An Open-Label Randomized Phase 1b/2 Study of the Efficacy and Safety of JNJ-64041757, a Live Attenuated Listeria Monocytogenes Immunotherapy, in Combination With Nivolumab Versus Nivolumab Monotherapy in Subjects With Advanced Adenocarcinoma of the Lung
Phase: PHASE1
Conditions: Adenocarcinoma of Lung
Sponsor: Janssen Research & Development, LLC

1
Status:  Approved,  Date:  4 January 2018
Janssen Research & Development *
Clinical Protocol
An Open-label Randomized Phase 1b/2 Study of the Efficacy and Safety of JNJ-64041757, 
a Live Attenuated Listeria monocytogenes Immunotherapy, in Combination with 
Nivolumab Versus Nivolumab Monotherapy in Subjects With Advanced Adenocarcinoma 
of the Lung
Protocol 64041757LUC2002; Phase 1b/2
Amendment 2
JNJ-64041757
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen 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. 
JNJ-64041757 is being investigated in Phase 1 and Phase 2 clinical studies.
Nivolumab is approved for marketing.
This study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
EudraCT NUMBER:         2016-002543-41
Status:
Approved
Date:
4 January 2018
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-124363113, 3.0
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.
NCT03371381

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Status:  Approved,  Date:  4 January 2018
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 19
TIME AND EVENTS SCHEDULE .............................................................................................................. 23
ABBREVIATIONS ...................................................................................................................................... 30
1.
INTRODUCTION................................................................................................................................ 32
1.1.
Background .................................................................................................................................... 32
1.1.1.
Current Treatment Standards and Unmet Medical Need in Advanced or Metastatic 
Non–Small-Cell Lung Cancer ..................................................................................................... 32
1.1.2.
Clinical Experience With Cancer Vaccines for Non–Small-Cell Lung Cancer ........................... 33
1.2.
LADD: An Immunotherapeutic Platform......................................................................................... 34
1.2.1.
Clinical Experience with LADD Lm-based Immunotherapeutics ................................................ 34
1.3.
JNJ-757: A Lung Cancer Directed Tumor Vaccine........................................................................ 35
1.3.1.
Nonclinical Experience with JNJ-757 ......................................................................................... 37
1.3.1.1.
Nonclinical in Vivo Efficacy of JNJ-757 ................................................................................... 37
1.3.1.2.
Nonclinical Biodistribution Studies with JNJ-757..................................................................... 37
1.3.1.3.
Nonclinical Toxicology Profile of JNJ-757 ............................................................................... 38
1.3.2.
Clinical Experience with JNJ-757 ............................................................................................... 38
1.4.
Nivolumab ...................................................................................................................................... 41
1.5.
Overall Rationale for the Study...................................................................................................... 43
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESES.......................................................................... 46
2.1.
Objectives and Endpoints .............................................................................................................. 46
2.2.
Hypothesis ..................................................................................................................................... 46
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 47
3.1.
Overview of Study Design.............................................................................................................. 47
3.1.1.
Phase 1b (Safety Run-in Phase)................................................................................................ 47
3.1.2.
Phase 2 (Randomized Phase).................................................................................................... 49
3.2.
Study Design Rationale.................................................................................................................. 52
4.
SUBJECT POPULATION.................................................................................................................. 54
4.1.
Inclusion Criteria ............................................................................................................................ 54
4.2.
Exclusion Criteria ........................................................................................................................... 57
4.3.
Prohibitions and Restrictions ......................................................................................................... 60
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 60
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 61
6.1.
Study Agent Administration............................................................................................................ 61
6.2.
JNJ-757 Dose Modifications .......................................................................................................... 61
6.2.1.
Cycle Delay................................................................................................................................. 61
6.2.2.
Monitoring During and After JNJ-757 Administration ................................................................. 62
6.3.
Nivolumab Dose Modifications....................................................................................................... 63
6.3.1.
Dose Change.............................................................................................................................. 63
6.3.2.
Cycle Delay................................................................................................................................. 63
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7.
TREATMENT COMPLIANCE............................................................................................................ 65
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 65
8.1.
Permitted Medications.................................................................................................................... 65
8.1.1.
JNJ-757 Preinfusion Medications ............................................................................................... 65
8.1.2.
JNJ-757 Postinfusion Medications ............................................................................................. 66
8.1.3.
Palliative Radiation ..................................................................................................................... 67
8.2.
Prohibited Medications................................................................................................................... 67
8.3.
Guidelines for the Prevention and Management of Toxicities ....................................................... 68
8.3.1.
JNJ-757....................................................................................................................................... 68
8.3.1.1.
Prophylaxis Against Listeria Infection After the Last Dose of JNJ-757 ................................... 68
8.3.1.2.
Treatment for Listeria Infection................................................................................................ 69
8.3.2.
Nivolumab................................................................................................................................... 70
8.3.2.1.
Gastrointestinal Adverse Events ............................................................................................. 70
8.3.2.2.
Hepatic Adverse Events .......................................................................................................... 71
8.3.2.3.
Endocrinopathies..................................................................................................................... 71
8.3.2.4.
Rash (Including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis) .................... 72
8.3.2.5.
Renal Adverse Events ............................................................................................................. 73
8.3.2.6.
Neurologic Adverse Events ..................................................................................................... 73
8.3.2.7.
Pulmonary Adverse Events ..................................................................................................... 74
8.3.2.8.
Uveitis and Visual Complaints................................................................................................. 74
8.3.2.9.
Lipase/Amylase Elevations...................................................................................................... 75
8.3.2.10.
Treatment of Nivolumab Related Infusion Reactions.............................................................. 75
8.4.
Subsequent Therapies................................................................................................................... 76
9.
STUDY EVALUATIONS .................................................................................................................... 76
9.1.
Study Procedures........................................................................................................................... 76
9.1.1.
Overview..................................................................................................................................... 76
9.1.2.
Screening Phase ........................................................................................................................ 77
9.1.2.1.
Determination of Mesothelin and PD-L1 Level........................................................................ 78
9.1.2.2.
Optional Prescreening Phase.................................................................................................. 78
9.1.3.
Treatment Phase ........................................................................................................................ 78
9.1.4.
Posttreatment Follow-up Phase ................................................................................................. 80
9.1.5.
End of Study ............................................................................................................................... 81
9.2.
Efficacy Evaluations....................................................................................................................... 81
9.2.1.
Evaluations ................................................................................................................................. 81
9.2.1.1.
Assessment of Disease Response and Progressive Disease ................................................ 82
9.2.1.2.
Treatment Beyond Progression............................................................................................... 82
9.2.1.3.
Discontinuation of Study Agent After Complete Response..................................................... 83
9.2.2.
Efficacy Endpoints ...................................................................................................................... 83
9.3.
Blood Culture and Bacterial Shedding Assessments for JNJ-757................................................. 83
9.4.
Nivolumab Pharmacokinetic Evaluations....................................................................................... 84
9.5.
Nivolumab Immunogenicity Evaluations ........................................................................................ 84
9.6.
Biomarkers ..................................................................................................................................... 84
9.6.1.
Sample Collection....................................................................................................................... 84
9.6.2.
Pharmacodynamic and Predictive Biomarker Evaluations......................................................... 84
9.6.3.
Primary Biomarker Assessment ................................................................................................. 85
9.6.4.
Exploratory Biomarker Evaluations ............................................................................................ 85
9.6.5.
Sample Collection and Handling ................................................................................................ 86
9.7.
Safety Evaluations ......................................................................................................................... 86
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 88
10.1.
Completion ..................................................................................................................................... 88
10.2.
Discontinuation of Study Treatment............................................................................................... 88
10.3.
Withdrawal From the Study............................................................................................................ 89
10.4.
Withdrawal From the Use of Research Samples........................................................................... 89
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11.
STATISTICAL METHODS................................................................................................................. 90
11.1.
Subject Information ........................................................................................................................ 90
11.2.
Sample Size Determination ........................................................................................................... 91
11.3.
Statistical Model for Probability of ORR......................................................................................... 91
11.4.
Efficacy Analyses ........................................................................................................................... 92
11.5.
Blood Culture and Bacterial Shedding Analyses ........................................................................... 92
11.6.
Nivolumab Pharmacokinetic Analyses........................................................................................... 92
11.7.
Nivolumab Immunogenicity Analyses ............................................................................................ 92
11.8.
Biomarker Analyses ....................................................................................................................... 93
11.9.
Patient-reported Outcomes Analyses ............................................................................................ 93
11.10.
Safety Analyses ............................................................................................................................. 93
11.11.
Data Monitoring Committee ........................................................................................................... 94
12.
ADVERSE EVENT REPORTING ...................................................................................................... 95
12.1.
Definitions ...................................................................................................................................... 95
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 95
12.1.2.
Attribution Definitions.................................................................................................................. 96
12.1.3.
Severity Criteria .......................................................................................................................... 97
12.2.
Special Reporting Situations.......................................................................................................... 97
12.3.
Procedures..................................................................................................................................... 97
12.3.1.
All Adverse Events...................................................................................................................... 97
12.4.
Serious Adverse Events................................................................................................................. 99
12.4.1.
Adverse Events of Special Interest........................................................................................... 100
12.4.2.
Pregnancy................................................................................................................................. 100
12.5.
Contacting Sponsor Regarding Safety......................................................................................... 100
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 101
13.1.
Procedures................................................................................................................................... 101
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 101
14.
STUDY AGENT INFORMATION..................................................................................................... 101
14.1.
Physical Description of Study Agent(s)........................................................................................ 101
14.2.
Packaging .................................................................................................................................... 102
14.3.
Labeling........................................................................................................................................ 102
14.4.
Preparation, Handling, and Storage............................................................................................. 102
14.5.
Drug Accountability ...................................................................................................................... 103
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 103
16.
ETHICAL ASPECTS ....................................................................................................................... 104
16.1.
Study-Specific Design Considerations......................................................................................... 104
16.2.
Regulatory Ethics Compliance..................................................................................................... 105
16.2.1.
Investigator Responsibilities ..................................................................................................... 105
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 105
16.2.3.
Informed Consent ..................................................................................................................... 106
16.2.4.
Privacy of Personal Data .......................................................................................................... 107
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 108
16.2.6.
Country Selection ..................................................................................................................... 108
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 109
17.1.
Protocol Amendments.................................................................................................................. 109
17.2.
Regulatory Documentation .......................................................................................................... 109
17.2.1.
Regulatory Approval/Notification .............................................................................................. 109
17.2.2.
Required Prestudy Documentation........................................................................................... 109
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 110
17.4.
Source Documentation................................................................................................................. 111
17.5.
Case Report Form Completion .................................................................................................... 111
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 112
17.7.
Record Retention ......................................................................................................................... 112
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17.8.
Monitoring .................................................................................................................................... 113
17.9.
Study Completion/Termination..................................................................................................... 114
17.9.1.
Study Completion/End of Study................................................................................................ 114
17.9.2.
Study Termination..................................................................................................................... 114
17.10.
On-Site Audits .............................................................................................................................. 114
17.11.
Use of Information and Publication.............................................................................................. 115
REFERENCES.......................................................................................................................................... 117
INVESTIGATOR AGREEMENT ............................................................................................................... 126
LIST OF ATTACHMENTS
Attachment 1:
New York Heart Association Criteria ........................................................................... 120
Attachment 2:
Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference ............... 121
Attachment 3:
Eastern Cooperative Oncology Group Performance Status Score ............................. 123
Attachment 4:
Anticipated Events ....................................................................................................... 124
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1:
Time and Events Schedule - Assessments and Procedures for Phase 1b and Phase 2......... 23
Table 2:
Criteria for Dose-limiting Toxicity in Phase 1b.......................................................................... 48
Table 3:
Laboratory Criteria for JNJ-757 Treatment After Cycle 1 ......................................................... 62
Table 4:
Nivolumab Cycle Delay or Discontinuation for Adverse Events ............................................... 64
Table 5:
Mandatory and Optional Concomitant Medications to be Administered with JNJ-757............. 66
Table 6:
Postinfusion Medications for Systemic Innate Immune Response to Bacterial Infection......... 67
Table 7:
Management and Follow-up of Immune-mediated Gastrointestinal Adverse Events .............. 70
Table 8:
Management and Follow-up of Immune-mediated Hepatic Adverse Events ........................... 71
Table 9:
Management and Follow-up of Endocrinopathies .................................................................... 72
Table 10:
Management and Follow-up of Rash........................................................................................ 72
Table 11:
Management and Follow-up of Renal Adverse Events ............................................................ 73
Table 12:
Management and Follow-up of Neurologic Adverse Events .................................................... 73
Table 13:
Management and Follow-up of Pulmonary Adverse Events .................................................... 74
Table 14:
Management and Follow-up of Uveitis and Visual Complaints ................................................ 74
Table 15:
Management and Follow-up of Nivolumab Infusion Reactions ................................................ 76
FIGURES
Figure 1:
Expression of Mesothelin by JNJ-757 Compared With CRS-207 ............................................ 36
Figure 2:
Dose-dependent Therapeutic Antitumor Efficacy of JNJ-757 in Mice ...................................... 37
Figure 3:
Natural Killer (NK) Cell Activation (CD69 Positivity) Over Time in Individual Subjects 
who Received JNJ-757 at a Dose of 1×108 Colony Forming Units on Day 1 of Each 
21-Day Cycle (Study 64041757LUC1001) ............................................................................... 39
Figure 4:
Absolute Lymphocyte Count Over Time in Individual Subjects who Received JNJ-757 
at a Dose of 1×108 Colony Forming Units on Day 1 of Each 21-Day Cycle 
(Study 64041757LUC1001) ...................................................................................................... 40
Figure 5:
Preliminary Data for Adaptive Immune Response by ELISpot Over Time in a Subject 
who Received JNJ-757 at a Dose of 1×108 Colony Forming Units on Day 1 of Each 
21-Day Cycle (Study 64041757LUC1001) ............................................................................... 41
Figure 6:
Prolongation of Survival with the Addition of JNJ-757 to a PD-1 Inhibitor in a 
Nonclinical Mouse Model of Lung Cancer ................................................................................ 44
Figure 7:
Study Flowchart ........................................................................................................................ 51
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Status:  Approved,  Date:  4 January 2018
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
02 August 2016
Amendment 1
02 June 2017
Amendment 2
04 January 2018
Amendments below are listed beginning with the most recent amendment.
Amendment 2 (04 January 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: To limit Phase 1b enrollment to subjects with mesothelin-positive status 
at screening, to modify the assessment schedules for biomarkers and core needle biopsy, and to add biomarker 
measurements.
The rationale for and description of the changes are listed below, and representative revisions are sometimes 
provided; when revisions are provided verbatim, bold font denotes new text and strikethrough denotes deleted text.
Applicable Section(s)
Description of Change(s)
Rationale: Mesothelin-positive status at screening will be required for all subjects enrolled (Phase 1b and Phase 2), 
not just those in Phase 2, to ensure that each enrolled subject has improved potential to benefit from both innate and 
adaptive immune responses elicited by JNJ-757.
Synopsis (Subject 
Population);
Synopsis (Biomarker 
Evaluations);
3.2. Study Design 
Rationale (Rationale for 
Biomarker Assessments);
4. Subject Population;
4.1. Inclusion Criteria
(Criterion 2);
9.1.2.1. Determination of 
Mesothelin and PD-L1 
Level;
9.6.3. Primary Biomarker 
Assessment
Added mesothelin-positive status (>0% positive tumor cells) as an inclusion criterion 
for subjects in Phase 1b.
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Status:  Approved,  Date:  4 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: Additional subjects may be enrolled in Phase 1b, as determined by the Safety Evaluation Team (SET),
to further explore safety and translational data before the decision to initiate the randomized Phase 2 portion of the 
study.
Synopsis (Overview of 
Study Design);
Synopsis (Statistical 
Methods);
1.5. Overall Rationale for 
the Study;
3.1.1. Phase 1b (Safety 
Run-in Phase);
3.1.1. Phase 1b (Safety 
Run-in Phase; Safety 
Evaluation Team [SET])
Figure 7 (Study 
Flowchart);
11.2. Sample Size 
Determination
Information (including an upper limit on the number of subjects) has been provided on 
additional subjects to be enrolled in Phase 1b as determined by the SET. Enrollment in 
Phase 2 will not begin until the SET has recommended proceeding, following the 
evaluation of safety and translational data from Phase 1b. Determination on tolerability 
of the regimen by the SET have been added.
Phase 1b will be a safety run-in phase of at least 6 subjects to evaluate the incidence of 
dose limiting toxicities (DLTs) and demonstrate the tolerability of the combination 
before initiation of the randomized Phase 2. Additional subjects (up to 30 in total) 
may be enrolled, as determined by the Safety Evaluation Team (SET), to further 
explore safety and translational data before the decision to initiate the 
randomized Phase 2.
Rationale: Core needle tumor biopsy sample collection was made mandatory for subjects in Phase 1b. Removed the 
soluble mesothelin and single nucleotide polymorphism from the biomarker assessments; added pentamer staining. 
These and other modifications were made to help evaluate the drug-clinical response relationship to improve 
translational data collected for the SET before initiating the Phase 2 portion of the study.
Synopsis (Biomarker 
Evaluations);
3.1.2. Phase 2 
(Randomized Phase)
Mandatory core needle on-study tumor biopsy samples will be collected from 
approximately 20 subjects who consent separately to an optional translational substudy 
(where local regulations permit), and correlated with mesothelin-directed peripheral 
adaptive immune response subjects in Phase 1b, with core needle tumor biopsy 
samples being required from subjects at selected sites in Phase 2 who consent 
separately to an optional tumor biopsy substudy (where local regulations permit).
Table 1 (Time and Events 
Schedule - Assessments 
and Procedures for Phase 
1b and Phase 2)
Several revisions and modifications were made to timing and assessments in Table 1.
9.6.1. Sample Collection
Details for sample collection have been revised and updated based on changes to 
biomarker assessments.
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Applicable Section(s)
Description of Change(s)
9.6.2. Pharmacodynamic 
and Predictive Biomarker 
Evaluations
The revisions shown below have been made, and some bullets have been separated or 
combined.
Pharmacodynamic (PD) biomarkers and translational data will be informed by 
available Phase 1 results, will be assessed before, during, and after treatment with 
JNJ-757, and may include the following:
3.
NK, CD4, and CD8 T cell number enumeration and activation status using 
standard activation markers (such as CD69) by flow cytometry in PBMCs.
4.
Soluble mesothelin levels, using appropriate techniques such as ELISA.
6.
Single nucleotide polymorphism of genes associated with the PD-1/PD-L1 
pathway and activated T cell phenotype.
9.
Infiltration and activation status of several immune cells subsets using 
appropriate 
techniques 
such 
as 
single 
color 
or 
multiplex 
immunocytochemistry of formalin fixed paraffin embedded (FFPE) tumor 
biopsies.
Rationale: Revisions were made to inclusion and exclusion criteria to clarify eligibility.
4.1 Inclusion Criteria 
(Criterion 2)

(In Phase 2 only) Mesothelin-positive status (>0% positive tumor cells), 
determined at a central laboratory using mesothelin immunohistochemistry 
(IHC) assay
4.1 Inclusion Criteria 
(Criterion 6)
Adequate hepatic function, defined as:

Serum 
aspartate 
aminotransferase 
(AST) 
and 
serum 
alanine 
aminotransferase (ALT) 1.5 times the upper limit of normal (ULN) if no 
liver metastases, and 3ULN with documented liver metastases

Total serum bilirubin 1.5xULN (unless due to Gilbert’s syndrome; if so, 
direct bilirubin 3xULN)
4.1 Inclusion Criteria 
(Criterion 9)
Before Cycle 1 Day 1 (Phase 1b) or randomization (Phase 2), a woman must be 
either:
4.2 Exclusion Criteria 
(Criterion 1)
Subjects with a history of brain metastasis must have completed treatment for brain 
metastasis for at least 28 days, and be neurologically stable and off steroids before 
enrollment Cycle 1 Day 1 (Phase 1b) or randomization (Phase 2).
4.2 Exclusion Criteria 
(Criterion 2)
Tumor with activating EGFR mutation or ALK translocation (EGFR and ALK results 
must be confirmed in the Screening Period for all non-smokers. A positive KRAS 
result may be used in lieu of an EGFR or ALK result).
4.2 Exclusion Criteria 
(Criterion 3)
More than 1 prior line of chemotherapy for metastatic disease (not including therapy 
given in the maintenance setting, or neoadjuvant or adjuvant therapy for locally 
advanced disease) (Phase 2).
4.2 Exclusion Criteria 
(Criterion 10)
Concurrent treatment with anti-TNFtherapies, systemic corticosteroids (prednisone 
dose >10 mg per day or equivalent), or other immunosuppressive drugs <14 days 
before Cycle 1 Day 1 (Phase 1b) or randomization (Phase 2).
4.2 Exclusion Criteria 
(Criterion 11)
A positive test result by medical history for human immunodeficiency virus (HIV) or 
acquired immune deficiency syndrome (AIDS).
4.2 Exclusion Criteria 
(Criterion 13)
History of clinically significant cardiovascular disease within 6 months of Cycle 1 
Day 1 (Phase 1b) or randomization (Phase 2) including, but not limited to:
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Applicable Section(s)
Description of Change(s)
4.2 Exclusion Criteria 
(Criterion 15)
Active second malignancy within 2 years prior to Cycle 1 Day 1 (Phase 1b) or
randomization (Phase 2).
4.2 Exclusion Criteria 
(Criterion 19)
Received an investigational drug (including investigational vaccines) or used an 
invasive investigational medical device within 28 days before enrollment Cycle 1 
Day 1 (Phase 1b) or randomization (Phase 2).
Rationale: The timing of disease response using computed tomography (CT) scans with IV contrast (or if 
necessary, magnetic resonance imaging [MRI] scans) of the chest, abdomen, and pelvis has been revised to allow 
the first assessment to occur at the same time as the on-treatment biopsy.
Synopsis (Overview of 
Study Design);
Table 1 (CT or MRI of 
chest, abdomen, and 
pelvis);
3.1.2. Phase 2 
(Randomized Phase);
9.2.1. Evaluations
Disease response will be assessed with Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1) criteria, using computed tomography (CT) scans with IV contrast (or if 
necessary, magnetic resonance imaging [MRI] scans) of the chest, abdomen, and pelvis 
at Week 8 (±7 days), then every 8 weeks (±7 days) during the first year, and then every 
12 weeks (±7 days) thereafter until disease progression, subsequent therapy, or 
completion of therapy. For subjects receiving on-treatment biopsy, the first 
assessment will be at Cycle 3 Day 8 (+3 days).
Rationale: Follow-up visits may be conducted by telephone after the first year, to reduce the burden for subjects not 
requiring follow-up blood cultures. The window for the visits is (±7 days).
Synopsis (Overview of 
Study Design);
3.1.2. Phase 2 
(Randomized Phase);
Figure 7 (Study 
Flowchart);
9.1.4. Posttreatment
Follow-up Phase
Follow-up visits (after the first year, these visits can be conducted by telephone contact 
or an alternative contact method per institution policy/practice) will be made every 
3 months (±14 7 days) after the last dose of study agent to obtain blood cultures (up to 
1 year for subjects who receive JNJ-757) and to determine survival, unless the 
subject has died, is lost to follow-up, or has withdrawn consent. For subjects in 
Group B and after the first year for subjects in Phase 1b and Group A, these visits 
may be conducted by telephone contact or an alternative contact method per 
institution policy/practice.
Rationale: Revisions and modifications were made throughout the protocol to increase clarity, to update the 
protocol based on revisions made during this amendment, or to correct omissions and errors.
Synopsis (Objectives, 
Endpoints, and 
Hypothesis);
2.1. Objectives and 
Endpoints;
9.2.2. Efficacy Endpoints
Disease control rate (stable disease for at least 16 weeks, complete response, or partial 
response)
To evaluate the safety of JNJ-757 in combination with nivolumab
Table 1 (multiple places);
Clarified that for Day 1 assessments, predose refers to before nivolumab and postdose 
refers to after the last study drug.
Table 1 (Brain MRI; 
required only for subjects 
with known brain 
metastasis);
9.2.1. Evaluations
Brain MRI to be done only as clinically indicated after the Screening Phase.
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Applicable Section(s)
Description of Change(s)
3.1.1. Phase 1b (Safety 
Run-in Phase);
3.1.2. Phase 2 
(Randomized Phase);
9.2.1.3. Discontinuation 
of Study Agent After 
Complete Response;
10.2. Discontinuation of 
Study Treatment
The maximum allowed duration of nivolumab or JNJ-757 treatment is 2 years.
3.1.1. Phase 1b (Safety 
Run-in Phase; Safety 
Evaluation Team [SET])
The following rules will be applied to determine that the combination of JNJ-757 and 
nivolumab is safe and tolerable:

If <2 of 6 (or <33%) evaluable subjects in Phase 1b experience a DLT during the 
first treatment cycle (ie, 28 days), then the selected doses and dose regimens for 
JNJ-757 + nivolumab combination therapy will be considered tolerable in 
subjects with advanced or metastatic NSCLC, and the study will proceed to Phase 
2.

If 2 of 6 evaluable subjects (or 33%) experience a DLT in the first treatment 
cycle, then the SET will examine the totality of available safety, translational,
and pharmacokinetic/PD data, and may recommend either stopping the study or 
expanding the Phase 1b population to a maximum of 12 subjects total to evaluate 
alternate doses and dose regimens.
Figure 7 (Study 
Flowchart)
Deleted the box for eligibility in Phase 2 (Randomized Phase).
3.2. Study Design 
Rationale (Rationale for 
Study Population)
Therefore, subjects with activating EGFR mutations or ALK translocations are 
excluded from participation in this study (EGFR and ALK results must be confirmed in 
the Screening Period for all non-smokers). KRAS mutations are mutually exclusive 
from EGFR and ALK translocations; therefore, a positive KRAS mutation does 
not require ALK testing.
6.3.2. Cycle Delay
Revised “autoimmune” to “immune-mediated”.
Table 4
Revised “Hepatitis” to “Hepatic toxicity”.
8.3.2. Nivolumab;
Table 7;
Table 8;
8.3.2.4. Rash (Including 
Stevens-Johnson 
Syndrome and Toxic 
Epidermal Necrolysis)
Revised “immune-related” to “immune-mediated”.
NCT03371381

JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
11
Status:  Approved,  Date:  4 January 2018
Applicable Section(s)
Description of Change(s)
Synopsis (Safety 
Evaluations);
3.1.2. Phase 2 
(Randomized Phase);
8. Prestudy and 
Concomitant Therapy;
9.1.3. Treatment Phase;
12.3.1. All Adverse 
Events
Any new or worsening adverse events that occur and all concomitant medications that 
are administered between when the informed consent form (ICF) is signed and 
100 days after the last dose of study agent will be recorded for subjects who enter the 
Screening Phase.
9.1.2.1. Determination of 
Mesothelin and PD-L1 
Level
Before enrollment proceeding into the Treatment Phase of the study, tumor tissue 
samples for each subject must be provided for assessment of tumor mesothelin-positive
status and PD-L1 level. The results must be reported by the central laboratory before 
Cycle 1 Day 1 (Phase 1b) or randomization (Phase 2).
9.1.4. Posttreatment 
Follow-up Phase
Subjects who have a treatment-related Grade 3 toxicity at the End-of-Treatment Visit 
will continue follow-up until recovery to Grade 1 or baseline, the AE is deemed 
irreversible, or for a maximum of 6 months after the last dose of study agent or the 
subject starts subsequent anticancer therapy. Subjects with treatment-related 
adverse events leading to discontinuation will continue follow-up until resolution or 
return to baseline, the AE is deemed irreversible, or end of study, whichever occurs 
first.
9.2.1. Evaluations
For Phase 2, radiographic scans may be submitted to a third-party core imaging 
laboratory for quality assessment and for audit purposes.
9.5. Nivolumab 
Immunogenicity 
Evaluations
Analysis will be performed by a central laboratory. Analysis will be performed under 
the supervision of the sponsor.
12.4.1. Adverse Events of 
Special Interest
Transient Persistent bacteremia will be followed as part of standard safety monitoring 
activities by the sponsor and will include both serial blood cultures after dosing in 
Cycle 1, and subsequent predose surveillance blood cultures during the treatment 
phase, at the End-of-Treatment visit, and during the follow-up phase, for 1 year after 
the completion of dosing with JNJ-757.
12.4.2. 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 beginning at the time a 
signed and dated ICF is obtained until 5 months (female subjects) or 7 months 
(male subjects) after the last dose of study agent.
14.2. Packaging
JNJ-757 drug product will be shipped and stored frozen at –60ºC or colder. It consists 
of attenuated Lm suspended in either 1.5 mL or 1.2 mL of Dulbecco’s phosphate-
buffered saline and 9% volume concentration glycerol.
Throughout the protocol
Revised “before enrollment (Phase 1b)” to “before Cycle 1 Day 1 (Phase 1b)”.
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
NCT03371381

JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
12
Status:  Approved,  Date:  4 January 2018
Amendment 1 (02 June 2017)
The overall reason for the amendment: To add a Phase 1b run-in Phase to assess the safety of the combination 
of JNJ-64041757 (JNJ-757) with nivolumab; to limit Phase 2 randomization to subjects with mesothelin-positive 
status at screening; to change the stratification for randomization to 3 levels of PD-L1; to modify the assessment 
schedules for biomarkers, disease evaluation, blood cultures, nivolumab pharmacokinetics, and nivolumab 
immunogenicity; to add measurements of patient-reported outcomes; and to update the nivolumab dosing 
schedule and safety evaluations based on revisions to product labeling for nivolumab.
The rationale for and description of the changes are listed below, and representative revisions are sometimes 
provided; when revisions are provided verbatim, bold font denotes new text and strikethrough denotes deleted 
text.
Applicable Section(s)
Description of Change(s)
Rationale: A Phase 1b Safety Run-in was added to the protocol to assess the safety of the combination of JNJ-757 
with nivolumab in subjects with advanced adenocarcinoma of the lung.
Throughout the protocol
Clarified that all subjects will receive nivolumab treatment, and that subjects in Phase 
1b and Group A of Phase 2 will receive JNJ-757.
Title
Changed “Phase 2” to “Phase 1b/2.” 
Cover Page
Clarified that JNJ-757 “is being investigated in Phase 1 and Phase 2 clinical studies.”
Time and Events 
Schedule
Clarified that biomarker assessments are required in Phase 2.
Synopsis (Overview of 
Study Design);
Synopsis (Statistical 
Methods)
Added descriptions of dose limiting toxicities (DLTs) and the Safety Evaluation Team 
(SET) in Phase 1b.
1.5. Overall Rationale for 
the Study
Added a description of the role of the Safety Evaluation Team (SET) to analyze the 
safety of the combination of JNJ-757 and nivolumab after the last subject dosed in 
Phase 1b has been observed for at least 28 days.
3.1. Overview of Study 
Design
Added Section 3.1.1. Phase 1b (Safety Run-in Phase) to describe the SET, DLTs, and 
the DLT rules.
Added Phase 1b to the Study Flowchart figure (Figure 7).
3.2. Study Design 
Rationale;
5. TREATMENT 
ALLOCATION AND 
BLINDING
Clarified that the randomization will occur in Phase 2, after the safety run-in phase.
4. SUBJECT 
POPULATION;
9.1.2. Screening Phase
Changed inclusion criteria, exclusion criteria, and screening phase methods to the 
following: “28 days before enrollment (Phase 1b) or randomization (Phase 2).”
Time and Events 
Schedule; 9.3. Blood 
Culture and Bacterial 
Shedding Assessments 
for JNJ-757
Clarified that the shedding profile of JNJ-757 will be studied for at least 20 subjects 
who receive JNJ-757 plus nivolumab “(in Phase 1b or in Phase 2 Group A).”
NCT03371381

JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
13
Status:  Approved,  Date:  4 January 2018
Applicable Section(s)
Description of Change(s)
11.1. Subject Information
Added this sentence: “The subjects in the safety run-in cohort will also be included 
in disposition and appropriate efficacy analyses and listed separately.”
Rationale: The Data Monitoring Committee (DMC) for Phase 2 was modified from an independent DMC to a 
Janssen DMC and the schedule and purpose of the DMC assessments were modified to improve monitoring of the 
benefits and risks of the combination of JNJ-757 with nivolumab.
Synopsis (Statistical 
Methods); 1.5. Overall 
Rationale for the Study; 
3.1.2. Phase 2 
(Randomized Phase); 
11.3. Statistical Model 
for Probability of ORR; 
11.11. Data Monitoring 
Committee
Changed the independent DMC to a Janssen DMC.
Changed the DMC schedule for Phase 2:

From: 20 subjects (safety) and 60 subjects (futility)

To: randomization of 40, 60, 80, 100, and 120 subjects (for ORR), every 3 months
(for safety), and as needed (based on the accumulating data)
Rationale: Revised the statistical analysis plan to use a Bayesian hierarchical logistic regression model, such that 
more subjects can be enrolled in a PD-L1 subgroup where the combination therapy is more effective. If the 
combination therapy is not effective in any PD-L1 level, then the study could be stopped early. 
Throughout the protocol
Clarified that PD-L1 levels for stratification in Phase 2 will be assessed centrally 
during the Screening Phase using submitted tumor material and the DAKO PD-L1 IHC 
28-8 pharmDx Assay.
Synopsis (Objectives, 
Endpoints, and 
Hypothesis; Overview of 
Study Design);
2.1. Objectives and 
Endpoints
Added PD-L1 subgroups to the primary endpoint: "To evaluate whether the efficacy of 
JNJ-757 combined with nivolumab is better than the efficacy of nivolumab 
monotherapy for subjects with mesothelin-positive relapsed/refractory Stage IIIB or 
Stage IV adenocarcinoma of the lung, by PD-L1 level"
Synopsis (Hypothesis); 
2.2. Hypothesis
"The primary hypothesis of the study is that the addition of JNJ-757 to nivolumab will 
result in a higher ORR compared with nivolumab monotherapy in at least one of the 
PD-L1 subgroups (<1%, 1-49%, or 50%) in subjects with relapsed or refractory 
Stage IIIB or Stage IV adenocarcinoma of the lung."
Synopsis (Overview of 
Study Design); 3.1.2. 
Phase 2 (Randomized 
Phase)
"Approximately 174 In Phase 2, a maximum of 140 subjects who meet all of the 
inclusion criteria and none of the exclusion criteria will be stratified in subgroups 
according to mesothelin status (>0% vs 0%) and programmed death receptor ligand 1 
(PD-L1) status (≥1% vs <1%), PD-L1 level (<1%, 1–49%, or 50%), using the 
DAKO PD-L1 IHC 28-8 pharmDx Assay, and then be assigned randomly (1:1) to 
receive JNJ-757 plus nivolumab (Group A) or nivolumab monotherapy (Group B). 
Throughout randomization, ORR will be monitored using a Bayesian hierarchical 
logistic regression model, such that more subjects may be enrolled in a PD-L1 
subgroup where the combination therapy is more effective. However, in such 
cases subjects will always be randomized to Group A or Group B at 1:1 ratio 
within that subgroup. If the combination therapy is not effective in any PD-L1 
subgroup, then the study could be stopped early."
Figure 7
Updated the stratification categories in the study flowchart.
NCT03371381

JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
14
Status:  Approved,  Date:  4 January 2018
Applicable Section(s)
Description of Change(s)
5. TREATMENT 
ALLOCATION AND 
BLINDING
"Central randomization will be implemented in Phase 2 of this study. Upon entry, 
eligible subjects will be randomly assigned 1:1 to treatment Groups A and B 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 mesothelin status (>0% vs 0%) and PD-L1 
status (≥1% vs <1%), which will be assessed during the Screening Phase using 
submitted tumor material. according to PD-L1 level (<1%, 1–49%, or ≥50%)."
11.2. Sample Size 
Determination
Updated to reflect the changes to the randomization and stratification.
Synopsis (Statistical 
Methods); [New section] 
11.3. Statistical Model 
for Probability of ORR
Added a description of the Bayesian hierarchical logistic regression model that will be 
used to estimate the posterior probability of observing an objective response (complete 
response or partial response) for each treatment group within each PD-L1 level.
Rationale: Study eligibility criteria, prohibitions, and prophylaxis against Listeria infection were modified based on 
emerging efficacy and safety data from the Phase 1 study of JNJ-757 in lung cancer.
Synopsis (Overview of 
Study Design); Time and 
Events Schedule; 3.1.2. 
Phase 2 (Randomized 
Phase)
Added assessments of blood cultures with a disease assessment or as clinically 
indicated during study treatment; as well as at 3, 6, 9, and 12 months after the last dose 
of JNJ-757.
3.2. Study Design 
Rationale
Added the rationale for blood culture and bacterial shedding surveillance, including 
data from clinical experience with CRS-207 and from the Phase 1 study 
(64041757LUC1001) of JNJ-757 in lung cancer.
Synopsis (Study 
Population); 4.2.
Exclusion Criteria
Added to Exclusion Criteria 8 and 10 anti-TNFtherapies or history of any other 
condition that may require the initiation of anti-TNFtherapies or other 
immunosuppressant medications during the study.
Added to Exclusion Criterion 12 any history of cardiac pacemakers, orthopedic screws, 
or metal plates.
Clarified in Exclusion Criterion 12 that subjects with venous access devices (eg, 
Port-a-Cath or Mediport), arterial and venous stents, dental implants, or breast implants
are permitted on the study.
4.3. Prohibitions and 
Restrictions
Added prohibitions and restrictions for subjects with indwelling venous access devices.
8.2. Prohibited 
Medications
Added anti-TNFα therapies or other immunosuppressants.
Added systemic antibiotics during the treatment phase (except the required antibiotic 
prophylaxis for Listeria infection after the last dose of JNJ-757).
8.3.1.1. Prophylaxis 
Against Listeria Infection 
After the Last Dose of 
JNJ-757; 10.2.
Discontinuation of Study 
Treatment
Detailed instructions were added regarding antibiotic prophylaxis against Listeria
infection in all subjects after the last dose of JNJ-757
8.3.1.2. Treatment for 
Listeria Infection
Added details regarding treatment for Listeria infection among subjects requiring an 
emergent placement of a prohibited implanted device, or in a subject with surveillance 
blood cultures positive for listeriosis.
NCT03371381

JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
15
Status:  Approved,  Date:  4 January 2018
Applicable Section(s)
Description of Change(s)
9.1.3. Treatment Phase
Added a description of the schedule for surveillance blood cultures and the appropriate 
management of a subject with a positive surveillance blood culture.
Added a description of the mandatory prophylactic antibiotic therapy after the last dose 
of JNJ-757.
9.3. Blood Culture and 
Bacterial Shedding 
Assessments for JNJ-757
Added details to the description of blood culture assessments.
10.2. Discontinuation of 
Study Treatment
Clarified that JNJ-757 treatment should be discontinued if predose peripheral 
surveillance cultures are positive for listeriosis or if the subject requires an emergent 
placement of a prohibited implanted device.
12.3.3. Adverse Events of 
Special Interest
Added a description of monitoring for bacteremia and positive surveillance blood 
cultures as adverse events of special interest.
Rationale: The schedule for disease evaluations was modified to reduce patient burden. 
Synopsis (throughout); 
Time and Events 
Schedule;
3.1.2. Phase 2 
(Randomized Phase);
Figure 7; 9.1.4.
Posttreatment Follow-up 
Phase;9.2.1. Evaluations
Reduced frequency of disease evaluations after the first year from every 8 weeks to 
every 12 weeks.
Reduced frequency of survival follow-up from every 2 months to every 3 months.
Removed the requirement for confirmation of response 4 weeks after initial response.
Throughout the protocol
Changed the windows for disease assessments from "+7 days" to "±7 days."
Time and Events 
Schedule (footnotes); 
9.1.3. Treatment Phase
Clarified that if nivolumab is permanently discontinued but the subject continues to 
receive treatment with JNJ-757, then the Day 15 visits of subsequent cycles will be 
optional.
9.1.4. Posttreatment 
Follow-up Phase
Clarified that for subjects who withdraw from treatment before disease progression, the 
results of subsequent tumor assessments should also be collected according to the study 
schedule until disease progression is radiographically documented or until subsequent 
therapy begins.
Rationale: The schedule for biomarker assessments was modified to strengthen the analyses of these endpoints. 
Synopsis (Biomarker 
Evaluations)
Clarified that markers of innate immune response will be measured in subjects treated 
with JNJ-757. 
Time and Events 
Schedule
Cytokines: clarified that they will be collected in 3 separate tubes (Cytokines LADD, 
Cytokines Nivolumab, and Clinical) and modified the assessment schedule.
NK panel: modified the assessment schedule.
Immune profile: changed from 3 tubes to 1 tube and modified the assessment schedule.
T-Cell proliferation/ICS, IFN-ELISpot, and TCR sequencing: modified the 
assessment schedule.
SNP, MDSC: removed assessments of these biomarkers.
NCT03371381

JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
16
Status:  Approved,  Date:  4 January 2018
Applicable Section(s)
Description of Change(s)
Rationale: In Phase 2, mesothelin positivity in the tumor was changed from a stratification factor to an eligibility 
criterion to ensure that subjects have the potential to benefit from both innate and adaptive immune responses 
elicited by JNJ-757.
3.2. Study Design 
Rationale
Added this sentence: "Mesothelin selection will ensure that each enrolled subject 
has the potential to benefit from both innate and adaptive responses elicited by 
JNJ-757."
4.1. Inclusion Criteria
Added mesothelin-positive status for Phase 2 to inclusion criterion 2.
9.1.2.1. Determination of 
Mesothelin and PD-L1 
Level
Clarified that mesothelin positive status (>0% positive tumor cells) is defined as tumor 
cells exhibiting positive membrane or cytoplasmic staining at any intensity.
9.6.3. Primary Biomarker 
Assessment
Clarified that positive mesothelin status will now be used as a study eligibility criterion 
in Phase 2.
Rationale: The assessment schedules for nivolumab pharmacokinetics and nivolumab immunogenicity were 
modified to strengthen the analyses of these endpoints.
Synopsis (Objectives, 
Endpoints, and 
Hypothesis);
2.1. Objectives and 
Endpoints
Added nivolumab pharmacokinetics (serum concentrations of nivolumab) and 
nivolumab immunogenicity (incidence of anti-nivolumab antibodies) to the secondary 
study objectives, and endpoints/assessments.
Time and Events 
Schedule
Rescheduled nivolumab pharmacokinetics assessments to the following study days: 
Cycle 1 Day 15; Cycle 2 Day 1; Day 1 of Cycles 3, 8, 12, 18, and 24; and End of 
Treatment. Rescheduled nivolumab immunogenicity assessments to the following 
days: Cycle 1 Day 1; Day 1 of Cycles 3, 8, 12, 18, and 24; and End of Treatment. 
3.2. Study Design 
Rationale
Added a rationale for the pharmacokinetics and immunogenicity assessments.
Rationale: In Phase 2, an exploratory objective and an exploratory endpoint were added to understand the effect of 
JNJ-757 combined with nivolumab treatment on patient-reported outcomes, including cancer symptoms and 
functional status, over time in subjects with NSCLC.
Synopsis (Objectives, 
Endpoints, and 
Hypothesis);
2.1. Objectives and 
Endpoints
Objectives: added "To assess patient-reported outcomes" as an exploratory objective.
Endpoints: added "NSCLC-SAQ and EORTC QLQ" as an exploratory endpoint.
Time and Events 
Schedule
Added assessments of patient-reported outcomes on Day 1 of each cycle and at the 
End-of-Treatment Visit.
3.2. Study Design 
Rationale
Added a rationale for including patient-reported outcomes assessments.
9.1.1. Overview
Clarified that PRO assessments should be conducted/completed before any tests, 
procedures, or other consultations to prevent influencing subject perceptions.
NCT03371381

JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
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Status:  Approved,  Date:  4 January 2018
Applicable Section(s)
Description of Change(s)
9.2. Efficacy Evaluations
In Section 9.2.1 Evaluations, added descriptions of the instruments that will be used for 
patient-reported outcomes.
In Section 9.2.2 Efficacy Endpoints. Added NSCLC-SAQ and EORTC QLQ to 
Efficacy Endpoints.
11.9. Patient-reported 
Outcomes Analyses
Added a description of the planned analysis of patient-reported outcomes.
Rationale: The nivolumab dosing schedule, pregnancy restrictions, and safety evaluations were modified to be 
consistent with revised product labeling for nivolumab.
Throughout the protocol
Changed nivolumab dose for all subjects from weight-based doses (3 mg/kg) to a fixed 
dose (240 mg), based on the approved dosage in the USPI for nivolumab.
Changed contraception and sperm/egg donation requirements: "at least 31 weeks after 
the last dose of study agent" 5 months (female subjects) or 7 months (male subjects) 
after the last dose of study agent."
Synopsis (Safety 
Evaluations);
Time and Events 
Schedule; 3.1.2. Phase 2 
(Randomized Phase);
8. PRESTUDY AND 
CONCOMITANT 
THERAPY; 9.1.3. 
Treatment Phase;
12.3.1. All Adverse 
Events
Clarified that adverse events and concomitant medications should be recorded until 
100 days after the last dose of study agent.
Table 4; 8.3.2.4. Rash 
(Including Stevens-
Johnson Syndrome and 
Toxic Epidermal 
Necrolysis)
Added Stevens-Johnson Syndrome and toxic epidermal necrolysis to possible adverse 
events of rash.
6.3.2. Cycle Delay;
Table 4
Updated the criteria to resume nivolumab treatment, based on revisions to product 
labeling for nivolumab and additional information from ongoing studies of nivolumab.
8.3.2.10. Treatment of 
Nivolumab Related 
Infusion Reactions
Added this statement: “If a nivolumab related infusion reaction occurs on Day 1 of 
a treatment cycle, then the scheduled dose of JNJ-757 should be withheld on that 
day. The subject can resume JNJ-757 treatment with the next scheduled dose of 
JNJ-757 on Day 1 of the next cycle of nivolumab treatment.”
Attachment 4: 
Anticipated Events
Updated the lists of disease-related and nivolumab-related adverse events based on 
currently available safety data.
Rationale: The background descriptions for JNJ-757 and nivolumab were updated with newer information.
1.2.1. Clinical Experience 
with LADD Lm-based
Immunotherapeutics
Modified to include information from the STELLAR study of CRS-207 with GVAX 
vaccine and cyclophosphamide, with or without nivolumab, in patients with pancreatic 
cancer.
1.3.2. Clinical Experience 
with JNJ-757
Modified to include updated safety and biomarker information from an ongoing Phase 
1 study of JNJ-757 in subjects with lung cancer (Study 64041757LUC1001).
NCT03371381

JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
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Status:  Approved,  Date:  4 January 2018
Applicable Section(s)
Description of Change(s)
1.4. Nivolumab
Updated to include additional information about the mechanism and action and safety 
of nivolumab.
1.5. Overall Rationale for 
the Study
Updated to include survival curves for the combination of JNJ-757 and a PD-1 
inhibitor from mouse models of lung cancer.
Clarified that based on currently available nonclinical and clinical data, the toxicity 
profiles of JNJ-757 and nivolumab are not anticipated to overlap.
Rationale: The role of continued study agent administration after suspected tumor flare was clarified. 
9.2.1.2. Treatment 
Beyond Progression; 
10.2. Discontinuation of 
Study Treatment
Clarified that subjects with solid tumors treated with immunotherapy may derive 
clinical benefit despite initial evidence of progressive disease (ie, tumor flare), and that 
subsequent responses will be reported in the eCRF. Clarified the conditions under 
which a subject with suspected tumor flare may be permitted to remain on study 
therapy. 
Rationale: The exclusion criterion for EGFR mutation or ALK translocation in nonsmokers was clarified.
3.2. Study Design 
Rationale; 4.2. Exclusion 
Criteria
Updated Criterion 2 to clarify that EGFR and ALK results must be confirmed in the 
Screening Period for all non-smokers.
Rationale: Revision to reflect the formulations that may be used in this study.
14.2 Packaging
Clarified that the JNJ-757 attenuated Lm is suspended in 
 
and that primary packaging consists of single-
use 2 mL glass vial(s) with gray butyl or bromobutyl stoppers.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
NCT03371381

JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
19
Status:  Approved,  Date:  4 January 2018
SYNOPSIS
An Open-label Randomized Phase 1b/2 Study of the Efficacy and Safety of JNJ-64041757, a Live 
Attenuated Listeria monocytogenes Immunotherapy, in Combination with Nivolumab Versus Nivolumab 
Monotherapy in Subjects With Advanced Adenocarcinoma of the Lung
JNJ-64041757 (formerly known as ADU-214 and henceforth referred to as JNJ-757) is a live-attenuated, 
double-deleted 
(LADD) 
Listeria 
monocytogenes
(Lm)-based 
immunotherapy 
containing 
an 
ActAN100-EGFRvIII (ActANE)-human mesothelin (hMeso) fusion expression vector. After infection 
and intracellular processing, JNJ-757 elicits a proinflammatory immune response resulting in recruitment 
and activation of innate and adaptive effector cells, ultimately leading to systemic mesothelin-specific 
CD4+ and CD8+ T-cell immunity. In patients with adenocarcinoma of the lung, the combination of 
JNJ-757 with nivolumab, a programmed death receptor-1 (PD-1) immune checkpoint inhibitor, has the 
potential to improve efficacy compared with nivolumab monotherapy, which is approved for treatment of 
non–small-cell lung cancer (NSCLC). 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
Endpoints/Assessments
Primary

To evaluate whether the efficacy of JNJ-757 combined 
with nivolumab is better than the efficacy of 
nivolumab monotherapy for subjects with mesothelin-
positive relapsed/refractory Stage IIIB or Stage IV 
adenocarcinoma of the lung, by PD-L1 level

Objective response rate (complete response plus 
partial response, based on RECIST 1.1 criteria)
Secondary

To compare the clinical benefit of JNJ-757 combined 
with nivolumab versus nivolumab monotherapy

Disease control rate (stable disease for at least
16 weeks, complete response, or partial 
response)

Duration of objective response

Progression-free survival

Overall survival

To evaluate the safety of JNJ-757 in combination with 
nivolumab

Incidence of adverse events

To correlate PD-L1 level with clinical activity

Disease control rate, duration of response, 
progression-free survival, and overall survival 
in biomarker subpopulations defined by PD-L1 
level

To assess the blood culture and shedding profile of 
JNJ-757

Blood cultures

Bacterial shedding samples 

To assess the pharmacokinetics and immunogenicity 
of nivolumab

Serum concentrations of nivolumab 

Incidence of anti-nivolumab antibodies
Exploratory

To monitor markers of innate and adaptive immune 
responses

Biologic markers of immune system activation

To evaluate other biomarkers that may be predictive of 
a response

Objective response rate in other biomarker 
subpopulations

To assess patient-reported outcomes 

NSCLC-SAQ and EORTC QLQ
EORTC QLQ=European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; 
NSCLC-SAQ=non–small-cell lung cancer self-administered questionnaire; PD-L1=programmed death receptor 
ligand 1; RECIST=Response Evaluation Criteria in Solid Tumors.
NCT03371381

JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
20
Status:  Approved,  Date:  4 January 2018
Hypothesis
The primary hypothesis of the study is that the addition of JNJ-757 to nivolumab will result in a higher 
objective response rate (ORR) compared with nivolumab monotherapy in at least one of the programmed 
death receptor ligand 1 (PD-L1) subgroups (<1%, 1-49%, or 50%) in subjects with relapsed or refractory 
Stage IIIB or Stage IV adenocarcinoma of the lung.
OVERVIEW OF STUDY DESIGN
This is a multicenter, open-label, randomized Phase 1b/2 study to determine if subjects with advanced 
relapsed/refractory adenocarcinoma of the lung will derive greater clinical benefit from the addition of 
JNJ-757 to nivolumab.
Phase 1b will be a safety run-in phase of at least 6 subjects to evaluate the incidence of dose limiting 
toxicities (DLTs) and demonstrate the tolerability of the combination. Additional subjects (up to 30 in 
total) may be enrolled, as determined by the Safety Evaluation Team (SET), to further explore safety and 
translational data before the decision to initiate the randomized Phase 2. All subjects in Phase 1b will 
receive nivolumab, administered at 240 mg IV over approximately 60 minutes, every 2 weeks, in 28-day 
cycles. After completion of the nivolumab infusion on Day 1 of each 28-day cycle, JNJ-757 will be 
administered at a dose of 1×109 colony-forming units (CFU) IV over approximately 60 minutes. The SET 
will be responsible for reviewing the safety and translational data during Phase 1b and for making a 
formal determination of whether the study will expand the Phase 1b cohort, modify the dosing regimen,
or proceed to the randomized phase (Phase 2) after the last subject dosed has been observed for at least 28 
days.
In Phase 2, a maximum of 140 subjects who meet all of the inclusion criteria and none of the exclusion 
criteria will be stratified in subgroups according to PD-L1 level (<1%, 1–49%, or 50%), using the 
DAKO PD-L1 IHC 28-8 pharmDx Assay, and then be assigned randomly (1:1) to receive JNJ-757 plus 
nivolumab (Group A) or nivolumab monotherapy (Group B). Throughout randomization, ORR will be 
monitored using a Bayesian hierarchical logistic regression model, such that more subjects may be 
enrolled in a PD-L1 subgroup where the combination therapy is more effective. However, subjects will 
always be randomized to Group A or Group B in a 1:1 ratio within that subgroup. If the combination 
therapy is not effective in any PD-L1 subgroup, then the study could be stopped early. In both groups, 
subjects will receive nivolumab, administered at 240 mg intravenously (IV) over approximately 60 
minutes, every 2 weeks, in 28-day cycles. In Group A, after completion of the nivolumab infusion on 
Day 1 of each 28-day cycle, JNJ-757 will be administered at a dose of 1×109 CFU IV over approximately 
60 minutes.
Disease response will be assessed with Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
criteria, using computed tomography (CT) scans with IV contrast (or if necessary, magnetic resonance 
imaging [MRI] scans) of the chest, abdomen, and pelvis at Week 8 (±7 days), then every 8 weeks 
(±7 days) during the first year, and then every 12 weeks (±7 days) thereafter until disease progression, 
subsequent therapy, or completion of therapy. For subjects receiving on-treatment biopsy, the first 
assessment will be at Cycle 3 Day 8 (+3 days).
In both phases of the study, treatment will continue until disease progression, unacceptable toxicity, 
protocol violation requiring discontinuation of study treatment, withdrawal of consent, noncompliance 
with study procedures, or the sponsor terminates the study. After discontinuing study treatment, subjects 
will be contacted by clinic visit or telephone every 3 months (±7 days) for survival follow-up until the 
subject withdraws consent or dies, or the sponsor terminates the study. Information on subsequent 
therapies (regimen, initiation dates, and stop dates) and best response (if available) will also be collected.
Among subjects who receive JNJ-757, surveillance blood cultures will be collected as follows: at the first 
4 visits of the Treatment Phase; on Day 1 of any subsequent cycle with a disease assessment, or as 
clinically indicated; at the End of Treatment visit (before prophylactic antibiotic therapy); and 3, 6, 9, and 
12 months after the last dose of JNJ-757. The end of the study will occur when 80% of the randomized 
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Status:  Approved,  Date:  4 January 2018
subjects have died, or approximately 3 years after the last subject is randomized, or the sponsor terminates 
the study.
SUBJECT POPULATION
Subjects must be 18 years of age and have histologically documented adenocarcinoma of the lung,
Stage IIIB or Stage IV disease, tumor biopsy positive for mesothelin and tumor biopsy material available 
for PD-L1 assessment in Phase 2, and Eastern Cooperative Oncology Group (ECOG) performance status 
of 0 or 1. Subjects must have progressive disease during or after platinum-based doublet chemotherapy. 
Subjects must have adequate bone marrow function, adequate hepatic function, and adequate renal 
function. Subjects are excluded from eligibility for the following: untreated brain metastases, activating
epidermal growth factor receptor (EGFR) mutation or ALK translocation, history of symptomatic 
interstitial lung disease, history of major implants or devices, or history of any other condition that may 
require the use of immunosuppressant medications such as anti-tumor necrosis factor alpha (TNF) 
therapy.
BIOMARKER EVALUATIONS
Pharmacodynamic biomarkers will be assessed before, during, and after treatment with JNJ-757. 
Biomarker analyses performed as part of the screening activities will include central assessment of 
mesothelin-positive status and PD-L1 level in tumor tissues. Tumor mesothelin status will be used as a 
study eligibility criterion and in Phase 2, subjects with mesothelin-positive tumors will be stratified based 
on PD-L1 level (<1%, 1-49%, or 50%). The primary endpoint of ORR will be assessed by PD-L1 level.
Markers of innate immune response, including changes in lymphocyte cell count and activation, and 
serum cytokines, will be measured as pharmacodynamic markers before, during, and after treatment with 
JNJ-757 when given in combination with nivolumab. Mandatory core needle on-study tumor biopsy 
samples will be collected from subjects in Phase 1b, with core needle tumor biopsy samples being 
required from subjects at selected sites in Phase 2 who consent separately to an optional tumor biopsy
substudy (where local regulations permit).
SAFETY EVALUATIONS
Safety evaluations will include adverse event monitoring, clinical laboratory tests, symptom-directed 
physical examinations, vital signs, and ECOG performance status. Any new or worsening adverse events 
occurring any time after signing the informed consent form (ICF) and up to 100 days after the last dose of 
study agent (JNJ-757 or nivolumab), as well as concomitant medications used throughout this time 
period, will be recorded for subjects who enter the Screening Phase. The severity of adverse events will 
be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE), Version 4.03. Adverse events indicative of inflammatory cytokine release will be followed as 
part of standard safety monitoring activities by the sponsor.
STATISTICAL METHODS
Phase 1b will be a safety run-in phase of at least 6 subjects to evaluate the incidence of DLTs and 
demonstrate the tolerability of the combination. Additional subjects (up to 30 in total) may be enrolled, as 
determined by the SET, to further explore safety and translational data before the decision to initiate the 
randomized Phase 2. The SET will be responsible for reviewing the safety and translational data during 
Phase 1b.
In Phase 2, a maximum of 140 subjects will be randomized. Based on preliminary data, it is estimated that 
60%, 25%, and 15% of mesothelin-positive subjects have a PD-L1 level of <1%, 1-49%, or ≥50%, 
respectively. The projected ORRs are as follows:
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JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
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Status:  Approved,  Date:  4 January 2018
PD-L1 (<1%)
PD-L1 (1-49%)
PD-L1 (≥50%)
Overall 
Group A (JNJ-757 plus nivolumab)
0.30
0.40
0.80
0.40
Group B (nivolumab)
0.10
0.20
0.40
0.17
Using frequentist methods, a sample size of 140 subjects will provide at least 90% power to test a 
difference of 17% versus 40% in the overall population, using a 2-sided alpha of 10%.
A Janssen Data Monitoring Committee (DMC) will review the ORR data after approximately 40, 60, 80, 
100, and 120 subjects have been randomized in Phase 2. The DMC may request additional ad-hoc reviews 
based on the accumulating data. Enrollment of subjects may be stopped during the DMC reviews. 
The accumulated ORR data from the eligible subjects will be used to estimate the posterior probability of 
observing an objective response (complete response or partial response) for each treatment group within 
each PD-L1 level. A Bayesian hierarchical logistic regression model will be used to calculate this 
probability. The details of the statistical model including specifications for prior distributions, decision 
rules to suspend accrual within a PD-L1 subgroup, hypothetical data scenarios, and operating 
characteristics will be provided in the Statistical Analysis Plan.
If accrual is stopped permanently in all PD-L1 subgroups, then the study is considered complete; 
otherwise, accrual will continued until a total of 140 subjects are randomized in Phase 2. The DMC may 
decide to expand any subgroup in which benefit of the combination has been demonstrated, to collect 
additional data within this subgroup.
The DMC will review safety data every 3 months. Enrollment of subjects may be stopped during the 
DMC reviews.
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Status:  Approved,  Date:  4 January 2018
TIME AND EVENTS SCHEDULE 
Table 1:
Time and Events Schedule - Assessments and Procedures for Phase 1b and Phase 2
Subjects
Assessments
Notes
Screening
Phase
Treatment Phase (28d Cycle)
End of 
Adverse 
Event 
Evaluation 
Period
Posttreatment 
Follow-up 
Phase
Day -28
to -1
Cycle 1
Cycle 2 and Cycle 3
Subsequent Cyclesa
EOT
100 days 
after the 
last dose of 
nivolumab 
(+7d)
Every 3
Months
(±7d)
D1
D2
D15
D1
D8
D15c
D1
D8b
D15c +30d
(+7d)
Subjects in Phase 1b and Group A of Phase 2 will receive JNJ-757 + nivolumab. Subjects in Group B of Phase 2 will receive nivolumab.
Screening/Administrative
All
Informed consent
X
All
Eligibility criteria
X
All
Weight, height
Height at 
screening only
X
X
X
X
All
Tumor sample
for mesothelin and PD-L1 
testing
Archivald or fresh 
sample required; 
may be collected 
in Screening 
Phase or in 
optional 
Prescreening 
Phase with 
separate ICF
(Section 9.1.2.2)
X
Ph2
Stratification
Mesothelin and 
PD-L1 results 
required before 
stratification and 
randomization
X
Study Agent Administration
All
Nivolumab infusion
240 mg IV over 
~60 min
X
X
X
X
X
X
Ph1b +
Ph2 
Group A
Pre- and post- JNJ-757 
infusion medications
See Section 8.1
X
X
X
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JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
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Status:  Approved,  Date:  4 January 2018
Subjects
Assessments
Notes
Screening
Phase
Treatment Phase (28d Cycle)
End of 
Adverse 
Event 
Evaluation 
Period
Posttreatment 
Follow-up 
Phase
Day -28
to -1
Cycle 1
Cycle 2 and Cycle 3
Subsequent Cyclesa
EOT
100 days 
after the 
last dose of 
nivolumab 
(+7d)
Every 3
Months
(±7d)
D1
D2
D15
D1
D8
D15c
D1
D8b
D15c +30d
(+7d)
Ph1b +
Ph2 
Group A
JNJ-757 infusion
1×109 CFU over 
~60 min
Administer after 
nivolumab 
infusion
Peripheral IV 
only
Observe for ~5 hr 
after infusion on 
C1D1 
X
X
X
Ph1b +
Ph2 
Group A
Required prophylactic 
antibiotic therapy
See 
Section 8.3.1.1
X
Disease Evaluations
All
CT or MRI of chest, 
abdomen, and pelvis
CT with IV 
contrast preferred
The same method 
should be used 
throughout the 
study
X
Week 8 (±7d), then every 8 weeks (±7d) during the first year, and then every 12 weeks (±7d) thereafter until disease 
progression, subsequent therapy, or completion of therapy. For subjects receiving on-treatment biopsy, the first 
assessment will be at C3D8 (+3d).
All
Brain MRI
Required only for 
subjects with 
known brain 
metastasis
X
As clinically indicated.
Ph2
Patient-reported outcomes
NSCLC-SAQ, 
EORTC QLQ, 
PGIC, PGIS
X
X
X
X
X
All
Survival status
X
NCT03371381

JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
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Status:  Approved,  Date:  4 January 2018
Subjects
Assessments
Notes
Screening
Phase
Treatment Phase (28d Cycle)
End of 
Adverse 
Event 
Evaluation 
Period
Posttreatment 
Follow-up 
Phase
Day -28
to -1
Cycle 1
Cycle 2 and Cycle 3
Subsequent Cyclesa
EOT
100 days 
after the 
last dose of 
nivolumab 
(+7d)
Every 3
Months
(±7d)
D1
D2
D15
D1
D8
D15c
D1
D8b
D15c +30d
(+7d)
Safety Assessments
All
Physical examination
Full physical 
exam at Screening
Symptom/disease-
directed at 
subsequent visits, 
with clinically 
relevant 
abnormalities 
reported as 
adverse events
X
X
Xb
X
X
X
X
X
X
X
All
ECOG performance status 
score
X
X
X
X
X
All
Heart rate, blood pressure, 
temperature, respiratory 
rate, and O2 saturation by 
pulse oximetry
On dosing days, 
record before 
nivolumab 
infusion, before 
JNJ-757 infusion, 
and at end of JNJ-
757 infusion
X
X
X
X
X
X
X
X
X
X
All
12-lead ECG
X
As clinically indicated
Ongoing Subject Review
All
Adverse events
See Section 12
Record all adverse events from signing of ICF until 100d after the last dose of study agent
All
Concomitant therapies
See Section 8
Record all concomitant therapies from signing of ICF until 100d after the last dose of study agent
NCT03371381

JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
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Status:  Approved,  Date:  4 January 2018
Subjects
Assessments
Notes
Screening
Phase
Treatment Phase (28d Cycle)
End of 
Adverse 
Event 
Evaluation 
Period
Posttreatment 
Follow-up 
Phase
Day -28
to -1
Cycle 1
Cycle 2 and Cycle 3
Subsequent Cyclesa
EOT
100 days 
after the 
last dose of 
nivolumab 
(+7d)
Every 3
Months
(±7d)
D1
D2
D15
D1
D8
D15c
D1
D8b
D15c +30d
(+7d)
Laboratory Assessments
All
Hematology
Serum chemistry
C1D1: no need to 
repeat test(s) if 
performed 7d 
before first dose
After C1D1: may 
be performed up 
to 3d before 
infusion
For parameters, 
see Section 9.7
X
X
X
X
X
X
X
X
All
Thyroid-stimulating 
hormone
Reflex to free T3, 
T4 if abnormal
X
X
Every 
other
cycle
All
Serum or urine pregnancy 
test (β-hCG)
Women of 
childbearing 
potential only; 
first test <14d 
before C1D1, 
second test <24hr 
before first dose
X
X
X
X
X
NCT03371381

JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
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Status:  Approved,  Date:  4 January 2018
Subjects
Assessments
Notes
Screening
Phase
Treatment Phase (28d Cycle)
End of 
Adverse 
Event 
Evaluation 
Period
Posttreatment 
Follow-up 
Phase
Day -28
to -1
Cycle 1
Cycle 2 and Cycle 3
Subsequent Cyclesa
EOT
100 days 
after the 
last dose of 
nivolumab 
(+7d)
Every 3
Months
(±7d)
D1
D2
D15
D1
D8
D15c
D1
D8b
D15c +30d
(+7d)
Blood Cultures
Ph1b +
Ph2 
Group A
Blood cultures
Peripheral blood 
samples for 
aerobic and 
anaerobic 
cultures.
If venous access 
device is in place, 
blood cultures at 
EOT and 
follow-up visits 
will be drawn 
through the 
device.
Predose
nivo
X
Predose
Predose
nivo
On Day 1 of each cycle 
with a disease assessment, 
or as clinically indicated
Before 
prophylactic 
antibiotic therapy
3, 6, 9, and 12 
months after 
the last dose of 
JNJ-757
Bacterial Shedding Assessments
All 
subjects 
in Ph1b +
Ph2 
Group A
(substudy 
only)
Fecal (stool or rectal 
swab), urine, and saliva 
(aerobic and anaerobic)
Subjects with a 
positive shedding 
result will be 
tested every 2-4d 
until a negative 
shedding result 
4hr after
JNJ-757
infusion
X
Predose
Predose
nivo
X
Nivolumab Pharmacokinetics and Immunogenicity
All
Nivolumab 
pharmacokinetics
Predose 
and 0.5hr 
postdose
Predose
nivo
(C8, 12, 
18, and 
24)
Predose
nivo
X
X
All
Nivolumab 
immunogenicity
Predose
nivo
Predose 
and 0.5hr 
postdose
Predose
nivo
(C8, 12, 
18, and 
24)
Predose
nivo
X
X
NCT03371381

JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
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Status:  Approved,  Date:  4 January 2018
Subjects
Assessments
Notes
Screening
Phase
Treatment Phase (28d Cycle)
End of 
Adverse 
Event 
Evaluation 
Period
Posttreatment 
Follow-up 
Phase
Day -28
to -1
Cycle 1
Cycle 2 and Cycle 3
Subsequent Cyclesa
EOT
100 days 
after the 
last dose of 
nivolumab 
(+7d)
Every 3
Months
(±7d)
D1
D2
D15
D1
D8
D15c
D1
D8b
D15c +30d
(+7d)
Biomarkers
All
Cytokines
One tube -
"Cytokines 
LADD" 
X
Predose 
nivo
and 2-
4hr 
postdose 
last 
study 
drug
X
Predose
Predose 
nivo
and 2-
4hr 
postdose 
last study 
drug
X
(C8, 12, 
18, and 
24)
Predose 
nivo
(C8, 12, 
18, and 
24)
One tube -
"Cytokines 
Nivolumab"
X
Predose
nivo
and 2-
4hr 
postdose
last 
study 
drug
X
Predose
and 2-4hr 
postdose
Predose 
nivo
and 2-
4hr 
postdose 
last study 
drug
X
Predose 
and 2-
4hr 
postdose
(C8, 12, 
18, and 
24)
Predose 
nivo
(C8, 12, 
18, and 
24)
X
One tube -
"Clinical"
X
Predose 
nivo
and 2-
4hr 
postdose 
last 
study 
drug
X
Predose 
nivo
and 2-
4hr 
postdose 
last study 
drug
X
Unschedulede
All
NK panel
One tube - "NK 
Panel"
Predose
nivo
X
Predose
Predose
nivo
X
Predose
Predose
nivo
X
X
All
Immune profile
One tube -
"Immune Profile"
Predose
nivo
X
Predose
Predose
nivo
X
Predose
Predose
nivo
X
X
All
HLA typing
One tube - "HLA"
X
NCT03371381

JNJ-64041757 
Clinical Protocol 64041757LUC2002 Amendment 2
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Status:  Approved,  Date:  4 January 2018
Subjects
Assessments
Notes
Screening
Phase
Treatment Phase (28d Cycle)
End of 
Adverse 
Event 
Evaluation 
Period
Posttreatment 
Follow-up 
Phase
Day -28
to -1
Cycle 1
Cycle 2 and Cycle 3
Subsequent Cyclesa
EOT
100 days 
after the 
last dose of 
nivolumab 
(+7d)
Every 3
Months
(±7d)
D1
D2
D15
D1
D8
D15c
D1
D8b
D15c +30d
(+7d)
Allb
T-Cell 
proliferation/ICS/Pentamer 
staining, IFN-ELISpot
Ten tubes -
"PBMC"
Collection may 
cease or 
timepoints 
modified based on 
emerging data
Predose
nivo
X
X
X
X
X
All
TCR sequencing
One tube - "TCR 
Sequence"
Samples will be 
collected and 
stored. Analysis 
will be triggered 
retrospectively 
based on 
emerging data.
X
X
C2 and 
should 
coincide 
with CT 
or MRI 
imaging 
at C3D8 
only 
Predose
X
X
Tumor Biopsy
Allb
CT- or FDG-PET/CT-
guided core needle tumor 
biopsy
Requires separate 
ICF
Screening biopsy 
4 weeks after the 
last chemotherapy
X
Should coincide with CT or MRI imaging at Cycle 3 Day 8. If a biopsy sample is collected during the study as part of 
standard care, a sample should be submitted for biomarker analysis.
-hCG=-human chorionic gonadotropin; CFU=colony-forming unit; C=Cycle; CT=computed tomography; d/D=day(s); ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
ELISpot=enzyme-linked immunospot assay; EORTC QLQ=European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; EOT=end-of-treatment; FDG-PET=fluorodeoxyglucose 
positron emission tomography; hr=hour; HLA=human leukocyte antigen; ICF=informed consent form; ICS=intracellular cytokine staining; IFN-=interferon gamma; IV=intravenous; MRI=magnetic resonance 
imaging; nivo=nivolumab; NK=natural killer; NSCLC-SAQ=non–small-cell lung cancer self-administered questionnaire; O2=oxygen; PD-L1=programmed death receptor ligand 1; PET=positron emission 
tomography; PGIC=patient global impression of change; Ph1b=Phase 1b; Ph2=Phase 2; PGIS=patient global impression of severity; TCR=T-cell receptor.
a. The start of each subsequent cycle may occur ±3 days of the scheduled day to accommodate the schedule of the site or subject.
b. All subjects in Phase 1b and required for subjects participating in the tumor biopsy substudy at selected sites approved by the sponsor in Phase 2.
c. If nivolumab is permanently discontinued but the subject continues to receive treatment with JNJ-757, then the Day 15 visits and evaluations will be optional in Cycle 3 or later.
d. Tumor samples (block or unstained tumor slides) may be either from archival tissue or newly obtained (if archival tissue is insufficient). Unstained slides must be made within 4 months prior to central 
laboratory assessment and stored in the dark at 2°–8°C.
e. Based on emerging data, adjustments to the planned schedule of assessments may be made by the sponsor to protect subject safety. One or more serum samples for selected cytokines (including but not limited 
to IFN gamma, TNF alpha, and IL-6) may be drawn after a suspected infusion-related reaction, and submitted to a 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.
NCT03371381

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Status:  Approved,  Date:  4 January 2018
ABBREVIATIONS
-hCG
-human chorionic gonadotropin
actA
actin assembly protein 
AIDS
acquired immune deficiency syndrome
ALT
alanine aminotransferase
ANOVA
analysis of variance
APC
antigen presenting cells 
AST
aspartate aminotransferase
BSC
best supportive care
CD4
cluster of differentiation 4
CD69
cluster of differentiation 69
CD8
cluster of differentiation 8
CFU
colony-forming unit
CNS
central nervous system
CR
complete response 
CRF
case report form(s) (paper or electronic as appropriate for this study)
CRO
contract research organization
CT
computed tomography 
CTLA-4
cytotoxic T lymphocyte associated antigen 4
DCR
disease control rate
DILI
drug-induced liver injury
DLT
dose limiting toxicity
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DOR
duration of response 
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form 
eDC
electronic data capture
EGFR
epidermal growth factor receptor
EGFRvIII
epidermal growth factor receptor variant III
ELISpot
enzyme-linked immunospot assay
EORTC QLQ
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire
FDG-PET/CT
fluorodeoxyglucose positron emission tomography/computed tomography
FFPE
formalin fixed paraffin embedded
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HRQOL
health-related quality of life
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HR
hazard ratio
HTA
Health Technology Assessment
ICF
informed consent form
ICH
International Conference on Harmonisation
ICS
intracellular cytokine staining
IEC
Independent Ethics Committee
IFN-γ
interferon gamma
IHC
immunohistochemistry
IPPI
Investigational Product Preparation Instructions
IRB
Institutional Review Board
ITT
intent to treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
NCT03371381

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Status:  Approved,  Date:  4 January 2018
IWRS
interactive web response system
LADD
live-attenuated, double-deleted
LD50
median lethal dose
LFT
liver function test
Lm
Listeria monocytogenes
MDSC
myeloid-derived suppressor cells 
MedDRA
Medical Dictionary for Regulatory Activities
MHC
major histocompatibility complex
MRI
magnetic resonance imaging
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NK
natural killer
NSCLC
non–small-cell lung cancer
NSCLC-SAQ
Non-Small Cell Lung Cancer Symptom Assessment Questionnaire
ORR
objective response rate 
PAP
Papanicolaou
PBMC
peripheral blood mononuclear cells
PD-1
programmed death receptor-1
PD-L1
programmed death receptor ligand 1
PD-L2
programmed death receptor ligand 2
PGIC
patient global impression of change
PGIS
patient global impression of severity
PET
positron emissions tomography
PFS
progression-free survival
PQC
Product Quality Complaint
PR
partial response
PRO
patient-reported outcome(s) 
RECIST 
Response Evaluation Criteria in Solid Tumors
SAQ
self-administered questionnaire
SET
Safety Evaluation Team
SIPPM
Site Investigational Product Procedures Manual
SUSAR
suspected unexpected serious adverse reaction
TCR
T-cell receptor
TNF
tumor necrosis factor alpha
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
USP
United States Pharmacopeia
NCT03371381

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1.
INTRODUCTION
JNJ-64041757 (formerly known as ADU-214 and henceforth referred to as JNJ-757) is a live-
attenuated, double-deleted (LADD) Listeria monocytogenes
(Lm)-based immunotherapy. 
JNJ-757 is engineered to encode and express human mesothelin and to efficiently deliver this 
tumor-associated antigen into major histocompatibility complex (MHC) Class I and Class II 
antigen-processing pathways. JNJ-757 is expected to be taken up specifically by phagocytic cells 
in the liver and spleen upon intravenous (IV) infusion. After infection and intracellular 
processing, JNJ-757 elicits a proinflammatory immune response resulting in the recruitment and 
activation of innate and adaptive effector cells, ultimately leading to systemic mesothelin-
specific CD4+ and CD8+ T-cell immunity. In patients with adenocarcinoma of the lung, the 
combination of JNJ-757 with nivolumab, a programmed death receptor-1 (PD-1) immune 
checkpoint inhibitor, may provide a synergistic effect to improve efficacy compared with 
nivolumab monotherapy, which is approved for treatment of non–small-cell lung cancer 
(NSCLC).
For the most comprehensive nonclinical and clinical information regarding JNJ-757, refer to the 
latest version and addenda of the Investigator's Brochure for JNJ-757. The term "sponsor" used 
throughout this document refers to the entities listed in the Contact Information page(s), which 
will be provided as a separate document.
1.1.
Background
1.1.1.
Current Treatment Standards and Unmet Medical Need in Advanced 
or Metastatic Non–Small-Cell Lung Cancer
Lung cancer is the leading cause of cancer mortality globally (WHO 2015).43 In the United 
States, lung cancer is the second most commonly diagnosed cancer with more than 
200,000 people diagnosed annually. It is the leading cause of cancer-related deaths and
approximately 160,000 people are estimated to succumb to the disease each year (Am Cancer 
Society 2014).2 Approximately 80% to 85% of the newly diagnosed cases of lung cancer are 
NSCLC (adenocarcinoma, squamous carcinoma, or large cell carcinoma) and 15% to 20% are 
small cell lung carcinoma (Molina 2008).24
Recently, a better understanding of the biology of NSCLC has translated into the incorporation 
of molecular testing and the introduction of targeted agents, including tyrosine kinase inhibitors 
and immunomodulatory agents that can provide significantly improved response rates and 
duration of response (DOR) in molecularly defined subsets of patients. However, the overall 
prognosis of patients diagnosed with lung cancer has not improved significantly; the 5-year 
survival rate remains below 18% overall and below 5% among patients with metastatic disease at 
diagnosis (SEER 2015).34
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The anti-PD-1 checkpoint inhibitor nivolumab has been approved for use as monotherapy in 
patients with metastatic lung cancer, after failure of first-line platinum doublet therapies. The 
approval was based on Phase 3 results demonstrating improved overall survival compared with 
single-agent docetaxel in squamous NSCLC (Brahmer 2015)6 and nonsquamous NSCLC 
(Borghaei 2015).5 While nivolumab has demonstrated impressive DOR in patients with NSCLC, 
a majority of patients will not respond to nivolumab when it is given as monotherapy
(Section 1.4). For patients with nonimmunogenic tumors, or in whom the immune system has not 
mounted effective anti-tumor T cell responses, the combination of nivolumab with a tumor 
vaccine may improve response rates, based on the complementary mechanisms of action of these 
agents.
1.1.2.
Clinical Experience With Cancer Vaccines for Non–Small-Cell Lung 
Cancer
Cancer vaccines are intended to induce or increase an adaptive immune response against 
malignant tumor cells (Rodriguez 2013).31 These vaccines can be divided into whole-cancer cell 
preparations that have been rendered replication incompetent and antigen-specific (glyco) 
peptides or antigen-specific recombinant proteins (Forde 2014; Mostafa 2014; Ruiz 2014).11,25,32
Whole-cell based vaccination approaches may be derived from individual patient tumors or 
allogeneic tumor cells, as in the NSCLC vaccine belagenpumatecel-1 (Lucanix®), and thus 
trigger adaptive immune responses against a variety of tumor-specific antigens (De Pas 2012).8
In contrast, antigen-specific peptide or protein immunotherapies, which are frequently 
augmented by immunoadjuvants or immunostimulants, are designed to induce adaptive immune 
responses against a specific antigen overexpressed in NSCLC. 
The current lack of clinical success with vaccines for NSCLC, despite multiple attempts, is 
believed to be caused by "immune evasion" (De Pas 2012).8 Data derived from nonclinical 
disease models and clinical studies indicate that NSCLC cells are able to generate a hostile 
immune environment in the tumor stroma through the secretion of immunosuppressive factors 
and the recruitment of suppressive immune cells of myeloid origin (myeloid-derived suppressor 
cells [MDSC]) or lymphoid origin (ie, regulatory T cells [Treg cells]). Defects in the processing 
and presentation of antigens in the NSCLC microenvironment may also contribute to the limited 
efficacy observed with the cancer vaccines investigated thus far (Rodriguez 2013).31
New approaches are needed that address the mechanisms of immune evasion in NSCLC. Antigen
processing and presentation defects may be overcome by more effectively engaging and 
activating dendritic cells and macrophages; tolerance to tumor antigens may be overcome by 
triggering a more robust and sustained adaptive immune response; and reducing Treg cells and 
MDSC may modulate the immune-suppressive tumor microenvironment (Wood 2014).42 In 
addition, the induction of immune responses against unmutated tumor antigens may overcome 
the requirement for neoantigen burden (Wood 2014).42
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1.2.
LADD: An Immunotherapeutic Platform
LADD Lm-based immunotherapeutics have the potential to address the immune evasion 
mechanisms described in NSCLC (Wood 2014).42 The LADD Lm-based platform features a 
deletion of 2 virulence genes (actin assembly protein [actA] and internalin B [inlB]) from the Lm
chromosome, which leads to a >1000-fold attenuation in virulence without loss of its ability to 
induce potent innate and adaptive cellular immunity (Brockstedt 2004).7
Lm-based 
immunotherapy takes advantage of the unique ability of the Gram-positive bacterium Lm to 
induce a powerful innate immune response, as well as a strong adaptive immune response, upon 
direct infection of antigen presenting cells (APC), with subsequent expression of the desired 
(multiple) tumor antigens (Wolf 2013).41
Within hours after IV infusion, the LADD Lm-based immunotherapeutic induces an 
inflammatory reaction reflecting activation of the innate immune response. This immediate 
reaction is followed over the next 7 to 10 days by an adaptive response as the T cells and B cells 
are activated by the dendritic cells and macrophages (ie, APC) in the liver and spleen. The direct 
and selective targeting of APCs by the LADD Lm-based platform stands in contrast to previous 
vaccine-based approaches, and delivers the antigen(s) encoded in its expression cassette directly 
to the high-efficiency MHC Class I and II antigen-presenting machinery (Wolf 2013).41 This 
mechanism of action may enhance antigen processing and presentation, as well as improve T-cell 
priming. Using repeated infusions, a more robust and sustained cytotoxic T-cell-mediated, 
antigen-specific immune response may be achieved (Wolf 2013).41 Emerging data indicate that 
its efficacy may be increased by the ability of Lm to directly reduce tumor-associated 
immunosuppression by inhibiting the expansion of Treg cells and MDSC in the tumor 
microenvironment, 
as 
well 
as 
downregulating 
their 
immunosuppressive 
ability
(Wallecha 2013).38 Thus, LADD Lm-based immunotherapeutics offer the potential to 1) 
repeatedly deliver tumor-specific antigens with superior efficiency, 2) enhance the emerging 
adaptive antitumor immune response, and 3) suppress the immune resistance of the tumor 
microenvironment. Several LADD Lm-based therapies, all derived from the ANZ-100 parental 
strain, are currently in development in multiple disease types, including CRS-207 (mesothelioma
[NCT01675765], pancreatic cancer [NCT02004262, NCT01417000], and ovarian cancer
[NCT02575807]), ADU-623 (astrocytoma [NCT01967758]), JNJ-64041809, hereafter referred 
to as JNJ-809 (prostate cancer [NCT02625857]), and JNJ-757 (lung cancer [NCT02592967]).
1.2.1.
Clinical Experience with LADD Lm-based Immunotherapeutics
The most studied LADD Lm-based immunotherapeutic is CRS-207, which was engineered to 
express human mesothelin. The safety and immunogenicity of CRS-207 was first assessed in a 
Phase 1 study of 17 patients with mesothelin-overexpressing tumors, including NSCLC, 
mesothelioma, pancreatic cancer, and ovarian-cancer (Le 2012).20 Treatment-related adverse 
events occurred predominantly within 4 hours from the start of the study treatment, and were 
indicative of a systemic innate immune response: fever, rigors/chills, nausea, dehydration, 
headache, and hypotension, mostly of Grade 1 or 2 severity, were reported. Transient and 
self-limiting laboratory abnormalities (lymphopenia, hypophosphatemia, and transaminitis) were 
noted and were thought to represent a temporary shift of lymphocytes and electrolytes out of the 
blood compartment. 
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Induction of proinflammatory chemokines and interferon gamma (IFN-γ), consistent with 
activation of innate immunity, as well as specific T-cell responses, were detected with minor 
differences in magnitude across all CRS-207 dose levels. Of the 3 subjects with NSCLC who 
were treated with CRS-207, all had tumors that expressed mesothelin in at least 50% of tumor 
cells. Two of 3 subjects were evaluated for listeriolysin O (an Lm-secreted virulence factor)-
specific T-cell responses. A statistically significant increase in IFN-CD8+ clones detected by 
enzyme-linked immunospot assay (ELISpot) demonstrated the subjects' ability to mount an 
immune response to the Lm platform. One subject, who received 1×109 colony-forming units 
(CFU) of CRS-207, showed a statistically significant increase in IFN-–producing CD8+ clones 
by ELISpot and mesothelin staining in 100% of tumor cells. This subject had stable disease by 
Response Evaluation Criteria in Solid Tumors (RECIST) at 91 days and long-term survival of 
26+ months (Le 2012).20 Based on the emerging safety profile and the immunologic activity, a 
CRS-207 dose of 1×109 CFU was selected as the recommended Phase 2 dose (Le 2012).20
The overall safety and efficacy results obtained from the Phase 1 and Phase 2 studies conducted 
with CRS-207 indicate that: (1) LADD Lm-based immunotherapeutics are generally well 
tolerated at a dose of 1×109 CFU and have a predictable and manageable safety profile that is 
consistent 
with 
activation 
of 
an 
innate 
immune 
response; 
(2) LADD 
Lm-based
immunotherapeutics containing a mesothelin expression cassette induce a robust and sustainable 
mesothelin-specific adaptive immune response; and (3) LADD Lm-based immunotherapeutics 
may extend overall survival, even in the absence of classical tumor responses (as defined by 
RECIST 1.1).
The STELLAR study (Safety and Therapeutic Efficacy of Live-attenuated Listeria/GVAX with 
Anti-PD1 Regimen – NCT02243371) is an ongoing Phase 2 study to evaluate survival, safety, 
and 
immune 
response 
following 
treatment 
with 
CRS-207, 
GVAX 
vaccine, 
and 
cyclophosphamide, with or without nivolumab, in patients with pancreatic cancer. Enrollment in 
this study is complete. Scheduled reviews of safety data by a Data Monitoring Committee 
(DMC) communicated no concerns regarding increased immunologic toxicities in the 
combination CRS-207 and nivolumab arm. 
Additional studies are investigating CRS-207 in combination with chemotherapy (mesothelioma; 
NCT02575807) and in combination with other immunotherapies such as epacadostat (ovarian 
cancer; NCT02291055). Refer to the JNJ-757 Investigator's Brochure for updated data regarding 
CRS-207 monotherapy and combination studies. Two other combination approaches are being 
pursued with another Listeria-based platform, investigating combinations of ADXS31-142 with 
pembrolizumab (prostate cancer; NCT02325557) or ADXS11-001 with MEDI4736 (head and 
neck cancer; NCT02291055).
1.3.
JNJ-757: A Lung Cancer Directed Tumor Vaccine
JNJ-757, similar to CRS-207, was engineered from the parent LADD Lm strain ANZ-100 to 
contain an ActANE-human mesothelin (hMeso) fusion expression vector. Mesothelin is fused in-
frame with portions of the actA and epidermal growth factor receptor variant III (EGFRvIII) 
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proteins (ActANE), which have been shown to augment expression and secretion of the antigen 
proteins, and may therefore lead to improved antigen presentation by the APC (Figure 1). 
Figure 1:
Expression of Mesothelin by JNJ-757 Compared With CRS-207
Lane
Strain
Antigen Cassette
ActA
P60
Ratio
1
Lm11
None
-
13.67
-
2
CRS-207
Mesothelin
0.56
8.6
0.07
3
JNJ-757
EGFRvIIIx5-Mesothelin
32.23
10.9
2.96
Mesothelin, a glycosylphosphatidylinositol-linked cell surface glycoprotein, is an established 
target in lung cancer drug development. Mesothelin has limited expression on the surface of 
normal tissues, including mesothelial cells lining the pleura, peritoneum, and pericardium, but is 
highly expressed in several human tumors, including 50% to 70% of lung adenocarcinomas 
(Hassan 2008; Thomas 2016).15,37 Based on this expression pattern, mesothelin has been targeted 
by numerous immune-directed approaches, including blocking antibodies (Hassan 2010),14
antibody-drug conjugates moieties (Ordóñez 2003),29 and immunotherapeutics (Le 2012).20
Evolving data show mesothelin expression in lung cancer is largely cytoplasmic and thus may 
not be amenable to therapies targeting membrane expression (Hassan 2008; Kachala 2014).15,19
However, this pattern of expression is not expected to impede an immune-based approach such 
as that elicited by JNJ-757.
Being derived from ANZ-100, JNJ-757 has the same genetic background as CRS-207, as well as 
2 other LADD Lm-based investigational agents, ADU-623 and JNJ-809. Emerging clinical safety 
data available from studies with ANZ-100, CRS-207, JNJ-809, and ADU-623 suggest that 
strains derived from the ANZ-100 platform share common clinical safety characteristics that 
appear to be unaffected by the specific antigen cassette. It is anticipated that the clinical safety 
characteristics described for ANZ-100 and derived strains, particularly CRS-207, which targets 
the same mesothelin tumor antigen, will also apply to JNJ-757. The recommended Phase 2 doses
for CRS-207, JNJ-809, and JNJ-757 have all been confirmed as 1×109 CFU.
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1.3.1.
Nonclinical Experience with JNJ-757
1.3.1.1.
Nonclinical in Vivo Efficacy of JNJ-757
The efficacy of JNJ-757 has been investigated in a pulmonary metastatic model of colorectal 
cancer-bearing mice. CT26 colon carcinoma cells engineered to express human mesothelin 
(CT26-hMeso; 2×106) injected into the tail vein of female BALB/c mice efficiently metastasize 
to the lungs (Francia 2011).12 In this model, infusion of JNJ-757 three days after tumor 
implantation resulted in a significant dose dependent survival benefit compared with vehicle or 
the control LADD Lm-based immunotherapeutic, Lm11 (Figure 2).
Figure 2:
Dose-dependent Therapeutic Antitumor Efficacy of JNJ-757 in Mice
CT26-hMeso-bearing mice were treated with vehicle (HBBS), empty LADD platform (Lm11), or JNJ-757 
at the indicated doses.
HBSS=Hank's balanced salt solution.
1.3.1.2.
Nonclinical Biodistribution Studies with JNJ-757
Nonclinical studies were performed to determine the biodistribution of JNJ-757 and to compare 
it with that of CRS-207 in the blood, spleen, liver, kidney, gall bladder, heart, lung, brain, and 
ovaries in BALB/c mice after IV administration. These studies determined that the highest 
number of JNJ-757 CFUs was observed in the liver and spleen within 24 hours after a single IV 
administration. This is consistent with previous studies examining the biodistribution of 
ANZ-100, which is the platform strain from which both JNJ-757 and CRS-207 are derived. Both 
CRS-207 and ANZ-100 were cleared from most tissues within 7 days after dosing. Similarly, 
JNJ-757 was cleared from all tissues by 7 days postinfusion. Based on these results, expression 
of the EGFRvIII-h Mesothelin fusion antigen by JNJ-757 does not alter the biodistribution of 
LADD Lm compared with CRS-207.
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1.3.1.3.
Nonclinical Toxicology Profile of JNJ-757
In vivo studies in BALB/c mice indicated that IV administration of 5×106 CFU of JNJ-757 
(known to elicit immune responses) leads to transient alterations in hematology comparable to 
those seen with CRS-207. All transient changes, including lymphopenia, thrombocytopenia 
(nadir on Day 2), and anemia (nadir on Day 4) resolved within 7 days after dosing. Transient 
changes in clinical chemistry parameters after JNJ-757 infusion (ie, decreases in albumin, 
alkaline phosphatase, glucose, and triglycerides) were comparable in magnitude and duration to 
those observed with CRS-207. Based on these results, expression of the EGFRvIII-hMesothelin 
fusion protein by JNJ-757 does not appear to alter the hematology profile or the clinical 
chemistry parameters of JNJ-757 compared with the mesothelin-expressing CRS-207.
The median lethal dose (LD50) of JNJ-757 is comparable to the LD50 of CRS-207 (4.6×107 CFU 
for JNJ-757 and 3.0×107 CFU for CRS-207). The results were also consistent with previous 
analysis done with ANZ-100.
Together these studies indicate that expression of the EGFRvIII-hMeso fusion antigen by 
JNJ-757 does not alter the biodistribution, hematologic parameters, clinical chemistry 
parameters, or the median lethality in BALB/c mice compared with CRS-207. The results 
support the hypothesis that changes resulting from exposure to the LADD Lm bacteria are 
independent of the expression of different fusion antigens.
1.3.2.
Clinical Experience with JNJ-757
A first-in-human study (64041757LUC1001) of JNJ-757 was initiated to identify the 
recommended Phase 2 dose, and to evaluate the safety and immunogenicity of JNJ-757 in 
subjects with advanced (Stage IIIb) or metastatic (Stage IV) NSCLC (adenocarcinoma). This 
dose-escalation study began enrolling on 10 December 2015; enrollment is complete in the dose 
escalation cohorts (Part 1), with the first dose cohort (1×108 CFU) enrolling 6 subjects, and the 
second dose cohort (1×109 CFU) enrolling 3 subjects. With no dose-limiting toxicities (DLTs)
identified in either the 1×108 CFU dose cohort or the 1×109 CFU dose cohort, the Safety 
Evaluation Team (SET) confirmed the safety of JNJ-757 at both doses, and identified the 1109
CFU dose level as the recommended Phase 2 dose. At the time of the SET meeting data cutoff 
(13 October 2016), 4 subjects were still undergoing therapy, and the maximum number of cycles 
administered to a single subject was 14.
Preliminary safety data from the ongoing Phase 1 study of JNJ-757 were consistent with the 
safety profile of CRS-207. Infusions of JNJ-757 were uncomplicated, with subjects typically 
experiencing low-grade fevers, chills/rigors, fatigue, and nausea and vomiting, beginning 
approximately 1.5 hours to 3 hours after completion of the JNJ-757 infusion. These symptoms 
were transient, typically resolving after 24 hours, and were effectively managed with supportive 
measures outlined in the protocol, allowing for repeated dosing.
Preliminary biomarker data for the 6 subjects who received JNJ-757 at a dose of 1×108 CFU on 
Day 1 of each 21-day cycle in Study 64041757LUC1001 were consistent with those reported for 
the other LADD Lm-based agents ANZ-100 and CRS-207 (Le 2012),20 confirming activation of 
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both innate and adaptive immune responses with JNJ-757 administration. Activation of the 
innate immune response was demonstrated by transient increases in serum cytokine levels and 
expression of markers of natural killer (NK) cell activation (eg, CD69) after JNJ-757 
administration, even with repeated dosing (Figure 3). These increases in NK-cell activation 
corresponded with transient decreases in peripheral absolute lymphocyte counts, consistent with 
margination of activated lymphocytes out of the peripheral circulation (Figure 4), which returned 
to baseline by Day 3 of each cycle. Finally, preliminary ELISpot assay analyses have confirmed 
the potential for JNJ-757 treatment to initiate antigen-specific T-cell responses, even at the 1×108
CFU dose, targeting the Lm antigen listeriolysin O (LLO), and the tumor antigens mesothelin 
and EGFRvIII (Figure 5). Refer to the Investigator's Brochure for the most recent updates of 
safety and translational data from the Phase 1 study.
Figure 3:
Natural Killer (NK) Cell Activation (CD69 Positivity) Over Time in Individual Subjects who
Received JNJ-757 at a Dose of 1×108 Colony Forming Units on Day 1 of Each 21-Day Cycle
(Study 64041757LUC1001)
CxDy=Cycle x Day y.
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Figure 4:
Absolute Lymphocyte Count Over Time in Individual Subjects who Received JNJ-757 at a Dose 
of 1×108 Colony Forming Units on Day 1 of Each 21-Day Cycle (Study 64041757LUC1001) 
CxDy=Cycle x Day y.
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Figure 5:
Preliminary Data for Adaptive Immune Response by ELISpot Over Time in a Subject who
Received JNJ-757 at a Dose of 1×108 Colony Forming Units on Day 1 of Each 21-Day Cycle
(Study 64041757LUC1001)
CxDy=Cycle x Day y; EGFRvIII=epidermal growth factor receptor variant III; LLO=listeriolysin O; 
PBMC=peripheral blood mononuclear cells; SFC=spot forming colonies.
1.4.
Nivolumab
Nivolumab (OPDIVO®) is a fully human IgG4 PD-1 immune checkpoint inhibitor that disrupts 
PD-1–mediated signaling and restores antitumor immunity. Cancer immunotherapy rests on the 
premise that tumors may be recognized as foreign rather than as self and may be effectively 
attacked by an activated immune system. An effective immune response in this setting is thought 
to rely on immune surveillance of tumor antigens expressed on cancer cells that ultimately 
results in an adaptive immune response and cancer cell death. Meanwhile, tumor progression 
may depend upon acquisition of traits that allow cancer cells to evade immunosurveillance and 
escape effective innate and adaptive immune responses (Dunn 2002; Jemal 2011; Pardoll 2003; 
Zitvogel 2006).9,17,30,44 Current immunotherapy efforts attempt to break the apparent tolerance of 
the immune system to tumor cells and antigens by either introducing cancer antigens by 
therapeutic vaccination or by modulating regulatory checkpoints of the immune system.
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T-cell stimulation is a complex process involving the integration of numerous positive as well as 
negative costimulatory signals in addition to antigen recognition by the T-cell receptor 
(Greenwald 2005).13 Collectively, these signals govern the balance between T-cell activation and 
tolerance. PD-1 is a member of the CD28 family of T-cell costimulatory receptors that also 
includes CD28, CTLA-4, ICOS, and BTLA (Nishimura 2001).26 PD-1 signaling has been shown 
to inhibit CD-28-mediated upregulation of IL-2, IL-10, IL-13, interferon-γ (IFN-γ) and Bcl-xL. 
PD-1 expression has also been noted to inhibit T-cell activation and expansion of previously 
activated cells. Evidence for a negative regulatory role of PD-1 comes from studies of PD-1-
deficient mice, which develop a variety of autoimmune phenotypes (Sharpe 2007).35 These 
results suggest that PD-1 blockade has the potential to activate anti-self T-cell responses, but 
these responses are variable and dependent upon various host genetic factors. Thus, PD-1 
deficiency or inhibition is not accompanied by a universal loss of tolerance to self antigens.
In vitro, nivolumab binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and inhibits the 
binding of PD-1 to its ligands programmed death receptor ligand 1 (PD-L1) and programmed 
death receptor ligand 2 (PD-L2) (IC50 ± 1 nM). Nivolumab binds specifically to PD-1 and not to 
related members of the CD28 family such as CD28, ICOS, CTLA-4 and BTLA. Blockade of the 
PD-1 pathway by nivolumab results in a reproducible enhancement of both proliferation and 
IFN-γ release in the mixed lymphocyte reaction. Using a cytomegalovirus re-stimulation assay 
with human peripheral blood mononuclear cells (PBMCs), the effect of nivolumab on antigen-
specific recall response indicates that nivolumab augmented IFN-γ
secretion from 
cytomegalovirus-specific memory T cells in a dose-dependent manner versus isotype-matched 
control. In vivo blockade of PD-1 by a murine analog of nivolumab enhances the anti-tumor 
immune response and results in tumor rejection in several immunocompetent mouse tumor 
models (MC38, SA1/N, and PAN02) (Wolchok 2009).40
As a single agent, the mean elimination half-life of nivolumab is approximately 25 days, with 
steady-state concentrations occurring by 12 weeks when 3 mg/kg is dosed every 2 weeks. The 
systemic accumulation is approximately 3.7-fold. In 2022 patients treated with single-agent 
nivolumab dosed at 3 mg/kg every 2 weeks, 11.4% patients tested positive for anti-nivolumab 
antibodies and 0.7% had neutralizing antibodies against nivolumab. These did not appear to 
affect the pharmacokinetics or incidence of infusion reactions (OPDIVO 2017).28
Nivolumab has been approved for the treatment of patients with NSCLC with progression during 
or after platinum-based chemotherapy, based on the results of Phase 3 studies in patients with 
squamous NSCLC (Brahmer 2015)6 and nonsquamous NSCLC (Borghaei 2015).5
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In the Phase 3 study of patients with nonsquamous NSCLC (Borghaei 2015),5 nivolumab
treatment improved overall survival compared with docetaxel treatment (hazard ratio [HR]=0.73; 
95% CI, 0.59-0.89; p=0.002). This improvement in overall survival was associated with an 
increased objective response rate (ORR) in the nivolumab arm (19% vs 12%; p=0.02). Despite 
the improved ORR, median progression-free survival (PFS) was not improved in the nivolumab 
arm compared with the docetaxel arm (2.3 vs 4.2 months). The rate of PFS at 1 year, however, 
was higher with nivolumab treatment (19% vs 8%), which may in part reflect the greatly 
improved DOR observed in the nivolumab arm compared with the docetaxel arm (median, 17.2 
vs 5.6 months).
The incidence of treatment-related adverse events was reduced in the nivolumab arm of each 
study, relative to their respective docetaxel control arm, with the greatest discrepancy observed 
in Grade 3-4 toxicities (10% in the nivolumab arm in both studies, compared with 54% and
55%, respectively, in the docetaxel control arm) (Brahmer 2015, Borghaei 2015).5,6 The 
incidence of serious adverse events was reduced in the nivolumab treatment arms (7% in both 
nivolumab treatment arms, versus 20% and 24%, respectively, in the docetaxel arms). The most 
frequently experienced adverse events (10%) in the nivolumab arms of both studies were 
fatigue (16%), decreased appetite (11%), and asthenia (10%) in the squamous population, and 
fatigue (16%), nausea (12%), decreased appetite (10%), and asthenia (10%) in the nonsquamous 
population, all of which occurred more frequently in the respective control arms. Selected 
adverse events (those with potential immunologic causes) occurred in <10% of subjects treated 
with nivolumab in either study and, with the exception of infusion reactions (which occurred in 
3% of subjects), the median time to onset was a few weeks after treatment.
The safety profile of nivolumab monotherapy as well as combination therapy is manageable and 
generally consistent across completed and ongoing clinical studies with no maximum tolerated 
dose reached at any dose tested up to 10 mg/kg. There was no pattern in the incidence, severity, 
or causality of adverse events to nivolumab dose level. Most adverse events were low-grade 
(Grade 1 to 2) with relatively few related high-grade (Grade 3 to 4) adverse events. Most high-
grade events were manageable with the use of corticosteroids or hormone replacement therapy 
(endocrinopathies) as instructed in the management algorithms provided in Section 6.3.2. In this 
study, nivolumab will be administered to all subjects at the dose and schedule approved for use 
in patients with NSCLC. For further information regarding nivolumab refer to the locally 
approved label applicable to the country in which the study is being conducted.
1.5.
Overall Rationale for the Study
The clinical activity of nivolumab has demonstrated the potential of immunologic approaches to 
provide clinical benefit to patients with lung cancer. Although nivolumab has demonstrated 
improved overall survival in 2 Phase 3 studies, with an ORR of 19% in each study, the majority 
of treated subjects do not respond to nivolumab monotherapy. There is an ongoing effort to 
investigate combinations that can build upon the established clinical efficacy of nivolumab and 
broaden the population of NSCLC patients that benefit from immunology-based therapy. 
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The addition of JNJ-757 may enhance the activity of nivolumab by inducing a new population of 
mesothelin-directed T cells. In mouse models of lung cancer, the combination of JNJ-757 and a 
PD-1 inhibitor prolonged survival beyond the survival seen with either agent alone (Figure 6).
Figure 6:
Prolongation of Survival with the Addition of JNJ-757 to a PD-1 Inhibitor in a Nonclinical 
Mouse Model of Lung Cancer
HBSS=Hank's balanced salt solution.
The potential ability of JNJ-757 to promote activation of both innate and adaptive immune 
responses provides a strong rationale to investigate the potential clinical synergy of the 
combination of JNJ-757 and nivolumab. Given their complementary mechanisms of action, it is 
hypothesized that the combination of JNJ-757 and nivolumab will provide increased efficacy 
relative to either agent alone in patients with adenocarcinoma of the lung.
All subjects in this study will receive nivolumab at 240 mg over approximately 60 minutes, 
every 2 weeks (Day 1 and Day 15 of each 28-day cycle). For those subjects in Phase 1b and 
those subjects randomized to the combination arm in Phase 2, JNJ-757 will be administered after 
completion of each Day 1 nivolumab infusion, to ensure that transient adverse events anticipated 
after JNJ-757 infusion will not interfere with nivolumab administration. Based on currently 
available clinical data, the safety profiles for LADD Lm-based immunotherapy and nivolumab 
appear to be non-overlapping: adverse events associated with LADD Lm-based immunotherapy
reflect proximal activation of the innate immune response (Section 1.2.1), while those associated 
with nivolumab are more consistent with delayed development of autoimmunity in a minority of 
patients (Section 1.4).
This study will monitor safety closely to ensure that subjects in both assigned treatment arms 
have the potential to achieve benefit from nivolumab. Safety will be assessed throughout study
treatment to ensure resolution of the anticipated JNJ-757 toxicities. Surveillance cultures will be 
obtained during the treatment and follow-up phases, to confirm the clearance of JNJ-757 after 
repeated dosing, and up to 1 year after prophylactic antibiotics.
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In Phase 1b, to ensure that the combination is tolerable without unanticipated toxicity, the SET 
will analyze the toxicity after the last subject dosed has been observed for at least 28 days. 
Enrollment in Phase 2 will not begin until the SET has recommended proceeding, following the 
evaluation of safety and translational data from Phase 1b.
In Phase 2, a Janssen DMC (see Section 11.11) will review the ORR data after approximately 
40, 60, 80, 100, and 120 subjects are randomized. The DMC may request additional ad-hoc 
reviews based on the accumulating data. It is anticipated the first ORR analysis will occur 
approximately 24 weeks after the first subject in Phase 2 has been randomized. Safety data will 
be reviewed every 3 months. Enrollment of subjects may be stopped during the DMC reviews.
Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement of both 
proliferation and IFN-γ release in the mixed lymphocyte reaction. JNJ-757 elicits an innate 
immune response capable of activating peripheral lymphocytes, and an adaptive immune 
response targeting the mesothelin tumor antigen. Therefore, the hypothesis is that a combination 
of the agents will be more effective than nivolumab alone. As seen in Figure 6, an improvement 
in survival when JNJ-757 was added to an anti-PD1 was demonstrated in nonclinical models; 
these data provide the rationale for testing the combination in patients with lung cancer.
Based on currently available clinical data, the safety profiles for LADD Lm-based 
immunotherapy and nivolumab are anticipated to be non-overlapping. All subjects will receive 
active therapy with nivolumab, which has been demonstrated to improve survival in the target 
population. Efficacy in the 2 arms will be compared on an ongoing basis, allowing for the 
potential closing of PD-L1 strata in which increased efficacy of the combination is not observed. 
These considerations strongly support the conduct of this study in an effort to improve treatment 
outcomes for eligible patients with mesothelin-expressing adenocarcinoma of the lung.
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2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESES
2.1.
Objectives and Endpoints
Objectives
Endpoints/Assessments
Primary

To evaluate whether the efficacy of JNJ-757 combined 
with nivolumab is better than the efficacy of 
nivolumab monotherapy for subjects with mesothelin-
positive relapsed/refractory Stage IIIB or Stage IV 
adenocarcinoma of the lung, by PD-L1 level

Objective response rate (complete response plus 
partial response, based on RECIST 1.1 criteria)
Secondary

To compare the clinical benefit of JNJ-757 combined 
with nivolumab versus nivolumab monotherapy

Disease control rate (stable disease for at least
16 weeks, complete response, or partial 
response)

Duration of objective response

Progression-free survival

Overall survival

To evaluate the safety of JNJ-757 in combination with 
nivolumab

Incidence of adverse events

To correlate PD-L1 levels with clinical activity

Disease control rate, duration of response, 
progression-free survival, and overall survival 
in biomarker subpopulations defined by PD-L1 
level

To assess the blood culture and shedding profile of 
JNJ-757

Blood cultures

Bacterial shedding samples 

To assess the pharmacokinetics and immunogenicity 
of nivolumab

Serum concentrations of nivolumab 

Incidence of anti-nivolumab antibodies
Exploratory

To monitor markers of innate and adaptive immune 
responses

Biologic markers of immune system activation

To evaluate other biomarkers that may be predictive of 
a response

Objective response rate in other biomarker 
subpopulations

To assess patient-reported outcomes 

NSCLC-SAQ and EORTC QLQ
EORTC QLQ=European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; 
NSCLC-SAQ=non–small-cell lung cancer self-administered questionnaire; PD-L1=programmed death receptor 
ligand 1; RECIST=Response Evaluation Criteria in Solid Tumors.
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
2.2.
Hypothesis
The primary hypothesis of the study is that the addition of JNJ-757 to nivolumab will result in a 
higher ORR compared with nivolumab monotherapy in at least one of the PD-L1 subgroups
(<1%, 1-49%, or 50%) in subjects with relapsed or refractory Stage IIIB or Stage IV 
adenocarcinoma of the lung.
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3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a multicenter, open-label, randomized Phase 1b/2 study to determine if subjects with 
advanced relapsed/refractory adenocarcinoma of the lung will derive greater clinical benefit from 
the addition of JNJ-757 to nivolumab. 
3.1.1.
Phase 1b (Safety Run-in Phase)
Phase 1b will be a safety run-in of at least 6 subjects to evaluate the incidence of dose limiting 
toxicities (DLTs) and demonstrate the tolerability of JNJ-757 administered in combination with 
nivolumab. Additional subjects (up to 30 in total) may be enrolled, as determined by the SET, to 
further explore safety and translational data before the decision to initiate the randomized 
Phase 2. All subjects in Phase 1b will receive nivolumab, administered at 240 mg IV over 
approximately 60 minutes, every 2 weeks, in 28-day cycles. After completion of the nivolumab 
infusion on Day 1 of each 28-day cycle, JNJ-757 will be administered at a dose of 1×109 CFU IV 
over approximately 60 minutes. Treatment will continue until disease progression, unacceptable 
toxicity, protocol violation requiring discontinuation of study treatment, withdrawal of consent, 
noncompliance with study procedures, or the sponsor terminates the study. The maximum 
allowed duration of nivolumab or JNJ-757 treatment is 2 years.
Dose-Limiting Toxicity (DLT)
To be evaluable for a DLT, a subject must receive 1 infusion of JNJ-757 in combination with 
nivolumab and either experience a DLT after initiation of JNJ-757 or be followed for 4 weeks 
without experiencing a DLT. Enrollment into Phase 1b will be staggered, with at least 72 hours 
between subjects for initiation of study treatment. Tolerability of the first dose should be 
confirmed after 72 hours and prior to treating the next subject.
A DLT includes any toxicity requiring permanent discontinuation of nivolumab (see 
Section 6.3.2), or a toxicity that meets any criterion for a DLT in Table 2. Toxicities will be 
graded for severity according to NCI-CTCAE Version 4.03. During the safety run-in phase, the 
DLT evaluation period is 28 days starting from the day of the first dose of study agent. Only 
toxicities that occur during the 28-day DLT evaluation period will be considered for DLT 
assessment. If for any reason, the safety of a subject is deemed not evaluable for DLT, the 
subject may be replaced.
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Table 2:
Criteria for Dose-limiting Toxicity in Phase 1b
DLT Criteria for Non-hematologic Toxicitya
Fever, chills, hypotension, or dyspnea
Grade 3 persisting >24 hours despite best supportive care
Fatigue
Grade 3 persisting ≥7 days despite best supportive care
Nausea/vomiting
Grade 3 persisting >72 hours days despite best supportive care
Hypertension
Grade 4
DLT Criteria for Hematologic Toxicitya
Neutropenia
Grade 3 with fever >38.5°C, or
Grade 3 persisting ≥7 days despite best supportive care, or
Grade 4
Thrombocytopenia
Grade 4
Anemia
Grade 4
DLT=dose-limiting toxicity.
a.       Toxicity graded according to the NCI-CTCAE, Version 4.03.
Safety Evaluation Team (SET)
In Phase 1b, the SET will be responsible for reviewing the safety and translational data and for 
making a formal determination of whether the study will expand the Phase 1b cohort, modify the 
dosing regimen, or proceed to the randomized phase (Phase 2). The SET will be chaired by the 
sponsor study-responsible physician. Membership will include a sponsor clinical scientist, 
statistician, clinical pharmacologist, and the Safety Management Team chair, along with 
additional sponsor staff as appropriate. Additionally, the investigators who have enrolled the 
safety run-in subjects will participate. Documentation of meeting outcomes will be maintained 
by the sponsor in the Study Master File.
The following rules will be applied to determine that the combination of JNJ-757 and nivolumab 
is safe and tolerable:

If <2 of 6 (or <33%) evaluable subjects in Phase 1b experience a DLT during the first 
treatment cycle (ie, 28 days), then the selected doses and dose regimens for JNJ-757 + 
nivolumab combination therapy will be considered tolerable in subjects with advanced or 
metastatic NSCLC.

If 2 of 6 evaluable subjects (or 33%) experience a DLT in the first treatment cycle, then 
the SET will examine the totality of available safety, translational, and pharmacokinetic/PD 
data, and may recommend either stopping the study or expanding the Phase 1b population to 
evaluate alternate doses and dose regimens.
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3.1.2.
Phase 2 (Randomized Phase)
In Phase 2, a maximum of 140 subjects who meet all of the inclusion criteria and none of the 
exclusion criteria will be stratified in subgroups according to PD-L1 level (<1%, 1–49%, or 
50%), using the DAKO PD-L1 IHC 28-8 pharmDx Assay, and then be assigned randomly (1:1)
to receive JNJ-757 plus nivolumab (Group A) or nivolumab monotherapy (Group B). 
Throughout randomization, ORR will be monitored using a Bayesian hierarchical logistic 
regression model, such that more subjects may be enrolled in a PD-L1 subgroup where the 
combination therapy is more effective. However, subjects will always be randomized to Group A 
or Group B in a 1:1 ratio within that subgroup. If the combination therapy is not effective in any 
PD-L1 subgroup, then the study could be stopped early. In both groups, subjects will receive 
nivolumab, administered at 240 mg IV over approximately 60 minutes, every 2 weeks, in 28-day 
cycles. In Group A, after completion of the nivolumab infusion on Day 1 of each 28-day cycle, 
JNJ-757 will be administered at a dose of 1×109 CFU IV over approximately 60 minutes.
A treatment cycle will be 28 days. Disease response will be assessed with RECIST 1.1 criteria, 
using computed tomography (CT) scans with IV contrast (or if necessary, magnetic resonance 
imaging [MRI] scans) of the chest, abdomen, and pelvis at Week 8 (±7 days), then every 8 weeks 
(±7 days) during the first year, and then every 12 weeks (±7 days) thereafter until disease 
progression, subsequent therapy, or completion of therapy. For subjects receiving on-treatment 
biopsy, the first assessment will be at Cycle 3 Day 8 (+3 days). Mandatory core needle on-study 
tumor biopsy samples will be collected from subjects in Phase 1b, with core needle tumor biopsy 
samples being required from subjects at selected sites in Phase 2 who consent separately to an 
optional tumor biopsy substudy (where local regulations permit). Treatment will continue until 
disease progression, unacceptable toxicity, protocol violation requiring discontinuation of study 
treatment, withdrawal of consent, noncompliance with study procedures, or the sponsor 
terminates the study. However, the maximum allowed duration of nivolumab or JNJ-757 
treatment is 2 years.
After discontinuing study treatment, subjects will be contacted by clinic visit or telephone every 
3 months (±7 days) for survival follow-up. Among subjects who receive JNJ-757, surveillance 
blood cultures will be collected as follows: at the first 4 visits of the Treatment Phase; on Day 1 
of any subsequent cycle with a disease assessment, or as clinically indicated; at the End of 
Treatment visit (before prophylactic antibiotic therapy); and 3, 6, 9, and 12 months after the last 
dose of JNJ-757. In the event that a subject cannot return to the study site, posttreatment 
surveillance blood cultures should be performed at a local laboratory and the results recorded in 
the subject source documentation and reported in the eCRF. After the first year, follow-up visits 
may be conducted by telephone contact or an alternative contact method per institution 
policy/practice. Information on subsequent therapies (regimen, initiation dates, and stop dates) 
and best response (if available) will be collected. Any new or worsening adverse events that 
occur and all concomitant medications that are administered between when the informed consent 
form (ICF) is signed and 100 days after the last dose of study agent will be recorded for subjects 
who enter the Screening Phase. Any subject with an ongoing adverse event will be followed 
beyond 100 days after the last dose of study agent, subjects will be followed for ongoing 
treatment-related adverse events and associated medications until all adverse events are resolved, 
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return to baseline, are deemed irreversible, or the subject starts subsequent anticancer therapy.
Adverse events, including those reflecting laboratory abnormalities, will be graded and 
summarized using National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) Version 4.03.
The study will consist of a Screening Phase, a Treatment Phase, and a Posttreatment Follow-up 
Phase. The clinical cutoff for the primary endpoint will occur 16 weeks after the last subject has 
been randomized. The end of the study will occur when 80% of the randomized subjects have 
died, or approximately 3 years after the last subject has been randomized, or the sponsor 
terminates the study. A study design scheme is provided in Figure 7. 
Data Monitoring Committee (DMC)
In Phase 2, a Janssen DMC (see Section 11.11) will review the ORR data after approximately 
40, 60, 80, 100, and 120 subjects are randomized. The DMC may request additional ad-hoc 
reviews based on the accumulating data. It is anticipated the first ORR analysis will occur 
approximately 24 weeks after the first subject in Phase 2 has been randomized. The DMC will 
review safety data every 3 months. Enrollment of subjects may be stopped during the DMC 
reviews.
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Figure 7:
Study Flowchart
Phase 1b (Safety Run-in Phase)
Phase 2 (Randomized Phase)
CFU=colony-forming units; DLT = dose-limiting toxicity; PD-L1= programmed death receptor ligand 1; SET = Safety Evaluation Team.
28-day cycles:
Day 1: nivolumab 240 mg IV, followed by JNJ-757 (1x109 CFU) Day 15: nivolumab 240 mg IV
<33% subjects with DLT: Regimen is tolerable. 
Expand Phase 1b or proceed to Phase 2.
33% subjects with DLT: Regimen is intolerable. SET 
evaluation and recommendations (eg, other regimens).
SET Evaluation
Screening Phase
Screening Phase
Randomization
Group A: 28-day cycles:
Day 1: nivolumab 240 mg IV, 
followed by JNJ-757 (1x109 CFU)
Day 15: nivolumab 240 mg IV
Group B: 28-day cycles:
Day 1, 15: nivolumab 240 mg IV
Treatment until disease progression, unacceptable toxicity, protocol violation requiring discontinuation of study treatment, 
withdrawal of consent, noncompliance with study procedures, or the sponsor terminates the study
Posttreatment follow-up every 3 months (±7 days) after treatment discontinuation 
until the subject dies or withdraws consent, or the sponsor terminates the study
Stratification by PD-L1 expression
(1%, 1-49%, or 50%)
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3.2.
Study Design Rationale
Rationale for Study Population
Subjects with advanced (Stage IIIb) or metastatic (Stage IV) lung adenocarcinoma who have 
completed treatment with platinum-based double therapy have limited treatment options. Among 
the most effective agents available to these subjects is nivolumab, a treatment that has been 
approved for use in this population and has previously demonstrated a response rate of 19% in 
patients with nonsquamous NSCLC (Borghaei 2015).5 Although this response rate led to 
improved overall survival in patients with nonsquamous NSCLC, the majority of treated subjects 
do not respond to nivolumab when given as a monotherapy. Participation in a clinical study to 
evaluate the potential of JNJ-757 to increase the proportion of subjects receiving clinical benefit 
from nivolumab is a reasonable option for these patients.
Patients with adenocarcinoma of the lung that is characterized by epidermal growth factor 
receptor (EGFR) mutations and ALK translocation have not demonstrated similar clinical benefit 
with nivolumab, and they have alternative, more effective, treatment options directed toward 
these driver mutations. Therefore, subjects with activating EGFR mutations or ALK 
translocations are excluded from participation in this study (EGFR and ALK results must be 
confirmed in the Screening Period for all non-smokers). KRAS mutations are mutually exclusive 
from EGFR and ALK translocations; therefore, a positive KRAS mutation does not require ALK 
testing.
Rationale for Randomized Controlled Design and Dose Selection
In Phase 2, randomization will be used to minimize bias in the assignment of subjects to 
treatment groups. Nivolumab will be administered to all subjects at 240 mg IV every 2 weeks, in 
28-day cycles. Subjects in Group A will also receive JNJ-757 1×109 CFU IV on Day 1 of each 
cycle (ie, every 28 days), after completion of the nivolumab infusion, to correspond with the 
schedule for nivolumab administration.
Rationale for Blood Culture and Bacterial Shedding Surveillance
As of February 2017, clinical experience with CRS-207 has identified 3 cases in which CRS-207 
has been cultured from patients after the completion of their prophylactic antibiotics. The 
persistence of CRS-207 in all cases was identified in patients with venous access devices that 
were in place during their therapy with CRS-207, and therefore these cases are consistent with 
colonization of the venous access device. In each case the subject was successfully treated with 
antibiotics, without requiring the removal of the venous access device, in keeping with ASCO 
guidelines (Schiffer 2013).32
In the ongoing Phase 1 study of JNJ-757 (64041757LUC1001), shedding samples (from feces, 
urine, and saliva) were collected into Listeria-specific culture medium from subjects 
administered JNJ-757 at several timepoints. All assessed shedding samples tested have been 
negative for growth of Lm. Blood samples also were collected into Listeria-specific culture 
medium at several timepoints. To date, 2 subjects have had blood cultures reported as positive 
for Listeria growth on the day of the first infusion, but in both cases subsequent blood cultures 
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were all negative for bacterial growth, consistent with previously reported results showing rapid 
clearance of CRS-207 from peripheral blood after IV administration (Le 2012).20
Surveillance cultures will therefore be obtained in this study during the treatment and follow-up 
phases, to confirm the clearance of JNJ-757 after repeated dosing, and up to 1 year after 
prophylactic antibiotics. In those subjects with indwelling venous access devices that are present 
during JNJ-757 dosing, additional blood cultures will be drawn through the venous access 
device, to document any evidence of colonization and allow for early treatment in accordance 
with ASCO guidelines (Schiffer 2013).32
Rationale for Pharmacokinetics and Immunogenicity Assessments
This is the first study where nivolumab and LADD Lm-based immunotherapy will be used 
concomitantly. LADD Lm-based immunotherapy may affect the pharmacokinetics and 
immunogenicity of nivolumab through modulation of immune response. Hence, it is important to 
characterize the pharmacokinetics and immunogenicity of nivolumab with and without JNJ-757.
Rationale for Biomarker Assessments
Mesothelin-positive status in tumor samples will be assessed prospectively. Mesothelin selection 
will ensure that each enrolled subject has the potential to benefit from both innate and adaptive 
responses elicited by JNJ-757. In Phase 2, PD-L1 levels will be used to ensure equal distribution 
of patients exhibiting tumor characteristics that may be associated with clinical outcomes with 
nivolumab treatment, and to ensure that JNJ-757 is adequately assessed in each of the PD-L1 
subgroups. The goal of the biomarker analyses is to evaluate the pharmacodynamics of JNJ-757 
and nivolumab and aid in evaluating the drug-clinical response relationship. Biomarker samples 
may be used to help address emerging issues and to enable the development of safer, more 
effective, and ultimately individualized therapies.
Rationale for Patient-reported Outcomes Assessments
The patient-reported outcomes (PRO) instruments in this study are the Non-Small Cell Lung 
Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) and the European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 and 
EORTC QLQ-LC13). The NSCLC-SAQ was developed in accordance with US FDA PRO 
Guidance and scientific best practices for use in clinical trials of NSCLC. This study will support 
validation efforts for this PRO. The EORTC-QLQ-C30 will be included to meet requirements for 
Health Technology Assessment (HTA) in Europe.
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4.
SUBJECT POPULATION
Adult subjects age 18 and older with advanced (Stage IIIB) or metastatic (Stage IV) 
adenocarcinoma of the lung are eligible for the study. Screening for eligible subjects will be 
performed within 28 days before Cycle 1 Day 1 (Phase 1b) or randomization (Phase 2). Central
confirmation of tumor mesothelin-positive status and PD-L1 level is required in all subjects and 
will use samples collected either in the Screening Phase or in the optional Prescreening Phase
described in Section 9.1.2.2.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed. 
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
18 years of age
2.
Criterion modified per Amendment 2
2.1. Disease-related criteria:

Histologically documented adenocarcinoma of the lung

Stage IIIB or Stage IV disease

Biopsy material available for central assessment of PD-L1 and mesothelin, 
consisting of either tumor block or unstained slides of tumor sample (archival 
tissue, or fresh biopsy if archival tissue is insufficient)

Mesothelin-positive status (>0% positive tumor cells), determined at a central 
laboratory using mesothelin immunohistochemistry (IHC) assay
3.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
4.
Progressive disease during or after platinum-based doublet chemotherapy, administered 
in the metastatic setting (continuation or switch maintenance therapy is permitted)
5.
Adequate bone marrow function, defined as:

Absolute neutrophil count (ANC) 1500/L (or 1.5×109/L)

Platelets 100,000/L (or 100×109/L)

Hemoglobin 10.0 g/dL
Administration of transfusions or growth factors will not be allowed within 7 days 
before collection of these hematology laboratory values
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6.
Criterion modified per Amendment 2
6.1. Adequate hepatic function, defined as:

Serum aspartate aminotransferase (AST) and serum alanine aminotransferase 
(ALT) 1.5 times the upper limit of normal (ULN) if no liver metastases, and 
3ULN with documented liver metastases

Total serum bilirubin 1.5xULN (unless due to Gilbert syndrome; if so, direct 
bilirubin 3xULN)
7.
Adequate renal function, defined as:

Calculated creatinine clearance 40 mL/min using the Cockcroft-Gault 
equation
8.
A woman of childbearing potential must have a negative serum (β-human chorionic 
gonadotropin [β-hCG]) or urine pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of hCG) within 14 days before the first dose of nivolumab and a second 
negative test within 24 hours before the first dose of nivolumab.
9.
Criterion modified per Amendment 2
9.1. 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 Cycle 1 Day 1 (Phase 1b) or randomization (Phase 2), a woman must be either:
a.
Not of childbearing potential defined as: 
o
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.
o
permanently sterile
Permanent 
sterilization 
methods 
include 
hysterectomy, 
bilateral 
salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral 
oophorectomy.
b.
Of childbearing potential and
o
practicing a highly effective method of contraception (failure rate of <1% 
per year when used consistently and correctly)
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 
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only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with JNJ-757 or nivolumab. 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.)
- 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 
agent, which may reduce the efficacy of the contraceptive method.
o
agrees to remain on a highly effective method while on the study agent and 
for 5 months (female subjects) or 7 months (male subjects) after the last 
dose of study agent.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal 
woman experiences menarche) 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, as described throughout the inclusion criteria.
10.
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction while on the study agent and for 5 months after the last dose of study agent
11.
To avoid risk of drug exposure through the ejaculate (even men with vasectomies), 
subjects must use a condom during sexual activity while on the study agent and for 
5 months (female subjects) or 7 months (male subjects) after the last dose of study 
agent. If the subject or their partner is a woman of childbearing potential, a condom is 
required along with another effective contraceptive method consistent with local 
regulations regarding the use of birth control methods for subjects participating in 
clinical studies and their partners. Donation of sperm is not allowed while on the study 
agent and for 7 months after the last dose of the study agent.
12.
Willing and able to adhere to the prohibitions and restrictions specified in this protocol
13.
Must sign an ICF indicating that he or she understands the purpose of, and procedures 
required for, the study and is willing to participate in the study
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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 2
1.1. Untreated brain metastases or other active central nervous system (CNS) 
metastases. Subjects with a history of brain metastasis must have completed treatment 
for brain metastasis for at least 28 days, and be neurologically stable and off steroids 
before Cycle 1 Day 1 (Phase 1b) or randomization (Phase 2).
2.
Criterion modified per Amendment 2
2.1. Tumor with activating EGFR mutation or ALK translocation (EGFR and ALK 
results must be confirmed in the Screening Period for all non-smokers. A positive 
KRAS result may be used in lieu of an EGFR or ALK result).
3.
Criterion modified per Amendment 2
3.1. More than 1 prior line of chemotherapy for metastatic disease (not including 
therapy given in the maintenance setting, or neoadjuvant or adjuvant therapy for locally 
advanced disease) (Phase 2).
4.
History of symptomatic interstitial lung disease.
5.
History of disallowed therapies, as follows:

In Phase 1b only: Prior exposure to anti-PD1, anti-PD-L1, anti-PD-L2, anti-CD137, 
or anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) antibody within 28 
days before the first dose of study agent

In Phase 2 only: Prior exposure to anti-PD1, anti-PD-L1, anti-PD-L2, anti-CD137, 
or anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) antibody

History of listeriosis or vaccination with a Listeria-based vaccine or prophylactic
vaccine
(eg,
influenza,
pneumococcal,
diphtheria,
tetanus,
and
pertussis
[dTP/dTAP]) within 28 days before the first dose of study agent

Chemotherapy within 28 days before the first dose of study agent

Radiation within 14 days before the first dose of study agent (exception: palliative 
radiotherapy for pain can be used ≥7 days before or after study agent)
6.
Any uncontrolled active systemic infection, active noninfectious pneumonitis, or any 
life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety or put the study outcomes 
at undue risk.
7.
Any active autoimmune disease or a documented history of autoimmune disease 
(excluded/exception to the rule: subjects with vitiligo or resolved childhood 
asthma/atopy, type 1 diabetes mellitus, subjects with hypothyroidism stable on hormone 
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replacement, Sjorgen’s syndrome, psoriasis not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger).
8.
History of any other condition that may require the initiation of anti-tumor necrosis 
factor alpha (TNFtherapies or other immunosuppressant medications during the 
study.
9.
Known allergy to both penicillin/amoxicillin and trimethoprim/sulfamethoxazole. 
Subjects who are only allergic to 1 of these antibiotics are allowed to enroll.
10.
Criterion modified per Amendment 2
10.1. Concurrent treatment with anti-TNF
therapies, systemic corticosteroids 
(prednisone dose >10 mg per day or equivalent), or other immunosuppressive drugs <14 
days before Cycle 1 Day 1 (Phase 1b) or randomization (Phase 2). Steroids that are 
topical, inhaled, nasal (spray), or ophthalmic solution are permitted.
11.
Criterion modified per Amendment 2
11.1. A positive test result by medical history for human immunodeficiency virus (HIV) 
or acquired immune deficiency syndrome (AIDS).
12.
History of major implant(s) or device(s), including but not limited to:

Prosthetic heart valve(s)

Cardiac pacemakers

Orthopedic screws

Metal plates

Artificial joints and prosthetics

Subjects with venous access devices (eg, Port-a-Cath or Mediport), arterial and 
venous stents, dental implants, or breast implants are permitted on the study.
13.
Criterion modified per Amendment 2
13.1. History of clinically significant cardiovascular disease within 6 months of Cycle 1 
Day 1 (Phase 1b) or randomization (Phase 2) including, but not limited to:

Myocardial infarction or unstable angina 

Clinically significant ventricular arrhythmia

Uncontrolled (persistent) hypertension: systolic blood pressure >160 mmHg; 
diastolic blood pressure >100 mmHg

Deep vein thrombosis, pulmonary embolism, stroke or transient ischemic 
attack before the first dose of the study agent

Congestive heart failure (New York Heart Association class III-IV
[Attachment 1])

Pericarditis/clinically significant pericardial effusion

Myocarditis

Endocarditis
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14.
Known active or chronic hepatitis B or hepatitis C as demonstrated by hepatitis B 
surface antigen (HBsAg) positivity and/or anti-hepatitis C virus (HCV) positivity, 
respectively. Subjects with clinically active or chronic liver disease, including liver 
cirrhosis, are also excluded.
15.
Criterion modified per Amendment 2
15.1. Active second malignancy within 2 years prior to Cycle 1 Day 1 (Phase 1b) or 
randomization (Phase 2). Exceptions that do not require a 2-year remission include: 
nonmelanoma skin cancer; cervical carcinoma in situ on biopsy; squamous 
intraepithelial lesion on Papanicolaou (PAP) smear; localized prostate cancer (Gleason 
score <6); resected melanoma in situ; or ductal carcinoma in situ.
16.
Evidence of active viral, bacterial, or systemic fungal infection requiring systemic 
treatment within 7 days before the first dose of the study agent. Subjects requiring any 
systemic antiviral, antifungal, or antibacterial therapy for active infection must have 
completed treatment no less than 7 days before the first dose of the study agent.
17.
Known allergies, hypersensitivity, or intolerance to JNJ-757 or its excipients (refer to 
Investigator's Brochure).
18.
Known allergies, hypersensitivity, or intolerance to nivolumab or its excipients (refer to 
locally approved label).
19.
Criterion modified per Amendment 2
19.1. Received an investigational drug (including investigational vaccines) or used an 
invasive investigational medical device within 28 days before Cycle 1 Day 1 (Phase 1b) 
or randomization (Phase 2).
20.
Currently enrolled in another interventional study.
21.
Pregnant, breast-feeding, or planning to become pregnant while enrolled in this study,
within 5 months after the last dose of study agent.
22.
Plans to father a child while enrolled in this study, within 7 months after the last dose of 
study agent.
23.
Any serious underlying medical or psychiatric condition (eg, alcohol or drug abuse),
dementia or altered mental status or any issue that would impair the ability of the
subject to receive or tolerate the planned treatment, to understand informed consent or
that in the opinion of the investigator would contraindicate the subject’s participation in
the study or that would confound the results of the study.
24.
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. Note: Subjects with planned surgical procedures to be 
conducted under local anesthesia may participate after consultation with the medical 
monitor. 
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4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation: Subject must agree to 
avoid intimate contact with individuals known to be at high risk of complications from listeriosis 
(eg, newborn infants, pregnant women, immunocompromised individuals) during the course of 
study treatment until completion of the mandatory antibiotic regimen.
Subjects with indwelling venous access devices in Phase 1b and Group A of Phase 2 must not 
have their device accessed for at least the first 4 days at the beginning of each cycle, must 
consent to blood cultures through the device at the End-of-Treatment visit and follow-up visits, 
and must have their first dose of posttreatment prophylactic antibiotic at the End-of-Treatment 
visit administered intravenously through the device.
If the subject is engaged in sexual activity, a condom is required. If the subject or their partner is 
a woman of childbearing potential, a condom and an additional highly effective contraceptive 
method should be used. The additional method of contraception should be consistent with local 
regulations regarding the use of birth control methods for subjects participating in clinical 
studies. Highly effective forms of contraception include:

established use of oral, injected, or implanted hormonal methods of contraception;

placement of an IUD or IUS;

barrier methods: condom with spermicidal foam/gel/film/cream/suppository or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; or

vasectomy
These precautions are required during the Treatment Phase and for 5 months (female subjects) or 
7 months (male subjects) after the last dose of study agent.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Central randomization will be implemented in Phase 2 of this study. Upon entry, eligible subjects 
will be randomly assigned 1:1 to treatment Groups A and B 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 
according to PD-L1 level (<1%, 1–49%, or ≥50%).
The interactive web response system (IWRS) will assign a unique treatment code, which will 
dictate the treatment assignment and matching study agent 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.
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Blinding
As this is an open-label study, blinding procedures are not applicable.
6.
DOSAGE AND ADMINISTRATION
6.1.
Study Agent Administration
For the purposes of this study, "study agent" refers to JNJ-757 and nivolumab, and a treatment 
cycle refers to 28 days. After Cycle 2, the start of each subsequent cycle may occur ±3 days of 
the scheduled day to accommodate the schedule of the site or subject.
All subjects will receive nivolumab at 240 mg as an IV infusion over approximately 60 minutes,
on Day 1 and Day 15 of each 28-day cycle. Normal saline (0.9% sodium chloride) should be
used to flush the peripheral IV line after administration of nivolumab.
Subjects in Phase 1b and in Group A of Phase 2 will receive JNJ-757 at a dose of 1×109 CFU,
administered as an IV infusion, after completion of the nivolumab infusion on Day 1 of each 
28-day cycle. The JNJ-757 infusion will be administered over approximately 60 minutes, with 
the option to increase the duration of the infusion if clinically indicated. Normal saline (0.9%
sodium chloride) should be used to flush the peripheral IV line to ensure that the entire
amount of JNJ-757 is delivered to the subject. Additional details are provided in the Site
Investigational Product Procedures Manual (SIPPM) and the Investigational Product Preparation 
Instructions (IPPI).
On Day 1 of each cycle, nivolumab and JNJ-757 must be administered through a peripheral
vein catheter; administration through a central venous catheter is prohibited. On Day 15 of each 
cycle, nivolumab may be administered through a peripheral or central venous catheter.
6.2.
JNJ-757 Dose Modifications
Any change to the JNJ-757 infusion (dose interruption or change in infusion rate) and the reason 
for the change must be recorded in the subject’s electronic case report form (eCRF). For a dose 
interruption, the duration of the interruption is to be recorded. 
6.2.1.
Cycle Delay
On the first day of each new cycle and before administration of nivolumab/JNJ-757, the 
investigator will evaluate the subject for any toxicity at least possibly related to JNJ-757 that 
would preclude/delay retreatment with JNJ-757. At a minimum, the laboratory parameters in 
Table 3 must be met before administration of JNJ-757.
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Table 3:
Laboratory Criteria for JNJ-757 Treatment After Cycle 1
Hematology
Absolute neutrophil count
1000/µL (or 1.0×109/L) with or without hematopoietic growth factors
Platelet count
75,000/ µL (or 75×109/L) with or without transfusion
JNJ-757 should be administered on Day 1 of each 28-day treatment cycle, after completion of the 
nivolumab infusion. A subject who skips a dose of JNJ-757 should continue to receive 
nivolumab as scheduled and restart JNJ-757 administration on Day 1 of the next nivolumab 
treatment cycle. Doses of JNJ-757 may be skipped as many times as needed until any toxicity
that is at least possibly related to JNJ-757 recovers to a level that allows administration of 
JNJ-757 on Day 1 of the next nivolumab treatment cycle.
If a delay in nivolumab treatment is needed for one of the reasons described in Section 6.3.2, 
then JNJ-757 should be delayed until the next Day 1 dose of nivolumab is administered. If 
JNJ-757 treatment is stopped completely, then the subject may continue to receive nivolumab
treatment after consultation with the medical monitor if, in the investigator’s opinion, the subject 
may benefit from nivolumab monotherapy without JNJ-757.
6.2.2.
Monitoring During and After JNJ-757 Administration
Monitoring During JNJ-757 Administration
Subjects must remain at the infusion center for monitoring for 5 hours after the end of the first 
infusion of JNJ-757. The 5-hour observation period may be reduced to a minimum of 2 hours 
starting with Cycle 2 if, in the opinion of the investigator, 1) the previous infusion was well 
tolerated without dose interruption or additional supportive measures; and 2) the subject’s 
expected toxicities can be managed as an outpatient.
Although not anticipated, if a subject experiences signs and symptoms consistent with 
inflammatory cytokine release (eg, Grade 2 or 3 fever, chills/rigor, nausea, vomiting, 
hypotension) during JNJ-757 administration, the infusion should be stopped immediately and 
best supportive care (BSC) should be initiated.

In the event that these acute, adverse events occurring during JNJ-757 administration resolve 
within 2 hours with BSC, the infusion may be restarted at a 50% reduced flow rate. The 
subject should be monitored for approximately 5 hours after the end of the infusion. 
Hospitalization for additional monitoring may be considered.

In the event that these acute, adverse events occurring during JNJ-757 administration are 
prolonged (lasting >2 hours to resolve despite BSC), the infusion must not be restarted. 
Hospitalization for additional monitoring should be considered.

In the event of a second acute adverse event after a previous stop and restart, the JNJ-757
infusion cannot be restarted a second time. The subject should be monitored for at least 
5 hours after the discontinuation of the infusion. Hospitalization for additional monitoring 
may be considered.
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Monitoring After JNJ-757 Infusion
After the observation period is completed, or if the observation period exceeds the clinic hours, 
hospitalization may be considered, at the investigator’s discretion, to facilitate continued safety 
monitoring. These admissions for observation should not be reported as serious adverse events.
6.3.
Nivolumab Dose Modifications
Each dose interruption for nivolumab, the reason for the interruption, and the duration of the 
interruption must be recorded in the eCRF.
6.3.1.
Dose Change
No dose reductions or dose escalations are permitted for nivolumab.
6.3.2.
Cycle Delay
Subjects in both groups will receive nivolumab at the dose and schedule approved for single-
agent treatment of patients with adenocarcinoma of the lung. Adverse events involving immune-
mediated toxicities have been reported with nivolumab (see Section 8.3.2); subjects should be 
monitored for these toxicities, which may be indications for cycle delays as well as treatment 
discontinuation. Guidelines for withholding nivolumab doses or permanent discontinuation of 
nivolumab, based on the approved labeling, are described in Table 4.
Criteria to Resume Treatment
A subject for whom nivolumab treatment is delayed should be assessed at least weekly for 
resolution of toxicity. Nivolumab treatment may be restarted at the same dose and schedule 
(240 mg by IV infusion every 2 weeks) when the adverse event returns to Grade 0 or 1 (or to 
Grade 2 for drug-related fatigue). Drug-related pulmonary toxicity, diarrhea, or colitis must 
resolve to baseline before nivolumab treatment is resumed. Subjects with drug-related 
endocrinopathies adequately controlled with only physiologic hormone replacement may resume 
treatment after consultation with the medical monitor. If nivolumab administration is delayed for 
>6 weeks due to toxicity, the subject must permanently discontinue nivolumab treatment.
If nivolumab treatment is delayed, then JNJ-757 should be delayed until the next Day 1 dose of 
nivolumab is administered, unless an additional delay in JNJ-757 treatment is needed for one of 
the reasons described in Section 6.2.1. If nivolumab treatment is stopped completely, then the 
subject may continue to receive JNJ-757 treatment after consultation with the medical monitor if, 
in the investigator’s opinion, the subject may benefit from JNJ-757 monotherapy without 
nivolumab.
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Table 4:
Nivolumab Cycle Delay or Discontinuation for Adverse Events
Adverse Event
Severity
Dose Modification
Colitis
Grade 2 diarrhea or colitis
Withhold dosea
Grade 3 or 4 diarrhea or colitis
Permanently discontinue
Pneumonitis
Grade 1 or 2 pneumonitis
Withhold dosea,b
Grade 3 or 4 pneumonitis
Permanently discontinue
Hepatic toxicity
AST or ALT >3 and 5xULN, or
total bilirubin >1.5 and 3xULN
Withhold dosea
AST or ALT >5xULN, or
total bilirubin >3xULN
Concurrent Grade 2 AST/ALT and total bilirubin
Permanently discontinue
Hypophysitis
Grade 2 or 3 hypophysitis
Withhold dosea
Grade 4 hypophysitis
Permanently discontinue
Adrenal insufficiency
Grade 2 adrenal insufficiency
Withhold dosea
Grade 3 or 4 adrenal insufficiency
Permanently discontinue
Type 1 diabetes mellitus
Grade 3 hyperglycemia
Withhold dosea
Grade 4 hyperglycemia
Permanently discontinue
Nephritis and renal 
dysfunction
Serum creatinine >1.5 and 6xULN
Withhold dosea
Serum creatinine >6xULN
Permanently discontinue
Skin
Grade 3 rash or suspected Stevens-Johnson 
syndrome (SJS) or toxic epidermal necrolysis 
(TEN)
Withhold dosea
Grade 4 rash or confirmed SJS or TEN
Permanently discontinue
Pancreatitis
Grade 3 pancreatitis
Withhold dosea,c
Grade 4 pancreatitis
Permanently discontinue
Uveitis
Grade 1 or 2 uveitis
Withhold dosea,d
Grade 3 or 4 uveitis
Permanently discontinued
Encephalitis
New-onset moderate or severe neurologic signs or 
symptoms
Withhold dosea
Immune-mediated encephalitis
Permanently discontinue
Other
Other Grade 3 adverse evente
  First occurrence
  Recurrence of same Grade 3 adverse event
Withhold dosea
Permanently discontinue
Life-threatening or Grade 4 adverse eventf
Permanently discontinue
Requirement for prednisone 10 mg per day or 
equivalent for >12 weeks
Permanently discontinue
Persistent Grade 2 or 3 adverse event lasting 
12 weeks
Permanently discontinue
Any adverse event, laboratory abnormality, or 
inter-current illness which, in the judgment of the 
investigator, warrants delaying the dose of study 
medication
Withhold dose
Any Grade 3 non-skin, drug-related adverse event 
lasting >7 daysg
Permanently discontinue
ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal.
a
Resume treatment when adverse event returns to Grade 0 or 1 (treatment can be resumed if AE is Grade 2 drug-
related fatigue). Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
nivolumab treatment is resumed. Subjects with drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement may resume treatment after consultation with the medical monitor.
b
Any Grade 2 drug-related pneumonitis or interstitial lung disease that does not resolve following dose delay 
and systemic steroids
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c
Any Grade 3 drug-related amylase or lipase abnormality that is not associated with symptoms or clinical 
manifestations of pancreatitis does not require dose delay. The medical monitor should be consulted for such 
Grade 3 amylase or lipase abnormalities.
d
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical therapy and does not 
improve to Grade 1 severity within the re-treatment period OR requires systemic treatment should result in 
discontinuation of nivolumab.
e
Grade 3 lymphopenia does not require dose delay.
f
With the exception of Grade 4 neutropenia ≤ 7 days, Grade 4 lymphopenia or leukopenia, and isolated Grade 4 
electrolyte imbalances/abnormalities that are not associated with clinical sequelae and are corrected with 
supplementation/appropriate management within 72 hours of their onset.
g
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation. Grade 3 drug-related endocrinopathies 
adequately controlled with only physiologic hormone replacement do not require discontinuation. Grade 3 drug-
related thrombocytopenia > 7 days associated with clinically significant bleeding requires discontinuation; other 
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation.
Toxicity grades are per NCI-CTCAE Version 4.0.3.
Source: Table based on OPDIVO (nivolumab) package insert (Revised February 2017).28
7.
TREATMENT COMPLIANCE
Nivolumab and JNJ-757 will be administered as IV infusions by qualified staff. The details of 
each administration will be recorded in the eCRF. 
8.
PRESTUDY AND CONCOMITANT THERAPY
All concomitant therapies will be recorded in the eCRF and in source documents throughout the 
study beginning with signing of the ICF and continuing until 100 days after the last dose of study 
agent for subjects who enter the Screening Phase. Beyond 100 days, concomitant therapies will 
be collected if the subject is being followed for treatment-related adverse events (see Section 
3.1.2).
8.1.
Permitted Medications
8.1.1.
JNJ-757 Preinfusion Medications
Mandatory and optional medications to be administered before the JNJ-757 infusion are outlined 
in Table 5. If symptoms consistent with a systemic innate immune response to bacterial infection 
(eg, fever, chills/rigor, nausea, vomiting, hypotension) are observed in Cycle 1 or Cycle 2, the 
premedication regimen may be modified at the investigator’s discretion. As outlined in Table 5, 
premedication with H2-antagonists and antiemetics may be introduced in the case of specific, 
severe, or prolonged toxicities.
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Table 5:
Mandatory and Optional Concomitant Medications to be Administered with JNJ-757
Premedication
Dose
Administration
Cycle 1
Cycle 2
Subsequent
Cycles
Mandatory Premedications
Saline
500 to 1000 mLa
IV: bolus starting ~1 hour 
before JNJ-757
X
X
X
Antihistamine
Diphenhydramine
50 mg 
Oral: 1 hour before study 
JNJ-757
or
IV: start 30 minutes before 
JNJ-757
Not
recommended
Xb
Xb
Antipyretic
Acetaminophen
650 to 1000 mg
Oral: 30 minutes before 
JNJ-757
X
X
X
Optional Premedications
H2-antagonist
Ranitidine 50 mg
IV: start ~30 minutes before 
JNJ-757
Not allowed
Optionalc
Optionalc
Antiemetic
Ondansetron
16 mg
IV: start ~30 minutes before 
JNJ-757
Not allowed
Optionalc
Optionalc
IV=intravenous.
a
If the nivolumab infusion is administered with saline, the volume of that infusion may be included in the 
calculation of total saline to be infused before JNJ-757 administration.
b
If clinical signs and symptoms indicative of a systemic innate immune response to bacterial infection are 
observed in Cycle 1, prophylactic antihistamine treatment should be introduced in subsequent cycles.
c
In the absence of nausea and vomiting in Cycle 1 requiring supportive care during or after study agent
administration, the prophylactic use of H2-antagonists and antiemetics in Cycle 2 and subsequent cycles is not 
recommended.
8.1.2.
JNJ-757 Postinfusion Medications
The anticipated symptoms associated with JNJ-757 treatment are thought to arise from the 
release of cytokines occurring within hours of the infusion, and typically resolve within 24 hours.
At the discretion of the investigator, postinfusion medications (Table 6 should be used during or 
immediately (ie, within 24 hours) after JNJ-757 administration for subjects experiencing 
symptoms consistent with systemic innate immune response to bacterial infection. Postinfusion 
medications may be continued for up to 48 hours after the infusion, as needed. Hospitalization 
for monitoring after JNJ-757 administration may be considered, if clinically indicated.
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Table 6:
Postinfusion Medications for Systemic Innate Immune Response to Bacterial Infection
Adverse Eventa
Supportive Therapy
Allergic reaction
Grade 1
Diphenhydramine 50 mg orally or IV
Grade 2 
Dexamethasone 4 mg orally or IV twice daily
Fever (38°C or 100.4°F)
Ibuprofen 400 to 800 mg orally, alternated with acetaminophen 650 to 1000 mg 
orally, every 4 hours
Rigors
Warming blanket, nonsteroidal anti-inflammatory drug (eg, ibuprofen, aspirin, 
naproxen), or narcotic (eg, morphine, meperidine) according to institutional 
standards
Hypotension
Saline 500 to 1000 mL IV bolus during the postinfusion observation period
Nausea/vomiting
Ondansetron 8 mg, according to institutional standards
IV=intravenous.
a
Adverse event during or after the JNJ-757 administration.
8.1.3.
Palliative Radiation
Only non-target bone lesions without lung tissue included in the planned radiation field may 
receive palliative radiotherapy. There should be a 1-week window between study agent
administration and any palliative radiation. Subjects should be closely monitored for any 
potential toxicity during and after receiving radiotherapy, and adverse events should resolve to 
Grade ≤1 prior to resuming study agent. Details of palliative radiotherapy should be documented 
in the source records and eCRF. Details in the source records should include the following: dates 
of treatment, anatomical site, dose administered and fractionation schedule, and adverse events. 
If warranted, symptoms requiring palliative radiotherapy should be evaluated for objective 
evidence of disease progression.
8.2.
Prohibited Medications
During the clinical study, subjects are anticipated to continue the use of prescribed medications 
documented during the screening procedures, consistent with study inclusion and exclusion 
criteria (Section 4.1 and Section 4.2). The following therapies are prohibited during the 
Treatment Phase (if administered, the subject may be removed from the study). The sponsor 
must be notified in advance (or as soon as possible thereafter) of any instances in which 
prohibited therapies are administered, to discuss the indication for these agents, and the 
suitability of the subject for further study treatment:

Anti-TNFα therapies or other immunosuppressants (including prednisone doses >10 mg/day 
or equivalent) (see Section 8.3.1.1)

Any anticancer chemotherapy or nonstudy immunotherapy (approved or investigational)

Another investigational product

Vaccinations (exception: killed vaccine for seasonal influenza is allowed)
In addition, the following therapies should not be administered during the Treatment Phase
unless medically necessary. Approval must be obtained from the sponsor’s medical monitor for a 
subject to continue dosing if therapy is given concurrently with the study agent:

Surgical procedure or intervention requiring general anesthesia or deep sedation
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
Systemic antibiotics (except the required antibiotic prophylaxis for Listeria infection after 
the last dose of JNJ-757 [Section 8.3.1.1])
The use of systemic antibiotics and conditions that require surgical intervention may put the 
subject at increased risk from further study therapy. If these interventions are medically required 
during the study, the study investigator must notify the sponsor’s medical monitor immediately 
to discuss the appropriateness and timing of any further study treatment. 
8.3.
Guidelines for the Prevention and Management of Toxicities
8.3.1.
JNJ-757
A majority of subjects receiving treatment with the LADD Lm-based immunotherapeutic 
CRS-207 (Phase 1: ~80%; Phase 2: ~60%), experienced clinical symptoms of a systemic innate 
immune response to bacterial infection including fever, chills/rigors, nausea, vomiting, and 
hypotension (Le 2012; Le 2015).20,21 Results from the Phase 1 study of JNJ-757 
(64041757LUC1001) are consistent with those from the CRS-207 studies. Clinical safety data 
derived from Phase 1 and 2 studies of CRS-207 indicate that timely initiation of supportive 
therapeutic measures ensured efficient clinical management of the symptoms. Moreover, a 
reduction of both the frequency and severity of these specific treatment-related adverse events 
was achieved when supportive care was provided before CRS-207 administration that was also 
used in the Phase 1 study of JNJ-757 and will be used in this study (Section 8.1.1).
8.3.1.1.
Prophylaxis Against Listeria Infection After the Last Dose of JNJ-757
After the last JNJ-757 infusion, mandatory prophylactic antibiotic therapy must be administered 
for 7 days with amoxicillin 
 (or trimethoprim/sulfamethoxazole 
 for subjects with penicillin allergy). The antibiotics should 
be initiated on the day of the End-of-Treatment visit, after collection of End-of-Treatment blood 
cultures (through peripheral vein and indwelling venous access device, if applicable) have been 
collected. Subjects who have a venous access device should have their first dose of antibiotic 
administered as an intravenous dose through the venous access device (
ampicillin or 
 
 trimethoprim/sulfamethoxazole [based on trimethoprim component] for subjects with 
penicillin allergy), followed by 6 days of oral antibiotic prophylaxis. 
Immunosuppressants such as anti-TNFtherapies or high-dose prednisone (>10 mg/day) are 
prohibited concomitant medications. If use of immunosuppressants is clinically indicated during 
therapy with JNJ-757 or nivolumab, hold further dosing with study treatment, and initiate oral 
antibiotic prophylaxis for listeriosis for the duration of the immunosuppressant therapy 
(recommended: oral 
 
a week). Prophylactic antibiotics should be 
initiated even when immunosuppressants are utilized after JNJ-757 therapy has been completed.
In addition, subjects requiring an emergent placement of a prohibited implanted device (see 
Section 4.2) while on therapy will discontinue JNJ-757 treatment and will receive an intravenous 
antibiotic course appropriate for the treatment of listeriosis for 14 days (see Section 8.3.1.2) as 
prophylaxis against colonization of the implant.
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8.3.1.2.
Treatment for Listeria Infection
Appropriate bacterial cultures, including blood cultures, should be performed when a Listeria
infection is suspected. Specifically, culture of cerebrospinal fluid should be obtained for subjects 
with suspected CNS infection. In such instances, analysis of cerebrospinal fluid should also 
include cell count, protein, glucose, Gram staining, and polymerase chain reaction analysis to 
determine the strain involved. In subjects who meet the following criteria while on study, 
antibiotic therapy should be initiated: 

Fever Grade 4 (>40.0ºC [104ºF] for >24 hours)

Persistent fever >39ºC (102.2ºF) for 48 hours

Infection Grade 3 

Evidence of abscess

Hypotension Grade 3

JNJ-757 isolation in culture from any site (other than blood) that is normally sterile 
(eg, cerebrospinal fluid, joint fluid)

Clinical signs or symptoms (eg, meningeal symptoms) or unexpected positive blood culture 
that in the judgment of the investigator necessitates starting antibiotics. 

Subjects requiring an emergent placement of a prohibited implanted device (see Section 4.2)
In addition, the identification of any predose, end-of-treatment, or post-therapy surveillance 
cultures (peripheral collections only) as positive for listeriosis, should result in the initiation of 
an IV antibiotic treatment with a regimen appropriate for the treatment of (wild-type) listeriosis
for 14 days. If, however, cultures obtained from venous access devices are positive after 
prophylactic antibiotic therapy, consistent with device colonization, the treating physician can 
consider administering IV antibiotics, through the device in accordance with ASCO guidelines, 
in an effort to salvage the venous access device (see Section 8.3.1.1).
If a Listeria infection is suspected or confirmed, 1 of the following IV antibiotic regimens is 
preferred for a minimum of 7 consecutive days. The regimen is determined according to whether 
the subject has a penicillin/amoxicillin allergy.

In subjects without a penicillin/amoxicillin allergy, initial doses of systemic (IV) ampicillin 
should be approximately 
 with gentamicin 
 in divided doses 
every 
 (with adjustments according to renal function and serum levels of 
gentamicin). 

In subjects with a penicillin/amoxicillin allergy, initial IV doses of trimethoprim/
sulfamethoxazole should be 
based on trimethoprim component) divided 
 per day, with gentamicin 
 in divided doses every 
 (with 
adjustments according to renal function and serum levels of gentamicin). 
If clinically indicated, use of broader-spectrum antibiotic treatment should be implemented, as 
appropriate for the clinical situation, in accordance with standard institutional practice.
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8.3.2.
Nivolumab
Therapy with immuno-oncology agents such as nivolumab may lead to specific immune-
mediated adverse events that differ in nature, severity, and duration compared with adverse 
events caused by agents with a different mode of action. Early recognition and management of 
these events may mitigate more severe toxicity. However, differential diagnoses including 
noninflammatory etiologies, as well as the effects of the underlying malignant disease or 
concomitant medication, should be evaluated according to standard medical practice. 
Management algorithms have been developed to assist investigators in assessing and managing 
specific immune-mediated adverse events, as summarized above in Table 4 and in the following 
sections. Guidelines for nivolumab dose delays are provided in Section 6.3.2.
8.3.2.1.
Gastrointestinal Adverse Events
Diarrhea and colitis have been observed in subjects receiving nivolumab (Table 7). Early 
recognition and treatment of diarrhea and colitis are critical to their management. Subjects 
should be advised to seek immediate medical evaluation if they develop new-onset diarrhea, 
blood in stool, or severe abdominal pain or if they have worsening of baseline diarrhea. In 
subjects with pre-existing diverticulosis and/or diverticulitis receiving concomitant medication 
with corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioid analgesics 
together with nivolumab, diverticular perforation has been observed.
Table 7:
Management and Follow-up of Immune-mediated Gastrointestinal Adverse Events
Grade 1
Symptomatic treatment according to institutional standards
Close monitoring; instruct subject to report worsening immediately and treat as Grade 2
Grade 2
5 days: Symptomatic treatment according to institutional standards
>5 days or recurrence: 0.5–1.0 mg/kg/d methylprednisolone.; consider prophylactic antibiotics;
Persistence or worsening despite steroids >3 days: treat as Grade 3/4
Improvement to Grade 1: taper steroids over at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, resume study therapy per protocol
Grade 3
Immediately: 1.0–2.0 mg/kg/d methylprednisolone IV; consider prophylactic antibiotics and
lower endoscopy
Persistence >3 days or recurrence: add infliximab 5 mg/kg (if no contraindication such as
perforation or sepsis)
Improvement to Grade 2 within 3 days: taper steroids over at least 1 month
Grade 4
The oral corticosteroid equivalent of the recommended IV dose may be considered for ambulatory 
subjects; the lower bioavailability of oral corticosteroids need to be considered. Clinical caution should 
be exercised, for subjects receiving concomitant medications of corticosteroids, NSAID, or opioid 
analgesics. In addition, be vigilant for signs and symptoms of potential perforation, especially in subjects 
with known diverticular disease. Narcotics should be used with caution as pain medicines may mask the 
signs of colonic perforation.
For nivolumab dose modification guidelines, refer to Table 4.
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8.3.2.2.
Hepatic Adverse Events
Hepatic AEs, including elevated liver function tests (LFTs) and, infrequently, drug-induced liver 
injury (DILI) have been observed after treatment with nivolumab (Table 8). Early recognition 
and treatment of elevated LFTs and DILI are critical to their management. Subjects should be 
advised to seek medical evaluation if they notice jaundice (yellow appearance of skin or sclera) 
or if they develop bruising, bleeding, or right-sided abdominal pain. Physicians should monitor 
LFTs prior to each nivolumab treatment.
Table 8:
Management and Follow-up of Immune-mediated Hepatic Adverse Events
Grade 1
Monitor LFTs as outlined in the protocol
Worsening: treat as Grade 2
Grade 2
Monitor every 3 days
Returning to baseline: resume per protocol monitoring
LFT elevation >5 days or worsening: 0.5 – 1.0 mg/kg/d methylprednisolone IV or oral
equivalent; consider prophylactic antibiotics
LFT return to Grade 1 or baseline: taper steroids over at least 1 month; resume routine
monitoring and resume study treatment per protocol
Grade 3-4
Monitor every 2 days;
Immediately: 1. –2.0 mg/kg/d methylprednisolone IV or IV equivalent; start prophylactic
antibiotics; consult gastroenterologist
Persistence >3 days or recurrence: add mycophenolate mofetil 1g twice daily; if no response within 
5 days consider other immunosuppressants per local guidelines
LFT return to Grade 2: stop immunosuppressants
LFT return to Grade 1: taper steroids over at least 1 month
For nivolumab dose modification guidelines, refer to Table 4.
8.3.2.3.
Endocrinopathies
Endocrinopathies have been observed after treatment with nivolumab (Table 9). The events are
typically identified through either routine periodic monitoring of specific laboratories values
(eg, thyroid-stimulating hormone [TSH]) or as part of a work-up for associated symptoms 
(eg, fatigue). Events may occur within weeks of starting treatment, but also have been noted to 
occur after many months (while still on treatment). More than 1 endocrine organ may be 
involved (eg, hypophysitis [pituitary inflammation] may need to be evaluated at the time adrenal 
insufficiency or thyroid disorder is suspected). Subjects should be advised to seek medical 
evaluation if they notice new-onset fatigue (or if baseline fatigue worsens), lightheadedness, or 
difficulty with vision.
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Table 9:
Management and Follow-up of Endocrinopathies
Asymptomatic TSH abnormality
TSH <0.5xLLN or TSH >2xULN or TSH >ULN in 2 subsequent 
measurements: include free T4 assessment prior/after subsequent cycles of 
nivolumab; consider endocrinology consult
Symptomatic endocrinopathy
Assess endocrine function with appropriate laboratory testing; consider 
pituitary MRI scan
With abnormal lab and pituitary scan: 1.0–2.0 mg/kg/d 
methylprednisolone IV or oral equivalent; initiate appropriate hormone 
therapy; consider prophylactic antibiotics
Clinical and laboratory improvement: taper steroids over at least 1 
month; subjects with adrenal insufficiency may need to continue steroids 
with mineralcorticoid component
Without abnormal lab and pituitary scan but symptoms persist: repeat 
laboratory assessments in 3 weeks and MRI in 4 weeks
Suspicion of adrenal crisis (eg, 
severe dehydration, hypotension, 
shock out of proportion to current 
illness)
Rule out sepsis
Immediately: initiate/stress dose of IV steroids with mineralocorticoid 
activity; fluids IV; consult endocrinologist
Adrenal crisis ruled out: treat as symptomatic endocrinopathy
General
Subjects on IV steroids may be switched to an equivalent dose of oral 
corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained 
clinical improvement is observed. The lower bioavailability of oral 
corticosteroids need to be considered
For nivolumab dose modification guidelines, refer to Table 4.
8.3.2.4.
Rash (Including Stevens-Johnson Syndrome and Toxic Epidermal 
Necrolysis)
Rash and pruritus are the most common skin immune-mediated adverse events observed after 
treatment with nivolumab (Table 10). The rash is typically focal with a maculopapular 
appearance, occurring on the trunk, back, or extremities. Most cases are of low or moderate 
grade. In some cases, rash and pruritus resolve without intervention. Stevens-Johnson Syndrome 
and toxic epidermal necrolysis have also been reported, including cases with a fatal outcome.
Subjects should be advised to seek medical evaluation if they notice new-onset rash. Early 
consultation with a dermatology specialist and a biopsy should be considered if there is 
uncertainty as to the cause of the rash, or if there is any unusual appearance or clinical feature 
associated with it.
Table 10:
Management and Follow-up of Rash
Grade 1-2
Immediately: Symptomatic therapy (eg, anti-histamines, topical steroids)
Persistence 2 weeks or recurrence: consider skin biopsy; consider 0.5-1.0 mg/kg/d 
methylprednisolone IV or oral equivalent; consider prophylactic antibiotics
Improvement to Grade 1: taper steroids over at least 1 month
Worsening to >Grade 2: treat as Grade 3-4
Grade 3-4
Immediately: consult dermatologist; consider skin biopsy; start 1.0-2.0 mg/kg/d methylprednisolone 
IV or IV equivalent; add prophylactic antibiotics
Improvement to Grade 1: taper steroids over at least 1 month
General
Subjects on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) 
at start of tapering or earlier, once sustained clinical improvement is observed. The lower 
bioavailability of oral corticosteroids need to be considered
For nivolumab dose modification guidelines, refer to Table 4.
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8.3.2.5.
Renal Adverse Events
Elevated creatinine and biopsy-confirmed tubulointerstitial nephritis and allergic nephritis are
infrequently observed after treatment with nivolumab (Table 11). Physicians should monitor 
creatinine regularly.
Table 11:
Management and Follow-up of Renal Adverse Events
Grade 1
Monitor creatinine weekly
Creatinine returns to baseline: continue monitoring per protocol
Creatinine increases: treat as Grade 2
Grade 2-3
Monitor creatinine every 3 days
Immediately: start 0.5-1.0 mg/kg/d methylprednisolone IV or oral equivalent; consider prophylactic 
antibiotics; consider renal biopsy
Improvement to Grade 1: taper steroids over at least 1 month
Persistence >7 days or worsening: treat as Grade 4
Grade 4
Monitor creatinine daily
Immediately: consult nephrologist; consider renal biopsy; start 1.0-2.0 mg/kg/d methylprednisolone IV
or IV equivalent; add prophylactic antibiotics 
Improvement to Grade 1: taper steroids over at least 1 month
General
Subjects on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) 
at start of tapering or earlier, once sustained clinical improvement is observed. The lower 
bioavailability of oral corticosteroids need to be considered
For nivolumab dose modification guidelines, refer to Table 4.
8.3.2.6.
Neurologic Adverse Events
Neurologic adverse events have been uncommonly observed after treatment with nivolumab
(Table 12). Neurologic adverse events may be central abnormalities (eg, aseptic meningitis or 
encephalitis) or peripheral sensory/motor neuropathies (eg, Guillain-Barre Syndrome). The onset 
has been observed as early as after a single treatment. Early recognition and treatment of 
neurologic adverse events is critical to their management. Subjects should be advised to seek 
medical evaluation if they notice impairment in motor function (eg, weakness), changes in 
sensation (eg, numbness), or symptoms suggestive of possible CNS abnormalities such as new 
headache or mental status changes.
Table 12:
Management and Follow-up of Neurologic Adverse Events
Grade 1
Monitor per protocol
Worsening: treat as Grade 2
Grade 2
Immediately: treat symptoms according to institutional standards; consider 0.5-1.0 mg/kg/d 
methylprednisolone IV or oral equivalent
Worsening: treat as Grade 3-4
Grade 3-4
Immediately: consult neurologist; treat symptoms according to institutional standards; start
1.0-2.0 mg/kg/d methylprednisolone IV or IV equivalent; prophylactic antibiotics
Worsening or atypical presentation: consider IV immunoglobulins or other immunosuppressive 
therapies according to institutional standards
Improvement to Grade 2: taper steroids over at least 1 month
General
Subjects on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) 
at start of tapering or earlier, once sustained clinical improvement is observed. The lower 
bioavailability of oral corticosteroids need to be considered.
For nivolumab dose modification guidelines, refer to Table 4.
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8.3.2.7.
Pulmonary Adverse Events
Pulmonary adverse events, including radiographic changes (eg, focal ground glass opacities and 
patchy infiltrates), indicative of drug-related pneumonitis have been observed in subjects 
receiving nivolumab (Table 13). These pulmonary adverse events are either asymptomatic or 
associated with symptoms such as dyspnea, cough, or fever. The initial occurrence of pulmonary 
adverse events may be as early as after a single dose of nivolumab or delayed after prolonged 
therapy. Early recognition and treatment of pneumonitis is critical to its management. Subjects 
should be advised to seek medical evaluation promptly if they develop new-onset dyspnea, 
cough, or fever or if they have worsening of these baseline symptoms.
Table 13:
Management and Follow-up of Pulmonary Adverse Events
Grade 1
Monitor for symptoms every 2-3 days; consider pulmonary and infectious-disease consult; re-image 
every 3 weeks
Worsening: treat as Grade 2
Grade 2
Monitor symptoms daily; re-image every 1-3 days; pulmonary and infectious-disease consultation; 
consider bronchoscopy and lung biopsy; consider hospitalization
Immediately: start 1.0 mg/kg/d methylprednisolone IV or oral equivalent; prophylactic antibiotics
Persistence for 2 weeks or worsening: treat as Grade 3-4
Improvement to Grade 1 or baseline: taper steroids over at least 1 month
Grade 3-4
Hospitalize; pulmonary and infectious-disease consult; consider bronchoscopy and lung biopsy
Immediately: 2-4 mg/kg/d methylprednisolone or IV equivalent; add prophylactic antibiotics;
Persistence for 2 days or worsening: add immunosuppression (eg, infliximab, cyclophosphamide, IV
immunoglobulins, or mycophenolate mofetil)
Improvement to Grade 2: taper steroids over at least 6 weeks
General
Subjects on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) 
at start of tapering or earlier, once sustained clinical improvement is observed. The lower 
bioavailability of oral corticosteroids need to be considered
For nivolumab dose modification guidelines, refer to Table 4.
8.3.2.8.
Uveitis and Visual Complaints
Immune therapies have been uncommonly associated with visual complaints (Table 14).
Inflammation of components within the eye (eg, uveitis) is an uncommon, but clinically 
important, event. An ophthalmologist should evaluate visual complaints with examination of the 
conjunctiva, anterior and posterior chambers, and retina. Complaints of double vision should also 
prompt medical evaluation. The differential diagnosis should include pituitary inflammation.
Table 14:
Management and Follow-up of Uveitis and Visual Complaints
Grade 1-2
Thorough eye examination
Topical corticosteroids should be considered
Persisting despite topical steroids, treat as Grade 3-4
Grade 3-4
Thorough eye examination
Systemic corticosteroids
For nivolumab dose modification guidelines, refer to Table 4.
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8.3.2.9.
Lipase/Amylase Elevations 
Asymptomatic elevations in lipase and amylase have been reported in nivolumab studies. Very 
few subjects have associated symptoms (eg, abdominal pain) or radiographic findings 
(eg, stranding) consistent with pancreatitis. Given that most events are asymptomatic, the 
recommended management is close observation. Physicians should ensure that subjects have no 
associated symptoms consistent with pancreatitis, such as abdominal pain. Corticosteroids do not 
seem to alter the natural history of lipase/amylase elevations. Laboratory values tend to fluctuate 
on a day-to-day basis and eventually return to baseline or low grade levels over the course of 
weeks, whether or not subjects receive corticosteroids. Asymptomatic elevations should be 
monitored approximately weekly.
8.3.2.10.
Treatment of Nivolumab Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce an infusion or hypersensitivity reaction. However, if such a reaction 
were to occur, it might be associated with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypotension, hypertension, bronchospasm, or other symptoms (Table 15).
If a nivolumab related infusion reaction occurs on Day 1 of a treatment cycle, then the scheduled 
dose of JNJ-757 should be withheld on that day. The subject can resume JNJ-757 treatment with 
the next scheduled dose of JNJ-757 on Day 1 of the next cycle of nivolumab treatment. 
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Table 15:
Management and Follow-up of Nivolumab Infusion Reactions
Grade 1
No intervention indicated; remain at bedside and monitor subject until recovery from symptoms, 
Consider diphenhydramine 50 mg or equivalent and or paracetamol (acetaminophen) 325 to 1000 mg at 
least 30 minutes before additional nivolumab administration
Grade 2
Stop nivolumab infusion; start IV saline infusion; give diphenhydramine 50 mg (or equivalent) IV
and/or paracetamol 325 to 1000 mg (acetaminophen); consider corticosteroids and bronchodilator 
therapy; remain at bedside and monitor subject until recovery from symptoms
Re-start infusion at 50% of initial rate: if no further complications ensue after 30 minutes, the rate 
may be increased to 100% of the original infusion rate; monitor subject closely.
Symptoms recur: stop and discontinue further nivolumab treatment at that visit; administer 
diphenhydramine 50 mg IV, and remain at bedside and monitor the subject until resolution of 
symptoms. The amount of nivolumab infused must be recorded in the eCRF.
Grade 3-4
Stop nivolumab infusion; start IV saline infusion; recommend bronchodilators, epinephrine 0.2 to 1 
mg of a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 
mg IV (or equivalent), as needed.
Subject should be monitored until the investigator is comfortable that the symptoms will not recur. 
Nivolumab will be permanently discontinued. Investigators should follow their institutional guidelines 
for the treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms. 
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral antihistamine, or 
corticosteroids).
General
Prophylactic medications (after initial event): diphenhydramine 50 mg (or equivalent) and/or 
paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before additional nivolumab 
administrations; if necessary, corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or 
equivalent) may be used
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the infusion of nivolumab.
For nivolumab dose modification guidelines, refer to Table 4.
8.4.
Subsequent Therapies
Any subsequent anticancer therapy administered after the study agent should be recorded in the 
eCRF. The start and end date and best response should be documented in the eCRF, if available.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule (Table 1) summarizes the frequency and timing of measurements 
applicable to this study. The study is divided into 3 phases: a Screening Phase (with an optional 
Prescreening Phase to collect tumor tissue), a Treatment Phase, and a Posttreatment Follow-up 
Phase. All subjects will continue follow-up for survival and subsequent anticancer therapy in the 
Posttreatment Follow-up Phase, except for those who additionally withdraw consent for 
continued study participation.
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After Cycle 2, the start of each cycle may occur ±3 days of the scheduled day to accommodate 
the schedule of the site or subject. The End-of-Treatment Visit may occur +7 days after the 
scheduled day. Assessments/procedures should be completed on the day indicated; if this is not 
possible because of a weekend, holiday, or emergency, the assessment/procedure should be 
completed within the timeframe noted in Table 1. Imaging studies should be completed within 
±7 days of the scheduled assessment.
All PRO assessments should be conducted/completed before any tests, procedures, or other 
consultations 
to 
prevent 
influencing 
subject 
perceptions. 
Blood 
collections
for 
pharmacodynamic/biomarker assessments should be kept as close to the specified time as 
possible. Actual dates and times of assessments will be recorded in the source documentation 
and on the laboratory requisition form or eCRF. Blood samples must be taken from a peripheral 
vein from the arm contralateral to the arm into which JNJ-757 is infused. Use of a central 
catheter to administer JNJ-757 is prohibited for the duration of the study.
Clinical laboratory results must be reviewed by the investigator before any study agent is 
administered. Repeat or unscheduled samples may be collected for safety reasons or for technical 
issues with the samples. Additional serum or urine pregnancy tests may be performed, as 
determined necessary by the investigator or required by local regulation, during the subject's 
participation in the study.
The blood volume will vary by treatment cycle. See Table 1 for details on sample collections and 
the laboratory manual for details on blood volumes.
9.1.2.
Screening Phase
The Screening Phase will include a review of medical history to determine eligibility for the 
study. All subjects must sign an ICF before the conduct of any study-specific procedures. 
Screening procedures, including radiographic imaging and 12-lead electrocardiogram (ECG), are 
to be performed up to 28 days before Cycle 1 Day 1 (Phase 1b) or randomization (Phase 2). 
Study assessments performed as part of the subject’s routine clinical evaluation within the 
28-day screening period can be used prior to signed informed consent. Retesting of abnormal 
laboratory screening values is allowed during the Screening Phase (to reassess eligibility). The 
last result obtained before Cycle 1 Day 1 (Phase 1b) or randomization (Phase 2) will be used to 
determine eligibility. An optional prescreening phase to minimize delay for central confirmation 
of tumor status is described in Section 9.1.2.2.
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9.1.2.1.
Determination of Mesothelin and PD-L1 Level
Before proceeding to the Treatment Phase of the study, tumor tissue samples for each subject 
must be provided for assessment of tumor mesothelin status and PD-L1 level. The results must 
be reported by the central laboratory before Cycle 1 Day 1 (Phase 1b) or randomization (Phase 
2). Tumor samples (block or unstained tumor slides) may be either from archival tissue or newly 
obtained (if archival tissue is insufficient). For the evaluation of mesothelin in tumor tissues, a 
validated assay will be used at the central lab. Mesothelin positive status (>0% positive tumor 
cells) is defined as tumor cells exhibiting positive membrane or cytoplasmic staining at any 
intensity. Tumor tissue will be assessed for PD-L1 staining, by the sponsor or sponsor's designee
using the DAKO PD-L1 IHC 28-8 pharmDx Assay, for which excisional, incisional, punch, or 
core biopsies are required. Fine needle aspirates or other cytology specimens are insufficient for 
PD-L1 analysis. Unstained slides must be made within 4 months prior to central laboratory 
assessment and stored in the dark at 2°–8°C.
9.1.2.2.
Optional Prescreening Phase
Subjects must have available tumor material for testing of mesothelin and PD-L1 to be eligible 
for the study. The purpose of the optional Prescreening Phase is to provide adequate time for the 
collection of archived formalin-fixed paraffin-embedded tumor tissue (block or unstained tumor 
slides) from primary or metastatic tumor material to be submitted to the laboratory along with 
the associated pathology reports. The tumor samples will be studied for mesothelin and PD-L1 
before the formal screening process for the study. A separate informed consent for this optional 
Prescreening Phase will permit collection of archival tumor material from the subject and testing 
of the mesothelin required for eligibility and PD-L1 levels required for stratification purposes in 
Phase 2.
9.1.3.
Treatment Phase
The Treatment Phase begins on Cycle 1, Day 1 with the administration of the first dose of 
nivolumab and continues until the completion of the End-of-Treatment Visit. Nivolumab should 
be administered within 3 days of randomization. The measurements collected at the time closest 
to, but before, the start of nivolumab administration will be defined as the baseline values for 
safety assessment and treatment decisions. Any new or worsening adverse events that occur and 
all concomitant medications that are administered between when the informed consent form 
(ICF) is signed and 100 days after the last dose of study agent will be recorded for subjects who 
enter the Screening Phase. Any subject with an ongoing adverse event will be followed beyond
100 days after the last dose of study agent, subjects will be followed for ongoing treatment-
related adverse events and associated medications until all adverse events are resolved, return to 
baseline, are deemed irreversible, or the subject starts subsequent anticancer therapy. See Section 
12 for complete details on adverse event reporting. 
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The study will be conducted in an outpatient setting. Subjects must remain at the infusion center 
for monitoring for 5 hours after the end of the first infusion of JNJ-757. At the investigator’s 
discretion, hospitalization after any study agent infusion may be considered, if clinically 
indicated, to facilitate safety monitoring. Subjects who have symptoms indicative of a systemic 
innate immune response to bacterial infection within 5 hours of the end of any infusion may be 
considered for hospitalization for continued observation, at the investigator’s discretion. These 
admissions for observation should not be reported as serious adverse events. Physician visits will 
be conducted on Days 1, 2, and 15 of Cycle 1, and Days 1 and 15 of subsequent cycles (if 
nivolumab is permanently discontinued but the subject continues to receive treatment with JNJ-
757, then the Day 15 visits of subsequent cycles will be optional). Subjects who undergo 
ELISpot assessments will be scheduled for additional physician visits at Day 8 of Cycles 2 and 3.
Required study procedures and assessments to be conducted during the Treatment Phase are 
outlined in Table 1. A focused medical history and symptom-directed physical exam will be 
conducted. Subjects will be evaluated throughout the Treatment Phase for possible toxicities and 
adverse events. Adverse event information will be collected using the NCI-CTCAE, 
Version 4.03. All new concomitant medications or changes to concomitant medications will be 
recorded. Clinical laboratory assessments will be reviewed before the administration of study 
agent. After Cycle 1, Day 1, laboratory tests may be performed up to 3 days before the scheduled 
infusion day.
On Day 1 of each cycle with a scheduled disease assessment (ie, every 8 weeks in the first year 
and then every 12 weeks), predose peripheral surveillance blood cultures will be performed as 
described in the Time and Events Schedule. If the results of the peripheral blood cultures are 
positive for listeriosis after receiving JNJ-757, the subject must discontinue subsequent therapy 
with JNJ-757 and be treated with an intravenous antibiotic therapy appropriate for the treatment 
of listeriosis (See Section 8.3.1.2).
The investigator will assess each subject’s response to therapy using the efficacy measurements 
and RECIST 1.1 disease response criteria outlined in Attachment 2, according to the schedule in 
Table 1. If progressive disease is diagnosed or if a subject discontinues study treatment for 
reasons other than withdrawal of consent, the subject should complete the End-of-Treatment 
Visit within 30 days (+7 days) and then enter the Posttreatment Follow-up Phase. For subjects 
who discontinue treatment before disease progression (for reasons such as an adverse event or 
investigator decision) radiologic assessments should be performed according to the protocol 
schedule until disease progression, initiation of subsequent therapy, withdrawal of consent from 
study participation, or study end.
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End-of-Treatment/Early Withdrawal
The End-of-Treatment Visit should be performed within 30 days (+7 days) after the last dose of 
study agent (JNJ-757 or nivolumab) for each subject, including those discontinuing treatment for 
any reason, except for withdrawal of consent for study participation. Subjects who discontinue 
treatment (due to progression of disease or unacceptable toxicity) and who are entering the 
Posttreatment Follow-up Phase should have the End-of-Treatment Visit completed before 
starting any new anticancer treatment to collect safety information, draw the required blood 
cultures, and initiate the required prophylactic antibiotics. If the subject is scheduled to start 
subsequent therapy, this visit should be performed as soon as possible after the last 
administration of study agent.
After the last JNJ-757 infusion, mandatory prophylactic antibiotic therapy must be administered 
(refer to Section 8.3.1.1). Study subjects who wish to withdraw from the study are required to 
complete the planned administration of antibiotics. End-of-Treatment assessments, including 
blood culture sample collection, should be performed prior to the initiation of the mandatory 
prophylactic antibiotics. All subjects who receive JNJ-757, including those withdrawing consent 
for further participation, should receive the full 7-day course of mandatory prophylactic 
antibiotics.
9.1.4.
Posttreatment Follow-up Phase
The Posttreatment Follow-up Phase starts after the End-of-Treatment Visit and ends with the end 
of study participation or end of study. Subjects who withdraw from treatment due to disease 
progression, unacceptable toxicity, or subject or investigator decision will enter the 
Posttreatment Follow-up Phase.
Follow-up visits will be made every 3 months (±7 days) after the last dose of study agent to 
obtain blood cultures (up to 1 year for subjects who receive JNJ-757) and to determine survival, 
unless the subject has died, is lost to follow-up, or has withdrawn consent. For subjects in 
Group B and after the first year for subjects in Phase 1b and Group A, these visits may be 
conducted by telephone contact or an alternative contact method per institution policy/practice.
Assessments that will occur at the Posttreatment Follow-up visits are summarized in Table 1. 
The first Posttreatment Follow-up visit should occur 100 days after the last dose of study agent.
Additional information on reporting of adverse events can be found in Section 12.
If the subject has died, the date and cause of death will be collected and documented in the 
eCRF. For subjects who withdrew from treatment before disease progression, the results of 
subsequent tumor assessments, conducted according to the study schedule, should also be 
collected until disease progression is radiographically documented, or until the subject initiates 
subsequent therapy.
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Subjects who have a treatment-related Grade 3 toxicity at the End-of-Treatment Visit will 
continue follow-up until recovery to Grade 1 or baseline, the AE is deemed irreversible, or the 
subject starts subsequent anticancer therapy. Subjects with treatment-related adverse events 
leading to discontinuation will continue follow-up until resolution or return to baseline, the AE is 
deemed irreversible, or end of study, whichever occurs first.
9.1.5.
End of Study
The end of the study will occur when 80% of the randomized subjects have died, or 
approximately 3 years after the last subject is randomized, or the sponsor terminates the study.
9.2.
Efficacy Evaluations
9.2.1.
Evaluations
Disease response will be assessed using CT scans with IV contrast (or if necessary, MRI scans)
of the chest, abdomen, and pelvis. The scans will be performed at Week 8 (±7 days), then every 
8 weeks (±7 days) during the first year, and then every 12 weeks (±7 days) thereafter, in 
accordance with the schedule outlined in Table 1 until disease progression, subsequent therapy, 
or completion of therapy. For subjects receiving on-treatment biopsy, the first assessment will be 
at Cycle 3 Day 8 (+3 days). Tumor measurements will occur as recommended by the RECIST 
1.1 criteria (Attachment 2).
Magnetic resonance imaging may be used to evaluate sites of disease that cannot be adequately 
imaged using CT. If MRI is used to assess a site of disease at baseline, then it must be the 
imaging technique for that site of disease at all subsequent response evaluations.
For subjects with known brain metastasis, brain MRI scans are required at baseline and as 
clinically indicated. Survival status will be assessed according to the schedule in Table 1.
All efficacy evaluations, including other sites of disease by radiologic imaging, physical 
examination, or other procedures as necessary, will be performed at the site. These assessments 
should be performed throughout the study at each timepoint using the same method of 
assessment used to assess disease at baseline. Response to treatment will be assessed by the 
investigator at the site and the results will be recorded in the eCRF. The results of radiologic
assessments performed after treatment discontinuation, as part of the standard of care at the site, 
should be recorded in the eCRF. Copies of the images must be retained at the site. For Phase 2, 
radiographic scans may be submitted to a third-party core imaging laboratory for quality 
assessment and for audit purposes. Further details regarding submission of these materials will 
be provided in the Imaging Manual.
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The PRO instruments in this study are NSCLC-SAQ, EORTC QLQ-C30, and EORTC 
QLQ-LC13. Validation of the NSCLC-SAQ is ongoing. It contains 7 items that assess cough, 
pain, dyspnea, fatigue, and poor appetite over a 7-day recall period. Three items (assessing cough 
and pain) assess peak intensity, and use response options range from “no [symptom]” to “very 
severe [symptom],” while the remaining items assess the frequency of symptoms (dyspnea, 
fatigue, and poor appetite) and use a rating scale from “never” to “always” (McCarrier 2016).22
A Patient Global Impression of Change (PGIC) and a Patient Global Impression of Severity 
(PGIS) will also be included at follow-up visits to provide anchor-based comparisons for the 
NSCLC-SAQ and support validation efforts for this PRO. The single-question PGIC and PGIS
should be administered prior to other PRO assessments.
The EORTC QLQ-C30 includes 30 items resulting in 5 functional scales (physical functioning, 
role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global 
health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items 
(dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The recall 
period is 1 week (the past week). The EORTC QLQ-C30 has been widely used among patients 
with cancer. Scores are transformed to a 0 to 100 scale (Aaronson 1993).1 The EORTC QLQ-
LC13 is a 13-item lung cancer-specific module of the EORTC QLQ-C30. It incorporates 1 
multiple-item scale to assess specific lung cancer symptoms including dyspnea and a series of 
single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, 
and hemoptysis (Bergman 1994).4
9.2.1.1.
Assessment of Disease Response and Progressive Disease
Assessments of disease response are to be conducted until disease progression, withdrawal of 
consent from study participation, or the end of study. For subjects who discontinue study agent
before disease progression is documented, disease assessments should continue during the 
Posttreatment Follow-up Phase according to the study schedule until disease progression is 
documented or subsequent therapy is initiated.
9.2.1.2.
Treatment Beyond Progression
Antitumor response patterns seen with immunotherapeutic agents may extend beyond the typical 
time course of responses seen with cytotoxic agents (Melosky 2016).23 Accumulating evidence 
indicates that a minority of patients with solid tumors treated with immunotherapy may derive 
clinical benefit despite initial evidence of disease progression (ie, tumor flare). At the time of
response assessment, subjects who meet the criteria for progressive disease per RECIST 1.1 but 
whose progression is attributed to tumor flare may be permitted to remain on study therapy, 
based on the investigator's assessment of clinical benefit, if the subject is clinically stable, meets 
all other study protocol eligibility criteria, and is tolerating the study agent(s). All decisions to 
continue treatment beyond suspected tumor flare must be discussed with the sponsor's medical 
monitor. An assessment of the benefit-risk of continuing with study therapy, as well as the 
subject's agreement to continue study therapy, must be documented in the study records.
Subsequent disease assessments will continue as scheduled, and results of these assessments will 
be reported in the eCRF.
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9.2.1.3.
Discontinuation of Study Agent After Complete Response
Subjects with a confirmed complete response (CR) at the next regularly scheduled scan may 
continue study agent at the discretion of the investigator. The maximum allowed duration of 
nivolumab or JNJ-757 treatment is 2 years. Study agent discontinuation may be considered for a 
subject with a CR if the subject has received at least 2 cycles of study treatment beyond the date 
when the initial CR was documented. The reason for discontinuation must be documented in the 
eCRF.
9.2.2.
Efficacy Endpoints
The efficacy endpoints are as follows:

ORR is defined as the proportion of subjects who achieve CR or partial response (PR), as 
assessed by the investigator, using RECIST 1.1 criteria (Attachment 2).

Disease control rate (DCR) is defined as the proportion of subjects with stable disease 
lasting for at least 16 weeks, PR, or CR.

DOR is defined as the time from the date of initial documentation of a response (CR or PR) 
to the date of first documented evidence of progressive disease or death from any cause.

PFS is defined as the time from the date of randomization until the date of first documented 
evidence of progressive disease (or relapse for subjects who experience CR during the 
study) or death from any cause, whichever comes first.

Overall survival is defined as the time from the date of randomization to the date of the 
subject’s death.

Change from baseline in PRO subscale scores as assessed by NSCLC-SAQ and EORTC 
QLQ30+LC13.
9.3.
Blood Culture and Bacterial Shedding Assessments for JNJ-757
Blood Cultures
Blood cultures should be performed for all subjects during the Treatment Phase, at the End-of-
Treatment visit, and during the Posttreatment Follow-up Phase, as outlined in Table 1. Refer to 
the laboratory manual for details. Every effort should be made to collect surveillance cultures at 
the site, using sponsor-supplied kits. However, in the event that a subject cannot return to the 
study site, posttreatment surveillance blood cultures should be performed at a local laboratory 
and the results recorded in the subject source documentation and reported in the eCRF.
Surveillance cultures positive for listeriosis will be reported to the sponsor's medical monitor 
within 24 hours of awareness irrespective of seriousness (ie, serious and nonserious adverse 
events) and will require enhanced data collection.
Bacterial Shedding 
The shedding profile of JNJ-757 will be studied for all subjects who receive JNJ-757 plus 
nivolumab in Phase 1b, and in Phase 2 Group A (tumor biopsy substudy only). The shedding of 
JNJ-757 will be studied in (1) feces by stool or rectal swab, (2) urine, and (3) saliva. Any subject
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with a positive shedding result will be tested every 2 to 4 days until a negative shedding result. 
Samples will be obtained as specified in Table 1. Refer to the laboratory manual for details.
9.4.
Nivolumab Pharmacokinetic Evaluations
Blood samples will be collected from subjects in both phases for determination of serum 
concentrations of nivolumab as specified in Table 1. Nivolumab concentration data will be 
summarized using descriptive statistics. Serum samples will be analyzed for nivolumab by a 
validated method.
9.5.
Nivolumab Immunogenicity Evaluations
Subjects in Phase 2 will be monitored for anti-nivolumab antibodies. Blood for serum 
anti-nivolumab antibody testing will be collected as specified in Table 1. Analysis will be 
performed under the supervision of the sponsor. Details on blood sample collection, processing, 
storage and shipping procedures are provided in the laboratory manual.
9.6.
Biomarkers
Biopsy and blood biomarker analyses are dependent upon the availability of appropriate 
biomarker assays and may be deferred or not performed if either during or at the end of the study 
it becomes clear that the analysis will have no scientific value. If the study is terminated early, 
completion of biomarker assessments will be based on justification and intended utility of the 
data.
9.6.1.
Sample Collection
Collection of blood samples will occur at the times specified in Table 1. Biomarker analyses 
indicated below will be performed in subjects in the tumor biopsy substudy, which includes all 
subjects in Phase 1b and subjects at selected sites approved by the sponsor in Phase 2. Subjects 
in the tumor biopsy substudy will undergo collection of samples for T-cell proliferation, 
intracellular cytokine staining, IFN-γ ELISpot, and pentamer staining. Mandatory core needle
on-study tumor biopsy samples will be collected as specified in Table 1 from subjects who 
consent separately to participate in the tumor biopsy substudy (where local regulations permit).
Deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein may be isolated from tumor 
biopsies for evaluation of tumor-associated biomarkers to better understand their correlation with 
clinical response. No pharmacogenomic analyses will be conducted on the biomarker samples. 
Samples of resected tissue from unscheduled diagnostic or surgical interventions may also be 
submitted and evaluated for further biomarker investigations of potential mechanisms of tumor 
response or resistance. Analyses from the tumor biopsy substudy will be reported separately.
9.6.2.
Pharmacodynamic and Predictive Biomarker Evaluations
Pharmacodynamic (PD) biomarkers and translational data will be informed by available Phase 1 
results, will be assessed before, during, and after treatment with JNJ-757, and may include the 
following:
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1.
Differential absolute lymphocyte count in peripheral blood.
2.
Cytokine release in plasma as analyzed using appropriate techniques such as 
electrochemiluminescence-based bridging immunogenicity assay (Meso Scale Discovery).
3.
NK, CD4, and CD8 T cell enumeration and activation status using standard activation 
markers (such as CD69) by flow cytometry in PBMCs.
4.
Lymphocyte subsets and expression levels of T cell costimulatory markers (by flow 
cytometry). Analyses may include, but not be limited to, the proportion of T-, B-, and 
NK-cells, proportion of memory- and effector T-cell subsets, and expression levels of PD-1, 
PD-L1, PD-L2, ICOS, and Ki67.
5.
Analysis of the diversity of the T-cell repertoire in correlation to clinical efficacy.
6.
Adaptive T-cell responses. The magnitude, breadth, and duration of antigen-specific 
responses to the tumor associated antigen mesothelin, as well as recall and de novo 
responses to control human leukocyte antigen (HLA) class II-restricted T-cell epitopes 
(cytomegalovirus, Epstein-Barr virus, influenza and tetanus toxoid), the Listeria antigen 
listeriolysin O, and the ActANE sequences will be evaluated using appropriate assays such as 
IFN-γ ELISpot and flow cytometric analysis of intracellular cytokine staining, markers of 
T-cell activation, and markers of proliferation.
7.
Infiltration and activation status of several immune cells subsets using appropriate
techniques such as single color or multiplex immunocytochemistry of formalin fixed 
paraffin embedded (FFPE) tumor biopsies.
9.6.3.
Primary Biomarker Assessment
Tumor sample collection and analyses will be performed before Cycle 1 Day 1 (Phase 1b) or 
randomization (Phase 2) as part of the screening activities, and will include central assessment of 
mesothelin status and PD-L1 level (Section 9.1.2.1). Tumor mesothelin status will be used as a 
study eligibility criterion and in Phase 2, subjects with mesothelin-positive tumors will be 
stratified based on PD-L1 level (<1%, 1-49%, or 50%). The primary endpoint of ORR will be 
assessed by PD-L1 level.
9.6.4.
Exploratory Biomarker Evaluations
Additional analyses may be carried out to assess immunosuppression in the blood and tumor 
microenvironment after treatment with JNJ-757. These analyses may include, but are not limited 
to, checkpoint expression in the tumor and blood, and expression of lung cancer and immune 
gene signatures (including, but not limited to, expansion of the T-cell or B-cell immune 
repertoire and tumor immune phenotyping) in the blood and tumor tissue that may be predictive 
of response or prognosis. Additionally, tumor genetics may be assessed on tumor tissues or from 
circulating DNA. The list of exploratory biomarkers to be evaluated will be informed by
available results of JNJ-757 Phase 1 biomarker assessments or results arising from other LADD 
Lm-based clinical studies or PD-1 inhibitor clinical studies. Other biomarker analyses are 
dependent upon the availability of appropriate biomarker assays. In the event that the study is 
terminated early, completion of biomarker assessments will be based on justification and 
intended utility of the data.
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9.6.5.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. Refer to the Time and Events Schedule (Table 1) for the timing and frequency 
of biomarker sample collections. Instructions for the collection, handling, storage, and shipment 
of samples are found in the laboratory manual that will be provided. Collection, handling, 
storage, and shipment of samples must be under the specified, and where applicable, controlled 
temperature conditions as indicated in the laboratory manual.
If it is determined at any time before study completion that additional material is needed from a 
formalin-fixed, paraffin-embedded tumor sample for the successful completion of the protocol-
specified analyses, the sponsor may request that additional material be retrieved from existing 
samples. In this case, such analyses would be specific to research related to the study agent or 
diseases being investigated.
9.7.
Safety Evaluations
The study will include evaluations of safety and tolerability outlined in the following sections 
according to the timepoints provided in Table 1. All subjects who receive at least 1 dose of study 
agent will be considered evaluable for safety. Any clinically relevant changes occurring during 
the study must be recorded on the Adverse Event section of the eCRF. Adverse events will be 
graded according to NCI-CTCAE, Version 4.03.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
continue follow-up by the investigator until resolution or until a clinically stable endpoint is 
reached (see also Section 9.1.4).
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.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology will be collected before each study agent
infusion, with the exception of TSH (with reflex testing), which will be collected on Day 1 of 
every other cycle. More frequent clinical laboratory tests may be performed if indicated by the 
clinical condition of the subject or by laboratory abnormalities that warrant more frequent 
monitoring. Screening laboratory results must be available to the investigator for evaluation 
before Cycle 1 Day 1 (Phase 1b) or randomization (Phase 2), and before each study agent
administration thereafter. The investigator must review the laboratory report(s), document this 
review, and ensure that any clinically relevant changes occurring during the study are recorded in 
the adverse event section of the eCRF. The laboratory reports must be filed with the source 
documents.
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The following tests will be performed:

Hematology 
-hemoglobin
-white blood cell count 
-absolute neutrophil count (ANC)
-absolute lymphocyte count (ALC)
-platelet count

Serum Chemistry Panel
-sodium
-total bilirubin
-potassium
-alkaline phosphatase
-creatinine
-lactate dehydrogenase 
-glucose
-calcium
-AST
-albumin
-ALT
-total protein

Thyroid function tests
-TSH, with reflex to free T3, T4 if abnormal

Serum pregnancy testing for women of childbearing potential only (urine, when serum is not 
available)
Electrocardiogram
The ECG must be reported locally for all subjects at Screening. Additional cardiovascular 
assessments should be performed as clinically appropriate to ensure subject safety. The clinical 
investigator will review the printout, including ECG morphology. Clinically relevant 
abnormalities noted at the time of Screening should be documented in the subject’s medical 
history and recorded on the eCRF.
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. Hypokalemia 
should be corrected before ECG collection.
Vital Signs
Vital signs include temperature, pulse rate, respiratory rate, SaO2 by pulse oximetry, and blood 
pressure (see Table 1 for frequency). Blood pressure and pulse rate measurements will be 
assessed with a completely automated device. Manual techniques will be used only if an 
automated device is not available, or to confirm abnormal results. Blood pressure and pulse rate 
measurements should be preceded by at least 5 minutes of rest in a quiet setting without 
distractions (eg, television, cell phones).
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Physical Examination
A full physical examination must be performed at Screening. Subsequently, symptom-directed 
and disease-directed physical examinations (includes all organ systems that were previously 
abnormal or involved with disease and documentation of any clinically relevant abnormalities in 
any organ) will be performed at the timepoints specified in Table 1. Height and weight will be 
measured at screening. Weight will also be measured at the start of each cycle, before study 
agent administration. Abnormal physical findings should be reported as adverse event if 
clinically indicated. 
ECOG Performance Status
The ECOG performance status scale, provided in Attachment 3, will be used to grade changes in 
the subject’s daily living activities. The frequency of ECOG performance status assessment is 
provided in Table 1.
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will complete the study if he or she has completed all protocol-specified procedures, 
has not been lost to follow-up, and has not withdrawn consent for study participation before the 
end of the study. In addition, subjects who die before the end of the study will be considered to 
have completed the study.
10.2.
Discontinuation of Study Treatment 
If study treatment must be discontinued, this will not result in automatic withdrawal of the 
subject from the study. In Group A, if the discontinuation of one study agent is indicated, the 
subject may continue the other agent as monotherapy at the same dose and schedule after 
consultation with the medical monitor if, in the investigator’s opinion, the subject may benefit 
from monotherapy. 
Study treatment should be discontinued if:

Occurrence of toxicity as noted in Section 8.3 or unacceptable toxicity

The investigator believes that for safety reasons (eg, adverse event) it is in the best interest 
of the subject to discontinue study treatment

The subject becomes pregnant 

Documented disease progression (see Section 9.2.1.2)

The subject receives concurrent (nonprotocol) anticancer treatment

Intercurrent illness prevents further administration of treatment

The subject refuses further treatment with study agent

Noncompliance with study treatment or procedure requirements that, in the opinion of the 
investigator or sponsor, preclude participation in the study for reasons of subject safety
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JNJ-757 treatment should be discontinued if predose peripheral surveillance cultures are positive 
for listeriosis or if the subject requires an emergent placement of a prohibited implanted device 
(refer to Section 8.3.1.2 for mandatory antibiotic treatment).
Study agent discontinuation may be considered for a subject with a CR if the next disease
assessment confirms CR and the subject has received at least 2 courses of JNJ-757 beyond the 
date when the initial CR was documented (see Section 9.2.1.3). The maximum allowed duration 
of nivolumab or JNJ-757 treatment is 2 years. If a subject discontinues study agent for any 
reason before the onset of disease progression, end-of-treatment and posttreatment assessments 
should be obtained and follow-up of scheduled disease assessments should be continued. The 
reason(s) a subject discontinues treatment should be recorded on the eCRF.
At the time of response assessment, subjects who meet the criteria for progressive disease per 
RECIST 1.1 but whose progression is attributed to tumor flare may be permitted to remain on 
study therapy, based on the investigator’s assessment of clinical benefit, if the subject is 
clinically stable, meets all other study protocol eligibility criteria, and is tolerating the study 
agent(s) (see Section 9.2.1.2).
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent
If a subject is lost to follow-up, every reasonable effort must be made by the study-site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow-up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study agent assigned to the withdrawn 
subject may not be assigned to another subject. If a subject withdraws from the study before the 
end of treatment, the End-of-Treatment Visit and Posttreatment assessments should be obtained.
10.4.
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 
separate informed consent for optional research samples.
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
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.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for future research (refer to Section 16.2.5,
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
Intent to treat (ITT) Population: The ITT population will include all randomized subjects 
classified according to their assigned treatment group, regardless of the actual treatment 
received. Subject disposition and efficacy analyses will be performed on data from the ITT 
population. The subjects in the safety run-in cohort will also be included in disposition and 
appropriate efficacy analyses and listed separately.
Safety Population (As Treated): The safety population will include all subjects who receive
1 dose of either of the study agents.
Biomarker Population: The biomarker population will include all subjects who receive 1 dose 
of study agent and have pretreatment and 1 posttreatment biomarker measurement.
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11.2.
Sample Size Determination
Phase 1b will be a safety run-in phase of at least 6 subjects to evaluate the incidence of DLTs 
and demonstrate the tolerability of the combination. Additional subjects (up to 30 in total) may 
be enrolled, as determined by the SET, to further explore safety and translational data before the 
decision to initiate the randomized Phase 2. A SET will be responsible for reviewing the safety 
and translational data during Phase 1b.
In Phase 2, a maximum of 140 subjects will be randomized. Based on preliminary data, it is 
estimated that 60%, 25%, and 15% of mesothelin-positive subjects will have a PD-L1 level of 
<1%, 1-49%, or ≥50%, respectively. The projected ORRs are as follows:
PD-L1 (<1%)
PD-L1 (1-49%)
PD-L1 (≥50%)
Overall 
Group A (JNJ-757 plus nivolumab)
0.30
0.40
0.80
0.40
Group B (nivolumab)
0.10
0.20
0.40
0.17
Using frequentist methods, a sample size of 140 subjects will provide at least 90% power to test 
a difference of 17% versus 40% in the overall population, using a 2-sided alpha of 10%.
Throughout randomization, ORR will be monitored using a Bayesian hierarchical logistic 
regression model, such that more subjects may be enrolled in a PD-L1 subgroup where the 
combination therapy is more effective. However, subjects will always be randomized to Group A 
or Group B in a 1:1 ratio within that subgroup. If the combination therapy is not effective in any 
PD-L1 subgroup, then the study could be stopped early.
11.3.
Statistical Model for Probability of ORR 
The DMC (see Section 11.11) will review the ORR data after approximately 40, 60, 80, 100, and 
120 subjects have been randomized in Phase 2. The DMC may request additional ad-hoc reviews 
based on the accumulating data. Enrollment of subjects may be stopped during the DMC 
reviews. 
The accumulated ORR data from the eligible subjects will be used to estimate the posterior 
probability of observing an objective response (CR or PR) for each treatment group within each 
PD-L1 level. A Bayesian hierarchical logistic regression model will be used to calculate this 
probability. The details of the statistical model including specifications for prior distributions, 
decision rules to suspend accrual within a PD-L1 subgroup, hypothetical data scenarios, and 
operating characteristics will be provided in the Statistical Analysis Plan.
If accrual is stopped permanently in all PD-L1 subgroups, then the study is considered complete; 
otherwise, accrual will continue until a total of 140 subjects are randomized in Phase 2. The 
DMC may decide to expand any subgroup in which benefit of the combination has been 
demonstrated, to collect additional data within this subgroup.
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11.4.
Efficacy Analyses
Continuous variables will be summarized using number of subjects (n), mean, standard 
deviation, median, minimum, and maximum. Discrete variables will be summarized with n and 
percent. Efficacy endpoints will be analyzed using the ITT population. 
Primary Endpoint
The number and percentage of subjects who have either CR or PR according to RECIST 1.1 
criteria as their best response will be calculated and compared between the 2 treatment groups 
using a chi-square test.
Secondary Endpoints
Time to response and DOR will be summarized for subjects who have a best response of CR or 
PR. No formal statistical test will be performed for DOR. Subgroup analysis will be performed 
for ORR, DCR, PFS, and overall survival to assess the consistency of treatment effects in 
subpopulations by PD-L1 level.
Kaplan-Meier product limit methods will be used to estimate the distribution of time-to-event 
variables. Cox proportional hazards model will be used to obtain the HR along with the 
associated 95% confidence intervals, and log-rank test will be used to test the treatment effect for 
PFS and overall survival. A subject without an event at the time of analysis will be censored. 
Detailed censoring rules will be provided in the statistical analysis plan. DCR will be analyzed 
using the same method as ORR.
11.5.
Blood Culture and Bacterial Shedding Analyses
Descriptive statistics will be used to summarize blood cultures and bacterial shedding as 
appropriate. 
11.6.
Nivolumab Pharmacokinetic Analyses
Nivolumab concentration data will be listed by visit and timepoint for subjects who receive at 
least 1 dose of nivolumab and have available serum concentrations. Descriptive statistics will be 
used to summarize nivolumab serum concentrations. Based on data, population PK analyses may 
be performed and summarized in a separate report.
11.7.
Nivolumab Immunogenicity Analyses
Immunogenicity analyses will be descriptive in nature and will include the number and 
percentage of subjects with anti-nivolumab antibodies at baseline and who develop
anti-nivolumab antibodies. A listing of subjects with anti-nivolumab antibodies will be provided. 
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11.8.
Biomarker Analyses
Descriptive statistics and graphical procedures will be used to summarize each biomarker. The 
associations of PD-L1 level with disease response or time-to-event endpoints will be assessed 
using the appropriate statistical methods (analysis of variance [ANOVA], Poisson regression, 
Fisher’s exact test, or Kaplan-Meier curve and Cox proportional hazards model, depending on 
the endpoint and biomarker). Correlation of baseline expression levels or changes in expression 
levels with response or time-to-event endpoints will identify responsive (or resistant) subgroups. 
Generalized linear models or other appropriate parametric or nonparametric models will be 
explored to identify treatment effect and time trends of biomarkers.
Planned biomarker analyses may be deferred if emerging study data show no likelihood of 
providing useful scientific information. Any biomarker samples received by the contract vendor 
or sponsor after the cutoff date will not be analyzed, and therefore, excluded from the biomarker 
analysis.
Changes in pharmacodynamic biomarkers over time will be summarized by treatment group. 
Associations between biomarker baseline levels and changes from baseline in such biomarkers 
and clinical response may be explored.
11.9.
Patient-reported Outcomes Analyses
PRO subscale scores will be descriptively summarized by treatment group at each timepoint and 
change from baseline will be compared between treatment groups.
11.10. Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse 
events are adverse events with onset during the Treatment Phase or that are a consequence of a 
pre-existing condition that has worsened since baseline. All reported treatment-emergent adverse 
events will be included in the analysis. For each adverse event, the percentage of subjects who 
experience at least 1 occurrence of the given event will be summarized by treatment group. In 
addition, comparisons between treatment groups will be provided if appropriate.
Summaries, listings, 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 pretreatment versus posttreatment cross-tabulations. A 
listing of subjects with any laboratory results outside the reference ranges will be provided.
Parameters with predefined NCI-CTCAE toxicity grades will be summarized. Change from 
baseline to the worst toxicity grade experienced by the subject during the study treatment will be 
provided as shift tables.
Electrocardiogram (ECG)
Electrocardiograms are included at screening only. Any other ECGs will be performed as 
clinically indicated and abnormalities will be reported as adverse events.
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, and blood pressure 
(systolic and diastolic) values and changes from baseline will be summarized at each scheduled 
timepoint.
Physical Examination
Physical examination findings will be listed as appropriate.
11.11. Data Monitoring Committee
For Phase 2, a Janssen DMC will be established to review the ORR and safety data on a regular 
basis. The DMC will consist of a minimum of 3 members with at least 1 clinician and a 
statistician, one of whom will chair the committee.
The DMC will review the ORR data after approximately 40, 60, 80, 100, and 120 subjects have 
been randomized, and will formulate recommended decisions/actions in accordance with the 
statistical decision rule of the ORR analysis. The DMC also will review safety data every 
3 months. The DMC may request additional ad-hoc reviews based on the accumulating data. It is 
anticipated the first ORR analysis will occur approximately 24 weeks after the first subject in 
Phase 2 has been randomized. Enrollment of subjects may be stopped during the DMC reviews.
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12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or noninvestigational) 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 noninvestigational) product, whether or not related 
to that medicinal (investigational or noninvestigational) 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*
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*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
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 JNJ-757, the expectedness of an adverse 
event will be determined by whether or not it is listed in the Investigator's Brochure. For 
nivolumab, the expectedness of an adverse event will be determined by whether or not it is listed 
in the locally approved labeling.
Adverse Event Associated With the Use of a Drug
An adverse event is considered associated with the use of a 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 NCI-CTCAE (Version 4.03) will be used to grade the severity of adverse events.
Any adverse event not listed in the NCI-CTCAE will be graded according to the investigator’s 
clinical judgment 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): Urgent intervention indicated.

Grade 5 (Death): Death.
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 agent that may require expedited reporting or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study agent

Suspected abuse/misuse of a sponsor study agent

Accidental or occupational exposure to a sponsor study agent

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study agent, eg, name confusion)

Exposure to a sponsor study agent from breastfeeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or nonserious, will be 
reported from the time a signed and dated ICF is obtained until 100 days after the last dose of 
study agent for subjects who enter the Screening Phase. Any subject with an ongoing adverse 
event will be followed beyond 100 days after the last dose of study agent, subjects will be 
followed for ongoing treatment-related adverse events and associated medications until all 
adverse events are resolved, return to baseline, are deemed irreversible, or the subject starts 
subsequent anticancer therapy. Serious adverse events must be reported using the Serious 
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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.
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 agent, 
must be recorded using medical terminology in the source document and the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the eCRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all 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, the sponsor will submit a safety report in narrative format to the investigators 
(and the head of the investigational institute where required).
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.
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind
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12.4.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form and Safety Report Form of the CRF, which must be completed and 
reviewed by a physician from the study site, and transmitted to the sponsor within 24 hours. The 
initial and follow-up reports of a serious adverse event should be transmitted electronically or by 
facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

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 agent or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

A standard procedure for protocol therapy administration will not be reported as a serious 
adverse event. Hospitalization for a complication of therapy administration will be reported 
as a serious adverse event.

A procedure for protocol/disease-related investigations (eg, surgery, scans, sampling for 
laboratory tests, or biomarker blood sampling). Hospitalization or prolonged hospitalization 
for a complication of such procedures remains a reportable serious adverse event.

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered serious adverse events. Any adverse event that results in a prolongation of 
the originally planned hospitalization is to be reported as a new serious adverse event.
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 
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efficacy will be reported if they fulfill the serious adverse event definition (refer to
Section 12.1.1, Adverse Event Definitions and Classifications).
12.4.1.
Adverse Events of Special Interest
Adverse events indicative of inflammatory cytokine release are expected after infusion of 
JNJ-757 and will be followed as part of standard safety monitoring activities by the sponsor, and 
managed in accordance with the guidelines in Section 8.3. Any inflammatory cytokine-related 
events considered to be serious should be reported to the sponsor’s medical monitor within 
24 hours of awareness according to the procedure described above for serious adverse events and 
will require enhanced data collection. 
Persistent bacteremia will be followed as part of standard safety monitoring activities by the 
sponsor and will include both serial blood cultures after dosing in Cycle 1, and subsequent 
predose surveillance blood cultures during the treatment phase, at the End-of-Treatment visit,
and during the follow-up phase, for 1 year after the completion of dosing with JNJ-757. Positive 
surveillance cultures will be reported to the sponsor’s medical monitor within 24 hours of 
awareness irrespective of seriousness (ie, serious and nonserious adverse events) following the 
procedure described above for serious adverse events, and will require enhanced data collection.
12.4.2.
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 beginning at the time a signed and dated ICF is 
obtained until 5 months (female subjects) or 7 months (male subjects) after the last dose of study 
agent. 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 
discontinue further study treatment. Because the effect of the study agent 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.
12.5.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
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13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.4, Serious Adverse Events). A sample of the suspected product should be maintained 
for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY AGENT INFORMATION
14.1.
Physical Description of Study Agent(s)
JNJ-757 
The JNJ-757 supplied for this study is formulated as: liquid in vial, translucent white suspension, 
formulated in phosphate-buffered saline + 9% glycerol, at a concentration/strength by viable cell 
count (colony count assay) of 1.0×109 CFU/mL. It will be manufactured and provided under the 
responsibility of the sponsor. Refer to the Investigator's Brochure for a list of excipients.
Nivolumab
Nivolumab is a sterile, preservative-free, nonpyrogenic, clear to opalescent, colorless to pale-
yellow liquid that may contain light (few) particles. Nivolumab injection for IV infusion is 
supplied in single-dose vials. Each mL of solution contains nivolumab 10 mg, mannitol (30 mg), 
pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), sodium chloride (2.92 mg), sodium citrate 
dihydrate (5.88 mg), and Water for Injection, United States Pharmacopeia (USP). The formulation 
may contain hydrochloric acid or sodium hydroxide to adjust the pH to 6.
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14.2.
Packaging
JNJ-757 
JNJ-757 drug product will be shipped and stored frozen at –60ºC or colder. It consists of 
attenuated Lm suspended in Dulbecco’s phosphate-buffered saline and 9% volume concentration 
glycerol. Primary packaging consists of single-use 2 mL glass vial(s) with gray butyl or 
bromobutyl stoppers and aluminum crimp seals with flip-off caps. The study agent is supplied in 
glass vials containing JNJ-757 at a concentration/strength by viable cell count (colony count 
assay) of 1.0×109 CFU/mL. It will be supplied to the site/pharmacy as bulk supply.
Nivolumab
Nivolumab will be shipped and stored under refrigeration at 2°C to 8°C (36°F to 46°F). Protect 
nivolumab from light by storing in the original package until time of use. Do not freeze or shake. 
Primary packaging consists of single-use 100 mg/10 mL single-dose vials.
14.3.
Labeling
JNJ-757 
Study agent labels will contain information to meet the applicable regulatory requirements. Each 
vial will contain a study-specific label with a unique identification number.
Nivolumab
Nivolumab labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
Refer to the pharmacy manual/study site investigational product and procedures manual for 
additional guidance on study agent preparation, handling, and storage, as well as handling of 
reconstituted and diluted solutions.
JNJ-757 is a live-attenuated double-deleted version of Lm that exhibits greatly reduced virulence 
by deletion of 2 genes encoding actA and inlB. JNJ-757 has been classified as a Risk Group 1 
agent. Individuals who prepare JNJ-757 for injection must take standard precautions (eg, use of 
gloves, laboratory coat, face protection, needle stick or sharps precautions) to avoid 
contamination or direct contact with the study agent (Siegel 2007).36 During the storage, 
preparation, and administration of individual study doses and for the disposal of materials used 
in the preparation and administration of this product, the study will adhere to applicable 
institutional infection-control procedures for Risk Group 1 agents (Wilson 2009).39
Environmental Precautions
Although shedding of LADD-based products has not been observed in previous studies, 
precautions should be exercised to avoid intimate contact (ie, exchange of bodily fluids) between 
subjects and individuals who are at high risk of complications of listeriosis (eg, newborn infants, 
pregnant women, immunocompromised individuals) from first infusion of JNJ-757 until 
completion of study-prescribed antibiotic regimen.
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14.5.
Drug Accountability
The investigator is responsible for ensuring that all study agent received at the site is inventoried 
and accounted for throughout the study. The study agent administered to the subject must be 
documented on the drug accountability form. All study agent will be stored and disposed of 
according to the sponsor's instructions. Study-site personnel must not combine contents of the 
study agent containers.
Study agent 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 agent must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. The return to the sponsor of unused study 
agent will be documented on the drug return form. When the study site is an authorized 
destruction unit and study agent 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 agent 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 agent will be supplied only 
to subjects participating in the study. Returned study agent must not be dispensed again, even to 
the same subject. Study agent may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study agent 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:

Recruitment tools

Study binder with all other necessary documentation (eg, protocol, Investigator’s Brochure 
for JNJ-757, locally approved label for nivolumab, sample ICF, Clinical Trial Agreement, 
Contact Information sheet[s])

Investigational Product Preparation Instructions (IPPI)

Pharmacy manual/SIPPM

Laboratory manual, laboratory operations manual, requisition forms, sampling supplies, and 
equipment, if necessary

Link to NCI-CTCAE Version 4.03: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-
06-14_QuickReference_5x7.pdf 

RECIST guidelines Version 1.1

IWRS manual and worksheets

Electronic data capture (eDC) manual
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
Materials for PRO collection
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
In this study, nivolumab will be administered to all subjects at the dose and schedule approved 
for use in patients with NSCLC. For those subjects randomized to the combination arm, JNJ-757 
will be administered after completion of each Day 1 nivolumab infusion, to ensure that the 
anticipated adverse events associated with JNJ-757 activation of the innate immune response will 
not interfere with nivolumab administration.
Thorough scientific evaluation of any promising treatment before market authorization is an 
ethical requirement. A discussion of the safety and efficacy of JNJ-757 is provided in 
Section 1.3. This is the first efficacy evaluation of the combination of JNJ-757 with nivolumab; 
hence, the benefits and risks of the combination are unknown. A DMC will review evolving 
safety data from this study and the Phase 1 study of JNJ-757. Other LADD Lm-based 
immunotherapeutics such as CRS-207, ADU-623, and JNJ-809 are being studied in combination
with immunotherapies including PD-L1 inhibitors. A discussion of the safety and efficacy of 
CRS-207 is provided in Section 1.2.1.
As with all clinical and pharmacology studies, there are risks associated with venipuncture and 
multiple blood sample collection. The blood sample collection scheme was designed to collect 
the minimum number of blood samples that accurately and completely describe the 
pharmacology of the study agent. This minimizes the number of venipunctures and the total 
volume of blood collected from each subject during the study. The volume of blood to be drawn 
is considered to be customary and acceptable for subjects participating in a cancer clinical study 
and is deemed reasonable for the time frame of the study, based upon the standard of the 
American Red Cross (2014).3 Blood cultures and shedding samples will also be collected in 
Group A, in accordance with established regulatory guidance.
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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)

JNJ-757 Investigator's Brochure (or equivalent information) and amendments/addenda

Locally approved label for nivolumab

Sponsor-approved subject recruiting materials

Sponsor-approved wallet study card

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and subject compensation programs, and the sponsor has received a copy of 
this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
Approval for the collection of optional samples for research and for the corresponding ICF must 
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this 
optional research component.
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During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB
(at least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study agent

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
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 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.
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Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not
affect the care the subject will receive for the treatment of his or her disease. Subjects will be told 
that alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow-up if needed and that their records 
may be accessed by health authorities and authorized sponsor personnel without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the ICF the subject is authorizing such access, which includes permission to obtain 
information about his or her survival status. It also denotes that the subject agrees to allow his or 
her study physician to recontact the subject for the purpose of obtaining consent for additional 
safety evaluations, and subsequent disease-related treatments, if needed.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the subject.
Subjects will be asked for consent to provide optional samples for research (where local 
regulations permit). After informed consent for the study is appropriately obtained, the subject or 
his or her legally acceptable representative will be asked to sign and personally date a separate 
ICF indicating agreement to participate in the optional research component. Refusal to 
participate in the optional research will not result in ineligibility for the study. A copy of this 
signed ICF will be given to the subject.
If the subject is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) and 
should personally date and sign the ICF after the oral consent of the subject is obtained.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
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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 pharmacodynamic and 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 JNJ-757 and 
nivolumab, to understand adenocarcinoma of the lung, to understand differential drug 
responders, and to develop tests/assays related to JNJ-757 and nivolumab. The research may 
begin at any time during the study or the poststudy storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 16.2.5, Long-Term Retention of Samples for Additional 
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.
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17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for nonacceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IEC/IRB (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
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 agent to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
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obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth. In cases where the subject is not 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.
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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: 
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 agent administration information; and date of study 
completion and reason for early discontinuation of study agent 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

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 
the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If the electronic source system is utilized, references made to 
the eCRF in the protocol include the electronic source system but information collected through 
the electronic source system may not be limited to that found in the eCRF. Data in this system 
may be considered source documentation.
17.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format.
All eCRF entries, corrections, and alterations must be made by the investigator or authorized 
study-site personnel. The investigator must verify that all data entries in the eCRF are accurate 
and correct. The study data will be transcribed by study-site personnel from the source 
documents onto an eCRF, if applicable. Study-specific data will be transmitted in a secure 
manner to the sponsor.
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Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documents. Data must be entered into 
the eCRF in English. The eCRF must be completed as soon as possible after a subject visit and 
the forms should be available for review at the next scheduled monitoring visit.
If necessary, queries will be generated in the eDC tool. If corrections to an eCRF are needed 
after the initial entry into the eCRF, this can be done in either of the following ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
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, periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The importance of timely disease assessments will be stressed. The sponsor 
will review the eCRF for accuracy and completeness during on-site monitoring visits and after 
transmission to the sponsor; any discrepancies will be resolved with the investigator or designee, 
as appropriate. After upload of the data into the study database they will be verified for accuracy 
and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
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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 to monitor this study.
The contract research organization (CRO) designated by 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 eCRF 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 eCRF are known to the sponsor and study-site personnel
and are accessible for verification by the sponsor study-site contact. If electronic records are 
maintained at the study site, the method of verification must be discussed with the study-site 
personnel. 
Direct access to source 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.
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17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study is considered completed with the last scheduled study assessment shown in the Time 
and Events Schedule (Table 1) for the last subject participating in the study. The final data from 
the study site will be sent to the sponsor (or designee) after completion of the final subject 
assessment at that study site, in the time frame specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. 
A study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study agent 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.
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17.11. Use of Information and Publication
All information, including but not limited to information regarding JNJ-757 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 JNJ-757, 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 
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. 
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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 and the results of clinical studies as required 
by law.
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20. Le DT, Brockstedt DG, Nir-Paz R, et al. A live-attenuated Listeria vaccine (ANZ-100) and a live-
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39. Wilson DE, Chosewood LC. Biosafety in microbiological and biomedical laboratories. US 
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Attachment 1:
New York Heart Association Criteria
The following table presents the New York Heart Association classification of cardiac disease:
Class Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of cardiovascular 
disease.
II
Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of minimal 
cardiovascular disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or angina pain.
Objective evidence of moderately severe 
cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or 
the anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased.
Objective evidence of severe 
cardiovascular disease.
Classification of Functional Capacity and Objective Assessment. Available at 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-
Failure_UCM_306328_Article.jsp. Accessed 22 January 2015.
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Attachment 2:
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
nontarget 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 
non-target 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 non-
target 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, non-target and new lesions for 
subjects with measurable disease; and another table integrates non-target and 
new lesions for subjects without measurable disease.
Confirmation of Response
In non-randomized 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.
Source: Eisenhauer 2009 10
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Attachment 3:
Eastern Cooperative Oncology Group Performance Status Score
Grade 
Eastern Cooperative Oncology Group Performance Status
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Source: Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair (Oken, 1982).27
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Attachment 4:
Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or nonserious) 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:
Disease-Related
Nivolumab Background Therapy
Local respiratory events
Alanine aminotransferase increased
  Bronchitis
Arthralgia
  Chest pain
Aspartate aminotransferase increased
  Cough
Asthenia
  Dyspneoa
Blood alkaline phosphatase increased
  Hemoptysis
Blood creatinine increased
  Plural effusion
Blood thyroid stimulating hormone increased
  Pneumonia
Constipation
  Wheezing
Cough
CNS metastasis events 
Decreased appetite
  Altered mental status
Diabetes mellitus
  Ataxia
Diarrhoea
  Bone pain
Dry mouth
  Headache
Hyperglycaemia
  Meningismus
Hyponatremia
  Seizures
Immune mediated colitis
  Spinal cord depression
Immune mediated encephalitis
Paraneoplastic syndromes
Immune mediated endocrinopathy
  Cushing syndrome
Immune mediated hepatitis
  Hypercalcaemia
Immune mediated nephritis
  Syndrome of inappropriate ADH production
Immune mediated pneumonitis
Immune mediated rash
Immune mediated renal dysfunction
Infusion reaction
Myalgia
Nausea/vomiting
Pruritus
Rash
ADH=antidiuretic hormone.
Reporting of Anticipated Events
All adverse events will be recorded in the eCRF 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 12.4, 
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 agent, the sponsor will report these events in an expedited 
manner.
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Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of prespecified 
anticipated events at an aggregate level. The ARC is a safety committee within the sponsor’s organization 
that is independent of the sponsor’s study team. The ARC will meet to aid in the recommendation to the 
sponsor’s study team as to whether there is a reasonable possibility that an anticipated event is related to 
the study agent.
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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INVESTIGATOR AGREEMENT
NCT03371381