Neoadjuvant Intralesional Injection of Talimogene Laherparepvec With Concurrent Preoperative Radiation in Patients With Locally Advanced Soft Tissue Sarcomas
Phase: PHASE1
Conditions: Soft Tissue Sarcoma
Sponsor: University of Iowa

1 
 
Amgen Protocol #: 20139075 
 
TITLE:  Neoadjuvant Intralesional Injection of Talimogene Laherparepvec with 
Concurrent Preoperative Radiation in Patients with Locally Advanced Soft Tissue 
Sarcomas 
 
 
Coordinating Center: 
 
 
Holden Comprehensive Cancer Center – University of Iowa. 
 
*Principal Investigator: 
Mohammed Milhem, M.D. 
Clinical Professor 
Division of Hematology, Oncology, & Blood and 
Marrow Transplantation 
Department of Internal Medicine 
University of Iowa Hospitals and Clinics 
C-32 GH 
(319) 356-2324 
Fax: (319) 353-8383 
mohammed-milhem@uiowa.edu 
 
Co-Investigators: 
 
  
 
 
Carryn Anderson, MD 
  
 
 
Clinical Associate Professor 
  
 
 
Department of Radiation Oncology 
  
 
 
University of Iowa Hospitals and Clinics 
 
 
 
01612D PFP 
  
 
 
(319) 353-8836 
 
 
 
carryn-anderson@uiowa.edu  
 
 
Benjamin J. Miller, MD  
 
 
Munir Tanas, MD 
Assistant Professor  
 
 
 
Assistant Professor 
Department of Orthopaedic Surgery  
 
Department of Surgical Pathology 
University of Iowa Hospitals and Clinics 
 
University of Iowa Hospitals and Clinics 
01008 JPP  
 
 
 
1026 ML 
(319) 356-2488  
 
 
 
(319) 335-6637 
benjamin-j-miller@uiowa.edu  
 
 
munir-tanas@uiowa.edu   
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Agent:  Talimogene Laherparepvec 
Other Agent(s):  Standard external beam radiation 
 
Investigational Agent  
IND# 
IND Sponsor  
Talimogene Laherparepvec 
16359 
Mohammed Milhem 
 
Protocol #: 20139075 
Protocol Version Date: 4/8/2014 
Amendment 1: 1/13/2014 
Amendment 2: 4/8/2014 
Amendment 3: 7/21/2014 
Amendment 4: 7/25/2014 
Amendment 5:  12/15/2014 
Amendment 6:  3/30/2015 
Amendment 7:  9/13/2015 
Amendment 8:  10/26/2015 
Amendment 9:  3/17/2016 
Amendment 10:  11/15/2016 
Amendment 11:  12/22/2017 
 
SCHEMA 
 
Study Timeline Schema: 
 
 
 
 
 
 
 
 
 
 
 
Phase 1b schema: 
 
 
 
 
 
 
 
 
 
 
 
 
SCREENING
ENROLLMENT
END OF TREATMENT
SAFETY FOLLOW-UP
END OF STUDY
 
Talimogene laherparepvec 
Up to 4 mL 
106 PFU/mL followed by 
108 PFU/mL Q-weekly 
+ 
Radiotherapy starting 
from week 4 
50Gy/25 fractions 
+ 
Surgery 4-6 weeks after 
XRT 
 
XRT 
Weekly Talimogene laherparepvec 
Day 1, Week 1 
End of Week 8 
End of Week 12, 13, or 14 
Follow up every 12 weeks through 24 months 
First dose of TVEC 
Complete XRT 
Complete TVEC MRI of tumor then Surgery 
Day 1 Week 4 

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SAFETY FOLLOW-UP
 
 
 
 
Table 1.  Phase 1b Dose De-escalation Schedule 
Number of Patients with DLT at a 
Given Talimogene Laherparepvec 
Dose 
Decision Rule 
> 2 
Dose level will be declared toxic. 
If this is the lowest dose level, stop the study due to 
excessive toxicity; otherwise enter three additional 
patients at the next lowest dose level. 
< 1 out of 3 
Enter three more patients at this dose level. 
< 1 out of 6 
This is the recommended dose for the subsequent 
pilot study. 
 
 
Talimogene Laherparepvec Dose Levels: 
Dose 0 = talimogene laherparepvec up to 4.0 mL of 108 PFU/mL dosed weekly 
Dose -1 = talimogene laherparepvec up to 4.0 mL of 108 PFU/mL dosed every 2 weeks. 
 Initial dose for all = talimogene laherparepvec up to 4.0 mL of 106 PFU/mL 
 
 
Phase 2 Schema: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase II 
Talimogene laherparepvec 
Up to 4 mL 
106 PFU/mL x 1 followed 
by 
108 PFU/mL Q-weekly 
+ 
Radiotherapy starting 
from week 4 
50Gy/25 fractions 
+ 
Surgery 4-6 weeks after 
XRT 
END OF TREATMENT
        SURVIVAL F-UP 
         END OF STUDY 
SCREENING
ENROLEMENT

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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................2 
1. 
BACKGROUND .................................................................................................................6 
1.1 
Disease Background.................................................................................................6 
1.2 
Talimogene Laherparepvec ......................................................................................6 
1.3 
Radiation Therapy in Sarcoma.................................................................................9 
1.4 
Rationale ................................................................................................................10 
2. 
REGISTRATION PROCEDURES ...................................................................................11 
3. 
OBJECTIVES ....................................................................................................................11 
3.1 
Primary Objectives .................................................................................................11 
3.2 
Secondary Objectives .............................................................................................11 
4. 
PATIENT SELECTION ....................................................................................................12 
4.1 
Eligibility Criteria ..................................................................................................12 
4.2 
Exclusion Criteria ..................................................................................................13 
5. 
TREATMENT PLAN AND STUDY SCHEMA ..............................................................15 
5.1 
Study Design ..........................................................................................................15 
5.2 
Study Agent Administration: Talimogene Laherparepvec ....................................17 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................21 
5.4 
Duration of Therapy ...............................................................................................22 
5.5 
Duration of Follow Up ...........................................................................................22 
5.6 
Criteria for Removal from Study ...........................................................................22 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................23 
6.1 
Dose Delays ...........................................................................................................23 
6.2 
Dose Limiting Toxicities .......................................................................................24 
6.3 
Dose Reductions ....................................................................................................24 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................25 
7.1 
Adverse Event Definitions .....................................................................................25 
7.2 
Adverse Event Characteristics ...............................................................................26 
7.3 
Comprehensive Adverse Events and Potential Risks List (CAEPR) .....................26 
7.4 
Important Potential Risks .......................................................................................28 
7.5 
PREGNANCY AND BREASTFEEDING ............................................................31 
7.6 
Other Relevant Information ...................................................................................33 
7.7 
Expedited Adverse Event Reporting ......................................................................33 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................38 
8.1 
Study Drug: Talimogene Laherparepvec ...............................................................38 
9. 
CORRELATIVE, AND SPECIAL STUDIES ..................................................................39 

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10. 
STUDY CALENDAR .......................................................................................................41 
10.1 
Study Procedures ...................................................................................................41 
10.2 
Screening Procedures: ............................................................................................42 
10.3 
Long Term Follow Up ........................................... Error! Bookmark not defined. 
11. 
MEASUREMENT OF EFFECT........................................................................................42 
11.1 
Pathologic Response ..............................................................................................43 
11.2 
Time to Disease progression (TTP) .......................................................................43 
11.3 
Other Response Parameters ...................................................................................43 
12. 
STATISTICAL CONSIDERATIONS...............................................................................44 
12.1 
Study Design/Endpoints.........................................................................................44 
REFERENCES ..............................................................................................................................45 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................48 
APPENDIX B 
RECIST GUIDELINES .............................................................................49 
APPENDIX C: 
CTCAE v.4.0 .............................................................................................50 
APPENDIX D:           CONTRAINDICATIONS AND ADVERSE EVENTS ............................51 
 
APPENDIX E: 
DATA AND SAFETY MONITORING PLAN…………………………53 
 
 
 

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1. BACKGROUND 
 
1.1 
Disease Background 
 
Adult soft tissue sarcomas (STS) constitute a wide heterogeneous group of very rare tumors, 
both in terms of histology and biological and clinical behavior. In contrast to major advances in 
the biological understanding of these heterogeneous subtypes, forward progress in the systemic 
treatment of sarcoma has been painstakingly slow. The prognosis of patients with metastatic or 
recurrent disease is poor and most of them will die from tumor progression. Taking into account 
differences in histology subtype, anatomic location of disease and age at disease onset, the 
overall median survival for patients with metastatic STS is approximately one year and only 
about 10% of these patients are alive at five years.1  
 
Control of localized disease is, therefore, of prime importance as evidenced by the National 
Comprehensive Cancer Network’s (NCCN) current treatment guidelines.2 Pisters et al 
demonstrated that histologic grade, depth of location, and positive surgical margins are key 
determinants of STS recurrence.3 However, patients typically present late with local tumor 
extensions into critical adjacent structures, making complete surgical resection with uninvolved 
margins difficult. Preoperative radiotherapy has been shown to significantly improve local 
disease control, functional outcomes and survival in patients with locally advanced STS.4-6 
 
1.2 
Talimogene Laherparepvec 
 
Talimogene laherparepvec (HSV-1 [strain JS1]/ICP34.5-/ICP47-/hGM-CSF) is an oncolytic 
immunotherapy, formerly known as OncoVEXGM-CSF, an immune-enhanced, oncolytic herpes 
simplex virus type 1 (HSV-1). Talimogene laherparepvec is a replication-competent HSV-1 
designed for intratumoral injection. Talimogene laherparepvec was constructed using a new 
isolate of HSV-1 (strain JS1; ECACC Accession Number 01010209) and has been sequenced. 
The neurovirulence factor ICP34.5 and the ICP47-encoding genes are functionally deleted in the 
virus. The ICP34.5 functional deletion allows the virus to replicate selectively in tumors. The 
role of ICP47 is to block antigen presentation to major histocompatibility complex (MHC) class I 
and II molecules by blocking the transporter associated with antigen processing 1 and 2 (TAP1, 
TAP2). This deletion also allows the increased expression of the US11 gene. This promotes virus 
growth in cancer cells without decreasing tumor selectivity. The virus contains the coding 
sequence for human GM-CSF, a pleotrophic cytokine involved in the stimulation of cellular 
immune responses.  
 
Development of talimogene laherparepvec was conducted in conjunction with the International 
Conference on Harmonization (ICH) guidance on oncolytic viruses. The therapeutic strategy for 
talimogene laherparepvec is to effect tumor cell death by lytic virus replication following direct 
intratumoral injection, combined with induction of an anti-tumor immune response enhanced by 
the local expression of GM-CSF. This combination of direct lysis of the injected tumor plus 
enhancement of the patient’s own immune response is intended to result in both local and distant 
tumor destruction, and to prevent future progression of disease. 
 

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The preparation and testing of the cell banks, viral seed stock, and talimogene laherparepvec 
clinical material were conducted in accordance with current Good Manufacturing Practices 
(cGMP), relevant ICH guidelines, European Directives, and the US Pharmacopeia and Title 21 
Code of US Federal Regulations. In particular, the European Pharmacopoeia (Ph Eur) 
monograph on viral vaccine testing, ICH considerations on Oncolytic Viruses, and Food and 
Drug Administration (FDA) Points to Consider – Characterization of Cell Lines Used to Produce 
Biologicals (1993) have been followed for the safety testing of talimogene laherparepvec.  
 
Talimogene laherparepvec has been studied in several clinical trials in multiple tumor types.  A 
summary of talimogene laherparepvec’s pertinent efficacy results and safety data follow. After 
intra-tumoral injection, talimogene laherparepvec is generally cleared from subjects’ blood and 
urine within 48 hours. Rarely, extremely low levels of virus have been detected on the surface of 
injected tumors for up to 2 weeks following a single dose. In most cases, this was observed in 
seronegative subjects in the phase 1 study, in which a higher first dose of talimogene 
laherparepvec was administered than has been used in subsequent studies. Subsequent studies 
have therefore used a lower initial dose (see below). No evidence of herpes infection attributable 
to talimogene laherparepvec has been documented in study subjects. While a number of 
individuals (subjects or medical personnel) have had reactivations of wild type HSV-1, which is 
not unexpected in the population as a whole, it was determined by culture of the virus and 
polymerase chain reaction (PCR) analysis not to be caused by talimogene laherparepvec. 
 
Please refer to the talimogene laherparepvec Investigator Brochure (IB) for descriptions of all 
available data. 
 
1.2.1 Talimogene Laherparepvec Clinical Experience 
 
Nine clinical studies have been or are being conducted in several advanced tumor types including 
advanced solid tumors, melanoma, squamous cell cancer of the head and neck, and pancreatic 
cancer.28 
 
These studies include a phase 1 study to evaluate the safety, bio-distribution, and biological 
activity of differing dose levels of talimogene laherparepvec in patients with advanced solid 
tumors.27 In this open-label, ascending-dose study, single doses of talimogene laherparepvec 
either 106, 107, or 108 plaque forming units/mL (PFU/mL) (up to 4 mL), were injected directly 
into a single metastatic skin or subcutaneous tumor of breast cancer, head and neck cancer, 
gastrointestinal cancer, or melanoma. This study, as reported by Hu et al, identified that subjects 
who are seronegative for HSV-1 more commonly developed febrile flu-like symptoms and 
erythematous skin rashes at higher initial doses of talimogene laherparepvec (107 and 108 
PFU/mL) compared to a decreased initial dose of 106 PFU/mL.27  
 
In a phase I/II upward-titration study to assess the safety and biological activity of three dose 
levels of talimogene laherparepvec (all initial doses were 106 PFU/mL, followed by subsequent 
doses of 106, 107 or 108 PFU/mL) a greater mean decrease in tumor size was observed in patients 
receiving subsequent doses of 107 PFU/mL or higher compared to those administered only 106 
PFU/mL for all doses.  The study also reported that none of the injected tumors in the lowest 
dose cohort (106 PFU/mL) had resolved by the end of the treatment period, whereas 36.5% 

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(12/32) of measurable tumors resolved (i.e., were no longer detectable) at the higher dose levels, 
suggesting that talimogene laherparepvec has a dose-related effect on tumor necrosis.26 Necrosis 
of injected tumors, confirmed on histopathology, was observed in both seropositive and 
seronegative subjects. These data supported the conclusion that an initial dose of 106 PFU/mL, 
followed by doses of 108 PFU/mL, was appropriate for use in further trials. This dose regimen 
has been used in several ongoing phase III of trials including in subjects with advanced stage 
melanoma.28 
 
Clinical data currently available indicate that talimogene laherparepvec has the potential to 
provide overall clinical benefit to patients with advanced melanoma (Talimogene Laherparepvec 
Investigator’s Brochure, 2012). In particular, a high rate of complete response (CR) was 
achieved (20% in the phase 2 study with talimogene laherparepvec in stage IIIc to IV 
melanoma).29  Response was still ongoing for all but 1 subject at the time of the last tumor 
evaluation, with a median duration of longest response of 223 days (Talimogene Laherparepvec 
Investigator’s Brochure, 2012). In addition, responses were observed in both injected and 
uninjected sites, including visceral sites. 
 
In another study, patients with stage III/IVA/IVB squamous cell cancer of the head and neck 
(SCCHN) were treated with intra-tumoral injections of talimogene laherparepvec in combination 
with chemoradiotherapy in a phase I/II study. Subjects received chemoradiotherapy (70 Gy/35 
fractions with concomitant cisplatin 100 mg/m2 on days 1, 22, and 43) and dose-escalating (106, 
106, 106, 106 pfu/mL for cohort 1; 106, 107, 107, 107 for cohort 2; 106, 108, 108, 108 for cohort 3) 
by intratumoral injection on days 1, 22, 43, and 64. Patients underwent neck dissection 6 to 
10 weeks later.  
 
The results from this study are reported in Harrington et al and indicate that seventeen patients 
were treated without delays to chemoradiotherapy or dose-limiting toxicity. Fourteen patients 
(82.3%) showed tumor response by Response Evaluation Criteria in Solid Tumors, and 
pathologic complete remission was confirmed in 93% of patients at neck dissection. HSV was 
detected in injected and adjacent uninjected tumors at levels higher than the input dose, 
indicating viral replication. All patients were seropositive at the end of treatment. No patient 
developed locoregional recurrence, and disease-specific survival was 82.4% at a median follow-
up of 29 months (range, 19-40 months).26 
  
1.2.2 Talimogene Laherparepvec Safety Experience 
 
An observational registry study is ongoing to investigate the long-term survival and safety of 
subjects previously treated with talimogene laherparepvec in any study.27 Preliminary safety data 
from the completed clinical studies for which adverse event data are available has shown that the 
most commonly (> 10%) occurring adverse events (without regard to causality and including 
talimogene laherparepvec given in combination with cisplatin and radiation) are nausea, 
vomiting, diarrhea, chills, pyrexia, fatigue, flu-like symptoms, injection site reactions, and 
myalgia.  Other common (> 1% and < 10%) reactions include arthralgia, pain in extremity, 
cellulitis, headaches, and dizziness. The adverse event profile, therefore, may include events 
related to talimogene laherparepvec, chemotherapy, radiation, tumor-related signs and 

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symptoms, disease progression, and/or a combination of these.26 Data thus far supports 
talimogene laherparepvec to be a safe and well tolerated immunotherapy in human subjects. 
 
Injection Site Reactions 
Talimogene laherparepvec is administered by direct injection into cutaneous, subcutaneous, and 
nodal tumor masses.  Injection site adverse events may occur, such as erythema, local skin 
discoloration, induration, warmth, and pain.  Infrequently, injected cutaneous tumor masses may 
undergo necrosis, predisposing the subject to local and/or systemic infections.  Similarly, 
injected pathologic lymph nodes may enlarge or become necrotic.  Uncommonly, necrotic lymph 
nodes may be the site of persistent drainage that requires corrective measures. In clinical studies, 
adverse events of “injection site pain” and “injection site reaction” were very common, occurring 
in ≥ 10% of talimogene laherparepvec-treated subjects.  Most events of injection site pain and 
injection site reaction in subjects receiving talimogene laherparepvec were mild to moderate in 
severity. Subjects seronegative at baseline for HSV-1, when given an initial dose of talimogene 
laherparepvec at a concentration of 106 PFU, do not appear to experience more exaggerated 
injection site reactions than those who are seropositive at baseline.   
 
Cellulitis 
Necrosis of cutaneous tumor masses and pathologic lymph nodes injected with talimogene 
laherparepvec may infrequently occur, predisposing to local/regional infection (ie, cellulitis). In 
clinical studies to date, cellulitis was common, occurring in ≥ 1% to < 10% of subjects treated 
with talimogene laherparepvec.   
 
Flu-like Symptoms 
Constitutional symptoms including chills, fatigue, headache, myalgia, and pyrexia may occur 
with talimogene laherparepvec.  Collectively, this constellation of symptoms may be described 
as “flu-like symptoms.”  In clinical studies to date, adverse events with the MedDRA preferred 
terms “chills,” “fatigue,” “headache,” “influenza like illness,” “myalgia,” and “pyrexia” were 
very common, occurring in ≥ 10% of subjects treated with talimogene laherparepvec.  Most of 
these events were mild to moderate in severity.  Subjects seronegative at baseline for HSV-1, 
when given an initial dose of talimogene laherparepvec at a concentration of 106 PFU, do not 
appear to experience more flu-like symptoms than those who are seropositive at baseline.  These 
symptoms are self-limiting and resolve without sequelae.   
 
1.3 
Radiation Therapy in Sarcoma 
 
The benefits of combination therapy with radiation and surgery in significantly improving local 
control in STS patients are well documented. Preoperative radiotherapy has been shown to 
significantly improve local disease control, functional outcomes and survival in patients with 
locally advanced STS.4-6 Recent review of literature indicates that about 10% of patients will 
have ≥ 95% tumor necrosis, and about 25% will achieve ≥ 80% tumor necrosis following 
preoperative radiation therapy alone.7-8  Further review indicates that only those patients who 
achieve ≥ 95% tumor necrosis with preoperative radiation have improved local and distant 
control as well as overall survival.8  Despite its reported benefits, radiotherapy is associated with 
a high rate of complications and significant functional morbidity. O’Sullivan et al compared 
preoperative versus postoperative external beam radiation (EBRT) for resectable extremity STS.  

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Long term follow up revealed no statistical difference in local control and cause specific 
survival, however, preoperative radiotherapy was associated with a significantly higher rate of 
acute wound complications (35% vs. 17%, p = 0.01) and a lower rate of late Grade 2– 4 fibrosis 
(32% vs. 48%, p = 0.07).9-10 Multiple retrospective reviews have similarly found high rates of 
acute wound complications in sarcoma patients ranging from 25% to 44%.11–14   These reported 
high rates of acute and late toxicities support the need for additional research to improve the 
safety profile of neoadjuvant radiotherapy. 
 
In addition, there is need to improve efficacy of the radiation treatments to achieve higher rates 
of tumor necrosis, and, to ensure resection of the tumor with clear margins for successful organ 
preserving treatment of sarcoma. 
 
 
1.4 
Rationale 
 
Immunotherapy has long been discussed as a promising method for the treatment of patients with 
solid tumors but thus far its exact role in sarcoma remains to be defined. Analysis of sera from 
sarcoma patients indicate the presence of both humoral and cellular immune responses against 
cancer-testis antigens commonly associated with sarcoma tumors and sarcoma cell lines, 
indicating that immune modulation may play a central role in sarcoma-genesis.15-17 Viruses have 
been used in the treatment of cancer since the early 20th century.16 Herpes simples virus type 1 
(HSV-1) is a highly lytic virus which infects a wide variety of human cell types and rapidly 
replicates itself, resulting in cell lysis and inflammation. This replication can be rendered tumor 
selective through deletion of the HSV-1 gene encoding ICP34.5.19-20 Talimogene laherparepvec, 
is a replication-competent, immune-enhanced HSV-1 for intratumoral injection. It is made from 
a new HSV-1 strain in which the neurovirulence genes encoding ICP34.5 and ICP47 have been 
deleted. The deletion of ICP34.5 allows for selective replication of the virus in tumor cells.  
Deletion of ICP47 prevents the inhibition of antigen presentation usually caused by the 
expression of this protein, and also promotes tumor-selective viral replication. In addition, the 
ICP34.5-gene has been replaced with the coding sequence for human granulocyte macrophage 
colony stimulating factor (GM-CSF), to enhance the immune response to tumor antigens 
released from virus replication.21-22 
 
The primary goal of this study is to improve on the 10% of patients who achieve ≥ 95% tumor 
necrosis historically seen with radiation therapy alone.7-8 Theoretically, replicating HSV-derived 
oncolytic agents are sufficient to cause impressive cell killing independent of any interactions 
with the immune system. Oncolytic HSV-1 elicits an immune response both to the HSV and to 
tumor-specific antigens. The expressed GM-CSF further stimulates a cytotoxic T cell response 
against tumor antigens released through viral oncolysis.21-22 The T-cell stimulation index and the 
level of immune response may have important correlation with clinical vaccine efficacy, as seen 
in the phase III trial by Small et al.30  Additionally, there is growing evidence that radiation 
induces immunogenic tumor cell death and alters the tumor microenvironment to enhance 
recruitment of antitumor T cells and, thus, enhancing the overall immune response.  
 
Finkelstein et al recently demonstrated enhanced antitumoral immune response following 
concurrent administration of dendritic cells and radiation compared to either therapy alone.23 

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Similarly, synergistic effect between talimogene laherparepvec injection and radiotherapy has 
been reported in melanoma patients.24-26 The efficacy and safety of talimogene laherparepvec is 
most mature in studies involving patients with malignant melanoma, pancreatic, and head and 
neck cancers.  At least nine clinical trials and extended protocols have been or are being 
conducted with over 400 subjects treated with talimogene laherparepvec.24-28 An observational 
registry study is ongoing to investigate the long-term survival and safety of subjects previously 
treated with talimogene laherparepvec in any study.27 The most commonly (> 10%) reported 
adverse reactions are nausea, vomiting, diarrhea, chills, pyrexia, fatigue, flu-like symptoms, 
injection site reactions, and myalgia.  Other common (> 1% and < 10%) reactions include 
arthralgia, pain in extremity, cellulitis, headaches, and dizziness. Concurrent therapy with 
talimogene laherparepvec, cisplatin, and EBRT in a recent phase II study was well tolerated and 
the adverse events were mostly mild (Grades 1 and 2). The most frequent toxicities and severity 
in this study were consistent with that seen with conventional chemoradiotherapy.26 Data thus far 
supports talimogene laherparepvec to be a safe and well tolerated immunotherapy in human 
subjects. 
 
 
2. REGISTRATION PROCEDURES 
 
NA; Single Institution study.  
 
3. OBJECTIVES 
 
3.1 
Primary Objectives 
 
Phase 1b: To determine the safety and tolerability of neoadjuvant talimogene laherparepvec in 
combination with preoperative EBRT as assessed by incidence of dose-limiting toxicities (DLT) 
in subjects with locally advanced high grade soft tissue sarcomas.  
 
Phase 2: To estimate the efficacy of neoadjuvant talimogene laherparepvec and radiotherapy as 
assessed by the pathological complete response rates (pCR) in subjects with histologically 
confirmed diagnosis of locally advanced STS that is unresectable with clear wide margins, for 
which preoperative radiotherapy is considered appropriate. 
 
For this study, pCR will be defined as ≥ 95% tumor necrosis following concurrent radiation 
therapy and talimogene laherparepvec. 
 
3.2 
Secondary Objectives 
 
- Overall response rate (ORR) as measured by RECIST 1.1 or a later tool for 
monitoring disease progression.  
- Time to progression  
- Overall survival rate (OS) at 5 years. 
- To further assess the safety of talimogene laherparepvec given concurrently with 
preoperative external beam radiation in sarcoma patients.  
 

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4. PATIENT SELECTION 
 
4.1 
Eligibility Criteria  
 
4.1.1 Subject has provided informed consent. 
 
4.1.2 Histologically confirmed diagnosis of locally advanced STS that is unresectable with 
clear wide margins, for which preoperative radiotherapy is considered appropriate. 
 
EXAMPLES:  
 Resectable stage IIB, III, and IV disease that are not suitable for surgically 
resection alone due to inability to achieve clear margins. 
 Including metastatic (stage IV) disease for which radiotherapy and surgical 
resection are indicated. 
 Except certain histologic subtypes: GIST, Desmoid, Ewing sarcoma, Kaposi 
sarcoma, and bone sarcomas. 
 
4.1.3 Previous treatment: prior systemic anti-cancer treatment consisting of chemotherapy, 
immunotherapy, or targeted therapy are allowed provided therapy completed at least 1 
year prior to enrollment.  
 No prior Talimogene laherparepvec or tumor vaccines allowed. 
 No prior radiation to the same tumor bed allowed. 
 
4.1.4 Age ≥18 years.  
 
4.1.5 Both men and women of all races and ethnic groups are eligible for this trial.  
 
4.1.6 ECOG performance status ≤1. 
 
4.1.7 Patient must have measurable disease: 
 Tumor size at least ≥ 5 cm in the longest diameter as measured by CT scan or MRI 
for which radiation is feasible. 
 
4.1.7.1 
Patient must have injectable disease (direct injection or ultrasound guided). 
 

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4.2 
Exclusion Criteria 
4.2.1 Certain histologic subtypes: GIST, Desmoid, Ewing sarcoma, Kaposi sarcoma, and bone 
sarcomas 
 
4.2.2 History or evidence of sarcoma associated with immunodeficiency states (e.g.: Hereditary 
immune deficiency, HIV, organ transplant or leukemia). 
 
4.2.3 Subjects with retroperitoneal and visceral sarcoma. 
 
4.2.4 History or evidence of gastrointestinal inflammatory bowel disease (ulcerative colitis or 
Crohn’s disease) or other symptomatic autoimmune disease including, inflammatory 
bowel disease, or history of any poorly controlled or severe systemic autoimmune disease 
(i.e., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, type I diabetes, or 
autoimmune vasculitis). 
 
4.2.5 History of other malignancy within the past 3 years except treated with curative intent 
and no known active disease present and has not received chemotherapy for ≥ 1 year 
before enrollment/randomization and low risk for recurrence. 
 
4.2.6 History of prior or current autoimmune disease.   
4.2.7 History of prior or current splenectomy or splenic irradiation. 
 
4.2.8 Active herpetic skin lesions  
 
4.2.9 Require intermittent or chronic treatment with an anti-herpetic drug (e.g., acyclovir), 
other than intermittent topical use. 
 
4.2.10 Any non-oncology vaccine therapies used for the prevention of infectious disease within 
28 days prior to enrollment and during treatment period. 
 
4.2.11 Concomitant treatment with therapeutic anticoagulants such as warfarin. 
 
4.2.12 Known human immunodeficiency virus (HIV) disease (requires negative test for 
clinically suspected HIV infection). 
 
4.2.13 Acute or chronic hepatitis B or hepatitis C infection (requires negative test for clinically 
suspected hepatitis B or hepatitis C infection).   
 
 Evidence of hepatitis B - 
1. Positive HBV surface antigen (indicative for chronic hepatitis B or recent acute 
hepatitis B). 
2. Negative HBV surface antigen but positive HBV total core antibody (indicative 
for resolved hepatitis B infection or occult hepatitis B) and detectable copies of 
HBV DNA by PCR (detectable HBV DNA copies suggest occult hepatitis B). 
  
 Evidence of hepatitis C - 

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1. Positive HCV antibody and positive HCV RNA by PCR (undetectable RNA 
copies suggest past and resolved hepatitis C infection). 
 
4.2.14 Female subjects who are pregnant or breast-feeding, or planning to become pregnant 
during study treatment and through 3 months after the last dose of study treatment. 
 
4.2.15 Female subjects of childbearing potential or male subjects who are unwilling to use 2 
highly effective methods of contraception during study treatment and through 3 months 
after the last dose of study treatment. See Section 7.5 for more details. 
 
4.2.16 Currently receiving treatment in another investigational device or drug study, or less than 
30 days since ending treatment on another investigational device or drug study(s). 
 
4.2.17 Other investigational procedures while participating in this study that could affect the 
primary objective of the study as determined by the PI are excluded.  
 
4.2.18 Subject previously has entered this study. 
 
4.2.19 Patients who are receiving any other investigational agents. 
 
4.2.20 Evidence of CNS metastases.   
 
4.2.21 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to talimogene laherparepvec. 
 
4.2.22 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
4.2.23 Patients on or requiring immunosuppressive therapies.   
 
4.2.24 Any of the following laboratory abnormalities:  
 Hemoglobin < 9.0 g/dL  
 Absolute neutrophil count (ANC) < 1500 per mm3  
 
 Platelet count < 100,000 per mm3  
 Total bilirubin > 1.5 × ULN 
  
 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN 
 Alkaline phosphatase > 2.5 × ULN 
 
 PT (or INR) and PTT (or aPTT) > 1.5 × ULN 
 Creatinine > 2.0 × ULN  
 
 
 
 
 

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5. TREATMENT PLAN AND STUDY SCHEMA 
 
5.1 
Study Design 
 
This is a single-arm open-label phase Ib and phase II clinical study assessing the safety and 
relative efficacy of concurrent talimogene laherparepvec in combination with radiotherapy in 
patients with soft tissue sarcomas. Patients will be treated with neoadjuvant radiation and weekly 
intratumoral injections of talimogene laherparepvec. Weekly injections of talimogene 
laherparepvec will be continued until surgery. Surgery will be performed 4-6 weeks from the end 
of radiation therapy to allow for resolution of acute toxicities per current standard of care. 
 
Phase 1b: 
The phase Ib portion of this study is to ensure the safety and tolerability of talimogene 
laherparepvec in combination with EBRT as assessed by incidence of dose-limiting toxicities 
(DLT). Although this combination has been shown to be safe and well tolerated in several other 
tumor types including melanoma and head & neck cancers, this combination has not been 
studied in sarcoma patients.  EBRT will be given at the standard dose for resectable soft tissue 
sarcomas according to the NCCN sarcoma guidelines.2 Patients will receive 50 Gy over 5 weeks, 
during which time they will be receiving weekly injections of talimogene laherparepvec. Weekly 
injections of talimogene laherparepvec will be continued until surgery 4-6 weeks later. Surgery 
will be performed 4-6 weeks from the end of radiation to allow for adequate tissue healing and 
resolution of acute toxicities. 
 
Talimogene laherparepvec will be dosed at an initial dose of up to 4.0 mL of 106 PFU/mL on day 
1 of week 1, followed by the target dose of up to 4.0 mL of 108 PFU/mL (Dose 0) three weeks 
later on day 1 of week 4, and dosed weekly until surgery. Initially 3 patients will be entered at 
the Dose 0 (following initial dose of up to 4.0 mL of 106 PFU/mL on day 1 of week 1) for 
talimogene laherparepvec and be monitored at this weekly dose through 4 injections, when safety 
issues will be addressed.  If none or one of the 3 patients shows a DLT, three more patients will 
be entered into the study at this dose and be monitored at this weekly dose through 4 injections.  
If none or one of these 6 patients shows a DLT, this is the dose that will be used for the phase II 
relative efficacy assessment. Otherwise, talimogene laherparepvec dose will be deescalated and 
dose -1 will be explored as outlined below in Table 1.  For this protocol DLT will be defined as 
an attributed adverse event (definite, probable or possible) that meets the criteria in Section 6.2.  
 
Phase 2: 
The phase 2 part of the study will provide an estimate of the relative treatment effect of 
talimogene laherparepvec in combination with preoperative EBRT in subjects with histologically 
confirmed diagnosis of locally advanced STS that is unresectable with clear wide margins, for 
which preoperative radiotherapy is considered appropriate, as measured by pathological response 
rates.  Twenty- three (23) patients will be enrolled into the phase 2 portion of this protocol.  
 
As above, patients will receive the first dose of talimogene laherparepvec 4.0 mL of 106 PFU/mL 
on day 1 of week 1, and followed three weeks later by weekly injections at Dose 0. Weekly 
injections of talimogene laherparepvec will be continued until surgery. The EBRT will be given 
at the standard dose for resectable soft tissue sarcomas according to the NCCN sarcoma 

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SAFETY FOLLOW-UP
guidelines.2 Patients will receive preoperative radiation at a dose of 50 Gy over 5 weeks starting 
around week 4, and continued concurrently with weekly injections of talimogene laherparepvec. 
Subjects should be followed by clinic visit every 12 weeks for approximately 24 months after the 
end of the treatment phase, at which time the initial survival data and disease recurrence will be 
assessed.   Subjects will be followed for an additional 3 years for survival and disease recurrence 
after that according to the standard-of-care.  Please see study calendar in Section 10.  
 
Study Timeline Schema:  
 
 
 
 
 
 
 
 
 
 
 
Phase 1b schema: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase 2 schema: 
 
 
 
 
 
 
 
 
 
 
 
SCREENING
ENROLLMENT
END OF TREATMENT
SAFETY FOLLOW-UP
END OF STUDY
 
Talimogene laherparepvec 
Up to 4 mL 
106 PFU/mL followed by 
108 PFU/mL Q-weekly 
+ 
Radiotherapy starting 
from week 4 
50Gy/25 fractions 
+ 
Surgery 4-6 weeks after 
XRT 
 
 
Phase II 
Talimogene laherparepvec 
Up to 4 mL 
106 PFU/mL x 1 followed 
by 
108 PFU/mL Q-weekly 
+ 
Radiotherapy starting 
from week 4 
50Gy/25 fractions 
+ 
Surgery 4-6 weeks after 
XRT 
END OF TREATMENT
        SURVIVAL F-UP 
         END OF STUDY 
SCREENING
ENROLEMENT
XRT 
Weekly Talimogene laherparepvec 
Day 1, Week 1 
End of Week 8 
End of Week 12, 13, or 14 
Follow up every 12 weeks through 24 months 
First dose of TVEC 
Complete XRT 
Complete TVEC MRI of tumor then Surgery 
Day 1 Week 4 

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Table 1.  
Number of Patients with DLT at a 
Given Talimogene Laherparepvec 
Dose 
Decision Rule 
> 2 
Dose level will be declared toxic. 
If this is the lowest dose level, stop the study due to 
excessive toxicity; otherwise enter three additional 
patients at the next lowest dose level 
< 1 out of 3 
Enter three more patients at this dose level 
< 1 out of 6 
This is the recommended dose for the subsequent 
pilot study 
 
Talimogene Laherparepvec Dose Levels: 
Dose 0 = talimogene laherparepvec up to 4.0 mL of 108  PFU/mL dosed weekly 
Dose -1 = talimogene laherparepvec up to 4.0 mL of 108 PFU/mL dosed every 2 weeks. 
 Initial dose for all = talimogene laherparepvec up to 4.0 mL of 106 PFU/mL 
 
Rationale for Talimogene Laherparepvec Dosing 
Multiple studies have documented the efficacy and safety of talimogene laherparepvec in 
melanoma and head and neck cancer patients.24-26  In a phase I study to evaluate the safety, bio-
distribution, and biological activity of differing dose levels of talimogene laherparepvec in 
patients with advanced solid tumors, Hu et al identified that subjects who are seronegative for 
HSV-1 more commonly developed febrile flu-like symptoms and erythematous skin rashes at 
higher initial doses of talimogene laherparepvec (107 and 108 PFU/mL) compared to a decreased 
initial dose of 106 PFU/mL.27 Additionally, in a phase I/II upward-titration study to assess the 
safety and biological activity of three dose levels of talimogene laherparepvec (all initial doses 
were 106 PFU/mL, followed by subsequent doses of 106, 107 or 108 PFU/mL) a greater mean 
decrease in tumor size was observed in patients receiving subsequent doses of 107 PFU/mL or 
higher compared to those administered only 106 PFU/mL for all doses.  The study also reported 
that none of the injected tumors in the lowest dose cohort (106 PFU/mL) had resolved by the end 
of the treatment period, whereas 36.5% (12/32) of measurable tumors resolved (i.e., were no 
longer detectable) at the higher dose levels, suggesting that talimogene laherparepvec has a dose-
related effect on tumor necrosis.26  For this study all subjects will be treated with an initial dose 
of talimogene laherparepvec 106 PFU/mL, followed by 108 PFU/mL for all subsequent doses in 
accordance with the currently approved maximum tolerated dosing per the above phase I studies.  
 
5.2 
Study Agent Administration: Talimogene Laherparepvec 
 
5.2.1 Talimogene Laherparepvec Dose Levels: 
 Initial dose for all = talimogene laherparepvec up to 4.0 mL of 106 PFU/mL 
 Dose 0 = talimogene laherparepvec up to 4.0 mL of 108  PFU/mL dosed weekly 
 Dose -1 = talimogene laherparepvec up to 4.0 mL of 108 PFU/mL dosed every 2 
weeks. 
 
Dosing Schedule: 
Patients will be treated with 50 Gy over 5 weeks and concurrent weekly injections of talimogene 

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laherparepvec. Weekly injections of talimogene laherparepvec will be continued until surgery, 
about 4-6 weeks later. 
 
Dosing Information: 
Talimogene laherparepvec will be only administered by intratumoral injection into soft tissue 
tumors with or without image ultrasound guidance. Talimogene laherparepvec must not be 
administered into visceral organ metastases.  
 
The initial dose of talimogene laherparepvec is up to 4.0 mL of 106 PFU/mL. Subsequent doses 
of talimogene laherparepvec are up to 4.0 mL of 108 PFU/mL. The maximum volume of 
talimogene laherparepvec administered at any dose is 4.0 mL for any individual lesion. The 
maximum dose in any one treatment is 4.0 mL. Investigators are encouraged to use the 
maximum amount whenever lesions allow. In response to severe AEs, dose delays and dose de-
escalations may be employed, but dose volume reduction for AEs is not allowed – see Section 6. 
However if in the course of administration of talimogene laherparepvec the subject cannot 
tolerate the full dose due to an injection-related AE such as pain, the total volume given should 
be recorded, and the reason for intolerance should be documented as an AE. 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
5.2.2 Lesion site preparation 
 Talimogene laherparepvec is only to be administered by intralesional injection into soft 
tissue tumors with or without image ultrasound guidance.  Talimogene laherparepvec 
must not be administered into visceral organ metastases.  
 The injection site may be pre-treated with a topical anesthetic agent or an injectable local 
anesthetic; however, a local anesthetic must not be injected directly into the lesion. 
 Swab the lesion and surrounding areas with alcohol, allow to dry. 
 
5.2.3 Lesion 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). 
 Inject talimogene laherparepvec intralesionally: 
a)  A single point of insertion is recommended; multiple insertion points may be used if 
the tumor is larger than the radial reach of the needle. 
b) Talimogene laherparepvec should be injected along multiple different tracks within 
the lesion in order to obtain as wide a dispersion as possible. 
c)  Distribute talimogene laherparepvec within the lesion through the insertion point 
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 Avoid premature extraction of needle. 
 After dosing, the injection site should be swabbed with alcohol and pressure should be 
applied with gauze for several seconds after injection. 
 The injection site should be covered with an absorbent pad and dry occlusive dressing. 
 Dispose materials used during injection (e.g., gloves, needles, gauze) in accordance with 
local/regional and institutional requirements for biohazardous waste. 
 
 
5.2.4 Radiation Therapy 
 
External beam radiation therapy will be given at the standard dose for resectable soft 
tissue sarcomas according to the NCCN sarcoma guidelines.2 Patients will receive 50 Gy 
over 5 weeks, during which time they will be receiving weekly injections of talimogene 
laherparepvec. Weekly injections of talimogene laherparepvec will be continued until 
surgery 4-6 weeks later. Surgery will be performed 4-6 weeks from the end of radiation 
to allow for adequate tissue healing and resolution of acute toxicities. 
 
Radiation therapy for this protocol is as per currently used standard pre-operative radiation 
therapy at the University of Iowa even for non-protocol patients. 
Selected guidelines from previously conducted Radiation Therapy Oncology Groups (RTOG) 
studies are briefly summarized for this protocol. 
 
Preoperative Radiation therapy (3D-CRT or IMRT)  
Either 3D conformal radiotherapy or intensity modulated radiation therapy may be utilized for 
adequate tumor coverage and to meet the dose constraints for critical normal structures. 
 
Radiation treatment planning scans and immobilization: 
CT scans with patient in a stable and comfortable position will be used for planning. MRI scans 
are optional and may be used for co-registration with CT for tumor localization as needed. 
VacLoc or other immobilization devices can be used for immobilization. 
 
Target volumes and treatment field: 
Gross Target Volume (GTV): Outline of the tumor as seen on CT or CT/MRI fusion.  
Clinical Target Volume (CTV): CTV = GTV plus 4 cm margins in the proximal and distal 
directions.  However the margin can be reduced if it extends  beyond the compartment, the field 
can be shortened to include the end of a compartment. The radial margin from the lesion should 
be 1 cm. It can be reduced in areas confined by the fascial barrier or bone or skin surface. 
Planning Target Volume (PTV): Include CTV and error of setup and organ motion. Typically 
PTV includes CTV plus 1 cm in all dimensions. Final PTV is usually GTV + 5 cm longitudinal 
and 2 cm radial, except where restricted by the compartment end, fascia, bone or skin surface.  

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Use of bolus on the skin surfaces is optional as needed. Where applicable, biopsy scars should be 
bolused with appropriate thickness specific to the energy of the photon beam.  
 
Dose Specifications: 
A dose of 50 Gy in 25 daily fractions will be prescribed to the planning target volume (PTV) 
using linear accelerator and megavoltage photon beams with energies of 6MV or greater. 
Prescribed dose should cover > 90% of the PTV. More than 95% of the PTV should receive > 
95% of the prescribed dose. No more than 20% of the PTV will receive ≥ 110% prescription 
dose. 
 
Precautions and Dose Constraints for critical structures: 
Radiation dose to normal tissues should be kept within the accepted normal tissue tolerances. 
Every effort should be made to: 
a) Avoid treating the full circumference of an extremity;  
b) Avoid treating anus, urogenital tract, perineum and genitalia; if the tumor is close to these 
structures, typically less than 50% volume of the anus and vulva should receive 30 Gy; less than 
50% volume of the testis should receive 3 Gy, if the patient prefers to reserve fertility;  
c) Avoid treating the lung, through use of appropriate shielding and treatment planning; less than 
20% of the lungs should receive 20 Gy (V20); 
d) Avoid dose maximums in areas where surgical scars will be placed; this may require 
reviewing treatment plans with the surgeon; 
e) If possible, avoid treating skin over areas commonly traumatized to full dose (e.g., the elbow, 
knee, shin, femoral neck). 
f) If possible, less than 50% of any joints (including shoulder, elbow and knee) should receive 50 
Gy.  
g) Less than 50% of kidney volumes should receive 18 Gy.  
h) No more than 50% of normal weight-bearing bone within the radiation field should receive 50 
Gy except when the tumor invades the bone or when there is circumferential involvement of the 
tumor more than a quarter of the bone or when the bone will be resected in a subsequent surgical 
resection after radiation. 
For any other normal tissue structures, no radiation dose more than the established TD5/5 limit 
should be given.  
 
Image Guidance and Verification Devices 
Portal films or conebeam CT images should be used for target localization and alignment. 
Daily conebeam CT will be preferred and dose from daily conebeam should be included in the 
final dosimetry. 
 
Postoperative Radiotherapy Boost  
External Beam or Brachytherapy boost can be given at the discretion of the radiation oncologist, 
to the positive tumor margin (residual tumor) only plus a margin of 1 cm within 2 weeks 
following surgery or after adequate wound healing has occurred. 
The target volume for postoperative radiotherapy will be the residual tumor bed as defined by the 
surgical and pathological findings.  
 
 

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External Beam Radiotherapy 
Postoperative external beam boost dose is 16 Gy in 8 fractions (once a day).  
 
Brachytherapy 
High-dose-rate (HDR) brachytherapy as a boost to the positive tumor margin can be 
used as an alternate to external beam radiotherapy. Brachytherapy catheters are 
placed at an interval of 0.5 -1.0 cm on the residual tumor bed (positive margin) plus a 
margin of 1 cm during surgery. Skin surface dose should be kept below 50% of the 
prescription dose unless positive margins occur in cutaneous or subcutaneous tissues. 
It is not necessary to include the entire surgical bed, drain sites and wound. 
Brachytherapy should not start until day 5 after the surgery (day 0) and must be 
completed within 2 weeks following surgery. 
 For HDR brachytherapy, 4 fractions of 3.4 Gy are delivered b.i.d, with an interval of 
 
at least 6 hours between fractions. 
 
Radiation Therapy Adverse Events  
Acute: Wound complications of any grade are expected to develop in about one third of patients. 
Other common radiation adverse events include: fatigue, regional alopecia, diarrhea, skin 
erythema and desquamation within the treatment fields, and reduction in blood counts. 
Long-term: Common long-term treatment adverse events include: lymphedema of the extremity 
receiving radiation and surgery, subcutaneous fibrosis, and joint stiffness. Much less common 
radiation adverse events include bowel injury, osteoradionecrosis, and bony fracture in the 
radiation field. There also is a risk of secondary malignancy occurring in the irradiated field.  
 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, etc., when appropriate. The reason(s) for treatment, dosage, and the 
dates of treatment should be recorded. 
 
All other protocol-required therapies including, topical anesthetic or an injectable local 
anesthetic medications used for pretreatment of the talimogene injection site and oral or systemic 
treatments required for management of immune-mediated AEs that are to be obtained 
commercially. 
 
Throughout the study, investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care. All prescription and nonprescription 
concomitant medication administered up to 28 days prior to enrollment, on an ongoing basis at 
enrollment, as well as changes in such concomitant medication, and any new concomitant 
medication taken while the subject is on study, should be recorded up to 30 days after the last 
dose of talimogene laherparepvec.  
  
 
 

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5.4 
Duration of Therapy 
 
Concurrent immunoradiotherapy with a total of 50 Gy of radiation and weekly talimogene 
laherparepvec intratumoral injections will be given over 5 weeks. Then, weekly intratumoral 
injections of talimogene laherparepvec will be continued until surgery is performed around 4-6 
weeks later. In the absence of treatment delays due to adverse event(s), treatment may continue 
until surgical resection of the tumor, or until one of the following criteria applies: 
 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), 
 
Patient decides to withdraw from the study, or 
 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
 
5.5 
Duration of Follow Up 
 
Safety Follow up Visit 
 
Upon permanent discontinuation from the study treatment for any reason, the following 
procedures will be performed approximately 30 (+7) days after the last dose of Talimogene 
Laherparepvec: 
 Recording of concomitant medications and AE/SAE(s) 
 Physical examination including weight, vital signs and ECOG performance status 
assessment 
 Local laboratory tests including the following: 
o Hematology panel 
o Chemistry panel 
o Serum or urine pregnancy test for female subjects of childbearing potential 
 
Long-term Follow up 
 
Following the end of treatment, subjects will be followed according to standard of care 
(approximately every 12 weeks), at the discretion of the treating physician, at which time disease 
recurrence and survival status will be assessed for up to 5 years.  Data for disease recurrence and 
survival status only will be collected per chart review, phone call or email.   
 
End of Study 
 
The end of study for each subject is defined as the date the subject withdraws full consent from 
the study, completes the safety follow-up visit or the long-term survival follow-up whichever is 
later, or death. 
 
5.6 
Criteria for Removal from Study 
 

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Talimogene laherparepvec is to be permanently discontinued for subjects meeting any of the 
following criteria: 
 The subject, for any reason, requires treatment with another anticancer therapeutic agent for 
treatment of the study disease (other than the exceptions noted in protocol, if applicable). In 
this case, discontinuation from the treatment occurs immediately upon introduction of the 
new agent.  
 Clinical relevant disease progression as defined in the study protocol.  
 Immune-mediated adverse events have been observed in subjects receiving talimogene 
laherparepvec.  These have included pauci-immune glomerulonephritis, vasculitis, and 
pneumonitis; however, immune-mediated adverse events can potentially involve any organ 
system. Permanently discontinue talimogene laherparepvec if dosing is delayed by more than 
4 weeks due to a Grade 2 or greater immune-mediated adverse event (with the exception of 
vitiligo), allergic reactions, or urticaria attributed to talimogene laherparepvec.  
 Plasmacytoma has been observed with the administration of talimogene laherparepvec. 
Permanently discontinue talimogene laherparepvec if development of a plasmacytoma is 
observed. 
 Any talimogene laherparepvec-related non-hematologic or hematologic toxicities Grade 3 or 
greater that, in the opinion of the investigator, would require a dose delay of greater than 4 
weeks (approximately 6 weeks from the previous dose) or discontinuation of therapy. 
 A female subject becomes pregnant or fails to use 2 highly effective methods of 
contraception (for those subjects who are able to conceive).  
 A female subject breast feeds while on study treatment. 
 A male subject fails to use a highly effective method of contraception as described in Section 
7.5. 
 Intercurrent medical illness that, in the judgment of the investigator, would make continued 
treatment with talimogene laherparepvec dangerous for the subject. 
 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Dose Delays 
 
If talimogene laherparepvec treatment was delayed due to adverse events or other reasons by > 1 
week, that dose will be deemed to have been missed and the subject will proceed to the next 
scheduled treatment visit.  
 
If dose-limiting toxicities occur, talimogene laherparepvec administration should be delayed 
until the DLT has resolved to at least CTCAE version 4.0 Grade 1 (see Appendix E). Dosing of 
talimogene laherparepvec could also be delayed for active herpetic cutaneous or mucosal lesions, 
herpes labialis, or active dermatoses in the region of the injected tumors. Talimogene 
laherparepvec should be discontinued for subjects with evidence of systemic herpetic infection, 
herpetic keratitis, encephalitis, or evidence of other disseminated herpetic infection or any 
herpetic infection requiring treatment with acyclovir or a similar agent. 
 

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If talimogene laherparepvec dosing is delayed by more than 4 weeks due to the occurrence of 
DLT or adverse events that are related to talimogene laherparepvec, then treatment should be 
discontinued. If talimogene laherparepvec dosing is delayed by more than 4 weeks for reasons 
other than treatment-related toxicity, the case must be reviewed by the sponsor of the 
investigator sponsor study (ISS) to determine if the subject can resume talimogene laherparepvec 
therapy. 
 
If the subject requires corticosteroid dosing of > 10 mg prednisone daily (or equivalent) and/or 
other immunosuppressive medication for related toxicities, talimogene laherparepvec dosing 
must be held until the corticosteroid dose has decreased to < 10 mg prednisone daily (or 
equivalent) and the administration of the other immunosuppressive medication has discontinued. 
 
6.2 
Dose Limiting Toxicities 
 
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 or related to the combination of talimogene 
laherparepvec and radiation therapy during treatment and up to 4 weeks after the last talimogene 
laherparepvec injection:  
 Grade 3 or greater immune-mediated adverse events  
 Grade 3 or greater allergic reactions. 
 Any grade plasmacytoma 
 Any other unexpected grade 3 or greater hematologic or non-hematologic toxicity, with the 
exceptions of:  
 Any grade of alopecia. 
 Expected radiation related skin toxicity of any grade. 
 Grade 3 arthralgia or myalgia. 
 Brief (< 1 week) grade 3 fatigue. 
 Grade 3 fever. 
 Grade 3 diarrhea or vomiting responding to supportive case. 
 
Of note, unless an alternative etiology has been identified, signs and symptoms of any disease 
process described above as a DLT should be considered immune-mediated.  
 
If unexpected DLT occurs, talimogene laherparepvec administration should be delayed until the 
DLT has resolved to at least CTCAE version 4.0 grade 1. If dosing is delayed by more than 4 
weeks due to the occurrence of unexpected adverse event that is considered related to talimogene 
laherparepvec, then the subject should be taken off treatment. 
 
6.3 
Dose Reductions  
Dose reductions with regards to changes in the concentrations of talimogene laherparepvec are 
not permitted.   
 
 Patients may require a reduction in the volume injected due to a disease response as outlined 
in Section 5.1.  

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 Additionally, subjects who miss two consecutive doses of talimogene laherparepvec due to a 
DLT should be reduced to a biweekly dosing (dose -1 as in section 5.1). 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting in addition to routine reporting. 
 
Information regarding the occurrence of adverse events will be collected from the time the 
subject signs the informed consent form and throughout their participation in the study, including 
a period of 30 days after the last dose of study drug (data on serious adverse events (SAEs) will 
be collected until resolution of the event unless otherwise noted).  Serious adverse events 
occurring outside the 30-day follow-up period, which are assessed as related to study drug, 
should be reported to Amgen, along with any SAE that the investigator feels should be reported.   
 
7.1 
Adverse Event Definitions 
 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  An adverse event can be any unfavorable and 
unintended sign (eg, including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of the drug, without any judgment about causality.  This includes any 
newly occurring event or previous condition that has increased in severity or frequency since the 
administration of drug. 
 
Following surgical resection of the tumor, non-serious adverse events consistent with an 
expected post-operative course will not be reported unless attributable to the study drug and/or 
meet the seriousness criteria.   
 
An adverse event is considered a serious adverse event (SAE) if it results in any of the 
following outcomes: 
1) Results in death 
2) Is a life-threatening event (ie, its occurrence places the patient or subject at immediate risk 
of death) 
3) Requires inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  
5) Is a congenital anomaly/birth defect 
6) Is an important medical event that may not result in death, be life threatening, or require 
hospitalization but may be considered serious when, based upon medical judgment, may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
 

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Suspected Adverse Reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
 
Unexpected Adverse Events  
An adverse event is considered “unexpected” if it is not listed in the table of expectedness within 
the Investigator Brochure or is not listed at the specificity or severity that has been observed; or, 
if an Investigator Brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
 
When talimogene laherparepvec is administered in combination with 1 or more approved 
antineoplastic agents, the expectedness determination should take into account the labeling of 
each specific marketed drug taken in combination based upon reference documents which will be 
included or referenced in the clinical study protocol.  The labeled events should, in general, be 
considered expected for at least one of the drugs in the combination.  The contribution of 
talimogene laherparepvec to the severity or frequency of the events is currently unknown.  
See Section 1.2.2 for adverse drug reactions that could be reasonably assumed to be associated 
with talimogene laherparepvec.  
 
7.2 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Appendix 
E) will be utilized for AE reporting.  If specific grading is not available in the CTCAE for a 
particular AE’s severity/intensity, the Investigator is to revert to the general definitions of Grade 
1 through 5 and use his/her best medical judgment.  The 5 general grades are: Grade 1 = mild, 
Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening or disabling, Grade 5 = death 
related to AE. 
 
Attribution of the AE: 
Investigators are required to assess whether there is a reasonable possibility that talimogene 
laherparepvec caused or contributed to the adverse event.  The following general guidance may 
be used. 
 Definite – The AE is clearly related to the study treatment. 
 Probable – The AE is likely related to the study treatment. 
 Possible – The AE may be related to the study treatment. 
 Unlikely – The AE is doubtfully related to the study treatment. 
 Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 

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All necessary supportive care shall be available to subjects. Additional treatment modifications 
should be considered depending upon the subject’s clinical situation. Talimogene laherparepvec 
treatment should be continued based on the potential risk/benefit assessment of the subject.   
 
7.3.1 Important Identified Risks  
 
Accidental Exposure of Healthcare Providers (HCP) to Talimogene Laherparepvec 
A needle stick injury, spill, or splash back during administration may result in accidental 
exposure of HCPs to talimogene laherparepvec. The ICP34.5 gene deletion is intended to allow 
only tumor selective replication and limited or no viral replication in normal tissues. However, 
talimogene laherparepvec injection can result in signs or symptoms of primary infection at the 
site of exposure. A few reports of accidental exposure in study personnel have been received. In 
one of the cases, the exposed physician developed clinical signs/symptoms of a herpetic 
whitlow-like lesion at the site of the accidental needle stick injury that resolved without sequelae. 
An initial antibody assay was positive for an HSV-type virus. A confirmatory PCR assay was 
conducted 10 days after the accidental exposure and was positive for a virus with the ICP47 
deletion, indicating that the virus was most likely talimogene laherparepvec. None of the other 
exposed individuals reported signs or symptoms of infection. In some cases oral acyclovir or 
valacyclovir was administered. 
 
Cellulitis at Site of Injection 
Intralesional administration of talimogene laherparepvec by injection has been associated with 
cellulitis at the injection site. In some cases, a local inflammatory reaction with localized tumor 
necrosis developed, and in other cases, a bacterial infection developed. In the pivotal clinical 
study, the subject incidence of adverse events in the bacterial cellulitis category was 6.2% (n = 
18) in the talimogene laherparepvec group and 1.6% (n = 2) in the GM-CSF group. The most 
frequently reported preferred term was cellulitis (5.8% in the talimogene laherparepvec group 
and 1.6% in the GM-CSF group). Seven subjects (2.4%) in the talimogene laherparepvec group 
and 1 subject (0.8%) in the GM-CSF group experienced serious adverse events of cellulitis. 
Fever, elevated white blood cell count, bacteremia or sepsis, and hospitalization for intravenous 
antibiotics were reported in 5 of the 7 cases in the talimogene laherparepvec group.  Subjects 
should be monitored closely for cellulitis and injection site reactions.  
 
Disseminated Herpetic Infection in Severely Immunocompromised Individuals 
Patients with immunosuppression for any reason were excluded from clinical trials with 
talimogene laherparepvec. Disseminated herpetic infection in severely immunocompromised 
individuals is defined as an important identified risk based on the nonclinical data and literature 
described below. Evidence of lethal systemic viral infection was observed in 100% of severe 
combined immunodeficiency (SCID) mice (deficient in T and B cells) following intratumoral 
injection of talimogene laherparepvec in a mouse colon carcinoma xenograft model. Similar 
findings were observed in up to 20% of BALB/c nude mice (primarily deficient in T-cell 
function) following intratumoral injection of talimogene laherparepvec in Ewing’s sarcoma and 
osteosarcoma xenograft models. Viral inclusion bodies and/or necrosis in enteric neurons in the 
gastrointestinal tract, adrenal gland, and skin were observed in both mouse strains; and in 
pancreatic Islet cells, eye, pineal gland, and brain of SCID mice. Lethality in 100% of animals 
following intracutaneous injection of wild-type HSV-1 in nude mice has been reported 

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(Hayashida et al, 1982; Yamamoto et al, 1985). The data in talimogene laherparepvec treated 
SCID mice indicate that severe toxicity associated with disseminated viral infection may occur in 
patients who are severely immunosuppressed. The data in the BALB/c nude mice suggest the 
potential for toxicity due to talimogene laherparepvec in patients with less severe 
immunosuppression. Consistent with the general literature, these data indicate an important role 
of host defenses including T and B cells in the immune response to talimogene laherparepvec 
and HSV-1 viruses.   
 
Immune-mediated Adverse Events 
Based on review of adverse events suggestive of an immune-mediated etiology across melanoma 
studies, immune-mediated adverse events considered possibly related to talimogene 
laherparepvec were reported in 2% of subjects treated with talimogene laherparepvec, and 
included events of vasculitis, glomerulonephritis, acute renal failure, pneumonitis, and worsening 
psoriasis. Other contributory factors were identified in several of these cases, including pre-
existing immune-mediated conditions, other concurrent medications, or intercurrent medical 
events. 
 
Plasma Cell Dyscrasia (Plasmacytoma) at the Injection Site 
A plasmacytoma was reported in 1 subject treated with talimogene laherparepvec in the pivotal 
clinical study. A plasmacytoma developed in the area of the injected tumor on the scalp after 9 
cycles of treatment with talimogene laherparepvec. Study treatment was permanently 
discontinued. On medical review, the event was determined likely to be a secondary 
plasmacytoma which developed at the injection site due to recruitment of plasma cells in 
response to the talimogene laherparepvec injections in a subject who had a pre-existing 
(smoldering) multiple myeloma. 
 
Other important identified risks include obstructive airway disorder and deep vein thrombosis.   
 
 
 
7.4 
Important Potential Risks 
 
Symptomatic Talimogene Laherparepvec Infection in Non-tumor Tissue in Treated 
Patients 
Talimogene laherparepvec is a modified HSV-1 virus, and is engineered to replicate selectively 
in tumor tissue. However, if infection by talimogene laherparepvec of non-tumor tissue in treated 
patients were to occur, this could lead to development of clinical signs or symptoms that would 
be anticipated to be similar to signs or symptoms of wild-type herpes virus infection. 
 
In mouse tumor models, viral lysis/tissue injury was limited to tumors. No clinical or 
pathological evidence of symptomatic infection or injury to normal tissues was observed in 
nonclinical models dosed by repeated intratumoral, intravenous, or subcutaneous injection, 
including mice dosed with up to 107 PFU talimogene laherparepvec (~60-fold over the highest 
proposed clinical dose, on a PFU/kg basis) via weekly subcutaneous injection for up to 3 months. 
 
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patients have been reported to date. In the pivotal clinical study, adverse events related to HSV 
infections were reported in 5.5% (n = 16) of subjects in the talimogene laherparepvec group and 
1.6% (n = 2) in the GM-CSF group. Most of the cases were reported as oral herpes and 1 case 
each was reported as herpes simplex and herpetic keratitis in the talimogene laherparepvec 
group. The subject with herpetic keratitis had a history of this event prior to enrollment in the 
study. Whether the reported lesions were due to wild-type herpes or to talimogene laherparepvec 
could not be confirmed as viral testing was not performed. 
 
Transmission of Talimogene Laherparepvec from Patient to Close Contacts or HCPs Via 
Direct Contact with Injected Lesions or Body Fluids (eg, Blood or Urine) Resulting in 
Symptomatic Infection (Primary or Reactivation) 
Proximity of close contacts and HCPs to lesions in treated patients in the absence of effective 
barriers may result in the unintentional exposure of these individuals to talimogene 
laherparepvec. Exposure may occur via direct contact with injected lesions or via contact with 
body fluids (eg, blood or urine). The likelihood of transfer of talimogene laherparepvec to a close 
contact or HCP increases if the contact has a break in the skin or mucous membranes. Signs or 
symptoms of infection would be anticipated to be similar to signs and symptoms of wild-type 
HSV infection.  
 
Biodistribution by quantitative polymerase chain reaction (qPCR) testing in clinical studies 
indicated that low copy numbers of viral DNA were sporadically detected from 1 hour to 1 week 
after intratumoral injection in blood and urine in 30% of subjects across all studies. Where 
subsequent samples were available, no viral DNA was detected at 2 weeks after injection. 
 
Shedding results showed that talimogene laherparepvec was detected on the surface of injected 
lesions for up to 2 weeks after injection in 8 of 72 (11%) subjects. Virus was not detected on the 
exterior surface of tumor dressings at any time point tested. 
 
Biodistribution was evaluated after single and multiple dosing by intravenous, subcutaneous or 
intratumoral injection in mice. Doses from 1 x 105 to 1 x 107 PFU/mL were evaluated (0.6 to 
60-fold higher compared to the maximum clinical dose). Across the studies, viral DNA was 
found most commonly at the site of injection regardless of administration route, which in the 
case of the tumor may reflect viral replication following intratumoral administration. Following 
intravenous administration of talimogene laherparepvec, viral DNA was detected in blood of 5 of 
6 animals through 56 days of dosing. After intratumoral injection, talimogene laherparepvec 
DNA was detected by PCR in tumor, blood, in tissues associated with immune related viral 
clearance (lymph nodes, spleen), and tissues with high blood perfusion (heart, lung, liver). Viral 
DNA was found in the brain in 2 of 91 samples collected. Viral DNA was not detected in bone 
marrow, eyes, lachrymal glands, nasal mucosa or feces at any time point. Following intratumoral 
injection, viral DNA was cleared from the blood of most animals within 2 weeks postdose and in 
all animals by 6 weeks after the last dose. Following subcutaneous dosing, viral DNA was 
excreted in urine in 22% of animals within 24 hours postdose and all were negative at 4 weeks 
postdose. 
 
Symptomatic Herpetic Infection Due to Latency and Reactivation of Talimogene 
Laherparepvec or Wild-type HSV-1 in Patients 

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Infection of tumor or non-tumor tissue could potentially lead to the establishment of latency and 
subsequent reactivation of talimogene laherparepvec if the virus came into contact with axonal 
nerve terminals and was transported to neuronal cell bodies. The genetic modifications made to 
talimogene laherparepvec do not prevent the virus from entering latency or subsequently 
reactivating. However, HSV-1 strains deficient in the ICP34.5 gene are unable to replicate 
efficiently in non-tumor cells, including neurons, and are impaired for establishment and 
reactivation from latency when compared to wild-type HSV-1 (Chou et al, 1990; Perng et al, 
1995; Perng et al, 1996, Robertson et al, 1992; Spivack et al, 1995). Thus, reactivated virus in 
nerve cells is expected to be less likely to lead to clinical signs or symptoms as compared to 
wild-type HSV-1. 
 
Co-infection of neurons already harbouring latent wild-type HSV-1 by talimogene laherparepvec 
could potentially stimulate the reactivation of latent wild-type HSV-1 in patients with prior 
infection. A febrile response associated with injection of talimogene laherparepvec might 
stimulate reactivation of wild-type HSV-1 in patients with prior exposure and latent HSV-1 
infection. 
 
Biodistribution studies in mice have detected low levels of talimogene laherparepvec in 
trigeminal ganglia (at levels 0.2-1.2% found in concurrent blood) through 28 days in 1 of 6 
animals following high dose intravenous administration (0.6 × 107 PFU, ~36-fold over the 
highest proposed clinical dose). Talimogene laherparepvec was undetectable in trigeminal 
ganglia in mice after subcutaneous administration.  
 
In a mouse model, talimogene laherparepvec was detected in the spinal dorsal root ganglia 
following injection into the foot. This suggests the virus had established latency in the nerve root 
innervating the site of injection. The virus was reactivated in ex vivo cell culture. The clinical 
applicability of these findings is not certain, as it is anticipated that host immunity will respond 
to protect the host from talimogene laherparepvec replication in non-tumor tissue in individuals 
with an intact immune system.  
 
 
 
Talimogene Laherparepvec-mediated Anti-GM-CSF Antibody Response 
There is a theoretical concern that transgene-derived expression of GM-CSF could induce an 
immune response reactive with endogenous GM-CSF. Antibodies against GM-CSF have been 
detected sporadically in the general population (up to 9.6%) (Meager et al, 1999). Case reports of 
cryptococcal meningitis and pulmonary alveolar proteinosis have been reported in association 
with auto-antibodies to GM-CSF (Rosen et al, 2013). Auto antibodies to GM-CSF were 
demonstrated to reproduce the disease of pulmonary alveolar proteinosis in nonhuman primates 
(Trapnell et al, 2009). It is not known whether such phenomena could be expected with the 
limited exposure anticipated with transgene expression of GM-CSF from talimogene 
laherparepvec. 
 
 
Impaired Wound Healing at Site of Injection 
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chronic inflammation, necrosis, and ulceration of tumor sites, and in the presence of other risk 
factors, delayed healing may result. In the pivotal clinical study, the incidence of adverse events 
in the impaired wound healing category was 5.5% (n = 16) in the talimogene laherparepvec 
group and 2.4% (n = 3) in the GM-CSF group. Wound complication, wound secretion, and 
wound infection were reported in ≥ 1% of subjects in the talimogene laherparepvec group. A 
serious adverse event of impaired healing was reported in an elderly subject following treatment 
with talimogene laherparepvec to a recurrent lower extremity melanoma lesion that resulted in a 
below the knee amputation 7 months after the last treatment. The subject had a history of 
peripheral vascular disease, prior radiation at the site of injection, and recurrent cellulitis in the 
area, all which were considered possible contributory factors.  All subjects should be monitored 
very closely for impaired wound healing especially in the setting of concurrent use of radiation 
therapy.   
 
Disseminated Herpetic Infection in Individuals with Deficiency in Cell-mediated Immunity 
Such as Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome 
(AIDS), Lymphoma, or Leukemia, or Who Require High Dose Steroids or Other 
Immunosuppressive Treatments Such as Post Organ Transplant 
Talimogene laherparepvec is a recombinant replication-competent HSV-1 type virus which is 
engineered to replicate selectively in tumor cells. Intratumoral injection of talimogene 
laherparepvec was 100% lethal in SCID mice (SCID model) and in up to 20% of athymic mice 
(nude mouse model). Refer to the characterization of the important identified risk of 
“disseminated herpetic infection in severely immunocompromised individuals” for a description 
of results of nonclinical studies in SCID mice and BALB/c nude mice (Section 7.2.3). 
 
The clinical relevance of these data to patients treated with talimogene laherparepvec is not clear. 
Wild-type HSV-1 infection in immunocompromised individuals is associated with dissemination 
of the virus and serious, life-threatening toxicity. Patients with immunosuppression were 
excluded from clinical trials with talimogene laherparepvec. The potential risk and potential 
benefits of treatment of patients with HIV/AIDS, leukemia, lymphoma, or patients who require 
treatment with chronic high dose steroids or other immunosuppressive agents such as those used 
in the post transplant setting should be considered prior to treatment. Talimogene laherparepvec 
is contraindicated in patients with severe immunodeficiency. 
 
 
Other Relevant Information 
Refer to the DCSI attached to this brochure as Appendix D for a description of current 
information related to adverse drug reactions, special warnings and precautions, 
contraindications, and risks for overdoses with talimogene laherparepvec.  
 
 
7.5 
PREGNANCY AND BREASTFEEDING 
 
Pregnancy 
No studies of the effects of talimogene laherparepvec on reproduction and development have 
been performed in humans. Talimogene laherparepvec should not be used during pregnancy. 
 

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Females: 
Pregnant women and women planning to become pregnant should not receive talimogene 
laherparepvec. Women who can become pregnant must use 2 highly effective birth control 
methods (either by her alone or in combination with her male partner) during treatment with 
talimogene laherparepvec and for at least 3 months after the last tumor injection of talimogene 
laherparepvec. Highly effective methods of contraception include: 
 Use of hormonal birth control methods: pills, shots, implants (placed under the skin by a 
health care provider) or patches (placed on the skin) 
 Intrauterine devices (IUDs) 
 Sexual activity with a male partner who has had a vasectomy (surgery to become sterile) 
 Prior surgery to tie her fallopian tubes (surgery to become sterile) 
 Condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide 
 
If a woman becomes pregnant or suspects she is pregnant, she must tell her doctor immediately 
and treatment with talimogene laherparepvec will be stopped. The study doctor should notify 
Amgen of the pregnancy, discuss any follow-up with the subject, and ask for information on the 
pregnancy outcome.  
 
Males: 
The potential for talimogene laherparepvec to be transferred via semen and its effect on sperm 
are unknown. Males with partners of childbearing potential, must agree for the duration of the 
treatment with talimogene laherparepvec and continuing for 3 months after the last tumor 
injection of talimogene laherparepvec to practice a highly effective method of birth 
control,(either by him or his female partner). Highly effective methods of contraception include: 
 Use of hormonal birth control methods: pills, shots, implants (placed under the skin by a 
health care provider) or patches (placed on the skin) 
 Intrauterine devices (IUDs) 
 Sexual activity with a male partner who has had a vasectomy (surgery to become sterile) 
 Prior surgery to tie her fallopian tubes (surgery to become sterile) 
 Condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide 
 
If a pregnancy occurs, the study doctor must be notified. The study doctor should notify Amgen 
of the pregnancy, discuss any follow-up with the subject (and/or his partner), and ask for 
information on the pregnancy outcome. If the female partner is already pregnant when the male 
subject begins treatment with talimogene laherparepvec, he must refrain from any sort of sexual 
activity that could expose his partner or the unborn baby to talimogene laherparepvec through 
semen, or wear a condom during sexual activity while receiving treatment with talimogene 
laherparepvec and for at least 3 months after the last tumor injection of talimogene 
laherparepvec. 
 
Breast Feeding: 
Amgen has not tested whether talimogene laherparepvec is present in breast milk nor assessed 
the effects of talimogene laherparepvec in breast-fed infants. Therefore, babies should not be fed 
breast milk produced during treatment with talimogene laherparepvec or for an additional 3 
months after the last tumor injection of talimogene laherparepvec. 

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7.6 
Other Relevant Information 
Refer to Appendix D of this document and the DCSI in the latest version of the talimogene 
laherparepvec Investigator’s Brochure for a description of current information related to 
contraindications and risks for overdoses with talimogene laherparepvec as well as information 
on the use of talimogene laherparepvec in special subject groups such as pregnant or breast 
feeding, pediatric, or geriatric populations. 
 
7.7 
Expedited Adverse Event Reporting 
 
7.7.1 Expedited Reporting Guidelines 
 
Reporting to the HCCC DSMC   
 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND 
within 30 Days of the Last Administration of the talimogene laherparepvec. 
 
All serious adverse events must be reported to the DSMC within the timeframes detailed below. 
Hospitalization 
Grade 1 and Grade 2 
Grade 3-5 
Resulting in 
 inpatient hospitalization 
10 calendar days 
1 business day initial; 
5 calendar day 
report 
Not resulting in 
inpatient hospitalization 
 
Not required 
Expedited AE reporting timelines are defined as: 
 “1 business day; 5 calendar days” - The AE must initially be submitted electronically using 
OnCore within 1 business day of learning of the SAE, followed by a complete expedited 
report within 5 calendar days of the initial notice. 
 “10 Calendar Days” – A complete expedited report on the AE must be submitted 
electronically via OnCore within 10 calendar days of learning of the AE. 
Serious adverse events that occur more than 30 days after the last administration of investigational   
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows: 
 
Expedited 24-hour notification followed by complete report within 5 calendar days for:            
 All Grade 3, 4, and Grade 5 SAEs 
 
Expedited 10 calendar day reports for: 
 Grade 2 SAEs resulting in hospitalization or prolongation of hospitalization 
 
Serious Adverse Events 
 
An adverse event is considered serious if it results in ANY of the following outcomes:   

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1. Death  
2. A life-threatening adverse event  
3. An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
5. A congenital anomaly/birth defect.  
6. Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).  
 
The investigator is responsible for ensuring that all SAEs observed by the investigator or 
reported by the subject that occur after signing of the informed consent through 30 (+ 7) days 
after the last dose of talimogene laherparepvec are submitted to institutional IRB and FDA. The 
SAE must be submitted to IRB within 10 working days following the investigator’s knowledge 
of the event via the Reportable Event Form (REF) in HawkIRB. 
 
 
Reporting Requirements 
 
Safety Reporting to Amgen 
The Sponsor/Investigator is responsible for compliance with expedited reporting requirements 
for serious, unexpected and related adverse events (SUSARs), for generation of SAE reports 
including narratives, and for periodic reporting to Amgen of SAEs as outlined in Table 2 and 
Table 3 below. Individual safety reports (Table 2) should be accompanied by the Fax Cover 
Form and sent to Amgen Global Safety, utilizing the fax of email information provided on the 
cover page.  Aggregate safety reporting (Table 3) including listings, tabulations and summary 
reports should be scanned and accompanied by the Fax Cover Form and sent to Amgen NASCR, 
utilizing the email information provided on the cover page.   
 
In addition to the requirements outlined in Table 2 and 3, Sponsor/Investigators are required to 
report direct exposures to talimogene laherparepvec (e.g., needle stick, splash back) of herpetic 
illness and all suspected herpetic events (refer to Section ‘Accidental Exposures to Talimogene 
Laherparepvec and Herpetic Events’). 
 
 
Table 2.  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.   
Individual reports should be faxed to 1-888-814-8653 or scanned and sent via email to svc-ags-in-us-

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@amgen.com.  
 
Table 3.  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.) 
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 no later than 1 calendar year after study 
completion 
Aggregate reports should be submitted via email to the Amgen NASCRT manager, accompanied by 
 the Fax Cover Form.  
 
Please refer to the ICH Guidelines E2A for safety related definitions and terminology: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/E2A_
Guideline.pdf. 
 
 
 
Accidental Exposures to Talimogene Laherparepvec and Herpetic Event Reporting  
 
In order to better assess and understand the potential risks to treated patients and/or third parties 
following the treatment of clinical trial subjects with talimogene laherparepvec, special reporting 
procedures apply for accidental exposures to talimogene laherparepvec and for suspected 
herpetic events. See Table 4 ‘Accidental Exposure and Herpetic Event Reporting Requirement 
Summary.’ Clinicians should review the Imlygic package insert (available online) for additional 
information on the safe handling of talimogene laherparepvec. 
 
Accidental Exposure of HCPs to Talimogene Laherparepvec  
 
HCPs involved in your clinical trial who were directly exposed to talimogene laherparepvec 
(e.g., needle stick, splash back) but who are without signs or symptoms of herpetic illness should 
be reported to Amgen at 1-855-IMLYGIC (1-855-465-9442).  
 
Suspected Herpetic Events  
 
Suspected herpetic events must be reported to Amgen within 24 hours of awareness. 
Reporting is required for: (1) suspected herpetic events in treated patients; (2) suspected herpetic 
events in at risk HCPs with direct or indirect exposure and 3) suspected herpetic events in treated 
patient’s close contacts, as outlined in Table 4.  
 

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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:  
- 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.  
o Reporting Process for HCPs and Close Contacts:  
 
- Sponsor Investigator should advise any HCPs and/or Close Contacts with suspected 
herpetic lesions to contact their personal physician to facilitate reporting to Amgen. 
Suspected herpetic lesions should be reported by the personal physician or exposed 
individual to Amgen at 1-855-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 4. 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?  
Responsible 
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 / 
Investigator  
Sponsor / 
Investigator 
and Amgen  
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 
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 
Collect swabs 
from 
suspected 
lesions (ideally 
within 3 days 
Yes, if consent 
obtained  
HCP or HCP’s 
Personal 
Physician  
HCP’s 
Personal 
Physician and 
Amgen  

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Reporting to the FDA  
 
It is the responsibility of the IND sponsor-investigator to comply with IND safety reporting as 
set forth in the Code of Federal Regulations, Section 312.32. This responsibility includes 
providing an annual IND report to the FDA. In addition: 
 
 The FDA will be notified via phone (800-332-1088) or fax (800-FDA-0178) within 7 
calendar days of any SAE that is associated with study treatment, is unexpected, and is 
fatal or life- threatening. 
 
 The FDA will be notified via fax (800-FDA-0178) or online submission 
(http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf) 
with a MedWatch (3500A or 3500) within 15 calendar days of any SAE that is associated 
with the study treatment, unexpected, and serious but not fatal or life-threatening. This 
includes any previous SAEs that were not initially deemed reportable, but are later 
determined to meet the criteria for reporting (i.e. by the DSMC). 
 
MedWatch 3500a Reporting Guidelines: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/ucm2007307.htm 
 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of 
the MedWatch 3500a form: 
 
 Treatment regimen (dosing frequency, combination therapy) 
 Protocol description (and number, if assigned) 
 Description of event, severity, treatment, and outcome, if known 
 Supportive laboratory results and diagnostics 
herpetic 
lesions  
event  
of appearance 
of symptoms)  
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  
*The laboratory conducting the qPCR testing on behalf of Amgen is Viracor.  

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 Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
 
8. PHARMACEUTICAL INFORMATION 
 
8.1 
Study Drug: Talimogene Laherparepvec 
 
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. The following dosage strengths will be made available: 
 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   
 
8.1.1 Packaging and Formulation of Investigational Product  
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 2 cc vial will contain approximately 1.15 mL of 
talimogene laherparepvec. Vials are appropriately filled to ensure that a sufficient deliverable 
dose is provided.  Each vial is intended for single use only.  
 
Vials will be sealed with rubber stoppers, Fluorotec-coated on the product side. The vial caps 
will be color coded and may be used to help distinguish between the 106 PFU/mL and 
108 PFU/mL vial concentrations. 
 
8.1.2 Drug storage 
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 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 2.   Acceptable Storage Temperature 
 
Talimogene laherparepvec is stable if maintained in accordance with the guidelines described in 
this document and the provided expiration date.   
Freezer Set Point (ºC) 
Acceptable Parameters: 
Acceptable Range: 
-80°C 
(+/- 10°C) 
-70° to -90° C or below 

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8.1.3 Agent Ordering and Agent Accountability 
Sponsors of clinical studies are required to establish a record of receipt, storage, use and 
disposition of all talimogene laherparepvec used to conduct a clinical study.  The Sponsor of the 
clinical study is responsible for ensuring that accountability is maintained and accurate at each 
clinical site where the study is conducted. At study activation or as required, initial shipments of 
talimogene laherparepvec 106 PFU/mL and 108 PFU/mL concentrations will be shipped to the 
contact and address provided by the Study Sponsor. It is the responsibility of the Study Sponsor 
to maintain the records of talimogene laherparepvec accountability in accordance with ICH GCP.   
 
Complete study drug information (including packaging, labeling, ordering, storage and 
disposition) is provided in the Talimogene laherparepvec Pharmacy Information Guide. 
 
 
9. CORRELATIVE, AND SPECIAL STUDIES 
 
The underlying hypothesis driving this clinical trial is that the induction of high titers of antibody 
by intra-tumoral talimogene laherparepvec will result in enhanced tumor recognition by the 
immune system, and subsequently leading to improved disease control. Patients treated on this 
study will undergo evaluation of immune response to treatment, including serologic response, 
and evaluation of the baseline and post-treatment cytokine profile and inflammatory response.  
 
The results will be used to correlate response to vaccination with subsequent clinical outcome. 
 
Blood Samples: 
Patient serologic and inflammatory response will be measured at baseline during Screening and 
prior to the Visit Week 1 injection of the study drug, and immediately preceding injections at 
Visit Weeks 4, 7, 10, 12 and 18 (+/- 1 week). 
 
With each collection, 1 Red top tube and 1 Green top tube for serum and mononuclear cells 
(MNC) will be collected for the following tests: 
 Cytokine Profile: IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-alpha, IFN-gamma, 
IFN-alpha, GM-CSF. 
 HSV serology. 
 NK-cell functional assay. 
 
Tumor Tissue Samples: 
The tumor biopsy samples will be used to study the relationship between the immune response 
induced by talimogene laherparepvec and clinical response or resistance to talimogene 
laherparepvec. Tumor slides will be systemically analyzed at baseline and post-treatment to 
evaluate changes in the number and/or type of immune cells infiltrating the tumor during 
treatment. The protocol may be modified to include analysis of the immune and cancer cells in 
the tumor to identify ribonucleic acid transcripts and/or proteins whose levels change with 
treatment, and to assess tumor specific mutations or epigenetic changes.  
 

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 As described above a pre-treatment biopsy sample must be obtained within 3 months 
from the initiation of treatment.  
 
 The biopsy sample will be assessed for baseline tumor infiltrating lymphocytes (TILs) by 
the same pathologist. This will include CD3, CD4, CD8, CD56, and FOXP3 positive 
cells. 
 
 Post treatment TILs, as above, will be assessed on the resected tumor at the end of 
treatment. 
 
Additionally, blood samples and tumor samples may be saved for any potential additional or 
future analyses such as tumor specific mutations or epigenetic changes (eg, somatic mutations) 
on tumor tissues. 
 
The study may be amended to include additional testing to ensure analytical methods produce 
reliable and valid data throughout the course of the study. This can also include, but is not 
limited to, investigation of unexpected results, incurred sample reanalysis, and analyses for 
method transfer and comparability. 
 
 
 

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10. STUDY CALENDAR 
10.1 
Study Procedures 
 
Study Treatment (week number)a 
Study 
Procedures 
Screen-
ing  
1i 
2 
3 
4i 
5 
6 
7i 
8 
9 
10i 
11 
12i 
Surgery 
(wks 
12-14) 
End of 
Treat-
menti 
Long-term 
follow up h 
General Assessments 
Progress Note 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Recording of 
Concomitant 
Medications 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Vital Signs b 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Physical 
Exam, 
including 
weight 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
Performance 
Status 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Review of 
AEs & SAEs c 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Talimogene 
laherparepvec 
injection j 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Correlative 
labs i 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
Radiation 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Survival 
Status/Disease 
Recurrence  
 
 
 
 
  
  
  
  
  
 
 
 
 
 
 
X 
Local Laboratory Tests d 
Pregnancy 
(serum or 
urine) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Chemistry d 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
CBC, 
differential, 
Platelets d 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Coagulation 
(PT or INR 
and PTT or 
aPTT) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST, ALT, 
AlkPhos, Bili, 
Albumind 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Thyroid 
Function 
Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical & Radiographic Tumor/Response Assessments 
Tumor biopsy 
Must be biopsy confirmed within 3 months prior to study enrollment 
 
Primary  
Tumor 
Assessment 
(MRI/CT)e, g 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
CT Chest, 
Abdomen, 
and Pelvis f  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 

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a. 
Assessments will occur on Day 1 (+/- 3 days) of the week number. 
b. 
Blood pressure, resting pulse, respiration rate, and temperature. 
c. 
All serious adverse events (SAEs) will be reported within 24 hours of the discovery of the event. 
d. 
May be monitored more frequently if indicated. 
e. 
Tumor assessment will be documented per RECIST. 
f. 
CT chest, abdomen, and pelvis at screening (up to 28 days prior to initiation of treatment), Weeks 12 and 18 (+/- 2 weeks), 
and then standard of care for up to 5 years, at discretion of treating physician. 
g. 
Primary tumor (MRI/CT) at screening (up to 28 days prior to initiation of treatment) and on Day 1 week 1 (or up to 28 days 
prior and before initiation of treatment) and on Day 1 week 12 (+ 2 weeks).  
h. 
Follow up per standard of care (approximately every 12 weeks), at the discretion of the treating physician.  Data for survival 
status and disease recurrence only will be collected.  
i. 
Correlative labs for serologic and inflammatory response; 1 Marble Red top and 1 Green top. See Section 9 (+/- 7 days). 
j. 
Talimogene laherparepvec will be given weeks 1 through 12 (+/- 2 weeks) when surgery is expected to be performed. The 
injections must be given the same day of the week +/- 3 days. 
 
10.2 
Screening Procedures: 
 
• Procedures to be completed within 28 days of enrollment/randomization and prior to first 
treatment (unless otherwise noted). 
o Informed Consent 
o Review of eligibility criteria 
o Recording of medical history and concomitant medications 
o Physical Exam (including weight) 
o ECG 
o Vital Signs (Blood pressure, resting pulse, respiratory rate, temp.) 
o Radiographic imaging (Chest, abdomen, and pelvis and all other sites of disease)  
o Imaging of primary tumor site 
 
• Laboratory Assessments 
o Within 28 days of enrollment and prior to first treatment. 
• 
HIV test: Required if clinically indicated 
• 
Hepatitis B and/or C tests: Required if clinically indicated 
o ≤ 10 days of enrollment 
• 
Hematology panel (with 5 part differential).  3 part differential if 5 part 
unable to be performed. 
• 
Chemistry panel 
• 
Coagulation panel 
• 
Thyroid function tests 
o ≤ 3 days of enrollment 
• 
Serum or urine pregnancy test for females of childbearing potential 
 
 
10.3 
Long-term Follow up 
 
After the end of treatment visit is completed, subjects will be followed according to standard of 
care (approximately every 12 weeks), at the discretion of the treating physician, at which time 
disease recurrence and survival status will be assessed for up to 5 years.  Data for disease 
recurrence and survival status only will be collected per chart review, phone call or email.   
 
11. MEASUREMENT OF EFFECT 
 

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11.1 
Pathologic Response  
 
At the end of the neoadjuvant therapy, patients will undergo resection of the treated tumor. The 
pretreatment biopsy and all the resected tumor samples must be reviewed by the same 
pathologist.  
 The percentage of post treatment tumor necrosis must be documented. The primary end 
point for this study is pathologic complete response (pCR), and is defined as ≥ 95% 
tumor necrosis following concurrent radiation therapy and talimogene laherparepvec.  
 
 Additional immunohistochemical studies will be performed as described in Section 9. 
 
11.2 
Time to Disease progression (TTP) 
 
TTP is defined as the time from Enrollment until objective tumor progression including local and 
distant recurrences. 
 
11.3 
Other Response Parameters 
 
The following response assessment guidelines may be amended during the course of the study if 
changes are made to the current RECIST Guidelines or if a new disease assessment tool becomes 
available.  
 
Response Measurement Criteria: 
 
• 
Measurements of the tumor in its largest dimension should be obtained at baseline and at 
the end of the treatment phase, prior to surgical resection.  
• 
Response criteria should be by RECIST. 
• 
Complete response is the disappearance of all target lesions. 
• 
Partial response is a 30% decrease in the sum of the longest dimensions of the 
target lesions, relative to baseline. 
• 
Progressive disease is an increase of 20% or more in the sum of the longest 
dimension of target lesions 
• 
Stable disease is a decrease in the tumor size of < 30% or an increase of < 20%. 
• 
Antitumor response by pathologic assessment will be performed on the resected tumors. 
• 
Pathologic assessment will be performed per institutional guidelines.  
• 
The percent of tumor necrosis and the percent of tumor-infiltrating lymphocytes 
will be documented. 
• 
Complete pathological response will be considered ≥ 95% pathologic tumor 
necrosis. 
 
Radiologic response will be evaluated in this study using the new international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
Please see Appendix B for more details of the RECIST Guidelines. 

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12. STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design/Endpoints 
 
Phase Ib 
The goal of this safety component is to confirm that the current standard dose (neoadjuvant 
administration of concurrent talimogene laherparepvec and external beam radiation therapy) used 
for melanoma patients is well tolerated within this population of sarcoma patients as well. Three 
(3) patients will be recruited for this standard dose.  If none of the three patients shows DLT, this 
dose will be used for the phase II relative efficacy assessment; otherwise, patients dose will be 
deescalated according to the procedure stated in the investigator brochure (dose -1 and dose -2 
will be explored). 
 
Phase II 
The endpoint of our phase II component of the study is the proportion of subjects with pathologic 
tumor necrosis ≥95%. This proportion has been roughly hypothesized to 10% under standard 
care. 
 
The optimal two-stage design to test the null hypothesis that P≤0.120 versus the alternative that 
P≥0.350 has an expected sample size of 13.13 and a probability of early termination of 0.705. If 
the neoadjuvant administration is actually not effective, there is a 0.041 probability of 
concluding that it is. If it is actually effective, there is a 0.196 probability of concluding that it is 
not (the target for this value was 0.200). After testing the concurrent administration on 9 patients 
in the first stage, the trial will be terminated if 1 or fewer respond (i.e. if 0 or 1 patient have 
pathologic tumor necrosis ≥95%). If the trial goes on to the second stage, a total of 23 patients 
will be studied. If the total number responding is less than or equal to 5, the neoadjuvant 
administration will be rejected.  
 
 
P1 
P2 
Stage 1 
Total 
Futility 
Threshold 
Type I 
power 
.12 
.35 
9 
23 
1 and 5 
0.041 
80% 
 
 
Data Analysis and Reporting 
As described in section 3 and section 11, the data for the primary endpoint, pathologic response, 
will be analyzed and reported once all subjects have undergone surgical resection. This will be 
compared to the historical data that suggest that 10% of sarcoma patients achieve pathologic 
complete response with neoadjuvant radiation therapy. 
 
Secondary Endpoint 
The secondary endpoints overall response rate by RECIST and toxicities will also be analyzed 
and reported with the initial analysis soon after all patients have completed surgery. Pertinent 
correlative studies will be reported at this time as well. 

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Other secondary endpoints described in section 3 and section 11, overall survival, and time to 
progression, will be evaluated and reported at 3 and 5 years from the last enrollment. 
 
 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX B 
RECIST GUIDELINES 
 
http://www.eortc.be/recist/documents/RECISTGuidelines.pdf 
 
 
 
 

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APPENDIX C: 
CTCAE V.4.0 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
 
 
 

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APPENDIX D: CONTRAINDICATIONS AND ADVERSE EVENTS 
 
CONTRAINDICATIONS 
Talimogene laherparepvec is contraindicated in patients with a history of life-threatening 
hypersensitivity to talimogene laherparepvec or any of its excipients. 
 
ADVERSE DRUG REACTIONS 
Gastrointestinal disorders SOC: 
Very Common (≥ 10%) 
 Nausea, Vomiting, Diarrhea, Constipation 
 
Common (≥1% and <10%) 
 Weight loss 
 
General disorders and administrative site condition SOC: 
Very Common (≥ 10%) 
 Chills, Pyrexia, Fatigue, Flu like symptoms, Injection site pain  
 
Common (≥1% and <10%) 
 Injection site reactions (including erythema, inflammation, warmth, pain [at injection site and 
at distant, non-injected lesions], swelling [at injection site and/or lymphadenopathy], or 
drainage may occur), Malaise 
 
Metabolism and nutrition disorders SOC: 
Common (≥1% and <10%) 
 Dehydration 
 
Blood and lymphatic system disorders SOC: 
Common (≥1% and <10%) 
 Anemia  
 
Uncommon (≥0.1% and <1%) 
 Plasmacytoma at the injection site 
 
Musculoskeletal and Connective tissue disorders SOC: 
Very Common (≥ 10%) 
 Myalgia, Arthralgia, Pain in extremity 
 
Infections and Infestations SOC: 
Common (≥1% and <10%) 
 Cellulitis (see Warnings and Precautions), Oral herpes 
 
Uncommon (≥0.1% and <1%) 
 Delayed wound healing 
 

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Injury, poisoning and procedural complications: 
Common (≥1% and <10%) 
 Bruising  
 
Vascular disorders SOC: 
Common (≥1% and <10%) 
 Flushing  
 
Nervous System Disorder SOC: 
Very Common (≥ 10%) 
 Headache 
 
Common (≥1% and <10%) 
 Dizziness  
 
Skin and subcutaneous tissue disorders SOC: 
Common (≥1% and <10%) 
 Vitiligo 
 
Respiratory, thoracic and mediastinal disorders SOC: 
Uncommon (≥0.1% and <1%) 
 Laryngeal swelling 
 
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES 
None known. 
 
OVERDOSE 
The maximum dose of talimogene laherparepvec that can be safely administered has not been 
determined. 
 
ABUSE AND DEPENDENCE 
Talimogene laherparepvec is not a controlled substance. There is no evidence that talimogene 
laherparepvec is habit forming or could lead to dependence. 
 
PEDIATRIC USE 
No studies of talimogene laherparepvec have been conducted in pediatric subjects. 
 
GERIATRIC USE 
There are subjects > 65 as well as > 75 years of age who have received talimogene 
laherparepvec. However, no adequate and well-controlled studies have been designed to 
specifically evaluate the use of talimogene laherparepvec in geriatric subjects. 
 
RENAL IMPAIRMENT 
No clinical studies have been conducted in patients with severe renal impairment. 
 

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HEPATIC IMPAIRMENT 
No clinical studies have been conducted in patients with severe hepatic impairment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX E:  DATA AND SAFETY MONITORING PLAN 
 
In accordance with the NIH policy on procedures for data and safety monitoring of clinical 
trials, the Holden Comprehensive Cancer Center (HCCC) has developed systems to ensure 
the safety of participants, the validity and integrity of research data, and compliance with the 
approved protocol. HCCC Principal Investigators are required to include a general 
description of a data and safety monitoring plan as part of each new interventional research 
protocol, which they develop and submit for review. 
All investigator-initiated protocols will contain an appropriately detailed Data and Safety 
Monitoring Plan (DSMP) that will be reviewed and approved by the DSMC or Committee 
Chair. The DSMC dictates what constitutes a satisfactory plan for each study. All 
interventional clinical trials require monitoring for data veracity and safety, including 
physiologic, toxicity- and dose-finding studies (phase I); efficacy studies (phase II); efficacy, 
effectiveness and comparative trials (phase III). The method and degree of monitoring 
needed is related to the degree of risk and should also be commensurate with size and 
complexity of the trial. The Clinical Research Safety Officer (CRSO) of the DSMC will be 
the primary interface with the study’s PI and research team to collect and assemble all 
required materials for review by the Committee. 
Risk Level 
This protocol has been assessed by the Data and Safety Monitoring Committee (DSMC) of 
the HCCC and by the sponsor-investigator as a Risk Level 4. Specifically, a risk-level 4 
clinical trial is one that has: 
– A risk of death (i.e., 100-day treatment-related mortality) of >5%, or, 
– A risk of a Grade 4 SAE (serious adverse event > 15%, or, 
– An investigator-sponsored investigational new drug (IND), or, 
– Gene therapy, gene manipulation, or viral vector systems, or, 
– High-risk clinical procedures performed solely for research purposes, or 
– A new chemical or drug for which there is limited or no available safety data in humans 
Required DSMP elements 
The Principal Investigator for institutional studies at the HCCC must include a trial-specific 
DSMP with each new protocol. The key items the plan must address are 
– A subject eligibility check-list (inclusion / exclusion criteria) 
– A list of expected toxicities 
– Stopping rules for suspension of accrual secondary to adverse events and safety 
parameters 
– PI’s estimate of the study’s risk level 

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The Principal Investigator is to ensure that all required data for monitoring is provided to the DSMC by 
way of the CRSO and the HCCC Protocol Manager. 
 
 

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Eligibility Checklist 
Subject ID: ____________________________________________ 
Date: ___________________ 
Inclusion criteria. All responses must be marked YES or NA for patient to be eligible 
 
1. Subject or subject’s legally acceptable representative has provided informed 
Yes 
No 
 
consent.  
 
2. Histologically confirmed diagnosis of locally advanced STS that is unresectable 
Yes 
No 
with clear wide margins, for which preoperative radiotherapy is considered 
appropriate.  
EXAMPLES: 
 
Resectable stage IIB, III, and IV disease that are not suitable for 
surgically resection alone due to inability to achieve clear margins. 
 
Including metastatic (Stage IV) disease for which radiotherapy and 
surgical resection are indicated. 
 
Except certain histologic subtypes: GIST, Desmoid, Ewing sarcoma, 
Kaposi sarcoma, and bone sarcomas. 
 
3. Previous treatment:  Prior systemic anti-cancer treatment consisting of  
Yes 
No 
chemotherapy, immunotherapy, or targeted therapy allowed provided 
therapy was completed at least one year prior to enrollment. 
 
No prior Talimogene laherparepvec or tumor vaccines allowed. 
 
No prior radiation to the same tumor bed allowed. 
 
4. Aged ≥ 18 years 
Yes 
No 
 
5. ECOG performance status ≤ 1. 
Yes 
No 
6. Patient must have measurable disease: 
Yes 
No 
 
Tumor size at least > 5 cm in the longest diameter as measured by CT scan 
or MRI for which radiation is feasible. 
 
7. Patient must have injectable disease (direct injection or ultrasound guided). 
Yes 
No 
 
 
 
 
 
 
Signature: _____________________________________________ 
Date: ___________________ 

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Eligibility Checklist 
Subject ID: ____________________________________________ 
Date: ___________________ 
Exclusion Criteria. All responses must be marked NO or NA for patient to be eligible 
1. Certain histologic subtypes: GIST, Desmoid, Ewing sarcoma,  
Kaposi sarcoma, bone sarcomas 
Yes 
No 
 
2. History or evidence of sarcoma associated with immunodeficiency states  
Yes 
No 
(e.g., Hereditary immune deficiency, HIV, organ transplant or leukemia) 
 
3. Subject with retroperitoneal and visceral sarcoma 
Yes 
No 
 
 
4. History or evidence of gastrointestinal inflammatory bowel disease (ulcerative 
Yes 
No 
colitis or Crohn’s disease) or other symptomatic autoimmune disease including 
inflammatory bowel disease or history of any poorly controlled or severe systemic  
autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, 
scleroderma, type I diabetes, autoimmune vasculitis) 
 
5. History of other malignancy within the past 3 years except if treated with 
Yes 
No 
curative intent and no known active disease present and has not received  
chemotherapy for > 1 year before enrollment / randomization and low risk for 
 
recurrence. 
 
6. History of prior or current autoimmune disease.  
Yes 
No 
 
7. History of prior or current splenectomy or splenic irradiation. 
Yes 
No 
 
8. Active herpetic skin lesions. 
Yes 
No 
 
9. Require intermittent or chronic treatment with an anti-herpetic drug  
Yes 
No 
(e.g., acyclovir), other than intermittent topical use. 
 
 
 
 
10. Any non-oncology vaccine therapies used for the prevention of infectious  
Yes 
No 
disease within 28 days prior to enrollment and during treatment period. 
 
11. Concomitant treatment with therapeutic anticoagulants such as warfarin. 
Yes 
No 
 
12. Known human immunodeficiency virus (HIV) disease (requires a negative 
Yes 
No 
test for clinically suspected HIV infection). 
 
13. Acute or chronic hepatitis B or hepatitis C infection (requires a negative  
Yes 
No 
 
test for clinically suspected hepatitis B or hepatitis C infection). 
 
Evidence of hepatitis B 
1. Positive HBV surface antigen (indicative for chronic hepatitis B or 
    recent acute hepatitis B) 
2. Negative HBV surface antigen but positive HBV total core 

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    antibody (indicative for resolved hepatitis B infection or 
    occult hepatitis B) and detectable copies of HBV DNA by PCR 
   (detectable HBV DNA copies suggest occult hepatitis B). 
 
Evidence of hepatitis C 
1. Positive HCV antibody and positive HCV RNA by PCR (undetectable 
    RNA copies suggest past and resolved hepatitis C infection). 
 
14. Female subjects who are pregnant or breast-feeding, or planning to  
become pregnant during study treatment and through 3 months after the 
Yes 
No 
last dose of study treatment. 
 
15. Female subjects of childbearing potential or male subjects unwilling to use 
Yes 
No 
2 highly effective methods of contraception during study treatment and through 
3 months after the last dose of study treatment.  See section 7.5 for more details. 
 
16. Currently receiving treatment in another investigational device or drug study,  
Yes 
No 
or less than 30 days since ending treatment on another investigational device or  
drug study(s). 
 
17. Other investigational procedures while participating in this study that could  
  
affect the primary objective of the study as determined by the PI  are excluded.  
Yes 
No 
 
 
18. Previously enrolled in this study. 
Yes 
No 
 
19. Receiving any other investigational agents. 
Yes 
No 
 
20. Evidence of CNS metastases. 
Yes 
No 
 
21. History of allergic reactions attributed to compounds of similar chemical or 
Yes 
No 
biologic composition to talimogene laherparepvec. 
 
22. Uncontrolled intercurrent illness including, but not limited to, ongoing or 
Yes 
No 
active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness / social situations that  
would limit compliance with study requirements. 
 
23. Receiving or requiring immunosuppressive therapies. 
Yes 
No 
 
24. Laboratory abnormalities: 
- Hemoglobin < 9.0 g/dL 
Yes 
No 
- Absolute neutrophil count (ANC) < 1500 per mm3 
Yes 
No 
- Platelet count < 100,000 per mm3 
Yes 
No 
- Total bilirubin > 1.5 X ULN 
Yes 
No 
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
Yes 
No 
   > 2.5 x ULN 
- Alkaline phosphatase > 2.5 x ULN 
Yes 
No 
- PT (or INR) and PTT (or aPTT) > 1.5 x ULN 
Yes 
No 
- Creatinine > 2.0 x ULN 
Yes 
No 
 

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Signature: _____________________________________________ 
Date: ___________________ 
 
Expected toxicities  
 
The following anticipated risks are identified due to this clinical trial: 
 Very Common side effects (which may affect more than 1 person in 10): 
o Flu like illness:  chills, fever, feeling tired, muscle pain, nausea and vomiting 
o Injection site pain 
o Headache 
o Joint pain 
o Arm or leg pain 
o Diarrhea  
o Constipation 
 
 Common side effects (which may affect between 1 and 10 people in every 100): 
o Injection site reactions:  bleeding, redness, swelling, inflammation 
o Skin infection caused by bacteria at the site of injection; symptoms may include 
fever, chills, redness or swelling at the injection site or site of the tumor, and may 
require hospitalization for antibiotic treatment  
o Wound complication at the injection site (secretion or discharge) 
o Pain: pain after procedure, in the tumor, in the abdomen, throat pain, pain in the 
armpit or groin 
o Abdominal discomfort 
o Areas of skin with loss of color (Vitiligo) 
o Cold sore or fever blister in mouth (Oral herpes) 
o Low red blood cell count (Anemia) 
o Not feeling well (Malaise) 
o Weight loss 
o Dehydration 
o Bruise 
o Dizziness 
o Skin or face becomes warm and reddened (Flushing) 
 

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 Uncommon side effects (which may affect between 1 and 10 in every 1000): 
o Injection site reactions: warmth, incision site infection 
o Swelling in the voice box area of your throat that might result in needing a surgical 
procedure on the neck to open a direct airway.  This occurred in a talimogene 
laherparepvec-treated patient who had a similar problem before treatment.  A tube 
might need to be inserted into the opening in your throat.  This tube may be 
connected to a machine to help you breathe.  
o Plasmacytoma (a collection of abnormal antibody-producing white blood cells) in the 
area where talimogene laherparepvec is injected.  Plasmacytoma may be associated 
with multiple myeloma (a cancer of plasma cells affecting the bone marrow). 
o 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 doctor or his/her study staff immediately.   
Other potential side effects 
 
 Allergic Reaction:  As with any medication, you may have an allergic reaction to 
talimogene laherparepvec.  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 doctor or his/her study 
staff immediately. If you have had an allergic reaction to talimogene laherparepvec or any of 
its ingredients, you should inform your doctor. 
 
 
Autoimmune Reactions: Autoimmune reactions to the body’s own tissues have been 
reported in some patients administered talimogene laherparepvec. Examples of autoimmune 
reactions that have been reported in patients receiving talimogene laherparepvec include 
inflammation of the kidneys (nephritis), blood vessels (vasculitis), lungs (pneumonitis) and 
worsening psoriasis.  It is possible that an autoimmune reaction could occur in any part of the 
body.  Please tell your doctor if you have had any type of autoimmune disease before 
treatment with talimogene laherparepvec, and all treatments you are receiving for the disease.   
Stopping Rules: 
As a phase II study, stopping rules do not apply. If a subject dies during active study 
treatment: 
– Trial will be placed on accrual hold until case review 
– The death will be reviewed by the principal investigator, IND medical monitor, and IND 
sponsor (and, as applicable, treating physician) 
– Adverse events, including deaths on study, will be reviewed at IND investigators’ 
meeting. 

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DSMC Monitoring and Compliance 
As a risk level 4 clinical trial, an independent Study Monitor/DSMC, or the DSMC Chair (or 
his designee), will review study data provided by the PI and the clinical research safety 
officer (CRSO). The appointed monitor or the DSMC chair (as appropriate) will 
communicate with the PI at least quarterly. Proceedings of the DSMC meeting will be 
summarized by the CRSO in a brief letter to the PI, a copy of which will be forwarded to the 
DSMC and PRMC. 
To secure protocol compliance and subject safety, the following are implemented: 
Accrual: 
Subject eligibility will be validated by the DSMC by reviewing the completed eligibility 
checklist in OnCore prior to the initiation of any study-specific procedures.  
Subject accrual data will be entered into the Holden Comprehensive Cancer Center’s clinical 
trials management software OnCore and be available to the clinical research safety officer 
(CRSO) and the protocol manager. 
Adverse events: 
Adverse events and serious adverse events will be reported as outlined in protocol Section 7: 
Adverse Events: List and Reporting Requirements. The principal investigator or designee 
will report adverse events to the DSMC via OnCore as outlined in protocol Section 7.7: 
Expedited Adverse Event Reporting.  The principal investigator or designee will report 
serious adverse events to the DSMC via OnCore as outlined in protocol Section 7.7.3:  
Reporting Procedures for Serious Adverse Events. 
Audits: 
Audits will be done at least quarterly and performed by the CRSO or designee. Audit 
reports will be provided to the study monitor (if appointed) and the DSMC chair for review 
and discussion with the study PI. Final audit reports are sent to the DSMC, the PRMC chair, 
the PI, the protocol manager, and the Human Subjects Office / IRB. 
At minimum, audits will: 
– 
validate eligibility of patients enrolled to the study 
– 
verify a signed informed consent document 
– 
determine protocol compliance 
– 
determine if SAEs were reported to appropriate internal and external regulatory agencies 
– 
compare veracity of data in research records with source documents 
– 
review investigational drug processing and documentation 
– 
assess cumulative AE and SAE reports for trends and compare to study stopping rules 
Annual report 
The principal investigator will provide an annual progress report to the DSMC and PRMC 
via the protocol manager. At minimum, the annual progress report will provide the 

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following: 
– 
Current trial status with a summary of study progress to date, including accrual 
difficulties or successes, modifications or amendments, brief overview of toxicities, AE 
and SAE, and unexpected findings or events.