Conditions: Squamous Cell Carcinoma Skin Cancer Keratoacanthoma Cutaneous Tumor Skin Cancer, Squamous Cell Lesion Skin
Keywords: Skin cancer Squamous cell Squamous Cell Carcinoma Skin lesion Keratoacanthoma talimogene laherparepvec
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
This is single arm Phase 2, single center study of talimogene laherparepvec (TVEC) to treat low risk cutaneous squamous cell carcinomas (cSCC).

Detailed description:
The purpose of this study is to assess the effect of Talimogene laherparepvec (TVEC) in patients diagnosed with lower risk cSCC in need of alternative therapeutic approaches.

Immune recognition and cytotoxic responses play an important role in the pathogenesis and progression of cutaneous squamous cell carcinoma (cSCC). TVEC is an HSV-1 oncolytic immunological agent FDA approved for the local treatment of unresectable recurrent melanoma. It is proposed that T-VEC directly destroys cancer cells and induces production of GM-CSF to enhance systemic antitumor immune priming. This proposed mechanism of action supports the novel approach to implement TVEC in the management of cSCC. Particularly, in patients with increased burden of primary tumors.

The study subjects enrolled in the study were Immunocompetent, \> 18 years of age, and diagnosed with at least one histologically confirmed primary low-risk cSCC according to the Brigham and Women staging system. Unresectable lesions or patients unable/unwilling to undergo standard of care treatment were eligible to participate. Study lesions included target lesions injected (TLIs) and target non-injected lesions (TNILs). TNILs were selected to evaluate for abscopal effect when feasible. The TLIs were treated according to TVEC FDA approved protocol and followed for 1yr after the 1st injection. The primary endpoint of the study was to evaluate the overall response rate, defined as the proportion of subjects who achieved complete response and partial response in the TLIs. Safety and adverse effect profile (AEs), duration of response, time to response, durable response rate, and time to progression, were the some of the secondary endpoints included.

Arms:
arm 1: The subject participation period will be approximately 48 weeks. This will include a screening visit, 4 injection visits and 5 follow up visits. Total length of study/patient is 8.5 to 10.5 months. TVEC will be administered by injection with a needle directly into one or more tumors.

Interventions: intervention 1: Injection of TVEC into target lesions - week 1-2 intervention 2: Injection of TVEC into target lesions 3wks after 1st injection intervention 3: Injection of TVEC into target lesions 2wks after 2nd injection intervention 4: Injection of TVEC into target lesions 2wks after 3rd injection
Intervention descriptions: intervention 1: Target lesions are identified and documented with measurements and photographs. Photographs will be taken with regional and close up view of the anatomical area and lesion.

Inject 0.5ml - 4ml (based on lesion size - section 7.1, Table 5) Talimogene laherparepvec at nominal concentration of 106 plaque forming units (PFU)/mL with approximately 1.15 mL in a 2 mL vial for the initial dose. This will be administered intralesionally to 1-3 cSCC lesions per anatomical site with a maximum of 5 injectable lesions per patient. intervention 2: Target lesions are identified and documented with measurements and photographs. Photographs will be taken with global and close up view of the anatomical area and lesion.

Inject 0.5ml - 4ml (based on lesion size) and number of lesions selected. Talimogene laherparepvec at nominal concentration of 108 PFU/mL with approximately 1.15 mL in a 2 mL vial for the second and subsequent doses. intervention 3: Target lesions are identified and documented with measurements and photographs. Photographs will be taken with global and close up view of the anatomical area and lesion.

Inject 0.5ml - 4ml (based on lesion size) and number of lesions selected.Talimogene laherparepvec at nominal concentration of 108 PFU/mL with approximately 1.15 mL in a 2 mL vial for the subsequent doses. intervention 4: Target lesions are identified and documented with measurements and photographs. Photographs will be taken with global and close up view of the anatomical area and lesion.

Inject 0.5ml - 4ml (based on lesion size) and number of lesions selected. Talimogene laherparepvec at nominal concentration of 108 PFU/mL with approximately 1.15 mL in a 2 mL vial for the subsequent doses.

Protocol document:
Prot_SAP_000.pdf: 
 
 
Official Title: 
A Single Arm Phase 2 Study of talimogene laherparepvec 
in patients with cutaneous squamous cell cancer 
NCT number: 
NCT03714828 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
07/24/2023 
 
 


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Study Title:  
A Single Arm Phase 2 Study of talimogene laherparepvec in patients with 
cutaneous squamous cell cancer 
 
 
 
 
 
Sponsor Investigator 
 
 
 
University of Arizona Cancer Center  
 
 
 
 
 
 
 
3838 N. Campbell Ave 
 
 
 
 
 
 
 
Tucson, AZ 85719  
 
 
Principal Investigator 
 
 
 
Clara Curiel MD 
 
 
 
 
 
 
 
University of Arizona Cancer Center 
 
 
 
 
 
 
 
3838 N. Campbell Ave 
 
 
 
 
 
 
 
Tucson, AZ 85719 
 
 
 
 
 
 
 
ccuriel@email.arizona.edu 
 
 
 
 
 
 
 
520-694-9075- office 
 
 
 
 
 
520-694-9029 
 
Co-Investigators 
 
 
 
 
Hina Arif Tiwari, MD 
 
 
 
 
 
 
 
Haiyen Cui, PhD 
 
 
 
 
 
 
 
Denise Roe, DrPH 
 
 
 
 
 
 
 
Delaney Stratton, PhD, DNP 
 
 
 
 
 
 
 
Mohammad Fazel, MD 
 
                    
 
 
The University of Arizona Cancer Center 
Study Site:  
 
 
 
 
3838 N. Campbell Ave 
 
 
 
 
 
 
 
Tucson, AZ 85719 
 
 
Commercial Agent(s) Supplier  
 
Amgen 
 
 
 
 
 
 
 
Fax: 888-814-8653  
 
 
 
 
 
 
 
Email: svc-ags-in-us@amgen.com 
 
 
Protocol Number, Version(s) and Date(s) 
Protocol number: 20167003.  
Version 10 – 07/24/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Investigator Agreement 
 
I have read, understand and will adhere to the protocol as written, that any changes to 
the protocol will be approved by the sponsor or sponsor-investigator and the IRB, 
except changes to eliminate an immediate hazard to study subjects.  
I agree to conduct this study in accordance with the current International Conference on 
Harmonization (ICH) guidance, the Good Clinical Practice (GCP) guidance, the 
Declaration of Helsinki, FDA regulations, local IRB and legal requirements.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7/5/2023 
__________________________   
 
 
_______________________ 
Signature 
 
 
 
 
 
 
Date (MM/DD/YY) 
 
 
 
Clara N. Curiel, MD 
__________________________ 
Name of Principal Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
1. INTRODUCTION / SYNOPSIS ................................................................................. 7 
1.1  
Phase ................................................................................................................. 7 
1.2 
Indication ............................................................................................................ 7 
1.3 
Endpoints ........................................................................................................... 7 
1.4 
Patient Population .............................................................................................. 8 
2. STUDY DESIGN ....................................................................................................... 8 
2.1 
Phase ................................................................................................................. 8 
2.2 
Number of centers .............................................................................................. 8 
2.3 
Number of subjects ............................................................................................ 8 
2.4 
The subject participation time period .................................................................. 8 
3. OBJECTIVES ......................................................................................................... 11 
3.1 
Primary Objective ............................................................................................. 11 
3.2  
Secondary Objective ........................................................................................ 11 
3.3 
Exploratory Objective ....................................................................................... 12 
4.0 BACKGROUND AND RATIONALE ........................................................................ 12 
4.1 
Disease/Condition ............................................................................................ 12 
4.2 
Investigational Product (24).............................................................................. 15 
4.3  
Preclinical Experience- Not applicable ............................................................. 16 
4.4 
Clinical Experience-Not applicable ................................................................... 16 
5.0 INVESTIGATIONAL PRODUCT ............................................................................. 16 
5.1 
Investigational Product ..................................................................................... 16 
5.2 
Investigational product supply .......................................................................... 17 
5.3 
Investigational Product Accountability .............................................................. 18 
5.4 
Storage ............................................................................................................ 19 
5.5 
Preparation of Talimogene Laherparepvec ...................................................... 19 
5.6 
Handling ........................................................................................................... 20 
6.0 SUBJECT ELIGIBILITY .......................................................................................... 22 
6.1 
Inclusion Criteria .............................................................................................. 23 
6.2 
Exclusion Criteria: ............................................................................................ 24 
6.3 
Enrollment ........................................................................................................ 26 
7.0 STUDY PLAN ......................................................................................................... 26 


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7.1 
IP/treatment regimen ........................................................................................ 26 
7.2 
Pre-medications ............................................................................................... 27 
7.3 
Rescue Medications – Not applicable .............................................................. 27 
7.4 
Excluded medications/treatments .................................................................... 27 
8.0 REQUIREMENTS FOR TREATMENT ................................................................... 27 
8.1 
Standard dose use ........................................................................................... 27 
8.2 
Dose reductions ............................................................................................... 27 
8.3 
IP treatment delays .......................................................................................... 28 
8.4 
Adverse Drug Reactions (ADRs) ...................................................................... 28 
8.5 
Definition of a Dose Limiting Toxicity (DLT) ..................................................... 31 
9.0 STUDY PROCEDURES ......................................................................................... 32 
9.1 
Screening- Visit 0 ............................................................................................. 32 
9.2 
Enrollment- Visit 1 ............................................................................................ 33 
9.3 
On IP treatment ................................................................................................ 33 
9.4 
Study Assessments .......................................................................................... 35 
9.4.1 
Tumor Measurements: ............................................................................... 35 
9.4.1.2 Clinical Management of TILs and TNILs ..................................................... 36 
9.4.2 
High Resolution Ultrasonography of Squamous Cell Cancer: ................... 38 
9.4.3 
Chart Review: Frequency of Nonmelanoma Skin Cancers (NMSCs) ........ 39 
9.5 
End of IP treatment .......................................................................................... 39 
9.5.1    Follow up .................................................................................................... 39 
9.6 
Early Treatment Termination ............................................................................ 40 
9.7 
Offset Range (or Treatment Window) .............................................................. 40 
9.8 
Off Study .......................................................................................................... 41 
10.0 .............................................................. PHARMACOKINETIC STUDIES- Not for this study
 
41 
10.1 Collection ......................................................................................................... 41 
10.2 Processing ....................................................................................................... 41 
10.3 Storage ............................................................................................................ 41 
10.4 Destruction ....................................................................................................... 41 
11.0 .............................................................................. DATA AND SAFETY MONITORING PLAN
 
41 
11.1 Identification of the DSMB obligated for oversight responsibilities ................... 41 


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11.2 Identification of the entity obligated for routine monitoring duties ..................... 41 
11.3 Monitoring progress and data review process .................................................. 41 
11.4 Process to implement study closure when significant risks or benefits are 
identified..................................................................................................................... 42 
Study stopping criteria will include the following: .................................................... 42 
Individual treatment stopping criteria will include the following: .............................. 43 
11.5 Description of adverse events and reporting procedures ................................. 43 
11.6 Plan for assuring data accuracy and protocol compliance ............................... 44 
11.7 Identification of the sponsor or funding agency, as applicable ......................... 44 
12.0 .................................................... ADDITIONAL SAFETY REPORTING REQUIREMENTS
 
44 
13.0 .. Accidental Exposures to Talimogene Laherparepvic and Herpetic Event Reporting
 
46 
13.1 Accidental Exposure of HCPs to Talimogene Laherparepvec .......................... 46 
13.2 Suspected Herpetic Events .............................................................................. 46 
14. MODIFIED RECIST CRITERIA – Appendix B ........................................................ 48 
15. REMOVAL OF SUBJECTS .................................................................................... 48 
16. STATISTICAL CONSIDERATIONS ........................................................................ 49 
16.1   Analysis Endpoints ........................................................................................... 49 
16.1.1   Primary Endpoint ....................................................................................... 49 
16.1.2 
Secondary Endpoints ............................................................................. 49 
16.1.3 
Exploratory Endpoint .............................................................................. 51 
16.2 Statistical Analysis ........................................................................................... 51 
16.2.1 Overall Response Rate (ORR) .................................................................... 51 
16.2.2   Safety and Adverse effects of talimogene laherparepvec in cSCC ............ 51 
16.2.3 Duration of overall response (DOR) of TILs. ................................................ 51 
16.2.4 Durable Response Rate of TILs. .................................................................. 51 
16.2.5 Time to progression (TTP) of TILs. .............................................................. 51 
16.2.6 
Time to response in TILs ........................................................................ 52 
16.2.7 Overall response rate (CR+PR) in TNILs ..................................................... 52 
16.2.8 Chart Review of Abscopal Effect ................................................................. 52 
16.3 Interim Analysis ................................................................................................ 52 
17. ANALYSIS .............................................................................................................. 52 


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17.1 Safety Analysis –see #16 ................................................................................. 52 
17.2  Efficacy Analysis –see #16 ............................................................................... 52 
17.3 Interim Analysis – see #16 ............................................................................... 52 
18. REGULATORY OBLIGATIONS .............................................................................. 52 
18.1 Informed Consent ............................................................................................. 52 
18.2 Institutional Review Board ................................................................................ 53 
19. ADMINISTRATIVE PROCEDURES ....................................................................... 53 
19.1  Investigator Responsibilities ............................................................................. 53 
19.2 Data and Safety Monitoring Board Protocol Review ........................................ 53 
19.3 Multicenter Trials- Does not apply to this study ................................................ 54 
19.3.1 
UACC DSMB and QA/QC Monitoring ..................................................... 54 
19.3.2 
Alternate DSMB Oversight ..................................................................... 54 
20. SUBJECT CONFIDENTIALITY............................................................................... 54 
21. STUDY DOCUMENTATION AND ARCHIVE ......................................................... 54 
22. DATA ...................................................................................................................... 54 
23. PROTOCOL DEVIATIONS ..................................................................................... 55 
24. ECOG- does not apply to this study ........................................................................ 55 
25. COMMON TOXICITY CRITERIA (CTCAE) ............................................................ 55 
26. STUDY SCHEDULE ............................................................................................... 56 
27. GLOSSARY - Not applicable .................................................................................. 57 
28. DEFINITIONS- Not applicable ................................................................................ 57 
29. REFERENCES ....................................................................................................... 57 
30.1 Appendix A- Measurement of Lesions and Digital Photography ...................... 60 
30.2 Appendix B- RECIST ....................................................................................... 61 
Response Criteria: .................................................................................................. 62 
30.3   Appendix C- Safety Reporting Submission Forms ........................................... 64 
 
 
 
 
 
 
 
 
 


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1. INTRODUCTION / SYNOPSIS 
1.1  
Phase  
This is a Phase 2, single center study to treat low risk cutaneous squamous cell 
carcinomas (cSCC).  
1.2 
Indication 
- Clinically consistent squamous cell carcinomas of the keratoacanthoma type and/or 
histologically confirmed other type of well-differentiated, low risk cSCC measuring > 
0.5 cm to < 5 cm.  
 
- Participants with cSCCs that are:  
- Low risk, according to Brigham and Women Hospital’s Tumor Staging(1) and the 
American Joint Committee on Cancer (Table 3),  
- “Unresectable” based on a series of clinical scenarios that include:  
1. Presence of co-morbidities that significantly influence the capacity of the 
patient to tolerate surgical procedures (e.g. significant stasis/edema in lower 
extremities lesions, patients predispose to wound dehiscence, etc.); and  
2. Participant with multiple cSCCs that increase the surgical burden of 
complications or tolerance for these repeated procedures 
3. Recurrent cSCC lesions after surgical intervention in areas where radiation 
treatment might be associated with increased complications  
4. Participant declines surgery or other standard treatments for cSCC 
- In the setting of study participants with tumor multiplicity, a maximum number of 3 
cSCCs may be treated per anatomical site. In this clinical setting, the tumors will be 
required to be at least be 10 cm apart.  
1.3 
Endpoints 
Primary Endpoint 
 
The primary end point is to evaluate the overall response rate (ORR) defined as 
proportion of subjects who achieved complete response (CR) and partial response (PR) 
in the cSCC Target injected lesions (TILs). 
 
Secondary Endpoints 
 
1. Safety and adverse effect profile of talimogene laherparepvec in cSCC. 
2. To measure time of response in cSCC TILs. 
3. To measure the duration of overall response (DOR) of TILs. 


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4. Assess durable response rate (DRR) of TILs. 
5. To measure the time to progression (TTP) of TILs. 
6. Overall response rate (ORR) (CR+PR) assessed by imaging technique (high 
frequency ultrasound).  This endpoint only applies to patients enrolled at the 
University of Arizona Cancer Center. 
7. Overall clinical response rate (CR+PR) of individual TILs with talimogene 
laherparepvec (not as overall subject response). 
8. Overall clinical response rate (CR+PR) in cSCC Target non-injected lesion(s) 
(TNILs). 
 
Exploratory Endpoint 
 
The exploratory endpoint is to evaluate the abscopal effect of TVEC by determining the 
frequency of non-melanoma skin cancers 24 months prior to the TVEC injections (or 
Visit 1), 12 months prior to the TVEC injections (or Visit 1), as compared to the 
frequency of non-melanoma skin cancers 12 months after the TVEC injections (or Visit 
4) and then 24 months after the last injection (or Visit 4) if available.  
1.4 
Patient Population 
The patient population for this study will be non-immunocompromised patients 
presenting with at least one eligible cSCC. The TILs should be located in anatomical 
sites other than head and neck.  
2. STUDY DESIGN 
2.1 
Phase 
This is a Phase 2, single site, single arm study. All subjects enrolled in the study will be 
treated with talimogene laherparepvec.  
2.2 
Number of centers 
There are two participating sites for this study: The University of Arizona Cancer Center 
and Honor Health Research Institute. 
2.3 
Number of subjects 
There will be approximately 20 subjects participating in this protocol. 
2.4 
The subject participation time period  
The subject participation period will be approximately 48 weeks. This will include a 
screening visit, 4 injection visits and 5 follow up visits. Total length of study/patient is 8.5 
to 10.5 months. 
 
 


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Table 1. Visit Schedule 
 
 
Screening Visit/V0 
Selection of study TILs. Low-risk cSCC with at least 1 lesion > 0.5 cm to < 5 cm. TILs 
will have partial biopsies for confirmatory diagnosis. A total of up to 5 TILs per subject 
can be selected for treatment with no more than 3 lesions in one anatomical area. TILs 
in the same anatomical area will need to be 10 cm apart from the other injected lesions. 
A high frequency ultrasound of the TILs will be performed at baseline prior to starting 
first injection.  
Selection of study TNILs. Lesions that are clinically suspicious of cSCC in the same 
anatomical location as TILs. Up to 10 TNILs can be followed with no more than 2 TNILs 
selected in the same anatomical area as a TIL. TNILs will have partial biopsies for 
confirmatory diagnosis. TNILs will be assessed by clinical measurement only without 
the use of ultrasound technique.  
Visit 1: First Injection Visit: One to four (1-4) weeks after V0 
• Target lesions (TILs and TNILs) are identified and documented with 
measurements and photographs. Photographs will be taken with regional and 
close up view of the anatomical area and lesion (Appendix A).  
• Inject 0.1ml – 4ml (based on TILs size – section 7.1, Table 5) Talimogene 
laherparepvec at nominal concentration of 106 plaque forming units (PFU)/mL 
with approximately 1.15 mL in a 2 mL vial for the initial dose. This will be 
administered intralesionally to 1-3 cSCC lesions per anatomical site with a 
maximum of 5 injectable lesions per patient. 
Visit 2: Second injection visit:  Three (3) Weeks after V1 
• Target lesions are identified and documented with measurements and 
photographs. Photographs will be taken with global and close up view of the 
anatomical area and lesion (Appendix A).  
• Inject 0.1ml – 4ml (based on TILs size) and number of lesions selected. 
Talimogene laherparepvec at nominal concentration of 108 PFU/mL with 


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approximately 1.15 mL in a 2 mL vial for the second and subsequent doses.  
Visit 3: Third injection visit:  Two (2) Weeks after V2 
• Target lesions are identified and documented with measurements and 
photographs. Photographs will be taken with global and close up view of the 
anatomical area and lesion. 
• Inject 0.1ml – 4ml (based on TILs size) and number of lesions selected. 
Talimogene laherparepvec at nominal concentration of 108 PFU/mL with 
approximately 1.15 mL in a 2 mL vial for the subsequent doses. 
Visit 4: Fourth injection visit:  Two (2) Weeks after V3 
• Target lesions are identified and documented with measurements and 
photographs. Photographs will be taken with global and close up view of the 
anatomical area and lesion (Appendix A). 
• Inject 0.1ml – 4ml (based on TILs size) and number of lesions selected. 
Talimogene laherparepvec at nominal concentration of 108 PFU/mL with 
approximately 1.15 mL in a 2 mL vial for the subsequent doses. 
  Visit 5: First Follow up visit: Four (4) weeks after V4  
• Target lesions are identified and documented with measurements and 
photographs. Photographs will be taken with global and close up view of the 
anatomical area and lesion (Appendix A).  
Visit 6: Second Follow up visit:  Four (4) weeks after V5 
• Target lesions are identified and documented with measurements and 
photographs. Photographs will be taken with global and close up view of the 
anatomical area and lesion (Appendix A). A repeat high-frequency ultrasound of 
target lesions will be completed to assess response from baseline. 
Visit 7: Third Follow up visit: Six (6) weeks after V6 
• Target lesions are identified and documented with measurements and 
photographs. Photographs will be taken with global and close up view of the 


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anatomical area and lesion (Appendix A). 
Visit 8: Fourth Follow up visit: Fourteen (14) weeks after V7 
• Target lesions are identified and documented with measurements and 
photographs. Photographs will be taken with global and close up view of the 
anatomical area and lesion (Appendix A). 
Visit 9: Telephone Follow up: twelve (12) months after first injection (V1) 
• Research coordinator will assess patient over the phone to determine if any 
changes have occurred to target lesions after V8. 
 
3. 
OBJECTIVES 
3.1 
Primary Objective 
1. To evaluate the ORR, defined as the proportion of subjects who achieved CR and 
PR in the cSCC TILs. 
3.2  
Secondary Objective 
1. To assess the safety and adverse effect profile of talimogene laherparepvec in low 
risk cSCC. This will be determined by incidence of all adverse events (AEs), grade ≥ 
3 AEs, safety adverse events (SAEs), and events requiring the discontinuation of 
study drug, local effects on the tumor (ie, pain, inflammation and ulceration), and any 
clinically significant laboratory values. 
 
2. To determine the time of response in cSCC TILs. This will be measured from the 
time from the first visit until objective tumor response (CR or PR) is identified.  
 
3. To measure the duration of overall response (DOR) of TILs. This will be measured 
from the time measurement criteria are met for CR or PR (whichever status is 
recorded first) until the first date that recurrence or progressive disease (PD) is 
objectively documented, taking as reference for PD the smallest measurements 
recorded since the treatment started. If no recurrence or PD is documented after PR 
or CR is observed the time measurement will be performed at Visit 8. 
 
4. To measure the durable response rate (DRR) of TILs. The duration of overall 
response is ORR lasting continuously for > than or equal to 6 months. 
 


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5. To measure the time to progression (TTP) of TILs. This will be measured from the 
time treatment is initiated until the first date that recurrence or progressive disease 
(PD) is objectively documented, taking as reference for PD the smallest 
measurements recorded since the treatment started.  
 
6. To measure the overall response rate (CR+PR) of TILs by high frequency ultrasound 
and correlate it with clinical overall response rate.  
 
7. Overall clinical response rate (CR+PR) of individual TILs injected with talimogene 
laherparepvec (not as overall subject response).  
 
8. To determine the overall clinical response rate (CR+PR) observed in TNILs that are 
present in the treated anatomical location (if applicable).  
 
3.3 
Exploratory Objective 
To determine the frequency of non-melanoma skin cancers 24 months prior to TVEC 
injections (or Visit 1), and then 12 months prior to the TVEC injections (or Visit 1), as 
compared to the frequency of non-melanoma skin cancers 12 months after the TVEC 
injections (or Visit 4) and then 24 months after the last injection (or Visit 4) if available.       
4.0 BACKGROUND AND RATIONALE 
4.1 
Disease/Condition 
Squamous cell skin cancer is the second most common cutaneous malignancy with 
estimated 700,000 cases of cutaneous SCC diagnosed each year in the US (2, 3). 
Based on certain characteristics, SCC of skin is classified into low-risk and high-risk 
disease. The features of low-risk disease are noted below (Table 2). According to 
Brigham and Women’s Hospital, a low risk cSCC has fewer than two high risk features 
(Table 3) (1). High-risk features include a diameter of at least two centimeters, poorly 
differentiated histology, tumor invasion beyond subcutaneous fat and perineural 
invasion of nerve(s) greater or less than 0.1 mm in depth(1). Surgery (Moh’s procedure) 
is the primary modality of treatment for cSCC of the head and neck with standard 
surgical resection recommended for SCC of other sites. Surgical excision has local 
failure rates of up to 15% (4).  
Despite reasonable response rates, surgical excision can be challenging in patients with 
multiple synchronous lesions, or with a recent lesion history of multiple cSCCs. In 
addition, surgical excision of lesions in certain locations, such as lower extremities, can 
result in poor wound healing, infections and long-term complications (5). Local therapies 
such as cryosurgery, electro-desiccation and curettage, topical therapies (imiquimod or 
5- fluorouracil), and photodynamic therapy, as well radiation therapy are other treatment 
options in low-risk SCC. According to the National Comprehensive Cancer Network, 
radiation therapy is the standard-of-care treatment for low risk cSCC for non-surgical 
candidates; however, it is recommended for patients older than 60 years because of 


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concerns of long-term sequelae (6). Adjuvant radiation and/or chemotherapy is used in 
patients with high-risk / advanced SCC as neo-adjuvant treatment, or adjuvant therapy 
to minimize the risk of local and distant recurrence. 
Table 2: Low- Risk features of cutaneous SCC (7) 
• Size <20 mm on trunk or extremities (excluding pre-tibia, hands, feet, nail units, 
and ankles) or <10mm in “mask areas” of face or <6mm in cheeks, forehead, 
scalp, and neck. 
• Well - defined borders 
• Primary tumors 
• No immunosuppression 
• Not a site of previous radiation therapy or chronic inflammation 
• Slow growing tumor 
• Absence of neurologic symptoms 
• Well or moderately differentiated tumor 
• Non adenoid (acantholytic), adenosquamous, or desmoplastic subtypes 
• Depth less than 2 mm or Clark level IV or V, • No perineural or vascular 
involvement  
 
Summary of American Joint Committee on Cancer (AJCC) and Brigham and Women’s 
Hospital (BWH) 
AJCC 
 
T1 
Tumor ≤ 2 cm in greatest dimension, with < 2 high-risk factors 
T2 
Tumor > 2 cm in greatest dimension, with ≥ 2 high-risk factors 
T3 
Tumor with invasion of orbit, maxilla, mandible or temporal bones 
T4 
Tumor with invasion of other bones or direct perineural invasion of 
skull base 
BWH 
 
T1 
0 high-risk factors 
T2 
1 high-risk factors 
T3 
2-3 high-risk factors 
T4 
≥ 4 high-risk factors 
Adapted from Karia et al. (1). 


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Immunotherapy in Cutaneous SCC  
Immune-evasion is a well-known mechanism by which cancer cells proliferate and 
spread. Immune checkpoint inhibition unmasks negative feedback of the cancer cells on 
cytotoxic immune response and is a proven therapeutic approach in multiple cancers 
including melanoma. A compromised immune-surveillance plays an important role in the 
pathogenesis of cutaneous SCC (8). A clear increase in the incidence of cutaneous 
SCC is noted in patients with immune deficiency and iatrogenic immune-suppression 
(post-transplant 
setting). 
cSCC 
is 
the 
most 
common 
cancer 
identified 
in 
immunosuppressed population (9). This experience supports the innovative approach to 
implement TVEC in cSCC. Immune-therapy has a definite role in treatment of 
cutaneous SCC. 
Imiquimod is a topical immune-modulator that works by binding to toll-like receptors 7 & 
8, inducing a T-cell mediated cytokine response cascade and tumor cell destruction. 
Imiquimod is currently approved for use in anogenital warts, actinic keratoses, and 
superficial basal cell carcinomas. It has been proven to be effective in squamous cell 
carcinoma in situ (10). Interferon is another immunomodulator currently used in 
treatment of multiple hematological malignancies and melanoma. In a European study, 
52 patients with cSCC were treated with intralesional interferon, complete response was 
observed in 59.6% of patients. On long-term follow up, ranging more 5 to 10 years, 
recurrence was observed in only 2 of the 52 patients treated with interferon, 
demonstrating that immune-modulation can be an effective treatment strategy in 
cutaneous SCC (11). The primary rationale for this protocol is based on the known 
effectiveness of immunological targeted therapies in cSCC such as PD-1/PD 1 
inhibition, imiquimod, and interferon.(12-16). 
Talimogene laherparepvec is an oncolytic immunological agent derived from herpes 
simplex virus type-1. It is genetically modified and engineered to replicate within tumors. 
It works by several mechanisms including direct destruction of cancer cells, production 
of GM-CSF to enhance systemic antitumor immune recognition and destruction of 
cancer cells. In the phase 3 trial that led to FDA approval of talimogene laherparepvec 
in unresectable IIIB to IV staged melanoma, 436 patients were randomly assigned to 
talimogene laherparepvec or GM-CSF. The study showed an improvement of durable 
response rates (16.3% vs. 2.3%, p<0.001) and overall response rate (26.4% vs. 5.7%, 
p<0.001) (ORR) (17). 
There is limited experience implementing TVEC in cSCC. One study identified 
effectiveness of oncolytic viruses in experiential SCC murine models with demonstration 
of systemic immunity (18). Other studies have also shown that the implementation of 
oncolytic viruses as a therapeutic approach for the treatment of cSCC—with HSV (19, 
20) and with Adenovirus (21-23). 
We hypothesize that talimogene laherparepvec can be an effective minimally invasive 
immune- therapy in low-risk, unresectable cSCC. Also, injection of talimogene 
laherparepvec in a SCC lesion can elicit a systemic anti-tumor response, resulting in a 


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therapeutic response beyond the location where the primary lesion is being treated. 
Nonclinical evaluation has also confirmed that GM-CSF enhances the immune 
response generated, enhancing both injected and uninjected tumor responses. As of 
the 23 February 2018 data cutoff date for this investigator’s brochure, 15 clinical studies 
(including two extension studies) have been or are being conducted in several 
advanced tumor types (advanced solid tumors, melanoma, squamous cell cancer of the 
head and neck [SCCHN], and pancreatic cancer). Ten studies were conducted in the 
setting of metastatic melanoma; eight of these studies employ(ed) talimogene 
laherparepvec as monotherapy and the remaining two studies employ talimogene 
laherparepvec in combination with either ipilimumab or pembrolizumab. As of the cutoff 
date, 893 subjects were treated with talimogene laherparepvec and have provided 
efficacy and/or safety data; 31 subjects from these studies entered the extension 
studies. A non-interventional registry study (20120139) is ongoing to investigate the 
long-term survival and safety of subjects previously treated with talimogene 
laherparepvec in prior clinical trials. In addition to the two expanded access  protocols, 
one each in the United States (US) and European Union (EU), are also ongoing. 
4.2 
Investigational Product (24) 
Talimogene laherparepvec (formerly known as OncoVEX GM-CSF) is an 
investigational, oncolytic immunotherapy based on a modified herpes simplex virus 
type-1 (HSV-1) that is designed to selectively replicate in tumor tissue and to stimulate a 
systemic antitumor immune response. In talimogene laherparepvec, the HSV-1 viral 
genes ICP34.5 (the “neurovirulence factor” that promotes viral replication in normal cells 
with an intact anti-viral response but is not required for replication in tumor tissue in 
which anti-viral responses are often defective) and ICP47 (which blocks antigen 
presentation by major histocompatibility complex molecules of infected cells) have been 
deleted. In addition, deletion of ICP47 leads to increased and earlier expression of 
US11 which enhances viral replication in infected tumor cells. The coding sequence for 
human granulocyte macrophage colony stimulating factor (GM-CSF) is inserted in place 
of ICP34.5, to enhance the immune response to tumor antigens released during 
oncolysis. Intralesional administration of talimogene laherparepvec results in oncolysis 
of cells within injected tumors. Iterative viral replication within permissive tumor tissue 
results in lytic cell destruction and local release of progeny virus as well as of tumor cell 
antigens. GM-CSF, the product of the viral transgene, is also produced locally to recruit 
and stimulate antigen presenting cells which, in addition to relevant tumor-derived 
antigens, are required for the initiation of a systemic antitumor immune response. 
Overall, this strategy is expected to result in the destruction of injected tumors via 
oncolysis and also uninjected sites of disease (including micro-metastases) via a 
systemic antitumor immune response, to curtail tumor progression and to reduce local 
and distant tumor recurrence. 
 
In a clinical study in subjects with melanoma that included quantitative polymerase 
chain reaction (qPCR) testing of talimogene laherparepvec DNA in blood, urine, 
injection site, occlusive dressings, oral mucosa, anogenital area, and suspected 


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herpetic lesions, talimogene laherparepvec DNA was present in all sites during the 
study. Among subjects with detectable talimogene laherparepvec DNA in the blood, 
urine, oral mucosa, and anogenital area, no samples had detectable talimogene 
laherparepvec DNA 30 days after the end of treatment. For subjects with detectable 
DNA in injected lesions, no samples had detectable talimogene laherparepvec DNA 60 
days after the end of treatment.  Currently, there is no clinical data available for 
talimogene laherparepvec DNA detection in treatment sites for cSCC. 
 
4.3  
Preclinical Experience- Not applicable 
 
The use of talimogene laherparepvec in the treatment of cSCCs has no 
preclinical data to report. 
4.4 
Clinical Experience-Not applicable 
 
There is no clinical experience on the use of talimogene laherparepvec with 
cSCC. 
5.0  INVESTIGATIONAL PRODUCT 
5.1 
Investigational Product  
In accordance with the protocol the following will be referred to as investigational 
product (IP): 
 
• Talimogene laherparepvec at nominal concentration of 106 plaque forming units 
(PFU)/mL with approximately 1.15 mL in a 2 cc vial for the initial dose  
 
• Talimogene laherparepvec at nominal concentration of 108 PFU/mL with 
approximately 1.15 mL in a 2 cc vial for the second and subsequent doses   
 
For each of the IP used, the preparation procedure(s) and storage condition(s) should 
comply with the instructions provided for each and every dose of the IP that is 
administered. 
 
• Description of Investigational Product  
 
Talimogene laherparepvec is an oncolytic immunotherapy based on herpes simplex 
virus type 1 (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. 
 


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5.2 
Investigational product supply 
Talimogene laherparepvec will be presented as a sterile, semi-translucent to opaque 
suspension, practically free from particles, preservative free frozen liquid in a single-use 
2.0cc 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 phosphate dihydrate, sodium dihydrogen 
phosphate dihydrate, sodium chloride, sorbitol, myo-inositol and Water for Injection 
(WFI).  Each 2cc 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 gray rubber stoppers, Fluorotec-coated on the product side. 
The vial caps will be color-coded and may be used to help distinguish between the 106 
PFU/mL and 108 PFU/mL vial concentrations. 
 
Information provided on the labels for talimogene laherparepvec will comply with ICH, 
GCP and local regulatory requirements. 
 
Examples of Product Labels (talimogene laherparepvec):  
 
Examples of Vial Labels (talimogene laherparepvec):   
 
 
 
 
 
 
Examples of Box Labels (talimogene laherparepvec):   
 


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5.3 
Investigational Product Accountability 
The Sponsor- investigator will take the following actions with regard to study drugs in 
concurrence with international regulatory requirements. All study medication will be 
delivered to the University of Arizona Cancer Center Research Pharmacy. The following 
items will be addressed with the Research Pharmacy Team. 
1. Upon receipt of clinical study materials the Clinical Research Pharmacy or 
designated individual on the study team will check the details of the supplies and 
document receipt on invoice and drug accountability record (DAR). 
2. The Pharmacy will keep study drugs in a locked and secure storage facility, 
accessible only to those individuals authorized by the investigator to dispense this study 
drug. All study drug will be stored separately from any other medications. 
3. The Pharmacy or designee will maintain a temperature log to ensure that study drug 
is stored at manufacturer recommended room temperature at all times. 


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4. The Pharmacy or designated individual will maintain an inventory.  This will include 
the description and quantity of study drug received during the course of this study, as 
well as a record of the materials that are dispensed and returned (how much, to whom, 
and when).  This inventory record shall indicate the quantity and description of all study 
drugs on hand at any time during the course of the study.   
5. At the conclusion or termination of this study, the Pharmacy and investigator agree 
to conduct a final drug supply inventory, to record the results of this inventory and all 
remaining study drug will be destroyed on site per institutional policies. 
6. The investigator agrees not to supply study drug to any person except study 
personnel and subjects in this study. 
5.4 
Storage 
Upon receipt, and to ensure stability of talimogene laherparepvec, vials must be stored 
under the conditions specified below.  
Talimogene laherparepvec is shipped by air courier or truck transit maintained at -70°C 
or below in a qualified shipper suitable for biological substance shipments.  Talimogene 
laherparepvec vials will arrive in a secondary packaging container and should be 
immediately (within 90 seconds) placed in a non-cycling freezer maintained at -70°C or 
below in a secured location until planned use.  The set point for the freezer should be at 
-80°C.  Frost-free, auto defrost freezers must not be used since they cycle to warmer 
temperatures several times a day. 
Table 3   Acceptable Storage Temperature 
 
Talimogene laherparepvec is stable if maintained in accordance with the guidelines 
described in this document and the provided expiration date.   
5.5 
Preparation of Talimogene Laherparepvec 
The following steps should be followed for drug preparation:  
For U.S. sites, the talimogene laherparepvec Safety Data Sheet categorizes the drug as 
a Bio Safety Level (BSL) 1, thus use of BSL 1 containment procedures is 
recommended.  Unless otherwise directed by local regulations: 
• The use of a microbiological safety cabinet or hood for the dispensing of 
talimogene laherparepvec or for dose preparation is not required.  
Freezer Set Point (ºC) 
Acceptable Parameters: Acceptable Range: 
-80°C 
(+/- 10°C) 
-70° to -90°C  


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• 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).   
• Any side room away from other subjects can be used for talimogene 
laherparepvec administration, although local/regional guidelines should be 
followed.  
Please follow local/regional guidelines where applicable. 
Materials Inventory 
• Sterile 18-26 gauge disposable needle(s) to withdraw talimogene 
laherparepvec from vials 
• Appropriately sized sterile syringe(s), based on administration strategy in the 
protocol 
• Laboratory coat, gloves and safety glasses 
• Alcohol swabs 
5.6 
Handling 
Thawing of Frozen Vials  
To ensure proper usage of talimogene laherparepvec at the investigator site, please 
follow the instructions below: 
 
• 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), as per local or BSL classification guidelines. 
 
• Determine which box labeled with the appropriate concentration, 106 PFU/mL or 108 
PFU/mL, is to be prepared  
• Remove the number of frozen vials from the box that have been calculated for 
administration and immediately (within 1 minute) return the remaining vials to the 
freezer.  Care should be taken to avoid unintended thawing of vials that will not be used.   
The time the vials are removed from the freezer must be recorded. 
 
• Thaw frozen vials until liquid at room temperature (20°C to 25°C or 68°F to 77°F).  
Thaw should take approximately 30 minutes.  Please ensure vial is protected from light 
during the thaw process. 
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. 


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• 
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. 
• Refer to Table 4 below for clinical handling storage times. 
• Discard materials used in the thawing (e.g., gloves) following appropriate 
local/regional or BSL classifications guidelines.    
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 appropriate 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 4 below for the Clinical Handling Timelines.  Discard 
any prepared syringes not used for administration within the specific times 
stated.   
 
• Discard materials used in the preparation (e.g., gloves, needles) in accordance 
with local/regional or BSL classification guidelines.   
Table 4: Clinical Handling Timelines 
General product handling considerations 
Thaw 
• Thaw frozen talimogene laherparepvec vials at 20°C to 25°C (68°F to 77°F) 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. 


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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. 
For 106 and 108 PFU/mL 
Thaw requirement Storage of vial from time of 
thaw completion  
Storage of prepared syringe 
from time of draw up from vial 
20°C (68°F) to  
25°C (77°F)  
9°C (48°F) to 
27°C (80°F) 
2°C (36°F) 
to 8°C 
(46°F) 
9°C (48°F) to 
27°C (80°F) 
2°C (36°F) to 
8°C (46°F) 
Thaw until fully 
liquid (approx. 30 
minutes at this 
temperature range 
for both  
106 and 108 
PFU/mL) 
4 hours 
for 106  
PFU/mL¹ 
12 hours for 
106 PFU/mL¹ 
2 hours for 
106 PFU/mL² 
4 hours for 
106 PFU/mL² 
4 hours 
for 108 
PFU/mL¹ 
48 hours for 
108 PFU/mL¹ 
4 hours for  
108 PFU/mL² 
8hours for  
108 PFU/mL² 
1If vial is stored at ambient or refrigerated temperatures after thaw then the IP must be withdrawn from 
the vial and administered immediately.  No syringe storage time is allowed after ambient or refrigerated 
storage in the vial has already occurred. 
2Syringe must be prepared immediately after thaw is complete. Where multiple syringes are being 
prepared then all syringes must be prepared in the minimum necessary time and any delays in 
preparation must be avoided. No thawed vial storage time (outside of time required for preparation of 
syringes) is allowed if syringe storage time is needed. 
 
6.0 
SUBJECT ELIGIBILITY 
Investigators will maintain an electronic subject log (in the UACC OnCore system) of all 
potential (i.e. consented) study subjects, which will include as applicable 


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(demographics, informed consent, eligibility, treatment assignment, on treatment, off 
treatment, follow up and off study dates).  
6.1 
Inclusion Criteria  
a. Able to give informed consent in English or Spanish 
b. Age > 18 
c. Have at least one >0.5 cm to <5.0 cm, histologically confirmed low risk 
cutaneous SCC (including kerathoacanthomas)  
• Size >0.5 cm on trunk or extremities (excluding face, neck feet, nail units, and 
ankles)  
• Clinically consistent with primary tumors. 
• Lesion considered unresectable (as defined in Section 1.2)  
• Recurrent lesions will be considered eligible if additional inclusion criteria are 
met.   
• No immunosuppression 
• Not a site of previous radiation therapy or chronic significant inflammation 
• Fast growing lesions (doubling in size over a 4 week period of time) will be 
included if they are clinically suggestive of cSCC of the keratoacanthoma 
type.  
• Well or moderately differentiated tumor as confirmed by skin biopsy 
• Depth less than 2 mm (for non KA type cSCC ) 
• No perineural or vascular involvement in preliminary biopsy. 
d. Partial biopsy of squamous cell skin cancer identified as a target lesion(s) to 
determine the histological differentiation of the tumor or other adverse 
histological features 
e. In patients with multiple lesions, up to 3 lesions in a similar anatomical site, 
(trunk, limbs etc) that is at least 10 cm apart can be selected.  
f. Maximum of 5 lesions per patient can be selected for treatment 
g. Adequate organ function determined within 28 days prior to enrollment, 
defined as follows: 
h. Hematology: 
• Absolute neutrophil count  ≥ 1500/mm3 (1.5x109/L) 
• Platelet count ≥ 75,000/mm3 (7.5x109/L)      
• Hemoglobin ≥ 8 g/dL (without need for hematopoietic growth factor or 
transfusion support) 
i. Renal 
• Serum creatinine ≤ 1.5 x upper limit of normal (ULN), OR 24-hour creatinine 
clearance ≥ 60 mL/min for subject with creatinine levels > 1.5 x ULN. (Note: 
Creatinine clearance need not be determined if the baseline serum creatinine 
is within normal limits. Creatinine clearance should be determined per 
institutional standard)  
j. Hepatic 
• Serum bilirubin ≤ 1.5 x ULN 
• Aspartate aminotransferase (AST) ≤ 2.5 x ULN 


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• Alanine aminotransferase (ALT) ≤ 2.5 x ULN  
k. Coagulation 
• International normalization ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN, 
unless the subject is receiving anticoagulant therapy, in which case PT and 
partial thromboplastin time (PTT)/ activated PTT (aPTT) must be within 
therapeutic range of intended use of anticoagulants.  
• PTT or aPTT ≤ 1.5 x ULN unless the subject is receiving anticoagulant 
therapy as long as PT and PTT/aPTT is within therapeutic range of intended 
use of anticoagulants. 
l. Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to enrollment. If urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required. 
6.2       Exclusion Criteria: 
a) Any patient with diagnosis of invasive cancer in the last 3 years with the 
exception of stage I and II melanoma, cutaneous BCC and SCCs will be 
excluded. 
b) Subjects on acitretin, capecitabine, topical chemotherapies or treatments. If 
participants have been on acitretin or capecitabine for up to 10 days, then no 
wash out period is required. If they have been on for more than 10 days, then 
they are required to do a wash out period of 30 days.  
c) Subjects on topical skin cancer directed therapies (fluorouracil, levulan-with 
photodynamic therapy, imiquimod, diclofenac, ingenol mebutate) will require a 30 
days wash out window if applied withing the same anatiomic location. If applied 
at other anatomical sites a 10 days wash out  period will be required. 
d) History or evidence of symptomatic autoimmune disease (eg, pneumonitis, 
glomerulonephritis, vasculitis, or other), or history of active autoimmune disease 
that 
has 
required 
systemic 
treatment 
(ie, 
use 
of 
corticosteroids, 
immunosuppressive drugs or biological agents used for treatment of autoimmune 
diseases) in past 2 months prior to enrollment. Replacement therapy (eg, 
thyroxine for hypothyroidism, insulin for diabetes or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a 
form of systemic treatment for autoimmune disease. 
e) Evidence of clinically significant immunosuppression such as the following: 
- 
Primary immunodeficiency state such as Severe Combined Immuno 
deficiency Disease 
- 
Acquired immunodeficiency syndrome 
- 
Concurrent opportunistic infection 
- 
Receiving systemic immunosuppressive therapy (> 2 weeks) including oral 
steroid doses > 10 mg/day of prednisone or equivalent  within 2 months prior 
to enrollment. 
f) Active herpetic skin lesions or prior complications of herpetic infection 
(e.g., herpetic keratitis or encephalitis). 


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g) Requires intermittent or chronic systemic (intravenous or oral) treatment with an 
antiherpetic drug (e.g., acyclovir), other than intermittent topical use. 
h) Previous treatment with talimogene laherparepvec or any other oncolytic virus 
i) Prior therapy with tumor vaccine 
j) Received live vaccine within 28 days prior to enrollment. 
k) Currently receiving treatment with another investigational device or drug study, or 
< 28 days since ending treatment with another investigational device or drug 
study(s) 
l) Other investigational procedures while participating in this study are excluded. 
m) Known to have acute or chronic active hepatitis B infection 
n) Known to have acute or chronic active hepatitis C infection 
o) History of other malignancy within the past 3 years with the following exceptions: 
- 
adequately treated mucosa associated lymphoid tissue (MALT) tumor 
- 
malignancy treated with curative intent and with no known active 
disease present for ≥ 3 years before enrollment and felt to be at low 
risk for recurrence by the treating provider 
- 
adequately treated non-melanoma skin cancer, lentigo maligna, stage I 
or II cutaneous melanoma,  without evidence of disease. 
- 
adequately treated cervical carcinoma in situ without evidence of 
disease 
- 
adequately treated breast ductal carcinoma in situ without evidence of 
disease 
- 
prostatic intraepithelial neoplasia without evidence of prostate cancer 
- 
adequately treated urothelial papillary noninvasive carcinoma or 
carcinoma in situ 
p) Subject has known sensitivity to talimogene laherparepvec or any of its 
components to be administered during dosing. 
q) Female subject is pregnant or breast-feeding, or planning to become pregnant 
during study treatment and through 3 months after the last dose of talimogene 
laherparepvec  
r) Female subject of childbearing potential who is unwilling to use acceptable 
method(s) of effective contraception during study treatment and through 
3 months after the last dose of talimogene laherparepvec. (Note: Women not of 
childbearing potential are defined as: Any female who is post-menopausal [age > 
55 years with cessation of menses for 12 or more months or less than 55 years 
but not spontaneous menses for at least 2 years or less than 55 years and 
spontaneous menses within the past 1 year, but currently amenorrheic (eg, 


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spontaneous or secondary to hysterectomy), and with postmenopausal 
gonadotropin levels (luteinizing hormone and follicle-stimulating hormone levels > 
40 IU/L) or postmenopausal estradiol levels (< 5 ng/dL) or according to the 
definition of "postmenopausal range" for the laboratory involved] or who have 
had a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).  
s) Sexually active subjects and their partners unwilling to use male latex condom to 
avoid potential viral transmission during sexual contact while on treatment and 
within 30 days after treatment with talimogene laherparepvec. 
t) Subject who is unwilling to minimize exposure with his/her blood or other body 
fluids to individuals who are at higher risks for HSV-1 induced complications such 
as immunosuppressed individuals, individuals known to have HIV infection, 
pregnant women, or children under the age of 1 year, during talimogene 
laherparepvec treatment and through 30 days after the last dose of talimogene 
laherparepvec. 
 
6.3 
Enrollment  
All subjects who complete the screening period of the study will be enrolled and 
assigned a unique sequential subject identification number. This number will be used to 
identify the subject throughout the clinical study and will be used on all applicable study 
documentation related to that subject. The subject identification number will remain 
constant throughout the study. 
 
The written informed consent document(s) must be signed and personally dated by the 
subject or by the subject’s legally authorized representative and completed to a fully 
executed informed consent document and processed per the institution standard 
operating procedures. 
 
 
Before subjects may be entered into the study, a copy of the written institutional  review 
board (IRB) approval of the protocol, informed consent form (ICF), and all other 
applicable subject information and/or recruitment material must be on file at the 
institution.  
7.0 
STUDY PLAN 
7.1 
IP/treatment regimen 
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 5. The maximum dose to be given is 4.0 ml per 
injection visit. 


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Table 5:  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 
> 0.1 to 0.5 cm 
0.1 mL 
7.2 
Pre-medications 
There are no medications that need to be taken before the injections however the 
patient will be given the choice to take Ibuprofen or acetaminophen prior to the 
injections. 
7.3 
Rescue Medications – Not applicable 
7.4 
Excluded medications/treatments  
The following medications and treatment are excluded during the entire study 
participation including follow up visits. 
• Oral medications: Acitretin, xeloda, vismodegib, and niacin/nicotinamide (see 
wash out periods for certain medications).  
• Topical medications at the anatomical study site: fluorouracil, levulan (with 
photodynamic therapy), imiquimod, diclofenac, ingenol mebutate. 
• Injectable medications: Fluorouracil (Adrucil) on the anatomical area of the 
targeted cSCC) during active participation in the study. 
Subjects can re-initiate systemic intervention once Visit 8 is completed. 
8.0 
REQUIREMENTS FOR TREATMENT  
8.1 
Standard dose use  
 
The standard dose for the study will be according to the dosing chart listed as Table 4 
under 7.1. The maximum total dose will be 4mL per injection visit.  
8.2 
Dose 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 (defined in dosing section) 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 


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adverse event such as pain, the total volume given should be recorded, and the reason 
for intolerance should be documented as an adverse event. 
8.3 
IP treatment delays 
If an unexpected DLT occurs, talimogene laherparepvec administration should be 
delayed until the DLT has resolved to at least CTCAE version 4.0 Grade 1.  If 
talimogene laherparepvec dosing is delayed by more than 6 weeks from the date of the 
planned dose due to the occurrence of an adverse event that is considered related to 
talimogene laherparepvec, the subject should be permanently taken off talimogene 
laherparepvec treatment. 
8.4 
Adverse Drug Reactions (ADRs)  
 
Important Identified Risks 
Important Identified Risks with talimogene laherparepvec treatment are listed below.  
Consult the current Investigator’s Brochure (IB) for the full information on the Identified 
and Potential Risks of talimogene laherparepvec. 
• Disseminated herpetic infection including serious cases of disseminated 
herpetic infection, have been reported in patients treated with talimogene 
laherparepvec.  
• Accidental exposure of healthcare providers (HCP) to talimogene 
laherparepvec. 
• Immune-mediated adverse reactions  
 
Important Potential Risk 
 
Important Potential Risks with talimogene laherparepvec treatment are listed below.  
Consult the current Investigator’s Brochure (IB) for the full information on the Identified 
and Potential Risks of talimogene laherparepvec. 
• Transmission of talimogene laherparepvec from patient to close contacts 
or HCPs via direct contact with injected lesions or body fluids resulting in 
symptomatic infection (primary or reactivation). 
• Symptomatic herpetic infection due to latency and reactivation of 
talimogene laherparepvec or wild-type HSV-1 in patients. 
• Talimogene laherparepvec-mediated anti-GM-CSF antibody response. 
 


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Adverse drug reactions observed in talimogene laherparepvec clinical trials are listed 
below in Table 6. Consult the current Investigator’s Brochure for the full information on 
ADRs.  
 
Table 6. ADRs Observed in Talimogene Laherparepvec Clinical Trials  
 
 
 
CIOMS Frequency 
 
 
(Very Common: ≥10% 
System Organ Class 
    Preferred Term 
Common: 1%-<10% 
Uncommon: <1%) 
General disorders and administration 
site conditions 
  
    Fatigue 
Very Common 
    Chills 
Very Common 
    Pyrexia 
Very Common 
    Influenza like illness 
Very Common 
    Malaise 
Common 
    Axillary pain 
Common 
    Injection site reactions* 
Very Common 
Gastrointestinal disorders 
  
    Nausea 
Very Common 
    Vomiting 
Very Common 
    Diarrhea 
Very Common 
    Constipation 
Very Common 
    Abdominal pain 
Common 
    Abdominal discomfort 
Common 
Musculoskeletal and connective tissue 
disorders 
  
    Myalgia 
Very Common 
    Arthralgia 
Very Common 
    Pain in extremity 
Very Common 
    Groin pain 
Common 
Skin and subcutaneous tissue 
disorders 
  
    Vitiligo 
Common 
    Rash 
Common 
    Dermatitis 
Common 
Infections and infestations 
  
    Cellulitis 
Common 
    Oral herpes 
Common 
    Incision site infection 
Uncommon 
Nervous system disorders 
  
    Headache 
Very Common 
    Dizziness 
Common 
Eye disorders 
 
   Herpetic keratitis 
Uncommon 


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CIOMS Frequency 
 
 
(Very Common: ≥10% 
System Organ Class 
    Preferred Term 
Common: 1%-<10% 
Uncommon: <1%) 
Respiratory, thoracic and mediastinal 
disorders 
  
    Oropharyngeal pain 
Common 
    Obstructive airway disorder 
Uncommon 
Metabolism and nutrition disorders 
  
    Dehydration 
Common 
Injury, poisoning and procedural 
complications 
  
    Contusion 
Common 
    Procedural pain 
Common 
    Wound complication 
Common 
    Wound secretion 
Common 
Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) 
  
    Tumour pain 
Common 
    Infected neoplasm 
Common 
    Plasmacytoma at the injection site 
Uncommon  
Investigations 
  
    Weight decreased 
Common 
Vascular disorders 
  
    Deep vein thrombosis 
Common 
    Flushing 
Common 
Blood and lymphatic system disorders 
  
    Anemia 
Common 
Immune system disorders  
 
   Worsening psoriasis 
Uncommon 
   Pneumonitis 
Uncommon 
   Glomerulonephritis 
Uncommon 
   Vasculitis 
Uncommon 
* Injection site reactions include: very common term of injection site pain, common terms of injection 
site erythema, injection site hemorrhage, injection site swelling, injection site reaction, injection site 
inflammation, secretion discharge, injection site discharge, uncommon term of injection site warmth. 


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Treatment of ADRs 
 
Subjects will receive medical treatment if injured as a result of study participation. The 
principal investigator and staff will help the participant get medical care for associated 
adverse events.  The subject or the subject’s insurance will be charged for that 
treatment. The study will not provide monetary compensation for medical treatment. 
Subjects do not lose legal rights to seek payment by signing the consent form. All 
reported ADRs will be documented according to safety monitoring and reporting 
standards (See Section 11 and 12).  
 
8.5 
Definition of a Dose Limiting Toxicity (DLT) 
Definitions of dose-limiting toxicity: 
Toxicity will be evaluated according to CTCAE version 4.0. DLT will be defined as any 
of the following talimogene laherparepvec-related toxicity during treatment and up to 30 
days after end of treatment.  
The following herpetic events should be considered as DLTs: 
• Serious herpetic events such as herpetic encephalitis, encephalomyelitis or 
disseminated herpetic infection. 
• Any herpetic events (with the exclusion of oral and genital outbreaks) that are at 
least possibly due to talimogene laherparepvec and 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. 
 
Consider also including the following as DLTs: 
• Grade 3 or greater immune-mediated adverse events. 
• Any grade plasmacytoma at or near the injection site or evidence of impaired 
wound healing at the injection site. 
• Grade 3 or greater allergic reactions considered at least possibly related to 
talimogene laherparepvec. 
• Grade 4 non-hematologic toxicity. 
• Grade 3 non-hematologic toxicity lasting > 3 days despite optimal supportive 
care; 
o Grade 3 fatigue will not be classified as DLT, irrespective of duration. 
• Any Grade 3 or higher non-hematologic laboratory value if: 
o medical intervention is required, or 
o the abnormality leads to hospitalization, or 
o the abnormality persists for > 1 week unless deemed not clinically 
important per both investigator and sponsor. 
• Grade 3 or 4 febrile neutropenia. 


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• Grade 4 thrombocytopenia associated with bleeding event requiring intervention. 
• Any other intolerable toxicity leading to permanent discontinuation of talimogene 
laherparepvec. 
• Grade 5 toxicity (ie. death). 
 
9.0     STUDY PROCEDURES  
9.1 
Screening- Visit 0 
Potential subjects will enter the screening period of the study after a completely 
executed informed consent has been obtained.  
 
• Review of inclusion/exclusion criteria  
 
• Medical and medication history and dermatological history review 
  
• Skin check by the study provider  
 
• Urine pregnancy test (72 hours before enrollment) 
 
• Screening blood work to include a complete blood count (CBC), comprehensive 
metabolic panel (CMP) and pregnancy test (hCG) if urine pregnancy test comes 
back positive or inconclusive 
 
• Identification of the target lesions for the study. One subject can have up to 5 
TILs. One to three TILs may be on the same anatomical area but will need to be 
10 cm apart. Up to 10 TNILs can be followed with no more than 2 TNILs selected 
in the same anatomical area as a TIL.  
 
• Photographing and measuring of the target lesions 
 
• Biopsy of any suspected non-target skin cancers (ie BCC). If a non-SCC skin 
cancer is confirmed the corresponding treatment should be completed prior to 
initiation of study intervention. 
 
• Partial biopsy of lesions suspicious for cSCC (both TILs and TNILs) that have not 
already been biopsied. A partial shave or small punch biopsy may be done to 
sample the tissue.  
 
• Vital signs obtained to include blood pressure, pulse, temperature, height and 
weight 
 
• Ultrasound of TILs at Radiology Department for baseline evaluation (Appendix B) 
 
• Assign screening number starting with the 2-digit site number followed by SCC 


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and a 3-digit sequential number, starting with -001 and increasing by one for 
each subject. If a subject fails the screening visit they may be replaced by an 
additional subject. 
9.2 
Enrollment- Visit 1 
• See 9.3 for enrollment visit details 
9.3 
On IP treatment 
Registered subjects will be treated with talimogene laherparepvec based on lesion size, 
administered at of 106 (1 million) PFU/mL administered intralesionally for the first visit 
and 108 (100 million) PFU/mL administered intralesionally for subsequent visits (V2-4). 
A full description of treatment plan and dosing is outlined in sections 2.4 and 7.1. 
 
Visit 1- First injection visit (7 - 28 days +/- 3 days) 
• Skin exam only of target lesions 
• Review of all blood work and confirmation to continue in the study 
• Review of the biopsies of SCC lesions to confirm SCC diagnosis 
• Assess adverse events 
• Assess con med changes 
• Complete inclusion/exclusion criteria 
• Assign subject study number starting with SCC-01 and continue to be assigned 
sequentially 
• Vital signs  
• Photograph and measure all target lesions (Appendix A) 
• Inject TILs  
• Provide patient education on any side effects to expect and the treatment of the 
injected sites 
• Schedule the next injection visit in 3 weeks 
 
Visit 2- Second injection visit (21 days +/- 3 days) 
• Vital signs  
• Review con meds 
• Assess for any adverse events 
• Skin exam only of target lesions 
• Photograph and measure all target lesions (Appendix A) 
• Inject TILs  
• Provide patient education on any side effects to expect and the treatment of the 
injected sites 
• Schedule the next injection visit in 2 weeks 
Visit 3- Third injection visit (14 +/- 3 days) 
• Vital signs  
• Review con meds 


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• Assess for any adverse events 
• Skin exam only of target lesions 
• Photograph and measure all target lesions (Appendix A) 
• Inject TILs  
• Provide patient education on any side effects to expect and the treatment of the 
injected sites 
• Complete bloodwork (CBC, CMP) 
• Schedule the next injection visit in 2 weeks.  
 
Visit 4- Fourth injection visit (14 +/- 3 days) 
• 
Vital signs  
• 
Review con meds 
• 
Assess for any adverse events 
• 
Skin exam only of target lesions 
• 
Photograph and measure all target lesions (Appendix A) 
• 
Inject TILs  
• 
Provide patient education on any side effects to expect and the treatment of the 
injected sites 
• 
Schedule the first follow up visit in 4 weeks. 
 
Visit 5- First follow up visit (28 +/- 7 days) 
• 
Vital signs  
• 
Review con meds 
• 
Assess for any adverse events 
• 
Skin exam only of target lesions 
• 
Photograph and measure all target lesions (Appendix A) 
• 
Schedule the second follow up visit in 4 weeks 
 
Visit 6- Second follow up visit (28 +/- 7 days) 
• 
Vital signs  
• 
Review con meds 
• 
Assess for any adverse events 
• 
Skin exam only of target lesions 
• 
Photograph and measure all target lesions (Appendix A) 
• 
Ultrasound of TILs at Radiology Department for follow-up evaluation(Appendix B) 
• 
Schedule the third follow up visit in 6 weeks 
 
Visit 7- Third follow up visit (42 +/- 10 days) 
• 
Vital signs  
• 
Review con meds 
• 
Assess for any adverse events 
• 
Skin exam only of target lesions 
• 
Photograph and measure all target lesions (Appendix A) 
• Schedule the next follow up visit in 14 weeks. 
Visit 8 - Fourth follow up visit (98 +/- 21 days) 


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• 
Vital signs  
• 
Review con meds 
• 
Assess for any adverse events 
• 
Skin exam only of target lesions 
• 
Photograph and measure all target lesions (Appendix A)  
 
Visit 9 – Telephone Follow up (356 +/- 31 days) after Visit 1 
• 
Assess for changes of target lesions 
• 
If active lesion(s) are noted by the participant, they will follow up with a 
dermatologist and their records will be requested 
9.4 
Study Assessments 
9.4.1 Tumor Measurements: 
Tumor measurements will be done at each visit. Imaging assessment with high 
frequency ultrasound will be done at baseline and at the second follow-up visit (Visit 6). 
At baseline, up to 5 TILs that are at least 10cm apart will be selected to be followed over 
the course of the study. Up to 10 TNILs can be followed with no more than 2 TNILs 
selected in the same anatomical area as a TIL.  Responses in TILs and TNILs will be 
measured serially. Clinical measurements will be performed with a millimeter measuring 
tape (Appendix A). All measurements will be selected that will be able to be followed 
clinically and for ultrasound evaluations.  The RECIST 1.1 (Appendix B) response 
criteria will be used to evaluate tumor response. Individual tumor measurements will 
also be conducted to determine clinical management of TILs and TNILs. The timeframe 
for the clinical (primary endpoint) and evaluation will be at Visit 6 and for high-frequency 
ultrasound (secondary endpoints) at Visit 6 as well.  
9.4.1.1 Tumor Response 
Complete Response (CR): Complete disappearance of all TILs (whether 
measurable or not, and no new lesions at the site of injection) confirmed by an 
assessment 8 weeks after the end of the injections (Visit 6).  
 
Partial Response (PR): Decrease in tumor burden ≥ 30% relative to baseline 
confirmed by an assessment 8 weeks after the end of the injections (Visit 6). 
 
Duration of Overall Response (DOR): DOR is when the time measurement 
criteria are met for CR or PR (whichever status is recorded first) until the first date 
that recurrence or progressive disease (PD) is objectively documented, taking as 
reference for PD the smallest measurements recorded since the treatment started. 
If no recurrence or PD is documented after PR or CR is observed the time 
measurement will be performed at Visit 6 for PR and Visit 8 for CR. 
 
Durable Response Rate (DRR): Measured from the time measurement criteria are 
met for CR or PR (whichever status is recorded first) with the response lasting 
continuously for > than or equal to 6 months. For PD, the reference will be the 


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smallest measurements recorded since the treatment started. 
 
Time to progression (TTP):  This will be measured from the time treatment is 
initiated until the first date that recurrence or progressive disease (PD) is objectively 
documented, taking as reference for PD the smallest measurements recorded since 
the treatment started.  
 
Progressive Disease (PD):  Progression is defined as >20% increase of at least 5 
mm in the sum of the longest diameters of the target lesions or increase in tumor 
burden ≥ 20% relative to nadir (minimum recorded tumor burden) or the 
appearance of one or more new lesions confirmed by an assessment 8 weeks after 
the end of the injections (Visit 6).  
• Rapid PD (RPD): Is defined as an increase of >50% in tumor burden for 
lesions >2 cm in diameter or 100% tumor burden increase for lesion ≤2cm 
between visits. 
 
Stable Disease (SD): Not meeting criteria for CR or PR, in absence of PD 
(Decrease of tumor size <30% to increase in size <20% of less than 5 mm in the 
sum of the longest diameters of the target lesions).  
 
9.4.1.2 Clinical Management of TILs and TNILs 
Along with assessing the overall tumor response (see Section 9.4.1.1, Tumor 
Response), each individual lesion will be assessed to determine appropriate clinical 
management. The RECIST 1.1 (Appendix B) response criteria will also be used to 
evaluate each individual tumor response.  
 
Individual Lesion Complete Response (IL-CR): Complete disappearance of 
target lesion (whether measurable or not, and no new lesion(s) at the site of the 
target lesion) confirmation by an assessment 8 weeks after the end of the injections 
(Visit 6).  
 
Individual Lesion Partial Response (IL-PR): Decrease in tumor burden ≥ 30% 
relative to baseline confirmed by an assessment 8 weeks after the end of the 
injections (Visit 6). 
 
Individual Lesion Progressive Disease (IL-PD):  Progression is defined as >20% 
increase of at least 5 mm in the sum of the longest diameters of the target lesions 
or increase in tumor burden ≥ 20% relative to nadir (minimum recorded tumor 
burden) or the appearance of one or more new lesions confirmed by an 
assessment 8 weeks after the end of the injections (Visit 6).  
• Individual Lesion Rapid PD (IL-RPD): Is defined as an increase of >50% in 
tumor burden for lesions >2 cm in diameter or 100% tumor burden increase 
for lesion ≤2cm between visits. 
 
Individual Lesion Stable Disease (IL-SD): Not meeting criteria for CR or PR, in 


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Individual Lesion 
Complete Response 
(IL-CR) 
Individual 
Lesion Partial 
Response (IL-
PR) 
Progressive Disease 
(PD) 
Stable Disease 
(SD) 
TILs 
• IL-CR to be 
determined at the 
latest by Visit 6 (8 
week follow up), and 
will be followed for 6 
months 
• No additional 
injections will be 
given to TILs who 
have achieved IL-CR 
prior to the 4th 
injection visit 
• If recurrent at any 
point after IL-CR has 
been documented, 
then alternative 
therapeutic 
intervention offered 
(surgical excision, 
radiation, intralesional 
therapy etc.) based 
on patient preference 
• IL-PR will be 
followed and 
assessed at 
Visit 6 (8 week 
follow up)  
• If IL-SD is 
documented at 
Visit 6 or 
beyond, 
alternative 
therapeutic 
intervention will 
be offered 
• If IL-PR 
continues, TIL 
will be closely 
followed until 
Visit 8, where 
alternative 
therapeutic 
intervention will 
then be offered 
 
• If IL-PD confirmed in 
two consecutive visits 
OR at Visit 6 (8 week 
follow up), TIL will be 
withdrawn and 
alternative therapeutic 
intervention given 
o If subject has 
additional TILs, will 
continue study 
participation 
o If subject has only 
one, subject will be 
withdrawn 
• If IL-RPD occurs, 
treatment will be 
deferred that visit and 
will be reevaluated 
next visit.  
o If IL-PD confirmed, 
lesion withdrawn 
from study and 
alternative 
therapeutic 
intervention 
o If subject has more 
than one TIL, then 
lesions will continue 
to be a part of the 
study 
 
• IL-SD will be 
followed and 
assessed up to 
Visit 6 (8 week 
follow up)  
• Alternative 
therapeutic 
intervention will 
be offered if no 
IL-CR or IL-PR 
is observed by 
Visit 6.  
TNILs 
• IL-CR to be 
determined at the 
latest by Visit 6 (8 
week follow up), and 
will be followed for 6 
months 
• If recurrent at any 
• IL-PR will be 
followed and 
assessed up to 
Visit 6 (8 week 
follow up)  
• Alternative 
therapeutic 
• IL-PD at Visit 3 will 
undergo alternative 
therapeutic 
intervention 
• IL-SD will be 
followed and 
assessed up to 
Visit 6 (8 week 
follow up)  
• Alternative 
therapeutic 
absence of PD (Decrease of tumor size <30% to increase in size <20% of less than 
5 mm in the sum of the longest diameters of the target lesions).  
 
Table 7. Management of individual TILs and TNILs 


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point after IL-CR has 
been documented at 
Visit 6, then 
alternative 
therapeutic 
intervention offered 
intervention will 
be offered if no 
IL-CR is 
observed by 
Visit 6 
intervention will 
be offered if no 
IL-CR is 
observed by 
Visit 6 
 
9.4.2 High Resolution Ultrasonography of Squamous Cell Cancer: 
The subjects will complete ultrasound assessments of their lesions at screening Visit 
(0), and at Visit 6 (second follow up visit). 
 
METHOD: 
Focused high frequency ultrasound of the skin lesion will be performed in department of 
medical imaging using clinical ultrasound equipment LOGIQ E9 (GE Healthcare, 
Milwaukee, WI) and S-3000 (Acuson; Siemens Medical Solutions, Mountain View, CA). 
Linear array transducers with upper frequencies of 8-18 MHz and 6-18 (5-14) MHz 
respectively utilized to obtain sonograms. Imaging will be performed using either custom 
made gel standoff pad or copious amount of cold ultrasound gel acting as standoff, 
especially in body parts where gel pad could potentially cause image degradation due to 
poor apposition. Scanning will be done gently without compression to avoid distortion of 
superficial lesions. Two-dimensional B-mode images will be acquired following 
transverse and longitudinal sweeps from right to left and from top to bottom. The 
ultrasound probe will be oriented along the longest dimension of the lesion to obtain 
sagittal and transverse measurements of the cancer. Calculations of lesion depth will be 
made at the deepest extension of the mass in either plane. Duplex Doppler will be used 
to evaluate tumor vascularity; spectral wave pattern and Doppler measurements will 
also be obtained.  
The subjects will receive ultrasound assessments of their TILs at screening visit (0), and 
at visit 6 (first follow up visit). 
 
IMAGE INTERPRETATION: 
Normal anatomy: The three layers of skin, epidermis (thickness 0.06-0.6 mm), dermis 
(thickness 1-4 mm) and hypodermis (subcutaneous tissues; thickness 5-20 mm) can be 
visualized on high frequency ultrasound.  The epidermis appears as the most 
superficial, well defined, hyperechoic, linear band producing the “entry echo” between 
the ultrasound gel and skin, which can be called as epidermal entry echo (EEE). Dermal 
layer below the epidermis is also hyperechoic, usually less echogenic than epidermis 
with hair follicles, vessels, and sebaceous glands appearing as hypoechoic areas within 
it. The hypodermis or subcutaneous tissue layer is hypoechoic with intervening 
hyperechoic connective tissue septa separating fat lobules. Underneath the skin, 
superficial fascia covering muscle may be identified linear hyperechoic structure (1, 2). 
Squamous cell carcinoma (SCC) is the second most common cancer of the skin after 
basal cell cancer which has a major tendency for local relapse and regional nodal 
involvement. Tumor infiltrates into the surrounding soft tissues, cartilage and bone. 
Sonographic appearance of SCC reveals inhomogeneous hypoechoic lesion with 


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marginal irregularities; Doppler may show the presence of low-resistance pulsatile flow 
signals within or at the periphery of the tumor. However, it could be challenging to 
image the cancer in presence of hyperkeratotic epidermis which leads to reflection and 
attenuation of the ultrasound waves. 
 
Following treatment anticipatory Sonographic changes in the lesion are expected with 
loss of inhomogeneous hypoechogenecity and reduced Doppler flow. The cancer may 
become progressively isoechoic with loss of conspicuity.  
 
9.4.3 Chart Review: Frequency of Nonmelanoma Skin Cancers (NMSCs) 
Participants’ charts will be reviewed to assess the number of nonmelanoma skin 
cancers before and after the intervention. The frequency of NMSCs before the 
intervention will include the 12 months before Visit 1 and the 24 months before Visit 1 if 
available. The frequency of NMSCs after the intervention will include the 12 months 
after the last injection visit (or Visit 4) and then 24 months after the last injection (or Visit 
4) if available. This exploratory objective is an effort to quantify the abscopal effect 
those participants may experience.  
9.5 
End of IP treatment 
 
Subjects that complete the planned treatment portion of the study will have move into 
the follow up period. 
9.5.1    Follow up 
Visit 5- First follow up visit (28 +/- 7 days)  
• 
Vital signs  
• 
Review con meds 
• 
Assess for any Adverse Events 
• 
Skin exam limited to all target lesions 
• 
Photograph and measure target lesions (Appendix A) 
• 
Schedule the next follow up visit in 4 weeks. 
 
Visit 6- Second follow up visit (28 +/- 7 days) 
• 
Vital signs  
• 
Review con meds 
• 
Assess for any Adverse Events 
• 
Skin exam limited to all target lesions  
• 
Photograph and measure target lesions (Appendix A) 
• 
Schedule second ultrasound to be completed on TILs before next follow up visit 
• 
Schedule the next follow up visit in 6 weeks. 
 
Visit 7- Third follow up visit (42 +/- 10 days)  
• 
Vital signs  
• 
Review concurrent meds 


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• 
Assess for any Adverse Events 
• 
Skin exam limited to all target lesions  
• 
Photograph and measure target lesions (Appendix A) 
• 
Schedule the next follow up visit in 14 weeks. 
Visit 8 - Fourth follow up visit (98 +/- 21 days)  
• 
Vital signs  
• 
Review con meds 
• 
Assess for any adverse events 
• 
Skin exam limited to all target lesions  
• 
If sites are free of disease, participant participation will be complete 
• 
Photograph and measure target lesions (Appendix A) 
• 
Complete subject payment form 
 
Visit 9 – Telephone Follow up (356 +/- 31 days) after Visit 1 
 
• 
Assess for changes of target lesions 
• 
If active lesion(s) are noted by the participant, they will follow up with a 
dermatologist and their records will be requested 
 
9.6 
Early Treatment Termination 
Subjects that terminate IP treatment prior to completing the planned treatment portion of 
the protocol will have an early termination visit within 30 days of ending the treatment 
portion of the study.  Subjects will have a termination visit with the following procedures 
completed: 
  
• Vital signs  
• Review concurrent meds 
• Assess for any Adverse Events 
• Skin exam limited to all target lesions  
• Photograph and measure Target lesions 
• Complete bloodwork (CBC, CMP) 
• Complete subject payment form 
9.7 
Offset Range (or Treatment Window) 
The range of days when a treatment can be given.  
• 
Visit 1 - 4: (+/-) 3 days 
• 
Visit 5 - 6: (+/-) 7 days 
• 
Visit 7: (+/-) 10 days 
• 
Visit 8: (+/-) 21 days 
• 
Visit 9: (+/-) 31 days 


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9.8 
Off Study 
Subjects will be considered off study when all planned treatment, early termination and 
follow-up visits have been completed, unless death or withdrawal of consent to continue 
participation occurs.  
10.0 PHARMACOKINETIC STUDIES- Not for this study 
10.1 Collection 
10.2 Processing 
10.3 Storage 
10.4 Destruction 
11.0 DATA AND SAFETY MONITORING PLAN 
11.1 Identification of the DSMB obligated for oversight responsibilities 
The University of Arizona Cancer Center Data Safety and Monitoring Board (DSMB) will 
provide ongoing oversight for this trial. This study has been assigned a high risk level by 
the DSMB. 
11.2 Identification of the entity obligated for routine monitoring duties 
Routine monitoring will be provided by the University of Arizona Cancer Center Quality 
Assurance/Quality Control (QA/QC) Program to ensure that the investigation is 
conducted according to protocol design and regulatory requirements. 
 
This trial will also undergo real-time monitoring by the PI and study team, including 
documentation of real-time monitoring of any new or ongoing safety issues and regular 
meetings every month with the study team to review data and safety events.  For 
individual participants, adverse events will be assessed every 4 weeks by the study 
coordinator according to the assessment schedule. A study-specific adverse event log 
will be reviewed and signed every four weeks by the PI. The PI will review all severe 
adverse events within 24 hours of reporting.  
 
11.3 Monitoring progress and data review process 
Routine monitoring of subject data will be conducted at least every month.  
The first routine monitoring visit will include at a minimum: 
• Informed consent – 100% of cases enrolled;  
• Subject eligibility – 100% of cases, up to three subjects; 


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• Data review – 100% of cases, up to three subjects. 
 
All subsequent monitoring visits will consist of randomly selected subject cases 
based on current enrollment and include continuing review of previously selected 
cases, as applicable. 
 
A monitoring visit report and follow-up letter will be completed approximately two 
weeks after the routine monitoring visit; a copy will be maintained in the study 
file. A query/finding form or an electronic record will also be completed by the 
monitor to request additional source documentation, clarification, information or 
corrections to the OnCore CRF and/or regulatory records. The Clinical Research 
Coordinator or other applicable staff responsible for the study will be given a 
copy of this form, or will be notified of the electronic record for resolution of 
queries/findings. The query/finding form will be maintained with a copy of the visit 
report for follow-up at the next monitoring visit. Electronic records will be 
available in the institution database or provided by the QA/QC Program staff.  
 
The Principal Investigator will ensure the accuracy, completeness, legibility and 
timeliness of the data reported in the OnCore Case Report Form (CRF), or other 
acceptable data formats. Source documentation supporting the study data should 
indicate the subject’s participation in the trial and should document the dates and 
details of study procedures, adverse events, and patient status.  
 
Case report forms, which include the inclusion/exclusion criteria form, adverse 
event forms and serious adverse event forms [other forms, depending on study] 
should be completed via the institution database or other acceptable data 
formats. All subject forms and study files will be stored in a secure area limited to 
authorized staff. 
 
Note: Routine monitoring of regulatory documents and test article will be 
conducted every three months. 
 
11.4 Process to implement study closure when significant risks or benefits are 
identified 
The PI will be advised of all study related AEs and will determine if the study at a 
certain point may need to be closed due the AEs.  
Study stopping criteria will include the following:  
• Death within 30 days after the investigational treatment at least possibly 
related to the study treatment. 
• Any herpetic event or complication requiring hospitalization that is at least 
possibly related to the investigational agent within 30 days to treatment. 


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Individual treatment stopping criteria will include the following:  
• 75% or greater number of TILs meeting criteria for withdrawal. 
• Identification of high-risk feature in one or more TILs during study 
participation.  
• Persistent discomfort (consecutive weeks of lesion pain, burning, or itching of 
Grade 2 or more). 
11.5 Description of adverse events and reporting procedures 
 
ADVERSE EVENTS  
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.  
 
Any and all adverse events will be recorded on the UMC adverse events record 
form and reviewed by the Principal Investigator. 
 
All adverse events will be classified using either the MedDRA term or NCI 
Common Terminology Criteria for Adverse Events (CTCAE) 4.0 and will address: 
• Grade 
• Relationship to study drug (not related, unlikely, possible, probable, definitely)  
• Causality other than study drug (disease related, concomitant medication 
related, intercurrent illness, other)   
• Date of onset, date of resolution 
• Frequency of event (single, intermittent, continuous) 
• Event outcome (resolved, ongoing, death) 
• Action taken (none, held, dose reduced, discontinued, medication given) 
 
 
SERIOUS ADVERSE EVENTS 
 
A serious adverse event (SAE) is any untoward medical occurrence that at 
 
any dose:  
 
1) Results in death;  
 
2) Is life-threatening; 
3) Requires in-patient hospitalization or prolongation of an existing hospital stay;  
 
4) Results in disability persistent or significant disability/incapacity, or: 
 
5) Is a congenital anomaly/birth defect.  
 
Note: A SAE may also be an important medical event, in the view of the investigator 
that requires medical or surgical intervention to prevent one of the outcomes listed 
above.  
 


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All serious adverse events, regardless of attribution, and any deaths will be reported 
within 24 hours of notification of the event to the sponsor and, if applicable, any 
collaborating entity. All serious adverse events and any deaths will be reported to the 
DSMB and to the University of Arizona Human Subjects Protection Program per the 
guidelines set forth in University of Arizona Cancer Center Data and Safety Monitoring 
Board Charter, Table 5: Adverse Event Reporting.  
 
 
All serious adverse events will be processed by the DSMB Coordinator monthly for 
initial trend analysis and fully reviewed by the DSMB, every three months. The DSMB 
coordinator will review the SAE reporting process to confirm reporting requirements are 
met. 
11.6 Plan for assuring data accuracy and protocol compliance 
Routine study activity and safety information will be reported to the DSMB on a 
monthly basis, or more frequently if requested. These reports will include: 
• Study activity, cumulative and for the period under review; 
• Safety (narrative description on non-serious and serious adverse events, 
protocol pre-determined early stopping rules for safety or treatment-emergent 
adverse events); 
• Predetermined protocol early stopping rules for efficacy/futility;  
• Status of study in relationship to stopping rules;   
• Current dose level of study agent;  
• Routine monitoring and protocol compliance (describe the monitoring process 
and identify the status of the monitoring); 
• Comments;  
• Attachments (AE data reviewed by the PI to compile the report, SAE letters 
and reports, results of any review(s), applicable correspondence with the IRB 
or other regulatory agencies 
 
 
Data, safety and study progress will be reported to: 
• Human Subjects Protection Program (IRB) at least annually; 
• Sponsor (if applicable) at least quarterly. 
11.7 Identification of the sponsor or funding agency, as applicable 
The PI will immediately notify; in writing, the funding agency, if applicable, any 
action resulting in a temporary or permanent suspension of the study. 
A copy of this correspondence will also be forwarded to the DSMB and the SRC.  
12.0 ADDITIONAL SAFETY REPORTING REQUIREMENTS  
Safety Reporting to Amgen  
The Investigator is responsible for compliance with expedited reporting 
requirements for serious, unexpected and related adverse events (SUSARs), for 


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generation of SAE reports including narratives, and for periodic reporting to Amgen 
of SAEs as outlined in Table 8 and Table 9 below.  Individual safety reports (Table 
8) should be accompanied by the Fax Cover Form provided in Appendix C, and 
sent to Amgen Global Safety, utilizing the fax or email information provided on the 
cover page.  Aggregate safety reporting (Table 9) including listings, tabulations and 
summary reports should be scanned and accompanied by the Fax Cover Form 
provided in Appendix C, and sent to Amgen NASCR, utilizing the email information 
provided on the cover page. In addition to the requirements outlined in Table 8 and 
9, 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 13.0 ‘Accidental Exposures to 
Talimogene Laherparepvec and Herpetic Events’).  
Table 8.  Expedited Reporting Requirements for Interventional Studies 
Safety Data  
Timeframe for Submission to 
Amgen  
Suspected Unexpected Serious Adverse 
Reaction (SUSARs)  
Individual reports sent to Amgen at 
time of expedited reporting to 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 C for Amgen 
template forms)  
Individual reports should be faxed to 1-888-814-8653 or scanned and sent via 
email to svc-ags-inus@amgen.com  
    
Table 9. 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 any body governing research 
conduct (e.g., RA, IRB, etc.)  


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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 
any body governing research 
conduct (e.g., RA, IRB, etc.) but not 
later than 1 calendar year after study 
completion  
Aggregate reports should be submitted via email to the Amgen NASCR manager, 
accompanied by the Fax Cover Form in Appendix C  
 
13.0 Accidental Exposures to Talimogene Laherparepvic 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 10 Accidental 
Exposure and Herpetic Event Reporting Requirement Summary’. 
13.1 Accidental Exposure of HCPs to Talimogene Laherparepvec 
HCPs involved in your clinical trial who were directly exposed to talimigene 
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).   
13.2 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. 
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.  Amgen does not require qPCR or other testing for wild type 
HSV-1.   
o Reporting Process for ISS Treated Patients:  


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- 
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. 
• Reporting Process for HCPs and Close Contacts: 
o Sponsor Investigator should advise any HCPs and/or Close Contacts 
with suspected herpetic lesions to contact their personal provider to 
facilitate reporting to Amgen.  Suspected herpetic lesions should be 
reported by the personal provider 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. 
 
 
Table 10. Accidental Exposure and Herpetic Event Reporting Requirement 
Summary 
 
 
Exposed Person 
 
Reporter 
Timeframe 
for 
Reporting  
to Amgen 
 
Report 
Mechanism 
Timing of 
Swab 
Collection 
qPCR 
Testing 
Required
? 
Responsib
le Party 
for Lesion 
Swabbing 
qPCR Test 
Result 
Distribution* 
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 
consent 
obtained 
Sponsor / 
Investigat
or 
Sponsor / 
Investigator 
and Amgen 


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HCP directly 
exposed to 
product (e.g., 
needle stick, 
splash back) 
without signs or 
symptoms of 
herpetic illness 
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 
N/A 
N/A 
N/A 
N/A 
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 
obtained  
HCP or 
HCP’s 
Personal 
Physician  
HCP’s 
Personal 
Physician 
and Amgen 
Close Contact 
(eg caregiver, 
spouse, child) 
with suspected 
herpetic lesions 
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 
obtained  
Close 
Contact’s 
Personal 
Physician  
 
Close 
Contact’s 
Personal 
Physician 
and Amgen 
 
13. 
QUALITY ASSURANCE MEASURES 
Per the UACC DSMB Charter, Internal Ad Hoc audits may be performed on any UACC 
clinical trial if identified for audit, the audit will be conducted by an identified audit team 
per the UACC DSMB Charter. A QA/QC representative will coordinate the audit team 
functions and a written audit report will be provided to the principal investigator and the 
DSMB 
14. 
MODIFIED RECIST CRITERIA – Appendix B 
15. 
REMOVAL OF SUBJECTS 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the provider or at the institution. If this 
occurs, the investigator, or designee, is to discuss with the subject the safe and 
appropriate processes for discontinuation from the investigational product, intervention 
or device. 
 


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Subjects that wish to discontinue active IP treatment/intervention/device may elect to 
continue with the other protocol required assessments. The investigator should discuss 
with the subject the options for continuation of the study schedule of assessments (i.e. 
blood work, scans, physical exams, diaries) and collection of data, including endpoints 
and adverse events. 
 
The investigator or designee must document the change in status of the subject’s 
participation in the study and as applicable, the level of follow up that is agreed to by the 
subject (i.e. agrees to follow up exams, adverse event review, phone contact, but not to 
further treatment and/or procedures).  
 
Subject withdrawal of consent for a study indicates that the subject does not wish to 
receive further protocol required therapies or procedures, and the subject does not wish 
to, or is unable to continue further study participation. Subject data only up to the time 
when consent is withdrawn will be included in the analysis of the study.  
16. 
STATISTICAL CONSIDERATIONS 
16.1   Analysis Endpoints 
 
16.1.1   Primary Endpoint 
The primary end point is to evaluate the overall response rate (ORR) defined as 
proportion of subjects who achieved CR and PR in the cSCC TILs. Clinical 
assessments will be done using a ruler or calipers. Digital photograph of the lesion(s) 
will be recorded each visit. Through clinical evaluation, CR will be defined as the 
complete disappearance of all TILs and PR will be defined as at least a 30% decrease 
in the sum of the diameters of TILs, taking as reference the baseline sum diameters. 
Progression is defined as >20% increase of at least 5 mm in the sum of the longest 
diameters of the TILs compared with the smallest sum of the longest diameter recorded 
or increase in tumor burden ≥ 20% relative to nadir (minimum recorded tumor burden) 
or the appearance of recurrent lesions confirmed by an assessment 8 weeks after the 
end of the injections (Visit 6). Stable disease (SD) is defined as decrease in tumor size 
<30% or an increase in size <20%. 
 
16.1.2 Secondary Endpoints 
 
1. To assess the safety and adverse effect profile of talimogene laherparepvec in 
low risk cSCC. Adverse events to be assessed according to National Cancer 
Institute Common Terminology. This will be determined by incidence of all 
adverse events (AEs), grade ≥ 3 AEs, safety adverse events (SAEs), and events 
requiring the discontinuation of study drug, local effects on the tumor (ie, pain, 
inflammation and ulceration), and any clinically significant laboratory values. 


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2. Time to response in cSCC TILS. Time to response is the time from first visit until 
objective tumor response (CR or PR) is identified 
 
3. Duration of overall response (DOR) of TILs. This will be measured from the time 
measurement criteria are met for CR or PR (whichever status is recorded first) 
until the first date that recurrence or progressive disease (PD) is objectively 
documented, taking as reference for PD the smallest measurements recorded 
since the treatment started. If no recurrence or PD is documented after PR or CR 
is observed the time measurement will be performed at Visit 8. 
 
4. Durable response rate of TILs. The duration of overall response is ORR lasting 
continuously for > than or equal to 6 months. 
 
5. Time to progression (TTP) of TILs. This will be measured from the time treatment 
is initiated until the first date that recurrence or progressive disease (PD) is 
objectively documented, taking as reference for PD the smallest measurements 
recorded since the treatment started.  
 
6. Overall response rate (CR+PR) of TILs assessed by imaging technique (high 
frequency ultrasound) and correlate it with clinical overall response rate. 
 
7. Overall clinical response rate (CR+PR) of individual TILs injected with talimogene 
laherparepvec (not as overall subject response). Overall response rate is defined 
as the proportion of injected lesions which achieved complete and partial 
response. 
 
8. Overall clinical response rate (CR+PR) in cSCC TNILs. Overall response rate is 
defined as the proportion of subjects who achieved complete and partial 
response in TNILs. cSCC TNILs will be categorized by distance to TILs.  Group 
1: < 5 cm, Group 2: 5 to 15 cm, Group 3: >15 cm. Response rates in TNILs will 
be measured using a ruler or calipers. Digital photograph of the lesion will be 
recorded each visit. Complete response of TNILs will be defined as the 
disappearance of all TNILs and partial response defined as at least a 30% 
decrease in the sum of the diameters of TNILs, taking as reference the baseline 
sum diameters. Progression is defined as 20% increase of at least 5 mm in the 
sum of the longest diameters of the TNILs compared with the smallest sum of the 
longest diameter recorded or increase in tumor burden ≥ 20% relative to nadir 
(minimum recorded tumor burden). Stable disease (SD) is defined as decrease in 
tumor size <30% or an increase in size <20% that is less than 5 mm in the sum 
of the longest diameters of the TNILs compared with the smallest sum of the 
longest diameter recorded. 
 
 


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16.1.3 Exploratory Endpoint 
 
The exploratory endpoint is to quantify the abscopal effect experienced by participants 
after their injections. Participants’ charts will be reviewed to assess the number of 
nonmelanoma skin cancers before and after the intervention. The frequency of NMSCs 
before the intervention will include the 12 month and 24 month period before the first 
injection visit (or Visit 1). The frequency of NMSCs after the intervention will include the 
12 months after the last injection visit (or Visit 4) and then 24 months after the last 
injection (or Visit 4) if available.  
16.2 Statistical Analysis 
Any patient who was treated with at least 1 dose of talimogene laherparepvec therapy 
will be included in safety and efficacy analysis. Descriptive statistics (mean, median, 
standard deviation, 25th percentile, 75th percentile, and range) will be presented for 
continuous variables, such as age.  Frequency counts will be presented for categorical 
variables such as sex and race.  
16.2.1 Overall Response Rate (ORR) 
The analysis of ORR will use a Simon two-stage optimum design to test that the 
proportion with ORR is > 80% (alternative hypothesis) versus ORR < 50% (null 
hypothesis). In the first stage, 7 patients will be recruited.  If < 4 have ORR the trial will 
be terminated.  If 5 or more have ORR, accrual will continue to the second stage.  In the 
second stage, an additional 13 patients will be recruited.  At the end of the second 
stage, if > 14 patients have ORR then TVEC will be considered promising for further 
study.  This design yields 80% statistical power with a one-sided alpha level of 0.05. 
16.2.2   Safety and Adverse effects of talimogene laherparepvec in cSCC 
Summary statistics (counts, percentage, mean, standard deviation, etc.) will be 
presented for the safety and adverse endpoint as appropriate.  Grading of adverse 
effects will be done as per CTCAE 4.03 grading of the National Cancer Institute.  
16.2.3 Duration of overall response (DOR) of TILs. 
Once a PR or CR has been established, the analysis will consist of Kaplan-Meier 
estimates. The analysis will also include a median and a 95% 1-sided exact confidence 
interval. 
16.2.4 Durable Response Rate of TILs. 
Once a PR or CR has been established, the analysis will consist of Kaplan-Meier 
estimates. We will consider durable response when continuously PR or CR is sustained 
for at least 6 months. The analysis will also include a median and a 95% 1-sided exact 
confidence interval. 
16.2.5 Time to progression (TTP) of TILs. 
The analysis of time to response will consist of Kaplan-Meier estimates. The median 
time and 95% confidence interval will be presented.    


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16.2.6 Time to response in TILs 
The analysis of time to response will consist of Kaplan-Meier estimates. The time to 
response data will be censored on those who do not respond at their last follow-up. The 
median time and 95% confidence interval will be presented.    
16.2.7 Overall response rate (CR+PR) in TNILs 
For each group, we will use a Simon two-stage optimum design to test that the 
proportion with ORR is > 80% (alternative hypothesis) versus ORR < 50% (null 
hypothesis). 
16.2.8 Chart Review of Abscopal Effect  
Summary statistics (counts, percentage, mean, standard deviation, etc.) will be 
presented for exploratory endpoint as appropriate. Statistical comparison of the number 
of non-melanoma skin cancers in the 12 month and 24 month period prior to the TVEC 
injections versus the number in the 12 months after the TVEC injections will be 
performed using the Wilcoxon Rank Sum Test. 
16.3 Interim Analysis 
In the first stage, the data will be evaluated in an ongoing manner and the investigators 
will be notified by the biostatistics team when: a. five subjects have demonstrated ORR 
or b. a total of 7 subjects have been recruited and < 4 of them demonstrate ORR.  
17. 
ANALYSIS 
17.1 Safety Analysis –see #16 
17.2  Efficacy Analysis –see #16 
17.3 Interim Analysis – see #16 
 
18. 
REGULATORY OBLIGATIONS 
18.1 Informed Consent 
Before a subject’s participation in the clinical study, the investigator or identified 
designee is responsible for obtaining written informed consent from the subject or 
legally authorized representative after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol 
specified procedures, investigational product, intervention or device are administered or 
initiated.  


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18.2 Institutional Review Board   
A copy of the protocol, proposed ICF, and all other applicable subject information will be 
submitted to the IRB for written approval. A copy of the written approval of the protocol 
and ICF must be on file at the institution before recruitment of subjects into the study.   
 
The investigator is responsible for obtaining IRB approval/renewal at least annually 
throughout the duration of the study. Copies of the investigator’s reports and the 
IRB continuance of approval must be on file at the institution.  
 
The investigator must submit study information to the IRB as required by all applicable 
guidelines and requirements. The investigator will obtain IRB approval for subsequent 
protocol amendments; except changes to eliminate an immediate hazard to study 
subjects, and changes to the informed consent document from the IRB prior to 
implementation.  
 
The investigator will notify the IRB of deviations from the protocol or serious adverse 
events occurring at the site and other serious adverse event reports occurring at or 
received from participating centers as applicable for multi-center trials following the IRB 
policies and procedures. 
19. 
ADMINISTRATIVE PROCEDURES 
19.1  Investigator Responsibilities 
The PI will conduct this study in accordance with the current International Conference 
on Harmonization (ICH) guidance, the Good Clinical Practice (GCP) guidance, the 
Declaration of Helsinki, FDA regulations, local IRB and legal requirements.  
  
19.2 Data and Safety Monitoring Board Protocol Review 
Initial DSMB protocol review will be conducted prior to SRC and IRB submissions.  
 
Any protocol revision or amendment that includes a potential change to any section of 
data and safety monitoring plan must be reviewed and approved by the DSMB prior to 
the protocol amendment submission to the IRB.  


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19.3 Multicenter Trials- Does not apply to this study 
19.3.1 UACC DSMB and QA/QC Monitoring 
19.3.2 Alternate DSMB Oversight  
20. 
SUBJECT CONFIDENTIALITY  
The principal investigator will ensure that the subject’s confidentiality is maintained in 
compliance with Federal regulations, the International Conference on Harmonization 
(ICH), and Good Clinical Practice (GCP) Guidelines.  
 
Oversight entities and/or regulatory authorities will be permitted direct access to review 
the subject’s original medical records, electronic medical records or certified copies for 
verification of study-related procedures and data. Direct access includes examining, 
analyzing, verifying, and reproducing any records and reports that are important to the 
evaluation of the study.  
21. 
STUDY DOCUMENTATION AND ARCHIVE  
The investigator will maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties. All persons authorized to make entries and/or corrections 
on CRFs will be included on the Delegation of Responsibilities Form.  
 
Source documents, data, and records from which the subject’s CRF data are obtained 
include, but are not limited to, hospital records, clinical/office/research charts, laboratory 
and pharmacy records, diaries, microfiches, radiographs, and correspondence. Source 
data will include information necessary for the reconstruction and evaluation of the trial.  
 
The principal investigator or sponsor-investigator is responsible for maintaining a 
comprehensive and centralized filing system of all study-related (essential) 
documentation as required per ICH Guidelines. This can be accomplished by the PI, 
through the site’s standard operating procedures and/or the institutions infrastructure. 
 
The investigator will follow ICH Good Clinical Practice Guidelines and the Code of 
Federal Regulations for records and record retention.  
22. 
DATA 
Applicable data as specified as required in the protocol will be reported/submitted in the 
case report form (CRF). Data reported in the case report forms that are derived from 
source documents must be consistent with the source documents or the discrepancies 
must be explained. CRFs will be completed via the UACC OnCore.  
 


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Additional procedures and assessments may be performed as the institution’s standard 
of care; however these data should remain in the medical records and should not be 
provided as part of the clinical study data unless it pertains to a serious adverse event.  
 
The investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on 
each individual administered the investigational product/intervention/device, or 
employed as a control in the investigation.  
23. 
PROTOCOL DEVIATIONS  
The investigator will conduct the study in conformance with this protocol, generally 
accepted standards of Good Clinical Practice and all applicable federal, state and local 
laws, rules, and regulations.  
 
Approvals or waivers for protocol deviations will be obtained from the sponsor-
investigator prior to occurring, except changes to eliminate an immediate hazard to 
study subjects. If immediate verbal approval is obtained, it will be documented by the 
research staff obtaining the approval and followed by a written protocol deviation form 
per the site standard operating procedures. The sponsor or the sponsor-investigator will 
sign the Protocol Deviation (Waiver) Approval Form or other similar document. The 
original will be filed in the regulatory binder and a copy will be placed in the subject’s 
research file. 
24. 
ECOG- does not apply to this study 
25. 
COMMON TOXICITY CRITERIA (CTCAE) 
 
CTCAE Version 4 will be used as reference to document AEs that occur in the study. 
 
 
 
 
 
 
 
 
 


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26. 
STUDY SCHEDULE 
 
1 = Complete medical history will include demographics 
2 = Hematology to include CBC, differential and platelet count 
3 = Chemistry to include chemistries, liver function tests 
4 = Tumor measurements, photographs 
5 = Tumor ultrasound will only be performed for patients enrolled at UACC 
6 = AE recording will begin on Visit 1 of the IP treatment/intervention/device   
7 = Verbal assessment of changes of target lesions 
Test or 
Procedure 
Screening 
Visit 0 
Treatment 
Visit 1 
Treatment 
Visit 2 
Treatment 
Visit 3 
Treatment 
Visit 4 
Follow-up 
1- 
Visit 5 
Follow-up 
2 
Visit 6 
Follow-up  
3 
Visit 7 
Follow-
up  4 
Visit 8 
Telephone 
Follow-up 
Early 
Term 
Visit 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical 
history 1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent 
meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical 
Exam  
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology 2 
X 
 
 
X 
 
 
 
 
 
 
X 
Serum 
chemistry 3  
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Urine 
or 
serum 
pregnancy 
test 
X 
 
 
 
 
 
 
 
 
 
 
Tumor 
evaluation 4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Tumor 
Ultrasound 
after visit5 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Skin biopsy  
X 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 6  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
IPTreatment  
Intervention 
Device 
(syringe) 
 
X 
X 
X 
X 
 
 
 
 
 
 
Telephone 
Assessment7 
 
 
 
 
 
 
 
 
 
X 
 


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27. 
GLOSSARY - Not applicable 
28. 
DEFINITIONS- Not applicable 
29. 
REFERENCES 
1. 
Karia PS, Jambusaria-Pahlajani A, Harrington DP, Murphy GF, Qureshi AA, 
Schmults CD. 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):327. 
2. 
Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated 
incidence of disease, nodal metastasis, and deaths from disease in the United States, 
2012. Journal of the American Academy of Dermatology. 2013;68(6):957-66. 
3. 
Rogers HW, Weinstock MA, Harris AR, Hinckley MR, Feldman SR, Fleischer AB, 
Coldiron BM. Incidence estimate of nonmelanoma skin cancer in the United States, 
2006. Archives of dermatology. 2010;146(3):283-7. 
4. 
Lansbury L, Bath-Hextall F, Perkins W, Stanton W, Leonardi-Bee J. Interventions 
for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled 
analysis of observational studies. BMJ. 2013;347:f6153. 
5. 
Jesitus J. Lower-leg wound healing requires creativity, skill. Dermatology Times 
[Internet]. 2011  [cited 2017. Available from: 
http://dermatologytimes.modernmedicine.com/dermatology-
times/news/modernmedicine/modern-medicine-feature-articles/lower-leg-wound-
healing-requi. 
6. 
Bichakjian C, Olencki T, Aasi S, Alam M, Anderson J, Blitzblau R, Bowen G, 
Contreras C, Daniels G, Decker R, Farma J. NCCN clinical practice guidelines in 
oncology (NCCN Guidelines): Squamous Cell Skin Cancer. National Comprehensive 
Cancer Network; 2017. 
7. 
Miller SJ, Alam M, Andersen J, Berg D, Bichakjian CK, Bowen G, Cheney RT, 
Glass LF, Grekin RC, Kessinger A. Basal cell and squamous cell skin cancers. Journal 
of the National Comprehensive Cancer Network. 2010;8(8):836-64. 
8. 
Alam M, Ratner D. Cutaneous squamous-cell carcinoma. New England Journal 
of Medicine. 2001;344(13):975-83. 
9. 
Genders RE, Osinga JAJ, Tromp EE, O'Rourke P, Bouwes Bavinck JN, 
Plasmeijer EI. Metastasis Risk of Cutaneous Squamous Cell Carcinoma in Organ 
Transplant Recipients and Immunocompetent Patients. Acta dermato-venereologica. 
2018. Epub 2018/02/07. doi: 10.2340/00015555-2901. PubMed PMID: 29405246. 
10. 
Love WE, Bernhard JD, Bordeaux JS. Topical imiquimod or fluorouracil therapy 
for basal and squamous cell carcinoma: a systematic review. Archives of dermatology. 
2009;145(12):1431-8. 
11. 
Ikić D, Padovan I, Pipić N, Čajkovac V, Kusić Z, DAKOVIĆ N, 
GREGUREK‐NOVAK T, SOLDO‐BELIĆ A, Spaventi Š, Belicza M. Interferon reduces 
recurrences of basal cell and squamous cell cancers. International journal of 
dermatology. 1995;34(1):58-60. 


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12. 
Hanlon A, Kim J, Leffell DJ. Intralesional interferon alfa-2b for refractory, 
recurrent squamous cell carcinoma of the face. Journal of the American Academy of 
Dermatology. 2013;69(6):1070-2. Epub 2013/11/19. doi: 10.1016/j.jaad.2013.02.032. 
PubMed PMID: 24238178. 
13. 
Ismail A, Yusuf N. Type I interferons: key players in normal skin and select 
cutaneous malignancies. Dermatology research and practice. 2014;2014:847545. Epub 
2014/02/12. doi: 10.1155/2014/847545. PubMed PMID: 24516470; PMCID: 
PMC3913103. 
14. 
Martin-Garcia RF. Imiquimod: an effective alternative for the treatment of 
invasive cutaneous squamous cell carcinoma. Dermatologic surgery : official publication 
for American Society for Dermatologic Surgery [et al]. 2005;31(3):371-4. Epub 
2005/04/22. PubMed PMID: 15841646. 
15. 
Ondo AL, Mings SM, Pestak RM, Shanler SD. Topical combination therapy for 
cutaneous squamous cell carcinoma in situ with 5-fluorouracil cream and imiquimod 
cream in patients who have failed topical monotherapy. Journal of the American 
Academy of Dermatology. 2006;55(6):1092-4. Epub 2006/11/14. doi: 
10.1016/j.jaad.2006.06.031. PubMed PMID: 17097406. 
16. 
Patel GK, Goodwin R, Chawla M, Laidler P, Price PE, Finlay AY, Motley RJ. 
Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in situ 
(Bowen's disease): a randomized, double-blind, placebo-controlled trial. Journal of the 
American Academy of Dermatology. 2006;54(6):1025-32. Epub 2006/05/23. doi: 
10.1016/j.jaad.2006.01.055. PubMed PMID: 16713457. 
17. 
Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, 
Delman KA, Spitler LE, Puzanov I, Agarwala SS. Talimogene laherparepvec improves 
durable response rate in patients with advanced melanoma. J Clin Oncol. 
2015;33(25):2780-8. 
18. 
Matsunaga A, Ueda Y, Yamada S, Harada Y, Shimada H, Hasegawa M, Tsujii H, 
Ochiai T, Yonemitsu Y. Carbon‐ion beam treatment induces systemic antitumor 
immunity against murine squamous cell carcinoma. Cancer. 2010;116(15):3740-8. 
19. 
Meshii N, Takahashi G, Okunaga S, Hamada M, Iwai S, Takasu A, Ogawa Y, 
Yura Y. Enhancement of systemic tumor immunity for squamous cell carcinoma cells by 
an oncolytic herpes simplex virus. Cancer gene therapy. 2013;20(9):493. 
20. 
Takasu A, Masui A, Hamada M, Imai T, Iwai S, Yura Y. Immunogenic cell death 
by oncolytic herpes simplex virus type 1 in squamous cell carcinoma cells. Cancer gene 
therapy. 2016;23(4):107. 
21. 
Hamada K, Zhang T, Desaki J, Nakashiro Ki, Itoh H, Tani K, Koyama Y, 
Hamakawa H. Carrier cell‐mediated cell lysis of squamous cell carcinoma cells by 
squamous cell carcinoma antigen 1 promoter‐driven oncolytic adenovirus. The journal 
of gene medicine. 2010;12(6):545-54. 
22. 
Old MO, Wise-Draper T, Wright CL, Kaur B, Teknos T. The current status of 
oncolytic viral therapy for head and neck cancer. World journal of otorhinolaryngology-
head and neck surgery. 2016;2(2):84-9. 
23. 
Saito A, Hamada K, Matsuoka T, Lee K-m, Fujisawa M, Kawabata M, Shirakawa 
T. Intravenous Injection Of Irradiated Tumor Cell Vaccine Carrying Oncolytic Adenovirus 
Can Suppress The Growth Of Multiple Lung Tumors In Mouse Squamous Cell 
Carcinoma Model. The Journal of Gene Medicine. 2012;14(11):664-5. 


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24. 
Investigator Brochure for Talimogene Laherparepvec2018. 
 


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30.  
APPENDICES 
30.1 Appendix A- Measurement of Lesions and Digital Photography 
 
Digital Photographic Guidelines for Serial Photographic Documentation of cSCC 
Location and selected target lesions (TILs and TNILs)  
• ID card with subject number, date and visit: two each 
• Close-up view with millimeter scale of the target area of the selected cSCC: two each 
• Global view of the target cSCC lesions area: two each 
 
Equipment 
Camera: Nikon Coolpix L127 with 16mp.  
 
Procedures 
In these clinical photographs for the duration of the study, the only variable allowed to 
change is the skin condition itself. Therefore, anything extraneous to the condition 
(furniture, etc.) is to be eliminated from the photographic field, starting at the entry visit 
through the final visit. The necessity of good end-of-study photographs should be 
stressed to patients to ensure their cooperation. Lighting, framing, and exposure must 
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30.2 Appendix B- RECIST 
 
   Modified-Response Evaluation Criteria in Solid Tumors (RECIST1.1) 
Quick Reference: 
 
Eligibility 
 
Only patients with measurable disease at baseline should be included in protocols 
where objective tumor response is the primary endpoint.  
 
Measurable disease - the presence of at least one measurable lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should 
be confirmed by histology.  
Measurable lesions - lesions that can be accurately measured in at least one 
dimension with longest diameter ≥ 5 mm using conventional techniques. 
Non-measurable lesions - all small lesions (longest diameter < 5 mm with 
conventional techniques) 
 
Methods of Measurement –  
• All measurements should be taken and recorded in metric notation, using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.  
• The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up.  
• Clinical lesions will only be considered measurable when they are superficial (e.g., 
skin nodules). For the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 
• Histology can be used to differentiate between PR and CR in rare cases (e.g., after 
treatment to differentiate between residual benign lesions (e.g. scar) and residual 
malignant lesions). 
 
• When the primary endpoint of the study is objective response evaluation, ultrasound 
(US) should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, 
subcutaneous lesions and thyroid nodules. US might also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical 
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Baseline documentation of Target Lesions 
• All measurable lesions up to a maximum of five TILs and ten TNILs per subject 
should be identified as target lesions and recorded and measured at baseline.  
• Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically).  
• A sum of the longest diameter (LD) will be calculated and reported as the baseline 
sum LD for both TILs and TNILs respectively. The baseline sum LD will be used as 
reference by which to characterize the objective tumor. 
Response Criteria: 
Evaluation of TILs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Response 
(CR): 
Disappearance of all TILs 
Partial Response 
(PR): 
At least a 30% decrease in the sum of the LD of TILs, taking as 
reference the baseline sum LD 
Progressive Disease 
(PD): 
>20% increase of at least 5 mm in the sum of the longest 
diameters of the target lesions 
Or increase in tumor burden ≥ 20% relative to nadir (minimum 
recorded tumor burden) 
Or the appearance of one or more new lesions confirmed by an 
assessment 8 weeks after the end of the injections (Visit 6).  
Stable Disease (SD): 
A decrease in tumor size <30% or an increase in size <20% that 
is less than 5 mm in the sum of LDs of the TILs compared with 
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Evaluation of TNILs 
Complete Response 
(CR): 
Disappearance of all TNILs  
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of TNILs, 
taking as reference the baseline sum LD 
Progressive Disease 
(PD): 
>20% increase of at least 5 mm in the sum of the longest 
diameters of the target lesions 
Or increase in tumor burden ≥ 20% relative to nadir (minimum 
recorded tumor burden) 
Or the appearance of one or more new lesions confirmed by an 
assessment at Visit 3.  
Stable Disease (SD):  
A decrease in tumor size <30% or an increase in size <20% that 
is less than 5 mm in the sum of LDs of the TNILs compared with 
the smallest sum of the LD recorded. 
 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for PD the smallest 
measurements recorded since the treatment started). In general, the patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria  
 
 
TILs 
TNILs 
Recurrent TILs 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD/PD 
No 
CR 
PR 
Any 
No 
PR 
SD 
Any 
No 
SD 
PD 
Any 
Yes or No 
PD 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of treatment.  
 
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the complete response status. 
 
 


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30.3   Appendix C- Safety Reporting Submission Forms 
Sample Fax Cover Form for Individual Safety Reports (Amgen Global Safety) 
 
 
 


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Sample Fax Cover Form for Aggregate Safety Reporting   
 
 
 


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Sample of Report of Suspected IMLYGIC™ (Talimogene laherparepvec) or Herpes 
Virus Associated Adverse Event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Sample of Pregnancy Notification Worksheet 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Sample of Lactation Notification Worksheet 
 
 
 
 

ICF_001.pdf: 
 
 
Official Title: 
A Single Arm Phase 2 Study of talimogene laherparepvec 
in patients with cutaneous squamous cell cancer 
NCT number: 
NCT03714828 
Document Type:  
Consent Form 
Date of the 
Document: 
Version 12/19/2022, IRB approved 12/22/2022 
 
 


Consent Version: 12/19/2022
Page 1 of 15
HSPP Use Only:
Consent form Medical v.Jan 2018
Consent to Participate in Research
Study Title: A Single Arm Phase 2 Study of talimogene laherparepvec (T-VEC) in patients with 
cutaneous squamous cell cancer
Principal Investigator & Sponsor: Clara Curiel, MD
Financial Support: Amgen
This is a consent form for research participation. It contains important information about this 
study and what to expect if you decide to participate. Please consider the information carefully. 
Feel free to discuss the study with your friends and family and to ask questions before making 
your decision whether or not to participate. If you have any questions, please discuss this with 
your study provider.
Summary of the research
You are being asked to participate in a study about talimogene laherparepvec (also known as 
OncoVEXGM-CSF or IMLYGIC®) in people with a healthy immune system with confirmed low-risk 
squamous cell carcinoma (see the “Why is this study being done” section). The study will take 
approximately 48 weeks. This will include a screening visit, 4 injection visits and 5 follow up 
visits, which are defined in greater depth under “What will happen if I participate in this study?” 
There is some risk of an allergic reaction, an autoimmune reaction or a reaction at the injection 
site. There is no direct benefit to you in participating in this study. 
Why is this study being done?
The purpose of this study is to find out more about talimogene laherparepvec (also known as 
OncoVEXGM-CSF or IMLYGIC®) in people with a healthy immune system with confirmed low-risk 
squamous cell carcinoma. Skin cancer is the uncontrolled growth of cells in the skin. Squamous 
cell carcinoma (SCC) is a type of skin cancer that is classified into low-risk and high-risk disease. 
Usually, low-risk SCC is treated with a surgical procedure, but surgery can be challenging when 
patients have: multiple SCCs on their body, when the SCC is on a challenging place on the body 
to remove or when patients are older or have diseases that place them at risk for surgery 
related complications. Immune therapy is a treatment that uses certain parts of a person’s 
immune system to fight disease. Immune therapy is a proven therapeutic approach in many 
cancers, including melanoma, another type of skin cancer. Talimogene laherparepvec (TVEC) is 
made from a modified herpes simplex virus type 1 (HSV-1, the “cold sore” virus). The virus’ 
genes were modified in a laboratory so that it produces a protein called human granulocyte 
macrophage colony-stimulating factor (GM-CSF), which multiplies and grows in tumor cells. 
Human GM-CSF is normally produced by various cells within the body and is used as a medicine 
to treat patients with white blood cell counts that are too low. This modified HSV-1 is not 
designed to change any of your genes, but instead produces a protein that acts on tumor cells 
and stimulates your immune system. TVEC is administered by injection with a needle directly 
Approved by University of Arizona
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into one or more tumors and works by directly destroying cancer cells and enhancing immune 
response to destroy cancer cells.
What will happen if I take part in this study? 
All subjects will receive TVEC. This study will not use placebo treatments.
This study will measure the tumor’s response over the course of four injections (given 2 weeks 
apart) of TVEC. Participation in the study involves 8 visits to the clinic and 1 phone call follow 
up. TVEC injections will be done at visits 1-4 (2-3 weeks apart). Tumor measurements will be 
done at each visit using photographs. High-frequency ultrasounds will be performed to assess 
lesions at the screening visit and second follow up visit (12-13 weeks from the screening visit). 
Skin biopsy tests will be done on each tumor to make sure that each tumor is a skin cancer. This 
procedure will be performed in the following manner: a small volume of local anesthetic 
(painkiller) will be injected into the skin at each test area to numb the area. A small piece of skin 
will be removed and will be covered with a small bandage. You will need to keep the sites clean, 
dry and covered until the area heals.  After you have completed your study treatment, the 
study team will review your patient chart to assess the number of nonmelanoma skin cancers 
before and after your study treatment.  
Please see below for the schedule you will follow if you participate in this study:
Screening Visit:
During the screening visit (visit 0), the provider will examine your suspected low-risk SCC lesions 
and perform partial skin biopsies to confirm the diagnosis. You will also have a blood test done 
to determine your overall health. For women of childbearing potential (or able to become 
pregnancy), you will be required to do a urine test to determine if you are pregnant. If the urine 
test comes back inconclusive, then a pregnancy blood test will be ordered. The provider will 
choose up to five lesions for treatment, with no more than three lesions in one anatomical 
Approved by University of Arizona
Date Approved: 12/22/2022


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area. A high-frequency ultrasound will be performed on the lesions so researchers can have a 
better sense of the size and depth without the need of removing it before treatment with TVEC. 
Your study provider and his/her staff will take photographs of areas of your body where your 
squamous cell cancer lesion is present to document how your tumor responds to study 
treatment. Your face and any tattoos or other marks on your body that might identify you may 
be temporarily covered up. The photographs will be taken during your regular study visits.
Visit 1: First Injection Visit:
One to two weeks after your screening visit, you will come in for your first injection with TVEC. 
Your lesions will be measured and photographed. Then you will receive 0.1–4 ml of TVEC 
(depending on lesion size) in each lesion the provider selects.
Visit 2: Second Injection Visit:
Three weeks after Visit 1, your lesions will be measured and photographed. Then, you will 
receive 0.1-4 ml of TVEC (depending on lesion size) in each lesion the provider selects.
Visit 3: Third Injection Visit:
Two weeks after Visit 2, your lesions will be measured and photographed. Then, you will 
receive 0.1-4 ml of TVEC (depending on lesion size) in each lesion the provider selects.
Visit 4: Fourth Injection Visit:
Two weeks after Visit 3, your lesions will be measured and photographed. Then, you will 
receive 0.1-4 ml of TVEC (depending on lesion size) in each lesion the provider selects.
Visit 5: First Follow-Up Visit:
Four weeks after Visit 4, your lesions will be measured and photographed.
Visit 6: Second Follow-Up Visit:
Four weeks after Visit 5, your lesions will be measured and photographed. A repeat high-
frequency ultrasound of target lesions will be performed, and compared to the ultrasound 
taken at your screening visit to evaluate your response.
Visit 7: Third Follow-Up Visit:
Six weeks after Visit 6, your lesions will be measured and photographed. 
Visit 8: Fourth Follow-Up Visit:
Fourteen weeks after Visit 7, your lesions will be measured and photographed. 
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Visit 9: Telephone Follow-Up:
One year after Visit 1, you will receive a phone call from the study coordinator asking you about 
your lesions. 
Post-Treatment Chart Review:
One year after Visit 4, the study team will review your patient chart in your medical record to 
assess the number of nonmelanoma skin cancers during the following timepoints:

Before your study treatment: 12 months before Visit 0.

After your study treatment: 12 months after Visit 4, and again at 24 months after Visit 4 
if available.      
This review would allow the study team to assess the rate of skin cancer development before 
and after your treatment with TVEC. The study team will not contact you during this review.
How long will I be in this study?
Participation in the study involves 8 visits to the clinic over the course of 48 weeks and 1 phone 
call follow up 1 year after Visit 1.
How many people will take part in this study?
Approximately 20 patients will be enrolled in this study at the University of Arizona Cancer 
Center.
What benefits can I expect from being in this study?
If you agree to participate in the study, you may have a direct medical benefit depending on your 
response to the study drug. We hope the information learned from this study will benefit other 
patients with cancer in the future. 
What risks, side effects or discomforts can I expect from being in the study?
As with any experimental drug it is impossible to foresee all potential risks.  Adverse drug 
reactions, or side effects, observed in patients given TVEC in clinical trials for metastatic 
(spreading) melanoma are listed below.
Very common (occurring in 1 or more out of 10 patients given TVEC):

Chills

Fever

Influenza-like illness: Symptoms can include fever, chills, cough, sore throat, runny or 
stuffy nose, muscle or body aches, headaches, or fatigue (tiredness)

Injection site reactions: Symptoms can include pain, redness, swelling, inflammation, or 
warmth at the injection site; or the release of blood or other fluid from the injection site

Upset stomach (nausea)

Vomiting
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Date Approved: 12/22/2022


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
Loose or watery stools (diarrhea)

Infrequent or difficult bowel movements (constipation)

Muscle or body aches

Joint pain

Pain in extremity

Headache

Tiredness (fatigue)
Common (occurring in at least 1, but fewer than 10, of 100 patients given TVEC):

General discomfort, illness, or feeling unwell (malaise)

Pain in the armpits

Pain or discomfort in the belly (abdomen)

Groin pain

Loss of skin color in blotches (vitiligo)

Rash

Inflammation of the skin (dermatitis) 

Cellulitis: Skin infection caused by bacteria at the site of injection, which may cause 
fever, chills, or redness or swelling at the injection site or site of the tumor, and may 
require hospitalization for antibiotic treatment.

Cold sore or blister in mouth (oral herpes)

Dizziness

Pain in the throat

Dehydration

Bruising

Procedural pain

Wound complication at the injection site (secretion or discharge)

Tumor pain

Infection in a new, abnormal tissue growth

Weight loss

Deep vein thrombosis (blood clot)

Skin or face becomes warm and reddened (flushing)

Anemia (low red blood cell count), which can increase infection risk

Inflammation of the lungs (pneumonitis)

Inflammation of the tiny filters in the kidneys (glomerulonephritis)

Inflammation of the blood vessels (vasculitis)

Vitiligo
Uncommon (occurring in fewer than 1 out of 100 patients given TVEC):

Incision site infection

Herpetic keratitis, a type of eye infection caused by herpes virus
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
Obstructive airway disorder, which causes difficulty breathing: If you have a tumor in 
your neck, your provider may warn you that you might experience compression of your 
airways during treatment with TVEC. This complication might require a surgical 
procedure on the neck to open a direct airway. A tube, which may be connected to a 
machine to help you breathe, might need to be inserted into the opening in your throat.

Plasmacytoma (a collection of abnormal antibody-producing white blood cells) in the 
area where TVEC was injected. Plasmacytoma may be associated with multiple myeloma 
(a cancer of white blood cells affecting the bone marrow).

Worsening psoriasis, a condition in which skin cells build up on the skin surface, forming 
scales and itchy, dry patches.

Symptoms of delayed wound healing at or around the injection site such as injection site 
discharge, foul odor, or dead tissue at the injection site. If you notice symptoms of 
delayed wound healing at the injection site(s), especially if you have risk factors such as 
diabetes, poor blood circulation, have had radiation to the site, you should contact the 
study provider or his/her study staff immediately. 
Allergic Reaction
You may have an allergic reaction to TVEC.  Symptoms of an allergic reaction in general may 
include headache, rash, itching, flushing, swelling, shortness of breath, nausea and sometimes 
vomiting.  Severe allergic reactions can cause dizziness, severe skin reactions, difficulty 
breathing or swallowing, a decrease in blood pressure, and could be life threatening.  If you 
have symptoms of an allergic reaction, you should contact the study provider or the study staff 
immediately.  If you have had an allergic reaction to TVEC or any of its ingredients, you should 
inform your provider.
Autoimmune Reactions
Autoimmune reactions to the body’s own tissues have been reported in some subjects 
administered TVEC.  It is possible that these reactions could occur in any part of the body.  
Examples of autoimmune reactions that have been reported in subjects receiving TVEC include 
inflammation of the kidneys (nephritis), blood vessels (vasculitis), or lungs (pneumonitis) and 
worsening psoriasis.  It is possible that an autoimmune reaction could occur in any part of the 
body. Please tell your provider if you have had any type of autoimmune disease before 
treatment with TVEC, and all treatments you are receiving for the disease.
Other potential side effects:  Transmission of TVEC
Can TVEC be spread to my family members or other close contacts and how long after 
treatment is this possible?
Approved by University of Arizona
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There have been no reported cases of spreading of TVEC to close contacts or family members in 
clinical trials to date.  However, TVEC could potentially be spread to your family members or 
other close contacts (household members, care-givers, sex partners, or someone you share a 
bed with) at any time after your tumor(s) are injected with TVEC.  This may occur if your family 
member or other close contact touches the injection site or has contact with your body fluids or 
with the inside of the dressing(s) covering your injection site(s). 
Spreading TVEC may be more likely if your close contact has a break in the skin or mucous 
membranes that comes into contact with your injection site or your body fluids.  In patients 
treated with TVEC in clinical trials, TVEC has been found on the surface of the injected tumors, 
into the second week after the injection, and on the outside of the dressings that covered these 
injection sites.  Talimogene laherparepvec have also been detected in patient’s blood and urine, 
and in the patient’s mucous membranes of the mouth and genitals no samples had detectable 
talimogene laherparepvec 30 days after the end of treatment. For patients who had talimogene 
laherparepvec presence in the surface of injected tumors, no sample had detectable 
talimogene laherparepvec 60 days after end of treatment. 
Are there any precautions I should take to prevent spread of talimogene
laherparepvec to others? 

Avoid touching or scratching the injection site.

Avoid direct contact with your injection sites and body fluids.

Injection sites should be covered for at least 7 days after the injection with
 
watertight dressings which allow for air exchange. If the dressing comes loose or
falls off prior to 7 days after the injection, it should be replaced right away with a
clean dressing. However, you may need to keep the dressing on longer if the
lesions at the injection sites or the injection sites are weeping or oozing.

You should always observe proper hygiene (wash your hands with warm water
and soap before and after touching your injected lesions or handling the dressings) to 
avoid potentially spreading TVEC to other persons.

Wear gloves while changing your dressings that cover your injection site.Place all used 
dressings and cleaning materials in a sealed plastic bag, and
throw them away as household waste or return to the study site for disposal as
you are instructed by the site staff.

Close contacts who are pregnant or who have a weakened immune system
should not touch injection sites, change your dressings or clean your injection
sites.

If you participate in this study, your provider and/or his staff will provide you with
additional instructions for injection site care.
Is there any risk to my family members or other close contacts if they are exposed to TVEC?
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If a close contact has been exposed to TVEC, it is possible that they could develop symptoms of 
a herpes type infection (see below).  However, the chance of this happening is low due to the 
changes in TVEC that make it different from the naturally occurring herpes simplex virus, but 
you should know how to recognize these symptoms.
What to do if you or a close contact develop any of the above symptoms:

If your close contacts are accidentally exposed to TVEC, they should clean the affected 
area on their body with soap and water and/or a disinfectant. If they develop signs or 
symptoms of herpes infection, ask them to call their provider, and you should report 
this to your study provider.

You should report any signs or symptoms to your study provider right away and you 
should ask your close contact to call their provider for evaluation and appropriate 
treatment.

You or your close contact may be asked to come to a clinic for a test that may be able to 
determine if these symptoms may be due to TVEC. 

Your close contact should report suspected herpetic lesions to Amgen (the 
manufacturer of TVEC) at 1-855-465-9442 and they will have the option to receive 
follow-up testing for further characterization of the infection.

This test is likely to be most reliable if it can be performed in the first 3 days after 
symptoms develop.
 
Symptoms that may be related to the naturally occurring herpes simplex virus (HSV-1) or 
TVEC:
Most adults in the population have been exposed to the naturally occurring herpes simplex 
(also known as “cold sore”) virus (HSV-1) (the “cold sore” virus).  Common signs and symptoms 
of the naturally occurring herpes simplex virus include:

Sores around the mouth (“cold sore”, “fever blister”) or the genitals (“genital sore”).

Blisters may develop on the fingers, ears, or face.

Eye infection (herpetic keratitis) with eye pain, light sensitivity, discharge from the eyes, 
or blurry vision.

Abdominal pain and infections and inflammation inside the abdomen (infrequently).

Rarely, serious infections of the brain (encephalitis) or spinal cord, causing paralysis 
(unable to move) have been reported.  Signs may include fever, confusion or other 
behavior changes, headache, numbness and pain in the legs, constipation, or difficulty 
with urination.

Life-threatening infections (disseminated herpes) can develop in people with a 
weakened immune system.
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After infection, the naturally occurring herpes virus may travel to spinal nerve roots.  The virus 
can reactivate from the nerve roots and cause recurrent cold sores or other signs of infection as 
described above.  Stress, other illness, or menstruation are common triggers for reactivation of 
the naturally occurring virus. Signs and symptoms of infection with TVEC could be similar to 
those described above, although TVEC has been changed to reduce the chance of this 
happening.
Can talimogene laherparepvec be transmitted through sexual contact?
The naturally occurring herpes simplex virus (HSV-1) can be transmitted through sexual 
contact. It is not known if talimogene laherparepvec will behave the same way, thus you 
or your partner should use a latex condom during treatment and for up to 30 days after 
your last dose when engaging in sexual activity to prevent possible transmission of 
talmogene laherparepvec. For those with latex allergies, polyurethane condoms may be 
used.
Who should not have contact with TVEC?
Persons with severely weakened immune systems should not be treated with TVEC, as 
they may be at increased risk for serious, life-threatening herpetic infections after 
receiving TVEC.  Tell your provider if you have a weakened immune system.
If your close contact or family member is pregnant or has a weakened immune system, they 
should not touch injection sites, change your dressings, or clean your injection sites.  Keep used 
dressings and cleaning materials away from pregnant women, newborns, and those with 
weakened immune systems.
Pregnant or breastfeeding women, and women planning to become pregnant, should not 
participate in this study. If you are unable to become pregnant for one of the following reasons, 
the use of birth control methods is not required during this study:

Your healthcare provider has confirmed that you are postmenopausal.

You have had your uterus, or both ovaries, or both fallopian tubes removed.
If you could become pregnant, you:

Should let your sexual partner know you are in this study.

Must agree to practice true sexual abstinence (not have sex) or use an acceptable 
method(s) of effective birth control during treatment and for an additional 3 months 
after the last dose of TVEC.

Must discuss your pregnancy prevention method with the study provider to
ensure it is acceptable. You should be aware that true sexual abstinence is
the only 100% effective method of birth control.
What if you become pregnant or breastfeed during the study?
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If you decide to participate in this study, you must agree to not become pregnant or to 
breastfeed. If you think you are pregnant or inadvertently become pregnant or breastfeed 
during treatment and for an additional 3 months after stopping TVEC you must tell the study 
provider or study staff right away. Treatment with TVEC may be stopped. The study provider 
will notify Amgen of the pregnancy or that you are breastfeeding. You will be asked to provide 
information on the pregnancy or breastfeeding outcome for you and the baby. There is a risk of 
transmitting herpes virus to the baby when passing through the birth canal of a mother with a 
genital herpes infection. You should tell your provider if you have had a genital herpes infection 
or think you may have one while on this study. Your provider may recommend a Caesarean 
Section if you have signs of a genital herpes infection around the time you will give birth.
What if your partner is pregnant when you begin this study or becomes pregnant during the 
study?
If your partner is pregnant when you begin this study or becomes pregnant during treatment 
and for an additional 3 months after stopping TVEC you must tell the study provider or the 
study staff right away. The study provider will notify Amgen of the pregnancy and ask to obtain 
information on the pregnancy outcome for both the mother and baby.
What are other risks associated with procedures done in this study?
Ultrasound scan:
High frequency sound waves are used to create an image of part of the inside of the body, such 
as the heart (for example, echocardiogram) using a small handheld sensor.  There are no known 
harmful effects from having an ultrasound scan.
Biopsy Skin Test
Brief discomfort may be felt when the local painkiller (lidocaine) is injected prior to skin 
biopsies; however, it is usually minimal. Some people experience discomfort from the biopsies 
despite the use of the painkiller, and there is a slight risk of an allergic reaction to the painkiller. 
There is a slight chance of infection following the biopsies. It is expected that you will have a 
small (1/4 – 1/2 inch) scar at the biopsy site(s), which may be permanent or may fade over 
time. In addition, rare complications associated with skin biopsies include moderate temporary 
bleeding, as well as a numbing sensation of the skin around the biopsy sites, which might or 
might not be reversible.
What other choices do I have if I do not take part in this study?
You can choose not to participate in this study. If you do not participate, there are other 
medical choices that do not include surgery to treat your SCCs, such as radiation therapy. 
Radiation therapy and intraregional chemotherapy are alternative treatments for SCCs that 
cannot have surgery done. The study provider can discuss other health care choices with you. 
You will not experience penalty or loss of benefits to which you are otherwise entitled.
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When will my participation in the study be stopped?
The study provider may take you out of the study:
•
If your health changes and the study is no longer in your best interest
•
If new information becomes available
•
If you do not follow the study rules
•
If the study is stopped by the investigator, IRB, or FDA.
Can I stop being in this study?
If you decide to take part in the study, you may leave the study at any time.  No matter what 
decision you make, there will be no penalty to you and you will not lose any of your usual 
benefits.  
Your participation is voluntary. If you decide to take part in the study, you may leave the study 
at any time. No matter what decision you make, there will be no penalty to you and you will not 
lose any of your usual benefits. Your decision will not affect your future relationship with the 
University of Arizona or Banner Health. If you are a student or employee at the University of 
Arizona, your decision will not affect your grades or employment status.
What happens if I am injured because I took part in this study?
Side effects (injury) can happen in any research study. These effects may not be your fault or the 
fault of the researcher involved. Known side effects have been described in this consent form. 
However, side effects that are not currently known may happen and require care. It is important 
that you tell your study provider if you feel that you have been injured because of taking part in 
this study.  You can tell the provider in person or call him/her at 520-626-6024 during office 
hours. During the evening and on weekends, call 520-694-6000 (after hours MD paging) and ask 
for the Medical Oncology physician on duty.
The study provider or study staff will help you get medical care for your injury or illness. You 
and/or your health insurance plan will be charged for this treatment.   The study will not pay for 
medical treatment.  This, however, does not waive your rights in the event of negligence. If you 
suffer an injury from participating in this study, you should seek treatment.  The University of 
Arizona and Banner-University Medical Center have no funds set aside for the payment of 
treatment expenses for this study.
What are the costs of taking part in this study?          
TVEC will be provided by Amgen at no charge to you, the patient.  There are no charges for the 
additional visits, tests or procedures that are required solely for this study. Therefore, you will 
not have any additional costs beyond those related to the standard treatment of your disease. 
You may be responsible for payment of any bills that your insurance may refuse to pay due to 
your standard care while participating in this research study.
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Will I be paid for taking part in this study?
You will not be compensated for your participation in this study.
Will my data or specimens be stored for future research?            
You will be assigned a unique subject identification number to de-identify your research data 
and specimens. This number will be used to identify you throughout the clinical study and will 
be used on all applicable study documentation related to you. The subject identification 
number will remain constant throughout the study. Your data and biospecimens may be used 
or distributed for future research. The investigators might request your skin biopsies or 
excisions to perform additional testing to understand the reason why you responded or did not 
respond to the study drug.
Will my specimens be sold for commercial profits?         
 Your data and specimens used in this research will not be sold for commercial profits. 
Will I hear back on any results that directly impact me?            
You will receive information regarding how you are doing with respect to your cancer. Results 
from the study will be posted on clinicaltrials.gov when available. 
Will Whole Genome Sequencing be done with my specimen?          
No Whole Genome Sequencing will be done with your specimen. 
Will my study-related information be shared, disclosed, and kept confidential?
Efforts will be made to protect your medical records and other personal information to the extent 
allowed by law.  However, we cannot guarantee absolute confidentiality.  Medical records of 
research study subjects are stored and kept according to legal requirements.  You will not be 
identified in any reports or publications resulting from this study.
It is anticipated that there will be circumstances where your study related information and 
Protected Health Information (PHI) will be released to persons and organizations described in 
this form. If you sign this form, you give permission to the research team to use and/or disclose 
your PHI for this study. Your information may be shared or disclosed with others to conduct the 
study, for regulatory purposes, and to help ensure that the study has been done correctly. 
These other groups may include:

Office for Human Research Protections, Food and Drug Administration, or other federal, 
state, or international regulatory agencies

Banner University Medical Group and Banner Health

The University of Arizona (UA) and the UA Institutional Review Board 

Your primary care physician or a specialist taking care of your health.
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Your PHI may no longer be protected under the HIPAA privacy rule once it is disclosed by the 
research team.  
What study-related information and PHI will be obtained, used or disclosed from my 
medical record at Banner?
Information related to this research study that identifies you and your PHI will be collected 
from your past, present, and future hospital and/or other health care provider medical records. 
The PHI you are authorizing to be used and/or disclosed in connection with this research study 
is:

Name

Address

Contact details

Date of birth

Medical records

Past medical history

Family history

Race

Ethnic origin
Demographic information to be disclosed may include, but is not limited to, your name, 
address, phone number, or social security number. 
Your existing health records may include information related to the diagnosis or treatment of 
sexually transmitted disease (STD), acquired immunodeficiency syndrome (AIDS), human 
immunodeficiency virus (HIV), other communicable diseases, genetic information (e.g., genetic 
testing), and/or alcohol and/or drug abuse. The study staff and investigator’s monitor may see 
this information while reviewing your regular health records for this study, but they WILL NOT 
create, collect, or disclose this type of information for the purposes of this research study.
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information. Be aware that this Federal law does not protect 
you against genetic discrimination by companies that sell life insurance, disability insurance, or 
long-term care insurance.
When will my authorization expire?
There is no expiration date or event for your authorization. Therefore, unless you cancel this 
authorization (as instructed below) this authorization will continue to be effective.
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Do I have to sign this authorization form?
You do not have to sign this authorization. However, if you decide not to sign, you will not be 
able to participate in this research study; and it will not affect any non-study Banner Health 
medical treatment or health care, payment, enrollment in any health plans, or benefits.
What do I need to know if I decide to cancel my authorization?
After signing the authorization, you may decide to cancel your previous authorization for the 
research team to use your PHI. If you cancel the authorization, you will no longer be able to 
stay in the research study. Please note that any PHI collected before you cancel the 
authorization may still be used. You may revoke the authorization by contacting the Principal 
Investigator in writing. Contact information is under “Who can answer my questions about the 
study” at the end of this document. 
Will access be limited to your research study record during this study?
You may not have access to the research information developed as part of this study until it is 
completed.
Who can answer my questions about this study?
If at any time you feel you have had a research-related injury, or for questions, concerns, or 
complaints about the study you may contact Clara Curiel, MD, at 520-694-6024.
For questions about your rights as a participant in this study or to discuss other study-related 
concerns or complaints with someone who is not part of the research team, you may contact 
the Human Subjects Protection Program Director at 520-626-8630 or online at 
https://research.arizona.edu/compliance/human-subjects-protection-program.
If you are injured as a result of participating in this study or for questions about a study-related 
injury, you may contact Clara Curiel, MD, at 520-694-6024.
If you have questions, concerns, or complaints about the use or sharing of your health 
information or would like a copy of the Banner Notice of Privacy Practices, you may contact the 
Banner Research HIPAA Liaison at BannerResearchCompliance@bannerhealth.com. 
To cancel your authorization for access to PHI you must notify the Principal Investigator in 
writing at the following address
Clara Curiel, MD
University of Arizona Cancer Center
3838 N. Campbell Ave.
Tucson, AZ 85719
An Institutional Review Board responsible for human subjects research at The University of 
Arizona reviewed this research project and found it to be acceptable, according to applicable 
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state and federal regulations and University policies designed to protect the rights and welfare 
of participants in research.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
Signing the consent form
I have read (or someone has read to me) this form, and I am aware that I am being asked to 
participate in a research study.  I have had the opportunity to ask questions and have had them 
answered to my satisfaction.  I voluntarily agree to participate in this study and I authorize the 
use and/or disclosure of my PHI. I am not giving up any legal rights by signing this form.  I will be 
given a signed copy of this form.
Printed name of subject
Signature of subject
Date
Investigator/Research Staff
I have explained the research to the participant or the participant’s representative before 
requesting the signature(s) above.  There are no blanks in this document.  A signed copy of this 
form has been given to the participant or to the participant’s representative.
Printed name of person obtaining consent
Signature of person obtaining consent
Date
Approved by University of Arizona
Date Approved: 12/22/2022