely, probably, or   possibly related) study medication regardless of the start date of the 
event. AEs with missing or partial onset date and time will be considered as treatment-emergent 
unless the onset date and time of an AE can be determined as earlier than that of the first dose, or 
later than 30 days after last study drug administration.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
An internal Janssen DMC, independent of the study team, will be established to review the 
efficacy and safety data in the randomization phase. The DMC will consist of a minimum of 
3 members with at least 1 clinician and a statistician, 1 of whom will chair the committee. The 
DMC will review the totality of data after approximately 40, 60, and 90 subjects have been 
enrolled, and will formulate recommendations on study conduct (see protocol Section 11.3). The 
DMC may request additional ad-hoc reviews as data accumulate. 
Additional details will be specified in a separate DMC charter.
4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Disease Characteristics
Subject eligibility will be summarized for all subjects with a non-missing informed consent date. 
Number of subjects who did not meet all inclusion/exclusion criteria will be summarized, 
together with the specific non-met criterion. A listing of subjects who didn’t meet all 
inclusion/exclusion criteria will be provided.
Subject enrollment will be summarized by country and site. 
The following baseline demographic and disease characteristics will be summarized:
-
Demographics: age (continuous), age category (< 65 years and 65 years), sex (male, 
female), race (white, non-white, unknown, and not reported), ethnicity (Hispanic, Non-
Hispanic, unknown, and not reported), height (cm), weight (kg), and ECOG performance 
status score (0, 1).
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Baseline disease characteristics: Tumor stage at initial diagnosis and study entry (0, I, II, III, 
IV, not applicable, unknown), time since initial diagnosis (years), and diagnosis subtype 
(squamous, non-squamous).
In addition, baseline laboratory tests will be summarized, as appropriate. The frequencies of CTC 
toxicity grade for these laboratory parameters at baseline will be provided, if applicable. 
General medical history will be summarized by body system and condition status as reported on 
eCRF. A listing will be generated for abnormal medical history. 
A listing for procedures performed after date of informed consent will be provided.  
Vital signs, including body temperature, pulse, systolic blood pressure and diastolic blood 
pressure at baseline will be summarized.
ECG results at baseline will be summarized by overall interpretation: normal, abnormal and 
clinically significant, abnormal and not clinically significant, and other. 
Spirometry measurement of percent predicted FEV1 will be summarized, if applicable. 
Categorical summary of the stratification factors will be also be presented.
4.2.
Disposition Information
Number of subjects who discontinued from treatment will be summarized, together with reason 
reported on eCRF. Number of subjects who discontinued from study and the reported reason on 
eCRF will be presented similarly. A listing for subject disposition will also be provided.
4.3.
Treatment Compliance
Refer to section 4.4.
4.4.
Extent of Exposure
Duration of treatment in months will be summarized, together with the number of treatment 
cycles. Descriptive statistics for the total dose received, total number of infusions, and relative 
dose intensity (%) will be provided for Daratumumab and Atezolizumab, respectively. 
The frequencies of actions planned prior to infusion start and taken during infusion will be 
summarized, together with reasons reported on eCRF.
For cross-over subjects, exposure data after initiation of cross-over treatment may be 
summarized separately, as applicable. 
4.5.
Protocol Deviations
The incidence of major protocol deviation, together with the corresponding deviation terms will 
be summarized. A listing of all major protocol deviations will be provided.  
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4.6.
Prior and Concomitant Medications
The number of lines of prior systemic therapy will be summarized descriptively as well as by the 
following categories: 1 and > 1. Frequency will also be presented for subjects selected types of prior 
therapies. A listing will be provided for prior cancer-related surgery or radiotherapy. 
Use of concomitant therapies will be provided by therapeutic class, pharmacologic class, and 
preferred term.  
Pre-infusion medications will be grouped by analgesics, antihistamines, and corticosteroids
(intermediate and long-acting). The incidence of pre-infusion medications will be presented by
the aforementioned groups and preferred terms. The same summary will be provided for post-
infusion medications.
4.7.
Subsequent Anti-cancer Treatments 
Subsequent anti-cancer treatments, including radiotherapy, surgery, and systemic therapy, will be
summarized. 
5.
EFFICACY
5.1.
Analysis Specifications
5.1.1.
Level of Significance
All 95% confidence intervals presented will be 2-sided. 
5.1.2.
Data Handling Rules
There is no imputation planned for missing efficacy endpoint values.
For cross-over subjects, efficacy data after initiation of cross-over treatment may be 
summarized separately, as applicable. 
5.2.
Primary Efficacy Endpoint
The primary efficacy endpoint is overall response rate (ORR). 
Definition
The primary endpoint is overall response rate (ORR), defined as the proportion of subjects who
achieve a response of partial response (PR) or better.
Analysis Methods
Analysis will be based on the ITT population, and response evaluable population. The number 
and percentage of subjects along with two-sided 95% exact confidence interval (CI) will be
provided by treatment group in the following response categories: CR, PR, ORR, stable disease 
(SD), clinical benefit rate (CBR), progressive disease (PD), and not evaluable (NE).
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Odds ratio of achieving response for Arm B over Arm A and its 95% confidence interval will be 
provided. 
ORR will also be presented by the subgroups specified in Section 2.4, as appropriate. 
5.3.
Major Secondary Efficacy Endpoints
5.3.1.
Duration of Response
Definition
Duration of response (DoR) is measured from date of first documented disease response to date 
of first objectively documented evidence of recurrence or progressive disease or death, 
whichever occurred first. DoR will be evaluated in subjects who have achieved response of PR 
or better. Duration of response is calculated in months as follows: 
DoR = (date of PD or censoring – date of first disease response + 1) / (365.25/12),
Deaths due to disease progression will be treated as an event on the date of death, unless disease 
progression is documented before death. Subjects who start Subsequent anti-cancer treatment for 
NSCLC will be censored at the last disease assessment no later than the start of Subsequent anti-
cancer treatments Subjects, who are lost to follow-up, withdraw consent, withdraw from study 
without disease progression, or die due to causes other than disease progression will be censored 
at the last disease assessment date.
Analysis Methods
The Kaplan-Meier method will be used to summarize DoR for responders in each treatment
group. The 25% Quantile, Median, and the 75% Quantile and their corresponding 95% CI will be
provided.
5.3.2.
Clinical Benefit Rate
Definition
Clinical benefit rate is defined as proportion of subjects who achieve disease control (CR, PR, or 
SD).
Analysis Methods
Analysis will be based on the ITT population, and response evaluable population. The number 
and percentages of subjects achieving clinical benefit will be provided by treatment group. In 
addition, two-sided 95% exact CI will also be provided. Odds ratio of achieving response for 
Arm B over Arm A, and its 95% confidence interval will be calculated, similar to ORR.
Stratified analysis may also be performed as sensitivity analysis. 
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5.3.3.
Progression Free Survival
Definition
Progression-free survival (PFS) is measured from randomization until the first documented
disease progression or death, whichever occurs first. PFS will be censored on the date of last 
tumor assessment documenting absence of tumor progression for subjects who have no 
documented progression and are still alive prior to data cutoff, dropout, lost to follow-up or the 
initiation of Subsequent anti-cancer treatment. Subjects with no tumor assessments after 
randomization their PFS will be censored on the date of randomization.  PFS is calculated in 
months as follows: 
PFS = (date of PD/death or censoring – date of randomization + 1) / (365.25/12).
Analysis Methods
The number and percentage of subjects who had a PFS event or were censored will be reported. 
The Kaplan-Meier method will be used to estimate the distribution of overall PFS for each 
treatment group, and the median PFS with 95% CI will be provided. In addition, the Kaplan-
Meier PFS curve will also be presented by treatment group. 
Hazard ratio (Arm B vs. Arm A) and its 95% confidence interval will be presented. In addition, 
3, 6, 12-months of PFS rate with 95% CI will be estimated by Kaplan-Meier method and 
reported for each treatment group.
PFS will also be presented by the subgroups specified in Section 2.4, as appropriate. 
5.3.4.
Overall Survival
Definition
Overall survival (OS) is defined as time from date of randomization to date of subject’s death 
from any cause. For subjects who are still alive at the end of study or lost to follow-up, OS will 
be censored on the date the subjects were last known to be alive. Overall survival is calculated in 
months as follows: 
OS = (date of death or censoring – date of randomization + 1) / (365.25/12).
Analysis Methods
The number and percentage of subjects who were died or still alive will be reported. The Kaplan-
Meier method will be used to estimate the distribution of OS for each treatment group, and the 
median OS with 95% CI will be provided. In addition, the Kaplan-Meier PFS curve will also be 
presented by treatment group. 
Hazard ratio (Arm B vs. Arm A) and its 95% confidence interval will be presented. In addition, 
3, 6, 12-months of OS rate with 95% CI will be estimated by Kaplan-Meier method and reported 
for each treatment group.
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OS will also be presented by the subgroups specified in Section 2.4, as appropriate. 
6.
SAFETY 
The safety profiles of Daratumumab will be evaluated by the incidence of adverse events (AEs), 
death, laboratory results, vital signs, physical examination findings, ECG results, and ECOG score
overtime.
Safety summaries will be provided by treatment received. The severity of AEs and the toxicity of 
laboratory parameters will be assessed using NCI CTC version 4.03. Adverse events are coded 
using latest version of MedDRA coding dictionary.
For cross-over subjects, safety data after initiation of cross-over treatment may be summarized 
separately, as appropriate. 
6.1.
Adverse Events
Unless otherwise specified, only TEAEs will be summarized. 
6.1.1.
Treatment Emergent Adverse Events
The following summaries will be provided for all TEAEs: 
-
An overview of TEAE will be provided, including the incidence of TEAE, serious TEAE, 
maximal grade of TEAE, treatment discontinuation due to TEAE, , and death due to TEAE. 
-
A listing of all TEAEs. 
In addition, the following summaries will be generated: 
-
TEAEs by system organ class (SOC) and preferred term (PT)
-
TEAEs by SOC, PT, and relationship to study medication
-
TEAEs by SOC, PT, and grade 3/4
-
Most common (at least 10%) TEAEs by SOC, PT, and grade 3/4
-
TEAEs by SOC, PT, and worst grade
-
Serious TEAEs by SOC and PT
-
Serious TEAEs by SOC, PT, and grade 3/4
-
Most common (at least 1%) serious TEAEs by SOC, PT, and grade 3/4
-
Grade 3 or 4 TEAEs by SOC and PT
-
Grade 3 or 4 TEAEs by SOC, PT, and relationship to study medication
The following summaries of treatment modifications due to TEAEs will be provided: 
-
Infusion delay due to TEAE by SOC, PT and relationship to study medication
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Infusion skipped due to TEAE by SOC, PT and relationship to study medication
-
Infusion interruption due to TEAE by SOC, PT and relationship to study medication
-
Infusion rate decreased due to TEAE by SOC, PT and relationship to study medication
-
Infusion aborted due to TEAE by SOC, PT and relationship to study medication
In addition, the following summaries will be generated: 
-
Study drug discontinuation due to TEAEs by SOC, PT, and grade 3/4
-
Treatment discontinuation due to TEAEs by PT and grade 3/4
-
Death due to TEAEs by PT and grade 3/4
6.1.2.
Adverse Events of Clinical Interest
6.1.2.1.
Infusion Related Reactions 
The incidence of infusion related reactions (IRRs), as flagged on the eCRF, will be presented by 
SOC, PT, and toxicity grade 3/4. Treatment modifications due to IRRs will also be summarized.
A listing of all IRRs will be provided.
6.1.2.2.
Dose Limiting Toxicity
The dose limiting toxicity observed during the safety run-in phase will be listed. 
6.1.2.3.
Immune-mediated Adverse Event
The incidence of immune-mediated adverse event, as flagged on the eCRF, will be presented by 
SOC, PT, and toxicity grade 3/4. Treatment modifications due to these events will also be 
summarized.
A listing of all immune-mediated AEs will be provided.
6.2.
Deaths
Number of subjects who died during the study and the primary cause of death will be 
summarized. In addition, all deaths within 30 days of last infusion will be summarized. 
A listing will be generated for all subjects who died during the study. 
6.3.
Clinical Laboratory Tests
Descriptive statistics for values and changes from baseline over time for these laboratory 
parameters will be provided. In addition, shifts from baseline toxicity grade to worst toxicity 
grade during treatment will be generated. 
6.4.
Vital Signs and Physical Examination Findings
Descriptive statistics will be provided for values and changes from baseline over time for vital 
signs. 
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6.5.
Electrocardiogram
Frequencies of overall interpretation of ECG results (normal, abnormal and clinically significant, 
abnormal and not clinically significant) over time will be provided. 
6.6.
Other Safety Parameters
6.6.1.
ECOG Performance Status
Frequencies of ECOG performance status (0, 1, 2, >2) over time will be summarized. 
7.
PHARMACOKINETICS/IMMUNOGENICITY/PHARMACODYNAMICS
For cross-over subjects, pharmacokinetics/immunogenicity/pharmacodynamics data after 
initiation of cross-over treatment may be summarized separately, as appropriate. 
7.1.
Pharmacokinetics 
Pharmacokinetic analyses will be performed on the pharmacokinetic-evaluable population. All 
serum concentrations below the lowest quantifiable concentration or missing data will be labeled 
as such in the concentration data presentation. Concentrations below the lowest quantifiable 
concentration will be treated as zero in the summary statistics. All subjects and samples excluded 
from the analysis will be clearly documented in the study report. 
Descriptive statistics (e.g., number of observations, mean, standard deviation, median, and range) 
will be used to summarize daratumumab and atezolizumab serum concentrations at each 
sampling time point. Line plot of mean (±SD) daratumumab and atezolizumab serum peak and 
trough concentrations over time will be provided. In addition, coefficient variation and geometric 
mean will be provided in the pharmacokinetic concentration summary.
7.2.
Immunogenicity 
Immunogenicity analyses will be performed on the immunogenicity-evaluable population. The 
incidence of anti-daratumumab and anti-atezolizumab antibodies will be summarized for all 
subjects who receive a dose of daratumumab or atezolizumab and have appropriate samples for 
detection of antibodies to daratumumab or atezolizumab. In addition, subjects who are positive 
for antibodies to daratumumab or atezolizumab will also be listed. 
Other immunogenicity analyses may be performed to further characterize the immune responses
that are generated.
8.
BIOMARKER
For each biomarker of interest, baseline values will be summarized by treatment group. . In 
addition, for each biomarker of interest, the values over time and change from baseline will be 
presented by treatment group. Appropriate figures may also be generated to aid data 
visualization.
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9.
HEALTH ECONOMICS
Not applicable.
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REFERENCES
1.
(FDA) 2007. Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. 
US Food and Drug Administration, Rockville, MD.
2.
Wolchok JD, Hoos A, O'Day S, et al 2009. Guidelines for the evaluation of immune therapy activity in solid
tumors: immune-related response criteria. Clin Cancer Res. 2009; 15(23):7412-7420.
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Attachment 1: Criteria For Dose Limiting Toxicity (Protocol Table 6)
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