Clinical trial NCT03597009
Conditions: Malignant Pleural Effusion Stage IV Metastatic Cancer Lung Cancer
Keywords: talimogene laherparepvec Nivolumab PleurX
Sponsor: UNC Lineberger Comprehensive Cancer Center
Start date: 2019-03-06; Completion date: 2020-02-12
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase Ib/II clinical trial to evaluate the feasibility of administering talimogene laherparepvec into the intrapleural space of subjects with malignant pleural effusion through a pleurX catheter.

Detailed description:
This is a phase 1b/II clinical trial that includes a safety run-in cohort to investigate the novel approach of administering intrapleural talimogene laherparepvec via a pleurX catheter in patients with known malignant pleural effusion (MPE).

In Phase Ib of this study, the safety of infusing talimogene laherparepvec directly into the pleural cavity of subjects diagnosed with MPE, through pleurX catheter, will be tested.

In Phase II of this study, after establishing the safety of the above mentioned approach, 24 subjects will enrolled and treated with intrapleural talimogene laherparepvec and IV nivolumab.

Arms: arm 1: Talimogene laherparepvec (TVEC) administered into the intrapleural space of subjects with malignant pleural effusion (MPE) via a pleurX catheter with or without nivolumab
Interventions: intervention 1: Talimogene laherparepvec (TVEC) intervention 2: Nivolumab
Intervention descriptions: intervention 1: Talimogene laherparepvec (TVEC) (4ml of 108 pfu/ml) for up to 9 cycles, with or without nivolumab intervention 2: Nivolumab (240 mg IV) will be co-administered with talimogene laherparepvec (TVEC) (4ml of 108 pfu/ml) for up to 9 cycles in the Dose Level 2 cohort

Protocol documents:
Prot_SAP_000.pdf: 
LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
July 22, 2019 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
Protocol Amendment #4 Version 1.0 
 
 
 
 
PROTOCOL AMENDMENT #4 
 
 
LCCC 1626: Phase Ib/II Study of IV Nivolumab and Intrapleural Talimogene 
Laherparepvec for Patients with Malignant Pleural Effusion 
 
AMENDMENT INCORPORATES (check all that apply): 
 X   Editorial, administrative changes 
       Scientific changes (IRB approval) 
X   Therapy changes (IRB approval) 
X    Eligibility Changes (IRB approval) 
 
Amendment Rationale: 
This amendment clarifies the requirement that a delay in administration of systemic therapy 
must be considered clinically acceptable in order for subjects to enroll in the study. 
In addition, language was added to clarify that subjects may proceed to systemic treatment 
in cohort one week following completion of study therapy. 
 
Editorial Change: 
1. Minor edits have been made in the document. Placement of hematology 
footnote number in Time and Events Table corrected. 
 
Therapy Change: 
2. The following language has been added to Section 4.1.1, “Cohort Enrollment 
– Safety Run-In:”  “One week following completion of study therapy, subjects 
may proceed to systemic therapy per their decision with their physician.” 
 
Eligibility Change: 
1. The inclusion criterion for Dose Level 1 previously stated:  “non-pleural 
disease is not considered a significant risk to the patient OR refractory to 
standard therapies.”  That criterion has been modified to state:  “Either no 
systemic therapy available per standard of care, or delay in administration of 
systemic therapy considered clinically acceptable.”  See Section 3.1.5. 
 
THE ATTACHED VERSION DATED July 22, 2019 INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
July 22, 2019 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
Protocol Amendment #4 Version 1.0 
 
 
 
 
PROTOCOL AMENDMENT #3 
 
 
LCCC 1626: Phase Ib/II Study of IV Nivolumab and Intrapleural Talimogene 
Laherparepvec for Patients with Malignant Pleural Effusion 
 
AMENDMENT INCORPORATES (check all that apply): 
X   Editorial, administrative changes 
      Scientific changes (IRB approval) 
      Therapy changes (IRB approval) 
X   Eligibility Changes (IRB approval) 
 
Amendment Rationale: As the result of recent FDA approvals making PD-1 frontline 
therapy in lung and other cancers, this protocol has been amended to remove the 
requirement for the enrollment of PD-1 naïve subjects. 
 
 
Editorial, Administrative Changes: 
• Updated funding source name, as CareFusion was purchased by Becton 
Dickinson and Company, and they are the new suppliers of the pleurX catheter 
• Editorial and administrative changes throughout the protocol 
• Updated Section 7.3.3.8 FDA Reporting to remove extraneous information 
included in the CRFs and LCCC SOPs 
• Removed reporting requirements for the NIH RAC as the NIH RAC is currently no 
longer regulating gene therapy studies outside of FDA and IBC reviews. 
• Updated staff titles in Section 7.4 Data and Safety Monitoring Plan 
 
 
Eligibility Changes: 
• Removed the required for subjects to have received prior therapy with an anti-PD-
1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T lymphocyte associated 
antigen 4 (CTLA-4) antibody prior to enrollment. 
 
THE ATTACHED VERSION DATED February 5, 2019 INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
July 22, 2019 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
Protocol Amendment #4 Version 1.0 
 
 
 
 
PROTOCOL AMENDMENT #2 
 
 
LCCC 1626: Phase Ib/II Study of IV Nivolumab and Intrapleural Talimogene 
Laherparepvec for Patients with Malignant Pleural Effusion 
 
AMENDMENT INCORPORATES (check all that apply): 
X   Editorial, administrative changes 
X   Scientific changes (IRB approval) 
X   Therapy changes (IRB approval) 
__  Eligibility Changes (IRB approval) 
 
Amendment Summary 
1. Section 1.8.2 Updating Aim, adding whole exome sequencing to RNA sequencing 
as part of correlative studies. DNA and RNA samples will be extracted from 
pleural fluid samples.   
2. Sections 2.1.2 and 2.4.1.2 corrected to state, Resolution (<50cc drainage over 
three consecutive every other day drainages) of pleural fluid accumulation 
accompanied by patient-defined improvement in symptoms (dyspnea, cough 
and/or chest pain).  
3. Section 2.4.0: viral shedding studies were removed 
4. Section 4.1.2: editorial changes explaining standard and study drug drainage.  
5. Section 6.1 Time and Event table updated to include Buccal Swab collection at 
pre-study and C1Day1 if required.  
6. Section 6.1, Time and Event table updated with clarification on Chest X-ray and 
their occurrence as needed and/or after three consecutive drainages of pleural 
fluids accompanied by patient-defined improvement in symptoms.  
7. Footnote for Table 2, #14 updated to include information about collection of 
pleural fluids at 4 time points, and dividing samples into two portions.  Portion 
one will be used for correlative studies, and the second portion will be distributed 
to the CTU lab for long-term storage for future studies. 
8. Sections 6.3, 6.4.2, 6.4.3, 6.4.4, 6.4.5, 6.4.6, and 6.5.1 updated to include 
clarification on when chest x-rays will be done 
9. Section 8.3, data analysis updated in accordance to changes in Phase II aim. 
10. Removed Bristol-Myers Squibb from list of sponsors 
 
THE ATTACHED VERSION DATED June 18, 2018 INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
July 22, 2019 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
Protocol Amendment #4 Version 1.0 
 
 
 
PROTOCOL AMENDMENT #1 
 
 
LCCC 1626: Phase Ib/II Study of IV Nivolumab and Intrapleural Talimogene 
Laherparepvec for Patients with Malignant Pleural Effusion 
 
AMENDMENT INCORPORATES (check all that apply): 
X  Editorial, administrative changes 
___ Scientific changes (IRB approval) 
___ Therapy changes (IRB approval) 
___ Eligibility Changes (IRB approval) 
 
Amendment Summary 
The protocol is revised to clarify that pleural, blood and urine samples collected prior to 
talimogene laherparepvec administration and 1 hour, 4 hours and 6 hours after 
talimogene laherparepvec administration at Cycle 1 Day 1, prior to talimogene 
laherparepvec administration at Cycle 1 Day 8, Cycle 2 Day 1, Cycle 2 Day 8, Cycle 3 
Day 1, Cycle 4 Day 1, and at the treatment discontinuation visit to assess viral shedding 
will be frozen and stored at -80°C for possible assessment of viral shedding for up to two 
years after study completion. It was also clarified that at Cycle 1 Day 1, Cycle 2 Day 1, 
Cycle 4 Day 1, and at the treatment discontinuation visit pleural fluid will be separated by 
the LCCC Immune Monitoring and Genomics Facility (IMGF) into two portions: one 
portion will be used for correlative studies, and the second portion will be stored for 
possible assessment of viral shedding. If insufficient amount of pleural fluid is collected, 
priority will be given to a sample used for correlative studies. The above mentioned 
clarifications were made in Sections 2.3.5, 6.4.1, 6.4.2, 6.4.3, 6.4.4, 6.4.5 and 6.5.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED April 26, 2018 INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
July 22, 2019 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
Protocol Amendment #4 Version 1.0 
 
 
LCCC 1626: Phase Ib/II Study of IV Nivolumab and Intrapleural Talimogene 
Laherparepvec for Patients with Malignant Pleural Effusion 
 
Principal Investigator 
Jared Weiss, MD 
Division of Hematology/Oncology 
3115 Physicians Office Bldg 
170 Manning Dr, CB# 7305 
Chapel Hill, NC 27599-7305 
919-966-3856 (PHONE)  919-966-6735 (FAX) 
Email: Jared_Weiss@med.unc.edu 
 
 
Biostatistician  
Allison Deal, MS 
Allison_Deal@med.unc.edu 
Phone: 919-966-1387    
Fax: 919-966-4244 
 
Clinical Protocol Office 
Lineberger Comprehensive Cancer Center 
The University of North Carolina at Chapel Hill 
450 West Drive, 3rd Floor, CB# 7295 
Chapel Hill, NC 27599-7295 
 
 
Sponsor:  Lineberger Comprehensive Cancer Center 
 
Funding Source: AMGEN, Becton Dickinson & Company 
 
Version: Amendment #4 Version 1.0 
Version Date: July 22, 2019 
 
IND# 17835


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
July 22, 2019 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
Protocol Amendment #4 Version 1.0 
 
 
LCCC 1626: Phase Ib/II Study of IV Nivolumab and Intrapleural Talimogene 
Laherparepvec for patients with malignant pleural effusion 
 
Principal Investigator 
Jared Weiss, MD 
Division of Hematology/Oncology 
3115 Physicians Office Bldg 
170 Manning Dr, CB# 7305 
Chapel Hill, NC 27599-7305 
919-966-3856 (PHONE)    919-966-6735 (FAX) 
Email: Jared_Weiss@med.unc.edu 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal regulations 
and ICH guidelines. 
 
Principal Investigator (PI) Name:_______________________ 
 
PI Signature: ___________________ 
 
Date:____________________ 
 
Version: Amendment #4 Version 1.0 
Version date: July 22, 2019 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
July 22, 2019 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
Protocol Amendment #4 Version 1.0 
 
 
LIST OF ABBREVIATIONS  
ACD 
Acid-citrate-dextrose 
ACTH 
Adrenocorticotropic hormone 
ADCC 
Antibody dependent cellular cytotoxicity 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
β-HCG 
Beta-human chorionic gonadotropin 
BMS 
Bristol-Myers Squibb 
BUN 
Blood urea nitrogen 
C 
Celsius 
CBC 
Complete blood count 
CBR 
Clinical benefit rate 
cc 
Cubic centimeter 
CCR7-CD45-RA+ or RA- 
Chemokine receptor 7-CD45-rheumatoid arthritis positive or 
negative 
CD 
Cluster of designation 
C1D1 
Cycle 1, day 1 
CPO 
Clinical Protocol Office 
CPR 
Cardio-pulmonary resuscitation 
CR 
Complete response 
CRP 
C-reactive protein 
CT 
Computer tomography 
CTLA-4 
Cytotoxic T-lymphocyte-associated protein-4 
CYP 
Cytochrome P450 
CV% 
Coefficient of variation percent  
dL 
Deciliter 
DILI 
Drug-induce liver injury 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
DSMC 
Data safety monitoring committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
F 
Fahrenheit 
FSH 
Follicle stimulating hormone 
5-FU 
5-fluorouracil 
GCP 
Good clinical practice 
GM-CSF 
Granulocyte-macrophage colony stimulating factor 
HBs-Ag 
Hepatitis B surface antigen 
HBc 
Hepatitis B core 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HLA-DR 
Huma leucocyte antigen D related 
HNSCC 
Head and Neck Squamous Cell Carcinoma 
HSV-1  
Herpes simplex virus 1 
huGM-CSF 
Human granulocyte-macrophage colony stimulating factor f 
IC50 
Concentration associated with 50%  inhibition of maximal effect  
ICP47 and ICP34.5 
Infected cell protein 47 or 34.5 
IDS 
Investigational drug service 
IFNγ 
Interferon-gamma 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
July 22, 2019 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
Protocol Amendment #4 Version 1.0 
 
 
Ig 
Immunoglobulin 
IHC 
Immunohistochemistry 
IL-6 
Interleukin-6 
IMIDs 
Immunomodulators 
IND 
Investigational new drug 
INR 
International normalized ratio 
I-O 
Immuno-oncology 
IP 
Intraperitoneal 
IRB 
Institutional review board 
irRC 
Immune-related response criteria 
ITIM 
Immunoreceptor tyrosine-based inhibition motif 
ITSM 
Immunoreceptor tyrosine-based switch motif 
IV 
Intravenous 
Kg 
Kilograms 
LCCC 
Lineberger Comprehensive Cancer Center 
LD50 
Lethal dose 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
mAb 
Monoclonal antibody 
MBS 
Modified Borg scale (of perceived dyspnea) 
MEL 
Melanoma 
mg 
Milligram 
Min 
Minute 
µL 
Microliter 
MPE 
Malignant Pleural Effusion 
MRI 
Magnetic resonance Imaging 
mRNA-seq 
Messenger ribonucleic acid-sequence 
MSI-H 
Microsatellite instability-high  
MTD 
Maximum Tolerated Dose 
NCCN 
North Carolina Cancer Network 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for 
Adverse Events 
NIH 
National Institutes of Health 
nM 
Nanomolar 
NS 
Normal saline 
NSCLC 
Non-small cell lung cancer 
OAT 
Organic anion transporter 
OATP 
Organic anion transporter polypeptide 
OHRE 
Office of Human Research Ethics 
ORR 
Overall response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PD 
Progressive disease 
PD-1 
Programmed cell death receptor-1 
PD-L1 or PD-L2 
Programmed cell death receptor ligand-1or -2 
PET 
Positron Emission Tomography 
PFS 
Progression free survival 
PFU 
Plaque-forming unit 
Pgp 
P-glycoprotein 
PHI 
Personal health information 
PI 
Principal investigator 
PK 
Pharmacokinetic(s) 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
July 22, 2019 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
Protocol Amendment #4 Version 1.0 
 
 
PO 
Per os (by mouth) 
PR 
Partial response 
PRC 
Protocol Review Committee 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QD 
Quaque die (once daily) 
QOD 
Quaque altera die (every other day) 
Q3 months 
Quaque (once every 3 months) 
Q2W or Q3W 
Quaque (once every 2 weeks) (once every 3 weeks) 
RBC 
Red blood cell 
RECIST 
Response evaluation criteria in solid tumors 
RNA 
Ribonucleic acid 
RR 
Response rate 
SAE 
Serious adverse event 
s.c. 
subcutaneous 
SD 
Stable disease 
SHP-1 or SHP-2 
Src homology region 2 domain-containing phosphatase-1 or -2 
SLM 
Study laboratory manual 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBNK 
T or B-cell natural killer 
TCRβ 
T cell receptor beta 
TNF 
Tumor necrosis factor 
TNFα 
Tumor necrosis factor alpha 
TPC 
Tunneled pleural catheter 
TPF 
Tissue Procurement Facility 
TVEC 
Talimogene laherparepvec 
Txt 
Treatment 
ULN 
Upper limit of normal 
UNC 
University of North Carolina 
USP 
United States Pharmacopeia 
VEGF 
Vascular endothelial growth factor 
V-type 
Variable-type 
 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
i 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ........................................................................................... vii 
1.0 BACKGROUND AND RATIONALE ..........................................................................4 
1.1 
Study Synopsis ......................................................................................................4 
1.2 
Malignant Pleural Effusions ..................................................................................4 
1.3 
PleurX Pleural Catheter System ............................................................................6 
1.4 
Nivolumab (BMS-936558) ...................................................................................7 
1.5 
Clinical Efficacy of Nivolumab in Humans ..........................................................9 
1.6 
Talimogene Laherparepvec .................................................................................10 
1.7 
Rationale for Combination of PD-1 Inhibitors with Talimogene Laherparepvec 
for MPE ..........................................................................................................................12 
1.8 
Correlative Studies ..............................................................................................13 
2.0 STUDY OBJECTIVES ................................................................................................14 
2.1 
Primary Objective ...............................................................................................14 
2.2 
Secondary Objectives ..........................................................................................14 
2.3 
Exploratory Objectives ........................................................................................14 
2.4 
Study Endpoints ..................................................................................................15 
3.0 PATIENT ELIGIBILITY ............................................................................................15 
3.1 
Inclusion Criteria .................................................................................................15 
3.2 
Exclusion Criteria ................................................................................................17 
4.0 TREATMENT PLAN ..................................................................................................20 
4.1 
Schema for LCCC 1626 ......................................................................................20 
4.2 
Study Treatments.................................................................................................23 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
ii 
4.3 
Dose Modifications/Delays .................................................................................25 
4.4 
Concomitant Medications/Treatments ................................................................31 
4.5 
Duration of Therapy ............................................................................................32 
4.6 
Duration of Follow Up ........................................................................................32 
4.7 
Removal of Patients from Protocol Therapy .......................................................32 
4.8 
Study Withdrawal ................................................................................................33 
5.0 DRUG INFORMATION .............................................................................................33 
5.1 
Talimogene Laherparepvec (ImlygicTM) .............................................................33 
5.2 
Additional important Nivolumab (Opdivo®) .....................................................36 
6.0 Evaluations and Assessments ......................................................................................39 
6.1 
Safety Run-in Cohort 1 (Talimogene Laherparepvec Only) ...............................39 
6.2 
Safety Run-in Cohort 2 and expansion (Combination) .......................................42 
6.3 
Pre-Study Assessments for Safety Run in Cohorts and Phase II (Tables 6.1 and 
6.2) 
 .............................................................................................................................45 
6.4 
Study Treatment Assessments (+/- 2 days) .........................................................46 
6.5 
Post-Treatment/Follow-up Assessments .............................................................50 
6.6 
Correlative Studies Procedures ...........................................................................51 
6.7 
Assessment of Safety ..........................................................................................52 
6.8 
Evaluation of Response by irRECIST [62] per Bohnsack et al. .........................52 
7.0 ADVERSE EVENTS ...................................................................................................54 
7.1 
Definitions ...........................................................................................................54 
7.2 
Documentation of non-serious AEs or SARs ......................................................56 
7.3 
SAEs or Serious SARs ........................................................................................56 
7.4 
Data and Safety Monitoring Plan ........................................................................61 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
iii 
8.0 STATISTICAL CONSIDERATIONS.........................................................................62 
8.1 
Study Design/Study Endpoints ...........................................................................62 
8.2 
Sample Size and Accrual.....................................................................................62 
8.3 
Data Analysis Plans .............................................................................................63 
9.0 STUDY MANAGEMENT ..........................................................................................63 
9.1 
Institutional Review Board (IRB) Approval and Consent ..................................63 
9.2 
Required Documentation.....................................................................................64 
9.3 
Registration Procedures.......................................................................................64 
9.4 
Data Management and Monitoring/Auditing ......................................................64 
9.5 
Adherence to the Protocol ...................................................................................64 
9.6 
Amendments to the Protocol ...............................................................................66 
9.7 
Record Retention .................................................................................................66 
9.8 
Obligations of Investigators ................................................................................66 
10 REFERENCES ............................................................................................................67 
11.0 APPENDICES ...........................................................................................................71 
11.1 
Appendix A: ECOG Performance Status ............................................................71 
11.2 
Appendix B: Cockcroft-Gault Formula...............................................................72 
11.3 
Appendix C: Treatment Algorithms for Nivolumab Therapy .............................73 
11.4 
Appendix D: Information Sheet for Trial Participants ........................................81 
11.5 
Appendix E: Patient Catheter Drainage Diary ....................................................86 
11.6 
Appendix F:  Borg Scale .....................................................................................88 
11.7 
Appendix G: NYHA – Functional Classification System ...................................89 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
4 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
We will conduct a Phase Ib/II trial that includes a safety run-in period using 3 +3 
dose escalation rules to evaluate the feasibility of administering talimogene 
laherparepvec into the intrapleural space of subjects with malignant pleural effusion 
(MPE) via a pleurX catheter. Initially, 3 patients will be treated with intrapleural 
talimogene laherparepvec in the first dose cohort. Since this study explores a new 
route of administration for talimogene lahereparevec, enrollment in the safety run-
in cohorts will be staggered requiring each patient to complete the 7-week safety 
assessment period (i.e., 3 cycles of TVEC including the seroconversion cycle) for 
evaluation of dose-limiting toxicity (DLT) before the next subject is enrolled.  If 
dose limiting toxicities (DLTs) occur in ≤1 patient treated with talimogene 
laherparepvec alone, we will treat 3 patients in the second cohort with intrapleural 
talimogene laherparepvec plus intravenous (IV) nivolumab (240mg). We anticipate 
reaching the Phase II (combination) dose without significant DLTs or drug 
toxicities in either cohort, and plan to treat a total of 24 patients with MPE’s with 
intrapleural talimogene laherparepvec and IV nivolumab. The primary endpoint of 
the study is to determine the rate of resolution of malignant pleural effusion 
following IV nivolumab combined with intrapleural injection of talimogene 
laherparepvec. We hypothesize that patients receiving this novel combination will 
achieve resolution 70% of the time compared to the null hypothesis of 45% with 
pleur-X catheter alone. In addition, we plan to conduct correlative studies using 
pleural cytology and blood samples. 
 
1.2 
Malignant Pleural Effusions 
Pleural fluid normally enters the pleural space through the systemic capillaries of 
both the parietal and the visceral pleura. It is then removed via lymphatic drainage 
by osmotic and oncotic gradients through the parietal pleura and by cellular 
mechanisms [1, 2]. For many years, the major mechanism in the pathogenesis of 
malignant pleural effusion (MPE) was thought to be associated with tumor 
blockade of local lymphatic outflow due to tumor dissemination in parietal pleura 
and mediastinal lymph nodes, which as a result impairs pleural fluid absorption [3, 
4]. However, the theory that all MPE form as a result of lymphatic obstruction via 
tumor blockade has been refuted. Rather, MPE formation constitutes a complex 
biological process incorporating tumor-host interactions in the vasculature, the 
immune system and other host cells in the pleural microenvironment, per the figure 
below (from Spella et al) [1, 5]. 
 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
5 
 
Additional mechanisms for MPE formation include increased vascular permeability 
through excessive plasma leakage [6]. Furthermore, tumor burden in the pleural 
space leads to hyperpermeable pleural vessels due to increased production of 
vasoactive mediators such vascular endothelial growth factor (VEGF) and 
angiopoietins by tumor cells [6].  Host cells have also been shown to contribute to 
MPE formation via the production of VEGF by transforming growth factor beta in 
mesothelial cells [7]. 
A recent interest has been the immune system’s role in MPE formation. 
Proinflammatory mediators like interleukin (IL)-6, tumor necrosis factor (TNF), 
and chemokine ligand 2 (CCL2) were found to be signaling molecules that 
triggered MPE formation in mouse models [8-11].  These molecules induce local 
and regional vascular hyperpermeability, angiogenesis, inflammation and recruit 
host inflammatory and mesothelial cells to the pleural space, which further secrete 
proinflammatory molecules leading to MPE development [8, 12]. Finally, tumor 
signaling attracts host cells, including granulocytes, macrophages, and lymphoids 
cells, to the pleural space. This tumor-host communication within the pleural space 
again leads to downstream signaling and the common pathways of inflammation, 
increased vascular leakage, angiogenesis which mediates MPE formation [13]. 
Clinically, nearly 50% of patients with metastatic malignancies develop a 
malignant pleural effusion. More than 80% of these cases are represented by 
cancers of the lung, breast, gastrointestinal system, ovaries or lymphoma. While 
malignant mesothelioma is the most common type of primary pleural tumor, lung 
and breast cancer are the most common malignancies found to be associated with 
MPE in male and female patients, respectively [1, 14, 15].   
 
The diagnosis of MPE implies advanced disease with median survival of four 
months, with lung cancer associated with the shortest survival [16]. Currently 
treatment for MPE centers on palliation of associated symptoms, most commonly 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
6 
dyspnea and respiratory distress.  Palliation of symptomatic malignant pleural 
effusion consists of serial thoracentesis, chemical pleurodesis and tunneled pleural 
catheter placement.  At this time there are clinical trials aimed at decreasing fluid 
formation including combination intrapleural bevacizumab (anti-VEGF) and 
cisplatin therapy for MPE from NSCLC (NCT01661790). These efforts highlight 
the need for novel approaches to the treatment of MPE. 
 
1.3 
PleurX Pleural Catheter System 
The PleurX tunneled pleural catheter (TPC) consists of a distally fenestrated 
silicone catheter with a proximal valve mechanism and a polyester cuff. The valve 
prevents passage of fluid or air in either direction until it is accessed. The TPC is 
currently indicated for intermittent, long-term drainage of symptomatic, recurrent 
pleural effusions including malignant pleural effusions and other pleural effusions 
refractory to medical management as a result of the underlying disease; in addition 
to this the TPC has recently been approved for instillation of chemical pleurodesis 
agents (Talc and Bleomycin)[17]],[18]. A primary goal of our proposed trial is to 
investigate the novel approach of administering intrapleural talimogene 
laherparepvec via pleurX catheter in patients with known malignant pleural 
effusion. A second goal is to demonstrate the potential additive or synergistic 
effects of local oncolytic viral therapy with systemic immunotherapy. To our 
knowledge, this is the first study to evaluate local tumor immune microenvironment 
of malignant pleural effusions. 
 
The PleurX Pleural Catheter is a treatment option for the management of patients 
with symptomatic recurrent malignant and nonmalignant pleural effusions that do 
not respond to medical management.  Using the PleurX pleural catheter system, 
patients can manage fluid accumulation through intermittent drainages at home 
with minimal physician intervention. The PleurX devices are indicated for 1) the 
palliation of dyspnea due to pleural effusion and 2) providing pleurodesis 
(resolution of the pleural effusion). 
 
The fenestrated portion of the catheter is inserted into the pleural space utilizing a 
guidewire needle, guidewire and peel-away introducer (Seldinger technique).  The 
portion of the catheter containing the cuff is tunneled subcutaneously, and the 
remaining portion is left external to the body. The cuff promotes tissue ingrowth 
which mitigates the risk of dislodgement and catheter related infection.  See Figure 
1 for an illustration of an implanted catheter.   
 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
7 
 
 
Figure 1 Implanted PleurX Catheter  
 
The catheters are typically placed on an outpatient basis in a hospital or clinic. After 
implantation, the initial drainage is performed by a clinician utilizing the specially 
designed drainage line using either wall-suction or vacuum bottles.   
 
Before being discharged, the patient and caregiver are educated by a clinician on 
how to drain accumulated fluid and take care of the catheter exit site. The drainage 
kits contain detailed instructions for use written specifically for home care and the 
necessary items to perform the drainage procedure at home. The patient or caregiver 
will periodically drain the effusion using the PleurX vacuum bottles in the home 
setting. Drainage regimens are prescribed by physicians and may include draining 
daily, bi-weekly, or only as needed.    
 
1.4 
Nivolumab (BMS-936558) 
Nivolumab is a potent and fully humanized mAb of the immunoglobulin IgG4 that 
directly blocks the interaction between PD-1 and its ligands, PD-L1 and PDL-2. 
This blockade enhances functional activity of the target lymphocytes to facilitate 
an antitumor immune response, leading to tumor regression and immune rejection 
of the tumor [19, 20]. OpdivoTM (Nivolumab) has been approved in the United 
States for the treatment of patients with unresectable or metastatic melanoma and 
disease progression following ipilumumab and, if BRAF V600 mutation positive, 
a BRAF inhibitor. It has also received approval for patients with metastatic non-
small cell lung cancer (NSCLC). Current dosing for melanoma therapy and NSCLC 
is fixed dose of 240mg every 2 weeks. Approval has been granted for patients with 
recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with 
disease progression on or after platinum-containing chemotherapy (dose is 240mg 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
8 
every 2 weeks). Nivolumab is under investigation for first line treatment of NSCLC 
and HNSCC in addition to a variety of other cancer states [21]. 
 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of 
neoplastic transformation has been known for decades [22]. Accumulating 
evidence shows a correlation between tumor-infiltrating lymphocytes (TILs) in 
cancer tissue and favorable prognosis in various malignancies [23-27].  In 
particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / 
FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-
term survival in many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to 
suppress immune control.  The normal function of PD-1, expressed on the cell 
surface of activated T-cells under healthy conditions, is to down-modulate 
unwanted or excessive immune responses, including autoimmune reactions.  PD-1 
(encoded by the gene PDCD1) is an immunoglobulin (Ig) superfamily member 
related to CD28 and CTLA-4 that has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [28, 29].  
The structure of murine PD-1 has been resolved [9].  PD-1 and family members are 
type I transmembrane glycoproteins containing an Ig Variable-type (V-type) 
domain responsible for ligand binding and a cytoplasmic tail which is responsible 
for the binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition 
motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).   
 
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70, all of 
which are involved in the CD3 T-cell signaling cascade [28, 30-32].  The 
mechanism by which PD-1 down modulates T-cell responses is similar to, but 
distinct from that of CTLA-4 as both molecules regulate an overlapping set of 
signaling proteins [13; 14].  PD-1 is expressed on activated lymphocytes including 
peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells [33, 
34].  Expression has also been shown during thymic development on CD4-CD8- 
(double negative) T-cells as well as subsets of macrophages and dendritic cells [35].   
 
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be 
induced in a variety of cell types, including non-hematopoietic tissues as well as in 
various tumors [35-38].  Both ligands are type I transmembrane receptors 
containing both IgV- and IgC-like domains in the extracellular region and short 
cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand 
to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is 
expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on 
antigen-presenting cells found in lymphoid tissue or chronic inflammatory 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
9 
environments.  PD-L2 is thought to control immune T-cell activation in lymphoid 
organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral 
tissues [39].  Although healthy organs express little (if any) PD-L1, a variety of 
cancers are known to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with 
melanoma (MEL) [40].  This suggests that the PD-1/PD-L1 pathway plays a critical 
role in tumor immune evasion and should be considered as an attractive target for 
therapeutic intervention. 
 Pre-clinical Findings  
PD-1 inhibitors like Nivolumab strongly enhance T-lymphocyte immune 
responses in cultured blood cells from healthy human donors, cancer patients, 
and primates.   In T-cell activation assays using human donor blood cells, the 
EC50 (concentration where 50% of the maximum effect is achieved) has been 
reported to be ~0.1 to 0.3 nM.  Levels of interleukin-2 (IL-2), tumor necrosis 
factor alpha (TNFα), interferon gamma (IFNγ), and other cytokines were 
modulated by MK-3475.  The antibody potentiates existing immune responses 
only in the presence of antigen and does not nonspecifically activate T-cells [21]. 
 
Using an anti-murine PD-1 analog antibody, PD-1 blockade has been shown to 
significantly inhibit tumor growth in a variety of syngeneic murine tumor 
models.  In these experiments in mice, anti-PD-1 therapy is synergistic with 
chemotherapeutic agents such as gemcitabine and 5-fluorouracil (5-FU) and 
combination therapy results in increased complete tumor regression rates in vivo 
[21]. 
 
Since the anti-tumor effect of nivolumab is driven through reactivation of adaptive 
immune response by blocking PD-1 expressed on T cells, but not direct binding to 
cancer cells, once the PD-1 on T cells are fully saturated by nivolumab, the shape 
of the exposure-response relationship among indications is expected to be similar. 
This is supported by exposure-response analysis in multiple indications. A flat 
exposure-response relationship was demonstrated between nivolumab exposure (or 
dose) and efficacy or safety within the dose range 3mg/kg and 240 mg. The 
similarity in efficacy between the tested dose regimens is further supported by 
comparisons of overall response rate (ORR)/survival outcomes for the tested dose 
regimens in the melanoma an HNSCC indications. Available pharmacokinetic 
results in subjects with various indications (melanoma, NSCLC, HNSCC and MSI-
H) support a lack of meaningful difference in PK among tumor types [21].  
1.5 
Clinical Efficacy of Nivolumab in Humans 
Nivolumab is active against human NSCLC and has FDA approval for the 
treatment of several cancers [41]. In NSCLC, nivolumab as monotherapy led to 
durable antitumor activity and improved survival in Phase I studies.  In a large 
Phase III study of NSCLC patients who progressed on platinum therapy, nivolumab 
had longer overall survival compared to docetaxel (12.2 vs. 9.4 months) and 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
10 
decreased grade 3 and 4 treatment-related adverse events [42].  Most recently, 
Nivolumab gained approval in HNSCC on 11/10/2016. In 361 patients with 
recurrent or metastatic HNSCC following platinum based therapy, Nivolumab 
showed a statistically significant increase in overall survival compared to single 
agent standard chemotherapy (7.5 vs. 5.1 months) [43].  
1.6 
Talimogene Laherparepvec 
Talimogene laherparepvec is an oncolytic immunotherapy based on a modified 
clinical strain of HSV-1 that has been designed to selectively replicate in cancer 
cells. Two HSV-1 genes are deleted, ICP47 and ICP34.5. Deletion of ICP47 allows 
for the presentation of tumor antigens following oncolytic viral replication and 
enhances anti-tumor immune responses. Deletion of ICP34.5 leads to functional 
limitations in non-dividing cells and renders the virus non-pathogenic. The human 
GM-CSF coding sequence is the inserted and replaces the gene encoding ICP34.5. 
This prevents recombination between talimogene laherparepvec and wild-type 
virus. Additionally, expression of GM-CSF results in local GM-CSF production to 
recruit and activate antigen-presenting cells [44-46]. Talimogene laherparepvec has 
gained FDA approval for the local treatment of unresectable cutaneous, 
subcutaneous, and nodal lesions in patients with melanoma recurrent after initial 
surgery [47].  
 Pharmaceutical and Therapeutic Background 
Nonclinical pharmacology studies, including in vitro studies of cytopathic effects 
and in vivo studies of efficacy in numerous tumor types, have been conducted with 
talimogene laherparpevec and its murine analog, OncoVEXmouse GM-CSF.  
Talimogene laherparepvec lyses a variety of in vitro human tumor cell lines in 
culture including colorectal cancer (HT29), breast cancer (MDA-MB-231), 
glioblastoma astrocytoma (U-87 MG), prostate adenocarcinoma (LNCaP), and 
malignant melanoma (SK-MEL-28) tested at a multiplicity of infection between 0.1 
and 5; essentially all tumor cells were killed less than 48 hours following infection 
in vitro [48]. Talimogene laherparepvec affects not only the tumors into which it is 
injected, but also distant non-injected tumors, demonstrating a systemic beneficial 
effect from local administration. Talimogene laherparepvec suppresses tumor 
recurrence upon re-challenge with the same tumor type, and remains effective when 
animals have undergone previous exposure to wild-type HSV or are 
immunosuppressed with cyclosporin. Talimogene laherparepvec has been tested to 
evaluate the combined effects of either radiation or chemotherapy in preclinical 
studies. Both combinations were tolerated and could support potential clinical 
studies with these other agents for the treatment of cancer [47]. 
 Pre-clinical Findings  
Talimogene laherparepvec has been tested for efficacy both in vitro and in vivo 
murine tumor models. It has been shown to eradicate or substantially inhibit tumor 
growth at doses comparable to those used in clinical studies. Nonclinical evaluation 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
11 
has also confirmed that GM-CSF enhances the immune response generated, 
enhancing both injected and uninjected tumor responses. 
 
In a B16 melanoma model, irradiated tumor cells alone did not stimulate significant 
anti-tumor immunity. However, irradiated tumor cells expressing murine 
granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated potent, 
specific, and durable anti-tumor immunity, requiring both CD4+ and CD8+ cells 
[49]. In murine models with subcutaneous melanoma, intratumoral G-CSF 
inoculation with inactivated HSV vectors resulted in greater, dose-dependent tumor 
inhibition and improved mouse survival compared with HSV alone [50].  
 
A number of pre-clinical studies evaluating the safety of talimogene laherparepvec 
have been completed. Subcutaneous (SC) in mice mouse, single intra-arterial dose 
in rat, single intraprostatic dose in dogs, and repeated intravenous (IV) dosing in an 
embryo-fetal developmental in the BALB/c mouse all demonstrated administration 
safety and tolerable toxicity profiles. The safety of a surrogate HSV-1 construct 
expressing murine GM-GSF (OncoVEXmGM-CSF) administered as a repeated SC 
injection was evaluated in BALB/c mice. High and multiple doses of talimogene 
laherparepvec were well tolerated in immune competent mice following SC, IV, or 
intralesional injection. A dose margin based on body weight of 60-fold for general 
safety is estimated using the no adverse effect level. Similarly, a dose margin of 60-
fold (based on body weight) for embryo-fetal development is estimated using the 
NOAEL (also the highest dose tested in Study 117250) following repeated SC 
injection in mice compared with the maximum dose to be administered to patients 
[47].  
 
Key findings following repeated SC administration of talimogene laherparepvec 
included increased white blood cells, lymphocytes, and neutrophils. There was 
evidence of transient immune activation (enlargement and increased germinal 
centers in the spleen, lymphoid hyperplasia in spleen and bone marrow). These 
effects are consistent with the normal response of animals to administration of a 
virus, and development of normal anti-viral immunity. As a general rule, mice 
treated with talimogene laherparepvec tended to seroconvert and develop anti-
HSV-1 antibodies. No evidence of overt toxicity to any cell type or organ, and no 
evidence of virally-associated neuropathology/neurovirulence were observed in 
talimogene laherparepvec-treated animals. 
 
There is no evidence of virally associated neuropathology/neurovirulence 
associated with talimogene laherparepvec in any animal treated. Two studies found 
10,000-fold less neurovirulence at the median lethal dose (LD50) following 
intracerebral injection of talimogene laherparepvec with deletion of ICP34.5 as 
compared to wild-type HSV [51, 52]. Additionally, no mortality was seen in mice 
treated with intranasal talimogene laherparepvec despite use of doses 100-fold 
greater than those doses associated with the LD50 for wild-type HSV-1 [53].  
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
12 
1.7 
Rationale 
for 
Combination 
of 
PD-1 
Inhibitors 
with 
Talimogene 
Laherparepvec for MPE 
Given talimogene laherparepvec’s efficacy and favorable toxicity profile as 
monotherapy, pre-clinical studies have evaluated combining talimogene 
laherparepvec with other immune-activating agents [54]. In pre-clinical studies in 
a melanoma mouse model, an oncolytic virus induced both local and distant tumor 
infiltration with CD4+ and CD8+ T cells. The addition of CTLA-4 blockade 
induced significant anti-tumor responses and protection from tumor re-challenge 
[55]. In a phase Ib study, the efficacy of talimogene laherparepvec plus ipilimumab 
was assessed in advanced melanoma. In 19 patients evaluated, there were no dose 
limiting toxicities. Objective response rate was 50% with 44% of patients achieving 
durable response lasting more than 6 months. Additionally, 18 month PFS and OS 
were 50% and 67%, respectively [56].  
 
Currently, combination therapy with talimogene laherparepvec and pembrolizumab 
is being investigated in two human populations: unresected melanoma and 
recurrent metastatic HNSCC. A two-part phase 1b/3 studying is being conducted 
in patients with unresectable stage IIIB-IV melanoma to evaluate the safety of 
talimogene 
laherparepvec 
in 
combination 
with 
pembrolizumab 
versus 
pembrolizumab alone. The phase 1b portion of the study was single armed 
evaluating safety of talimogene laherparepvec and pembrolizumab combination. 
Twenty-one patients received intralesional injections of talimogene laherparepvec 
on a dose-escalation basis up to ≤4 mL at 108 PFU/mL dose every 2 weeks. 
Pembrolizumab 240mg IV every 2 weeks was initiated at 5 weeks after the initial 
talimogene laherparepvec dose. Treatment was continued until disease progression 
per immune-related response criteria (irRC), no injectable lesions, study treatment 
intolerance, or 2 years of treatment. No DLTs were reported and seven patients 
reported treatment-related Grade 3 adverse events. Of the 21 patients in the phase 
1b study, results yielded confirmed ORR (57.1%), CR rate by irRC (23.8%), and 
disease control rate (71.4%). The phase 3 study investigating the safety and efficacy 
of talimogene laherparepvec in combination with pembrolizumab versus 
pembrolizumab alone is currently underway [47, 57]. Additionally an NCI-led 
Phase II trial has been proposed for combination talimogene laherparepvec and 
nivolumab in refractory T-cell lymphoma and advanced non-melanoma skin 
cancers.  
 
Based on these observations, we propose to conduct a Phase II trial that includes a 
safety run-in cohort to investigate the novel approach of administering intrapleural 
talimogene laherparepvec via a pleurX catheter in patients with known MPE. After 
establishing the safety of this approach, we plan to treat a total of 24 patients with 
MPE’s with intrapleural talimogene laherparepvec and IV nivolumab. We 
hypothesize that patients receiving this novel combination will achieve resolution 
70% of the time compared to the null hypothesis of 45% with pleur-x catheter alone. 
In addition, we plan to conduct correlative studies using pleural cytology and blood 
samples as outlined below. 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
13 
In clinical practice, chemotherapy (bleomycin) and irritant agents (such as talc) 
have been administered to the pleural space.  Out of an abundance of caution, we 
conduct a phase I study as described to ensure safety while infusing talimogene 
laherparepvec.  However, we note that knowledge of the mechanism of action and 
previous safety data with subcutaneous injection suggest low risk of novel adverse 
events from this mechanism of injection. Further, phase I data of the combination 
of subcutaneous talimogene laherparepvec further support the safety of this 
combination [58]. 
1.8 
Correlative Studies 
We hope to define changes in the tumor immune microenvironment elicited by 
combination of intrapleural talimogene laherparepvec and IV Nivolumab therapy 
in patients with maligant pleural effusions. The tumor immune microenvironment 
is a complex mixture of competing cellular phenotypes.  Thus an optimal predictor 
of response to immunomodulatory therapy will likely include features that describe 
tumor genetics, tumor-related immunosuppression, and any existent but insufficient 
anti-tumor immune response. Correlative studies will be run in both pleural fluid 
and blood samples.  
 
We hypothesize that (1) patients treated with nivolumab + talimogene 
laherparepvec will show increased effector lymphocytic infiltrates, decreased 
regulatory cell populations, and increased clonal expansion of tumor-infiltrating T 
cells; moreover, (2) a robust integrated model that predicts response vs. resistance 
can be made from a set of key clinical, tumor, and immune features. 
 Aim 1 
Pleural fluid and blood samples will be analyzed by flow cytometry at three time 
points: pre-treatment, 3 weeks post initial therapy, and 9 weeks post initial therapy.  
Pleural fluid derived single-cell suspensions will be stained with fluorescently-
labeled antibodies to quantify cytotoxic T cells , effector helper T cells , and 
regulatory T cells. Regulatory T cells will also be sub-fractionated into naïve, 
effector, effector memory , and central memory .  T cells will also be analyzed for 
the expression of regulatory proteins PD1 and CTLA4.  B cells will be quantified 
as naïve  vs. activated.We will also quantify myeloid-derived suppressor cells  and 
tumor-associated macrophages .  Non-naïve T cells and B cells will be sorted and 
TCRβ/IgH repertoires will be amplified and sequenced. Lymphocyte subset 
frequencies and TCRβ/IgH repertoires from peripheral blood will be evaluated for 
similarity with tumor and controls using the Morisita-Horn index and Kruskal-
Wallis significance testing. 
 Aim 2 
We will perform RNA sequencing and whole exome sequencing (WES) to analyze 
the tumor and local pleural immune microenvironment by gene expression profiling 
on pre-treatment samples. RNA and DNA will be extracted from pleural fluid 
samples. mRNA-Seq libraries will made and sequence data will be processed, 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
14 
filtered, and aligned and transcript abundance quantitated. DNA libraries will be 
made to perform whole exome sequencing. Determination of molecular subtypes 
and relative expression of gene signatures associated with immune cellular and 
functional phenotypes along with inference of T cell and B cell receptor repertoire 
characteristics from mRNA-seq data will be performed. We will consider the 
following features as potential determinants of response: age, performance status, 
smoking status, tumor type and histology, total dose of nivolumab and talimogene 
laherparepvec received, molecular subtype, expression of PD-1 ligands, expression 
of immune phenotypic gene signatures, and TCRβ/IgH repertoire characteristics. 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective  
 Phase I: Characterize the safety and tolerability of intrapleural injection of 
talimogene laherparepvec alone and in combination with IV nivolumab 
 Phase II:  Resolution (<50cc drainage over three consecutive every other day 
drainages) of pleural fluid accumulation accompanied by patient-defined 
improvement in symptoms (dyspnea, cough and/or chest pain).. 
2.2 
Secondary Objectives  
 Estimate progression free survival (PFS) following nivolumab and talimogene 
laherparepvec per irRECIST. 
 Estimate overall survival (OS). 
 Estimate rates of response (RR) via irRECIST.   
 Further characterize the toxicity profile of intrapleural talimogene laherparepvec 
administered alone and in combination with IV nivolumab (Phase II). 
 Describe modified Borg Scale of Perceived Dyspnea over the course of therapy 
(Provided in 11.6 Appendix F:  Borg Scale). 
2.3 
Exploratory Objectives 
Via multi-parametric flow cytometry and mRNA-sequencing methods: 
 Explore tumor molecular subtype and immune gene expression signatures 
 Explore comprehensive T-cell quantification and phenotyping, including the 
change in effector lymphocytic infiltrates, regulatory T cell populations, and clonal 
expansion of tumor-infiltrating T cells  


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
15 
 Explore if it is possible to predict signature response vs. resistance expression 
from key clinical, tumor, and immune features. 
 Measure expression of PD-1, PD-L1, PD-L2, and other immune check point 
molecules  
2.4 
Study Endpoints  
 Primary Endpoint 
2.4.1.1 Phase I: Clinician assessed toxicity will be classified and graded according 
to the National Cancer Institute’s Common Terminology Criteria for 
Adverse Events (NCI-CTCAE, version 5.0). 
2.4.1.2 Phase II: Resolution (<50cc drainage over three consecutive every other 
day drainages) of pleural fluid accumulation accompanied by patient-
defined improvement in symptoms (dyspnea, cough and/or chest pain). 
 Secondary Endpoints 
2.4.2.1 Median PFS. PFS will be defined as the time from D1 of treatment until 
death or progression. 
2.4.2.2 Median OS. OS is defined as the time from D1 of treatment to death from 
any cause. 
2.4.2.3 Tumor response will be defined as the proportion of patients with reduction 
in tumor (irCR+irPR) per irRECIST criteria outlined in section 6.8. 
2.4.2.4 Clinician assessed toxicity will be classified and graded according to the 
National Cancer Institute’s Common Terminology Criteria for Adverse 
Events (NCI-CTCAE, version 5.0). 
2.4.2.5 Use of modified Borg rating scale for perceived dyspnea (10 point scale 
from 1 to 10 which measures perception of dyspnea) [59, 60] (Provided in 
11.6 Appendix F:  Borg Scale).  
 
3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to participate in this study: 
 Signed a written IRB-approved informed consent and HIPAA authorization for the 
trial. 
 Be ≥ 18 years of age on day of signing informed consent. 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
16 
 ECOG Performance Status ≤ 2. (See Appendix A: ECOG Performance Status). 
 Histologically or cytologically confirmed stage IV metastatic cancer.  
 Confirmation of malignant pleural effusion via imaging (CXR, CT scan, 
ultrasound, MRI, or PET/CT) and cytology for which pleurX catheter placement is 
standard of care. 
• 
Dose Level 1: Either no systemic therapy available per standard of care, or 
delay in administration of systemic therapy considered clinically 
acceptable. 
 
• 
Dose Level 2/Phase II: Nivolumab alone would be an acceptable standard 
treatment OR have a tumor type with prior data for PD1 efficacy OR non-
pleural disease is not considered a significant risk to the patient OR 
refractory to standard therapies.  
 Demonstrate adequate organ function as defined in the table below. All screening 
labs should be performed within 14 days of treatment initiation.  
 
System 
Laboratory Value2 
Hematological 
 
Absolute neutrophil count 
(ANC) 
≥1000 /µL 
Platelets 
≥50,000 / µL 
Hemoglobin 
≥10 g/dL (acceptable to reach this through 
transfusion)  
Renal 
 
Calculated creatinine clearance 
(Cockcroft-Gault)1 
≥45 mL/min  
Coagulation 
 
INR or PT 
≤ 1.5 x ULN unless the subject is receiving 
anticoagulant therapy, in which case PT and 
PTT/aPTT must be within therapeutic range of 
intended use of anticoagulants 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Pulmonary 
 
Pulse Oximetry 
At least 90% on room air  
(OR 95% on oxygen) 
Cardiac 
 
EKG 
No clinically relevant cardiac dysfunction  
Troponin 
< 0.3  


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
17 
System 
Laboratory Value2 
1. See Appendix B (Section 11.2) for Cockcroft-Gault formula. 
2. Hematology and other lab parameters that are ≤ grade 2 BUT still meet criteria for study 
entry are allowed. Furthermore, changes in laboratory parameters during the study should not 
be considered adverse events unless they meet criteria for dose modification(s) of study 
medication outlined by the protocol and/or worsen from baseline during therapy. 
 
 Recovered from all reversible toxicities related to their previous treatment (other 
than alopecia) to ≤grade 1 or baseline; exceptions to this criterion may be allowed 
following review by the principal investigator for toxicities that are not expected to 
be exacerbated by nivolumab or talimogene laherparepvec.  Grade 2 peripheral 
neuropathy will not result in exclusion as neither study agent would be expected to 
exacerbate it. 
 No history of untreated brain metastasis.  Treated brain metastases must not be 
known to be progressive, symptomatic, or currently requiring > 10 mg of 
prednisone or prednisone equivalents within two weeks prior to study drug 
administration. 
 Females of childbearing potential must have a negative serum pregnancy test within 
72 hours prior to receiving the first dose of study medication. Females of 
childbearing potential must agree to use 2 methods of effective contraception or 
abstain from heterosexual sex throughout the treatment period and for 5 months 
after the last dose of study treatment. Females of childbearing potential are women 
who have not been surgically sterilized (have undergone a hysterectomy, bilateral 
tubal ligation, or bilateral oophorectomy) or have not been free of menses for >1 
year. 
 Male patients with female partners must have had a prior vasectomy or agree to use 
an adequate method of contraception (i.e. double barrier method: condom plus 
spermicidal agent) starting with the first dose of study therapy through 7 months 
after the last dose of study treatment. 
 As determined by the enrolling physician or protocol designee, ability or 
willingness of the patient to understand and comply with study procedures. 
 
3.2 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria will not be able to 
participate in this study: 
 Receiving any investigational agent, or using an investigational device, currently 
or within 28 days or 5 half-lives of Day 1 of treatment on this study, whichever is 
longer. 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
18 
 Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1.   
 Has had a prior monoclonal antibody within 4 weeks prior to study Day 1, or who 
has not recovered to, ≤ Grade 1 toxicity at baselines from adverse events due to 
agents administered more than 4 weeks earlier. Exceptions to these criteria may be 
allowed at the discretion of the investigator for toxicities that are not expected to 
be exacerbated by nivolumab or talimogene laherparepvec (e.g., alopecia, 
peripheral neuropathy, etc). 
 Any concurrent chemotherapy, IP, biologic or hormonal therapy for cancer 
treatment. Concurrent use of hormonal therapy for non-cancer-related conditions 
(e.g., hormone replacement therapy) is acceptable. 
 Major surgery within 28 days prior to day 1 of study treatment from which the 
patient has not completely recovered. 
 Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the first dose 
of trial treatment. 
 Has a known secondary malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, or in situ cervical cancer that has undergone potentially curative therapy.   
 Has an active automimmune disease requiring systemic treatment within the past 3 
months or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents; subjects 
with resolved childhood asthma/atopy would be an exception to this rule.  Subjects 
that require intermittent use of bronchodilators or local steroid injections would not 
be excluded from the study.  Subjects with hypothyroidism stable on hormone 
replacement or Sjorgen’s syndrome will not be excluded from the study. 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment. Subjects with vitiligo, Grave’s disease, or psoriasis not 
requiring systemic treatment (within the past 2 years) are not excluded. 
 Has a history of non-infectious pneumonitis that required steroids; currently active 
non-infectious pneumonitis; or evidence of interstitial lung disease. 
 Has an active infection requiring systemic therapy or history of uncontrolled 
infection. 
 Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the subject’s 
participation for the full duration of the trial, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator.  This includes 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
19 
known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. This also includes unstable angina, 
serious uncontrolled cardiac arrhythmia, uncontrolled infection, or myocardial 
infarction ≤ 6 months prior to study entry. 
 Has inadequate home environment or social support to safely complete the trial 
procedures. 
 Is pregnant or breastfeeding. 
 Known human immunodeficiency virus (HIV), hepatitis C virus (HCV) or evidence 
of active hepatitis B virus (HBV).  
 Has a multi-loculated pleural effusion that would not lead to relief of dyspnea from 
drainage of a single loculation. 
 Current active hepatic or biliary disease (with exception of patients with Gilbert's 
syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator 
assessment). 
 Active herpetic skin lesions or prior complications of herpetic infection or requires 
intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic 
drug (e.g., acyclovir), other than intermittent topical use. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
20 
 
4.0 
TREATMENT PLAN 
4.1 
Schema for LCCC 1626 
 
Talimogene laherparepvec (TVEC) will be given intrapleural (IP) instillation for up to 9 cycles 
(includes seroconversion dose 4ml of106 pfu/mL) in Dose Level cohorts 1 and 2. Nivolumab (240 
mg IV) will be co-administered with talimogene laherparepvec (4ml of 108 pfu/mL) for up to 9 
cycles in the Dose Level 2 cohort, with 3 week interval between cycle 1 and cycle 2 to allow for 
seroconversion.  Patients will be allowed to continue nivolumab monotherapy per standard of care 
(240 mg IV Q2W) as long as they are responding to therapy (i.e., until disease progression, untoward 
toxicity, or withdrawal for other reasons).  
 
 
This Phase Ib/II trial includes a safety run-in period using 3 + 3 dose escalation 
rules to evaluate the feasibility of administering talimogene laherparepvec into the 
intrapleural space of patients with MPE via a pleurX catheter.  All infusions of 
talimogene laherparepvec will occur in 200cc normal saline (NS) followed by 20cc 
of sterile saline to clear the catheter, regardless of dose.  Subjects will be instructed 
to avoid drainage for at least 24 hours, then to drain the catheter (and flush with 20 
cc of sterile saline) when next needed to palliate shortness of breath, consistent with 
standard of care use of the pleurX catheter. If a patient becomes dyspneic <24 hours 
after talimogene laherparepvec administration, they should consult the 
interventional pulmonology team at UNC to determine if catheter drainage is 
necessary. Patients who experience severe shortness of breath <24 hours after 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
21 
intrapleural talimogene laherparepvec will be allowed to have their catheter 
drained. 
 Cohort Enrollment – Safety Run-in 
Since this is the first time talimogene lahereparevec is being given in the 
intrapleural space (i.e. new route of administration), enrollment in safety run-in 
cohorts 1 and 2 will be staggered. Each subject will be required to complete the 7-
week safety assessment period (i.e. 3 cycles of TVEC including the seroconversion 
cycle) of dose-limiting toxicity (DLT) before the next subject is enrolled. During 
the safety run-in period starting in Dose Level 1, patients will only receive 
intrapleural talimogene laherparepvec . The first dose of talimogene laherparepvec 
will be administered on Cycle 1, Day 1 at 4ml of 106 pfu/mL in 200 cc normal saline 
(intrapleurally) to seroconvert HSV-seronegative patients. Three weeks will be 
given for seroconversion. Subsequent doses of talimogene laherparepvec at 4ml of 
108 pfu/mL will then be administered IP every two weeks (Q2W) starting on Cycle 
2, Day 1 for up to 8 cycles. Patients will be assessed for dose limiting toxicity (DLT) 
related to IP administration of talimogene lahareparepvec after they have completed 
at least 3 cycles (i.e. 7 weeks) of monotherapy. If ≥2 patients experience DLT, the 
study will be discontinued. If 1 patient out of 3 has DLT, 3 additional patients will 
be recruited and treated at the same dose level.  If 0 out of 3 patients or ≤ 1 patient 
out of 6 has a DLT, the study will proceed to Dose Level 2.  One week following 
completion of study therapy, subjects may proceed to systemic therapy per their 
decision with their physician. 
 
In Dose Level 2 (expected Phase II dose), the first 3 patients will receive both IP 
talimogene laherparepvec and IV nivolumab. The first dose of talimogene 
laherparepvec will be administered on Cycle 1, Day 1 at 4mL of 106 pfu/mL in 200 
cc normal saline (IP) to seroconvert HSV-seronegative patients. Three weeks will 
be given for seroconversion. Subsequent doses of talimogene laherparepvec at 4ml 
of 108 pfu/mL + Nivolumab 240 mg IV will be administered every two weeks 
starting on Cycle 2, Day 1 for up to 8 cycles of therapy. Patients will be assessed 
for DLTs related to IP administration of talimogene lahareparepvec after 
seroconversion and 2 cycles of combination therapy (i.e.,7 weeks of study 
treatment). If ≥2 patients experience DLT, the study will be discontinued. If 1 
patient out of 3 has DLT, 3 additional patients will be recruited and treated at the 
same dose level.  If 0 out of 3 or ≤ 1 patient out of 6 has a DLT in the dose level 2 
cohort, the study will recruit additional patients in Phase II at this dose level and 
accrue  a total of 24 patients as per study goal.  All patients treated at dose level 2 
in Phase I or Phase II, will be included in analyses of safety and efficacy.  Safety 
stopping rules will ensure the safety of subjects receiving combination treatment in 
Phase II (see Statistical Considerations in section 9.0.) 
 
Subjects may continue talimogene laherparepvec for up to 9 cycles (i.e. alone or 
with nivolumab) until resolution of pleural effusion or they experience systemic 
disease progression. Subjects who have resolution of pleural effusion as defined by 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
22 
the primary endpoints may continue nivolumab monotherapy per standard of care 
until disease progression (see section 4.2 for details on treatment and section 6.5.2). 
 
 TPC drainage 
Tunneled pleural catheter drainage during both Phase Ib/II will occur as follows: 
 
Standard Drainage -  
Drainage will take place either in the subject’s home or in a suitable clinical area. 
All drainages after placement should be performed using standard aseptic technique 
and, unless connected to an inpatient drainage device, should be performed using 
PleuX vacuum drainage bottles.  All drainage volumes should be recorded in the 
subject’s diary.  The subject must contact the clinical site once he/she has drained 
<50mL on 3 consecutive drainages performed every other day.  
 
 
Study Drug Drainage -  
Following IP infusion of TVEC via the TPC, patients will allow the product to 
dwell for 24 hours.  After 24 hours the patients will drain their TPC either fully or 
up to the point of symptom development (chest pain/pressure, progressive dyspnea, 
intractable coughing).  Following drainage of the dwelled product, the patients will 
follow an every other day (QOD) drainage schedule.  Patients will drain as fully as 
possible, stopping at the point of symptom development.   
 
In the event patients develop dyspnea after IP infusion of TVEC they will be 
allowed to drain their TPC earlier than 24 hours.   
  
 Definitions of Dose Limiting Toxicities (DLT) – Safety Run-in 
A DLT is defined as the development of any new non-hematologic treatment-
related grade 3-5 adverse event during or up to 14 days following the third IP dose 
of talimogene laherparepvec. This results in a 7 week DLT period.  
 
• All subjects with grade 4 DLT events will be permanently discontinued 
from the study 
• All subjects with  ≥ grade 3 DLTs of myocarditis or pneumonitis will be 
permanently discontinued from the study  
• I.e., if > 1 scheduled dose of talimogene laherparepvec is missed due to 
study treatment-related toxicity, talimogene laherparepvec will be 
permanently discontinued and this event will be considered a DLT 
 
The following adverse events are considered exceptions: 
• Grade 3 laboratory-defined events that are asymptomatic and resolve 
without permanent sequelae to grade 0-1 within a week (ex. a grade 3 LFT 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
23 
elevation that occurs in the absence of symptoms, resolves to G1 within a 
week and does not result in any change in liver function). 
• Alkaline-phosphatase elevation in patients with known bone metastases 
• Pneumothorax, catheter-related complications or other intrapleural effects 
that are attributed to the standard of care catheter, disease state, or pre-
existing medical problems that are not unexpected. 
• G3 diarrhea or nausea that resolve to G1 or lower within 48 hours 
• Any grade 3-infusion/hypersensitivity reaction symptoms that resolve to 
grade 0-1 with dose interruption, infusion rate reduction, or supportive care.   
• Reactions attributed to nivolumab alone that would be expected in standard 
of care use may result in permanent cessation of treatment for an individual 
patient, but will not result in a DLT. Such a patient will be replaced. 
(Example: an infusion reaction of grade 3 to nivolumab consistent with that 
occasionally seen in standard of care use). 
• Tumor lysis syndrome 
• Any AE determined to be unrelated to study treatment 
• Events related to disease progression/relapse 
  
In addition, the following will be considered DLTs when treatment-related: 
• Pleuritic pain refractory to opioid therapy 
• Acute respiratory distress syndrome 
 Safety Assessment Period - Safety run-in: 
The safety assessment period for DLT assessment encompasses 3 cycles of study 
treatment (i.e. 7 weeks total). Three weeks will be given for seroconversion 
following the first dose of talimogene laherparevec (4 x 106 pfu). Subsequent doses 
of talimogene laherparepvec (4 x 108 pfu) will be given alone or with nivolumab 
(240 mg IV) every two weeks starting on Cycle 2, Day 1 for up to 8 cycles of 
therapy. Patients will be assessed for DLTs after seroconversion and 2 cycles of 
talimogene lahareparepvec given alone or with nivolumab every 2 weeks. Cohorts 
will be enrolled according to 3+3 rules and each subject must complete the safety 
assessment period before the next patient is treated (see above study schema).  If 
≥2 patients experience DLT in a dose cohort, the study will be discontinued.  
4.2 
Study Treatments 
Agent 
Pre-medications 
Dose/Frequency 
Route 
Schedule 
talimogene 
laherparepvec 
(1st dose only)1 
30 min prior to IP 
talimogene 
laherparepvec 
give anti-pyretic 
& anti-nausea 
meds (e.g., 500 
mg 
acetaminophen & 
10 mg 
prochlorperazine) 
4x106 pfu; next 
dose of 
talimogene 
laherparepvec 
given 3 weeks 
later 
via pleurX 
catheter and 
allow product 
to dwell for at 
least 24 hours  
 
D1 cycle 1 only; 
subsequent dose 
given three weeks 
later  
talimogene 
laherparepvec  
(Subsequent 
doses)1 
4x108 pfu every 
2 weeks X 8 
doses 
via pleurX 
catheter and 
allow product 
to dwell for at 
D1 cycle 2 of 
study for up to 8 
cycles given every 
2 weeks (14 days) 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
24 
least 24 hours 
until fluid stops 
re-accumulating 
(i.e., resolution of 
pleural effusion) 
or until systemic 
disease 
progression 
Nivolumab 
See section 4.3.3 
for management 
of infusion-
related reactions 
associated with 
nivolumab  
240 mg every 2 
weeks 
IV over 30 
minutes 
Starting on D1 of 
Cohort 2 Dose 
Level 2 and 
beyond; 
Every 2 weeks (14 
days) until disease 
progression (per 
RECIST or irRC) 
or withdrawal for 
other reasons 
1. See Appendix D -Information Sheet for Caregivers, Family Members or other Close Contacts to 
Clinical Trial Participants being given Talimogene Laherparepvec).  
 
Talimogene laherparepvec (4 mL) at a concentration of 106 (1 million) plaque-
forming units (pfu)/mL will be administered into the pleurX catheter for a total dose 
of 4 X106 pfu for the first dose.  Subsequently, talimogene laherparepvec (4 mL) at 
a concentration of 108 (100 million) pfu/mL will be administered every two weeks 
into the pleurX catheter. Dosing with talimogene laherparepvec will be continued 
until pleural fluid stops re-accumulating or until systemic disease progression. 
Subjects who have resolution of pleural effusion as defined by the primary 
endpoints may continue nivolumab monotherapy per standard of care until disease 
progression. The dose rationale for talimogene laherparepvec therapy is based on 
the OPTiM trial in melanoma and subsequent analysis [44, 61].  
 
All IP infusions of talimogene laherparepvec will be in 200cc NS followed by 20cc 
of sterile saline to flush the catheter. Subjects will be instructed to allow the product 
to dwell for at least 24 hours after which they should next drain the catheter when 
next needed to palliate shortness of breath, consistent with standard of care use of 
the catheter.  Subjects or their caregivers will be instructed to use medical gloves 
when draining the catheter and to avoid physical contact with fluid drained from 
the catheter.  Standard drainage bottles will be used.  Subjects will be allowed to 
either add bleach to the bottle then dispose per standard procedures or return to the 
investigators for disposal.  These precautions will be advised permanently after 
study initiation (See Appendix D -Information Sheet for Caregivers, Family 
Members or other Close Contacts to Clinical Trial Participants being given 
Talimogene Laherparepvec).  
 
Nivolumab 240 mg will be administered (per standard of care) as a 30-minute IV 
infusion on D1 of each cycle every two weeks.   
 
Nivolumab and talimogene laherparepvec may be administered in either order.  
Administration of the two agents should be within 30 hours of each other. 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
25 
4.3 
Dose Modifications/Delays 
 Talimogene laherparepvec Dose Modifications/Delays 
There will be no dose modifications allowed for talimogene laherparepvec during 
the study. Talimogene laherparepvec will be administered as described in section 
4.2 above. Talimogene laherparepvec administration will either be withheld or 
permanently discontinued depending on the severity of event related to its 
administration. If a grade 4 DLT occurs, talimogene laherparepvec will be 
permanently discontinued.  If grade 3 DLTs occur with talimogene laherparepvec 
administration as described in section 4.1.2 (Definition of DLTs), the next dose of 
talimogene laherparepvec will be withheld and will not be given until symptoms 
have resolved to ≤ grade 1. If > 1 scheduled dose of talimogene laherparepvec is 
missed due to toxicity, talimogene laherparepvec will be permanently discontinued. 
 
Doses up to 4 mL at dose strength of 108 pfu/mL every 2 weeks (maximum 
cumulative dose of 222.5 x 108 pfu) have been administered in clinical studies, with 
no evidence of DLT.  The maximum cumulative dose of talimogene laherparepvec 
planned for this trial is 9 total administrations (including initial seroconversion 
dose). See section 5.1.6, for warnings and precautions related to talimogene 
laherparepvec administration. Patients may receive premedication with an anti-
pyetic and anti-nausea medication (e.g., acetaminophen 500mg PO and 
prochloraperizine 10mg PO) prior to every talimogene laherparepvec injection. 
 
 Nivolumab Dose Modifications/Delays 
 
Toxicity grades per NCI-CTCAE Criteria v5.0 
Adverse Reaction 
Severity 
Dose Modification 
 
Colitis 
Grade 2 diarrhea or colitis 
Withhold dosea 
Grade 3 diarrhea or colitis 
Withhold dosea  when 
administered as a single 
agent 
 
Permanently discontinue 
when administered with 
ipilimumab 
Grade 4 diarrhea or colitis 
Permanently discontinue 
Pneumonitis 
Grade 2 pneumonitis 
Withhold dosea 
Grade 3 or 4 pneumonitis 
Permanently discontinue 
Hepatitis/non-HCCb 
Aspartate aminotransferase (AST)/ or 
alanine aminotransferase (ALT) more than 3 
and up to 5 X the ULN or total bilirubin > 
1.5 and up to 3X ULN 
Withhold dosea 
AST or ALT more than 5X ULN or total 
bilirubin > 3X ULN 
Permanently discontinue 
Hepatitis/HCCb 
If AST/SLT is within normal limits at 
baseline and increases to more than 3 and up 
to 5 times the ULN or total bilirubin more 
than 1.5 and up to 3 times the ULN 
 
If AST/ALT is more than 1 and up to 3 
 
Withhold dosec 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
26 
times ULN at baseline and increases to more 
than 5 and up to 10 times the ULN 
 
If AST/ALT is more than 3 and up to 5 
times ULN at baseline and increases to more 
than 8 and up to 10 times ULN 
 
If AST/ALT is more than 3 and up to 5 
times ULN at baseline and increases to more 
than 8 and up to 10 times the ULN 
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 more than 1.5 and up to 6X 
ULN 
Withhold dosea 
Serum creatinine more than 6X ULN 
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 
Encephalitis 
New-onset moderate or severe neurologic 
signs or symptoms 
Withhold dosea 
Immune-mediated encephalitis 
Permanently discontinue 
 
 
 
 
Other 
Other Grade 3 adverse reaction 
First occurrence 
 
Recurrence of same Grade 3 adverse 
reaction 
 
Withhold dosea 
 
Permanently discontinue 
 
Life-threatening or Grade 4 adverse reaction 
Permanently discontinue 
Grade 3 myocarditis 
Permanently discontinue 
Requirement for 10 mg per day or greater 
prednisone or equivalent for more than 12 
weeks 
Permanently discontinue 
Persistent Grade 2 or 3 adverse reactions 
lasting 12 weeks or longer 
Permanently discontinue 
a) Resume treatment when adverse reaction returns to Grade 0 or 1.  
b)  HCC: hepatocellular carcinoma 
c) Resume treatment when AST/ALT returns to baseline. 
 
4.3.2.1 Dose Delay Criteria for Nivolumab  
Because of the potential for clinically meaningful nivolumab-related AEs 
requiring early recognition and prompt intervention, management algorithms 
have been developed for suspected AEs of selected categories [see Appendix C 
section 11.3]. 
 
Dose delay criteria apply for all drug-related AEs. Nivolumab must be delayed 
until treatment can resume.  
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
27 
Nivolumab administration should be delayed for the following: 
Any Grade ≥ 2 non-skin, drug-related AE, with the following exceptions: 
• 
Grade 2 drug-related fatigue or laboratory abnormalities do not require a 
treatment delay 
• 
Any Grade 3 skin, drug-related AE 
 
Any Grade 3 drug-related laboratory abnormality, with the following 
exceptions for lymphopenia, leukopenia, AST, ALT, total bilirubin, or 
asymptomatic amylase or lipase: 
• 
Grade 3 lymphocyte count decreased or white blood cell decreased does 
not require dose delay. 
• 
If a subject has a baseline AST, ALT, or total bilirubin that is within 
normal limits, delay dosing for drug-related Grade ≥ 2 toxicity. 
• 
If a subject has baseline AST, ALT, or total bilirubin within the Grade 
1 toxicity range, delay dosing for drug-related Grade ≥ 3 toxicity. 
• 
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 Investigator should be consulted for such 
Grade ≥ 3 amylase or lipase abnormalities. 
 
Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of 
the investigator, warrants delaying the dose of study medication. 
4.3.2.2 Criteria to Resume Nivolumab Treatment 
Subjects may resume treatment with study drug when the drug-related AE(s) 
resolve to Grade ≤1 or baseline value, with the following exceptions: 
• 
Subjects may resume treatment in the presence of Grade 2 fatigue  
• 
Subjects who have not experienced a Grade 3 drug-related skin AE may 
resume treatment in the presence of Grade 2 skin toxicity  
• 
Subjects with baseline Grade 1 AST/ALT or total bilirubin who require 
dose delays for reasons other than a 2-grade shift in AST/ALT or total 
bilirubin may resume treatment in the presence of Grade 2 AST/ALT OR 
total bilirubin 
• 
Subjects with combined Grade 2 AST/ALT AND total bilirubin values 
meeting discontinuation parameters should have treatment permanently 
discontinued 
• 
Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved 
to baseline before treatment is resumed. Subjects with persistent Grade 1 
pneumonitis after completion of a steroid taper over at least 1 month may 
be eligible for retreatment if investigator allows. 
• 
Subjects with drug-related endocrinopathies adequately controlled with 
only physiologic hormone replacement may resume treatment if the 
investigator allows it, but this should be documented clearly in the 
electronic case report form (eCRF). 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
28 
If the criteria to resume treatment are met, the subject should restart treatment at 
the next scheduled time point per protocol. However, if the treatment is delayed 
past the next scheduled time point per protocol, the next scheduled time point will 
be delayed until dosing resumes. 
 
If treatment is delayed or interrupted for > 6 weeks, the subject must be 
permanently discontinued from study therapy, except as specified in the 
discontinuation section.  
4.3.2.3 Management Algorithms for Nivolumab 
Guidelines for the management of immune-related events can be found in the 
approved United States Product insert.  
 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity 
and duration than AEs caused by other therapeutic classes. Nivolumab is 
considered an I-O agent in this protocol. Early recognition and management of 
AEs associated with immuno-oncology agents may mitigate severe toxicity.  
 
Management algorithms (See Appendix C, section 11.3) have been developed to 
assist investigators in assessing and managing the following groups of AEs:  
o Gastrointestinal,  
o Renal,  
o Pulmonary,  
o Hepatic,  
o Endocrinopathies,  
o Skin, and 
o Neurological.  
 
For subjects expected to require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an AE, consider recommendations provided in 
the algorithms. These algorithms are found in the Nivolumab IB and in Appendix 
C, section 11.3 of this protocol. The guidance provided in these algorithms should 
not replace the Investigator’s medical judgment but should complement it. 
4.3.2.4 Discontinuation Criteria for Nivolumab 
Treatment should be permanently discontinued for the following: 
• Any Grade 2 drug-related uveitis or 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  
• Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with 
the following exceptions: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reaction, or infusion reaction of any duration 
requires discontinuation 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
29 
o Grade 3 drug-related endocrinopathies adequately controlled with 
only physiologic hormone replacement do not require 
discontinuation 
o Grade 3 drug-related laboratory abnormalities do not require 
treatment discontinuation except those noted below 
• Grade 3 drug-related platelet count decreased > 7 days or associated with 
bleeding requires discontinuation 
• Any drug-related hepatic abnormality that meets the following criteria 
require discontinuation:  
o AST or ALT > 8 x ULN 
 
o Total bilirubin > 5 x ULN 
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• Any Grade 4 drug-related adverse event or laboratory abnormality, except 
for the following events which do not require discontinuation: 
o Isolated Grade 4 amylase or lipase abnormalities that are not 
associated with symptoms or clinical manifestations of 
pancreatitis and decrease to < Grade 4 within 1 week of onset.  
o 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 
o Grade 4 lymphocyte count decreased or white blood cell decreased 
o Grade 4 drug-related endocrinopathy adverse events, such as 
adrenal 
insufficiency, 
ACTH 
deficiency, 
hyper- 
or 
hypothyroidism, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement 
(corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with 
and approval from the Investigator  
• Any dosing interruption lasting > 6 weeks with the following exceptions: 
o Dosing delays or interruptions to allow for prolonged steroid 
tapers to manage drug-related adverse events are allowed. Prior to 
re-initiating treatment in a subject with a dosing interruption 
lasting > 6 weeks, the Investigator must be consulted. Tumor 
assessments should continue as per protocol even if dosing is 
interrupted or delayed 
o Dosing interruptions or delays lasting > 6 weeks that occur for 
non-drug-related reasons may be allowed if approved by the 
Investigator. Prior to re-initiating treatment in a subject with a 
dosing interruption lasting > 6 weeks, the Investigator must be 
consulted. Tumor assessments should continue as per protocol 
even if dosing is interrupted 
• Permanently discontinue nivolumab for grade 3 myocarditis 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
30 
• Any adverse event, laboratory abnormality, or intercurrent illness which, 
in the judgment of the Investigator, presents a substantial clinical risk to 
the subject with continued nivolumab dosing 
 Management of Nivolumab Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. 
However, if such a reaction were to occur, it might manifest with fever, chills, 
rigors, headache, rash, pruritis, arthralgias, hypo- or hypertension, bronchospasm, 
or other symptoms of allergic-like reactions.  
 
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. 
Infusion reactions should be graded according to NCI CTCAEv5.0 guidelines. 
 
Treatment recommendations are provided below and may be modified based on 
local treatment standards and guidelines as appropriate: 
 
For Grade 1 symptoms during nivolumab infusion: (Mild reaction; infusion 
interruption not indicated; intervention not indicated). Remain at bedside and 
monitor subject until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes 
before additional nivolumab administrations. 
 
For Grade 2 symptoms during nivolumab infusion: (Moderate reaction requires 
therapy or infusion interruption but responds promptly to symptomatic treatment 
[e.g., antihistamines, non-steroidal anti- inflammatory drugs, narcotics, 
corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 
24 hours).  
 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 
1000 mg (acetaminophen); remain at bedside and monitor subject until resolution 
of symptoms. Corticosteroid or bronchodilator therapy may also be administered 
as appropriate. If the infusion is interrupted, then restart the infusion at 50% of the 
original infusion rate when symptoms resolve; if no further complications ensue 
after 30 minutes, the rate may be increased to 100% of the original infusion rate. 
Monitor subject closely. If symptoms recur, then no further nivolumab will be 
administered at that visit. Administer diphenhydramine 50 mg IV, and remain at 
bedside and monitor the subject until resolution of symptoms. The amount of study 
drug infused must be recorded on the electronic case report form (eCRF). The 
following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) should be administered 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. 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
31 
 
For Grade 3 or Grade 4 symptoms during nivolumab infusion: (Severe 
reaction, Grade 3: prolonged [i.e., not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae 
[e.g., renal impairment, pulmonary infiltrates]). Grade 4: (life threatening; pressor 
or ventilatory support indicated).  
 
Immediately discontinue infusion of the therapeutic antibody. Begin an IV infusion 
of normal saline, and treat the subject as follows. 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. The offending therapeutic antibody 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 (e.g., appearance of a 
localized or generalized pruritis within 1 week after treatment), symptomatic 
treatment may be given (e.g., oral antihistamine, or corticosteroids). 
 
4.4 
Concomitant Medications/Treatments 
Patients on the trial are allowed to receive all supportive care therapy needed to 
alleviate symptoms related to their cancer diagnosis or other medical problems at 
the investigator’s discretion. No treatments should be withheld due to a patient’s 
participation in this study. Prophylaxis for infusion-related reactions should be 
employed per institutional guidelines (also refer to Section 4.3.3).  
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing trial.  If there is a clinical indication for one of these or 
other medications or vaccinations specifically prohibited during the trial, 
discontinuation from trial therapy or vaccination may be required.  The investigator 
should discuss any questions regarding this with the Bristol-Meyers-Squibb (BMS) 
Clinical team.  The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the subject's primary physician.   
 Special warnings and precautions 
• Nivolumab is associated with immune-related AEs. Subjects should be 
monitored continuously as an AE with nivolumab may occur at any time 
during or after discontinuation of therapy.  
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
32 
• For suspected immune-related reactions, adequate evaluation should be 
performed to confirm etiology or exclude other causes. Based on the 
severity of the adverse reaction, nivolumab should be withheld and 
corticosteroids administered. If immunosuppression with corticosteroids is 
used to treat an AE, a taper of at least 1-month duration should be initiated 
upon improvement. Rapid tapering may lead to worsening of the AE. Non-
corticosteroid immunosuppressive therapy should be added if there is 
worsening or no improvement despite corticosteroid use. 
4.5 
Duration of Therapy 
In the absence of treatment delays due to AEs, treatment may continue until the end 
of study-defined treatment or until: 
• Disease progression (Note: treatment may continue until progression is 
confirmed by repeat scan approximately 6 weeks later to rule out 
pseudoprogression based on investigator discretion) 
• Inter-current illness that prevents further administration of treatment 
• Unacceptable toxicity  
• Pregnancy 
• Patient decides to withdraw from study treatment, OR 
• General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
4.6 
Duration of Follow Up 
After stopping study therapy, subjects should be followed as described in the time 
and events table in Section 6.0 and in the follow up section in 6.5.  After two years 
of follow-up as described in the time and events tables, subsequent follow-up will 
be per standard of care.  Subjects can be contacted by phone or followed via medical 
records every 3 months (+/- 15 days) for follow up information on disease 
progression and survival until death.    
 
4.7 
Removal of Patients from Protocol Therapy 
Patients will be removed from protocol therapy and the PI notified when any of the 
criteria listed in section 4.5 apply.  The reason for discontinuation of protocol 
therapy will be documented on the eCRF.   
 
In case a patient decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the patient should be asked if she or he may still be contacted for 
further scheduled study assessments or have relevant information on PFS and OS 
accessed from their medical record. The outcome of that discussion should be 
documented in both the medical records and in the eCRF. 
 
Excessive patient withdrawals from protocol therapy or from the study can render 
the study un-interpretable; therefore, unnecessary withdrawal of patients should be 
avoided. 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
33 
4.8 
Study Withdrawal 
If a patient decides to withdraw from the study (and not just from protocol therapy) 
all efforts should be made to complete and report study assessments as thoroughly 
as possible. The investigator should contact the patient or a responsible relative by 
telephone or through a personal visit to establish as completely as possible the 
reason for the study withdrawal. A complete final evaluation at the time of the 
patient’s study withdrawal should be made with an explanation of why the patient 
is withdrawing from the study. If the reason for removal of a patient from the study 
is an adverse event, the principal specific event will be recorded on the eCRF. 
 
5.0 
DRUG INFORMATION 
5.1 
Talimogene Laherparepvec (ImlygicTM) 
Please refer to the Talimogen laherparepvec pharmacy information guide for 
additional information. 
 Description 
Talimogene laherparepvec is a sterile suspension of live, attenuated herpes-simplex 
virus -1 (HSV-1) that has been genetically modified to express huGM-CSF. The 
parental virus for talimogene laherparepvec was a primary isolate, which was 
subsequently altered using recombinant methods to result in gene deletions and 
insertions. 
 Supplier/How Supplied 
Talimogene laherparepvec will be presented as a sterile, semi-translucent to opaque 
solution for injection (opacity is different for each concentration) preservative-free 
frozen liquid in a single use 2 mL cyclic olefin polymer (COP) plastic resin vial.  
Each vial will contain talimogene laherparepvec at a nominal concentration of 106 
PFU/mL or 108 PFU/mL in an aqueous sodium phosphate buffer with sodium 
chloride, sorbitol and myo-inositol added as stabilizers and water for injection 
(WFI).  Vials are appropriately filled to ensure that a sufficient deliverable dose is 
provided.  Each 2 mL vial will contain approximately 1.15 mL of talimogene 
laherparepvec with a 1.0 mL deliverable volume.  Each vial is intended for single 
use only. 
 
Vials will be sealed with gray rubber stoppers, fluorotec-coated on the product side.  
The vial caps will be color coded and may be used to help distinguish between the 
106 PFU/mL and 108 PFU/mL vial concentrations.  The supply for 106 PFU/mL 
vials will be packaged separately from the supply for the 108 PFU/mL vials. 
• The 106 PFU/mL strength is supplied in a box containing 10 vials. 
• The 108 PFU/mL strength is supplied in a box containing 20 vials. 
 
For additional information please refer to the talimogene laherparepvec pharmacy 
information guide. 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
34 
 Storage, Handling and Dispensing 
Talimogene laherparepvec must be stored in a non-cycling freezer maintained at a 
set point of -80oC in a secured location until planned use.  Cycling, frost-free, auto 
defrost freezers must not be used since they cycle to warmer temperatures several 
times a day.  Vials should be kept within the secondary container to protect from 
light.  The table below outlines the storage temperature requirements. 
 
Storage of Talimogene Laherparepvec - Freezer Set Point 
 
 
 
 
 
 
 
All infusions of talimogene laherparepvec will be in 200cc NS followed by 
injection of 20cc sterile saline to clear the catheter. Subjects will be instructed to 
allow the product to dwell for at least 24 hours after which they should next drain 
the catheter when next needed to palliate shortness of breath, consistent with 
standard of care use of the catheter.  Subjects or their caregivers will be instructed 
to use medical gloves when draining the catheter and to avoid physical contact with 
fluid drained from the catheter.  Standard drainage bottles will be used.  Subjects 
will be allowed to either add bleach to the 60 cc syringe or bottle and then dispose 
per standard procedures or return to the investigators for disposal.  These 
precautions will be advised permanently after study initiation (See Appendix D -
Information Sheet for Caregivers, Family Members or other Close Contacts 
to Clinical Trial Participants being given Talimogene Laherparepvec).  
 
 Preparation 
All personnel handling talimogene laherparepvec or material contaminated with 
talimogene laherparepvec must observe institutional safety precautions. 
 
Preparation to occur in biological safety cabinet per institutional guidelines. 
 
Clean talimogene laherparepvec vial stopper with an alcohol swab. 
 
Withdraw 1ml from each of 4 vials, using a sterile 18-26 gauge disposable needle, 
for a total volume of 4ml. 
 
For additional information please refer to the talimogene laherparepvec 
pharmacy manual.  
 
Freezer Set Point 
(ºC) 
Acceptable 
Variation 
Acceptable Range 
-80°C 
± 10°C 
-90°C to -70°C 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
35 
 Return and Retention 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Amgen, Inc. or designee, the amount dispensed to the subjects and 
the amount remaining at the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy (e.g., 
UNC IDS drug destruction policy). It is the Investigator’s responsibility to arrange 
for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional 
guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 Warnings and Precautions (talimogene laherparepvec) 
Accidental Exposure 
Accidental exposure may lead to transmission of herpetic infection. Healthcare 
providers who are immunocompromised or pregnant should not administer 
talimogene laherparepvec. Protective clothing and gloves should be worn during 
preparation and administration of talimogene laherparepvec. 
 
Herpetic Infection 
Herpetic infections have been reported in patients treated with talimogene 
laherparepvec. Healthcare providers exposed to talimogene laherparepvec are 
encouraged to report suspected herpetic infections as well.  Disseminated herpetic 
infection may also occur in immunocompromised patients. Patients who develop 
suspicious herpes-like lesions should follow standard hygienic practices to prevent 
viral transmission. Suspected herpetic lesions should be reported to Amgen at 1-
855-465-9442; patient or close contacts have the option of follow-up testing for 
further characterization of infection. Healthcare providers exposed to talimogene 
laherparepvec are encouraged to report the suspected herpetic infections to Amgen 
at 1-855-465-9442.  Talimogene laherparepvec is sensitive to acyclovir.  
 
Please see section 11.4 Appendix D: Information sheet for caregivers, family 
members or other close contacts to clinical trial participants being given 
talimogene laherparepvec. 
 
Immune-mediated events 
Talimogene laherparepvec may result in immune-mediated events including 
glomerulonephritis, vasculitis, pneumonitis, worsening of psoriasis, and vitiligo. 
 
Common adverse events (≥ 25%) in talimogene laherparepvec-treated patients 
were fatigue, chills, pyrexia, nausea, influenza-like illness, and injection site pain. 
 
Please refer to the talimogene laherparepvec investigators brochure for 
additional information on identified and potential risks. 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
36 
5.2 
Additional important Nivolumab (Opdivo®) 
See 
the 
prescribing 
information 
for 
Opdivo® 
(Nivolumab) 
at 
http://packageinserts.bms.com/pi/pi_opdivo.pdf for more detailed information. 
 Description 
Nivolumab injection drug product is a sterile, non-pyrogenic, single-use, isotonic 
aqueous solution formulated at 10mg/10 mL. The vials supplied contain 100 mg.  
Nivolumab is a sterile, preservative-free, non-pyrogenic clear to opalescent, 
colorless to pale-yellow liquid that may contain light (few) particles for IV 
administration. Nivolumab will be administered as standard of care following the 
institutional guidelines. 
 Packaging and Labeling 
Primary Packaging (Volume)/Label type: Carton of 5 or 10 vials 
Secondary Packaging (Qty)/Label type: 10-cc Type 1 flint glass vials stoppered 
with butyl stoppers and sealed with aluminum seals. 
 Storage and Handling 
Store nivolumab under refrigeration at 20C to 80C (360F-460F) in the original 
package until time of use. Protect from light and freezing. Do not shake the vial. 
 
If stored in a glass front refrigerator, vials should be stored in the carton. 
Recommended safety measures for preparation and handling of nivolumab include 
laboratory coats and gloves. 
 Dose, Schedule and Administration 
See section 4.3.2 
 
Nivolumab will be given every two weeks at a dose of 240 mg to be administered 
as a 30 minute IV infusion. 
 
Subjects may be dosed no less than 12 days from the previous dose of drug. There 
are no premedications recommended for nivolumab on the first cycle. 
 
Subjects should be carefully monitored for infusion reactions during nivolumab 
administration. If an acute infusion reaction is noted, subjects should be managed 
according to institutional guidelines (See section 4.3.3). 
 
Doses of nivolumab may be interrupted, delayed, or discontinued depending on 
how well the subject tolerates the treatment. 
 Preparation 
Follow institutional guidelines for Nivolumab preparation or see the nivolumab 
prescribing information for preparation instructions. Nivolumab Injection, 100 
mg/10 mL (10 mg/mL) is to be administered as an IV infusion through a 0.2-micron 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
37 
to 1.2-micron pore size, low-protein binding polyether sulfone (PES) membrane in-
line filter at the protocol-specified dose. It is not to be administered as an IV push 
or bolus injection. Nivolumab injection can be infused undiluted (10 mg/mL) or 
diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP 
to protein concentrations as low as 1 mg/mL. Care must be taken to assure sterility 
of the prepared solution as the product does not contain any antimicrobial 
preservative or bacteriostatic agent. 
 Stability 
Nivolumab solution for injection can be stored after preparation at room 
temperature for no more than 4 hours. This includes room temperature storage of 
the infusion in the IV container and time for administration of the infusion OR 
under refrigeration at 20C to 80C (360F-460F) for nor more than 24 hours from the 
time of infusion preparation. 
 Return and Retention of Nivolumab 
Partially used and completely used vials will be destroyed per institutional 
guidelines. 
 Adverse Events Associated with Nivolumab 
The adverse events listed below have been reported in patients receiving 
nivolumab. See section 4.3 for further instruction on the management adverse 
events associated with nivolumab therapy.  
 
• Immune-mediated pneumonitis: Defined as requiring use of corticosteroids 
and no clear alternate etiology, including fatal cases have occurred with 
nivolumab treatment. 
• Immune-mediated colitis: Defined as requiring use of corticosteroids and 
no clear alternate etiology, including fatal cases have occurred with 
nivolumab treatment. 
• Immune-mediated hepatitis: Defined as requiring use of corticosteroids and 
no clear alternate etiology have occurred with nivolumab treatment. 
• Immune-mediated endocrinopathies: Hypophysitis, adrenal insufficiency, 
hypo- and hyper-thyroidism, and type I diabetes mellitus have occurred 
with nivolumab treatment. 
• Immune-mediated nephritis and renal dysfunction: Defined as renal 
dysfunction or ≥Grade 2 increased creatinine, requirement for 
corticosteroids, and no clear alternate etiology, can occur with nivolumab 
treatment. 
• Immune-mediated rash: Severe rash (including rare cases of fatal toxic 
epidermal necrolysis) can occur with nivolumab treatment. 
• Immune-mediated encephalitis: Withhold nivolumab in patients with new-
onset moderate to severe neurologic signs or symptoms. 
• Other immune-mediated adverse reactions: Monitor for as described in 
4.3.2. 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
38 
• Complications of allogeneic human stem cell transplant after nivolumab: 
Monitor for hyper acute graft-versus-host disease (GVHD). Transplant 
related mortality has occurred. 
• Infusion reactions: Severe infusion reactions have been reported in <1.0% 
of patients in clinical trials of nivolumab. See section 4.3.3 for information 
on the management of nivolumab-related infusion reactions. 
 
 
 Use in Pregnancy 
If a patient inadvertently becomes pregnant while on treatment with nivolumab, the 
patient will immediately be removed from the study.  The site will contact the 
patient at least monthly and document the patient’s status until the pregnancy has 
been completed or terminated.  
 
 Use in Nursing Women 
It is unknown whether nivolumab is excreted in human milk.  Since many drugs 
are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, patients who are breast-feeding are not eligible for 
enrollment. 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
39 
6.0 
Evaluations and Assessments 
6.1 
Safety Run-in Cohort 1 (Talimogene Laherparepvec Only) 
Assessments 
 
Pre-
Study1 
Treatment Period2 
Cycle 1 is 3 weeks in length, subsequent cycles are Q2W 
 
Follow up 
Cycle 1 
Day 11,2 
 
Cycle 1 
Day 8 
Cycle 2 
Day 1 
Cycle 2 
Day 8 
Cycle 3 
Day 1 
Cycle 4 
Day 1 
Cycle 5 - 9 
Day 1 
End 
of 
TXT3 
Long 
Term FU3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
HSV-1 antibody 
X 
 
 
 
 
 
 
 
 
 
History4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EKG 
X 
 
 
 
 
 
X 
 
 
 
Troponin 
X 
 
 
 
 
 
X 
 
 
 
Chest X-ray 
X 
As needed and/or after three consecutive drainages with <50cc drainage (every 
other day drainages) of pleural fluid drainage accompanied by patient-defined 
improvement in symptoms (cough, chest pain and/or dyspnea). 
X 
 
Tumor measurement5 
X 
 
 
 
 
 
 
X5 
X5 
X 
Pregnancy test1 
X 
 
 
 
 
 
 
 
 
 
Hematology6 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistries6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Liver function tests6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation7 
X 
 
 
 
 
 
 
 
 
 
Toxicity Assessment  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
talimogene laherparepvec IP 
Q3W 106 PFU   
 
X 
 
 
 
 
 
 
 
 
talimogene laherparepvec IP 
Q2W 108 PFU   
 
 
 
X 
 
X 
X 
X 
 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
40 
 
Assessments 
Pre-
Study1 
Treatment Period2 
Cycle 1 is 3 weeks in length, subsequent cycles are Q2W 
Follow up 
Cycle 1 
Day 11,2 
Cycle 1 
Day 8 
Cycle 2 
Day 1 
Cycle 2 
Day 8 
Cycle 3 
Day 1 
Cycle 4 
Day 1 
Cycle 5 - 9 
Day 1 
End 
of 
TXT3 
Long 
Term FU3 
Patient Diary8 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood / urine / pleura samples to 
assess viral shedding 
 
X9 
 
X9 
X9 
 
X9 
X9 
X9 
 
X9 
 
Blood sample for correlative 
studies10 
 
X 
 
X 
 
 
X 
 
X 
 
Tumor biopsy  
X11 
 
 
 
 
 
 
 
 
 
Collection of pleural drainage12 
 
X 
 
X 
 
 
 
 
X 
 
Buccal Swab 
X14 
X15 
 
 
 
 
 
 
 
 
Modified Borg13 
 
X 
 
X 
 
 
X 
 
X 
 
Survival analysis 
 
 
 
 
 
 
 
 
 
X 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
41 
Key to Time and Events Table Footnotes 
1. Radiological assessments, EKG and physical exam may be performed up to 4 weeks prior to day 1 of 
treatment.  Other evaluations except for pregnancy must be performed within 2 weeks prior to Cycle 1 
Day 1 of treatment. Serum B-HCG must be performed within 72 hours prior to first dose of study 
medication for women of child-bearing potential.  Screening labs performed within 72 hours prior to 
Cycle 1 Day 1 do not need to be repeated on C1D1.  
 
2. The first treatment cycle with talimogene laherparepvec is 3 weeks (21 days) in length to allow for 
seroconversion (See Schema in 4.1).  Subsequent treatment cycles are to be repeated every 2 weeks (14 
days) X 8 cycles or until progression, whichever occurs first.  A window of +/- 2 days applies to all 
study visits within the treatment period.   
 
3. The end of treatment/safety follow up visit should only occur when patients permanently stop study 
treatment and should be performed 30 days (+/-7 days) after the last dose of study medication. Patients 
who have an ongoing ≥grade 2 or serious AE (SAE) at this visit will continue to be followed until the 
event is resolved or deemed irreversible by the investigator. Patients stopping talimogene laherparepvec 
should be monitored for at least 30 days for emerging AEs after discontinuing the drug.  After two years 
of follow-up per standard of care (Q3 months +/- 15 days) as outlined in the time and events table, 
subsequent follow up will be by phone contact or via medical records to document disease progression 
and survival information until death (Q3 months +/- 15 days). 
 
4. Complete history at baseline only (to include smoking history), thereafter focused history on 
symptoms/toxicity; physical exam to include height (baseline only), examination of the skin, weight, 
pulse oximetry, and vital signs. 
 
5. Tumor imaging should remain consistent throughout study and performed at baseline, just prior to D1 
of cycle 5, at progression or the end of treatment (i.e. completion of cycle 9), and should include those 
thought by investigator to best capture status of disease.  Examples include PET, contrasted computed 
tomography (CT) of the chest, abdomen and pelvis, and bone scan.  Imaging following completion of 
study procedures should be per standard of care for the relevant disease sate. 
 
6. Hematology: CBC with differential and platelet count; Liver function tests: total bilirubin, direct 
bilirubin, AST (SGOT), ALT (SGPT), and alkaline phosphatase, direct bilirubin if indicated, at screening 
only. Serum chemistry: potassium, sodium, calcium, creatinine, chloride, glucose, magnesium, 
phosphorus, BUN, albumin, uric acid, and total protein.   
 
7. Coagulation: PT or INR and PTT or aPTT 
 
8. Patient drainage diary (See Appendix E in  Section 11.5) 
 
9. Collect urine, pleura and 5 mL of blood (lavender top EDTA tube) at each time point denoted below. 
Additional details on sample collection provided in the study laboratory manual. 
• 
C1D1: pre-dose, 1 hr post dose, 4 hrs post dose and 6 hrs post dose samples 
• 
Collect predose samples on C1D8/C2D1/C2D8/C3D1/C4D1 and at end of treatment 
 
10. Blood samples will be collected for correlative studies (at pretreatment, 3 weeks post treatment, 9 weeks 
post treatment, and end of treatment according to lab manual. 
 
11. Tumor biopsy will be collected for correlative studies. All subjects in this study will have had pleural 
catheter placed as standard of care, which will allow for fresh biopsy collection. If for some reason fresh 
biopsy cannot be collected, archival tumor will be accepted.  
  
12. If feasible, Pleural fluid will be collected for correlative studies at the following time points: pre 
treatment, 3 weeks post treatment, 9 weeks post treatment, and end of treatment, according to the lab 
manual.  
 
13. Modified Borg Rating of Perceived Dyspnea (MBS) will be used to assess level of exertion (Provided 
in 11.6 Appendix F:  Borg Scale). 
 
14. Buccal swab for matched normal genomic DNA 
15. Repeat if insufficient sequencing.  


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
42 
6.2 
Safety Run-in Cohort 2 and expansion (Combination) 
 
Assessments 
Pre-
Study1 
Treatment Period2 
Cycle 1 is 3 weeks in length, subsequent cycles are Q2W 
Follow up 
Cycle 1 
Day 11 
Cycle 1 
Day 8 
Cycle 2 
Day 1 
Cycle 2 
Day 83 
Cycle 3 
Day 1 
Cycle 4 
Day 1 
C5 – 9N 
Day 1 
End of 
TXT4 
Long 
Term FU4 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
HSV-1 antibody 
 X 
 
  
  
  
  
  
  
  
  
History5 
X 
 
 
 
 
 
 
 
 
 
Physical exam5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
EKG 
X 
 
 
 
 
 
X 
 
 
 
Troponin 
X 
 
 
 
 
 
X 
 
 
 
Chest x-ray 
X 
As needed and within 21 days of final drainage ≤ 50 mL 
X 
 
Tumor measurement6 
X 
  
  
 
  
  
 
X6 
X6 
X  
Pregnancy test1 
X 
  
  
  
  
  
  
  
  
  
Hematology7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Serum chemistries7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Liver function tests7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Coagulation8 
X 
 
 
 
 
 
 
 
 
 
Toxicity Assessment  
X 
X 
X 
X 
X 
 X 
X 
X 
X 
X  
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
talimogene laherparepvec IP Q3W 
106 PFU   
  
X 
 
 
 
 
 
 
  
  
talimogene laherparepvec IP Q2W 
108 PFU9   
 
 
 
X 
 
X 
X 
X 
 
 
Nivolumab IV Q2W 
 
X 
 
X 
 
X 
X 
X 
 
 
Patient diary10 
 
X 
X 
X 
X 
X 
X 
X 
X 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
43 
Assessements 
Pre-
Study1 
Treatment Period2 
Cycle 1 is 3 weeks in length, subsequent cycles are Q2W 
Follow up 
Cycle 1 
Day 11 
Cycle 1 
Day 8 
Cycle 2 
Day 1 
Cycle 2 
Day 83 
Cycle 3 
Day 1 
Cycle 4 
Day 1 
C5 – 9N 
Day 1 
End of 
TXT4 
Long 
Term FU4 
Blood/urine/pleura samples to 
assess viral shedding 
 
X11 
X11 
X11 
X11 
X11 
X11 
 
X11 
 
Blood sample for correlative 
studies12 
 
X 
 
X 
 
  
X 
  
X 
  
Tumor biopsy13  
X 
  
 
  
 
  
  
  
 
  
Collection of pleural drainage14 
  
X 
 
X 
 
  
X 
  
X 
  
Buccal Swab 
X16 
X17 
 
 
 
 
 
 
 
 
Modified Borg15 
 
X 
 
X 
 
 
X 
 
X 
 
Survival analysis 
  
  
 
  
 
  
  
  
  
X 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
44 
Key to Time and Events Table Footnotes 
 
1. Radiological assessments, EKG and physical exam may be performed up to 4 weeks prior to day 1 
of treatment.  Other evaluations except for pregnancy must be performed within 2 weeks prior to 
Cycle 1 Day 1 of treatment. Serum B-HCG must be performed within 72 hours prior to first dose of 
study medication for women of child-bearing potential.  Screening labs performed within 72 hours 
prior to Cycle 1 Day 1 do not need to be repeated on C1D1.  
 
2. The first treatment cycle with talimogene laherparepvec is 3 weeks in length (21 days) to allow for 
seroconversion (See Schema in 4.1). Subsequent treatment cycles are to be repeated every 2 weeks 
(14 days) X 8 cycles or until progression, whichever occurs first.  A window of +/- 2 days applies 
to all study visits within the treatment period.   
 
3. Visit may be deemed optional at the behest of the investigator. 
 
4. The end of treatment/safety follow up visit should only occur when patients permanently stop study 
treatment and should be performed 30 days (+/-7 days) after the last dose of study medication. 
Patients who have an ongoing ≥grade 2 or serious AE (SAE) at this visit will continue to be followed 
until the event is resolved or deemed irreversible by the investigator. Patients stopping nivolumab 
should be monitored for at least 100 days after discontinuing the drug for the emergence of SAEs.  
After two years of follow-up per standard of care (Q3 months +/- 15 days) as outlined in the time 
and events table, subsequent follow up will be by phone contact or via medical records to document 
disease progression and survival information until death (Q3 months +/- 15 days). 
 
5. Complete history at baseline only (to include smoking history); thereafter focused history on 
symptoms/toxicity physical exam to include height (baseline only), examination of the skin, weight, 
pulse oximetry, and vital signs. 
 
6. Tumor imaging should remain consistent throughout study, and should include those thought by 
investigator to best capture status of disease.  Examples include PET, contrasted computed 
tomography (CT) of the chest, abdomen and pelvis, and bone scan.  During the treatment period 
scans should occur prior to Cycle 5 Day 1 and every 4 cycles after that until progression. Imaging 
following completion of study procedures should be per standard of care for the relevant disease 
state. 
 
7. Hematology: CBC with differential and platelet count; Liver function tests: total bilirubin, AST 
(SGOT), ALT (SGPT), and alkaline phosphatase; direct bilirubin if indicated, at screening only. 
Serum chemistry: potassium, sodium, calcium, creatinine, chloride, glucose, magnesium, 
phosphorus, BUN, albumin, uric acid, and total protein.   
 
8. Coagulation: PT or INR and PTT or aPTT 
 
9. Talimogene Laherparepvec administration only through Cycle 9. 
 
10. Patient drainage diary (See Appendix E in  Section 11.5) 
 
11. Collect urine, pleura and 5 mL of blood (lavender top EDTA tube) at each time point denoted below. 
Additional details on sample collection provided in the study laboratory manual 
• C1D1: predose, 1 hr post dose, 4 hrs post dose and 6 hrs post dose samples 
• Collect predose samples on C1D8/C2D1/C2D8/C3D1/C4D1 and at end of treatment 
 
12. Blood samples will be collected for correlative studies (3x 8mLs whole blood in ACD tubes will be 
collected to evaluate for clonally restricted circulating B and T cells). 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
45 
13. Tumor biopsy will be collected for correlative studies. All subjects in this study will have had pleural 
catheter placed as standard of care, which will allow for fresh biopsy collection. If for some reason 
fresh biopsy cannot be collected, archival tumor will be accepted.  
  
14. Pleural fluid will be collected studies at the following time points: pre treatment, 3 weeks post 
treatment, 9 weeks post treatment, and end of treatment, separated by the LCCC Immune Monitoring 
and Genomics Facility (IMGF) into two portions: one portion (prioritized) will be used for 
correlativestudies and the second portion will be distributed to CTU lab for long term storage.  
 
15. Modified Borg Rating of Perceived Dyspnea (MBS) will be used to assess level of exertion 
(Provided in 11.6 Appendix F:  Borg Scale).  
 
16. Buccal swab for matched normal genomic DNA 
 
17. Repeat if insufficient sequencing. 
 
6.3 
Pre-Study Assessments for Safety Run in Cohorts and Phase II (Tables 6.1 and 
6.2) 
Screening evaluations are to be conducted within 2 weeks prior to start of protocol 
therapy.  Scans for tumor evaluation must be done within 4 weeks prior to the start 
of therapy.  (Note: Hematology and other lab parameters that are ≤ grade 2 BUT 
still meet criteria for study entry are allowed. Furthermore, changes in laboratory 
parameters during the study should not be considered adverse events unless they 
meet criteria for dose modification(s) of study medication outlined by the protocol 
and/or worsen from baseline during therapy).  Pre-study assessments include: 
 
Complete medical history (including smoking history) and physical examination 
(including skin exam, height, and weight)  
ECOG Performance Status (see appendix A) 
Laboratory evaluations:  
• CBC with differential 
• Serum chemistries (potassium, sodium, calcium, creatinine, chloride, 
glucose, magnesium, phosphorus, BUN, albumin, uric acid, and total 
protein) 
• Liver function tests (total bilirubin, direct bilirubin if indicated, alkaline 
phosphatase, AST, ALT) 
• Troponin 
• Serum pregnancy test in women of childbearing potential (Note: pregnancy 
test to be done within 72 hours of day 1 of treatment) 
• Coagulation (PT/INR) 
• HSV-1 antibody test 
• Blood samples collected for correlative studies 
EKG 
Chest x-ray after thoracentesis (baseline) 
Concomitant medication(s): All concomitant medications will be recorded.   
Tumor evaluation: CT or MRI scan of the neck, results from physical examination 
head and neck, and chest imaging (x-ray or CT scan at discretion of physician)  


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
46 
Tumor biopsy: All subjects will have catheter placed per standard of care, therefore 
fresh biopsy should be easily accessible. If fresh biopsy is unavailable, archival will 
be accepted. 
Toxicity evaluation: Use NCI CTCAEv5.0 for notation of any baseline toxicity 
Modified Borg Scale of Perceived Dyspnea (Provided in 11.6 Appendix F:  Borg 
Scale): Scale ranging from 0 (no dyspnea) to 10, which evaluates perceived level 
of shortness of breath.  
 
6.4 
Study Treatment Assessments (+/- 2 days) 
 Cycle 1/Day 1 Safety Run-in/Phase II expansion (6.1, 6.2) 
Physical examination (including weight and symptom directed medical history  
ECOG Performance Status (see appendix A) 
Laboratory evaluations (to be obtained prior to treatment):  
• CBC with differential 
• Serum chemistries (potassium, sodium, calcium, creatinine, chloride, 
glucose, magnesium, phosphorus, BUN, albumin, uric acid, and total 
protein) 
• Liver function tests (total bilirubin, direct bilirubin, alkaline phosphatase, 
AST, ALT) 
• Serial sampling of blood/urine/pleura to assess viral shedding (pre-dose & 
1hr, 4hr and 6hr post dose samples) following IP talimogene laherparepvec. 
Pleural fluid will be separated by the LCCC Immune Monitoring and 
Genomics Facility (IMGF) into two portions: one portion will be used for 
correlative studies, and the second portion will be distributed to the CTU 
laboratory for long term storage at -80°C for possible assessment of viral 
shedding for up to two years after study completion. If insufficient amount 
of pleural fluid is collected, priority will be given to a sample used for 
correlative studies. 
• Blood samples collected for correlative studies 
Concomitant medication(s): All concomitant medications will be recorded.   
Toxicity evaluation: Use NCI CTCAE v5.0 
Collection of Pleural drainage: prior to talimogene laherparepvec administration, if 
feasible 
For Safety run-in cohort 1 (6.1): Administer premedications, followed by 
talimogene laherparepvec only 4 x106 pfu via pleurX catheter 
For Safety run-in cohort 2 and Phase II expansion (6.2): Administer premedications 
, followed by talimogene laherparepvec 4 x106 pfu via pleurX catheter + 240 mg 
nivolumab IV 
Modified Borg Scale of Perceived Dyspnea (Provided in 11.6 Appendix F:  Borg 
Scale): Scale ranging from 0 to 10, which evaluates perceived level of shortness of 
breath. 
Patient Catheter drainage diary 
Chest x-ray within 21 days of the final drainage of ≤ 50 mL, if applicable. 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
47 
 Cycles 1 & 2/Day 8 Safety Run-in/Phase II expansion (6.1, 6.2) 
Physical examination (including weight)  
ECOG Performance Status (see appendix A) 
Laboratory evaluations (to be obtained prior to treatment):  
• CBC with differential 
• Serum chemistries (potassium, sodium, calcium, creatinine, chloride, 
glucose, magnesium, phosphorus, BUN, albumin, uric acid, and total 
protein) 
• Liver function tests (total bilirubin, direct bilirubin, alkaline phosphatase, 
AST, ALT) 
• Blood/urine/pleura samples to assess viral shedding (pre-dose). Samples 
will be frozen and stored for future research for up to two years after study 
completion. 
Concomitant medication(s): All concomitant medications will be recorded.   
Toxicity evaluation: Use NCI CTCAEv5.0 
Review patient diaries 
Chest x-ray as needed clinically and/or after three consecutive drainages with 
<50cc drainage (every other day drainages) of pleural fluid drainage accompanied 
by patient-defined improvement in symptoms (cough, chest pain and/or dyspnea). 
 
For Phase II expansion only: Once safety is established for the combination, the 
Day 8 visit during cycles 1 and 2 may be deemed optional and not required at the 
behest of the investigator. 
 
 Cycle 2 Day 1 Safety Run-in/Phase II expansion (6.1, 6.2) 
Physical examination (including weight and symptom directed medical history)  
ECOG Performance Status (see appendix A) 
Laboratory evaluations (to be obtained prior to treatment):  
• CBC with differential 
• Serum chemistries (potassium, sodium, calcium, creatinine, chloride, 
glucose, magnesium, phosphorus, BUN, albumin, uric acid, and total 
protein) 
• Liver function tests (total bilirubin, direct bilirubin, alkaline phosphatase, 
AST, ALT) 
• Blood/urine/pleura samples to assess viral shedding (pre-dose). Pleural 
fluid will be separated by the LCCC Immune Monitoring and Genomics 
Facility (IMGF) into two portions: one portion will be used for correlative 
studies, and the second portion will be distributed to the CTU laboratory for 
long term storage at -80°C for possible assessment of viral shedding for up 
to two years after study completion. If insufficient amount of pleural fluid 
is collected, priority will be given to a sample used for correlative studies. 
• Blood samples collected for correlative studies 
Concomitant medication(s): All concomitant medications will be recorded.   
Toxicity evaluation: Use NCI CTCAEv5.0 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
48 
Collection of Pleural drainage: prior to talimogene laherparepvec administration  
Modified Borg Scale of Perceived Dyspnea (Provided in 11.6 Appendix F:  Borg 
Scale): Scale ranging from 0 to 10, which evaluates perceived level of shortness of 
breath.  
For Safety run-in cohort 1 (6.1): (premeds) Administer talimogene laherparepvec 
only 4 x108 pfu via pleurX catheter 
For Safety run-in cohort 2 and Phase II expansion (6.2): (premeds) Administer 
talimogene laherparepvec 4 x108 pfu via pleurX catheter + 240 mg nivolumab IV 
Patient diaries 
Chest x-ray as needed and/or after three consecutive drainages with <50cc drainage 
(every other day drainages) of pleural fluid drainage accompanied by patient-
defined improvement in symptoms (cough, chest pain and/or dyspnea).  
 Day 1/Cycle 3 Safety Run-in/Phase II expansion (6.1, 6.2) 
Physical examination (including weight and symptom directed medical history)  
ECOG Performance Status (see appendix A) 
Laboratory evaluations (to be obtained prior to treatment):  
• CBC with differential 
• Serum chemistries (potassium, sodium, calcium, creatinine, chloride, 
glucose, magnesium, phosphorus, BUN, albumin, uric acid, and total 
protein) 
• Liver function tests (total bilirubin, direct bilirubin, alkaline phosphatase, 
AST, ALT) 
• Blood/urine/pleura samples to assess viral shedding (pre-dose). Samples 
will be frozen and stored for future research for up to two years after study 
completion. 
Concomitant medication(s): All concomitant medications will be recorded.   
Toxicity evaluation: Use NCI CTCAEv5.0 
Patient diaries 
Chest x-ray as needed and/or after three consecutive drainages with <50cc drainage 
(every other day drainages) of pleural fluid drainage accompanied by patient-
defined improvement in symptoms (cough, chest pain and/or dyspnea).  
 
For Safety run-in cohort 1 (6.1): Administer talimogene laherparepvec only 4 x108 
pfu via pleurX catheter 
For Safety run-in cohort 2 and Phase II expansion (6.2 and 6.3): (premeds) 
Administer talimogene laherparepvec 4 x108 pfu via pleurX catheter + 240 mg 
nivolumab IV 
 Day 1/Cycle 4 Safety Run-in/Phase II expansion (6.1, 6.2) 
Physical examination (including weight and symptom directed medical history)  
ECOG Performance Status (see Section 11.1) 
Laboratory evaluations (to be obtained prior to treatment):  
• CBC with differential 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
49 
• Serum chemistries (potassium, sodium, calcium, creatinine, chloride, 
glucose, magnesium, phosphorus, BUN, albumin, uric acid, and total 
protein) 
• Troponin 
• Liver function tests (total bilirubin, direct bilirubin, alkaline phosphatase, 
AST, ALT) 
• Blood/urine/pleura samples to assess viral shedding (pre-dose). Pleural 
fluid will be separated by the LCCC Immune Monitoring and Genomics 
Facility (IMGF) into two portions: one portion will be used for correlative 
studies, and the second portion will be distributed to the CTU laboratory for 
long term storage at -80°C for possible assessment of viral shedding for up 
to two years after study completion. If insufficient amount of pleural fluid 
is collected, priority will be given to a sample used for correlative studies. 
• Blood samples collected for correlative studies 
EKG  
Concomitant medication(s): All concomitant medications will be recorded.   
Toxicity evaluation: Use NCI CTCAEv5.0 
Collection of Pleural drainage: prior to talimogene laherparepvec administration 
Modified Borg Scale of Perceived Dyspnea (Provided in 11.6 Appendix F:  Borg 
Scale): Scale ranging from 0 to 10, which evaluates perceived level of shortness of 
breath. 
Patient diaries 
Chest x-ray as needed and/or after three consecutive drainages with <50cc drainage 
(every other day drainages) of pleural fluid drainage accompanied by patient-
defined improvement in symptoms (cough, chest pain and/or dyspnea). 
 
For Safety run-in cohort 1 (6.1): (premeds) Administer talimogene laherparepvec 
only 4 x108 pfu via pleurX catheter 
For Safety run-in cohort 2 and Phase II expansion (6.2): (premeds) Administer 
talimogene laherparepvec 4 x108 pfu via pleurX catheter + 240 mg nivolumab IV 
 Day 1/Cycle 5-N Safety Run-in/Phase II expansion (6.1, 6.2) 
Physical examination (including weight and pulse oximetry)  
ECOG Performance Status (see appendix A) 
Laboratory evaluations (to be obtained prior to treatment):  
• CBC with differential 
• Serum chemistries (potassium, sodium, calcium, creatinine, chloride, 
glucose, magnesium, phosphorus, BUN, albumin, uric acid, and total 
protein) 
• Liver function tests (total bilirubin, direct bilirubin, alkaline phosphatase, 
AST, ALT) 
Concomitant medication(s): All concomitant medications will be recorded.   
Toxicity evaluation: Use NCI CTCAEv5.0 
Tumor evaluation: CT or MRI scan of the neck, results from physical examination 
head and neck, and chest imaging (x-ray or CT scan at discretion of physician). 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
50 
Scans are to be performed prior to Cycle 5 Day 1 and every 4 cycles after until 
disease progression. 
 
For Safety run-in cohort 1 (6.1): Administer talimogene laherparepvec only 4 x108 
pfu via pleurX catheter per standard of care of related disease state 
 
For Safety run-in cohort 2 and Phase II expansion (6.2): Administer talimogene 
laherparepvec 4 x108 pfu via pleurX catheter + 240 mg nivolumab IV 
Patient diaries 
Chest x-ray as needed and/or after three consecutive drainages with <50cc drainage 
(every other day drainages) of pleural fluid drainage accompanied by patient-
defined improvement in symptoms (cough, chest pain and/or dyspnea).  
6.5 
Post-Treatment/Follow-up Assessments 
 End of Treatment Safety Run-in/Phase II expansion (6.1, 6.2) (+/- 7 days) 
Physical examination (including weight and symptom directed medical history)  
ECOG Performance Status (see appendix A) 
Laboratory evaluations:  
• CBC with differential 
• Serum chemistries (potassium, sodium, calcium, creatinine, chloride, 
glucose, magnesium, phosphorus, BUN, albumin, uric acid, and total 
protein) 
• Liver function tests (total bilirubin, direct bilirubin, alkaline phosphatase, 
AST, ALT) 
• Blood/urine/pleura samples to assess viral shedding. Pleural fluid will be 
separated by the LCCC Immune Monitoring and Genomics Facility (IMGF) 
into two portions: one portion will be used for correlative studies, and the 
second portion will be distributed to the CTU laboratory for long term 
storage at -80°C for possible assessment of viral shedding for up to two 
years after study completion. If insufficient amount of pleural fluid is 
collected, priority will be given to a sample used for correlative studies. 
• Blood samples collected for correlative studies 
Concomitant medication(s): All concomitant medications will be recorded.   
Toxicity evaluation: Use NCI CTCAEv5.0 
Collection of Pleural drainage if feasible 
Modified Borg Scale of Perceived Dyspnea (Provided in 11.6 Appendix F:  Borg 
Scale): Scale ranging from 0 to 10, which evaluates perceived level of shortness of 
breath.  
Patient diaries 
Chest x-ray as needed and/or after three consecutive drainages with <50cc drainage 
(every other day drainages) of pleural fluid drainage accompanied by patient-
defined improvement in symptoms (cough, chest pain and/or dyspnea).  
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
51 
The end of treatment/safety follow up visit should only occur when patients 
permanently stop study treatment and should be performed 30 days (+/-7 days) after 
the last dose of study medication. Patients who have on ongoing ≥grade 2 or serious 
AE (SAE) at this visit will continue to be followed until the event is resolved or 
deemed irreversible by the investigator.   
 
Subjects discontinuing nivolumab should be monitored for at least 100 days after 
discontinuing the drug for the emergence of SAEs.   
 Subsequent Follow-up  
Subjects withdrawn from study therapy will be followed every 3 months (+/- 15 
days) per standard of care. These visits will be limited to history of any subsequent 
cancer treatments, an assessment of any SAE’s considered to be possibly or 
probably related to study treatment until resolution, and survival status. After two 
years of follow-up as described in the time and events tables, subsequent follow-up 
will be per standard of care and subjects will be contacted by phone or via medical 
records for progression and survival information (every 3 months +/- 15 days) until 
death. 
6.6 
Correlative Studies Procedures 
Peripheral blood, pleural fluid, and tumor biopsy samples will be collected as a part 
of this study, according to the time and events table above.  Tumor biopsies will be 
classified as for research purposes only.  Peripheral blood will be processed 
according to TPF standard protocol for generating viably frozen PBMC fractions.  
Pleural fluid samples will be processed fresh; half of each sample will be allocated 
for flow cytometry studies and half for RNA sequencing. 
 
Pleural fluid and tumor biopsy samples will undergo RNA extraction and 
preparation of next generation sequencing libraries for RNA sequencing and T cell 
receptor repertoire sequencing according to 
Immune Monitoring 
and 
Immunogenomics Facility (IMGF) protocols.  The RNA sequencing studies are 
classified as genetic research and will include information regarding somatic 
mutations.  This will be included in the informed consent documentation supporting 
this trial. 
 
Handling of Biospecimens Collected for Correlative Research 
Biospecimens collected for this study will be stored in the Lineberger 
Comprehensive Cancer Center (LCCC) Tissue Procurement Facility (TPF), or if 
needed, in a secure off-site storage facility. All biospecimen samples will be 
obtained in accordance with procedures outlined in the LCCC 1626 Study 
Laboratory Manual and stored in containers with controlled access. Each sample 
will be assigned a unique code number and no identifiable personal health 
information (PHI) will be on the specimen label.  Information about the patient’s 
disease will be linked to the specimens stored in the repository database. TPF-
associated research staff, LCCC Bioinformatics staff who support the TPF database 
and the LCCC Data Warehouse, and researchers with IRB-approval for access to 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
52 
PHI for each subject in this study will be able to link specimens to relevant medical 
information. Some results from laboratory analyses that occurred during the 
patient’s participation in the clinical study may also be included. This information 
may be important for understanding how the patient’s cancer developed and 
responded to treatment. 
 
Storage Time: 
• The biospecimen will be used first and foremost for research purposes 
outlined within the confines of this protocol. Samples will be 
discarded/destroyed after relevant data are collected for this study, unless 
consent was obtained from the patient to use tissue for other research 
purposes (e.g., TPF consent form was signed by the patient).  In this 
circumstance, there is no time limit on how long biospecimens may be 
stored. 
• The investigator must agree to abide by policies and procedures of the TPF 
facility and sign a letter of research agreement for ethical and appropriate 
conduct of their research that utilizes specimens obtained from the TPF 
facility (e.g., Use of leftover specimens will require a protocol outlining the 
research plan for biospecimen use).  
 
Compliance Statement 
Biospecimen collection for this study will be conducted in full accordance to all 
applicable University of North Carolina (UNC) Research Policies and Procedures 
and all applicable Federal and state laws and regulations including 45 CFR 46, and 
the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule. 
Any episode of noncompliance will be documented. 
 
The investigators will perform the study in accordance with this protocol, will 
obtain consent and assent (unless a waiver is granted), and will report unexpected 
problems in accordance with The UNC IRB Policies and Procedures and all federal 
requirements. Collection, recording, and reporting of data will be accurate and will 
ensure the privacy, health, and welfare of research subjects during and after the 
study.  
6.7 
Assessment of Safety  
Any patient who receives treatment on this protocol will be evaluable for toxicity.  
Each patient will be assessed periodically for the development of any toxicity 
according to the Time and Events tables.  Toxicity will be assessed according to 
the NCI CTCAE v5.0. 
6.8 
Evaluation of Response by irRECIST [62] per Bohnsack et al.  
 
New measurable lesions in irRECIST:  
New measurable lesions will not necessarily constitute PD or preclude partial 
response (PR).  Rather, the difference between the current size of a measurable 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
53 
lesions and its size prior to meeting criteria for measurability will be added to the 
sum of tumor measurements.  
 
Definition of Response Using irRECIST 
irComplete Response (irCR): Complete disappearance of all lesions 
(whether measurable or not) and no new lesions.  Lymph nodes must 
decrease to <10mm in short axis.  Confirmation of a response is not 
mandatory.  It is the judgment of the investigator whether a nonmeasurable 
radiographic nodule is likely cancerous; only nodules felt likely cancerous 
will preclude the judgement of irCR. 
 
• irPartial Response (irPR): Decrease in tumor burden ≥ 30%, in total 
measured tumor burden relative to baseline, non-target lesions are irNN, 
and no unequivocal progression of new non-measurable lesions  
 
• irNon CR/Non-PD (irNN): No target disease was identified at baseline and 
at follow up the patient fails to meet criteria for irCR or irPD. 
 
• irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the 
absence of irPD. 
 
• irProgressive Disease (irPD): At least 20% and minimum 5 mm absolute 
increase in total measured tumor burden compared to nadir, or irPD for non-
target or new on-measureable lesions. Confirmation of progression is 
recommended minimum of 4 weeks after the first irPD assessment.  
 
• Nonprogressive disease: Measurable disease is not required for this study.  
Patients with CR at the time of study entry or otherwise nonmeasurable 
disease will be assessed for progression.  In the event of PD, this should be 
noted.  In the absence of meeting criteria for progression, nonprogressive 
disease should be coded (NPD). 
 
Immune-related Best Overall Response (irBOR):  
IrBOR is the best response observed during the relevant time period.  Of note, when 
total tumor burden increases and the patient is maintained on therapy, and tumor 
then shrinks (pseudo-progression) the second measurement will be utilized. 
 
Designation of pseudo-progression:  
The phenomenon of pseudo-progression is of particular interest in this trial. For the 
purpose of this trial, pseudo-progression will be defined as any > 10% increase in 
tumor burden followed by a > 10% decrease in tumor burden prior to change in 
therapy.  Such occurrences will be noted for the purpose of exploratory hypothesis-
generating analyses. 
 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
54 
7.0 
ADVERSE EVENTS 
7.1 
Definitions  
 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of a 
drug) in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal product, whether or not related to the medicinal product.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the 
result of an AE (e.g., surgical insertion of central line) need not be considered AEs 
and should not be recorded as an AE.  Disease progression should not be recorded 
as an AE, unless it is attributable by the investigator to the study therapy. 
 
From the time of treatment through 30 days following cessation of treatment, all 
adverse events must be reported by the investigator. Such events will be recorded 
at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.3. The investigator will make every attempt to follow all subjects with 
non-serious adverse events for outcome. 
 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable 
possibility that the drug is the cause.   Reasonable possibility means that there is 
evidence to suggest a causal relationship between the drug and the AE.  A suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any adverse event caused by a drug.   
 
Causality assessment to a study drug is a medical judgment made in consideration 
of the following factors: temporal relationship of the AE to study drug exposure, 
known mechanism of action or side effect profile of study treatment, other recent 
or concomitant drug exposures, normal clinical course of the disease under 
investigation, and any other underlying or concurrent medical conditions.  Other 
factors to consider in considering drug as the cause of the AE: 
• Single occurrence of an uncommon event known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome) 
• One or more occurrences of an event not commonly associated with drug 
exposure, but otherwise uncommon in the population (e.g., tendon rupture); 
often more than once occurrence from one or multiple studies would be 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
55 
needed before the sponsor could determine that there is reasonable 
possibility that the drug caused the event.   
• An aggregate analysis of specific events observed in a clinical trial that 
indicates the events occur more frequently in the drug treatment group than 
in a concurrent or historical control group 
 Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not 
consistent with the applicable product information (e.g., Investigator’s Brochure 
(IB) for an unapproved investigational product or package insert/summary of 
product characteristics for an approved product).  Unexpected also refers to AEs or 
SARs that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.   
 Serious AE or SAR 
An AE or SAR is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
• Death; 
• Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred); 
• Requires inpatient hospitalization (>24 hours) or prolongation of 
existing hospitalization;* 
• Results in congenital anomaly/birth defect; 
• Results in a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions; 
• Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in 
the definition.  For reporting purposes, also consider the occurrences of 
pregnancy as an event which must be reported as an important medical 
event. 
• Potential drug induced liver injury (DILI) is also considered an 
important medical event.  
• Suspected transmission of an infectious agent (e.g., pathogenic or 
nonpathogenic) via the study drug is an SAE.  
• Although pregnancy, overdose, and cancer are not always serious by 
regulatory definition, these events must be handled as SAEs. 
 
 
*Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
56 
therapy, resection of primary tumor, or elective surgery, will not be considered 
serious adverse events. 
 
Pregnancy that occurs during the study must also be reported as an SAE. 
 
Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the BMS and 
Amgen in the same timeframe as SAEs to meet certain local requirements. 
Therefore, these events are considered serious by BMS for collection purposes. 
● Is a new cancer (that is not a condition of the study); 
● Is associated with an overdose. 
7.2 
Documentation of non-serious AEs or SARs 
For non-serious AEs or SARs, documentation must begin from day 1 of study 
treatment and continue through the 100 day follow-up period after nivolumab 
treatment is discontinued.  Subjects should be followed for AEs for at least 30 days 
after talimogene laherparepvec is discontinued.   
 
Collected information should be recorded in the Case Report Forms (CRF) for that 
patient.  Please include a description of the event, its severity or toxicity grade, 
onset and resolved dates (if applicable), and the relationship to the study drug.  
7.3 
SAEs or Serious SARs  
 Timing 
After informed consent but prior to initiation of study medications, only SAEs 
caused by a protocol-mandated intervention will be collected (e.g., SAEs related to 
invasive procedures such as biopsies, medication washout).  
 
For any other experience or condition that meets the definition of an SAE or a 
serious SAR, recording of the event must begin from day 1 of study treatment and 
continue at least through the 100 day follow-up period after treatment is 
discontinued. Ultimately, the event should be followed until resolution of 
symptoms or the investigator determines that symptoms have improved to the 
fullest extent possible. 
 Documentation and Notification 
SAEs or Serious SARs must be recorded in the SAE console within Oncore™ for 
that patient within 24 hours of learning of its occurrence.   
 Reporting  
7.3.3.1 IRB Reporting Requirements: 
The UNC-IRB will be notified of all SAEs that qualify as an Unanticipated 
Problem as per the UNC IRB Policies using the IRB’s web-based reporting 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
57 
system (see section 9.5.3) within 7 days of the Investigator becoming aware of 
the problem.   
7.3.3.2 Pregnancy 
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or 
lactation in a subject (spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before 
treatment allocation/randomization must be reported by the investigator if they 
cause the subject to be excluded from the trial, or are the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.   
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject occurring while the subject 
is on study or within 30 days of the subject’s last dose of talimogene 
laherparepvec or within the period stipulated for continued contraceptive use for 
WOCBP (5 months) and sexually active men (7 months) after the subject’s last 
dose of nivolumab should be recorded as SAEs.  The patient is to be discontinued 
immediately from the study for a pregnancy event.  
 
The Investigator will follow the female subject until completion of the pregnancy, 
and must document the outcome of the pregnancy (either normal or abnormal 
outcome) and report the condition of the fetus or newborn to the UNC study 
coordinator. If the outcome of the pregnancy was abnormal (e.g., spontaneous or 
therapeutic abortion), the Investigator should report the abnormal outcome as an 
AE. If the abnormal outcome meets any of the serious criteria, it must be reported 
as an SAE.   
 
7.3.3.3 Laboratory Test Abnormalities 
The following laboratory abnormalities should be documented and reported 
appropriately as AEs: 
• any laboratory test result that is clinically significant or meets the definition 
of an SAE 
• any laboratory abnormality that required the subject to have study drug 
discontinued or interrupted 
• any laboratory abnormality that required the subject to receive specific 
corrective therapy.  
 
7.3.3.4 Overdose 
An overdose is defined as the accidental or intentional administration of any dose 
of a product that is considered both excessive and medically important. All 
occurrences of overdose must be reported as an SAE. 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
58 
7.3.3.5 Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x rays, and any other potential safety assessments, whether 
or not these procedures are required by the protocol, should also be recorded as a 
non-serious or serious AE, as appropriate, and reported accordingly. 
 
7.3.3.6 Amgen Reporting Requirements: 
Please refer to the table below regarding policy for reporting SUSARs, and 
other safety related data to Amgen. 
 
Expedited Reporting Requirements for Interventional Studies 
Safety Data 
Timeframe for Submission to Amgen 
Suspected Unexpected Serious 
Adverse Reaction (SUSARs) 
Individual reports sent to Amgen at time of 
expedited reporting to the IRB and/or FDA  
Serious Adverse Events (SAEs) 
(related) 
Individual reports sent to Amgen at time of 
expedited reporting to IRB and/or FDA  
Pregnancy/Lactation 
Individual reports sent within 10 days of 
Sponsor/Investigator awareness (Use Amgen 
template forms provided for the study to 
report pregnancy or lactation events). 
Individual reports should be faxed to 1-888-814-8653 or scanned and sent via 
email to svc-ags-in-us@amgen.com. 
 
Aggregate reports should be submitted via email to the non-Amgen sponsored 
Clinical Research (NASCR) manager accompanied by the Aggregate Safety 
Reporting fax transmittal form for Investigator Sponsored Studies provided for 
the study.  
 
Please refer to the ICH Guidelines E2A for safety related definitions and 
terminology: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Effic
acy/E2A/Step4/E2A_Guideline.pdf 
 
7.3.3.7 Suspected Herpetic Events 
Suspected herpetic events must be reported to Amgen within 24 hours of 
awareness.  Reporting is required for: (1) suspected herpetic events in treated 
patients; (2) suspected herpetic events in at risk health care professionals with 
direct or indirect exposure and 3) suspected herpetic events in treated patient’s 
close contacts.  
 
In addition to reporting these events, suspected herpetic lesions should be 
swabbed and submitted for quantitative polymerase chain reaction testing for the 
detection of talimogene laherparepvec. Samples should be collected using 
appropriate technique and a flocked swab from site supplies. This test is likely to 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
59 
be more reliable if performed within the first three days of symptom 
appearance. Amgen does not require quantitative polymerase chain reaction or 
other testing for wild type herpes simplex virus-1. See section below on reporting 
process for health care providers which should be followed if herpetic lesions are 
suspected. 
 
Reporting Process for Treated Patients: 
 Any suspected herpetic lesion should be reported to Amgen at 1-855-465-
9442 or 1-855-IMLYGIC, evaluated by the sponsor/investigator and 
swabbed for quantitative polymerase chain reaction testing 
 Once an initial report has been made, additional materials will be provided, 
including reporting forms and supplies needed for shipment of swab 
samples. Amgen will require patient consent for quantitative polymerase 
chain reaction testing, which must be obtained prior to swabbing. 
 
Reporting process for health care providers and close contacts:  
 Sponsor investigator should advise any health care providers and/or close 
contacts with suspected herpetic lesions to contact their personal physician 
to facilitate reporting to Amgen. Suspected herpetic lesions should be 
reported by the personal physician or exposed individual to Amgen at 1-
855-465-9442. Once an initial report has been made, additional materials 
will be provided, including reporting forms and supplies needed for 
shipment of swab samples. Amgen will require patient consent for 
quantitative polymerase chain reaction testing, which must be obtained 
prior to swabbing. 
7.3.3.8 FDA Expedited Reporting requirements for studies conducted under an 
IND: 
A sponsor must report any suspected adverse reaction that is both serious and 
unexpected to the FDA. The sponsor must report an adverse event as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between 
the drug and the adverse event. Refer to Section 7.1.2 for the definition of SAR.  
 
The sponsor must submit each IND safety report on FDA Form 3500A.  
 
Timing 
FDA must be notified of potential serious risks within 15 calendar days after the 
sponsor determines the event requires reporting. FDA must be notified of 
unexpected fatal or life-threatening suspected adverse reactions as soon as 
possible but in no case later than 7 calendar days after the sponsor’s initial receipt 
of the information. If the results of a sponsor’s investigation show that an adverse 
event not initially determined to be reportable is reportable, the sponsor must 
report such suspected adverse reaction in an IND safety report as soon as possible, 
but in no case later than 15 calendar days after the determination is made. 
 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
60 
Follow-up 
The sponsor must promptly investigate all safety information it receives. Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available.  
 
Notification of Investigators 
The sponsor must notify all participating investigators (i.e., all investigators to 
whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks, from clinical trials or any 
other source, as soon as possible, but in no case later than 15 calendar days after 
the sponsor determines that the information qualifies for reporting.  
 
Process 
If the sponsor deems that an event is both a serious SAR AND unexpected, it must 
also (in addition to OncoreTM) be recorded on the MedWatch Form 3500A as per 
21 CFR 312.32.  Unexpected adverse events or adverse reaction refers to an event 
or reaction that is not listed in the investigator’s brochure or is not listed at the 
specificity or severity that has been observed; or if an investigator’s brochure is not 
required or available, is not consistent with the risk information described in the 
general investigation plan or elsewhere in the current IND application.   
 
The FDA must be notified or any unexpected or life-threatening suspected adverse 
reactions as soon as possible, but no later than 7 calendar days of learning of the 
event. 
 
Additional Reporting Requirements 
The following additional items must be reported via IND safety report: 
• Findings from other studies. The sponsor must report any findings from 
epidemiological studies, pooled analysis of multiple studies, or clinical 
studies, whether or not conducted under an IND, and whether or not 
conducted by the sponsor, that suggest a significant risk to humans 
exposed to the drug.  
• Findings from animal or in vitro testing. The sponsor must report any 
findings from animal or in vitro testing, whether or not conducted by the 
sponsor, that suggest a significant risk in humans exposed to the drug, 
such as reports of mutagenicity, teratogenicity, or carcinogenicity, or 
reports of significant organ toxicity t or near the expected human 
exposure. 
• Increased rate of occurrence of serious suspected adverse reactions. 
 
Additional Guidance 
Please refer to 21CFR312.32 and “Guidance for Industry and Investigators: 
Safety Reporting Requirements for INDs and BA/BE Studies” for additional 
information and reporting requirements. All IND Safety Reports will be 
submitted in accordance with these regulations/guidances.  
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
61 
7.3.3.9 Institutional Biosafety Committee (IBC) 
In addition to the local IRB, any qualifying serious adverse events (SAEs) must 
be reported to the Institutional Biosafety Committee (IBC). The IBC is 
responsible for reviewing recombinant DNA research conducted at or sponsored 
by the institution for compliance with NIH Guidelines as specified in Section III, 
Experiments covered by the NIH Guidelines and approving those research 
projects that are found to conform with the NIH Guidelines. As such, the IBC is 
charged with ensuring compliance with all surveillance, data reporting and 
adverse event reporting requirements set forth in the NIH Guidelines. 
7.4 
Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of patient safety in 
this trial with periodic reporting to the Data and Safety Monitoring Committee 
(DSMC).  
 
Meetings/teleconferences will be held at a frequency dependent on study accrual, 
and in consultation with the study Biostatistician.  These meetings will include the 
investigators as well as study coordinators, data coordinators, regulatory associates, 
clinical data management associates, and any other relevant personnel the principal 
investigators may deem appropriate.  At these meetings, the research team will 
discuss all issues relevant to study progress, including enrollment, safety, 
regulatory, data collection, etc. 
 
The team will produce summaries or minutes of these meetings. These summaries 
will be available for inspection when requested by any of the regulatory bodies 
charged with the safety of human subjects and the integrity of data including, but 
not limited to, the oversight (Office of Human Research Ethics (OHRE) Biomedical 
IRB, the Oncology Protocol Review Committee (PRC) or the North Carolina 
TraCS Institute Data and Safety Monitoring Board (DSMB).   
 
The UNC LCCC Data and Safety Monitoring Committee (DSMC) will review the 
study on a regular (quarterly to annually) basis, with the frequency of review based 
on risk and complexity as determined by the UNC Protocol Review Committee.  
The principal investigator will be responsible for submitting the following 
information for review: 1) safety and accrual data including the number of patients 
treated; 2) significant developments reported in the literature that may affect the 
safety of participants or the ethics of the study; 3) preliminary response data; and 
4) summaries of team meetings that have occurred since the last report.  Findings 
of the DSMC review will be disseminated by memo to the principal investigator, 
PRC, and the UNC IRB.   
 
 
 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
62 
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
Study Design/Study Endpoints 
A 3 + 3 dose escalation scheme will be used for Dose Level 1 safety run-in followed 
by Dose Level 2 evaluation for the primary endpoint. In Phase I, patients will be 
assigned in cohorts of 3, starting with Dose Level 1. The acceptable dose will be 
defined as the highest dose at which ≤1 out of 6 patients have experienced a dose 
limiting toxicity (DLT). We anticipate that 3 patients will be accrued to Dose Level 
1 without DLTs and that there will be no DLTs in Dose Level 2 cohort.  
 
The primary study will be the phase II portion (Dose Level 2), where the primary 
endpoint is rate of resolution of pleural effusion. All patients treated at dose level 2 
in Phase I or Phase II, will be included in analyses of safety and efficacy. 
8.2 
Sample Size and Accrual 
The null hypothesis that the true rate of resolution of pleural effusion is 45% (Van 
Meyer 2011) will be tested against a two-sided alternative. The null hypothesis will 
be rejected if 15 or more responses are observed in 24 patients. A one group chi-
squared test with a 0.100 two-sided significance level will have 80% power to 
detect the difference between the null hypothesis proportion of 45% and the 
alternative proportion of 70% when the sample size is 24. This sample size was 
calculated using nQuery Advisor v7.0.  
 
For the phase II portion, sequential boundaries will be used to suspend the trial if 
excessive numbers of patients experience an unacceptable toxicity. If the study 
reaches a stopping boundary, it may be terminated by the PI, or submitted to the 
Data and Safety Monitoring Committee with a description of the failures to date 
and a rationale for why the study should be continued. An unacceptable toxicity is 
defined as any grade 3-5 adverse event attributed to therapy (with exceptions; see 
section 4.1.1 Definitions of Dose Limiting Toxicities (DLT) – Safety Run-in). The 
accrual will be halted if the number of patients with unacceptable toxicity is equal 
to or exceeds bn out of n patients with full toxicity follow-up (see table below). 
This is a Pocock type stopping boundary that assumes that an unacceptable toxicity 
rate of 0.20 is acceptable. If the true rate is equal to 0.20, the probability of crossing 
the boundary is 0.05.  
 
Number of 
Patients, n 
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Boundary, bn 
- 
- 
3 4 4 4 5 5 6 6 6 7 7 7 8 8 8 8 9 9 
Number of 
Patients, n 
21 22 23 24 25 26 27 28 29 30 
 
 
 
 
 
 
 
 
 
 
Boundary, bn 
9 10 10 10 11 11 11 11 12 12 
 
 
 
 
 
 
 
 
 
 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
63 
Additionally, during the safety run-in (as indicated in section 4.1.1 of the protocol) 
if ≥2 subjects experience a DLT at either dose level then the study will be 
discontinued. 
 
Any death (other than death related to progressive disease) within 30 days of study 
drug administration will result in the study pausing whereupon the study will be 
placed on hold until an appropriate evaluation of the cause of death and a plan of 
correction, if necessary, is established.  
 
8.3 
Data Analysis Plans 
For the Phase I primary objective, we will summarize the toxicities of the patients.  
For the Phase II primary objective of estimating the rate of resolution of the 
malignant pleural effusion re-accumulation following IV nivolumab combined with 
intrapleural injection of talimogene laherparepvec, the percent of patients will be 
reported with a 95% confidence interval, and compared to the nullusing a chi-
squared test.   
 
Response rates and adverse events will be reported. Progression free survival, 
overall survival, and time to symptomatic pleural re-accumulation will be estimated 
using the Kaplan-Meier method.  Available quality of life data will be summarized 
over the course of the study.   
9.0 
STUDY MANAGEMENT 
9.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration of 
Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that the 
patient understands the implications of participating in the study, the patient will be 
asked to give consent to participate in the study by signing an IRB-approved 
consent form. 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
64 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
9.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Protocol Office (CPO) at the University of North Carolina. 
• A copy of the official IRB approval letter for the protocol and informed 
consent 
• IRB membership list 
• CVs and medical licensure for the principal investigator and any sub-
investigators who will be involved in the study. 
• Form FDA 1572 appropriately filled out and signed with appropriate 
documentation  
• Financial Disclosures  
• CAP and CLIA Laboratory certification numbers and institution lab 
normal values 
• Executed clinical research contract 
9.3 
Registration Procedures 
All patients must be registered with the CPO at the University of North Carolina 
before enrollment to study.  Prior to registration, eligibility criteria must be 
confirmed with the UNC Study Coordinator.  To register a patient, call the CPO 
at 919-966-4432 Monday-Friday 9:00 am – 5:00 pm EST or email the UNC Project 
Manager. 
 
9.4 
Data Management and Monitoring/Auditing 
The CPO of the UNC LCCC will serve as the coordinating center for this trial. Data 
will be collected through a web based clinical research platform, OnCore®. All data 
will be collected and entered into OnCore® by research coordinators from UNC 
LCCC.  
 
As an investigator initiated study, this trial will also be audited by the LCCC 
compliance committee every six or twelve months. 
 
9.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.   


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
65 
 Emergency Modifications 
UNC investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior UNC or their 
respective institution’s IRB/IEC approval/favorable opinion.   
 
For any such emergency modification implemented, a UNC IRB modification form 
must be completed by UNC Research Personnel within five (5) business days of 
making the change.   
 Single Patient/Subject Exceptions 
Eligibility single subject exceptions are not permitted for Lineberger 
Comprehensive Cancer Center Investigator Initiated Trials under any 
circumstances. Other types of single subject exceptions may be allowed if proper 
regulatory review has been completed in accordance with Lineberger 
Comprehensive Cancer Center’s Single Subject Exceptions Policy. 
 Other Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  
• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance meets any 
of the following criteria:  
• Has harmed or increased the risk of harm to one or more research 
participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs, please follow the guidelines below: 
 
Protocol Deviations: UNC personnel will record the deviation in OnCore®, and 
report to any sponsor or data and safety monitoring committee in accordance with 
their policies.  Deviations should be summarized and reported to the IRB at the time 
of continuing review. 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
66 
Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB online 
mechanism used to report Unanticipated Problems.   
 
 
Unanticipated Problems: Any events that meet the criteria for “Unanticipated 
Problems” as defined by UNC’s IRB must be reported by the study personnel using 
the IRB’s web-based reporting system.   
9.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated 
and documented by the Principal Investigator at UNC.  It should also be noted that 
when an amendment to the protocol substantially alters the study design or the 
potential risk to the patient, a revised consent form might be required.  All protocol 
amendments will be submitted to Amgen for review. 
 
The written amendment, and if required the amended consent form, must be sent to 
UNC’s IRB for approval prior to implementation.   
9.7 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction 
of the clinical research study. 
 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study 
investigator.  In the case of a study with a drug seeking regulatory approval and 
marketing, these documents shall be retained for at least two years after the last 
approval of marketing application in an International Conference on Harmonization 
(ICH) region.  In all other cases, study documents should be kept on file until three 
years after the completion and final study report of this investigational study. 
9.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study staff 
members, adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion. 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
67 
 
The Principal Investigator will be responsible for assuring that all the required data 
will be collected and entered into the eCRFs. Periodically, monitoring visits will be 
conducted and the Principal Investigator will provide access to his/her original 
records to permit verification of proper entry of data. At the completion of the 
study, all eCRFs will be reviewed by the Principal Investigator and will require 
his/her final signature to verify the accuracy of the data. 
 
10.0 REFERENCES 
1. 
Spella, M., A.D. Giannou, and G.T. Stathopoulos, Switching off malignant 
pleural effusion formation-fantasy or future? J Thorac Dis, 2015. 7(6): p. 
1009-20. 
2. 
Zocchi, L., Physiology and pathophysiology of pleural fluid turnover. Eur 
Respir J, 2002. 20(6): p. 1545-58. 
3. 
Meyer, P.C., Metastatic carcinoma of the pleura. Thorax, 1966. 21(5): p. 
437-43. 
4. 
Sahn, S.A., Pleural diseases related to metastatic malignancies. Eur Respir 
J, 1997. 10(8): p. 1907-13. 
5. 
Stathopoulos, G.T. and I. Kalomenidis, Malignant pleural effusion: tumor-
host interactions unleashed. Am J Respir Crit Care Med, 2012. 186(6): p. 
487-92. 
6. 
Yano, S., et al., Production of experimental malignant pleural effusions is 
dependent on invasion of the pleura and expression of vascular endothelial 
growth factor/vascular permeability factor by human lung cancer cells. Am 
J Pathol, 2000. 157(6): p. 1893-903. 
7. 
Gary Lee, Y.C., et al., Transforming growth factor beta induces vascular 
endothelial growth factor elaboration from pleural mesothelial cells in vivo 
and in vitro. Am J Respir Crit Care Med, 2002. 165(1): p. 88-94. 
8. 
Stathopoulos, 
G.T., 
et 
al., 
Host-derived 
interleukin-5 
promotes 
adenocarcinoma-induced malignant pleural effusion. Am J Respir Crit 
Care Med, 2010. 182(10): p. 1273-81. 
9. 
Stathopoulos, G.T., et al., Tumor necrosis factor-alpha promotes malignant 
pleural effusion. Cancer Res, 2007. 67(20): p. 9825-34. 
10. 
Stathopoulos, G.T., et al., A central role for tumor-derived monocyte 
chemoattractant protein-1 in malignant pleural effusion. J Natl Cancer Inst, 
2008. 100(20): p. 1464-76. 
11. 
Yeh, H.H., et al., Autocrine IL-6-induced Stat3 activation contributes to the 
pathogenesis of lung adenocarcinoma and malignant pleural effusion. 
Oncogene, 2006. 25(31): p. 4300-9. 
12. 
Psallidas, I., et al., Secreted phosphoprotein-1 directly provokes vascular 
leakage to foster malignant pleural effusion. Oncogene, 2013. 32(4): p. 528-
35. 
13. 
Stathopoulos, G.T., Translational advances in pleural malignancies. 
Respirology, 2011. 16(1): p. 53-63. 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
68 
14. 
Roberts, M.E., et al., Management of a malignant pleural effusion: British 
Thoracic Society Pleural Disease Guideline 2010. Thorax, 2010. 65 Suppl 
2: p. ii32-40. 
15. 
Davies, H.E. and Y.C. Lee, Management of malignant pleural effusions: 
questions that need answers. Curr Opin Pulm Med, 2013. 19(4): p. 374-9. 
16. 
Heffner, J.E., P.J. Nietert, and C. Barbieri, Pleural fluid pH as a predictor 
of survival for patients with malignant pleural effusions. Chest, 2000. 
117(1): p. 79-86. 
17. 
CareFusion, PleurX Pleural Catheter Kit. 2015. 
18. 
Chalhoub, M., et al., Experience with indwelling pleural catheters in the 
treatment of recurrent pleural effusions. Ther Adv Respir Dis, 2016. 
19. 
Brahmer, J.R., et al., Phase I study of single-agent anti-programmed death-
1 (MDX-1106) in refractory solid tumors: safety, clinical activity, 
pharmacodynamics, and immunologic correlates. J Clin Oncol, 2010. 
28(19): p. 3167-75. 
20. 
Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. N Engl J Med, 2012. 366(26): p. 2443-54. 
21. 
Squibb, B.-M., Nivolumab Investigator's Brochure. 2015 (Version 14). 
22. 
Disis, M.L., Immune regulation of cancer. J Clin Oncol, 2010. 28(29): p. 
4531-8. 
23. 
Brown, J.A., et al., Blockade of programmed death-1 ligands on dendritic 
cells enhances T cell activation and cytokine production. J Immunol, 2003. 
170(3): p. 1257-66. 
24. 
Dong, H., et al., Tumor-associated B7-H1 promotes T-cell apoptosis: a 
potential mechanism of immune evasion. Nat Med, 2002. 8(8): p. 793-800. 
25. 
Francisco, L.M., P.T. Sage, and A.H. Sharpe, The PD-1 pathway in 
tolerance and autoimmunity. Immunol Rev, 2010. 236: p. 219-42. 
26. 
Sharpe, A.H. and G.J. Freeman, The B7-CD28 superfamily. Nat Rev 
Immunol, 2002. 2(2): p. 116-26. 
27. 
Thompson, R.H., et al., PD-1 is expressed by tumor-infiltrating immune 
cells and is associated with poor outcome for patients with renal cell 
carcinoma. Clin Cancer Res, 2007. 13(6): p. 1757-61. 
28. 
Talmadge, J.E., M. Donkor, and E. Scholar, Inflammatory cell infiltration 
of tumors: Jekyll or Hyde. Cancer Metastasis Rev, 2007. 26(3-4): p. 373-
400. 
29. 
Usubutun, A., et al., Prognostic factors in renal cell carcinoma. J Exp Clin 
Cancer Res, 1998. 17(1): p. 77-81. 
30. 
Deschoolmeester, V., et al., Tumor infiltrating lymphocytes: an intriguing 
player in the survival of colorectal cancer patients. BMC Immunol, 2010. 
11: p. 19. 
31. 
Diez, M., et al., Histopathologic prognostic score in colorectal 
adenocarcinomas. Anticancer Res, 1998. 18(1B): p. 689-94. 
32. 
Galon, J., et al., Type, density, and location of immune cells within human 
colorectal tumors predict clinical outcome. Science, 2006. 313(5795): p. 
1960-4. 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
69 
33. 
Hodi, F.S. and G. Dranoff, The biologic importance of tumor-infiltrating 
lymphocytes. J Cutan Pathol, 2010. 37 Suppl 1: p. 48-53. 
34. 
Kloor, M., Lymphocyte infiltration and prognosis in colorectal cancer. 
Lancet Oncol, 2009. 10(9): p. 840-1. 
35. 
Hillen, F., et al., Leukocyte infiltration and tumor cell plasticity are 
parameters of aggressiveness in primary cutaneous melanoma. Cancer 
Immunol Immunother, 2008. 57(1): p. 97-106. 
36. 
Lee, H.E., et al., Prognostic implications of type and density of tumour-
infiltrating lymphocytes in gastric cancer. Br J Cancer, 2008. 99(10): p. 
1704-11. 
37. 
Leffers, N., et al., Prognostic significance of tumor-infiltrating T-
lymphocytes in primary and metastatic lesions of advanced stage ovarian 
cancer. Cancer Immunol Immunother, 2009. 58(3): p. 449-59. 
38. 
Nishimura, H., T. Honjo, and N. Minato, Facilitation of beta selection and 
modification of positive selection in the thymus of PD-1-deficient mice. J 
Exp Med, 2000. 191(5): p. 891-8. 
39. 
Hiraoka, 
N., 
Tumor-infiltrating 
lymphocytes 
and 
hepatocellular 
carcinoma: molecular biology. Int J Clin Oncol, 2010. 15(6): p. 544-51. 
40. 
Liotta, F., et al., Frequency of regulatory T cells in peripheral blood and in 
tumour-infiltrating lymphocytes correlates with poor prognosis in renal cell 
carcinoma. BJU Int, 2011. 107(9): p. 1500-6. 
41. 
BMS, Nivolumb Package Insert. Bristol Myers Squibb, 2017: p. 1-23. 
42. 
Borghaei, H., et al., Nivolumab versus Docetaxel in Advanced 
Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med, 2015. 373(17): 
p. 1627-39. 
43. 
Ferris, R.L., et al., Nivolumab for Recurrent Squamous-Cell Carcinoma of 
the Head and Neck. N Engl J Med, 2016. 375(19): p. 1856-1867. 
44. 
Andtbacka, R.H., et al., Talimogene Laherparepvec Improves Durable 
Response Rate in Patients With Advanced Melanoma. J Clin Oncol, 2015. 
33(25): p. 2780-8. 
45. 
MacKie, R.M., B. Stewart, and S.M. Brown, Intralesional injection of 
herpes simplex virus 1716 in metastatic melanoma. Lancet, 2001. 
357(9255): p. 525-6. 
46. 
Hu, J.C., et al., A phase I study of OncoVEXGM-CSF, a second-generation 
oncolytic herpes simplex virus expressing granulocyte macrophage colony-
stimulating factor. Clin Cancer Res, 2006. 12(22): p. 6737-47. 
47. 
Amgen, Talimogene Laherparepvec. 2015(Version 5.0). 
48. 
Liu, B.L., et al., ICP34.5 deleted herpes simplex virus with enhanced 
oncolytic, immune stimulating, and anti-tumour properties. Gene Ther, 
2003. 10(4): p. 292-303. 
49. 
Dranoff, G., et al., Vaccination with irradiated tumor cells engineered to 
secrete 
murine 
granulocyte-macrophage 
colony-stimulating 
factor 
stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl 
Acad Sci U S A, 1993. 90(8): p. 3539-43. 
50. 
Toda, M., R.L. Martuza, and S.D. Rabkin, Tumor growth inhibition by 
intratumoral inoculation of defective herpes simplex virus vectors 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
70 
expressing granulocyte-macrophage colony-stimulating factor. Mol Ther, 
2000. 2(4): p. 324-9. 
51. 
Chou, J., et al., Mapping of herpes simplex virus-1 neurovirulence to 
gamma 134.5, a gene nonessential for growth in culture. Science, 1990. 
250(4985): p. 1262-6. 
52. 
Bolovan, C.A., N.M. Sawtell, and R.L. Thompson, ICP34.5 mutants of 
herpes simplex virus type 1 strain 17syn+ are attenuated for neurovirulence 
in mice and for replication in confluent primary mouse embryo cell cultures. 
J Virol, 1994. 68(1): p. 48-55. 
53. 
Hudson, S.J., R.D. Dix, and J.W. Streilein, Induction of encephalitis in SJL 
mice by intranasal infection with herpes simplex virus type 1: a possible 
model of herpes simplex encephalitis in humans. J Infect Dis, 1991. 163(4): 
p. 720-7. 
54. 
Johnson, D.B., I. Puzanov, and M.C. Kelley, Talimogene laherparepvec (T-
VEC) for the treatment of advanced melanoma. Immunotherapy, 2015. 7(6): 
p. 611-9. 
55. 
Zamarin, D., et al., Localized oncolytic virotherapy overcomes systemic 
tumor resistance to immune checkpoint blockade immunotherapy. Sci 
Transl Med, 2014. 6(226): p. 226ra32. 
56. 
Puzanov, I., et al., Talimogene Laherparepvec in Combination With 
Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV 
Melanoma. J Clin Oncol, 2016. 34(22): p. 2619-26. 
57. 
Harrington, K.J., et al., Phase I/II study of oncolytic HSV GM-CSF in 
combination with radiotherapy and cisplatin in untreated stage III/IV 
squamous cell cancer of the head and neck. Clin Cancer Res, 2010. 16(15): 
p. 4005-15. 
58. 
Corrigan, P.A., et al., Talimogene Laherparepvec. Ann Pharmacother, 
2017: (Epub ahead of print PMID 28351167). 
59. 
Wilson, R.C. and P.W. Jones, A comparison of the visual analogue scale 
and modified Borg scale for the measurement of dyspnoea during exercise. 
Clin Sci (Lond), 1989. 76(3): p. 277-82. 
60. 
Boshuizen, R.C., A.D. Vincent, and M.M. van den Heuvel, Comparison of 
modified Borg scale and visual analog scale dyspnea scores in predicting 
re-intervention after drainage of malignant pleural effusion. Support Care 
Cancer, 2013. 21(11): p. 3109-16. 
61. 
Andtbacka, R.H., et al., Patterns of Clinical Response with Talimogene 
Laherparepvec (T-VEC) in Patients with Melanoma Treated in the OPTiM 
Phase III Clinical Trial. Ann Surg Oncol, 2016. 
62. 
Bohnsack O, H.A., Ludajic K, Adaptation of the immune related response 
criteria: irRECIST. Annals of Oncology 2014. 25((suppl_4)): p. iv361-
iv372. 
 
 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
71 
11.0 APPENDICES 
11.1 
Appendix A: ECOG Performance Status 
 
Score 
Definition 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light hours 
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 
In bed or chair more than 50% of waking hours 
4 
Totally confined to bed or chair – cannot carry on any self-care. 
5 
Dead 
 
 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
72 
11.2 
Appendix B: Cockcroft-Gault Formula  
Males: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)       . 
72 x serum creatinine (mg/dL) 
Females: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)        
x 0.85 
72 x serum creatinine (mg/dL) 
 
 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
73 
11.3 
Appendix C: Treatment Algorithms for Nivolumab Therapy 
Algorithms are presented for management of GI, renal, hepatic, pulmonary, 
endocrine, skin and neurological toxicities are provided. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
74 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
75 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
76 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
77 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
78 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
79 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
80 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
81 
 
11.4 
Appendix D: Information Sheet for Trial Participants 
Study LCCC 1626 
 
Information Sheet for Caregivers, Family Members or other Close Contacts to 
Clinical Trial Participants being given Talimogene Laherparepvec 
 
 
Dear Family Member, Caregiver or Other Close Contacts: 
 
A family member or close contact of yours has been enrolled in a clinical trial in 
which the Sponsor of the trial is collecting information regarding potential transfer of 
the investigational drug to close contacts.  The clinical trial participants (your family 
member or close contact that is enrolled in the study) are being asked to provide 
information to you so that you understand what information the sponsor would like 
to collect from third parties.  A close contact is considered a person that lives with 
the clinical trial participant (household member), care-giver, sex partner, or shares a 
bed with the clinical trial participant or conducts other activities that could involve 
exchange of bodily fluids through close physical contact  
 
The purpose of this surveillance program is to identify any cases of suspected 
transmission to third parties by contact with talimogene laherparepvec treated 
subjects.  
 
What is the Study Drug, Talimogene Laherparepvec? 
Talimogene laherparepvec is an investigational drug that is being studied for the 
treatment of certain types of cancer. Talimogene laherparepvec contains a weakened 
form of the Herpes Simplex Virus Type 1 (the “cold sore” virus or “HSV-1”).  
  
Can talimogene laherparepvec be spread to family members or other close 
contacts and how long after the subject is treated is this possible? 
Talimogene laherparepvec could potentially be spread to family or people who have 
close physical or intimate contact with the clinical trial participant after tumor(s) are 
injected with the study drug.  So far there have been no reported cases in clinical trial 
participants who have received talimogene laherparepvec of spreading talimogene 
laherparepvec to family members or other close contacts.  In clinical trials so far, no 
talimogene laherparepvec has been detected outside of the dressing that is placed on 
top of the site where it was injected.   
 
The naturally occurring herpes simplex virus is not transmitted through the air or 
water droplets (such as when coughing or sneezing).  Spreading occurs through direct 
contact from one person to another, particularly if a cold sore or genital sore is 
present.  The virus is “shed” from active sores, and may be present even if the person 
has no symptoms (for example, kissing or having sexual intercourse or other intimate 
contact). It may also be spread by sharing a razor, towel, dish that has come in contact 
with a sore or bodily fluids.  


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
82 
 
Spreading (transmission) of talimogene laherparepvec may be similar to spreading of 
the naturally occurring herpes simplex virus.  Unlike the naturally occurring virus, 
however, talimogene laherparepvec is administered into tumor lesions and is not 
expected to be able to replicate effectively in other noncancerous tissues.  There have 
been no cases of spreading of talimogene laherparepvec to close contacts reported in 
clinical studies to date.   
 
Small amounts of talimogene laherparepvec have been detected in subjects’ blood 
and urine for up to 1 week after injection. In subjects treated with talimogene 
laherparepvec in clinical trials, talimogene laherparepvec has been found on the 
surface of the injected tumors, into the second week after the injection, but not on the 
outside of the dressings that covered these injection sites. Close contacts should avoid 
direct contact with the injection sites. 
 
Close contacts or family members who are pregnant or have weakened immune 
systems should not touch injection sites, change dressings or clean injection sites. 
Newborns (babies who are one month or less in age) should not come into contact 
with the injection sites.  Used dressings and cleaning materials should be kept away 
from pregnant women, newborns and those with weakened immune systems.  
 
It is not known if talimogene laherparepvec virus can appear in mucous membranes 
of the lips and mouth or genitals of treated subjects. A clinical study is ongoing to 
determine if talimogene laherparepvec can be detected in the mouth area and genital 
area of treated subjects. To protect against possible sexual transmission of talimogene 
laherparepvec, subjects treated with talimogene laherparepvec or their partners 
should use latex condoms during sexual contact while on treatment and until 30 days 
after the end of treatment with talimogene laherparepvec. For those with latex 
allergies, polyurethane condoms may be used.  
  
Spreading talimogene laherparepvec may be more likely if you have a break in your 
skin or a mucous membrane comes into contact with an injection site or body fluids 
of a treated subject.  The clinical trial participant is given instructions on how to care 
for the lesions and areas that have been injected and how to avoid spreading 
talimogene laherparepvec to close contacts.     
 
What Can Happen if I am Exposed to Talimogene Laherparepvec?  
The naturally occurring type of HSV can cause a variety of symptoms, for example 
cold sores. Due to the changes in talimogene laherparepvec that make it different from 
the naturally occurring HSV, the chance of developing a herpes type infection is low, 
but you should know how to recognize these symptoms.   
If talimogene laherparepvec  were transmitted from a talimogene laherparepvec  
treated clinical trial participant to a third party, if any symptoms were observed, these 
might be expected to be similar to those that are typical with the naturally occurring 
herpes simplex virus such as:  


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
83 
• Sores around the mouth (“cold sore”, “fever blister”) or genitals (“genital 
sore”).   
• Blisters may develop on the fingers, ears or face. 
• Eye infection (herpetic keratitis) with eye pain, light sensitivity, discharge 
from the eyes or blurry vision. 
• Abdominal pain and infections, and inflammation inside the abdomen 
(infrequently). 
• Rarely, serious infections of the brain (encephalitis) or spinal cord causing 
paralysis (unable to move) have been reported. Signs may include fever, 
confusion or other behaviour changes, headache, numbness and pain in the 
legs, constipation or difficulty with urination. 
• Life-threatening infections (disseminated herpes) can develop in people with 
a weakened immune system. 
 
After infection, the naturally occurring herpes virus may travel to spinal nerve roots.  
The virus can reactivate from the nerve roots and cause recurrent cold sores or other 
signs of infection as described above. Stress, other illness, or menstruation are 
common triggers for reactivation of the naturally occurring herpes simplex virus.   
 
Who Should Not Have Contact with Talimogene Laherparepvec? 
Persons with weakened immune systems, newborns and pregnant women should not 
come in contact with the lesions or areas that have been injected with talimogene 
laherparepvec or body fluids of treated subjects.   
Close contacts or family members who are pregnant or have weakened immune 
systems should not touch injection sites, change dressings or clean injection sites.  
Newborns should not come into contact with the injection sites. Used dressings and 
cleaning materials should be kept away from pregnant women, newborns and those 
with weakened immune systems. 
 
What Happens if There is Contact and Transmission Occurs? 
Talimogene laherparepvec is sensitive to the antiviral drug acyclovir and any possible 
infection may be treated with this drug in its usual doses by your doctor.   
If transmission of talimogene laherparepvec to a close contact is suspected, your 
doctor may want to determine if talimogene laherparepvec is present. This will 
depend on the symptoms observed, but if for example a cold sore appears, a swab 
may be taken for analysis.  These tests will be most reliable if the testing is done 
within the first 3 days of symptoms occurring, but you should report to your health 
care provider at any time symptoms appear.  Before any samples or information about 
your health or symptoms is collected your authorization will be requested in writing. 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
84 
What Precautions Can Be Taken to Avoid Being Exposed to Talimogene 
Laherparepvec? 
• Avoid direct contact with the treated subject’s pleurX site and any fluid draining 
from the pleura. 
• Wear gloves if changing dressings which cover the treated subject’s pleurX 
catheter.  Wear gloves when draining pleurX cathether starting from the first day 
of the study and as long as the cathether is in place, even if the subject is no longer 
receiving talimogene laherparepvec . 
• Place all used dressings and cleaning materials for the pleurX in a sealed, plastic 
bag, and throw them away as household waste or return to the study site for 
disposal depending on local guidance. 
• Before standard disposal, bleach should be added to fluid drained from the pleurX 
catheter after study initiation.  Alternatively, it is acceptable to return the fluid to 
the investigators for safe disposal. 
• The treated subject should avoid touching or scratching the pleurX site. 
• The treated subject should always observe proper hygiene (wash hands with warm 
water and soap after touching the pleurX or any fluid that drains from the catheter 
to avoid spreading talimogene laherparepvec to other persons. 
• If the treated subject develops any mouth or genital herpetic lesions (for example 
a painful fluid filled blister) during treatment with talimogene laherparepvec or 
during the follow-up period of the clinical trial, they should avoid activities that 
could increase the possibility of transmission such as sharing straws, drinking 
glasses or engaging in sexual activity until the lesions fully resolve.    
o The naturally occurring herpes simplex virus (HSV-1) can be transmitted 
through sexual contact. It is not known if talimogene laherparepvec will 
behave the same way, thus treated subjects or their partners should use a 
latex condom when engaging in sexual activity to prevent possible 
transmission of talimogene laherparepvec during the treatment with 
talimogene laherparepvec and until 30 days after the end of treatment. 
For those with latex allergies, polyurethane condoms may be used. 
• Close contacts or family members who are pregnant or have weakened immune 
systems should not touch the pleurX site, pleural fluid or related bandages. 
Newborns should not come into contact with the pleurX site. Used dressings and 
cleaning materials should be kept away from pregnant women, newborns and 
those with weakened immune systems.  
 
If you are accidentally exposed to talimogene laherparepvec, you should clean the 
affected area on your body with soap and water and/or a disinfectant. If you develop 
signs or symptoms of a herpes infection, call your doctor.  
You or your doctor should report suspected herpetic lesions to Amgen (the 
manufacturer of talimogene laherparepvec) at 1-855-IMLYGIC for the option of 
follow-up testing.  Please indicate that you are a close contact of a patient 
participating in study LCCC1626 at UNC. 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
85 
 
If You/Minor Child Experience an Illness That Might be Related to Talimogene 
Laherparepvec 
1. Please IMMEDIATELY let your doctor know.  
2. Your close contact or family member should call their doctor and provide this 
information sheet. They should also call Amgen to report their signs or 
symptoms at 1-855-IMLYGIC. Please indicate that you/minor child are a 
close contact of a patient participating in study LCCC1626 at UNC. 
3. Please give this information sheet to the Doctor that is treating you and have 
them contact Amgen Medical Information at 1-800-722-6436.  Your doctor 
should indicate that you/minor child are a close contact of a patient 
participating in study LCCC1626 at UNC. 
 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
86 
11.5 
Appendix E: Patient Catheter Drainage Diary  
 
 
PleuRx® Drainage Schedule & 
Patient Instructions 
 
 
 
Please drain fluid through the catheter every other day using a one liter bottle.  
You should drain fluid until there is no more fluid coming out or you develop 
chest pain or persistent cough.  You should drain no more than 1 liter (1000 cc) 
of fluid every other day. 
 
Instructions to All Patients: 
 
Keep track of each of your PleuRx® catheter drainages using the attached PleuRx® 
Catheter Diary.  Complete all of the information in this diary unless the information 
does not apply to you, in which case you should enter N/A for Not Applicable.  For 
the pain question, please enter a number from 0 to 10 describing any pain you had 
from your catheter drainage, where 0 equals No Pain and 10 equals the Worst 
Possible Pain.  If you took any medicines for pain you had from your catheter 
drainage, please tell us what medicines you took and how much of those medicines 
you took in the Pain Med Details section.  Finally, please tell us if you had any 
problems or complications from your catheter drainage and describe them in the 
Problem Details section.  If you have any questions about your catheter drainage or 
completion of this diary, please talk with your physician. 
 
If you drain <50ml of fluid from your PleuRx® catheter for three consecutive 
drainages, please call your doctor to see if the catheter needs to be flushed or 
removed. 
 
Contact numbers: 
 
Dr. Jared Weiss: 919-966-3856 (office)  
Dr. Jason Akulian: 919-966-2531(office) 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
87 
 
PleuRx® Catheter Diary 
 
 
 
Date 
 
Time 
Drainag
e 
Fluid
 
Drainage 
Fluid 
C
 
Any Pain? 
Pain 
(0-10) 
 
Meds for Pain? 
 
Pain 
Med 
 
Any 
Problems/ 
C
i
i
 
Problem Details 
 
 
 
 
□Yes □No
□Yes □No 
 
□Yes □No 
 
 
 
 
 
□Yes □No
□Yes □No 
 
□Yes □No 
 
 
 
 
 
□Yes □No
□Yes □No 
 
□Yes □No 
 
 
 
 
 
□Yes □No
□Yes □No 
 
□Yes □No 
 
 
 
 
 
□Yes □No
□Yes □No 
 
□Yes □No 
 
 
 
 
 
□Yes □No
□Yes □No 
 
□Yes □No 
 
 
 
 
 
□Yes □No
□Yes □No 
 
□Yes □No 
 
 
 
 
 
□Yes □No
□Yes □No 
 
□Yes □No 
 
 
 
 
 
□Yes □No
□Yes □No 
 
□Yes □No 
 
 
 
 
 
□Yes □No
□Yes □No 
 
□Yes □No 
 
 
 
 
 
□Yes □No
□Yes □No 
 
□Yes □No 
 
 
 
 
 
□Yes □No
□Yes □No 
 
□Yes □No 
 
 
 
 
 
□Yes □No
□Yes □No 
 
□Yes □No 
 
Page      of   
 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
88 
 
11.6 
Appendix F:  Borg Scale 
 
*Instruction for Borg Dypsnea Scale 
 
Use this scale to rate the difficulty of your breathing. 
 
It starts at number 0 where your breathing is causing no difficulty at all and progresses 
through to number 10 where your breathing difficulty is maximal. 
 
How much difficulty is your breathing causing you right now? 
 
0 
Nothing at all 
0.5 
Very, very slight (just noticeable) 
1 
Very slight 
2 
Slight 
3 
Moderate 
4 
Somewhat severe 
5 
Severe 
6 
 
7 
Very severe 
8 
 
9 
Very, very severe (almost maximal) 
10 
Maximal 
 
 
 


LCCC 1626 
 
CONFIDENTIAL 
PI: Jared Weiss 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment #4 Version 1.0 
 
 July 22, 2019 
 
89 
11.7 
Appendix G: NYHA – Functional Classification System 
 
Class 
Symptoms 
Class I 
No limitation of physical activity. 
Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea 
(shortness of breath). 
Class II  
Slight limitation of physical activity. 
Comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, or 
dyspnea. 
Class III 
Marked limitation of physical activity. 
Comfortable at rest. Less than ordinary 
activity causes fatigue. 
Class IV 
Unable to carry on any physical activity 
without discomfort. Symptoms of heart 
failure at rest. If any physical activity is 
undertaken, discomfort increases.