A Phase 1 Study of Talimogene Laherparepvec and Panitumumab in Patients With Locally Advanced Squamous Cell Carcinoma of the Skin (SCCS)
Phase: PHASE1
Conditions: Locally Advanced Skin Squamous Cell Carcinoma, Metastatic Skin Squamous Cell Carcinoma, Recurrent Skin Squamous Cell Carcinoma
Sponsor: Rutgers, The State University of New Jersey

Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
1 
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IRB Form Version 12.18.2018 
Title of Project: A Phase I Study of Talimogene Laherparepvec and Panitumumab 
in Patients with Locally Advanced Squamous Cell Carcinoma of the Skin (SCCS) 
Principal Investigator: 
Name: Adam Berger, MD 
Division & Department: Surgical Oncology 
Contact Information: 732-235-7563; ab2047@cinj.rutgers.edu 
PROTOCOL VERSION AND DATE: v10, March 23, 2023 
CONFIDENTIAL 
This document is confidential and the property of the Rutgers Cancer Institute of New Jersey. 
No part of it may be transmitted, reproduced, published, or used without prior written 
authorization from the study sponsor. 
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Official Title: 
A Phase 1 Study of Talimogene Laherparepvec and 
Panitumumab in Patients with Locally Advanced 
Squamous Cell Carcinoma of the Skin (SCCS). 
NCT number: 
04163952 
Document Type: 
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
04/12/2023 

 
 
 
Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
2 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
PROTOCOL AMENDMENTS 
The current version of the protocol was released on 09-09-2020 and includes the following 
Amendments, 1-18 into the version approved by Rutgers IRB on 09/05/2019. 
Amendment # 
Section 
Page(s) Protocol Change 
1 
1.3 
9 
Insertion: Patients who are not eligible for surgery are only 
allowed to continue protocol therapy past 3 cycles if clinical 
benefit, defined as partial response (PR), or stable disease 
(SD), is achieved. This also assumes that separate systemic 
options are not available for patient after protocol therapy of 3 
cycles. 
2 
1.3 
10 
“Peripheral blood will be collected on day 1, day 22, day 36, 
and on the day of tumor resection” is replaced with 
“Peripheral blood will be collected prior to treatment, at the 
time of definitive surgery or biopsy, and at the time of 
progression, if applicable”. 
3 
1.3.1; Table 1 
10-11 
IHC and Flow Cytometry at Day 64 deleted. 
“Baseline labs within 14 days of treatment” is replaced with 
“Baseline labs, blood tests, and EKG (electrocardiogram), 
need to be done within 14 days of treatment”.  
4 
1.7.2.1 
17 
“Panitumumab is an FDA-approved agent for use in SCCS” 
is replaced with  “Panitumumab is FDA-approved for use in 
patients with wild-type RAS (defined as wild-type in both K-
RAS and N-RAS as determined by an FDA-approved test) 
metastatic colorectal cancer (mCRC).” 
5 
1.7.5.4 
22 
Text in “Table 6: Clinical Handling Times Outside Labelled 
Storage Conditions” modified. “48 hours (inclusive of 16 
hours maximum in the syringe)” modified to “48 hours 
(inclusive of 8 hours maximum in the syringe)” 
6 
1.7.5.4 
24 
Duplicate bullet under Figure 3 “o *Avoid premature 
extraction of needle c” deleted 
7 
1.7.6.3 
27 
Several changes made to Table 8 
8 
1.7.6.3 
28, 29 
A New Table, “Table 10. Algorithm for Dose 
Modifications for Infusion Reactions” was added 
9 
1.7.6.3 
29 
Other toxicities of panitumumab were added as sub-item 9)” 
under section 1.7.6.3 
10 
1.7.9 
32 
Added Section 1.7.9  
Dose-Limiting Toxicity 
Dose-limiting toxicity is defined as any occurrence of CTCAE 
grade 3 or greater adverse event in four weeks following the 
administration of the study products except grade 3 laboratory 
values not deemed clinically significant, grade 3 fatigue which 
resolves within 72 h of holding or modifying protocol therapy 
and grade 3 rash, as the latter is an already known potential 
side effect of panitumumab. 
 
11 
1.7.9.1 
32 
Added section “1.7.9.1 Talimogene laherparepvec DLTs” 
12 
1.7.11 
33 
Added Section 1.7.11 
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
3 
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IRB Form Version 12.18.2018 
 
Amendment # 
Section 
Page(s) Protocol Change 
Staggering Interval between the First Three Consecutive 
patients 
The staggering interval between the first three consecutive 
patients will be 2 weeks past the first infusion of the 
combination therapy (Cycle 1,Day 21). The staggering 
interval of 2 weeks was based on the median time to the 
development of dermatologic or most severe skin/ocular 
toxicity of 15 days after the first dose of panitumumab (US 
Package Insert, panitumumab Solution for Intravenous 
Infusion, 2006). 
13 
1.8.1.2 
34 
“all patients will have peripheral blood samples collected prior to 
treatment, at the time of definitive resection or post-treatment, at 
restaging time points and at the time of progression, if applicable” 
is replaced with “all patients will have peripheral blood samples 
collected prior to treatment, at the time of definitive surgery or 
biopsy, and at the time of progression, if applicable”. 
14 
6.1.2 
43 
“We plan to start monitoring the treatment safety after 5 
patients are recruited.” Was replaced with “We will employ a 
3 + 3 study design in the first six patients enrolled. This will 
allow for early detection of unexpected safety signals and 
will allow for rapid implementation of measures to diminish 
the risk of toxicity to subsequently enrolled subjects.”  
Added the statement “The interim safety assessment will 
start and includes the rules of the 3+3 design based on the 
incidence of DLTs.” 
“We plan to start monitoring the treatment safety after 5 
patients are recruited.” was  modified to “We plan to 
continue monitoring the treatment safety after the first 6 
patients are recruited.” 
15 
6.1.5.2 
47 
The text under “Section 6.1.5.2 Reporting SAEs using 
commercially available drugs” modified. 
 
16 
1.3.1 
 
 
 
1.3.2 
 
 
1.8.1 
 
 
 
4.8.2 
11 
 
 
 
11 
 
 
33 
 
 
 
41 
Table 1 to reflect footnote 1 addition “Following surgery, patients 
will have radiographic assessments every 12 weeks to monitor 
disease status.” 
Revised to read: “[…] after 9 weeks of study treatment, then every 
12 weeks following surgery to monitor disease status.”   
Added: Specimen, including tissue and blood, will be banked for 
the studies described below and for potential future studies. 
Specimens will be analyzed once funding becomes available. 
Removed patient compensation. Revised to read: Subjects will not 
be compensated for participation in this research study.  
17 
 
 
1.1 
 
 
 
9 
 
Principal Investigator changed to Adam Berger, MD 
Revised to read: The overall treatment strategy described in this 
protocol is to treat locally advanced/unresectable SCCS with at 
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
4 
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IRB Form Version 12.18.2018 
 
Amendment # 
Section 
Page(s) Protocol Change 
 
 
1.8.1.1 
 
 
 
 
 
 
 
1.8.1.1 
 
 
1.8.1.1 
 
 
 
34 
 
 
 
 
 
 
 
35 
 
 
36 
least 3 cycles of talimogene laherparepvec in combination with 
panitumumab, and monitor patients for disease response.  
Laboratory Evaluations and Procedures/Correlative Studies: 
Overview of Possible Molecular Investigations modified.  
Added: Tumors will be stored frozen in RNAlater media, and total 
RNA will be extracted to identify gene expression changes within 
the tumor and variations in immune cell populations using a 
CyberSort strategy.   
Added: and flow cytometry will be performed on cells isolated from 
peripheral blood 
Added: Part of the tumor sample will be placed in complete media 
on wet ice 
18 
Figure 1 
 
Table 1 
 
 
 
 
Table 1 
 
Table 1 
 
 
2.4 
 
 
4.1 B 
11 
 
11 
 
 
 
 
12 
 
12 
 
 
 
 
37 
 
 
38 
Updated Figure 1 Study Design 
Revised Table 1 headings to read: 
Day 22 (Week 4) 
Day 36 (Week 6) 
Post- surgery or Bx follow up9 
Follow up (every 12 weeks for 2 years10 
Added: 9- Post-surgical follow up visit (14-28 days from surgery) 
or post-biopsy visit (30 days from biopsy) 
Added: 10- Follow up imaging and visits should be measured 
from the time of surgery or biopsy, if considered unresectable. 
The window for blood draws/visits/scans during follow up is ± 7 
days. 
Added: and Duke University Medical Center - Duke Cancer 
Center 
Added: and Duke University Medical Center - Duke Cancer 
Center 
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
5 
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DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
Amendment # 
Section 
Page(s) Protocol Change 
19 
Figure 1 
 
Table 1 
 
 
 
 
1.3.2 
 
 
 
 
 
 
 
 
 
 
1.7.4.1 
 
2.4 
 
4.1.B 
12 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
 
 
 
 
19 
 
38 
 
39 
Updated Figure 1 Study Design 
Modified: Footnote 10 ± 7 days changed to ± 14 days. 
Added: CBC with Differential requirement for Day 1  
Added: CBC with Differential, Basic Metabolic Panel + Mg, and 
Hepatic Function Panel requirement forDay 22  
Added: If a patient undergoes surgery after 3 cycles of TVEC and 
is rendered disease-free at the time of surgery, they will 
considered a clinical complete response (NED-no evidence of 
disease). If this is the case, there will be no index lesion to follow 
on subsequent imaging and thus no need for RECIST criteria 
assessment. These patients will be followed by clinical exam as 
well as the standard imaging outlined in Table 1. If they develop a 
biopsy-proven recurrence of their disease, they will be considered 
a treatment failure and come off study. If a patient undergoes 
surgery but continues to have an index lesion that can be 
followed by RECIST assessment, this lesion will continue with 
response assessments. 
Modified: 100 mg changed to 1000 mg 
Added: and and NYU Langone Health. 
Added: and and NYU Langone Health 
20 
Table 1 
13 
Added to footnote 10: After one year of follow-up, if patient 
remains without evidence of recurrence, subsequent follow-up will 
be at the discretion of the treating investigator but should not be 
less frequent than every 6 months for the second year of follow-
up. 
21 
1.8.1.1. 
 
 
 
 
1.8.1.2. 
 
 
1.8.1.3. 
 
2.4 
36 
 
 
 
 
37 
 
 
38 
 
39 
Added: Samples will be transferred to NYU for analysis. 
Deleted: by the Cancer Institute Immune Monitoring Shared 
Resource Facility 
Deleted: the Cancer Institute Immune Monitoring Shared 
Resource Facility 
Added: Samples will be transferred to NYU for analysis. 
Deleted: in the Immune Monitoring Shared Resource Facility at 
the Rutgers Cancer Institute of New Jersey 
Added: at NYU Langone Health 
 
 
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
6 
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IRB Form Version 12.18.2018 
 
Table of Contents  
Skip To Section: Hold CTRL + Click (Below) To Follow Link in Blue 
 
1.0 
Research Design 
 
 
1.1 
Purpose/Specific Aims 
 
 
1.2 
Research Significance 
 
 
1.3 
Research Design and Methods 
 
 
1.4 
Preliminary Data 
 
 
1.5 
Sample Size Justification 
 
 
1.6 
Study Variables 
 
 
1.7 
Drugs/Devices/Biologics 
 
 
1.8 
Specimen Collection 
 
 
1.9 
Data Collection 
 
 
1.10 
Timetable/Schedule of Events 
 
 
2.0 
Project Management 
 
 
2.1 
Research Staff and Qualifications 
 
 
2.2 
Research_Staff_Training 
 
 
2.3 
Resources Available 
 
 
2.4 
Research Sites 
 
 
3.0 
Multi_Center_Research 
 
 
3.1 
Outside Research 
 
 
4.0 
Subject_Considerations 
 
 
4.1 
Subject Selection and Enrollment Considerations 
 
 
4.3 
Subject Randomization 
 
 
4.4 
Secondary Subjects 
 
 
4.5 
Number of Subjects 
 
 
4.6 
Consent Procedures 
 
 
4.7 
Special Consent Populations 
 
 
4.8 
Economic Burden and/or Compensation For Subjects 
 
 
4.9 
Risks_of_Harm_Potetial_for_Benefits_to_Subjects 
 
 
4.10 
Secondary Data – Record/Chart Reviews, Databases, Tissue Banks, Etc. 
 
 
4.11 
Chart/Record Review Selection 
 
 
4.12 
Secondary Specimen Collection 
 
 
5.0 
Special Considerations 
 
 
5.1 
Health Insurance Portability and Accountability Act (HIPAA) 
 
 
5.2 
Family Educational Rights and Privacy Act (FERPA) 
 
 
5.3 
NJ Access to Medical Research Act 
 
 
5.4 
General_Data_Protection_Regulation_(GDPR) 
 
 
5.5 
Code of Federal Regulations Title 45 Part 46 (Vulnerable Populations) 
 
 
6.0 
Data_Management_Plan 
 
 
6.1 
Data_Analysis 
 
 
6.2 
Data Security 
 
 
6.3 
Data Safety And Monitoring 
 
 
6.4 
Reporting Results 
 
 
6.5 
Data Sharing 
 
 
6.6 
Secondary_Use_of_the_Data 
 
 
7.0 
Research_Repositories_Specimens_and/or_Data 
 
 
8.0 
Approvals_Authorizations 
 
 
9.0 
Bibliography 
 
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
7 
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IRB Form Version 12.18.2018 
 
 
10.0 
Appendices 
 
 
 
Pro2018002628
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
8 
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IRB Form Version 12.18.2018 
 
List of Abbreviations 
 
5-FU 
5-Fluorouracil 
ADCC 
Antibody dependent Cell-mediated Cytotoxicity 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
APCs 
Antigen Presenting Cells 
AST 
Aspartate Aminotransferase 
BRS 
Biospecimen Repository Service 
BSL 
Biosafety level 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CINJ 
Cancer Institute of New Jersey 
CINJOG 
Cancer Institute of New Jersey Oncology Group 
cm 
Centimeter 
CR 
Complete response 
CRF 
Case Report Form 
CT 
Computer Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T Lymphocyte 
DSMP 
Data Safety Monitoring Plan 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EGFR 
Epidermal Growth Factor Receptor 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 
HCP 
HealthCare Professional 
HHS 
Department of Health and Human Services 
HSV 
Herpes Simplex Virus 
ICH 
International Council for Harmonization 
IFN- 
Interferon gamma 
IHC 
Immunohistochemistry 
IRB 
Institutional Review Board 
irPFS 
Immune-related Progression-free Survival 
irRC 
Immune-related Response Evaluation Criteria in Solid Tumors 
IVIG 
Intravenous immunoglobulin 
kg 
kilograms 
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
9 
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IRB Form Version 12.18.2018 
 
LD 
Longest Diameter 
mcg/µg 
Micrograms 
MHC 
Major Histocompatibility Complex 
mL 
milliliters 
MRI 
Magnetic Resonance Imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NK 
Natural Killer 
OHRP 
Office of Human Research Protection 
OHRS 
Office of Human Research Services 
OS 
Overall Survival 
PBMC 
Peripheral blood mononuclear cells 
PD 
Progressive disease 
PD-L1 
Programmed Death-Ligand 1 
PET 
Positron Emission Tomography 
PFU 
Plaque Forming Unit 
PHI 
Protected health information 
PI 
Principal Investigator 
PR 
Partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RWJUH 
Robert Wood Johnson University Hospital 
SAE 
Serious adverse event 
SCCS 
Squamous Cell Carcinoma of the Skin 
sCr 
Serum creatinine 
SD 
Stable disease 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia 
m 
Micrometer 
 
 
 
 
 
 
Pro2018002628
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
10 
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DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
1.0 Research Design 
 
1.1 Purpose/Specific Aims 
The purpose of this protocol is to serve as a phase I/II study of talimogene laherparepvec in combination 
with panitumumab in locally advanced or metastatic squamous cell carcinoma of the skin (SCCS).  The 
primary hypothesis is that panitumumab, an antibody against Epidermal Growth Factor Receptor (EGFR), 
exhibits antitumor activity in patients with advanced squamous cell carcinoma of the skin and it may be 
enhanced when combined with talimogene laherparepvec, a HSV-1–derived oncolytic immunotherapy 
designed to selectively replicate within tumors and produce granulocyte macrophage colony-stimulating 
factor (GM-CSF) to enhance systemic antitumor immune responses, when delivered preoperatively.  The 
overall treatment strategy described in this protocol is to treat locally advanced/unresectable SCCS with at 
least 3 cycles of talimogene laherparepvec in combination with panitumumab, and monitor patients for 
disease response.  Patients will go on to surgical resection if adequate disease response is achieved; 
otherwise, patients who are receiving clinical benefit will be allowed to continue therapy.  We will assess 
the safety, clinical efficacy and pathologic responses to treatment with talimogene laherparepvec in 
combination with panitumumab. The prospect is that the data derived from this study will lead to a large 
randomized trial testing the efficacy of this approach in this disease if this approach is tolerable with 
evidence of clinical efficacy, and that the correlates described in this protocol will identify potential candidate 
biomarkers of response to combination therapy.  
 
A. Objectives  
Primary: 
1) To determine the safety of the combined treatment of talimogene 
laherparepvec and panitumumab. 
2) To determine the preliminary efficacy of the combined treatment of 
talimogene laherparepvec and panitumumab, in comparison to single-agent 
panitumumab by historical control.  
Secondary: 
1) To assess the clinical efficacy of panitumumab in combination with 
intratumoral talimogene laherparepvec in terms of immune-related 
progression-free survival (irPFS) at 12 months, PFS hazard ratio, overall 
response rate (ORR), 1-year survival, overall survival (OS) and time to 
resectability.  
2) To measure the pathologic complete response rate to panitumumab 
combined with talimogene laherparepvec. 
3) Assess the response of injected and non-injected tumor deposits after 
panitumumab and talimogene laherparepvec. 
4) Assess the time to initial response.   
5) Assess the durable response rate. 
6) To analyze the following molecular correlates with response to therapy to 
confirm mechanism of action, and identify potential future targeted strategies 
and biomarkers of response: 
A) Mutation load in tumor tissue by next generation sequencing 
B) DNA mutation signature in tumor tissue pre- and post-therapy by next 
generation sequencing 
C) mRNA signature in tumor tissue pre-and post-therapy by Nanostring 
technology 
D) Immune cell populations and immune profile in pre- and post-therapy 
tumor tissue and peripheral blood by flow cytometry and IHC 
 
Pro2018002628
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
11 
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IRB Form Version 12.18.2018 
 
B. Hypotheses / Research Question(s) 
For efficacy, we hypothesize that the combination of panitumumab and talimogene laherparepvec  
will improve the response rate in advanced SCCS from 25% with single agent panitumumab [1] to 
47% (near doubling of response rate to justify added expense and time required for administration 
of second drug as well as potential for additional toxicities). 
1.2 Research Significance: 
1.2.1  Squamous cell carcinoma of the skin: 
SCCS is the second most common type of skin cancer, and while precise estimates of incidence are 
challenging [2], it has been approximated that in the United States there are 700,000 new cases of SCCS 
diagnosed annually, with an estimated 3,932-8,791 deaths in 2012 [3].  In addition, the number of cases 
has consistently risen over the past 20 years [4, 5].  The majority of SCCS cases are localized and curable 
with early detection and surgery; however, the incidence of locally advanced and metastatic cases is rising, 
with a subset of cases paralleling the metastatic potential of malignant melanoma [3]. A study by Karia, et 
al., found the incidence of nodal metastases to be 3.7-5.4% [3], and although SCCS is known to metastasize 
to distant sites, 80% of those that metastasize localize to regional lymph nodes [6]. Survival has been 
documented to have an inverse correlation with both larger size and increasing number of lymph nodes 
involved [7, 8]. 
 
The mainstay of therapy for most cases of SCCS is surgical resection, with many surgically amenable cases 
easily cured [9].  However, certain high risk tumors, such as those involving bone or nerve branches, and 
recurrent tumors, still present a therapeutic challenge [9].  In cases of locally advanced disease or 
metastases to the regional lymph nodes, surgery followed by adjuvant radiation therapy has shown to 
improve outcomes as compared to either alone in monotherapy [10, 11].  However, treatment with radiation 
therapy is also associated with fatigue, nausea, vomiting and poor aesthetic or functional outcomes, 
important considerations in the population of older adults with comorbidities [9].  Chemotherapy is often 
reserved for metastatic disease or locally advanced disease not amenable to surgery or radiation.  
Historically, treatment decisions for patients with SCCS have been derived from regimens used in other 
squamous cell cancers, with suggestions of antitumor activity using regimens containing combinations of 
cisplatin, bleomycin, 5-fluorouracil (5-FU) and methotrexate [12-14].  However, these trials were small and 
not randomized, with suggestion of only modest benefit at the expense of significant toxicity [15-17].  In 
addition, while squamous cancers often share similar anatomic origins and histologies, SCCS likely has a 
unique biology driven by external insults such as ultraviolet radition, resulting in a high mutational load.  
Although most of these mutations are likely ‘passenger mutations’ that do not drive tumor growth, they may 
lead to protein alterations that can serve as neo-antigens which stimulate T-cell immunity, making them 
ideal candidates for an immunotherapy approach as has been previously reported [18]. 
 
1.3 Research Design and Methods 
We plan to enroll 30 patients with locally advanced SCCS.  We will collect peripheral blood and biopsy 
tumor tissue from all patients prior to treatment.  Patients will receive an initial dose of talimogene 
laherparepvec 106 PFU/mL on day 1 to seroconvert to HSV positive to reduce the rate and severity of 
injection reactions.  On day 22, patients will begin combination therapy with panitumumab at 6 mg/kg and 
talimogene laherparepvec at 108 PFU/mL, followed by this schedule every 2 weeks for 3 cycles.  Patients 
will then be evaluated for surgical resection after the administration of the third cycle of combinatorial 
therapy (approximately day 64).  Surgery may commence at this time point, or the decision may be made 
by surgical and medical oncologist investigators to continue therapy for up to three more cycles if it is felt 
that the tumor may respond further with additional therapy. Patients who are not eligible for surgery are 
only allowed to continue protocol therapy past 3 cycles if clinical benefit, defined as partial response (PR), 
or stable disease (SD), is achieved. This also assumes that separate systemic options are not available for 
patient after protocol therapy of 3 cycles. We will collect tumor tissue again post-treatment, either at the 
Pro2018002628
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
12 
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IRB Form Version 12.18.2018 
 
time of surgical resection, if applicable, or by re-biopsy.  Patients will also receive a biopsy at progression, 
if applicable (Figure 1). Peripheral blood will be collected prior to treatment, at the time of definitive surgery 
or biopsy, and at the time of progression, if applicable. Patients who are not resected but continue on 
protocol therapy will have PBMC sampled every three months or at progression if applicable.  
 
Figure 1.  Study Design 
 
 
1.3.1 Study evaluation parameters and the schedules: 
Study evaluation parameters and the schedules of assessment are presented in the Table 1. A window of 
+/- 3-days is allowed for all study assessments indicated on this trial except for which otherwise indicated. 
However, dosing windows for talimogene laherparepvec are Day 22 + 3 days for the initial dose and +/- 3 
days for any subsequent cycles; dosing would be taken into account in the schedules of assessment. 
 
Table 1.  Study evaluation parameters and the schedules of assessment: 
Evaluation 
Pre
-Tx 
Day 1 
(Week 
1) 
Day 22 
(Week 
4) 
Day 36 
(Week 6) 
& every 2 
weeks 
during Tx 
Phase  
Day 64   
± 1 
week 
At 
surgery 
or Bx 
Post- 
surgery 
or Bx 
follow 
up9 
Follow 
up 
(every 
12 
weeks 
for 2 
years10) 
At pro-
gression 
History & 
Physical 
Exam 
ECOG PS 
Tumor Site 
Assessment 
 
 
X2 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
Pregnancy 
Test 
X2 
 
 
 
 
 
 
 
 
Talimogene 
laherparepvec 
Treatment 
 
X 
X 
X 
 
 
 
 
 
Panitumumab 
Treatment 
 
 
X 
X 
 
 
 
 
 
Toxicity 
Assessment 
X 
X 
X 
X 
 
 
X 
X 
 
Photo of 
Tumor 
X4 
 
 
 
X4 
 
 
 
X4 
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Protocol Title: A Phase I Study of Talimogene 
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Skin (SCCS) 
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Surgical 
evaluation 
 
 
 
 
X4 
 
 
 
 
Tumor Biopsy 
or Resection 
X3 
 
 
 
 
X 
 
 
X5 
CBC with 
Differential 
X2 
X 
X 
X 
 
 
 
X 
 
Basic 
Metabolic 
Panel + Mg 
X2 
X 
X 
X 
 
 
 
X 
 
Hepatic 
Function 
Panel 
X2 
X 
X 
X 
 
 
 
X 
 
Radiographic 
Assessments1 
X1 
 
 
 
X1 
 
 
X1 
X5 
DNA 
Sequencing 
X6 
 
 
 
 
X6 
 
 
X6 
mRNA 
Sequencing 
X7 
 
 
 
 
X7 
 
 
X7 
IHC and Flow 
Cytometry 
X8 
 
 
 
 
X8 
 
 
X8 
1- Tumor assessments as indicated by investigator (e.g. PET/CT, CT C/A/P, MRI) as needed, no more than 1 month prior to treatment. 
First assessment to be followed by evaluation by surgery for complete surgical resection. Photos and scans to be completed at each 
restaging time point. Surgeon will assess optimal timing of procedure once therapy initiated. Following surgery, patients will have 
radiographic assessments every 12 weeks to monitor disease status. Patients who did not have surgery will have radiologic 
assessments every 12 weeks.  
2- Baseline labs, blood tests, and EKG (electrocardiogram), need to be done within 14 days of treatment. 
3- First biopsy within 30 days of initial treatment. 
4- Photo of tumor at baseline and with restaging time points. Surgical evaluation must commence. Decision may be made to proceed 
with 3 more cycle of systemic therapy if it is thought tumor will continue to respond.  
5- Within 30 days of recurrence. 
6- Partial DNA sequencing using FoundationOne™ genomic profiling will be done on tumor tissue. 
7- mRNA sequencing by Nanostring nCounter system will be done on peripheral blood and tumor tissue. 
8- Immunohistochemistry and targeted Flow Cytometry will be done on peripheral blood and tumor tissue. 
9- Post-surgical follow up visit (14-28 days from surgery) or post-biopsy visit (30 days from biopsy) 
10- Follow up imaging and visits should be measured from the time of surgery or biopsy, if considered unresectable. The window for 
blood draws/visits/scans during follow up is ± 14 days. After one year of follow-up, if patient remains without evidence of recurrence, 
subsequent follow-up will be at the discretion of the treating investigator but should not be less frequent than every 6 months for the 
second year of follow-up. 
 
 
1.3.2  Assessing Tumor Response: 
Response to combination panitumumab and talimogene laherparepvec will be assessed by RECIST criteria 
v 1.1 [19] shown in Table 2 as well as by immune related response criteria (irRC) [20] after 9 weeks of study 
treatment, then every 12 weeks following surgery to monitor disease status.  The patient will have re-staging 
imaging as decided by the investigator to compare to the images obtained at baseline.  Response will be 
evaluated by RECIST criteria v 1.1 for complete response (CR), partial response (PR), stable disease (SD) 
or progressive disease (PD).  Patients who experience a PR or CR will have confirmatory imaging 
completed at 4-6 weeks. Patients who experience PD but are clinically well may be allowed to continue on 
study, with a confirmatory scan done 4 weeks (+/- 1 week) to determine disease status per irRC. New 
lesions detected by clinical assessment at a treatment visit will only trigger an unscheduled tumor response 
assessment if clinically indicated and felt to be in the patient’s best interests by the treating investigator.  If 
a patient undergoes surgery after 3 cycles of TVEC and is rendered disease-free at the time of surgery, 
they will considered a clinical complete response (NED-no evidence of disease). If this is the case, there 
will be no index lesion to follow on subsequent imaging and thus no need for RECIST criteria assessment. 
These patients will be followed by clinical exam as well as the standard imaging outlined in Table 1. If they 
develop a biopsy-proven recurrence of their disease, they will be considered a treatment failure and come 
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Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
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off study. If a patient undergoes surgery but continues to have an index lesion that can be followed by 
RECIST assessment, this lesion will continue with response assessments. 
 
Table 2.  RECIST Criteria v 1.1: 
Response 
Criteria 
Complete Response (CR) 
Disappearance of all target lesions; confirmed at a later time by an 
independent review committee or the principal investigator 
Partial Response (PR) 
At least a 30% decrease in the sum of the longest diameter (LD) of 
target lesions, taking as reference the baseline sum (LD); confirmed 
at a later time by an independent review committee or the principal 
investigator 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR, nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the 
treatment started 
Progressive Disease (PD) 
At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded since the treatment 
started or the appearance of one or more new lesions; in addition to a 
20% increase above the nadir for PD, a 5-mm absolute increase is 
required 
 
In determining whether or not the tumor burden has increased or decreased per irRC, the investigator 
should consider all target and non-target lesions as well as any incremental new lesion(s). Upon repeat 
imaging, PD will be confirmed if ANY of the following occur by irRC:  
 
Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared to nadir  
 
Non-target disease resulting in initial diagnosis of PD is worse (qualitative assessment)  
 
New lesion resulting in initial diagnosis of PD is worse (qualitative assessment)  
 
Additional new lesion(s) since last evaluation  
 
Additional new non-target lesion progression since last evaluation  
 
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be discontinued from 
trial therapy. Upon repeat imaging, PD will have failed to be confirmed if ALL of the following occur by irRC:  
 
Tumor burden is < 20 % or < 5 mm absolute increase compared to nadir  
 
Non-target disease resulting in initial diagnosis of PD is stable or improved (qualitative 
assessment)  
 
New lesion resulting in initial diagnosis of PD is stable or improved (qualitative assessment)  
 
No incremental new lesion(s) since last evaluation  
 
No incremental new non-target progression since last evaluation  
 
If repeat local site imaging fails to confirm PD by irRC and the subject continues to be clinically stable, 
treatment may continue and follow the regular imaging schedule. When feasible, subjects should not be 
discontinued until PD is confirmed by the local site investigator radiology assessment. This allowance to 
continue treatment despite initial radiologic PD takes into account the observation that some subjects can 
have a transient tumor flare in the first few months after the start of immunotherapy, and then experience 
subsequent disease response. Subjects who are deemed clinically unstable are not required to have repeat 
tumor imaging for confirmation of PD.  
 
1.3.3 Assessing Toxicity and Adverse Events: 
All patients who receive one dose of protocol therapy will be evaluable for assessment of toxicity. Prior to 
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
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Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
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each cycle, the treating physician will fully assess the patient’s condition with respect to possible treatment 
related toxicities. All adverse events, whether observed by the physician or reported by the patient, 
occurring during the active portion of therapy, or up to 30 days after the last dose of treatment will be graded 
by a numerical score according to the NCI’s Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.0 (see http://ctep.cancer.gov/reporting/ctc.html) and recorded in the patient’s medical record. For 
the purposes of reporting laboratory abnormalities, only Grade 3-4 adverse events will be recorded on the 
adverse event CRF pages. Grade 1-2 laboratory abnormalities will not be recorded on the adverse event 
CRF pages. Information entered on the adverse event CRF pages will include:  
1) Specific type and duration of reaction (i.e., start and stop dates, resolution)  
2) Severity/grade  
3) Relationship to study drug (causality, attribution)  
4) Management of the event, if treated with medication and other actions taken to alleviate the 
clinical event  
5) Whether or not it was considered a SAE  
A preexisting condition is one that is present at the start of the study. A preexisting condition will be recorded 
as an adverse event if the frequency, intensity, or the character of the condition worsens during the study 
period. 
 
1.3.4 Study Duration: 
For each subject, this study will consist of a 28-day screening period followed by an initial dose of 
talimogene laherparepvec on day 1, combination therapy with panitumumab and talimogene laherparepvec 
on day 22 and continuing every 2 weeks for 3 cycles.  Patients will then be evaluated for surgical resection 
after the administration of the third cycle of combinatorial therapy (approximately day 64).  Surgery may 
commence at this time point, or investigators may continue therapy for up to three more cycles.  
 
The subject’s participation in the study will be considered to have ended at the time of the last visit/30 days 
after last drug intake. However, the patients will have a follow-up period of 104 weeks. Thus, the overall 
duration of the study for participants will be approximately 127 weeks. The study will be considered to have 
ended after the last subject has completed the last follow-up period in the study. 
 
1.4 Preliminary Data 
1.4.1 Panitumumab in SCCS:  
Anti-EGFR antibodies have been shown to have activity in squamous carcinomas of the skin [21].  In 2011, 
Maubec, et al., studied the anti-EGFR monoclonal antibody Cetuximab in 36 patients with unresectable 
SCCS and found a disease control rate of 69% [22].  Multiple published case and retrospective reports 
have documented tumor responses in patients with SCCS treated with Cetuximab, including one from our 
institution demonstrating an impressive complete response in an elderly patient with SCCS [23] (Figure 2).  
Panitumumab, a monoclonal antibody which inhibits the activity of the EGFR, is increasingly in use for 
systemic treatment of patients with advanced SCCS. In addition to EGFR inhibition, panitumumab induces 
antibody dependent, cell mediated cytotoxicity (ADCC) [24]. Panitumumab has shown activity in squamous 
carcinomas of the head and neck, and lung in combination with chemotherapy and/or radiation therapy [25-
28], where its addition has been demonstrated to improve both median overall survival and progression 
free survival with an acceptable toxicity profile. Panitumumab has been studied prospectively as a single 
agent in a small cohort of patients with advanced SCCS [1]. While the sample size was small, panitumumab 
produced impressive response rates, including a best overall response rate of 31%, a complete response 
rate of 12.5%, as well as a median progression free survival and overall survival of 8 and 11 months, 
respectively [1]. Because of the impressive responses seen in some patients such as the case reported by 
our institution, current NCCN guidelines for treatment of advanced SCCS disease [29] include EGFR 
inhibitors as an option. Nonetheless, rigorous randomized, prospective trials assessing the effectiveness of 
EGFR inhibitors in SCCS are lacking.  Additionally, resistance may develop quickly, making studies 
examining combination therapies warranted [30].   
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
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Figure 2. Clinical complete response to Cetuximab in a 92-year old man. Images from left to right: 
Patient prior to Cetuximab and six weeks after Cetuximab. Cetuximab was administered weekly 
from July to October 2008. The clinical CR lasted through patient’s last follow up in 2009 (7 months). 
 
 
 
 
1.4.2 Talimogene Laherparepvec:  
Talimogene laherparepvec is a modified HSV-1, customized into an oncolytic virus via deletion of two non-
essential viral genes [31, 32] which results in attenuated viral pathogenicity, enhanced selectivity for 
intratumoral replication, reduced virally-induced suppression of antigen presentation and enhanced 
replication of HSV mutants within tumors [31, 33, 34].  Talimogene laherparepvec is additionally modified 
by insertion of the gene encoding for human GM-CSF, which results in the local production of GM-CSF to 
recruit and activate antigen presenting cells (APCs) that ultimately initiate a tumor-specific T cell response 
[31].  The eventual response is the induction of anti-tumor immunity both locally in infected and uninfected 
cells, and systemically through the priming of a tumor-specific immune response [31-33].  In early phase 
studies,  talimogene laherparepvec demonstrated an acceptable toxicity profile, the most common side 
effects being low grade fevers, chills, myalgias and injection site reactions, and showed biological activity 
in several tumor types [35, 36].  In a phase III study of 436 patients with unresectable stage IIIb-IV 
melanoma, talimogene laherparepvec improved durable response rates compared to GM-CSF alone 
(16.3% vs 2.1%) as well as overall response rates (26.4% vs 5.7%) [31].  
 
1.4.3 Talimogene Laherparepvec in SCCS:   
Viral therapy has shown preliminary evidence of efficacy in squamous cell malignancies.  The H101 
adenovirus is approved in China for the treatment of head and neck squamous cell cancer based on 79% 
response rate when combined with chemotherapy vs a response rate of 40% with chemotherapy alone in 
a phase III trial [37].  Squamous skin lesions are ideal for viral therapy as they are highly amenable to 
intratumoral injection.  In addition, SCCS is an ideal candidate for immunotherapy as it is a tumor type 
prone to a heavy mutation burden given its reliance on UV radiation for initiation, and research on other 
immunotherapies has suggested that the responses  are more robust in tumors with high mutation burden 
[18]. Talimogene laherparepvec has a large genome with numerous nonessential genes that can be 
manipulated to reduce pathogenecity and improve effectiveness, and it lends itself to broad applications as 
the herpes virus can infect a wide range of host cells [33, 38].  Further, talimogene laherparepvec has been 
shown to have a tolerable safety profile, and in the context of other investigational therapies has a low rate 
of grade 3 or 4 adverse events, which is of particular importance when considering this patient population 
and the future of combined therapies [31, 35, 36]. 
 
1.4.4  Combination Talimogene Laherparepvec and Panitumumab in SCCS:  
While EGFR expression is known to be high in squamous tumors [21], and impressive responses have 
been seen with panitumumab, only 10-20% of patients treated with EGFR inhibition have a clinical benefit.  
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
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Further, activating mutations in EGFR are rare in head and neck squamous tumors, but dramatic responses 
to EGFR inhibition are still seen, suggesting that other processes, such as increased ADCC activity, are at 
work in promoting this response [39-42].  Clinical trials to determine if combination strategies of EGFR 
inhibition with immune stimulating therapies may thus be superior and  are warranted.  Talimogene 
laherparepvec in combination with panitumumab could broaden the anti-tumor response by priming the 
locoregional microenvironment where the virus could induce pro-inflammatory cytokines and increase the 
expression of tumor antigens and PD-L1 by tumor cells and MHC class 1 molecules [33, 40]. This is 
particularly important since treatment with EGFR-inhibiting antibodies has been shown to promote EGFR-
specific cellular immunity through the interaction of EGFR(+) tumor cells and FcγRIIIa on NK cells, the 
induction of IFN-γ-dependent expression of DC maturation markers, and the initiation of adaptive immune 
responses via NK cell-induced DC maturation, which enhance cross-presentation to CTL specific for EGFR 
[41]. 
 
1.5 Sample Size Justification 
The combination of panitumumab and talimogene laherparepvec will be considered of no interest for further 
evaluation if the response rate in advanced SCCS is 25% (p0) or less, and considered an improved 
treatment if the response rate in advanced SCCS is 47% (p1) or higher. Denote the true response rate by 
p. Using the Simon's two-stage design [43], we will test H0: p≤p0 vs.  H1: p>p1 with 80% power and 
alpha=5% (one-sided). In the first stage, 13 patients will be accrued. If there are 3 or fewer responses in 
these 13 patients, we will terminate the study and reject the drug (combination of panitumumab and 
talimogene laherparepvec). Otherwise, 17 additional patients will be accrued for a total of 30 patients. If 
12 or more responses are observed in 30 patients, the null hypothesis will be rejected and we will conclude 
the success of the drug.  
 
The combination therapy approach would be considered to have limited safety if unanticipated toxicity from 
talimogene laherparepvec is observed. If the proportion of talimogene-laherparepvec related grade ≥ 3 
toxicities that result in hospitalization or delays/cancellation of planned surgery is less than 30% of the 
subjects accrued, then the study accrual may continue. These toxicities do not include fever or injection 
site reaction which are known side effects of talimogene laherparepvec. The toxicity will be independently 
monitored by the Human Research Oversight Committee which will communicate any safety concerns 
directly to all participating Investigators.  
 
1.6 Study Variables 
 
1.6.1 Independent Variables, Interventions, or Predictor Variables  
The following variables will be examined for treatment outcomes of efficacy and safety, and/or predict 
outcomes or performance. 
 
Treatment 
 
Duration of treatment 
 
Baseline measures of disease 
 
Baseline mutation load in tumor tissue 
 
Baseline DNA mutation signature in tumor tissue 
 
Baseline mRNA signature in tumor tissue  
 
Baseline Immune cell populations and immune profile in tumor tissue 
 
1.6.2 Dependent Variables or Outcome Measures  
The following variables will be examined for change as a result treatment or as predictors. 
 
AEs 
 
Preliminary efficacy of the combined treatment of talimogene laherparepvec and panitumumab, 
in comparison to single-agent panitumumab by historical control  
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
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Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
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 
irPFS at 12 months 
 
PFS HR 
 
ORR 
 
1-year survival 
 
OS 
 
Time to resectability  
 
Pathologic complete response rate 
 
Response of injected and non-injected tumor deposits 
 
time to initial response 
 
durable response rate 
 
Change from baseline mutation load in tumor tissue 
 
Change from baseline DNA mutation signature in tumor tissue 
 
Change from baseline mRNA signature in tumor tissue  
 
Change from baseline Immune cell populations and immune profile in tumor tissue 
 
1.7 Drugs/Devices/Biologics 
There are no investigational agents involved in this study.  Both panitumumab and talimogene 
laherparepvec are FDA approved drugs. 
  
1.7.1 Pharmaceutical information (Panitumumab and Talimogene Laherparepvec): 
 
1.7.1.1 Panitumumab 
Panitumumab is a recombinant, human IgG2 kappa monoclonal antibody that binds specifically to 
the human EGFR.  
 
Panitumumab Injection for Intravenous Use is manufactured by Amgen Inc., One Amgen Center 
Drive Thousand Oaks, CA 91320-1799.   
 
Panitumumab Injection for Intravenous Use is a sterile, colorless, pH 5.6 to 6.0 liquid for 
intravenous (IV) infusion. It is available in 20 mg/mL single use vials for dosages of 100 mg/5 mL, 
200 mg/10 mL or 400 mg/20 mL.  Store vials in the original carton under refrigeration at 2 to 8 ˚C 
(36 to 46 ˚F) until time of use.  Protect from direct sunlight.  Do not freeze.  Since panitumumab 
does not contain preservatives, any unused portion remaining in the vial must be discarded.  The 
diluted infusion solution of panitumumab should be used within 6 hours of preparation if stored at 
room temperature or within 24 hours of dilution if stored at 2 to 8 ˚C (36 to 46 ˚F).For more 
information on this agent, refer to the FDA approved Package Insert. 
 
1.7.1.2 Talimogene Laherparepvec 
 
Talimogene laherparepvec is an oncolytic immunotherapy based on HSV-1 which is capable of 
generating an immune response specific to a subject’s tumor.  Talimogene laherparepvec induces 
viral lysis of tumor cells, followed by stimulation of a tumor-specific immune response. 
 
Talimogene laherparepvec is manufactured by BioVex, Inc., a subsidiary of Amgen Inc., One 
Amgen Center Drive, Thousand Oaks, California 91320-1799. 
 
Talimogene laherparepvec is presented as a sterile, semi-translucent to opaque suspension, 
practically free from particles, and preservative free frozen liquid in a single-use 2.0 cc Crystal 
Zenith Resin vial.  Each vial will contain talimogene laherparepvec at a nominal concentration of 
106 PFU/mL or 108 PFU/mL for intratumoral injection in a solution containing disodium hydrogen 
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
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phosphate dihydrate, sodium dihydrogen phosphate dihydrate, sodium chloride, sorbitol, myo-
inositol and water for Injection.  Each 2.0 cc vial will contain approximately 1.15 mL of talimogene 
laherparepvec.  Vials are appropriately filled to ensure that a sufficient deliverable dose is provided.  
Each vial is intended for single use only.  Vials will be sealed with rubber stoppers, Fluorotec-coated 
on the product side. The vial will be labelled with concentrations 106 PFU/mL or 108 PFU/mL. 
 
1.7.2  Treatment Plan 
1.7.2.1  General Considerations: 
The experimental aspect of this protocol is in the use of panitumumab and talimogene 
laherparepvec in patients with locally advanced or recurrent SCCS. Panitumumab is FDA-approved 
for use in patients with wild-type RAS (defined as wild-type in both K-RAS and N-RAS as 
determined by an FDA-approved test) metastatic colorectal cancer (mCRC). The safety and optimal 
dosing of talimogene laherparepvec was established in melanoma [31], and it is an FDA-approved 
agent for metastatic melanoma.  
 
1.7.2.2 Interim Safety Assessment and Stopping rules:  
We plan to start monitoring the treatment safety after 5 patients are recruited. Monitoring will 
continue after every subsequent patient. The stopping rule will be determined by the posterior 
probability of the event rate of the either hospitalizations or delays/cancellation in planned surgery, 
due to treatment related toxicities. Specifically, the early stopping will be triggered when the 
posterior probability that more than 40% patients are either hospitalized or delayed/ cancelled in 
surgery due to treatment related toxicities is greater than 90%. Additional information is presented 
in section 6.3.2. 
 
1.7.3  Sequence of Treatment: 
1.7.3.1  Prior to Therapy 
Prior to initiating therapy patients will undergo staging with history, physical and radiologic 
assessments to determine the extent of disease.  Initial biopsy will be procedure from the primary 
site or regional lymph nodes.  Samples will be used for confirmation of diagnosis and for molecular 
studies as described. 
 
1.7.3.2  Therapy with Panitumumab and Talimogene Laherparepvec 
Patients who are eligible for and consent to enroll onto this trial will receive an initial dose of 106 
PFU/mL of talimogene laherparepvec on day 1. On day 22 patients will begin combination therapy 
with panitumumab at 6 mg/kg and talimogene laherparepvec at 108 PFU/mL, followed by this 
schedule every 2 weeks +/- 3 days for 3 cycles. However, dosing windows for talimogene 
laherparepvec are Day 22 +/- 3 days for the initial dose and +/- 3 days for any subsequent cycles. 
Patients will receive therapy for a total of 9 weeks prior to first restaging scans and assessment for 
definitive therapy.  The decision may be made to offer up to 3 more cycles of therapy prior to 
surgery if it is felt that the tumor may continue to respond.  
 
1.7.3.3  After Therapy with Panitumumab and Talimogene Laherparepvec 
After day 64 of therapy  +/- 7 days, patients will be evaluated for surgical resection. At the 
conclusion of treatment, we will collect peripheral blood and tumor tissue again post-treatment, 
either at the time of surgical resection, if applicable, or by re-biopsy.  Patients will also receive a 
biopsy at progression, if applicable. Patients who are considered to be not candidates for definitive 
surgery and/or radiation therapy after the conclusion of 6 cycles, and who are benefitting from 
treatment with CR, PR or stable disease will be given the option to continue on protocol therapy.  
 
 
 
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
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1.7.4 Dose Calculations: 
 
1.7.4.1 Panitumumab 
The recommended dose of panitumumab is 6 mg/kg, administered as an intravenous infusion over 
60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 
30 to 60 minutes. Doses higher than 1000 mg should be administered over 90 minutes. 
 
1.7.4.2 Talimogene Laherparepvec 
The total volume of talimogene laherparepvec to be prepared will be based on investigator 
evaluation of injectable lesions and estimation of the total volume needed based on the Talimogene 
Laherparepvec Injection Volume Guideline Based on Tumor Size (Table 3).  Prescribe the 
estimated total volume by rounding up to the nearest 1.0 mL. 
The maximum volume of talimogene laherparepvec administered at any dose is 4.0 mL for any 
individual lesion.  The maximum dose in any one treatment is 4.0 mL.  Use the maximum amount 
whenever lesions allow.  
The recommended volume of talimogene laherparepvec to be injected into the tumor(s) is 
dependent on the size of the tumor(s) and should be determined according to the injection volume 
guideline in Table 3. 
 
Table 3. Talimogene Laherparepvec Injection Volume Guideline Based on Tumor Size: 
Tumor Size (longest dimension) 
Maximum Injection Volume 
> 5.0 cm 
4.0 mL 
> 2.5 cm to 5.0 cm 
2.0 mL 
> 1.5 cm to 2.5 cm 
1.0 mL 
> 0.5 cm to 1.5 cm 
0.5 mL 
≤ 0.5 cm 
0.1 mL 
 
All reasonably injectable lesions (cutaneous, subcutaneous and nodal disease that can be injected 
with or without ultrasound guidance should be injected with the maximum dosing volume available 
on an individual dosing occasion.  On each treatment day, prioritization of injections is 
recommended as follows: 
1)  Any new injectable tumor that has appeared since the last injection 
2)  By tumor size, beginning with the largest tumor  
3)  Any previously uninjectable tumor(s) that is now injectable  
 
Within the guidelines of the algorithm in the Table 3 and the prioritization model above, it is 
recommended that each lesion receive the maximum amount possible at each visit before moving 
on to the next lesion, subject to tumor-specific limitations (such as inability to inject the full amount 
into the lesion).  Lesions should be injected until the maximum volume per day (4.0 mL) has been 
reached or there are no further injectable lesions, whichever comes first. 
 
1.7.5 Treatment Administration: 
 
1.7.5.1  Panitumumab Preparation 
Prepare the solution for infusion, using aseptic technique, as follows: 
1)  Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration.  Although panitumumab should be colorless, the solution may contain a 
small amount of visible translucent-to-white, amorphous, proteinaceous, panitumumab particulates 
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Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
21 
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IRB Form Version 12.18.2018 
 
(which will be removed by filtration; see below). Do not shake. Do not administer panitumumab if 
discoloration is observed. 
2)  Withdraw the necessary amount of panitumumab for a dose of 6 mg/kg. 
3)  Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. Doses higher than 
1000 mg should be diluted to 150 mL with 0.9% sodium chloride injection, USP. Do not exceed a 
final concentration of 10 mg/mL. 
4)  Mix diluted solution by gentle inversion. Do not shake. 
 
1.7.5.2  Panitumumab Administration 
Panitumumab will be administered in combination with talimogene laherparepvec on day 22 (week 
3), day 36 (week 5), and to be continued on every 2 weeks thereafter. 
 
1)  Administer using a low-protein-binding 0.2 μm or 0.22 μm in-line filter.  
2)  Panitumumab must be administered via infusion pump.  
a) Flush line before and after panitumumab administration with 0.9% sodium chloride 
injection, USP, to avoid mixing with other drug products or intravenous solutions. Do 
not mix panitumumab with, or administer as an infusion with, other medicinal products. 
Do not add other medications to solutions containing panitumumab.  
b) Infuse doses of 1000 mg or lower over 60 minutes through a peripheral intravenous 
line or indwelling intravenous catheter. If the first infusion is tolerated, administer 
subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg 
over 90 minutes. 
3)  Use the diluted infusion solution of panitumumab within 6 hours of preparation if stored at room 
temperature, or within 24 hours of dilution if stored at 2 to 8 °C (36 to 46 F). DO NOT FREEZE.  
4)  Discard any unused portion remaining in the vial. 
 
1.7.5.3  Talimogene Laherparepvec Preparation 
 
1)  Receipt: 
To ensure the stability of talimogene laherparepvec, vials must be received, unpacked and placed 
into storage within 90 seconds. The pharmacy team should have a plan of action to allow for quick 
and efficient transfer of the box of vials into the freezer (for example, by placing the shipper box 
close to the freezer before opening the shipper box and completing the next steps of the process).   
2) Storage: 
To ensure stability and quality are maintained, the product must be stored correctly upon receipt 
and for the duration of the study under the conditions specified below.   
Talimogene laherparepvec must be stored in a non-cycling freezer maintained at a set point of -80 
oC 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.  Table 4 below outlines the storage temperature 
requirements.  
 
Table 4.  Acceptable Storage Temperature: 
 
 
 
To ensure GCP compliance with regards to the storage of biological products, talimogene 
laherparepvec should be segregated and stored on its own shelf in the freezer.  Sites should also 
refer to local guidance on storing clinical trial drugs. 
3)  Temperature Monitoring: 
Freezer Set Point (ºC) 
Acceptable Variation 
Acceptable Range 
-80 °C 
( 10 °C) 
-90 to -70 °C 
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
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IRB Form Version 12.18.2018 
 
Temperature monitoring of the storage temperatures, via a manual or electronic temperature log, 
of all locations where talimogene laherparepvec is stored is required.  Actual temperature, plus 
range of temperatures (minimum/maximum), must be documented. 
Due to the temperature sensitivity of talimogene laherparepvec, the chosen device specifications 
should be checked carefully to ensure the device covers the specified temperature ranges required.  
Temperature monitoring equipment should be serviced and calibrated in accordance with the 
manufacturer’s guidelines and/or institutional policies. 
Temperature excursions described below apply only to frozen product in storage.  
4)  Temperature Excursion: 
A temperature excursion occurs when a Product is exposed to temperatures outside of its 
recommended storage range.  Excursion temperature limits are defined in Table 5. 
 
Table 5.  Frozen Storage Temperature Excursion Limits: 
Required Storage 
Temperature Range 
Temperature(s) outside 
required storage range 
Temperature excursion when 
the duration exceeds 
-80°C ± 10°C 
< -90°C 
(colder than -90°C) 
0 minutes 
≥ -69°C to ≤ -45°C 
1512 cumulative hours (63 
cumulative days) 
> -45°C 
(warmer than -45°C) 
0 minutes 
 
For temperatures colder than -90°C and warmer than -45°C, report the excursion using the 
Investigator Sponsored Studies Temperature Excursion Submission Form ensuring that all details 
on the form are completed fully and accurately.  
For temperatures within the range -69°C to -45°C, record each event within this range on the 
Temperature Excursion Tracking Log; cumulative duration time of the temperature excursions 
within this range should be captured. Once a cumulative period of 1512 hours has been reached, 
the site should submit the Temperature Excursion Submission Form making sure all relevant details 
on the form are completed fully and accurately. 
Under no circumstances should any product impacted by an actual or suspected temperature 
excursion be administered to or by subjects before a temperature excursion assessment is 
completed by Amgen.  Pending such an assessment, all product(s) suspected of being exposed to 
a temperature excursion should be quarantined under the appropriate storage conditions.   
5)  Reporting of temperature excursions during clinical administration is not required. 
6)  Talimogene laherparepvec is open-label bulk supply that can be used across study subjects.  
7)  Talimogene laherparepvec is supplied in two concentrations and the concentration that is to be 
prepared will be based on which visit the administration will occur on: 
 
106 PFU/mL or the first dose only 
 
108 PFU/mL for the second and all subsequent doses 
8)  The talimogene laherparepvec Safety Data Sheet categorizes the drug as a BioSafety Level 
(BSL) 1, thus use of BSL 1 containment procedures is recommended.  
 
The use of a microbiological safety cabinet or hood for the dispensing of talimogene 
laherparepvec or for dose preparation is not required for the 2.0 cc Crystal Zenith Resin 
stoppered vials filled with approximately 1 mL of talimogene laherparepvec that will be 
used in this study.   
 
Talimogene laherparepvec may be safely drawn up into syringes in the room used for 
product administration, although this may also optionally occur elsewhere (e.g., in the 
pharmacy).   
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
23 
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IRB Form Version 12.18.2018 
 
 
Any side room away from other subjects can be used for talimogene laherparepvec 
administration, although local/regional guidelines should be followed.  
 
1.7.5.4.  Talimogene Laherparepvec Administration 
Talimogene Laherparepvec will be administered as a single agent on day 1 (week 1), and thereafter 
in combination with Panitumumab on day 21 (week 3), and to be continued on weeks 5 and every 
2 weeks thereafter.  
 
All personnel handling the talimogene laherparepvec or material contaminated with talimogene 
laherparepvec must observe safety precautions (e.g., wear a laboratory coat, safety glasses and 
gloves). 
 
1)  Determine which box labeled with the appropriate concentration, 106 PFU/mL or 108 PFU/mL, 
is to be prepared.  
2)  Remove the number of frozen vials from the box that have been calculated for administration.   
 
*Care should be taken to avoid unintended thawing of vials that will not be used.  *Talimogene 
laherparepvec must be properly labeled in accordance with current ICH GCP and local/regional 
requirements prior to dispensing for administration.  The time the vials are removed from the 
freezer must be recorded.   
3)  Thaw frozen vials until liquid at room temperature (15 °C to 30 °C or 59 °F to 86 °F).  Thaw 
should take approximately 30 minutes.  Please ensure vial is protected from light during the 
thaw process, using the original carton or a light protective bag (with adequate space, 
approximately 2.5 cm between each vial). 
Please Note:  During the thaw process sites should adhere to local procedures to ensure 
the required temperature is maintained and monitored.  
During the thaw: 
 
Leave vials undisturbed, except to gently swirl to check for completion of thaw. 
 
Never shake vials vigorously, especially during the thawing process. 
After the thaw: 
 
Gently swirl the vial to ensure the contents are mixed to a homogeneous solution 
free of ice. 
 
Carefully check the vial for damage (e.g. cracks).  Quarantine damaged vials and 
obtain further instructions for destruction and reporting. 
 
Please refer to Table 6 for the clinical handling storage times. 
 
Discard materials used in the thawing (e.g. gloves) following appropriate 
local/regional or BSL classification guidelines. 
4) Preparation of Dosing Syringe for Injection 
 
All personnel handling talimogene laherparepvec or material contaminated with 
talimogene laherparepvec must observe safety precautions (e.g. wear a laboratory 
coat, safety glasses and gloves) as per local/regional or BSL classification 
guidelines. 
 
The prepared talimogene laherparepvec dosing syringe must be properly labeled 
in accordance with current ICH GCP and local/regional or BSL classification 
requirements prior to administration. 
 
Clean talimogene laherparepvec vial stopper with an alcohol swab. 
 
Withdraw the volume of talimogene laherparepvec required with the appropriate 
number of sterile syringe(s) and 22-26 gauge needle(s).  Cap each syringe as 
per local practice. 
 
Please refer to the Table 6 for the Clinical Handling Timelines.  Discard any 
prepared syringes not used for administration within the specific times stated.   
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
24 
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IRB Form Version 12.18.2018 
 
 
Discard materials used in the preparation (e.g. gloves, needles) in accordance with 
local/regional or BSL classification guidelines.   
 
Table 6: Clinical Handling Times Outside Labelled Storage Conditions 
General product handling considerations 
Thaw 
 
Thaw frozen talimogene laherparepvec vials at 15°C to 30°C (59°F to 86°F) protected from light until 
fully liquid (approx. 30 minutes at the stated temperature range).  Do not expose vials to higher 
temperatures. 
 
Swirl gently.  Do not shake. 
 
Do not refreeze thawed talimogene laherparepvec. 
 
Storage and Preparation 
 
Store talimogene laherparepvec (in vial or syringe) protected from light at all times until 
administration. 
 
Due to the absence of a preservative in the formulation please minimize storage time in the syringe 
where possible.     
 
Please note that storage of 106 and 108 PFU/mL talimogene laherparepvec in the vial followed by in 
the syringe is permitted for the same storage condition only e.g. both vial and syringe stored in the 
refrigerator. When thawed 106 and 108 PFU/mL is stored in both vial and syringe, the storage time in 
syringe cannot exceed allowable syringe storage time and the cumulative vial and syringe storage 
time cannot exceed the total allowable storage time. See below for specific details on allowable 
durations for each container and temperature combination. 
 
Administration 
 
If talimogene laherparepvec is not administered within the timeframes and not handled at the 
temperatures indicated, then it must be discarded. 
 
Reporting of temperature excursions during clinical administration is not required. 
Total storage time for thawed 106 PFU/mL product 
2°C to 8°C (36°F to 46°F) 
up to 25°C (77°F)* 
12 hours 
(inclusive of 4 hours maximum in the syringe) 
4 hours 
(inclusive of 2 hours maximum in the syringe) 
Total storage time for thawed 108 PFU/mL product 
2°C to 8°C (36°F to 46°F) 
up to 27°C (80°F)* 
48 hours (inclusive of 8 hours maximum in the 
syringe) 
4 hours 
(inclusive of 4 hours maximum in the syringe) 
*This covers temperatures from 9°C to 27°C (48°F to 80°F) 
 
5)  Administration: 
 
Administration of talimogene laherparepvec  requires specific training which is provided 
during site initiation and must be completed, by individuals involved in administration, prior 
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Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
25 
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IRB Form Version 12.18.2018 
 
to undertaking any administration related activities.  Successful completion of the training 
must be documented. 
Intralesional Administration of Talimogene Laherparepvec 
 
The following steps should be followed for drug administration:  
Materials Inventory 
o 
Laboratory coat, gloves and safety glasses (or as required in accordance with 
local/regional or BSL classification guidelines for administration)   
o 
Dosing syringe(s) for injection filled with talimogene laherparepvec  
o 
Sterile 22-26 gauge needle(s) for injection 
o 
Alcohol swabs 
o 
Absorbent pad and dry occlusive dressing 
Lesion site preparation 
o 
Talimogene laherparepvec is only to be administered by intralesional injection into 
cutaneous, subcutaneous and nodal lesions with or without image ultrasound 
guidance.  Talimogene laherparepvec must not be administered into visceral organ 
metastases.   
o 
The injection site may be pre-treated with a topical anesthetic agent or an 
injectable local anesthetic; however, a local anesthetic must not be injected directly 
into the lesion. Please note that the anesthetic should not be mixed together with 
Talimogene laherparepvec in the same syringe. 
o 
Swab the lesion and surrounding areas with alcohol, allow to dry. 
Lesion injection 
o 
All personnel handling talimogene laherparepvec or material contaminated with 
talimogene laherparepvec must observe safety precautions (e.g. wear a laboratory 
coat, safety glasses and gloves) in accordance with local/regional or BSL 
classification guidelines for administration).   
o 
Inject talimogene laherparepvec intralesionally: 
 
A single point of insertion is recommended; multiple insertion 
points may be used if the tumor is larger than the radial reach of 
the needle. 
 
Talimogene laherparepvec should be injected along multiple 
different tracks within the lesion in order to obtain as wide a 
dispersion as possible 
 
Distribute talimogene laherparepvec within the lesion through the 
insertion point using the radial reach of the needle in different 
directions to evenly distribute (Figure 3) 
 
Figure 3.  Different Tumor Lesions and Needle Insertion Points. 
 
o 
Avoid premature extraction of needle.  
o 
After dosing, the injection site should be swabbed with alcohol and pressure should 
be applied with gauze for several seconds after injection. 
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Version Number: v10, March 23, 2023 
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
26 
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IRB Form Version 12.18.2018 
 
o 
Please ensure that gloves worn by the person administering the injection is 
discarded and a fresh pair of gloves is worn prior to proceeding to the next step.      
o 
The injection site should be covered with an absorbent pad and dry occlusive 
dressing. Please ensure a fresh pair of gloves is worn when handling the absorbent 
pad and dressing to prevent cross contamination with talimogene laherparepvec. 
Please also ensure that the outside of the dressing is wiped down with an alcohol 
swab to further minimize any cross contamination. 
o 
Discard materials used during injection (e.g., gloves, needles, gauze) in 
accordance with local/regional or BSL classification guidelines,  
Subject Counseling Information 
o 
Advise subjects on the potential for secondary exposure, e.g., broken skin. 
o 
Advise subjects on careful wound care.  Provide the subject with the current 
version of the Injection Site Care Instruction Document. 
o 
The presence of necrotic or ulcerating lesions may predispose the subject to local 
and/or systemic infections such as cellulitis, bacteremia, etc.  Advise subjects on 
careful wound care.  Infection precautions are recommended if tumor necrosis 
results in open wounds.   
o 
For Additional Information Related to Exposure to Talimogene Laherparepvec 
please refer to the latest version of your Investigator Brochure (IB) and Safety Data 
Sheet. 
 
1.7.6  Dose Modifications: 
Dose modifications will follow the guidelines below. In general, therapy will continue with grade 1 or 
tolerable grade 2 toxicities. Intolerable grade 2, grade 3, or grade 4 toxicities will result in holding therapy 
as follows: 
 
 
  
1.7.6.1 Dose modification guidelines for talimogene laherparepvec: 
Reductions 
Dose reductions with regards to changes in the concentrations of talimogene laherparepvec are 
not permitted. However, patients may require a reduction in the volume injected due to a disease 
response or due to local toxicity at the injection site. However, if in the course of administration of 
talimogene laherparepvec the subject cannot tolerate the full dose due to an injection-related 
adverse event such as pain, the total volume given should be recorded, and the reason for 
intolerance should be documented as an adverse event. 
 
1.7.6.2. Talimogene Laherparepvec Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation: 
If talimogene laherparepvec treatment was delayed by > 2 weeks, that dose will be deemed to have 
been missed and the subject will proceed to the next scheduled treatment visit. Dose reductions of 
talimogene laherparepvec is not permitted, other than a reduction in the volume injected due to a 
disease response. CTCAE 4.0 criteria listed in Table 7 are used to determine toxicity grades. 
If a subject experience any of the following treatment-related toxicities, talimogene laherparepvec 
administration should be delayed until the toxicity has resolved to at least CTCAE grade 1 or 
baseline (Table 7): 
 
grade 2 or greater immune-mediated adverse events, with the exception of vitiligo. 
 
grade 2 or greater allergic reactions. 
 
any other grade 3 or greater hematologic or non-hematologic toxicity. 
 
Table 7. CTCAE 4.0 Criteria: 
Symptom 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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Version Number: v10, March 23, 2023 
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
27 
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IRB Form Version 12.18.2018 
 
Pruritis 
Mild or localized 
Intense or 
widespread; 
intermittent; skin 
changes from 
scratching (e.g., 
edema, papulation, 
excoriations, 
oozing/crusts); oral 
intervention 
indicated; limiting 
instrumental ADL 
Intense or widespread; 
or constant; limiting 
self-care, ADLS or 
sleep; corticosteroid or 
immunosuppressive 
therapy indicated 
N/A 
Purpura 
Combined area of 
lesions covering 
<10% BSA 
Combined area of 
lesions covering 
10-30% BSA; 
bleeding with 
trauma 
Combined area of 
lesions covering >30% 
BSA; spontaneous 
bleeding 
N/A 
Rash 
(Acneiform) 
Papules and/or 
pustules covering 
<10% BSA, which 
may or may not 
be associated 
with pruritus or 
tenderness 
Papules and/or 
pustules covering 
10-30% BSA, which 
may or may not be 
associated with 
symptoms or 
pruritus or 
tenderness; or 
associated with 
psychosocial 
impact; or limiting 
instrumental ADL 
Papules and/or 
pustules covering 
>30% BSA, which may 
or may not be 
associated with 
symptoms or pruritus 
or tenderness; or 
limiting self-care ADL; 
or associated with local 
super infection with 
oral antibiotics 
indicated 
Papules and/or 
pustules covering 
any % BSA, 
which may or may 
not be associated 
with symptoms or 
pruritus or 
tenderness and 
are associated 
with extensive 
super infection 
with IV antibiotics 
indicated; or life-
threatening 
consequences 
Rash 
(Maculo-
papular) 
Macules/papules 
covering <10% 
BSA with or 
without symptoms 
(e.g., pruritus, 
burning, 
tightness) 
Macules/papules 
covering 10-30% 
BSA with or without 
symptoms (e.g., 
pruritus, burning, 
tightness); or 
limiting instrumental 
ADL 
Macules/papules 
covering >30% BSA 
with or without 
symptoms (e.g., 
pruritus, burning, 
tightness); limiting self-
care ADL 
N/A 
Nail 
Discoloration 
Asymptomatic; or 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated 
N/A 
N/A 
N/A 
Nail Loss 
Asymptomatic 
Symptomatic 
N/A 
N/A 
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Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
28 
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IRB Form Version 12.18.2018 
 
separation of nail 
bed from nail 
plate; or nail loss 
separation of nail 
bed from nail plate; 
or nail loss; limiting 
instrumental ADL 
Nail Ridging 
Asymptomatic; or 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated 
N/A 
N/A 
N/A 
 
Subjects who are receiving talimogene laherparepvec may not receive systemic antiherpetic drugs 
(e.g., acyclovir, valacyclovir, famciclovir), but may receive a topically administered antiherpetic drug 
more than 20 cm from a talimogene laherparepvec injection site. Dosing should be permanently 
discontinued if, in the opinion of the investigator, the subject develops clinical evidence of any 
systemic herpes infection (such as encephalitis or disseminated infection). If the subject requires 
corticosteroid dosing of > 10 mg prednisone daily (or equivalent) for related toxicities, talimogene 
laherparepvec dosing must be withheld until the corticosteroid dose has decreased to < 10 mg 
prednisone daily (or equivalent). In clinical trials, subjects receiving systemic immunosuppressive 
therapy (>2 weeks) including oral steroid doses > 10 mg/day of prednisone or equivalent within 7 
days prior to enrollment were excluded due to the potential risk of disseminated herpetic infection 
(based on animal data) in patients with immunocompromised conditions including those who 
require chronic high-dose steroids or other immunosuppressive agents. Thus, at this time there is 
no data to support use of talimogene laherparepvec in patients requiring > 10 m of prednisone. 
  
Talimogene laherparepvec treatment should be continued based on the potential benefit/risk 
assessment of the subject.  If talimogene laherparepvec dosing is delayed by more than 4 weeks 
from the date of the planned dose (i.e., approximately 6 weeks or 7 weeks depending whether the 
patient is receiving Q2W or Q3W dosing from the previous dose) due to the occurrence of an 
adverse event that is considered related to talimogene laherparepvec, the subject must be 
permanently withdrawn from talimogene laherparepvec treatment. 
Talimogene laherparepvec is to be permanently discontinued for subjects meeting any of the 
following criteria: 
 
For phase I or Ib studies, subject develops DLT during the DLT evaluation period. 
 
The subject, for any reason, requires treatment with another anticancer therapeutic 
agent for treatment of the study disease. In this case, discontinuation from the 
treatment occurs immediately upon introduction of the new agent. 
 
Confirmed PD. 
 
A grade 2 or greater immune-mediated adverse event (with the exception of vitiligo) or 
allergic reactions attributed to talimogene laherparepvec that would require a dose 
delay of greater than 4 weeks from the date of the planned dose (i.e., approximately 6 
weeks from the previous dose). NOTE: immune-mediated glomerulonephritis, 
vasculitis, and pneumonitis and exacerbation of psoriasis have been observed in 
subjects receiving talimogene laherparepvec in clinical trials. Most of these subjects 
had a history of other autoimmune disease and/or prior treatment with agents that 
offered plausible alternative etiologies, however, immune-mediated adverse events 
can potentially involve any organ system. 
 
Any other talimogene laherparepvec-related non-hematologic or hematologic toxicities 
grade 3 or greater occur that, in the opinion of the investigator, would require a dose 
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
29 
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IRB Form Version 12.18.2018 
 
delay of greater than 4 weeks from the date of the planned dose (i.e., approximately 6 
weeks from the previous dose). 
 
The subject develops clinical evidence of any systemic herpes infection (such as 
encephalitis or disseminated infection). 
 
A female subject becomes pregnant or fails to use acceptable method(s) of effective 
contraception (for those subjects who are able to conceive). 
 
A female subject breast feeds while on study treatment. 
 
Concurrent medical illness that, in the judgment of the investigator, would make 
continued treatment with talimogene laherparepvec dangerous for the subject. 
For additional information related to special warnings and precautions for the use of talimogene 
laherparepvec, please refer to the latest version of the Investigator’s Brochure.  
 
1.7.6.3.  Panitumumab 
Toxicities include: Cutaneous reactions (rash, dermatitis acneiform, erythema, dry skin, pruritis, 
PPE), diarrhea, nausea, electrolyte disturbances (hypomagnesemia, hypocalcemia, hypokalemia), 
paronychia, ocular disorders, interstitial lung disease, infusion-related reactions, vomiting, 
constipation, abdominal pain, fatigue, pyrexia, mucositis, and anorexia.   
 
1) Renal impairment 
No clinical studies have been conducted in patients with renal impairment. 
 
2) Hepatic impairment 
No clinical studies have been conducted in patients with hepatic impairment. 
 
3) Dose Modifications for Dermatologic Toxicity: 
Withhold panitumumab for dermatologic toxicities that are grade 3 or higher or are considered 
intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue 
panitumumab. If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically 
improved after withholding no more than two doses of panitumumab, treatment may be resumed 
at 50% of the original dose. If toxicities recur, permanently discontinue panitumumab (Table 8). If 
toxicities do not recur, subsequent doses of panitumumab may be increased by increments of 25% 
of the original dose until the recommended dose of 6 mg/kg is reached. 
 
Table 8.  Panitumumab dose modification for dermatologic toxicity: 
Grade 
Dose Modification 
Grade 1 
No dose modification of panitumumab  
Grade 2 
No dose modification of panitumumab  
Grade 3/4 
1st Occurrence: Delay infusion 1 to 2 weeks. If there is improvement, continue 
panitumumab dose at a 50% of the original dose. If there is no improvement, 
discontinue panitumumab.  
2nd Occurrence: Delay infusion 1 to 2 weeks. If there is improvement, continue 
panitumumab dose at a 40% of the original dose. If there is no improvement, 
discontinue panitumumab. 
3rd Occurrence: Delay infusion 1 to 2 weeks. If there is improvement, continue 
panitumumab dose at a 30% of the original dose. If there is no improvement, 
discontinue panitumumab. 
4th Occurrence: Discontinue panitumumab. 
 
 
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
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In one study [44], dermatologic toxicities occurred in 90% of patients and were severe (grade 3 and 
higher) in 15% of patients receiving panitumumab.  The clinical manifestations included, but were 
not limited to acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, 
and fissures.  Monitor patients who develop dermatologic or soft tissue toxicities while receiving 
panitumumab for the development of inflammatory or infectious sequelae.  Withhold or discontinue 
panitumumab for dermatologic or soft tissue toxicity associated with severe or life-threatening 
inflammatory or infectious complications.  Patients should be advised to avoid sun exposure while 
receiving panitumumab. 
 
In previous reports, the Common Terminology Criteria for Adverse Events (CTCAE) 4.0 (Table 7) 
have been used for EGFR-associated rash. 
 
4) Interstitial Lung Disease (ILD) 
ILD may be acute in onset and has been observed in 1.3 % of patients, and some cases have been 
fatal. If patients experience worsening of respiratory symptoms such as dyspnea, cough and fever, 
panitumumab should be interrupted and the patient should be promptly investigated. If ILD is 
confirmed, panitumumab should be discontinued and the patient treated appropriately.  
 
5) Electrolyte Abnormalities 
Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia 
occurred in up to 7% [45] of patients across clinical trials. Monitor patients for hypomagnesemia 
and hypocalcemia prior to initiating treatment with panitumumab, periodically during treatment, and 
for up to 8 weeks after the completion of treatment.  Other electrolyte disturbances, including 
hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. 
 
6) Infusion Reactions 
In one study [44], 4% of patients receiving panitumumab experienced infusion reactions, and 1% 
of patients experienced severe infusion reactions (grade 3-4).  Infusion reactions, manifesting as 
fevers, chills, dyspnea, bronchospasm, and hypotension, can occur following panitumumab 
administration. Table 9 and 10 show the grading criteria for infusion reactions and dose 
modifications for infision reactions, respectively.  Fatal infusion reactions occurred in post-
marketing experience.  
 
Table 9. Grading Infusion Reactions: 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Infusion 
Reaction 
Transient 
flushing or rash; 
drug fever 
<38˚C (<100 ˚F) 
Rash; flushing, 
urticaria; 
dyspnea; drug 
fever ≥38 ˚C 
(≥100 ˚F) 
Symptomatic bronchospasm with or 
without urticaria; parenteral 
medication(s) indicated; allergy 
related edema/angioedema; 
hypotension 
Anaphylaxis 
 
Table 10. Algorithm for Dose Modifications for Infusion Reactions: 
Grade 
Dose Modification 
Grade 1 
Stop the infusion. 
Consider additional anti-histamines and/or corticosteroid medications. 
Resume the panitumumab dose at a 50% slower rate. 
Consider administering prophylactic anti-histamine and corticosteroid medications 
and/or acetaminophen for subsequent doses. 
Grade 2 
Stop the infusion. 
Consider additional anti-histamines and/or corticosteroid medications. 
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Protocol Title: A Phase I Study of Talimogene 
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Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
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Resume the panitumumab dose at a 50% slower rate. 
Consider administering prophylactic anti-histamine and corticosteroid medications 
and/or acetaminophen for subsequent doses. 
Grade 3 
Stop the infusion. 
Administer appropriate medical therapy including epinephrine, anti-histamines, 
corticosteroids, bronchodilators and supplemental oxygen. 
Observe subject until complete resolution of all signs and symptoms. 
Permanently discontinue panitumumab. 
Grade 4 
Stop the infusion. 
Administer appropriate medical therapy including epinephrine, anti-histamines, 
corticosteroids, bronchodilators and supplemental oxygen. 
Observe subject until complete resolution of all signs and symptoms. 
Permanently discontinue panitumumab. 
No further study therapy. 
 
All patients will be pre-medicated with diphenhydramine hydrochloride 50 mg (or an equivalent anti-
histamine) IV 30-60 minutes prior to the first dose of panitumumab in order to prevent an infusion 
reaction.  At the discretion of the investigator, dexamethasone 20 mg (or an equivalent steroid), 
and an H2 blocker may also be administered.  Approximately 90% of severe infusion reactions 
occurred with the first infusion despite pre-medication with anti-histamines. 
 
Once the infusion rate has been decreased due to an infusion reaction, it will remain decreased for 
all subsequent infusions.  If the subject has a second infusion reaction at the slower infusion rate, 
the subject should receive no further panitumumab treatment. 
 
Panitumumab will be immediately and permanently discontinued for serious infusion reactions that 
are life threatening and/or require hospitalization.   
 
7) Photosensitivity 
Exposure to sunlight can exacerbate dermatologic toxicity.  Advise patients to wear sunscreen and 
hats and limit sun exposure while receiving panitumumab. 
 
8) Ocular Toxicities 
Keratitis and ulcerative keratitis, both known risk factors for corneal perforation, have been reported 
with panitumumab.  Monitor for evidence of keratitis or ulcerative keratitis.  Interrupt or discontinue 
panitumumab for acute or worsening keratitis. 
 
9) Other Toxicities 
Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and 
sepsis have been observed in patients treated with panitumumab. 
Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin 
sloughing has also been observed in patients treated with panitumumab. 
  
1.7.6.4 Talimogene Laherparepvec   
The most commonly reported adverse drug reactions (very common, ≥ 10%) in talimogene 
laherparepvec-treated patients were fatigue, chills, pyrexia, nausea, influenza-like illness, and 
injection site pain. Adverse events such as vomiting diarrhea, constipation, myalgia, arthralgia, 
extremity pain, headache and abdominal pain, were also reported as very common.  
 
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
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Dose reductions with regards to changes in the concentrations of talimogene laherparepvec are 
not permitted.  However, patients may require a reduction in the volume injected due to a disease 
response or due to local toxicity at the injection site. 
 
Dose delays are allowable.  If severe/grade 4 toxicities occur, talimogene laherparepvec 
administration should be delayed until the toxicity has resolved to at least a grade 1. Dosing of 
talimogene laherparepvec could also be delayed for active herpetic cutaneous or mucosal lesions, 
herpes labialis, antiviral therapy, or active dermatoses in the region of the injected tumors.  
 
If talimogene laherparepvec treatment was delayed due to adverse events or other reasons by > 2 
week, that dose will be deemed to have been missed and the subject will proceed to the next 
scheduled treatment visit. 
 
If talimogene laherparepvec dosing is delayed by more than 4 weeks (approximately 6 weeks from 
the previous dose) due to adverse events that are related to talimogene laherparepvec, then 
treatment should be discontinued.  If talimogene laherparepvec dosing is delayed by more than 4 
weeks (approximately 6 weeks from the previous dose) for reasons other than treatment-related 
toxicity, the case must be reviewed by the sponsor of the investigator sponsored study (ISS) to 
determine if the subject can resume talimogene laherparepvec therapy. 
 
If the subject requires corticosteroid dosing of > 10 mg prednisone daily (or equivalent) and/or other 
immunosuppressive medication for related toxicities, talimogene laherparepvec dosing must be 
held until the corticosteroid dose has decreased to < 10 mg prednisone daily (or equivalent) and 
the administration of the other immunosuppressive medication has discontinued. 
 
1)  Immune-mediated Adverse Events 
Immune-mediated adverse events have been observed in subjects receiving talimogene 
laherparepvec.  These included pauci-immune glomerulonephritis, vasculitis, and pneumonitis; 
however, immune-mediated adverse events can potentially involve any organ system.  
 
Permanently discontinue talimogene laherparepvec if dosing is delayed by more than 4 weeks due 
to a Grade 2 or greater immune-mediated adverse event (with the exception of vitiligo), allergic 
reactions, or urticaria attributed to talimogene laherparepvec.  
 
2)  Plasmacytoma 
Plasmacytoma has been observed with the administration of talimogene laherparepvec. 
Permanently discontinue talimogene laherparepvec if development of a plasmacytoma is observed. 
 
3)  Injection Site Reactions 
Talimogene laherparepvec is administered by direct injection into cutaneous, subcutaneous, and 
nodal tumor masses.  Injection site adverse events may occur, such as erythema, local skin 
discoloration, induration, warmth, and pain.  Less frequently, injected cutaneous tumor masses 
may undergo necrosis, predisposing the subject to local and/or systemic infections.  Similarly, 
injected pathologic lymph nodes may enlarge or become necrotic.  Uncommonly, necrotic lymph 
nodes may be the site of persistent drainage that requires corrective measures. In clinical studies, 
adverse events of “injection site pain” and “injection site reaction” were very common, occurring in 
≥ 10% of talimogene laherparepvec-treated subjects.  Most events of injection site pain and 
injection site reaction in subjects receiving talimogene laherparepvec were mild to moderate in 
severity. Subjects seronegative at baseline for HSV-1, when given an initial dose of talimogene 
laherparepvec at a concentration of 106 PFU/mL, do not appear to experience more exaggerated 
injection site reactions than those who are seropositive at baseline.   
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
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4)  Cellulitis 
Necrosis of cutaneous tumor masses and pathologic lymph nodes injected with talimogene 
laherparepvec may infrequently occur, predisposing to local/regional infection (i.e., cellulitis). In 
clinical studies to date, cellulitis was common, occurring in ≥ 1% to < 10% of subjects treated with 
talimogene laherparepvec.   
 
5)  Flu-like Symptoms 
Constitutional symptoms including chills, fatigue, headache, myalgia, and pyrexia may occur with 
talimogene laherparepvec.  Collectively, this constellation of symptoms may be described as “flu-
like symptoms”.  In clinical studies to date, adverse events with the MedDRA preferred terms 
“chills”, “fatigue”, “headache”, “influenza like illness”, “myalgia”, and “pyrexia” were very common, 
occurring in ≥ 10% of subjects treated with talimogene laherparepvec.  Most of these events were 
mild to moderate in severity.  Subjects seronegative at baseline for HSV-1, when given an initial 
dose of talimogene laherparepvec at a concentration of 106 PFU/mL, do not appear to experience 
more flu-like symptoms than those who are seropositive at baseline.  These symptoms are 
self-limiting and resolve without sequelae.   
 
1.7.7  Supportive Care Guidelines: 
1.7.7.1. Panitumumab 
Anti-emetics: Low emetogenicity.  Follow local anti-emetic policy. 
Supportive medications: Hydrocortisone, chlorphenamine and paracetamol can be given for 
chills/fever/rigor during the infusion, if required.  
 
Treatment of dermatologic reactions may include a moisturizer, sun screen (SPF >15 UVA/UVB), 
topical steroids and/or oral antibiotics. Advise patients to wear sunscreen, a hat and limit sun 
exposure.  Further recommendations are below: 
 
1) Antibiotics: The benefit of routine antibiotics in uncomplicated (uninfected) rash is unclear.  
Some clinicians have used oral minocycline (Minocin), mupirocin (Bactroban), or topical 
clindamycin (Cleocin).  Rash complicated by cellulitis should be treated with appropriate 
antibiotics based on clinical judgment or microbial sensitivity analysis. 
2) Anti-histamines: Diphenhydramine (Benadryl) or hydroxyzine (Atarax) may be helpful to 
control itching. 
3) Topical Steroids: The benefit of topical steroids is unclear.  Topical hydrocortisone cream 
will be provided for pruritus not relieved with anti-histamine use. 
4) Retinoids: There are no data to support the use of retinoids.  Use is not advised. 
5) Benzoyl Peroxide: Benzoyl peroxide should NOT be used as it may aggravate rash. 
6) Makeup:  Makeup may be used to cover the rash, but it should not make the rash worse.  
Dermatologist-approved make up should be used (e.g., Dermablend).  Makeup should be 
removed with a skin-friendly liquid cleanser (e.g., Neutrogena, Dove, Ivory Skin Cleansing 
Liqui-Gel). 
7) Moisturizers: Emollients should be used to prevent and alleviate skin dryness (e.g., 
Neutrogena Norwegian Formula Hand Cream, Vaseline Intensive Care Advanced Healing 
Lotion). 
8) Over-the-Counter Medications: Over-the-counter acne vulgaris medications (e.g., benzoyl 
peroxide) should not be used and could make the rash worse. 
 
 
1.7.7.2  Talimogene Laherparepvec  
Throughout the study, investigators may prescribe supportive care medications as needed for 
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Protocol Title: A Phase I Study of Talimogene 
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Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
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treatment of talimogene laherparepvec toxicities. These include but are not limited to treatment 
for peri-injectional fever and chills, for which antipyretics and antihistamines (i.e. acetaminophen, 
indomethacin and diphenhydramine) may be prescribed.  
 
1.7.8 Important Identified and Potential Risks 
 
1.7.8.1 Panitumumab 
Consult the current Investigator’s Brochure (IB) for the full information on the Identified and 
Potential Risks of panitumumab and Adverse Drug Reactions (ADRs). 
1.7.8.1 Talimogene laherparepvec 
Consult the current Investigator’s Brochure (IB) for the full information on the Identified and 
Potential Risks of talimogene laherparepvec and Adverse Drug Reactions (ADRs). 
  
1.7.9 
Dose-Limiting Toxicity 
Dose-limiting toxicity is defined as any occurrence of CTCAE grade 3 or greater adverse event in 
four weeks following the administration of the study products except grade 3 laboratory values not 
deemed clinically significant, grade 3 fatigue which resolves within 72 h of holding or modifying 
protocol therapy and grade 3 rash, as the latter is an already known potential side effect of 
panitumumab. 
 
1.7.9.1 Talimogene laherparepvec DLTs 
For Talimogene laherparepvec, the following events should also be considered as DLTs.  
 
Herpetic events: 
o 
Serious herpetic events such as herpetic encephalitis, encephalomyelitis or 
disseminated herpetic infection. 
o 
Any herpetic events confirmed due to talimogene laherparepvec that require 
treatment with acyclovir or similar anti-viral agent. Talimogene laherparepvec 
treatment should be suspended if treatment is required with systemic acyclovir or 
other anti-virals. If ongoing anti-viral treatment is required, talimogene 
laherparepvec treatment should be permanently discontinued. 
 
Any grade plasmacytoma at or near the injection site or evidence of impaired wound 
healing at the injection site. 
 
Grade 3 non-hematologic toxicity lasting > 3 days despite optimal supportive care; 
 
Grade 3 fatigue will not be classified as DLT, irrespective of duration. 
 
Any Grade 3 or higher non-hematologic laboratory value if the abnormality fails to respond 
to medical intervention, or leads to hospitalization, or persists for > 1 week unless deemed 
not clinically important per both investigator and sponsor. 
 
Any other intolerable toxicity leading to permanent discontinuation of talimogene 
laherparepvec. 
  
1.7.10 Drug/Device Accountability and Storage Methods 
 
1.7.9.1 Drug Products Storage and Security 
The investigator or an approved representative (e.g., pharmacist) will ensure that all drugs and any 
other study related material is stored in a secured area, under recommended temperature 
monitored storage conditions, in accordance with applicable regulatory requirements. 
To prevent theft or diversion, the drugs will be stored in a securely locked, substantially constructed 
cabinet or enclosure appropriate for a drug. Any actual or suspected theft or diversion must be 
reported immediately. 
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
35 
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1.7.11 Staggering Interval between the First Three Consecutive patients 
The staggering interval between the first three consecutive patients will be 2 weeks past the first 
infusion of the combination therapy (Cycle 1,Day 21). The staggering interval of 2 weeks was 
based on the median time to the development of dermatologic or most severe skin/ocular toxicity 
of 15 days after the first dose of panitumumab (US Package Insert, panitumumab Solution for 
Intravenous Infusion, 2006). 
 
1.8   
Specimen Collection 
 
1.8.1 Primary Specimen Collection 
 
1.8.1.1 Laboratory Evaluations and Procedures/Correlative Studies: Overview of Possible Molecular 
Investigations: 
 
 
Specimen, including tissue and blood, will be banked for the studies described below and for potential future 
studies. Specimens will be analyzed once funding becomes available. Samples will be transferred to NYU 
for analysis. 
 
 
FoundationOneTM genomic profile from paraffin embedded tumor samples taken before 
panitumumab and talimogene laherparepvec combination therapy, at the time of definitive 
surgery or biopsy, and at progression, if applicable 
 
mRNA sequencing by Nanostring of tumor tissue before therapy, at the time of definitive 
surgery or biopsy, and at progression, if applicable 
 
IHC analysis of immune cell populations and immune profile in peripheral blood and tumor 
tissue before therapy, at the time of definitive surgery or biopsy, and at progression, if 
applicable 
 
Flow cytometry analysis of immune cell populations and immune profile in peripheral blood 
before therapy, at the time of definitive surgery or biopsy, and at progression, if applicable 
 
The laboratory investigations for this hypothesis generating study will be comprehensive.  Partial DNA 
sequencing using FoundationOneTM will be done in order to look for a battery of known DNA mutations 
related to cancer and quantify mutation load in pre-treatment tissue, and correlate with clinical 
response, and examine the DNA mutation signature in tumor tissue pre- and post-therapy for 
biomarkers of response to therapy or resistance.  FoundationOneTM is targeted DNA sequencing that 
is performed on paraffin embedded tumor samples.  As a pan-cancer test, FoundationOneTM is 
designed to interrogate the entire coding sequence of 236 cancer-related genes (3,769 exons) plus 47 
introns from 19 genes often rearranged or altered in cancer.  These genes are known to be somatically 
altered in human solid cancers based on recent scientific and clinical literature.   
 
mRNA sequencing using the Nanostring nCounter system will be done to examine the mRNA signature 
in tumor tissue pre- and post-therapy to identify potential future targeted strategies and to shed light on 
how protein production is altered when the tumor is treated with panitumumab and talimogene 
Laherparepvec, and correlate with clinical response for biomarkers of response to therapy or 
resistance.  Tumors will be stored frozen in RNAlater media, and total RNA will be extracted to identify 
gene expression changes within the tumor and variations in immune cell populations using a CyberSort 
strategy.  Analysis of the immune cells from the tumor will be conducted using a PanCancer Immune 
Profiling panel and analysis of the cancer cells from the tumor will be conducted using a PanCancer 
Pathways Panel provided by Nanostring.  The PanCancer Immune Profiling panel profiles up to 770 
gene markers of human immune responses to all cancer types, including analysis of 24 different 
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
36 
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IRB Form Version 12.18.2018 
 
immune cell types and 30 common cancer antigens and genes that represent many categories of 
immune 
responses 
including 
checkpoint 
blockade 
genes 
(see: 
http://www.nanostring.com/products/pancancer_immune/). The PanCancer Pathways Panel profiles 
up to 770 gene markers of all major pathways, including 606 pathway genes and 124 driver genes (see: 
http://www.nanostring.com/products/pancancer).  Once the cDNA library is created, analysis will be 
performed by bioinformatics. 
 
IHC will be done to analyze immune cell populations and the immune profile on pre- and post-therapy 
tumor tissue, and flow cytometry will be performed on cells isolated from peripheral blood to confirm 
mechanism of action, and correlated with response to identify potential biomarkers of response or 
resistance.  IHC on H&E stain will examine the immune cell infiltrate on tumor tissue, including 
differentiating between an influx of inflammatory cells and necrosis by way of markers of inflammation 
as an indicator of apoptosis.  Additionally, IHC will help determine the pattern of immune cell infiltration 
in tumor tissue, which has been correlated with response to immunotherapy.  Finally, IHC will be used 
to determine immune cell types both at baseline in pre-treatment, and after treatment in tumor tissue, 
including leukocytes (CD45+), T cells (CD3+), cytotoxic T cells (CD8+), regulatory T cells (FOXP3+), 
NK cells (NKP45), as well as markers of cell death by apoptosis (annexin) versus inflammation 
(granzyme).   
 
Targeted flow cytometry will evaluate the frequencies, activation/differentiation, functionality, and co-
inhibitory molecule expression of immune cell populations in peripheral blood before and after 
treatment.  This will include the frequencies of T and NK cell subsets using antibodies for CD3, CD4, 
CD8, CD11b, CD11c, CD14, CD16, CD19, CD25, CD56, and FoxP3. Special attention will be paid to 
CD8 T cell:CD4Treg and NK:CD4 Treg cell ratios, with the assumption that increased effector cells 
(CD8 and NK cell subsets versus Treg subsets) will be an indicator of mechanism of action, and a 
biomarker positively associated with responsiveness to treatment.  We will also examine activation and 
differentiation of T cell subsets using additional antibodies for HLA-DR, CD38, CD57, CCR7, CD45RA 
and CD45RO, with the assumption that activation and differentiation toward effector and memory 
responses versus exhaustion will be a biomarker positively associated with responsiveness to 
treatment.  T cell functionality before and after treatment will be analyzed by assessing intracellular 
cytokine and effector molecule production using antibodies to CD107, granzyme B, IFN-γ, IL-2, and 
TNF-α, where increased expression will be confirmation of mechanism of action.  Finally, expression 
of the T cell inhibitory molecules PD-1, TIM-3, 2B4, Lag-3, and CTLA-4 on CD8+ T cells and their ligands 
(PD-L1, PD-L2, Gal9, CD48, CD80, CD86) will be evaluated on antigen presenting cells (MHC-II+) and 
tumor cells (CD45-) using respective monoclonal antibodies to these molecules, assuming that reduced 
expression of other T cell co-inhibitory molecules will both confirm mechanism of action and be a 
biomarker positively associated with responsiveness to treatment.    
 
1.8.1.2 Tissue to be Collected: 
All patients must have a diagnosis of SCCS prior to enrolling onto this protocol.  This diagnosis is typically 
achieved by a biopsy from either the primary site or FNA from a locoregional lymph node.  However, the 
scant amount of tissue obtainable from a FNA would not be adequate for the molecular biology aspects of 
this protocol including the pathology department for confirmation of diagnosis of SCCS, FoundationOneTM 
for DNA sequencing, for mRNA sequencing, and for use in IHC and flow cytometry analyses.   
 
Thus, all patients enrolled on the protocol will have an incisional/core biopsy from the primary site prior to 
panitumumab and talimogene laherparepvec.  Incisional biopsy is favored over other types such as core 
biopsy, as incisional biopsy has the best chance of supplying an adequate tumor sample. 
 
After therapy, additional tissue will be obtained either at the time of surgery, or with a repeat biopsy if the 
patient is not a candidate for surgery, prior to further systemic or radiation treatment.   
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Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
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Additionally, all patients will have peripheral blood samples collected prior to treatment, at the time of 
definitive surgery or biopsy, and at the time of progression, if applicable. 
 
1.8.1.3 Collection and Handling Procedures: 
Collection and handling procedures will be performed at RWJUH, New Brunswick campus. 
1)  Prior to the day of the procedure, OHRS will be informed of the pending biopsies. 
2)  Incisional or excisional biopsy will be obtained from the primary site and BRS notified. 
3)  Tissues will be sent to RWJUH pathology and research specimens will be transported by BRS. 
4) At RWJUH Pathology: 
 
A) Part of the tumor sample will be made into a paraffin embedded block; a part  
will be used to confirm SCCS and the remainder will be sent to FoundationOneTM. 
 
B) Part of the tumor sample will be placed in complete media on wet ice and sent as soon as 
possible to the Cancer Institute Immune Monitoring Shared Resource Facility.   
 
Samples will be transferred to NYU for analysis. 
 
1.8.2 Secondary Specimen Collection 
N/A 
 
1.9 Data Collection 
 
1.9.1 Primary Data Collection 
 
Informed consent must be obtained prior to commencing any research procedures or data collection. This 
protocol will be available at the Rutgers Cancer Institute of New Jersey (CINJ)/Robert Wood Johnson 
University Hospital (RWJUH) in New Brunswick. The protocol is also currently under review at other 
institutions, which may participate in this study protocol.  
A subset of the National Cancer Institute (NCI) CRFs, in electronic format, will be utilized. Completion of 
the electronic CRFs (eCRFs) will be done in accordance with the instructions in a study specific data capture 
plan. All eCRFs will be completed by clinical research coordinators of the OHRS. The eCRFs will be 
maintained in a confidential format in a secure database. 
Completion of eCRFs will occur in accordance with NCI guidelines. Baseline (pre-study) eCRFs (e.g., 
enrollment, medical history, concomitant medications, disease assessment, etc.) will be completed no later 
than 14 days after the start of treatment. Treatment eCRFs (e.g., drug administration, adverse events, 
chemistries, etc.) will be completed no later than 14 days following each cycle of treatment. Off-treatment 
information (e.g., follow-up, best response, etc.) will be completed no later than 14 days after the end of 
protocol treatment. 
A research chart (i.e., shadow chart) is maintained at OHRS for each patient enrolled. Copies of significant 
study source documents will be maintained in the research chart. Examples of source document copies 
that will be maintained in the research chart include: signed informed consent form, documents that verify 
eligibility and treatment, documents that verify Grade 3-4 adverse events, and response. This information 
will be updated on a prospective basis and will be confidentially maintained at the OHRS. 
If a patient does not receive any protocol therapy, baseline data will be collected and submitted on the pre-
study and follow-up electronic case report forms (eCRF). The reason for not starting protocol therapy will 
be documented in the “follow-up eCRF."  
Case report form completion instructions and training will be provided to each participating institution prior 
to study activation at the participating institution. 
Study evaluation parameters and the schedules of assessment are presented in the Table 1. A window of 
+/- 3-days is allowed for all study assessments indicated on this trial except for which otherwise indicated. 
 
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Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
38 
RESERVED FOR IRB STAMP 
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IRB Form Version 12.18.2018 
 
1.9.2 Secondary Data Collection 
N/A 
 
1.10 Timetable/Schedule of Events 
Study evaluation parameters and the schedules of assessment are presented in the Table 1.  
 
2.0 Project Management 
 
2.1 Research Staff and Qualifications 
 
2.2 Research Staff Training 
The investigator is responsible for giving information about the study to all staff members involved in the 
study or in any element of subject management, both before starting any study procedures and during the 
course of the study (e.g. when new staff become involved). The investigator must assure that all study staff 
members are qualified by education, experience and training to perform their specific responsibilities. These 
study staff members must be listed on the study centre authorisation form, which includes a clear 
description of each staff member’s responsibilities. This list must be updated throughout the study, as 
necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the investigator and 
for ensuring their compliance with the protocol. Additional information will be made available during the 
study when new staff become involved in the study and as otherwise agreed upon with either the 
investigator or the study monitor. 
 
2.3 Resources Available 
 
2.2.1 Facilities 
The shared resources of Rutgers Cancer Institute of New Jersey are specialized service facilities that 
support the cancer research efforts of its members. The facilities include 
 
Advanced Microscopy 
 
Biomedical Informatics 
 
Biometrics 
 
Biospecimen Repository and Histopathology Service 
 
Immune Monitoring and Advanced Genomics 
 
Flow Cytometry/Cell Sorting 
 
Genome Editing 
 
Metabolomics 
 
Pharmacokinetics/ Pharmacodynamics 
 
Population Science Research Support 
 
Research Pharmacy 
 
 
2.4 Research Sites 
This protocol is available at the Rutgers Cancer Institute of New Jersey (CINJ)/Robert Wood Johnson 
University Hospital (RWJUH) in New Brunswick, Duke University Medical Center - Duke Cancer Center, 
and NYU Langone Health. The protocol is also currently under review at other institutions, which may 
participate in this study protocol. All biopsies and subsequent surgeries will be performed at the facilities 
participating in the study. Correlative studies will be performed at NYU Langone Health. 
 
 
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
39 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
3.0 Multi-Center Research 
Rutgers CINJ will coordinate and monitor the study under the direction of PI, Dr. Adam Berger, MD. 
3.1 Outside Research 
Please see section 2.4 and section 3.0 above. 
4.0 Subject Considerations 
 
4.1 Subject Selection and Enrollment Considerations 
 
A. Recruitment Details 
This protocol is open to both men and women, and all races. 
 
B. Source of Subjects  
Patients will be recruited from the Rutgers Cancer Institute of New Jersey, Robert Wood Johnson 
University Hospital, Duke University Medical Center - Duke Cancer Center, and NYU Langone 
Health. 
 
C. Method to Identify Potential Subjects 
A copy of the institution’s IRB-approved informed consent document and written justification for any 
changes made to the informed consent for this protocol must be on file at the Rutgers Cancer 
Institute of New Jersey’s Office of Human Research Services (OHRS) before any participating 
institution may enter patients.  
 
To register eligible patients on this study, each site will contact OHRS. Contact information will be 
provided at the time of site activation. The signed and dated eligibility checklist, completed 
signature page of the consent form and additional source documents if requested by OHRS will 
need to be provided. Once OHRS verifies eligibility, the patient is considered on study. Patients 
must not start protocol treatment prior to enrollment. 
 
If a patient does not receive any protocol therapy, baseline data will be collected and submitted on 
the pre-study and follow-up electronic case report forms (eCRF). The reason for not starting 
protocol therapy will be documented in the “follow-up eCRF." Case report form completion 
instructions and training will be provided to each participating institution prior to study activation at 
the participating institution. 
 
D. Subject Screening 
 Inclusion Criteria 
A patient is eligible for enrollment if all of the following inclusion criteria are met: 
1) Age 18 years or greater. 
2) Histologically confirmed SCCS that is a) locally advanced or metastatic for which 
curative surgery or radiation would be difficult or impossible, or b) recurrent after 
initial surgery, chemotherapy, or radiation therapy, or c) considered to have 
aggressive features including the following: tumors 2 cm or more, tumors invading 
deep tissues such as muscle, cartilage or bone; tumors showing perineural 
invasion, and/or tumors metastatic to loco-regional lymph nodes. Patients may 
have had prior surgical interventions or been treated with investigational agents 
with residual or recurrent  
disease. 
3) Tumor suitable for direct or ultrasound-guided injection defined as at least one 
cutaneous, subcutaneous, or nodal lesion, or aggregate of lesions, ≥ 10 mm in 
diameter. 
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Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
40 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
4) ECOG Performance Status ≤ 2. 
5) No prior treatment with panitumumab or talimogene laherparepvec for advanced 
disease. 
6) Prior surgery or radiation is allowed if there is documented progression in the 
radiated/resected area or elsewhere by RECIST criteria v 1.1. 
7) Measurable disease by RECIST criteria v 1.1. 
8) Patients with a history of hematologic or solid organ transplant will be considered 
if they do not require high dose steroids or high dose immunosupressants for 
disease control or control of transplant rejection, and have adequate hematologic, 
renal, and hepatic function as specified below. Current medications must be 
reviewed with transplant pharmacy team to exclude potentially serious interactions 
and case discussed with the study PI. 
9) Patients with autoimmune disorders will be considered if they do not require high 
dose steroids or other immunosuppressants for disease control. Prednisone in 
daily doses up to 10 mg and inhaled steroids are acceptable. 
10) Adequate organ function is required, as defined by ALL of the following: 
a. -Absolute neutrophil count (ANC) ≥ 1500/uL 
b. -Platelet count ≥ 100,000/mm2 
c. -Hemoglobin ≥ 9 g/dL 
d. -Total bilirubin < 1.5x institutional ULN; if patient has conditions of 
congenital hyperbilirubinemia, then patient must have isolated 
hyperbilirubinemia (e.g., no other liver function test abnormalities) with 
maximum bilirubin < 2x institutional ULN 
e. -AST or ALT ≤ 2.5x institutional ULN in absence of liver metastases; 
≤ 5x ULN in presence of liver metastases 
f. 
-Alkaline phosphatase < 2.5x institutional ULN 
g. -Creatinine < 1.5x institutional ULN or calculated creatinine clearance 
≥ 60 mL/min as estimated using the Cockcroft-Gault formula. 
 
 Exclusion Criteria 
A patient is not eligible for enrollment if any of the following exclusion criteria are met: 
1) Age < 18 years. 
2) Pregnant women. Women of childbearing age must be willing to undergo a 
pregnancy test prior to therapy and to use adequate contraception (e.g., hormonal 
or barrier method of contraception or abstinence) for the duration of the study and 
6 months thereafter.  Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately.  Menopausal status will be defined as one or more of successful 
hysterectomy, bilateral tubal ligation or bilateral oophorectomy, amenorrhea ≥  12 
consecutive months without another cause, or a documented serum follicle 
stimulating hormone (FSH) ≥ 35 mIU/mL. 
3) Tumor not suitable for direct or ultrasound-guided injection. 
4) Prior treatment with talimogene laherparepvec  for advanced disease.  
5) Second primary malignancy only if treatment would interfere with the patient’s 
participation in this trial in the opinion of the treating physician. Clear exceptions 
are 1) patient had a second primary malignancy but has been treated and disease 
free for at least 3 years, 2) in situ carcinoma (e.g., in situ carcinoma of the cervix) 
and, 3) additional skin cancers that have been definitively treated by surgery and/or 
radiation. Patients with chronic lymphocytic leukemia will be allowed if their blood 
counts are within acceptable hematologic parameters and if they are not currently 
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
41 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
requiring cytotoxic or biologic anticancer treatment (supportive treatment such as 
IVIG is permitted).  
6) Patients with active, uncontrolled infections including active herpetic infections or 
chronic herpetic infections requiring anti-viral therapy (e.g., acyclovir). 
7) Patients without adequate organ function as documented above. 
8) History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to panitumumab, talimogene laherparepvec  or other agents used in 
the study. 
9) History of interstitial pneumonitis, pulmonary fibrosis, or evidence of interstitial 
pneumonitis. 
 
E. Recruitment Materials  
N/A 
 
4,2 Secondary Subjects 
N/A 
 
4.3 Subject Randomization 
This will be a one arm Phase I study.  There will be no randomization. 
 
4.4 Secondary Subjects 
N/A 
 
4.5 Number of Subjects 
 
4.5.1 Total Number of Subjects 
This study plans to enroll 30 patients with locally advanced SCCS.  
 
4.5.2 Total Number of Subjects If Multicenter Study 
N/A 
 
4.5.3 Require Number of Subjects to Complete Research 
N/A 
 
4.5.4 Feasibility of Recruiting 
Based on past experiences with recruiting locally advanced SCCS patients at CINJ, it is expected that the 
intended number of 30 patients can be recruited within 12 months of this study opening.  
 
4.6 Consent Procedures 
 
4.6.1 Consent 
4.6.1,1 Documenting Consent 
Prior to study entry, the investigator, or a person designated by the investigator, will explain the 
nature, purpose, benefits and risks of participation in the study to each subject, subject’s legally 
acceptable representative or impartial witness. Written informed consent must be obtained prior to 
the subject entering the study (before initiation of any study-related procedure and administration 
of the drugs). Sufficient time will be allowed to discuss any questions raised by the subject. 
The sponsor will provide a sample informed consent form. The final version controlled form must 
be agreed to by the sponsor and the IRB and must contain all elements included in the sample 
form, in language readily understood by the subject. Each subject’s original consent form, 
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
42 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
personally signed and dated by the subject or by the subject’s legally acceptable representative 
and by the person who conducted the informed consent discussion, will be retained by the 
investigator. The investigator will supply subjects with a copy of their signed informed consent form. 
The informed consent form may need to be revised during the study should important new 
information become available that may be relevant to the safety of the subject or as a result of 
protocol amendments. In this instance, approval should always be given by the IRB. It is the 
investigator’s responsibility to ensure that all subjects subsequently entered into the study and 
those currently in the study sign the amended form. This is documented in the same way as 
described above. Subjects who have completed the study should be informed of any new 
information that may impact on their welfare/wellbeing. 
The investigator should, with the consent of the subject, inform the subject’s primary physician 
about their participation in the clinical study. 
 
4.6.1.2 Waiver of Documentation of Consent 
N/A 
 
4.6.1.3 Waiver or Alteration of Consent Process  
N/A 
 
4.6.2 Consent Process 
A copy of the institution’s IRB-approved informed consent document and written justification for any 
changes made to the informed consent for this protocol must be on file at the Rutgers Cancer Institute of 
New Jersey’s Office of Human Research Services (OHRS) before any participating institution may enter 
patients.  
 
To register eligible patients on this study, each site will contact OHRS. Contact information will be provided 
at the time of site activation. The signed and dated eligibility checklist, completed signature page of the 
consent form and additional source documents if requested by OHRS will need to be provided. 
The PI shall seek such consent only under such circumstances that provide the prospective patient 
opportunity to consider whether or not to participate, and that minimize the possibility of coercion or undue 
influence. The information given to the patient or the representative shall be in a language understandable 
to the subject or representative. The informed consent document may not include any exculpatory language 
through which the subject or representative is made to waive any of the subject’s legal rights or releases, 
or appears to release the investigator, the sponsor or the institution from liability for negligence. 
 
4.7 Special Consent/Populations 
 
4.7.1 Minors-Subjects Who Are Not yet Adults  
N/A; Children younger than 18 years of age are not eligible for this trial.  SCCS is exceedingly rare in this 
population, and it is not expected that subjects of this age group will otherwise be eligible. 
 
4.7.2 Non-English Speaking Subjects 
It is not expected that non-English subjects will be a significant number among the 30 eligible patients. If 
the subject/representative cannot speak English, we will obtain the services of an interpreter fluent in both 
English and the language understood by the subject/representative. The interpreter may be a member of 
the research team, a family member, or friend of the subject/representative.  
The interpreter will read the consent document or the translated consent document with the 
subject/representative. In addition, the interpreter will explain the details in such a way that the 
subject/representative understands what it would be like to take part in the research study.  
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
43 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
 
4.8 Economic Burden and/or Compensation for Subjects 
 
 
4.8.1 Expenses  
Subjects will have tests and procedures that are part of regular medical care (not part of the research), and 
the subjects or the subjects’ insurance company or third party provider will be responsible for these costs, 
including co-payments and deductibles. The doctor and other health care providers will bill the cost of 
regular medical care to subjects or the subjects’ health insurance company in the usual way. However, 
some health insurance plans will not pay the costs for people taking part in studies. Subject is to check with 
health plan or insurance company to find out what they will pay for. Taking part in this study may or may 
not cost your insurance company more than the cost of getting regular treatment. Before deciding to 
participate in the study, one should check with health insurance company to find out exactly what it will pay 
for under their policy. If the insurance does not pay for the charges of regular medical care, the sponsor will 
be contacted and may be able to reimburse. 
Subjects will not need to pay for study drugs or tests and procedures that are done just for this research 
study. 
If subject has any questions about insurance coverage, including any out of pocket expenses, or which 
laboratory or facilities you are allowed to have tests at, a financial counselor will be made available to you 
upon request. 
4.8.2 Compensation/Incentives 
Subjects will not be compensated for participation in this research study.  
 
4.9 Risks of Harm/Potetial for Benefits to Subjects 
 
4.9.1 Potential Risks:  
Potential risks to the patient, secondary to panitumumab, include hypersensitivity reaction, rash, 
thrombosis, hypomagnesemia, hypocalcemia and pulmonary complications.  Potential risks to the patient, 
secondary to talimogene laherparepvec, include fever, flu-like illness and injection site reactions.  These 
will be monitored as detailed in the adverse events section.  In terms of the individual's cancer, there is a 
risk of the treatment being ineffective, and by extension, the possibility of disease progression. 
 
 4.9.2 Consent Procedures: 
Because of the above potential risks, informed consent must be obtained prior to commencing any research 
procedures.  The PI shall seek such consent only under such circumstances that provide the prospective 
patient opportunity to consider whether or not to participate, and that minimize the possibility of coercion or 
undue influence. The information given to the patient or the representative shall be in a language 
understandable to the subject or representative. The informed consent document may not include any 
exculpatory language through which the subject or representative is made to waive any of the subject’s 
legal rights or releases, or appears to release the investigator, the sponsor or the institution from liability for 
negligence. 
 
4.9.3 Potential Benefits: 
The benefits of participating in this study may be improvement in a patient's cancer either as a 
measure of disease activity or quality of life improvements. 
 
4.9.4  Risk-Benefit Ratio: 
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Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
44 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
All risks and benefits of this treatment will be discussed with the patient prior to enrollment on this study. 
Along these lines, the basic principles of what we are hoping to accomplish with the combination of 
panitumumab and talimogene laherparepvec followed by surgery will be explained. The potential risks 
detailed in Section 4.9.1 will be made clear as well, along with what measures are in place to minimize 
these risks. 
 
Alternative treatment will also be discussed. These options include beginning standard chemotherapy if 
applicable, anti-EGFR monoclonal antibody monotherapy, monitoring off therapy, or enrolling in another 
clinical trial. Additionally, the importance of the knowledge gained through this study will be discussed with 
the patient. 
 
All told, with the combination of employing proper patient selection and study termination criteria, close 
clinical and lab follow-up (both of the cancer as well as other relevant body systems), and the medical 
knowledge of panitumumab and talimogene laherparepvec (as FDA-approved medications for oncologic 
medical purposes in head and neck cancer, colon cancer and melanoma), we believe the potential benefits 
outweigh the risks of the trial. 
 
 
4.10 Secondary Data – Records/Chart Reviews/Databases/Tissue Banks/etc. 
N/A 
 
4.11 Chart/Record Review Selection 
 
In compliance with GCP guidelines, the medical records/medical notes, etc., should be clearly marked and 
permit easy identification of a subject’s participation in the specified clinical study. 
The investigator/authorized staff must record all data relating to protocol procedures, drug administration, 
laboratory data, safety data and efficacy ratings on the CRFs/eCRFs provided for the study. The 
investigator, by completing the signature log, may formally designate authority to complete CRFs/eCRFs to 
appropriately qualified staff. Any data management queries and items not adequately explained will be 
returned to the investigator by the monitor for clarification/correction. The investigator must ensure that data 
queries are dealt with promptly. Copies of all data changes and clarifications must be retained by the 
investigator and filed with the CRFs. 
The investigator must, as a minimum, provide an electronic signature (e-signature) to each case report 
book to attest to the accuracy and completeness of all the data. If any changes are made to the eCRF after 
a form has been locked and electronically signed, the investigator will be required to perform an additional 
e-signature authorising agreement with any new information or changes to the eCRF. 
All corrections on the eCRF will be automatically tracked and a reason for change is always required. In 
the eCRF, the audit trail function will allow the changes made to be viewed on each item entered.  
If requested, the investigator will provide the sponsor, applicable regulatory agencies and applicable EC 
with direct access to any original source documents.  
 
4.12 Secondary Specimen Collection 
N/A 
 
5.0 Special Considerations 
 
5.1 Health Insurance Portability and Accountability Act (HIPAA) 
N/A 
 
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
45 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
5.2 Family Educational Rights and Privacy Act (FERPA) 
N/A 
 
5.3 NJ Access to Medical Research Act 
N/A 
 
5.4 General Data Protection Regulation (GDPR) 
N/A 
 
5.5 Code of Federal Regulations Title 45 Part 46 (Vulnerable Populations) 
N/A 
 
6.0 Data Management Plan 
 
6.1 Data Analysis 
 
6.1.1 Statistical Considerations 
This is a pilot feasibility study that will assess the safety and preliminary efficacy of this approach. As a 
phase I trial, safety of the combination will be assessed and the study stopped early for subject safety 
according to stopping rules defined in section 6.3.2 below. A two-stage design often used for phase II 
studies will be applied with the objective of estimating response rate as a measure of efficacy.  
Descriptive statistics for all outcome measures and patient characteristics will be provided. The response 
rate of the drug will be assessed according to the decision rule based on Simon’s Two-Stage Design 
outlined in the Sample Size Justification Section. As a secondary outcome, the pCR will be calculated and 
reported with its 95%confidence interval. The estimation of progression-free survival (PFS) and overall 
survival (OS) will be performed by the Kaplan-Meier product limit method. Logrank test and Cox proportional 
hazards model will be used to explore the associations between outcome measures (PFS and OS) and 
patient characteristics.  
 
6.1.2 Interim Safety Assessment and Stopping rules 
We will employ a 3 + 3 study design in the first six patients enrolled. This will allow for early detection of 
unexpected safety signals and will allow for rapid implementation of measures to diminish the risk of toxicity 
to subsequently enrolled subjects. The interim safety assessment will start and includes the rules of the 
3+3 design based on the incidence of DLTs. We plan to continue monitoring the treatment safety after the 
first 6 patients are recruited. Monitoring will continue after every subsequent patient. The stopping rule will 
be determined by the posterior probability of the event rate of the either hospitalizations or 
delays/cancellation in planned surgery, due to treatment related toxicities. Specifically, the early stopping 
will be triggered when the posterior probability that more than 40% patients are either hospitalized or 
delayed/ cancelled in surgery due to treatment related toxicities is greater than 90%. Assuming a non-
informative prior, we calculated the posterior probability of toxicity related event rate of 40% given that k 
events are observed out of the first n patients, using the beta distribution with shape parameter 1+k and 
scale parameter 1+n-k.  Table 10 highlights the posterior probability that more than 40% patients are either 
hospitalized or delayed/cancelled in surgery due to treatment related toxicities being greater than 90%. If 6 
or more toxicity related events that meet these criteria of resulting in hospitalization or delays/cancellation 
of planned surgery out of the first 10 patients are observed, the trial will be stopped. 
Note that each cell of Table 11 contains the posterior probability that the true toxicity related event rate is 
greater than 40% given that k events are observed out of the first n patients. The prior distribution will be 
updated based on the number of events observed at each monitoring, and thus resulting posterior 
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
46 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
probability of the event rate greater than 40% will also be updated. The study PI (Dr. Berger) then will 
contact the Biometrics division at the Rutgers Cancer Institute of New Jersey to obtain the updated stopping 
rule after each scheduled monitoring. 
 
Table 11. Posterior probability of toxicity related event rate of 40% given that k events are observed out of the first n patients 
 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
5 
0.821 
0.959 
0.996 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
6 
0.710 
0.904 
0.981 
0.998 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
7 
0.594 
0.826 
0.950 
0.991 
0.999 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
8 
0.483 
0.733 
0.901 
0.975 
0.996 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
9 
0.382 
0.633 
0.834 
0.945 
0.988 
0.998 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
10 
0.296 
0.533 
0.753 
0.901 
0.971 
0.994 
0.999 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
11 
0.225 
0.438 
0.665 
0.842 
0.943 
0.985 
0.997 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
12 
0.169 
0.353 
0.574 
0.771 
0.902 
0.968 
0.992 
0.999 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
13 
0.124 
0.279 
0.486 
0.692 
0.850 
0.942 
0.982 
0.996 
0.999 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
14 
0.091 
0.217 
0.403 
0.610 
0.787 
0.905 
0.966 
0.991 
0.998 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
15 
0.065 
0.167 
0.329 
0.527 
0.716 
0.858 
0.942 
0.981 
0.995 
0.999 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
16 
0.046 
0.126 
0.264 
0.448 
0.641 
0.801 
0.908 
0.965 
0.989 
0.997 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
17 
0.033 
0.094 
0.209 
0.374 
0.563 
0.737 
0.865 
0.942 
0.980 
0.994 
0.999 
1.000 
1.000 
1.000 
1.000 
1.000 
1.000 
18 
0.023 
0.070 
0.163 
0.308 
0.488 
0.667 
0.814 
0.912 
0.965 
0.988 
0.997 
0.999 
1.000 
1.000 
1.000 
1.000 
1.000 
19 
0.016 
0.051 
0.126 
0.250 
0.416 
0.596 
0.755 
0.872 
0.943 
0.979 
0.994 
0.998 
1.000 
1.000 
1.000 
1.000 
1.000 
20 
0.011 
0.037 
0.096 
0.200 
0.350 
0.524 
0.691 
0.826 
0.915 
0.965 
0.988 
0.996 
0.999 
1.000 
1.000 
1.000 
1.000 
21 
0.008 
0.027 
0.072 
0.158 
0.290 
0.454 
0.624 
0.772 
0.879 
0.945 
0.979 
0.993 
0.998 
1.000 
1.000 
1.000 
1.000 
22 
0.005 
0.019 
0.054 
0.124 
0.237 
0.388 
0.556 
0.713 
0.836 
0.919 
0.965 
0.987 
0.996 
0.999 
1.000 
1.000 
1.000 
23 
0.004 
0.013 
0.040 
0.096 
0.192 
0.328 
0.489 
0.650 
0.787 
0.886 
0.947 
0.978 
0.992 
0.998 
0.999 
1.000 
1.000 
24 
0.002 
0.009 
0.029 
0.074 
0.154 
0.274 
0.425 
0.586 
0.732 
0.846 
0.922 
0.966 
0.987 
0.996 
0.999 
1.000 
1.000 
25 
0.002 
0.007 
0.021 
0.056 
0.122 
0.226 
0.364 
0.521 
0.674 
0.801 
0.892 
0.948 
0.978 
0.992 
0.998 
0.999 
1.000 
26 
0.001 
0.005 
0.015 
0.042 
0.095 
0.184 
0.309 
0.458 
0.613 
0.750 
0.855 
0.926 
0.966 
0.987 
0.995 
0.999 
1.000 
27 
0.001 
0.003 
0.011 
0.031 
0.074 
0.148 
0.259 
0.399 
0.551 
0.695 
0.813 
0.898 
0.950 
0.978 
0.992 
0.997 
0.999 
28 
0.000 
0.002 
0.008 
0.023 
0.057 
0.119 
0.215 
0.343 
0.490 
0.637 
0.766 
0.864 
0.929 
0.967 
0.987 
0.995 
0.998 
29 
0.000 
0.002 
0.006 
0.017 
0.044 
0.094 
0.176 
0.291 
0.431 
0.578 
0.715 
0.825 
0.903 
0.952 
0.979 
0.992 
0.997 
 
6.1.3 Preliminary Efficacy Assessment 
6.1.3.1 Primary Hypothesis: 
For efficacy, we hypothesize that the combination of panitumumab and talimogene laherparepvec  will 
improve the response rate in advanced SCCS from 25% with single agent panitumumab [1] to 47% 
(near doubling of response rate to justify added expense and time required for administration of second 
drug as well as potential for additional toxicities). 
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Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
47 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
6.1.3.2 Sample Size Justification and Stopping Rules: 
A detailed analysis for sample size justification is presented in Section 1.5. 
 
The combination therapy approach would be considered to have limited safety if unanticipated toxicity 
from talimogene laherparepvec is observed. If the proportion of talimogene-laherparepvec related 
grade ≥ 3 toxicities that result in hospitalization or delays/cancellation of planned surgery is less than 
30% of the subjects accrued, then the study accrual may continue. These toxicities do not include fever 
or injection site reaction which are known side effects of talimogene laherparepvec. The toxicity will be 
independently monitored by the Human Research Oversight Committee which will communicate any 
safety concerns directly to all participating Investigators.  
 
6.1.3.3 Secondary endpoints to be captured include: 
- 
To assess the clinical efficacy of panitumumab in combination with intratumoral talimogene 
laherparepvec in terms of immune-related progression-free survival (irPFS)at 12 months, 
overall response rate (ORR), 1-year survival, overall  survival (OS) and time to resectability.  
- 
To measure the pathologic complete response rate to panitumumab combined with talimogene 
laherparepvec. 
- 
Assess the response of injected and non-injected tumor deposits after panitumumab and 
talimogene laherparepvec. 
- 
Assess the time to initial response.  
- 
Assess the durable response rate. 
- 
To analyze the following molecular correlate with response to therapy to confirm mechanism 
of action, and identify potential future targeted strategies and biomarkers of response: 
A) Mutation load in tumor tissue by next generation sequencing 
B) DNA mutation signature in tumor tissue pre- and post-therapy by next generation 
sequencing 
C) mRNA signature in tumor tissue pre-and post-therapy by Nanostring technology 
D) Immune cell populations and immune profile in pre- and post-therapy tumor tissue 
and peripheral blood by flow cytometry and IHC 
 
6.1.4  Outcome Measures: 
All efficacy analysis will be based on the intention to treat population, which will include all enrolled patients. 
The primary outcome is the response rate to combination treatment with panitumumab and talimogene 
laherparepvec by RECIST 1.1 criteria in patients with advanced SCCS. 
Secondary outcomes include best overall response rate, durable response rate and duration of response, 
progression free survival, overall survival in patients who receive panitumumab and talimogene 
laherparepvec.  Molecular correlates will also be obtained and descriptive statistics applied.  
 
PFS is defined as the number of months from the date of enrollment to the date of death or progression, 
whichever occurred earlier (per RECIST 1.1). If neither death nor progression is observed during the study, 
PFS data will be censored at the last valid tumor assessment. If patient is rendered disease free from 
surgical removal of tumor (section 1.3.2), progression is determined to be the date of diagnosis of 
recurrence. 
Overall survival is defined as the time from the date of patient enrollment to date of death or the date last 
known alive. 
Best Overall Response Rate (ORR) is defined as the best response as recorded from the start of study 
drug until disease progression. Patients without a post-baseline tumor assessment will be considered to be 
non-evaluable for best ORR. To classify best ORR as stable disease (SD), there should be a qualifying SD 
assessment at least 6 weeks from enrollment. Overall Response Rate (ORR) is defined as the proportion 
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
48 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
of patients with a best ORR characterized as either a Complete Response (CR) or Partial Response (PR) 
relative to the total number of evaluable patients. Only patients with measurable disease at baseline will be 
included in the analysis of the objective response. 
Durable response rate is defined as the percent of patients with complete response or partial response 
maintained continuously for a minimum of 6 months. Response duration is defined as the time from initial 
response until documented progression. 
For subjects converted to resectable and surgical resection is performed (complete or partial), response 
endpoints will be censored at the time of surgery. However, these patients will still be followed for PFS and 
OS. 
 
6.1.5 Toxicity Monitoring and Adverse Event Reporting: 
All patients who receive one dose of protocol therapy will be evaluable for assessment of toxicity. Prior to 
each cycle, the treating physician will fully assess the patient’s condition with respect to possible treatment 
related toxicities. All adverse events, whether observed by the physician or reported by the patient, 
occurring during the active portion of therapy, or up to 30 days after the last dose of treatment will be graded 
by a numerical score according to the NCI’s Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.0 (see http://ctep.cancer.gov/reporting/ctc.html) and recorded in the patient’s medical record. For 
the purposes of reporting laboratory abnormalities, only Grade 3-4 adverse events will be recorded on the 
adverse event CRF pages. Grade 1-2 laboratory abnormalities will not be recorded on the adverse event 
CRF pages. Information entered on the adverse event CRF pages will include:  
6) Specific type and duration of reaction (i.e., start and stop dates, resolution)  
7) Severity/grade  
8) Relationship to study drug (causality, attribution)  
9) Management of the event, if treated with medication and other actions taken to alleviate the 
clinical event  
10) Whether or not it was considered a SAE  
 
A preexisting condition is one that is present at the start of the study. A preexisting condition will be recorded 
as an adverse event if the frequency, intensity, or the character of the condition worsens during the study 
period. 
 
6.1.5.1. Adverse Event Reporting Requirements: 
An adverse experience is defined as any unintended or abnormal clinical observation that is not of 
benefit to the patient. Either the condition was not present prior to exposure to the study therapy, 
or it has worsened in intensity or frequency following exposure to the study therapy. 
 
All “unexpected” (defined below) and/or “serious” (defined below) adverse events occurring during 
the active portion of therapy, or up to 30 days after the last dose of treatment, will be reported to 
the OHRS at (732) 235-7577 or (732) 235-8675. Events will be promptly reported, in writing, to the 
local IRB in accordance with IRB policy. If a death or a life-threatening event occurs, the IRB will 
be notified within 24-hours of initial receipt of information. All other SAEs must be reported to the 
IRB within three to ten days of initial receipt of information. Written follow-up reports are required 
when additional information is needed to fully characterize the event. Copies of each report sent to 
the IRB will be kept in the study regulatory file. 
 
In addition to reporting to the local IRB, reporting to external bodies such as industry and/or the 
FDA may be necessary. The Oncology group affiliates site will report all SAEs to the OHRS and 
will also be responsible for forwarding SAE reports to the IRB and FDA. In addition, information 
included in the SAE form will be provided to the PI/sponsor or its representative as soon as it is 
available. Moreover, an SAE line-listing will be sent to the PI/sponsor at least every 6 months. 
 
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Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
49 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
6.1.5.2 Reporting SAEs using commercially available drugs: 
The PI shall notify the FDA of any adverse experience related to the use of Talimogene 
Laherparepvec and Panitumumab combination that is both serious and unexpected, as soon as 
possible and in no event later than 15 calendar days after the PI’s discovery of the event. Each 
written 
notification 
may 
be 
submitted 
on 
FDA 
Form 
MedWatch 
3500A 
http://www.fda.gov/medwatch/safety/3500a.pdf (fax # 1-800-FDA-0178). The PI shall also notify 
the FDA by telephone or by facsimile transmission of any unexpected fatal or life-threatening 
experiences associated with the use of Talimogene Laherparepvec and Panitumumab 
combination, as soon as possible but no later than 7 calendar days from the PI’s discovery of the 
event information. 
 
6.1.5.3 Safety Reporting to Amgen  
The Sponsor/Investigator is responsible for compliance with expedited reporting requirements for 
serious, unexpected and related adverse events (SUSARs), for generation of SAE reports including 
narratives, and for periodic reporting to Amgen of SAEs as outlined in Table 12 and Table 13 below. 
Individual safety reports (Table 12) should be accompanied by the Fax Cover Form provided in 
Appendix 1, and sent to Amgen Global Safety, utilizing the fax or email information provided on the 
cover page. Aggregate safety reporting (Table 13) including listings, tabulations and summary 
reports should be scanned and accompanied by the Fax Cover Form provided in Appendix 2, and 
sent to Amgen NASCR, utilizing the email information provided on the cover page. In addition to 
the requirements outlined in Table 12 and 13, Sponsor/Investigators are required to report direct 
exposures to talimogene laherparepvec (e.g., needle stick, splash back) of herpetic illness and all 
suspected herpetic events (refer to Section 6.3.6.4, ‘Accidental Exposures to Talimogene 
Laherparepvec and Herpetic Events’). 
 
Table 12. Expedited Reporting Requirements for Interventional Studies: 
Safety Data 
Time frame for Submission to Amgen 
Suspected Unexpected Serious Adverse 
Reaction (SUSARs) 
Individual reports sent to Amgen at time of expedited 
reporting to 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. (Refer to Appendix 4 
and Appendix 5 for Amgen template forms) 
 Individual reports should be faxed to 1-888-814-8653 or scanned and sent via email to svc-ags-in- us@amgen.com 
 
 
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
50 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
Table 13. Aggregate Reports: 
Safety Data 
Timeframe for submission to Amgen 
Adverse events (all serious and non-serious 
adverse events, regardless of relatedness) 
Line listing and summary tabulation of all 
adverse events sent annually AND at end of 
study 
US IND Annual Safety Report 
Annually 
Other Aggregate Analyses (any report containing 
safety data generated during the course of the study) 
At time of ISS sponsor submission to anybody 
governing research conduct (e.g., RA, IRB, etc.) 
Final (End of Study) Report, including: 
 
Unblinding data for blinded studies 
 
Reports of unauthorized use of a 
marketed product 
At time of ISS sponsor submission to anybody 
governing research conduct (e.g., RA, IRB, etc.) 
but not later than 1 calendar year after study 
completion 
Aggregate reports should be submitted by email to the Amgen NASCR manager, accompanied by the Fax Cover Form 
shown in Appendix 2. 
Please refer to the ICH Guidelines E2A for safety related definitions and terminology: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/E2A_
Guideli ne.pdf. 
6.1.5.4 Accidental Exposures to Talimogene Laherparepvec and Herpetic Event Reporting  
In order to better assess and understand the potential risks to treated patients and/or third parties 
following the treatment of clinical trial subjects with talimogene laherparepvec, special reporting 
procedures apply for accidental exposures to talimogene laherparepvec and for suspected herpetic 
events. See Table 14 for a summary of reporting requirements. Clinicians should review the Imlygic 
package insert (available online) for additional information on the safe handling of talimogene 
laherparepvec. 
Table 14. Accidental Exposure & Herpetic Event Reporting Requirement Summary: 
Exposed 
Person 
Reporter 
Timeframe 
for Reporting 
to Amgen 
Report    
Mechanism 
Timing of 
Swab 
Collection 
qPCR 
Testing
? 
Responsible 
Party for 
Lesion 
Swabbing 
qPCR Test 
Result 
Distribution 
n* 
Treated 
Patients 
with 
suspected 
herpetic 
lesions 
Sponsor / 
Investigator 
Within 24 
hours of 
Sponsor / 
Investigator 
awareness 
Contact 
Amgen at 
1-855-
IMLYGIC 
(1-855-
465-9442) 
to report 
event 
Collect 
swabs from 
suspected 
lesions 
(ideally 
within 3 days 
of 
appearance 
of 
symptoms) 
Yes, if 
consen
t 
obtaine
d 
Sponsor / 
Investigator 
Sponsor / 
Investigator 
and Amgen 
HCP 
directly 
exposed to 
product 
(e.g., 
needle 
stick, 
splash 
back) 
without 
signs or 
HCP’s 
Personal 
Physician 
or 
impacted 
person 
Within 24 
hours of 
Reporter 
awareness 
Contact 
Amgen at 
1-855-
IMLYGIC 
(1-855-
465-
9442) 
to report 
N/A 
N/A 
N/A 
N/A 
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
51 
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IRB Form Version 12.18.2018 
 
symptoms 
of herpetic 
illness 
event 
HCP 
directly or 
indirectly 
exposed to 
product 
with 
suspected 
herpetic 
lesions 
HCP’s 
Personal 
Physician 
or impacted 
person 
Within 24 
hours of 
Reporter 
awareness 
Contact 
Amgen at 
1-855-
IMLYGIC 
(1-855-
465-9442) 
to report 
event 
Collect 
swabs from 
suspected 
lesions 
(ideally 
within 3 days 
of 
appearance 
of 
symptoms) 
Yes, if 
consent 
obtaine
d 
HCP or 
HCP’s 
Personal 
Physician 
HCP’s 
Personal 
Physician and 
Amgen 
Close 
Contact (e.g. 
caregiver, 
spouse, 
child) with 
suspected 
herpetic 
lesions 
Sponsor / 
Investigator 
, Close 
Contact’s 
Personal 
Physician 
or Close 
Contact 
Within 24 
hours of 
Reporter 
awareness 
Contact 
Amgen at 
1-855-
IMLYGIC 
(1-855-
465-9442) 
to report 
event 
Collect 
swabs from 
suspected 
lesions 
(ideally 
within 3 days 
of 
appearance 
of 
symptoms) 
Yes, if 
consent 
obtaine
d 
Sponsor / 
Investigator, 
Close 
Contact’s 
Personal 
Physician 
Sponsor / 
Investigator 
, Close 
Contact’s 
Personal 
Physician 
and Amgen 
*The laboratory conducting the qPCR testing on behalf of Amgen is Viracor. 
6.1.5.5 Accidental Exposure of HCPs to Talimogene Laherparepvec  
HCPs involved in your clinical trial who were directly exposed to talimogene laherparepvec (e.g., 
needle stick, splash back) but who are without signs or symptoms of herpetic illness should be 
reported to Amgen at 1-855-IMLYGIC (1-855-465-9442).  
6.1.5.6 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 HCPs with direct or indirect exposure and 3) suspected herpetic events in treated 
patient’s close contacts, as outlined in Table 13. An example of the Suspected IMLYGIC™ 
(Talimogene laherparepvec) or Herpes Virus Associated Adverse Event can be found in Appendix 
3. 
In addition to reporting these events, suspected herpetic lesions should be swabbed and submitted 
for qPCR 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 be more reliable 
if performed within the first three days of symptom appearance, however, all lesions should be 
swabbed, regardless of the timing of presentation.  Amgen does not require qPCR or other testing 
for wild type HSV-1. 
 
6.1.5.7 Reporting Process for ISS Treated Patients:  
Any suspected herpetic lesion should be reported to Amgen at 1-855-IMLYGIC  (1-855-465-9442), 
evaluated by the Sponsor/Investigator and swabbed for qPCR  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 
qPCR testing, which must be obtained prior to swabbing.   
6.1.5.8 Reporting Process for HCPs and Close Contacts:   
Sponsor/Investigator should advise any HCPs and/or Close Contacts with suspected herpetic 
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PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
52 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
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-
IMLYGIC (1-855-465-9442). Once an initial report has been made, additional materials will be 
provided, including reporting forms and supplies needed for the shipment of swab samples. Amgen 
will require patient consent for qPCR testing, which must be obtained prior to swabbing.  
6.1.6  Definition of Serious Adverse Events: 
A serious adverse event (experience) is one that results in any of the following outcomes: 
 
1)  Death 
 
2)  Threat to life (immediate risk of death from the reaction) 
 
3)  Inpatient hospitalization or prolongation of existing hospitalization 
 
4)  Persistent or significant disability/incapacity 
 
5)  Congenital anomaly/birth defect 
 
6)  Intervention required to prevent one of the above outcomes listed in this definition 
 
The definition of serious adverse event (experience) also includes important medical events. Medical and 
scientific judgment will be exercised in deciding whether expedited reporting is appropriate in other 
situations, such as important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above. These events will usually be considered serious. Examples of such 
events are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization. 
 
6.1.6.1  Definition of Related: 
There is a reasonable possibility that the drug caused the adverse experience. That is, the event 
is judged by the investigator to be possibly, probably or definitely related to the treatment. 
 
6.1.6.2  Definition of Unexpected: 
Any adverse drug experience and/or specificity, that is not included in the current investigator’s 
brochure and/or package insert. 
 
6.1.7  Removal of Patients from Study/Off Study Criteria 
In the absence of treatment delays due to adverse events, treatment may continue until one of the following 
criteria applies: 
 
a) Intercurrent illness of SAE that prevents further administration of treatment,  
 
b) Patient decides to withdraw from the study,  
 
c) Noncompliance with treatment plan,  
 
d) General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator, 
 
e) Protocol violation - any patient found to have entered this study in violation of the 
protocol might be discontinued from the study at the discretion of the Principal 
Investigator. 
 
6.2 Data Security 
Wherever feasible, Electronic Data Capture (EDC) will be utilized for collecting subject data. All study 
personnel are required to have a computer and internet connection available for entry of clinical data. All 
entries in the eCRF will be made under the e-signature of the person performing the action. This 
electronic signature consists of an individual and confidential username and password combination. Only 
PI/Investigator authorized users will have access to the eCRF as appropriate to their study 
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Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
53 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
responsibilities. Users must have successfully undergone software application training prior to entering 
data into the eCRF. 
For non EDC elements, the PI will ensure that appropriate data entry methods are used (e.g. double data 
entry) and suitable queries are raised to resolve any missing or inconsistent data. 
 
6.2.1  Case Report Forms: 
A subset of the National Cancer Institute (NCI) CRFs, in electronic format, will be utilized. Completion of 
the electronic CRFs (eCRFs) will be done in accordance with the instructions in a study specific data 
capture plan. All eCRFs will be completed by clinical research coordinators of the OHRS. The eCRFs will 
be maintained in a confidential format in a secure database. 
 
6.2.2  Data Submission Timeline and Forms: 
Completion of eCRFs will occur in accordance with NCI guidelines. Baseline (pre-study) eCRFs (e.g., 
enrollment, medical history, concomitant medications, disease assessment, etc.) will be completed no later 
than 14 days after the start of treatment. Treatment eCRFs (e.g., drug administration, adverse events, 
chemistries, etc.) will be completed no later than 14 days following each cycle of treatment. Off-treatment 
information (e.g., follow-up, best response, etc.) will be completed no later than 14 days after the end of 
protocol treatment. 
 
6.2.3  Research Charts: 
A research chart (i.e., shadow chart) is maintained at OHRS for each patient enrolled. Copies of significant 
study source documents will be maintained in the research chart. Examples of source document copies 
that will be maintained in the research chart include: signed informed consent form, documents that verify 
eligibility and treatment, documents that verify Grade 3-4 adverse events, and response. This information 
will be updated on a prospective basis and will be confidentially maintained at the OHRS. 
 
6.2.4  Reports: 
Publications and annual reports for submission to the IRB will be written by the Rutgers Cancer Institute of 
New Jersey PI using the data captured on the e-CRFs. Results will be communicated at scientific meetings 
and all reasonable efforts must be made to seek publication in a peer-reviewed scientific journal. 
 
6.3 Data and Safety Monitoring  
Monitoring of this study will occur in accordance with the Cancer Institute’s NCI approved Data and Safety 
Monitoring Plan (DSMP). An “initiation audit” will be conducted in accordance with the DSMP following 
enrollment of the first two (2) or three (3) patients. Subsequent audits will occur on an annual basis prior to 
annual IRB continuing review, if the findings from the initiation audit were satisfactory. More frequent audits 
of patient data and study conduct will occur if necessary. Prior audit findings and/or situations that may 
arise during the course of the study will determine the need for more frequent auditing. All audit findings 
will be reported to the Cancer Institute’s Human Research Oversight Committee and the PI. 
 
6.4 Reporting Results 
A. Sharing of Results with Subjects  
N/A 
B. Individual Results  
N/A 
C. Aggregate Results  
N/A 
 
6.4.1 Professional Reporting 
Results will be communicated at scientific meetings and all reasonable efforts will be made to seek 
publication in a peer-reviewed scientific journal. 
Pro2018002628
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
54 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
 
6.4.2 ClinicalTrials.Gov Registration and Data Reporting 
The study will be be registered by the PI with  https://orra.rutgers.edu/clinicaltrialsgov. Summary of the 
study results will be posted to the CTG site as and when available.  
 
6.5 Data Sharing   
After information that could identify patients (PHI) has been removed, de-identified information or 
biospecimens  collected for this research may be used by or distributed to investigators for other 
research. 
 
6.6 Secondary Use of the Data 
After information that could identify identify patients (PHI) has been removed, de-identified information 
collected for this research may be used by or distributed to investigators for other research. 
 
7.0 Research Repositories – Specimens and/or Data 
Your leftover tissue samples will be stored in the Cancer Institute of New Jersey Biorepository 
Service (BRS), which is owned and operated by the Rutgers Cancer Institute of New Jersey. The 
repository is at 195 Little Albany Street, New Brunswick, NJ, 08903 and operates through BRS 
SOPs (IRB 0220100249/CINJ protocol 001006). 
 
8.0 Approvals/Authorizations 
N/A 
 
 
 
Pro2018002628
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Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
55 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
9.0 Bibliography 
 
1. 
Foote, M.C., et al., Phase II study of single-agent panitumumab in patients with incurable 
cutaneous squamous cell carcinoma. Ann Oncol, 2014. 25(10): p. 2047-52. 
2. 
Karia, P.S., et al., Evaluation of American Joint Committee on Cancer, International Union 
Against Cancer, and Brigham and Women's Hospital tumor staging for cutaneous squamous cell 
carcinoma. J Clin Oncol, 2014. 32(4): p. 327-34. 
3. 
Karia, P.S., J. Han, and C.D. Schmults, Cutaneous squamous cell carcinoma: estimated 
incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J 
Am Acad Dermatol, 2013. 68(6): p. 957-66. 
4. 
Hacker, S.M. and F.P. Flowers, Squamous cell carcinoma of the skin. Will heightened awareness 
of risk factors slow its increase? Postgrad Med, 1993. 93(8): p. 115-21, 125-6. 
5. 
Marks, R., The epidemiology of non-melanoma skin cancer: who, why and what can we do about 
it. J Dermatol, 1995. 22(11): p. 853-7. 
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Alam, M. and D. Ratner, Cutaneous squamous-cell carcinoma. N Engl J Med, 2001. 344(13): p. 
975-83. 
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Clayman, G.L., et al., Mortality risk from squamous cell skin cancer. J Clin Oncol, 2005. 23(4): p. 
759-65. 
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Navarrete-Dechent, C., et al., High-risk cutaneous squamous cell carcinoma and the emerging 
role of sentinel lymph node biopsy: A literature review. J Am Acad Dermatol, 2015. 73(1): p. 127-
37. 
9. 
Parikh, S.A., V.A. Patel, and D. Ratner, Advances in the management of cutaneous squamous 
cell carcinoma. F1000Prime Rep, 2014. 6: p. 70. 
10. 
Oddone, N., et al., Metastatic cutaneous squamous cell carcinoma of the head and neck: the 
Immunosuppression, Treatment, Extranodal spread, and Margin status (ITEM) prognostic score 
to predict outcome and the need to improve survival. Cancer, 2009. 115(9): p. 1883-91. 
11. 
Veness, M.J., Treatment recommendations in patients diagnosed with high-risk cutaneous 
squamous cell carcinoma. Australas Radiol, 2005. 49(5): p. 365-76. 
12. 
Cartei, G., et al., Oral 5-fluorouracil in squamous cell carcinoma of the skin in the aged. Am J Clin 
Oncol, 2000. 23(2): p. 181-4. 
13. 
Ikegawa, S., et al., Cisplatin combination chemotherapy in squamous cell carcinoma and adenoid 
cystic carcinoma of the skin. J Dermatol, 1989. 16(3): p. 227-30. 
14. 
Jarkowski, A., 3rd, et al., Systemic Therapy in Advanced Cutaneous Squamous Cell Carcinoma 
(CSCC): The Roswell Park Experience and a Review of the Literature. Am J Clin Oncol, 2014. 
15. 
Guthrie, T.H., Jr., et al., Cisplatin-based chemotherapy in advanced basal and squamous cell 
carcinomas of the skin: results in 28 patients including 13 patients receiving multimodality 
therapy. J Clin Oncol, 1990. 8(2): p. 342-6. 
16. 
Sadek, H., et al., Treatment of advanced squamous cell carcinoma of the skin with cisplatin, 5-
fluorouracil, and bleomycin. Cancer, 1990. 66(8): p. 1692-6. 
17. 
Shin, D.M., et al., Phase II and biologic study of interferon alfa, retinoic acid, and cisplatin in 
advanced squamous skin cancer. J Clin Oncol, 2002. 20(2): p. 364-70. 
18. 
Snyder, A., et al., Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J 
Med, 2014. 371(23): p. 2189-99. 
19. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
20. 
Hodi, F.S., et al., Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients 
With Advanced Melanoma Treated With Pembrolizumab. J Clin Oncol, 2016. 34(13): p. 1510-7. 
21. 
Gaffney, D.C., H.P. Soyer, and F. Simpson, The epidermal growth factor receptor in squamous 
cell carcinoma: An emerging drug target. Australas J Dermatol, 2014. 55(1): p. 24-34. 
Pro2018002628
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           9/21/2023

 
 
 
Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
56 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
22. 
Maubec, E., et al., Phase II study of cetuximab as first-line single-drug therapy in patients with 
unresectable squamous cell carcinoma of the skin. J Clin Oncol, 2011. 29(25): p. 3419-26. 
23. 
Kim, S., M. Eleff, and N. Nicolaou, Cetuximab as primary treatment for cutaneous squamous cell 
carcinoma to the neck. Head Neck, 2011. 33(2): p. 286-8. 
24. 
Lopez-Albaitero, A. and R.L. Ferris, Immune activation by epidermal growth factor receptor 
specific monoclonal antibody therapy for head and neck cancer. Arch Otolaryngol Head Neck 
Surg, 2007. 133(12): p. 1277-81. 
25. 
Pajares, B., et al., Differential outcome of concurrent radiotherapy plus epidermal growth factor 
receptor inhibitors versus radiotherapy plus cisplatin in patients with human papillomavirus-
related head and neck cancer. BMC Cancer, 2013. 13: p. 26. 
26. 
Vermorken, J., et al., Safety and Efficacy of Panitumumab (pmab) in HPV Positive (+) and HPV 
Negative (−) Recurrent/metastatic (R/M) Squamous Cell Carcinoma of the Head and Neck 
(SCCHN): Analysis of the Phase 3 SPECTRUM Trial. European Journal of Cancer. 47: p. 13. 
27. 
Vermorken, J.B., et al., Cisplatin and fluorouracil with or without panitumumab in patients with 
recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-
label phase 3 randomised trial. Lancet Oncol, 2013. 14(8): p. 697-710. 
28. 
Wirth, L.J., et al., Phase I dose-finding study of paclitaxel with panitumumab, carboplatin and 
intensity-modulated radiotherapy in patients with locally advanced squamous cell cancer of the 
head and neck. Ann Oncol, 2010. 21(2): p. 342-7. 
29. 
National Comprehensive Cancer, N., Squamous Cell Skin Cancer (Version 1.2015). 2014. 
30. 
Mavropoulos, J.C., B. Aldabagh, and S.T. Arron, Prospects for personalized targeted therapies 
for cutaneous squamous cell carcinoma. Semin Cutan Med Surg, 2014. 33(2): p. 72-5. 
31. 
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. 
32. 
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. 
33. 
Dharmadhikari, N., J.M. Mehnert, and H.L. Kaufman, Oncolytic virus immunotherapy for 
melanoma. Curr Treat Options Oncol, 2015. 16(3): p. 326. 
34. 
Taneja, S., et al., Enhanced antitumor efficacy of a herpes simplex virus mutant isolated by 
genetic selection in cancer cells. Proc Natl Acad Sci U S A, 2001. 98(15): p. 8804-8. 
35. 
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. 
36. 
Senzer, N.N., et al., Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-
encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic 
melanoma. J Clin Oncol, 2009. 27(34): p. 5763-71. 
37. 
Xia, Z.J., et al., [Phase III randomized clinical trial of intratumoral injection of E1B gene-deleted 
adenovirus (H101) combined with cisplatin-based chemotherapy in treating squamous cell cancer 
of head and neck or esophagus]. Ai Zheng, 2004. 23(12): p. 1666-70. 
38. 
Varghese, S. and S.D. Rabkin, Oncolytic herpes simplex virus vectors for cancer virotherapy. 
Cancer Gene Ther, 2002. 9(12): p. 967-78. 
39. 
Chung, C.H., et al., Increased epidermal growth factor receptor gene copy number is associated 
with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol, 2006. 24(25): p. 
4170-6. 
40. 
Spranger, S., et al., Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor 
microenvironment is driven by CD8(+) T cells. Sci Transl Med, 2013. 5(200): p. 200ra116. 
41. 
Srivastava, R.M., et al., Cetuximab-activated natural killer and dendritic cells collaborate to trigger 
tumor antigen-specific T-cell immunity in head and neck cancer patients. Clin Cancer Res, 2013. 
19(7): p. 1858-72. 
42. 
Trivedi, S., et al., Immune biomarkers of anti-EGFR monoclonal antibody therapy. Ann Oncol, 
2015. 26(1): p. 40-7. 
Pro2018002628
           4/12/2023
           9/21/2023

 
 
 
Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
57 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
43. 
Simon, R., Optimal two-stage designs for phase II clinical trials. Control Clin Trials, 1989. 10(1): 
p. 1-10. 
44. 
Van Cutsem, E., et al., Open-label phase III trial of panitumumab plus best supportive care 
compared with best supportive care alone in patients with chemotherapy-refractory metastatic 
colorectal cancer. J Clin Oncol, 2007. 25(13): p. 1658-64. 
45. 
Price, T.J., et al., Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-
type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-
label, non-inferiority phase 3 study. Lancet Oncol, 2014. 15(6): p. 569-79. 
 
 
 
Pro2018002628
           4/12/2023
           9/21/2023

 
 
 
Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
58 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
10.0 Appendices 
Appendix 1. 
Sample Fax Cover Form for Individual Safety Reports (Amgen Global Safety) 
 
Pro2018002628
           4/12/2023
           9/21/2023

 
 
 
Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
59 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
Appendix 2.  
Sample Fax Cover Form for Aggregate Safety Reporting 
 
Pro2018002628
           4/12/2023
           9/21/2023

 
 
 
Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
60 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
Appendix 3.  
Sample of Report of Suspected IMLYGIC™ (Talimogene laherparepvec) or Herpes 
Virus Associated Adverse Event  
 
 
 
 
 
Pro2018002628
           4/12/2023
           9/21/2023

 
 
 
Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
61 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
Appendix 4.  Sample of Pregnancy Notification Worksheet 
 
 
 
 
Pro2018002628
           4/12/2023
           9/21/2023

 
 
 
Version Number: v10, March 23, 2023 
Protocol Number: #091804 
PI Name: Adam Berger, MD 
Protocol Title: A Phase I Study of Talimogene 
Laherparepvec and Panitumumab in Patients with 
Locally Advanced Squamous Cell Carcinoma of the 
Skin (SCCS) 
62 
RESERVED FOR IRB STAMP 
DO NOT MODIFY THIS SPACE 
 
 
 
IRB Form Version 12.18.2018 
 
Appendix 5. Sample of Lactation Notification Worksheet 
 
 
 
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           9/21/2023