A Phase II Study of Combining Talimogene Laherparepvec (T-VEC) (NSC-785349) and MK-3475 (Pembrolizumab) (NSC-776864) in Patients With Advanced Melanoma Who Have Progressed on Anti-PD1/L1 Based Therapy
Phase: PHASE2
Conditions: Advanced Melanoma, Recurrent Melanoma, Stage III Cutaneous Melanoma AJCC v7, Stage IIIA Cutaneous Melanoma AJCC v7, Stage IIIB Cutaneous Melanoma AJCC v7, Stage IIIC Cutaneous Melanoma AJCC v7, Stage IV Cutaneous Melanoma AJCC v6 and v7, Unresectable Melanoma
Sponsor: National Cancer Institute (NCI)

 
 
 
Version Date: 
October 15, 2021 
 
TO:  
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS; CTSU 
 
FROM: 
SWOG Operations Office (email:  protocols@swog.org)  
 
RE: 
S1607, "A Phase II Study of Combining Talimogene Laherparpvec (T-VEC) (NSC-
785349) and Pembrolizumab (MK-3475) (NSC-776864) in Patients with Advanced 
Melanoma Who Have Progressed on Anti-PD1/L1 Based Therapy.” Study Chairs: 
Drs. S. Hu-Lieskovan and A. Ribas  
 
REVISION #10  
 
Study Chair: Siwen Hu-Lieskovan, M.D., Ph.D. 
Phone number: 801/585-0308 
E-mail: siwen.hu-lieskovan@hci.utah.edu 
 
Action Codes 
(✓) 
Expedited review allowed 
(✓) 
Patients Must be Informed*  
(✓) Formal Re-Consent Required* 
(✓) Verbal notification allowed (in some cases, see below) 
(✓) 
Consent Must Be Amended*  
 
* 
See “Patient Notification and Use of Consent Addendum” and “Regulatory 
Considerations” instructions below.  
 
Key Updates   
(✓)  
Informed Consent changes 
(✓)  
Other: pembrolizumab drug section 
 
Sites using the CIRB as their IRB of record: The protocol and/or informed consent form changes have 
been approved by the CIRB and must be activated within 30 days of the CIRB posting of this notice.  
 
Sites not using the NCI CIRB:  Per CTMB Guidelines, the protocol updates and/or informed consent 
changes must be approved by local IRBs within 90 days of distribution of this notice. 
 
 
REVISION #10 
 
The above referenced study has been revised with the following changes in response to the Request for 
Rapid Amendment (RRA) for Pembrolizumab (MK3475) received on October 4, 2021 from Elad Sharon, 
M.D. (sharone@mail.nih.gov), Jeffrey Moscow, M.D. (jeffrey.moscow@nih.gov), and Meg Mooney, M.D. 
(mooneym@ctep.nci.nih.gov).. The associated Action Letter is attached.  
 
Protocol Changes 
 
1. 
The version date has been updated. 
 
2. 
Section 3.1c:  Pembrolizumab CAEPR (Version 2.6, July 15, 2021) has been updated as follows: 
 
x 
Added New Risk:  
x 
Rare but Serious: Hepatobiliary disorders - Other (sclerosing cholangitis) 
 
x 
Decrease in Risk Attribution: 
x 
Changed to Rare but Serious from Less Likely: Blood and lymphatic system disorders - 
Other (immune thrombocytopenic purpura) 

 
S1607 
 
Revision #10 (contd.) 
 
Page 2 
 
 
 
 
x 
Provided Further Clarification: 
x 
Thrombotic thrombocytopenic purpura is now reported as Blood and lymphatic system 
disorders - Other (immune thrombocytopenic purpura). 
 
Model Consent Form Changes 
 
1. 
The version date has been updated. 
 
2. 
Page 6-8:  Under the heading “Risk Profile for pembrolizumab”, the list of pembrolizumab risks 
has been updated as follows: 
 
Added New Risk: 
a. Rare: Swelling of the gallbladder 
 
 
Patient Notification and use of Consent Addendum: 
 
Please note that the information provided below regarding patient notification and amendments to local 
consent forms reflects SWOG’s minimum requirements.  Sites should refer to the policies/procedures of 
the IRB of record to determine whether they have any more stringent requirements. 
 
SWOG has determined that the changes above that are bolded may affect a patient’s willingness to 
participate in the study; therefore, SWOG requires that patients be notified of these changes.  
 
Who must be informed?   
 
x 
 All patients currently on study treatment with pembrolizumab. 
 
How must patients be notified? 
x 
Notification must take place either via the attached Consent Addendum or via amended consent 
form by next study visit.  After the change has been discussed with the patient, the patient must 
sign and date either the Consent Addendum or the 10/15/21 version of the consent form. 
 
What is the notification deadline and process? 
x 
Patients must be notified by their next scheduled visit or within 90 days after CTSU distribution of 
this revision, whichever is sooner. 
x 
Sites using the NCI CIRB as their IRB of record:  CIRB has approved the attached Consent 
Addendum; therefore, the Consent Addendum may be utilized immediately to notify patients of 
these changes.  
x 
Sites not using the NCI CIRB as their IRB of record:  If local IRB approval of the Consent 
Addendum is required before sites may utilize it, the site must still notify patients verbally prior to 
the notification deadline and notification must be documented in the patient chart.  The site must 
then obtain patient signature on the Consent Addendum or updated consent form once the 
addendum and/or revised consent is locally approved.  
 
Regulatory Considerations: 
 
Do local consent forms need to be updated? 
x It depends.  If your site will utilize the updated consent form for notification and formal reconsent 
then local consent forms must be updated.  If your site will not utilize updated consent form for 
notification and formal reconsent then local consent forms need not be updated.  
 
The updated protocol and model informed consent can be accessed from the CTSU website 
(www.ctsu.org).  Please discard any previous versions of the documents and replace with the updated 
versions. Please contact melanomaquestion@crab.org or 206/652-2267 with any questions. 
 

 
S1607 
 
Revision #10 (contd.) 
 
Page 3 
 
 
 
This study has been reviewed and approved by the NCI’s Central Institutional Review Board (CIRB).  
 
This memorandum serves to notify the NCI and SWOG Statistics and Data Management Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE  
Jia Chen – UCLA 
Austin Vega-Crespo – UCLA 

S1607 
Consent Addendum Revision #10 
Version Date 10/15/2021 
 
 
Informed Consent Addendum Model for S1607 
 
S1607, “Study Title for Study Participants: Testing the combination 
of talimogene laherparepvec and pembrolizumab in patients with 
advanced melanoma who have progressed on anti-PD-1/L1 therapy 
 
The following information should be read as an update to the original Consent form that you read and 
signed at the beginning of the study. Unless specifically stated below, all information contained in that 
original Consent Form is still true and remains in effect. Your participation continues to be voluntary. You 
may refuse to participate, or may withdraw your consent to participate at any time, and for any reason, 
without jeopardizing your future care at this institution or your relationship with your study doctor. 
 
New or additional information 
 
The following new risk has been identified with the Pembrolizumab (MK-3475) updates: 
 
Added New Risk: 
1) Rare: Swelling of the gallbladder 
 
Patient Signature and Date  
 
By signing this form, I acknowledge that I have read the information above or had it read to me. I have 
discussed it with a member of the study team and my questions have been answered. I understand that I 
will be given a copy of this form.  
 
Participant’s signature (or legally authorized representative) _____________________________ 
 
 
Date of signature_________________________ 
 
 
Signature of person(s) conducting the informed consent discussion________________________ 
 
 
Date of signature  
 _____________________________________ 
 
 

 
S1607 
 
Page 1 
 
Version Date 10/15/2021 
 
 
 
PRIVILEGED COMMUNICATION 
 
 
FOR INVESTIGATIONAL USE ONLY 
 
SWOG 
 
TITLE PAGE 
 
A PHASE II STUDY OF COMBINING TALIMOGENE LAHERPAREPVEC (T-VEC) (NSC-785349) AND 
PEMBROLIZUMAB (MK-3475 ) (NSC-776864) IN PATIENTS WITH ADVANCED MELANOMA WHO 
HAVE PROGRESSED ON ANTI-PD1/L1 BASED THERAPY  
 
NCT#02965716 
 
STUDY CHAIRS: 
 
AGENTS: 
 
Siwen Hu-Lieskovan, M.D., Ph.D. (Medical Oncology) 
NCI Supplied Investigational Agents: 
University of Utah Medical Center (UT003) 
Pembrolizumab (MK-3475)  
Huntsman Cancer Institute 
(NSC-776864) 
2000 Circle of Hope, RS-2703 
 
Salt Lake City, UT 84112 
 
Phone: 801/585-0308 
Talimogene Laherparepvec (T-VEC) 
E-mail: siwen.hu-lieskovan@hci.utah.edu 
(NSC-785349) 
 
IND Sponsor: DCTD, NCI –  
 
   
 
Antoni Ribas, M.D., Ph.D. (Medical Oncology) 
BIOSTATISTICIANS:  
University of California Los Angeles (CA006) 
 
10833 Le Conte Ave, Factor 11-934 
Michael C. Wu, Ph.D. 
Los Angeles, CA 90095 U.S.A. 
James Moon, M.S.  
Phone: 310/206-3928 
SWOG Statistics and Data Management Center 
FAX: 310/825-2493 
1100 Fairview Ave N., M3-C102 
E-mail: aribas@mednet.ucla.edu  
P.O. Box 19024 
 
Seattle, WA 98109 
ECOG-ACRIN STUDY CHAMPION: 
Phone: 206/667-4623 FAX: 206/667-4408  
Ann W. Silk, M.D. 
E-mail: mcwu@fredhutch.org  
Rutgers Cancer Institute of New Jersey 
E-mail: jmoon@fredhutch.org  
195 Little Albany Street 
Room 4561 
New Brunswick, NJ 08903 
Phone: 732/235-9843 
FAX: 732/235-8808 
E-mail: ann.w.silk@cinj@rutgers.edu  
 
PARTICIPANTS 
 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG 
 
 
 

 
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TABLE OF CONTENTS 
 
TITLE PAGE ......................................................................................................................................1 
PARTICIPANTS .................................................................................................................................1 
TABLE OF CONTENTS......................................................................................................................2 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION .....................4 
SCHEMA ...........................................................................................................................................5 
1.0 
OBJECTIVES ........................................................................................................................6 
1.1 
Primary Objective(s) ...............................................................................................................6 
1.2 
Secondary Objective(s) ...........................................................................................................6 
1.3 
Translational Objectives ..........................................................................................................6 
2.0 
BACKGROUND .....................................................................................................................7 
2.1  
Overview................................................................................................................................7 
2.2  
Local and visceral ORR with talimogene laherparepvec (T-VEC) alone ......................................8 
2.3 
Correlative Studies Background...............................................................................................9 
2.4  
Inclusion of Women and Minorities...........................................................................................9 
3.0 
DRUG INFORMATION ...........................................................................................................9 
3.1 
Pembrolizumab (MK-3475) (NSC-776864) ............................................................................. 10 
3.2 
Talimogene Laherparepvec (T-VEC, AMG 678; OncoVEXGM-CSF, IMLYGIC ™) (NSC 785349, IND 
BB) ...................................................................................................................................... 20 
4.0 
STAGING CRITERIA ............................................................................................................ 39 
5.0 
ELIGIBILITY CRITERIA........................................................................................................ 39 
5.1 
Disease Related Criteria ....................................................................................................... 40 
5.2 
Prior/Concurrent Therapy Criteria .......................................................................................... 40 
5.3 
Clinical/Laboratory Criteria .................................................................................................... 41 
5.4 
Specimen Submission Criteria ............................................................................................... 42 
5.5 
Regulatory Criteria ................................................................................................................ 42 
6.0 
STRATIFICATION FACTORS ............................................................................................... 43 
7.0 
TREATMENT PLAN ............................................................................................................. 43 
7.1 
Treatment ............................................................................................................................ 43 
7.2 
Full CDUS Reporting Requirement ........................................................................................ 45 
7.3 
Prohibited and Cautionary Concomitant Medications............................................................... 45 
7.4 
Criteria for Removal from Protocol Treatment  ......................................................................... 45 
7.5 
Discontinuation of Treatment ................................................................................................. 46 
7.6 
Follow-Up Period .................................................................................................................. 46 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS ........................................... 46 
8.1 
NCI Common Terminology Criteria for Adverse Events ........................................................... 46 
8.2 
Dose Modifications ............................................................................................................... 47 
8.3 
White blood Cell Growth Factors............................................................................................ 57 
8.4 
Dose Modification Contacts ................................................................................................... 57 
8.5 
Adverse Event Reporting....................................................................................................... 57 
9.0 
STUDY CALENDAR............................................................................................................. 58 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS  ................................................. 61 
10.1 
Measurability of Lesions ........................................................................................................ 61 
10.2 
Objective Status at Each Disease Evaluation.......................................................................... 62 
10.3 
Best Response ..................................................................................................................... 64 
10.4 
Performance Status .............................................................................................................. 64 
10.5 
Progression-Free Survival ..................................................................................................... 65 
10.6 
Time to Death....................................................................................................................... 65 
10.7 
Durable Response Rate ........................................................................................................ 65 
10.8 
Response in the Injected Lesions  .......................................................................................... 65 
10.9 
Response in visceral lesions.................................................................................................. 65 
10.10 
Response in non-injected (non-visceral) lesions...................................................................... 65 
11.0 
STATISTICAL CONSIDERATIONS ....................................................................................... 65 
11.1 
Cohort A: Patients who have injectable lesions and measurable visceral diseases .................... 65 
11.2 
Cohort B: Patients who have injectable lesions and no visceral lesions .................................... 66 

 
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11.3 
Data and Safety Monitoring ................................................................................................... 68 
12.0 
DISCIPLINE REVIEW ........................................................................................................... 68 
13.0 
REGISTRATION GUIDELINES ............................................................................................. 68 
13.1 
Registration Timing  ............................................................................................................... 68 
13.2 
Investigator/Site Registration ................................................................................................. 68 
13.3 
OPEN Registration Requirements .......................................................................................... 71 
13.4 
Registration Procedures ........................................................................................................ 72 
13.5 
Exceptions to SWOG registration policies will not be permitted. ............................................... 73 
14.0 
DATA SUBMISSION SCHEDULE ......................................................................................... 73 
14.1 
Data Submission Requirement .............................................................................................. 73 
14.2 
Master Forms ....................................................................................................................... 73 
14.3 
Data Submission Procedures ................................................................................................ 73 
14.4 
Data Submission Overview and Timepoints ............................................................................ 74 
15.0 
SPECIAL INSTRUCTIONS ................................................................................................... 76 
15.1 
Translational Medicine .......................................................................................................... 76 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS .............................................................. 80 
17.0 
BIBLIOGRAPHY .................................................................................................................. 88 
18.0 
APPENDIX........................................................................................................................... 89 
18.1 
Anti-PD-1 and Anti-PD-L1 Agents .......................................................................................... 90 
18.2 
Translational Medicine Methods............................................................................................. 91 
18.3 
Site Requirements Based on Guidelines from the NIH Office of Scientific Policy (OSP) (Adapted 
for CTEP-sponsored T-VEC Protocols) .................................................................................. 98 
18.4 
Additional Reporting Requirements for talimogene laherparepvec (T-VEC) associated adverse 
events, biosafety incidents, and accidental exposure of Health Care Providers (HCPs) to 
talimogene laherparepvec (T-VEC) ...................................................................................... 100 
18.5 
Information Sheet for Caregivers, Family Members, and Other Close Contacts to Clinical Trial 
Participants Being Given talimogene laherparepvec (T-VEC) and for Non-Study Health Care 
Providers (HCP) ................................................................................................................. 110 
18.6 
Information Sheet for Patients Receiving Talimogene Laherparepvec (T-VEC) ....................... 114 
18.7 
Instructions for Talimogene Laherparepvec (T-VEC) Injection Site Care ................................. 118 
18.8 
Information Related to Exposure to Talimogene Laherparepvec (T-VEC) ............................... 120 
18.9 
Receiving Instructions for NCI-supplied Talimogene laherparepvec (NSC 785349) ................. 121 
18.10 
NCI Temperature Exposure Log Talimogene laherparepvec (NSC 785349)............................ 122 
 

 
S1607 
 
Page 4 
 
Version Date 10/15/2021 
 
 
 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient 
enrollments: 
 
Submit study data directly to the 
Lead Cooperative Group unless 
otherwise specified in the 
protocol: 
 
CTSU Regulatory Office 
1818 Market Street, 
Suite 1100 
Philadelphia, PA19103 
 
Fax: 215-569-0206 
 
Email:  
 
CTSURegulatory@ctsu.coccg.org  
 
For more information, call the CTSU 
Help Desk at 888-823-5923 or the 
Regulatory Help Desk at 866-651-
CTSU. 
 
 
Please refer to the patient 
enrollment section of the protocol for 
instructions on using the Oncology 
Patient Enrollment Network (OPEN) 
which can be accessed at 
https://www.ctsu.org/OPEN_SYSTE
M/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com. 
 
 
 
Data collection for this study will be 
done exclusively through Medidata 
Rave.  Please see the data 
submission section of the protocol 
for further instructions.  
 
Do not submit study data or forms to 
CTSU Data Operations. Do not copy 
the CTSU on data submissions. 
 
Other Tools and Reports: Institutions 
participating through the CTSU 
continue to have access to other 
tools and reports available on the 
SWOG Workbench. Access this by 
using your active CTEP-IAM userid 
and password at the following url: 
 
https://crawb.crab.org/TXWB/ctsulog
on.aspx  
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at 
https://www.ctsu.org.  Access to the CTSU members’ website is managed through the Cancer Therapy 
and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and requires 
user log on with CTEP-IAM username and password.  
 
For patient eligibility questions contact the SWOG Data Operations Center by phone or email: 
 
206-652-2267 
melanomaquestion@crab.org  
For treatment or toxicity related questions contact the Study PI of the Coordinating Group. 
 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help 
Desk by phone or e-mail: 
 
CTSU General Information Line: 
888-823-5923 
ctsucontact@westat.com  
 
All calls and correspondence will be triaged to the appropriate CTSU representative. 
 
The CTSU Web site is located at https://www.ctsu.org  
 

 
S1607 
 
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Version Date 10/15/2021 
 
 
 
SCHEMA 
 
Patients with advanced/metastatic melanoma who have progressed on anti-PD1/L1 therapy  
prior to registration. 
 
 
 
REGISTRATION 
 
 
 
Scan/Skin Exam 
Biopsy and blood draw* 
Archival tumor (prior to anti-PD1/L1), Optional but strongly recommended 
 
 
 
Continuous talimogene laherparepvec (T-VEC) + pembrolizumab (MK-3475)  
(Scan/Skin Exam at Week 9, 13 and then every 12 weeks) 
 (Blood draw at Week 2, 4 and 10*) 
(Biopsy at D28*, both injected and un-injected) 
 
 
 
Progression  
(Blood draw and optional biopsy*) 
 
 
 
Off Treatment 
 
 
 
 
 
* See Section 15.1. 
 
 
 
1
64
q21
Baseline
Imaging/
Skin Exam #1
Blood #1
Tumor Biopsy #1
Optional Archival 
Tumor before 
prior anti-PD1/L1
Day 28+/-7
Tumor Biopsy #2
(Injected and 
un-injected)
Week 9
Imaging/
Skin Exam #2
T-VEC
Pembrolizumab
22
28
T-VEC
Pembrolizumab
43
57
8
T-VEC
Pembrolizumab
Week 2
Blood #2
T-VEC
Pembrolizumab
Disease 
Progression
85
T-VEC
Pembrolizumab
Blood #5
Optional
Tumor Biopsy #3
(Most fast-growing)
One cycle is 21 days (3 weeks). MD evaluation, PE, Vitals, PS, and labs on first day of each cycle.
T-VEC
Pembrolizumab
Week 10
Blood #4
Week 13
Imaging/
Skin Exam #3
Week 4
Blood #3
Q12 week
Imaging/
Skin Exam

 
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Version Date 10/15/2021 
 
 
 
1.0 
OBJECTIVES 
 
This study will enroll two separate cohorts (see Section 6.0) to assess the efficacy of talimogene 
laherparepvec (T-VEC) in combination with pembrolizumab (MK-3475).  Each cohort will be 
analyzed independently. 
 
1.1 
Primary Objective(s) 
 
To evaluate the objective response rate (confirmed complete and partial responses) of 
treatment with talimogene laherparepvec (T-VEC) in combination with pembrolizumab 
(MK-3475) following progression on prior anti-PD-1 or anti-PD-L1 therapy alone or in 
combination with other agents different from talimogene laherparepvec (T-VEC). 
 
1.2 
Secondary Objective(s) 
 
a. 
To estimate the durable response rate (as defined in Section 10.7) 
 
b. 
To estimate the objective response rate (ORR) defined as confirmed and 
unconfirmed, complete and partial responses in the injected lesions. 
 
c. 
To estimate the ORR in the non-visceral, non-injected lesions. 
 
d. 
To estimate the ORR in the visceral lesions (Cohort A). 
 
e. 
To estimate the median progression-free survival (PFS). 
 
f. 
To estimate the median overall survival (OS). 
 
g. 
To evaluate the toxicity of the regimen. 
 
1.3 
Translational Objectives 
 
a. 
To evaluate whether adding talimogene laherparepvec (T-VEC) to PD1 blockade 
can increase T-cell infiltration into tumors and whether change in T-cell infiltration 
is associated with response. 
 
b. 
To evaluate whether adding talimogene laherparepvec (T-VEC) to PD1 blockade 
can increase TCR clonality in tumors and in peripheral blood and whether 
increased TCR clonality is associated with response. 
 
c. 
To evaluate whether intra-tumoral injection of talimogene laherparepvec (T-VEC) 
can improve the tumor immune microenvironment. 
  
d. 
To evaluate whether tumor mutational load, mutations in the IFN pathway, and 
circulating tumor DNA profile are associated with response to talimogene 
laherparepvec (T-VEC) plus pembrolizumab (MK-3475) therapy in the anti-PD1/L1 
therapy refractory melanoma patients. 
 
 

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2.0
BACKGROUND
2.1 
Overview
The programmed cell death 1 (PD-1) pathway represents a major immune checkpoint, 
which may be hijacked by tumor cells to overcome active T-cell immune surveillance. 
(1,2,3) The ligands for PD-1 (PD-L1 and PD-L2) can be constitutively expressed or can be 
induced on the surface of cancer cells in response to interferons produced by tumor-
infiltrating lymphocytes, which provides a mechanism for the cancer cells to avoid immune 
surveillance. (4) Preclinical data have shown that PD-1 and/or PD-L1 blockade using 
monoclonal antibodies enhances tumor-specific T-cell activation, T-cell infiltration into the 
tumors, cytokine production, anti-tumor effector function, and clearance of tumor cells by 
the immune system. PD-1 therapy also modulates the level of interleukin-2 (IL-2), tumor 
necrosis factor alpha (TNFα), interferon gamma (IFNγ), and other cytokines in the tumor 
microenvironment.
Pembrolizumab (MK-3475) was the first anti-PD-1 antibody approved by FDA for advanced 
melanoma patients. (5) Studies have indicated that tumor regression following therapeutic 
PD-1 blockade requires 1) pre-existing CD8+ T-cells that are 2) negatively regulated by 
PD-1/PD-L1-mediated adaptive immune resistance. (6) Without these two requirements 
PD-1 blockade therapy is unlikely effective
Talimogene laherparepvec (T-VEC, formerly known as OncoVEXGM-CSF) is an oncolytic 
virus based on a modified herpes simplex virus type-1 (HSV-1). Itis designed to selectively 
replicate in tumor tissue and to stimulate local and systemic antitumor immune response
(Figure 1). Intralesional administration of talimogene laherparepvec (T-VEC) results in 
oncolysis of tumor cells 
and 
local 
release 
of 
progeny virus as well as 
of tumor cell antigens. 
Viral 
pathogens 
are 
strong 
inducers 
of 
interferon responses, and 
their intratumoral injection 
results in a change in the 
tumor microenvironment 
that is more permissive to 
a 
T-cell 
response. 
Furthermore, 
GM-CSF, 
the product of the viral 
transgene, 
is 
also 
produced locally to recruit 
and 
stimulate 
antigen-
presenting cells. Overall, 
this strategy is expected 
to result in the destruction 
of injected tumors via 
oncolysis 
and 
also 
uninjected 
sites 
of 
disease (including micro-metastases) via a systemic antitumor immune response.
Talimogene laherparepvec (T-VEC) has been tested for efficacy in a variety of in vitro (cell 
line) and in vivo murine tumor models and has been shown to eradicate tumors or 
substantially inhibit their growth at doses comparable to those used in clinical studies. Nine 
clinical studies have been or are being conducted in several advanced tumor types 
(melanoma, squamous cell cancer of the head and neck [SCCHN], and pancreatic cancer), 
Figure 1: Proposed mechanism of action of T-VEC.
Response
Progression
T-VEC
Injections*
Combined Therapy 
Response
Anti-PD-1/L1
Single Agent
Progression
*T-VECMechanismofAc on:
1. T-VECvirusesonlyreplicateinthetumorcells,causingtumorcelllyses,
releasingmorevirusesandtumoran gen,causinglocalinflamma on.
2. TheviralconstructisengineeredtoproduceGM-CSF,a ractsdendri c
cellstoprocessandpresenttumoran gentoTcells.
3. InterferonreleasedbyinflammatorycellscaninducePD-L1expressionin
thetumors,servingthera onaletocombineT-VECwithPD1/L1blockade

 
S1607 
 
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Version Date 10/15/2021 
 
 
 
with a total of 427 subjects treated with talimogene laherparepvec (T-VEC). Results of the 
pivotal Phase III trial (OPTiM) in melanoma have shown that talimogene laherparepvec (T-
VEC) treatment as monotherapy results in durable responses (at least 6 months of 
continuous response) and objective responses in 16% and 26% of subjects with regional 
or distant metastases and limited visceral involvement, as compared to 2% and 5.7% in 
patients treated with GM-CSF. (7) The treatment was well tolerated with adverse events 
primarily including flu-like symptoms and injection site reactions. A Phase Ib/II study of 
ipilimumab with or without talimogene laherparepvec (T-VEC) in Stage IIIB-IV melanoma 
is ongoing. Preliminary data of 18 patients with Stage IIIB–IV M1c melanoma suggest much 
higher complete and ORRs with the combination than have been seen with either agent 
alone. (8) ORR was 56% (95% CI 31–79%), with complete responses in 33%, partial 
responses in 22% and stable disease in 17%. In responders, mean/median time to 
investigator-assessed response was 18.8/22.9 weeks (range 11.1–25.0). Flow cytometry 
showed a higher increase in the number of activated CD8 T-cells in patients with disease 
control. No dose-limiting toxicities were observed, and most reported toxicities were 
apparently related to ipilimumab. The randomized Phase II portion of the trial is currently 
ongoing, and a trial in combination with pembrolizumab (MK-3475) in PD-1 blockade naïve 
melanoma patients is also ongoing. 
 
In this protocol we want to focus on those patients who do not respond to PD-1/L1 blockade 
because there are no pre-existing tumor antigen-specific T-cells in their tumors ready to 
attack the cancer, or they are lost after a period of responses. (9,10,11,12,13) We 
hypothesize that this lack of sufficient immune activation can be addressed by a 
combination therapy with an immune activating oncolytic virus. 
 
2.2  
Local and visceral ORR with talimogene laherparepvec (T-VEC) alone 
 
The OPTiM trial included 3274 evaluable baseline and new lesions from 285 evaluable 
patients and 259 (91 %) of the 285 evaluable patients had three or more lesions (14). 
 
a. 
Injected Lesions 
Of a total of 2116 lesions injected with T-VEC from 277 patients, 1361 (64 %) 
lesions had a decrease in size of ≥50 % including 995 (47 %) lesions that resolved 
completely. Median time to response of responding injected lesions from baseline 
was 9.3 weeks. Among 277 patients evaluable for response in injected lesions, 37 
% had ≥50 % decrease in total tumor area of injected lesions and 16 % had 
complete resolution of injected lesions. The ORR in these patients was 32 % (15 
% CR). 
 
b. 
Un-injected Non-Visceral Lesions 
A total of 981 un-injected, non-visceral lesions (cutaneous, subcutaneous, or 
nodal) from 177 patients were evaluable, 331 (34 %) lesions decreased in size by 
≥50 %, and 212 (22 %) had CR. Among 177 patients evaluable for response, 21 
% had ≥50 % decrease in total tumor area of un-injected non-visceral lesions and 
14 % CR, which corresponded to an ORR of 18 % and a CR rate of 6 %. 
 
c. 
Visceral Lesions 
Of a total of 177 individual visceral lesions from 79 patients, twenty-seven (15 %) 
decreased in size by ≥50 %, and 16 (9 %) CR. Evaluable visceral lesions were 
located in the lung (77 %), liver (8 %), adrenal gland (6 %), spleen (3 %), kidney 
(3 %), pancreas (1 %), and the thyroid, brain, and gastrointestinal tract (<1 % 
each). Among responding visceral lesions, 81 % were in the lung, 15 % in the liver, 
and 4 % in the thyroid. Among 79 patients evaluable for response in visceral 
lesions, 10 % had a ≥50 % decrease in total tumor area of visceral lesions and 6 
% had complete resolution of visceral lesions. ORR was 14 % and the CR rate 
was 3 %. 

 
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2.3 
Correlative Studies Background  
 
Please refer to translational medicine proposal. 
 
 
2.4  
Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to 
measure differences of intervention effects.  The anticipated accrual in the ethnicity/race 
and sex categories is shown in the table below. 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American 
Indian/ Alaska 
Native 
0 
1 
0 
0 
1 
Asian 
0 
1 
0 
0 
1 
Native 
Hawaiian or 
Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
1 
1 
0 
0 
2 
White 
13 
28 
1 
1 
43 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
14 
31 
1 
1 
47 
 
 
3.0 
DRUG INFORMATION 
 
Investigator Brochures  
 
For information regarding Investigator Brochures, please refer to SWOG Policy 15. 
 
For this study, talimogene laherparepvec 
(T-VEC) and pembrolizumab (MK-3475) 
are 
investigational and are being provided under an IND held by the National Cancer Institute.  The 
Investigator Brochures may be obtained by accessing PMB’s Online Agent Order Processing 
(OAOP) application (https://ctepcore.nci.nih.gov/OAOP).  
 
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status and a “current” password.  Questions 
about IB access may be directed via email to IBcoordinator@mail.nih.gov or by phone 240/276-
6575 Monday through Friday between 8:30 am and 4:30 pm (ET). 
 
 

 
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3.1 
Pembrolizumab (MK-3475) (NSC-776864) 
 
a. 
Pharmacology 
 
Pembrolizumab (MK-3475) is a humanized MAb of the IgG4/kappa isotype.  The 
programmed cell death 1 (PD-1) receptor is an inhibitory receptor expressed by T-
cells.  When bound to either of its ligands, PD-L1 or PD-L2, activated PD-1 
negatively regulates T-cell activation and effector function.  The pathway may be 
engaged by tumor cells expressing PD-1 ligands to suppress immune control.  
pembrolizumab (MK-3475) blocks the negative immune regulatory signaling by 
binding to the PD-1 receptor, inhibiting the interaction between PD-1 and its 
ligands, and thereby promoting the host immune system to recognize tumor cells 
as foreign bodies to be eliminated.  
 
b. 
Pharmacokinetics 
 
The pharmacokinetic profile of pembrolizumab (MK-3475), with low clearance and 
limited volume of distribution, is typical for therapeutic antibodies.  Elimination half -
life after IV administration was approximately 14 to 21.6 days.   Steady state 
concentration levels were achieved within 16 weeks of treatment when tested at 3 
and 10 mg/kg dosing as administered at 2 week intervals.  During repeated dosing 
of 2 or 10mg/kg Q3W, steady state in trough concentrations appeared to have 
been achieved after approximately three months.  Furthermore, pembrolizumab 
(MK-3475) has a low potential of eliciting the formation of anti-drug antibodies.        
 
c. 
Adverse effects  
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below).  Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements'  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 3793 patients. 
Below is the CAEPR for pembrolizumab (MK-3475). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER.  If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
Version 2.6, July 15, 20211 
 
 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
Specific Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia2 
 

 
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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
Specific Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
 
 
Blood and 
lymphatic system 
disorders - Other 
(immune 
thrombocytopenic 
purpura)2 
 
 
Lymph node 
pain2 
 
CARDIAC DISORDERS 
 
 
Myocarditis2 
 
 
Pericarditis2 
 
ENDOCRINE DISORDERS 
Adrenal 
insufficiency2 
Endocrine 
disorders - 
Other 
(thyroiditis)2 
Hyperthyroidism
2 
Hypophysitis2 
Hypopituitarism 2 
Hypothyroidism 2 
EYE DISORDERS 
Uveitis2 
Eye disorders - 
Other (Vogt-
Koyanagi-Harada 
syndrome) 
GASTROINTESTINAL DISORDERS 
Abdominal 
pain 
Colitis2 
Diarrhea2 
Diarrhea2 (Gr 2) 
Mucositis oral2 
Nausea 
Nausea (Gr 2) 
Pancreatitis2 
Small intestinal 
mucositis2 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 
Chills2 

 
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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
Specific Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
Fatigue 
Fatigue (Gr 2) 
Fever2 
HEPATOBILIARY DISORDERS 
Hepatobiliary 
disorders - 
Other 
(autoimmune 
hepatitis)2 
 
Hepatobiliary 
disorders - Other 
(sclerosing 
cholangitis) 
IMMUNE SYSTEM DISORDERS 
Anaphylaxis2 
Cytokine release 
syndrome2 
Immune system 
disorders - Other 
(acute graft-
versus-host-
disease)2,3 
Immune system 
disorders - Other 
(hemophagocytic 
lymphohistiocytosi
s)2 
Immune 
system 
disorders - 
Other 
(pseudoprogre
ssion/tumor 
inflammation)2 
 
Immune 
system 
disorders - 
Other 
(sarcoidosis)2 
 
Serum sickness2 
INFECTIONS AND INFESTATIONS 
Infection4 
INJURY, POISONING AND PROCEDURAL 
COMPLICATIONS 

 
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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
Specific Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
 
Infusion related 
reaction 
INVESTIGATIONS 
Alanine 
aminotransfera
se increased2 
Alkaline 
phosphatase 
increased 
Aspartate 
aminotransfera
se increased2 
Blood bilirubin 
increased 
CPK increased 
 
GGT increased 
 
Serum amylase 
increased 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
Hyponatremia 
 
Metabolism and 
nutrition disorders 
- Other (diabetic 
ketoacidosis)2 
 
Metabolism and 
nutrition disorders 
- Other (type 1 
diabetes mellitus)2 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
Arthralgia2 
Arthralgia2 (Gr 2) 
Arthritis2 
Avascular 
necrosis2 
Back pain 
Joint effusion2 
Joint range of 
motion 
decreased 
Musculoskelet
al and 
connective 

 
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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
Specific Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
tissue disorder 
- Other 
(tenosynovitis)
2 
Myalgia2 
Myositis2 
NERVOUS SYSTEM DISORDERS 
Guillain-Barre 
syndrome2 
Nervous system 
disorders - Other 
(myasthenic 
syndrome)2 
Nervous system 
disorders - Other 
(neuromyopathy)2 
Nervous system 
disorders - Other 
(non-infectious 
encephalitis)2 
Nervous system 
disorders - Other 
(non-infectious 
meningitis)2 
Nervous system 
disorders - Other 
(non-infectious 
myelitis) 
Nervous system 
disorders - Other 
(polyneuropathy)2 
Paresthesia 
Peripheral motor 
neuropathy2 
RENAL AND URINARY DISORDERS 
Renal and urinary 
disorders - Other 
(autoimmune 
nephritis)2 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
Cough 
 
Pleuritic pain2 
 

 
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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
Specific Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
Pneumonitis2 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Bullous 
dermatitis2 
 
Erythema 
multiforme2 
Erythroderma 
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
Pruritus2 
Pruritus2 (Gr 2) 
Rash 
acneiform2 
Rash maculo-
papular2 
Rash maculo-
papular2 (Gr 2) 
Skin and 
subcutaneous 
tissue 
disorders - 
Other 
(dermatitis)2 
Skin 
hypopigmen-
tation2 
 
Stevens-Johnson 
syndrome2 
 
Toxic epidermal 
necrolysis 
Urticaria2 
VASCULAR DISORDERS 
 
Vasculitis2 
 
1 
This table will be updated as the toxicity profile of the agent is revised.  Updates 
will be distributed to all Principal Investigators at the time of revision.  The 
current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
2 Immune-mediated adverse reactions have been reported in patients receiving 
MK-3475 (pembrolizumab).  Adverse events potentially related to MK-3475 
(pembrolizumab) may be manifestations of immune-mediated adverse events. 
In clinical trials, most immune-mediated adverse reactions were reversible and 
managed with interruptions of MK-3475 (pembrolizumab), administration of 
corticosteroids and supportive care. 
3 
Acute graft-versus-host disease has been observed in patients treated with MK-

 
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3475 (pembrolizumab) who received hematopoeitic stem cell transplants. 
4 
Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC. 
 
Adverse events reported on MK-3475 (pembrolizumab) trials, but for which 
there is insufficient evidence to suggest that there was a reasonable 
possibility that MK-3475 (pembrolizumab) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (pancytopenia); Disseminated intravascular coagulation; 
Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; 
Heart failure; Myocardial infarction; Pericardial effusion; Pericardial tamponade; 
Ventricular arrhythmia 
EYE DISORDERS - Eye pain 
GASTROINTESTINAL 
DISORDERS 
- 
Abdominal 
distension; 
Ascites; 
Constipation; Duodenal hemorrhage; Dysphagia; Gastritis; Gastrointestinal 
disorders - Other (diverticulitis); Gastrointestinal disorders - Other (intestinal 
obstruction); Gastrointestinal disorders - Other (intussusception); Oral pain; Rectal 
hemorrhage; Small intestinal perforation; Upper gastrointestinal hemorrhage; 
Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema 
face; Edema limbs; Facial pain; Gait disturbance; General disorders and 
administration site conditions - Other (general physical health deterioration); 
Generalized edema; Malaise; Non-cardiac chest pain; Pain 
INVESTIGATIONS 
- Cholesterol high; Creatinine 
increased; Fibrinogen 
decreased; Lymphocyte count decreased; Neutrophil count decreased; Platelet 
count decreased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; 
Hyperglycemia; 
Hyperkalemia; 
Hypertriglyceridemia; 
Hyperuricemia; 
Hypoalbuminemia; Hypokalemia; Hypophosphatemia; Metabolism and nutrition 
disorders - Other (failure to thrive); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; 
Generalized muscle weakness; Musculoskeletal and connective tissue disorder - 
Other (groin pain); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Aphonia; Depressed level of consciousness; 
Dysarthria; Edema 
cerebral; 
Encephalopathy; Headache; 
Hydrocephalus; 
Lethargy; Meningismus; Nervous system disorders - Other (brainstem herniation); 
Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Nephrotic syndrome; 
Proteinuria; Renal and urinary disorders - Other (hydronephrosis); Urinary 
incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; 
Hypoxia; Laryngeal inflammation; Pleural effusion; Pneumothorax; Respiratory 
failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Skin 
and subcutaneous tissue disorders - Other (drug eruption) 
VASCULAR DISORDERS - Hypertension; Peripheral ischemia; Thromboembolic 
event 
 
 

 
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Note: MK-3475 (pembrolizumab) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other 
agent, or the combination may result in events never previously associated with 
either agent. 
 
1. 
Pregnancy and Lactation:  
 
The central function of the PD-1/PD-L1 pathway is to maintain immune 
tolerance to the fetal allograft, and its important role in maintaining 
pregnancy has been recently emphasized in literature [4-6, 4-7] The PD-
L1 molecule expressed at the uteroplacental interface effectively protects 
the concepti from maternal T-cell-mediated immunity. Blockade of PD-L1 
signaling has been shown in murine models of allogeneic pregnancy [4-6, 
4-7] to abrogate fetomaternal tolerance to the concepti and to result in an 
increase in fetal resorption. The evidence from these experimental results 
indicates that there is a theoretical risk associated with the administration 
of pembrolizumab (MK-3475) to women of child-bearing potential 
(WOCBP). It is therefore anticipated that the inhibition of PD-1 by 
treatment with anti-PD-1 monoclonal antibody (i.e., pembrolizumab) 
during pregnancy would have detrimental effects that might include 
increased rates of abortion and stillbirth. Women/men of reproductive 
potential should use an effective contraceptive method while on treatment 
and through 120 days after the last dose of pembrolizumab (MK-3475). 
 
It is not known whether pembrolizumab (MK-3475) is excreted in human 
milk.  Because of the potential for drugs to be excreted in human milk, the 
risk to the nursing infant cannot be excluded and therefore pembrolizumab 
(MK-3475) should not be administered to nursing mothers. 
 
2. 
Drug Interactions:  
No studies on pharmacodynamic drug interactions have been performed.  
Due to potential drug interactions, a complete patient medication list, 
including pembrolizumab (MK-3475), should be screened prior to initiation 
of and during treatment with pembrolizumab (MK-3475). See Section 8.0 
Toxicities to be Monitored and Dosage Modifications 
 
d. 
Dosing and Administration 
See Section 7.0 Treatment Plan 
 
e. 
How Supplied 
Pembrolizumab (MK-3475) is supplied by Merck & Co., Inc. and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI. Pembrolizumab (MK-
3475) injection is a sterile, preservative-free, clear to opalescent, colorless to 
slightly yellow solution for intravenous use.  Each vial contains 100 mg of 
pembrolizumab (MK-3475) in 4 mL of solution. Each 1 mL of solution contains 25 
mg of pembrolizumab (MK-3475) and is formulated in: L-histidine (1.55 mg), 
polysorbate 80 (0.2mg), sucrose (70 mg), and Water for injection, USP. 
 
 

 
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f. 
Storage, Preparation & Stability 
 
1. 
Preparation:  
 
Pembrolizumab (MK-3475) solution for infusion must be diluted prior to 
administration.  Allow the required number of vials to equilibrate to room 
temperature.  Do not shake the vials.  Do not use if opaque or extraneous 
particulate matter other than translucent to white proteinaceous particles 
is observed.  Do not use if discolored.  To prepare the infusion solution 
add the dose volume of pembrolizumab (MK-3475) to an infusion bag 
containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, 
USP.  Gently invert the bag 10-15 times to mix the solution.  The final 
concentration must be between 1 mg/mL to 10 mg/mL. 
 
Compatible IV bag materials: PVC plasticized with DEHP, non-PVC 
(polyolefin), EVA, or PE lined polyolefin 
 
2. 
Storage:  
 
Store intact vials between 2°C - 8°C (36°F - 46°F).  Do not freeze.  Protect 
from light by storing in the original box.   
 
If a storage temperature excursion is identified, promptly return 
pembrolizumab (MK-3475) to between 2-8°C and quarantine the supplies.  
Provide a detailed report of the excursion (including documentation of 
temperature 
monitoring 
and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
3. 
Stability:  
 
Refer to the package insert for expiration.  
 
Administer prepared solutions immediately after preparation.  If not 
administered immediately, prepared solutions may be stored refrigerated 
for up to 24 hours.  Pembrolizumab (MK-3475) solutions may be stored at 
room temperature for a cumulative time of up to 6 hours.  This includes 
room temperature storage of liquid drug product solution in vials, room 
temperature storage of infusion solution in the IV bag, and the duration of 
infusion. 
 
4. 
Route of Administration:  
 
IV infusion only.  Do not administer as an IV push or bolus injection. 
 
5. 
Method of Administration:  
 
Infuse over approximately 30 minutes (range: 25 - 40 minutes) using an 
infusion set containing a low-protein binding 0.2 to 5 μm in-line filter made 
of polyethersulfone or polysulfone.  Infusion rate should not exceed 6.7 
mL/min.  A central line is not required; however if a subject has a central 
venous catheter in place, it is recommended that it be used for the infusion.  
Do not co-administer other drugs through the same infusion line.  
Following the infusion, flush the IV line with normal saline. 
 

 
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Compatible infusion set materials: PVC plasticized with DEHP or DEHT, 
PVC 
and 
tri-(2-ethylhexyl) 
trimellitate, 
polyethylene 
lined 
PVC, 
polyurethane, or polybutadiene. 
 
 
g. 
Drug Ordering & Accountability 
1. 
Drug Ordering  
 
Starter supplies will not be provided. NCI supplied agents may be 
requested by the Principal Investigator (or their authorized designee) at 
each participating institution. Pharmaceutical Management Branch (PMB) 
policy requires that drug be shipped directly to the institution where the 
patient is to be treated. PMB does not permit the transfer of agents 
between institutions (unless prior approval from PMB is obtained). The 
CTEP assigned protocol number (S1607) must be used for ordering all 
CTEP supplied investigational agents. The responsible investigator at 
each participating institution must be registered with CTEP, DCTD through 
an annual submission of FDA Form 1572 and a CV. If there are several 
participating investigators at one institution, CTEP-supplied investigational 
agents for the study should be ordered under the name of one lead 
investigator at that institution.  Active CTEP-registered investigators and 
investigator-designated shipping designees and ordering designees can 
submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application.  Access to OAOP requires the -establishment of a 
CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status and a “current” password.  For 
questions about drug orders, transfers, returns, or accountability, call or 
email PMB any time. Refer to the PMB’s website for specific policies and 
guidelines related to agent management.  
 
Confirmation of patient’s enrollment is required for initial supply. 
 
2. 
Drug Handling and Accountability (NCI logs or other) 
The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page.  Store and maintain separate NCI Investigational 
Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
 
3. 
Drug return and/or disposition instruction  
 
Drug Expiration: PMB will send a stock recovery letter when the agent is 
no longer suitable for use. All undispensed drug supplies should be 
returned to the PMB. When it is necessary to return study drug, 
investigators should return the study drug to the PMB using the NCI 
Return Agent Form available on the NCI home page 
(http://ctep.cancer.gov). 
 
h. 
Contact Information 
 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/  
 
NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov  
 
 

 
S1607 
 
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PMB policies and guidelines:  
http://ctep.cancer.gov/branches/pmb/agent_management.htm   
 
PMB Online Agent Order Processing (OAOP) application:  
https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx   
 
CTEP Identity and Access 
Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/  
 
CTEP 
Associate 
Registration 
and 
IAM 
account 
help:  
ctepreghelp@ctep.nci.nih.gov  
 
PMB email:  PMBAfterHours@mail.nih.gov  
 
PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
3.2 
Talimogene Laherparepvec (T-VEC, AMG 678; OncoVEXGM-CSF, IMLYGIC ™) (NSC 
785349) 
 
a. 
Pharmacology 
 
1. 
Classification: Oncolytic immunotherapy. 
 
2. 
Product Description:  
 
Talimogene laherparepvec (T-VEC) is an investigational oncolytic virus 
based on a modified herpes simplex virus type-1 (HSV-1).  It selectively 
replicates in tumor tissue and induces oncolysis of tumor cells resulting in 
a systemic antitumor immune response specific to subjects’ tumor.    
 
3. 
Mechanism of Action:  
 
Talimogene laherparepvec (T-VEC) is an attenuated herpes simplex virus 
type 1 (HSV-1) derived by functional deletion of 2 genes, ICP34.5 and 
ICP47, and insertion of coding sequence for human granulocyte 
macrophage colony stimulating factor (GM-CSF).  Deletion of ICP34.5 
allows T-VEC replication in tumor tissue; normal cells are able to protect 
against T-VEC infection as they contain intact anti-viral defense 
mechanisms.  Deletion of ICP47 prevents down-regulation of antigen 
presentation molecules and increases the expression of HSV US11 gene, 
which enhances viral replication in tumor cells.  GM-CSF recruits and 
activates antigen presenting cells which can process and present tumor-
derived antigens to promote an effector T-cell response. 
 
Talimogene laherparepvec (T-VEC) 
was approved for intratumoral 
injections in cutaneous, subcutaneous and/or nodal lesions at the 
following dose and schedules: 
x 
1st dose at 1 x 106 PFU/mL for a maximum volume of 4mL 
x 
•2nd dose 3 weeks later at 1 x 108PFU/mL for a maximum of 4mL 
 
All sequence doses every two weeks at 108PFU/mL for a maximum of 4mL 
for treatment with single agent Talimogene laherparepvec (T-VEC). In this 
protocol Talimogene laherparepvec (T-VEC) is given every three weeks. 
 

 
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b. 
Pharmacokinetics and activity of talimogene laherparepvec (T-VEC) 
 
1. 
Absorption:  
Talimogene laherparepvec (T-VEC) is injected directly into the tumor 
lesions. 
 
2. 
Pharmacokinetics of Talimogene laherparepvec (T-VEC):  
 
The 
biodistribution and 
shedding of intralesionally 
administered 
talimogene laherparepvec (T-VEC) are being investigated in an ongoing 
study measuring talimogene laherparepvec (T-VEC) DNA and virus in 
blood, oral mucosa, urine, injection site, and occlusive dressings.  In the 
initial 20 patients with melanoma who received talimogene laherparepvec 
(T-VEC) intralesional injection at a dose and schedule similar to that of the 
clinical study, available data indicate that talimogene laherparepvec (T-
VEC) DNA was present in the blood in 17 (85%) patients and in urine of 4 
(20%) patients during the study.  The peak levels of talimogene 
laherparepvec (T-VEC) DNA in the urine were detected on the day of 
treatment.  Infectious talimogene laherparepvec (T-VEC) virus was 
detected at the site of injection in 3 (15%) patients at a single time point 
each, and all within the first week after the initial injection.  The exterior of 
the occlusive dressings was positive for talimogene laherparepvec (T-
VEC) DNA in 14 (70%) patients during the study; however, no infectious 
virus was detected on the exterior of the occlusive dressing.  The number 
of patients with measurable levels of talimogene laherparepvec (T-VEC) 
DNA on the exterior of occlusive dressings declined over time with no 
measurable DNA by the third treatment in 13 patients tested. 
 
3. 
Antitumor Activity:  
 
Talimogene laherparepvec (T-VEC) demonstrated initial biological activity 
as monotherapy in subjects with advanced solid tumors with metastases 
in the skin or subcutaneous (SC) tissue as evidenced by necrosis or 
apoptosis in tumor biopsies (Study 001/01). 
 
In a phase III trial in melanoma (Study 005/05 “A Randomized Phase III 
Clinical Trial to Evaluate the Efficacy and Safety of treatment with 
OncoVEXGM-CSF Compared to Subcutaneously Administered GM-CSF 
in Melanoma Patients with Unresectable Stage IIIb, IIIc and IV Disease”), 
talimogene laherparepvec (T-VEC) demonstrated an improvement in the 
primary endpoint, durable response rate (DRR) (defined as complete 
response [CR] or partial response [PR] maintained for ≥ 6 months 
continuously and which had its onset on the first 12 months of treatment): 
16.3% vs. 2.1%.  Overall survival (OS) was a secondary endpoint.  At the 
primary analysis, median OS was 23.3 (95% confidence interval [CI]:  
19.5, 29.6) months in the talimogene laherparepvec (T-VEC) arm and 18.9 
(95% CI:  16.0, 23.7) months in the GM-CSF arm (hazard ratio [HR] 0.79; 
95% CI: 0.62, 1.00; p = 0.051).  At final analysis, with an additional follow-
up of 5 months (median 49 months [range, 37-63]), median OS remained 
4.4 months longer for talimogene laherparepvec (T-VEC) compared with 
GM-CSF (23.3 vs 18.9 months; HR 0.79, 95% CI:  0.62-1.00, P = 0.0494, 
descriptive).  Results from the phase 2 study in melanoma (002/03) also 
support the efficacy of talimogene laherparepvec (T-VEC) for the 
treatment of melanoma. 
 

 
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Response to talimogene laherparepvec (T-VEC) can be delayed, and the 
phenomenon sometimes referred to as “pseudoprogression” has been 
observed.  In the pivotal clinical trial, the median time to response onset 
was 4.1 months (ranged from 1.2 to 16.7 months).  Approximately 50% of 
the patients ultimately achieved a response had evidence of increase in 
the size of existing lesions and/or development of new lesions.  
Pseudoprogression can also be seen with other immunotherapies.  
Patients may continue treatment if there was increase in the size of 
existing lesions or development of new lesions, as long as the investigator 
determined that initiation of a new treatment was not required. 
 
c. 
Talimogene laherparepvec (T-VEC) Safety Profile:  
 
 
As of a June 30, 2015 data cutoff, 486 subjects have received talimogene 
laherparepvec (T-VEC) (with doses from 104 to 108 PFU/mL) and have provided 
safety data across 15 studies (Investigator’s Brochure, 2015).  Thirty-one of these 
subjects continued into the extension phase of two of these studies; a detailed 
summary of safety results is available in Table 6-3 of the Talimogene 
Laherparepvec Investigator’s Brochure (2015). 
 
Overall, most adverse events (AEs) reported in subjects administered talimogene 
laherparepvec (T-VEC) are non-serious and primarily include flu-like symptoms 
and injection site reactions (Investigator’s Brochure, 2015).  Most fatal AEs 
reported in subjects administered talimogene laherparepvec (T-VEC) were 
reported in the setting of disease progression.  In the Phase III study (005/05), the 
three most frequent AEs observed in the talimogene laherparepvec (T-VEC) group 
were fatigue (36.2% GM-CSF, 50.3% talimogene laherparepvec (T-VEC), chills 
(8.7%, 48.6%, respectively), and pyrexia (8.7%, 42.8%, respectively).  The 
following table also include AEs that occurred with a higher incidence in the 
talimogene laherparepvec (T-VEC) group compared with the GM-CSF group. 
 
d. 
Important Identified Risks with Talimogene laherparepvec (T-VEC): 
 
 
1. 
Injection site reactions:   
 
Talimogene laherparepvec (T-VEC) has been injected into cutaneous, 
subcutaneous and nodal tumor lesions.  Injection site reactions may 
include erythema, discoloration, induration and pain.  Necrosis at injected 
site may also occur. 
 
2. 
Cellulitis at site of injection:   
 
Intra-lesional administration of talimogene laherparepvec (T-VEC) has 
been associated with cellulitis at the injection site, and systematic infection 
may develop.  In the Phase III melanoma clinical study, the incidence of 
AEs in the bacterial cellulitis category was 6.2% in the T-VEC group (vs. 
1.6% in the GM-CSF group). 
 
3. 
Impaired wound healing at site of injection:   
 
Impact healing at the injection site has been reported, and the risk may be 
increased in settings with underlying risk factors (e.g. previously radiated 
or poorly vascularized areas).  One patient with peripheral vascular 
disease had an amputation of lower extremity due to injection of non-
healing wound after talimogene laherparepvec (T-VEC) injection.  In the 
Phase III melanoma clinical study, the impaired wound healing occurred 

 
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in 5.5% of patients in the talimogene laherparepvec (T-VEC) group (vs. 
2.4% in the GM-CSF group). 
 
4. 
Immune-mediated AEs:   
 
Across melanoma studies, immune-mediated adverse events considered 
possibly related to talimogene laherparepvec (T-VEC) were reported in 2% 
of subjects treated with talimogene laherparepvec (T-VEC) (and included 
events of vasculitis, glomerulonephritis, acute renal failure, pneumonitis, 
and worsening psoriasis.  Most cases were grade 2 or 3.  One grade 4 
case (glomerulonephritis) was reported, which resolved with treatment, 
and no fatal cases were reported.  Other contributory factors were 
identified in several of these cases, including pre-existing immune-
mediated conditions, other concurrent medications, and intercurrent 
medical events. 
 
5. 
Plasmacytoma at the injection site:   
 
A case was reported in the Phase III melanoma clinical study.  The 
plasmacytoma developed the area of the injected tumor on the scalp after 
9 cycles of treatment with talimogene laherparepvec (T-VEC).  On medical 
review, the event was felt to be consistent with recruitment of plasma cells 
in response to the talimogene laherparepvec (T-VEC) injections and the 
patient had a pre-existing (smoldering) multiple myeloma.  This case was 
considered possibly related to the treatment. No other cases of 
plasmacytoma have been reported in clinical trials with talimogene 
laherparepvec (T-VEC) to date.  
 
6. 
Obstructive airway disorder:   
 
In the Phase III melanoma clinical study (005/05), one (0.3%) subject 
treated with talimogene laherparepvec (T-VEC) reported the adverse 
event of obstructive airways disorder.  The event was grade 4 and 
resolved with sequelae.  The female subject was previously treated with 
high-dose interleukin-2 and experienced an acute respiratory failure 
requiring intubation.  The subject complained of breathing problems after 
discharge.  Four to 6 weeks later, she received the first dose of talimogene 
laherparepvec (T-VEC) (two 1 - 1.5 cm lesions in the right supraclavicular 
fossa).  Thirteen days after the second talimogene laherparepvec (T-VEC) 
dose, the subject presented with acute respiratory distress requiring an 
emergency tracheostomy.  Imaging showed a mass in the larynx on the 
contralateral side and adjacent lymph node.  Etiology of the laryngeal 
mass was unclear.  A temporal relationship to talimogene laherparepvec 
(T-VEC) treatment was present.  Study medication was permanently 
discontinued. 
 
7. 
Disseminated herpetic infection in SEVERELY immunocompromised 
individuals (defined as those with any severe congenital or acquired 
cellular and/or humoral immune deficiency):   
 
Talimogene 
laherparepvec 
(T-VEC) 
has 
not 
been 
studied 
in 
immunocompromised patients.  However, based on animal data (see 
Section 5.2 of IB), patients who are severely immunocompromised (e.g., 
patients with severe congenital or acquired cellular and/or humoral 
immune deficiency) may be at an increased risk of disseminated herpetic 
infection and should not be treated with talimogene laherparepvec (T-

 
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VEC).  “Disseminated herpetic infection in severely immunocompromised 
individuals” is defined as an important identified risk based on preclinical 
toxicology with talimogene laherparepvec (T-VEC) as well as clinical 
observations of wild-type HSV-1 infection in immunocompromised 
patients.  In preclinical studies in 100% SCID mice (devoid of T and B 
cells) and 20% BALB/c nude mice (deficient in T cells and partially 
deficient in B cell function), viral inclusion bodies and necrosis were 
observed in multiple organs, including neurons of the GI tract, adrenal 
gland, eyes, skins and brain. 
 
8. 
Deep vein thrombosis. 
 
e. 
Important Potential Risks with Talimogene laherparepvec (T-VEC): 
 
1. 
Disseminated herpetic infection in immunocompromised individuals 
(defined as those with HIV/ AIDS, leukemia, lymphoma, common variable 
immunodeficiency, or those who require high-dose steroids or other 
immunosuppressive agents):   
 
Note, for patients who are severely immunocompromised (completely 
lacking T with complete or partially impaired B cell function), disseminated 
herpetic infection is an “identified” AE (see section of talimogene 
laherparepvec (T-VEC) Identified Risks.  It is unknown whether patients 
who are not severely immunocompromised (those with conditions limited 
to T cell dysfunction such as HIV, AIDS, or patients with common variable 
immunodeficiency or those who require chronic treatment with steroids or 
other immunosuppressive agents) are at increased risk.  The potential risk 
of disseminated herpetic infection and the potential benefits of treatment 
should be considered before administering talimogene laherparepvec (T-
VEC) to these patients. 
 
2. 
Symptomatic talimogene laherparepvec (T-VEC) infection in normal 
tissues:   
 
In mouse tumor models, viral lysis/tissue injury was limited to tumors in 
immunocompetent animals.  There was no clinical or pathological 
evidence of symptomatic infection or injury to normal tissues after 
repeated intratumoral, intravenous, or subcutaneous injection, including 
mice dosed with up to 107 PFU talimogene laherparepvec (T-VEC) (~60-
fold over the highest proposed clinical dose, on a PFU/kg basis) via weekly 
subcutaneous injection for up to 3 months.   
 
No human cases of confirmed infection of non-tumor tissues by 
talimogene laherparepvec (T-VEC) have been reported.  While 5.5% of 
patients treated with talimogene laherparepvec (T-VEC) (vs 1.6% in the 
BM-CSF group) reported oral or corneal herpes infection, it is not 
confirmed whether the source was wide-type herpes or talimogene 
laherparepvec (T-VEC).  Patients who develop herpes-like lesions should 
follow stand hygienic practice to prevent viral transmission.   
 
3. 
Symptomatic herpetic infection due to latency and reactivation of 
talimogene laherparepvec (T-VEC) or wild-type HSV-1:   
 

 
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Co-infection of neurons already harboring latent wild-type HSV-1 by 
talimogene laherparepvec (T-VEC) 
could potentially stimulate the 
reactivation of latent wild-type HSV-1 in patients with prior infection.   
 
 
Talimogene laherparepvec (T-VEC) Infection of tumor or non-tumor 
tissues could potentially lead to establishment of latency and subsequent 
reactions of talimogene laherparepvec (T-VEC) if the virus comes into 
contact with axonal nerve terminals and was transported to neuronal cell 
bodies.  In mice, biodistribution studies have detected low levels of 
talimogene laherparepvec (T-VEC) in trigeminal ganglia through 28 days 
in 1 of 6 animals following high-dose IV administration (0.6 × 106 PFU, 
~36-fold over the highest proposed clinical dose).  Talimogene 
laherparepvec (T-VEC) was undetectable in trigeminal ganglia in mice 
after subcutaneous administration.   
 
4. 
Recombination of talimogene laherparepvec (T-VEC) with wild-type HSV-
1:   
 
This event has not been reported in the Phase III melanoma clinical study. 
The genetic modifications made to talimogene laherparepvec (T-VEC) 
only attenuate the virus, either by limiting replication to tumor cells and 
neurovirulence (by deletion of ICP34.5) or enhancing immune detection of 
infected cells (by eliminating ICP47), none of the theoretical products of 
recombination between wild-type HSV-1 and talimogene laherparepvec 
(T-VEC) would have increased virulence.  The likelihood of recombination 
occurring is low, and if recombination occurred, the virulence of the 
recombinants would be no greater than wild-type HSV-1, and symptoms 
will be reduced compared to wild-type HSV-1.  Management with systemic 
antivirals would be the same. 
 
5. 
Talimogene laherparepvec (T-VEC)-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.  Autoantibodies against GM-CSF is detected in 9.6% general 
population.   It is not known whether such phenomena could be expected 
with the limited exposure anticipated with transgene expression of GM-
CSF from talimogene laherparepvec (T-VEC). 
 
f. 
Special Precautions: 
 
1. 
Accidental exposure of healthcare providers (HCP) to talimogene 
laherparepvec (T-VEC):   
 
A needle stick injury, spill, or splash back during administration may result 
in accidental exposure of healthcare providers (HCPs) to talimogene 
laherparepvec (T-VEC).  The ICP34.5 gene deletion is intended to allow 
only tumor selective replication and limited or no viral replication in normal 
tissues.  The signs or symptoms of primary infection at the site of exposure 
are expected to be similar to what is seen with wild-type HSV-1.  The 
severity of symptoms is expected to be reduced compared to what is seen 
with wild-type HSV-1.  Talimogene laherparepvec (T-VEC) is sensitive to 
acyclovir.  In one case of exposure of study personnel to talimogene 

 
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laherparepvec (T-VEC), the exposed physician developed clinical signs of 
a herpetic whitlow-like lesion at the site of an accidental needle stick that 
resolved after treatment with acyclovir. 
 
2. 
Transmission of talimogene laherparepvec (T-VEC) from patient to close 
contacts or HCPs via direct contact with infected lesions or body fluids 
resulting in symptomatic infection (primary or reactivation):   
 
A clinical study is in progress to inform whether talimogene laherparepvec 
(T-VEC) is present in saliva or oral or genital secretions of treated patients.  
The likelihood of transfer of talimogene laherparepvec (T-VEC) 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, although the 
reduced potential to replicate in normal tissue may result in less severe 
clinical manifestations.  Shedding results showed that talimogene 
laherparepvec (T-VEC) 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. 
 
3. 
Loss of efficacy in patients treated with systemic acyclovir for 
complications:   
 
Talimogene laherparepvec (T-VEC) retained an intact thymidine kinase 
gene, and is therefore sensitive to acyclovir and acyclovir may attenuate 
activity of talimogene laherparepvec (T-VEC).  The risks and benefits of 
talimogene laherparepvec 
(T-VEC) 
treatment before administering 
acyclovir or other anti-viral agents indicated for management of herpetic 
infection will need to be considered.  Other treatments, such as foscarnet, 
may be used as an alternative for acyclovir. 
 
g. 
Effects  
1. 
Comprehensive Adverse Effects and Potential Risk List(s) CAEPRs):  
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by body 
system. In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset 
of AEs (SPEER) is a list of events that are protocol specific exceptions to 
expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification. Frequency is provided based on 
389 patients. Below is the CAEPR for talimogene laherparepvec (T-VEC). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 
in parentheses next to the AE in the SPEER.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 

 
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Version 2.1, August 22, 20171 
 
 Adverse Events with Possible  
 Relationship to Talimogene laherparepvec (T-VEC, 
IMLYGIC) 
 (CTCAE 5.0 Term) 
[n= 517] 
 
 Specific 
Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER)  
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
Anemia (Gr 2) 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
Abdominal pain 
(Gr 2) 
 
Constipation 
 
Constipation (Gr 
2) 
 
Diarrhea 
 
Diarrhea (Gr 2) 
Nausea 
 
 
Nausea (Gr 2) 
Vomiting 
 
 
Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 
Chills 
 
 
Chills (Gr 2) 
Fatigue 
 
 
Fatigue (Gr 2) 
Fever 
 
 
Fever (Gr 2) 
Flu like symptoms 
 
 
Flu like 
symptoms (Gr 2) 
Injection site reaction2  
 
Injection site 
reaction2 (Gr 2) 
 
Pain3 
 
Pain3 (Gr 2) 
IMMUNE SYSTEM DISORDERS 
 
 
 
Autoimmune 
disorder4 
 
INFECTIONS AND INFESTATIONS 
 
 
Infections and 
infestations - 
Other (herpetic 
keratitis) 
 
 
 
Infections and 
infestations - 
Other (oral 
herpes) 
 
 
 
Skin infection5  
Skin infection5 
(Gr 2) 
INJURY, POISONING AND PROCEDURAL 
COMPLICATIONS 
 
 
Wound 
complication6 
 
 
INVESTIGATIONS 
 
 
Weight loss 
 
Weight loss (Gr 
2) 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
 
 
Dehydration 
 
 

 
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 Adverse Events with Possible  
 Relationship to Talimogene laherparepvec (T-VEC, 
IMLYGIC) 
 (CTCAE 5.0 Term) 
[n= 517] 
 
 Specific 
Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER)  
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
 
 
Arthralgia 
 
Arthralgia (Gr 2) 
 
Myalgia 
 
Myalgia (Gr 2) 
 
Pain in 
extremity 
 
Pain in extremity 
(Gr 2) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED 
(INCL CYSTS AND POLYPS) 
 
 
 
Neoplasms benign, 
malignant and 
unspecified (incl 
cysts and polyps) - 
Other 
(plasmacytoma at 
the injection sites) 
 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
 
 
Headache 
 
Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
 
 
Pharyngolaryn-
geal pain 
 
Pharyngolaryn-
geal pain (Gr 2) 
 
 
Respiratory, thoracic 
and mediastinal 
disorders - Other 
(obstructive airway 
disorder)7 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Pruritus 
 
 
 
Rash8 
 
 
 
Skin and 
subcutaneous 
tissue disorders 
- Other 
(dermatitis) 
 
 
 
Skin and 
subcutaneous 
tissue disorders 
- Other 
(vitiligo)4 
 
 
VASCULAR DISORDERS 
 
 
Flushing 
 
 
 
Thromboemboli
c event 
(venous) 
 
 

 
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 Adverse Events with Possible  
 Relationship to Talimogene laherparepvec (T-VEC, 
IMLYGIC) 
 (CTCAE 5.0 Term) 
[n= 517] 
 
 Specific 
Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER)  
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
 
 
Vascular disorders - 
Other (carotid artery 
blowout syndrome)9 
 
1 This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of 
revision.  The current version can be obtained by contacting 
pio@ctep.nci.nih.gov.  Your name, the name of the investigator, the 
protocol and the agent should be included in the e-mail. 
2 Injection site reactions may include redness, swelling, and bleeding. 
3 Pain can occur in the tumor, injection sites and nodal draining (axilla and 
groin etc) lymph nodes. 
4 Several events which are autoimmune-mediated, such as acute kidney 
injury (acute renal failure), glomerulonephritis (nephritis), worsening of 
psoriasis, pneumonitis, vasculitis, and vitiligo (areas of skin with loss of 
color) have been observed in clinical trials of talimogene laherparepvec. 
5 Skin infection (cellulitis) can be complicated with local and systemic 
infection, tissue necrosis, and ulceration, or wound complications. 
6 Wound complication may occur at the injection site and may include 
wound infection and poor healing. 
7 Obstructive airway disorder has occurred in one patient with Head and 
Neck Squamous cell carcinoma (HNSCC) with a suproventricular mass 
who developed acute respiratory distress requiring a trachetomy 13 
days after the second dose of T-VEC.  Imaging showed a mass in the 
larynx and adjacent lymph nodes on the contralateral side. 
8 Rash may include rash maculo-papular and erythematous rash. 
9 Carotid artery blowout syndrome was observed in a HNSCC patient 
treated with T-VEC in combination with anti-PD-1 who had been 
previously treated with localized (neck) radiation and lymph node 
dissection. 
 
Adverse events reported on talimogene laherparepvec (T-VEC, 
IMLYGIC) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that talimogene 
laherparepvec (T-VEC, IMLYGIC) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
GASTROINTESTINAL DISORDERS - Ascites; Dry mouth; Dysphagia; 
Gastrointestinal disorders - Other (odynophagia); Mucositis oral 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Edema limbs; Malaise 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other 
(oral candidiasis) 

 
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INJURY, 
POISONING 
AND 
PROCEDURAL 
COMPLICATIONS 
- 
Bruising; Dermatitis radiation; Fracture 
INVESTIGATIONS - Neutrophil count decreased; White blood cell 
decreased 
METABOLISM AND NUTRITION DISORDERS - Hypokalemia 
NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Dysgeusia 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Insomnia 
RESPIRATORY, 
THORACIC 
AND MEDIASTINAL 
DISORDERS - 
Dyspnea; Pneumonitis4 
 
Note: Talimogene laherparepvec (T-VEC, IMLYGIC) in combination with 
other agents could cause an exacerbation of any adverse event currently 
known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
 
Note: In animal models talimogene laherparepvec has demonstrated 
several potential risks as detailed below: 
1) Talimogene laherparepvec has not been tested in severely 
immune compromised patients.  In animal models, injection of 
talimogene laherparepvec in immune-deficient mice resulted in 
disseminated infection. 
2) Transmission of talimogene laherparepvec to health care 
professionals and personnel in close contact is possible. 
3) Latent infection of talimogene laherparepvec in the neurological 
system has been observed in mice at high dose of T-VEC, 
although the clinical implication in human patients is not clear. 
 
2. 
Pregnancy and Lactation:  
 
Adequate and well-controlled studies with talimogene laherparepvec (T-
VEC) in pregnant women have not been conducted. In animal studies, no 
effects on embryo-fetal development have been seen. In pregnant women 
who have an infection with wild-type HSV-1 (primary or reactivation), there 
is potential for the virus to cross the placental barrier and also a risk of 
transmission during birth due to viral shedding. Infections with wild-type 
HSV-1 have been associated with serious adverse effects, including multi-
organ failure and death, if a fetus or neonate contracts the wild-type 
herpes infection. While there are no clinical data to date on talimogene 
laherparepvec (T-VEC) infections in pregnant women, if talimogene 
laherparepvec (T-VEC) were to act like wild-type HSV-1, there is potential 
risk to the fetus or neonate. Women of childbearing potential and men 
should be advised to use an effective method of contraception to prevent 
pregnancy prior to study entry, during the study participation, and for four 
months after the last dose of talimogene laherparepvec (T-VEC). Per the 
IMLYGIC™ 
package insert, talimogene laherparepvec (T-VEC) 
is 
contraindicated during pregnancy. 
 
There is no information regarding the transfer of talimogene laherparepvec 
(T-VEC) into human milk and its effects on milk production. According to 
the manufacturer’s package insert, it is recommended to either discontinue 
nursing or to discontinue talimogene laherparepvec (T-VEC) while 
nursing. 
 
 

 
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3. 
Drug Interactions:  
 
No drug interaction studies have been conducted with talimogene 
laherparepvec (T-VEC), however, talimogene laherparepvec (T-VEC) is 
sensitive to acyclovir. Acyclovir or other anti-herpetic viral agents may 
interfere with the effectiveness of talimogene laherparepvec (T-VEC).  
 
h. 
Dosing & Administration  
 
See Section 7.0 Treatment Plan 
 
1. 
Dose and Schedule of T-VEC: 
 
a. 
1st dose of T-VEC: 1 x 106 PFU/mL with a maximum volume of 4 
mL with all lesions combined (or according to the dose escalation 
schedule for Phase I trial).   
b. 
2nd dose: Should be at least 3 weeks AFTER the 1st dose (To allow 
for development of neutralization anti-herpes antibodies): 1 x 108 
PFU/mL with a maximum volume of 4 mL with all lesions 
combined (or according to the dose escalation schedule for Phase 
I trial).   
 
2. 
Special handling and precautions:  
 
a. 
T-VEC is an attenuated version of HSV-1.  Use protective 
equipment when preparing and administering this agent according 
to the institutional guidelines.  In the event of an accidental 
occupational exposure through a splash to the eyes or mucous 
membranes, flush with clean water for at least 15 minutes.  In the 
event of exposure to broken skin or needle stick, clean the site 
thoroughly with soap and water or a virucidal disinfectant such as 
1% sodium hypochlorite or Virkon®.  
 
b. 
In the event of a secondary exposure (e.g., leakage through 
occlusive dressing to subject or contacts) to T-VEC, clean the site 
thoroughly with soap and water or a virucidal disinfectant. Seek 
healthcare provider for signs of systemic (fever, aches, nausea, 
and malaise) or local (fever, pain, redness and swelling) infection. 
 
c. 
Healthcare providers who are immunocompromised or pregnant 
should not administer talimogene laherparepvec (T-VEC) and 
should not come into direct contact with talimogene laherparepvec 
(T-VEC) injection sites or body fluids of treated patients. 
 
d. 
See Section 3.2f.2 for additional handling precautions. 
 
3. 
Administration: 
 
a. 
Route of Administration: Intratumoral/intralesional injection 
 
b. 
Talimogene laherparepvec (T-VEC) is to be administered by 
intralesional injection into cutaneous, subcutaneous and nodal 
lesions with or without image ultrasound guidance. Talimogene 
laherparepvec (T-VEC) must not be administered into visceral 

 
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organ metastases. Do NOT administer talimogene laherparepvec 
(T-VEC) intravenously. 
 
The volume of talimogene laherparepvec (T-VEC) to be injected into 
each lesion is depended on the size of the lesion. The total injection 
volume at each treatment visit should not exceed 4mL for all 
injected lesions combined. 
 
Injection site may be pre-treated with a topical or a local anesthetic 
agent; however, a local anesthetic must not be injected directly into 
the lesion. Clean the lesion and surrounding areas with an alcohol 
swab and let dry. 
 
c. 
Talimogene laherparepvec (T-VEC) injection volume guideline:  
 
Lesions should be injected until either the maximum volume is 
reached or there are no further injectable lesions (as determined 
by the treating investigator), whichever comes first.  The total 
injection volume for each treatment visit should not exceed 4 mL 
for all injected lesions combined. 
 
Tumor Size (longest 
dimension) 
Maximum Injection 
Volume 
PER Lesion 
> 5 cm 
4mL 
> 2.5 cm to 5cm 
2 mL 
> 1.5 cm to 2.5 cm 
1 mL 
> 0.5 cm to 1.5 cm 
0.5 mL 
≤ 0.5 cm 
0.1 mL 
 
4. 
Intralesional injection guidance: 
 
All reasonably injectable lesions (cutaneous, subcutaneous and 
nodal disease that can be injected with or without ultrasound 
guidance) should be injected with the maximum dosing volume 
available on an individual dosing occasion.  On each treatment 
day, prioritization of injections is recommended as follows: 
x 
any new injectable tumor that has appeared since the last 
injection; 
x 
by tumor size, beginning with the largest tumor;  
x 
any previously uninjectable tumor(s) that is now injectable.  
 
Within the injection volume guidelines in the table above, it is 
recommended that each lesion receive the maximum amount 
possible at each visit before moving on to the next lesion, subject 
to tumor-specific limitations (such as inability to inject the full 
amount into the lesion).  Lesions should be injected until the 
maximum volume per day (4mL) has been reached or there are 
no further injectable lesions, whichever comes first. 
 

 
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a. 
A single point of injection is recommended; multiple insertion 
points may be used if the tumor is larger than the radial reach of 
the needle.  
b. 
Inject talimogene laherparepvec (T-VEC) along multiple different 
tracks within the lesion in order to obtain as wide a dispersion as 
possible. 
c. 
Distribute talimogene laherparepvec (T-VEC) within the lesion 
through the insertion point using the radial reach of the needle in 
different directions to evenly distribute. 
 
 
d. 
Avoid premature extraction of the needle. 
 
e. 
After dosing, the injection site should be swabbed with alcohol and 
pressure should be applied with gauze for several seconds after 
injection. 
 
f. 
Cover the injection site with an absorbent pad and dry occlusive 
dressing. 
 
g. 
Injected lesion care: see Section 18.6. 
 
5. 
Disposal 
 
Dispose of all materials that have come in contact with talimogene 
laherparepvec (T-VEC) (e.g., vial, syringe, needle, any cotton or gauze) in 
accordance with local institutional procedure for biohazardous drugs. 
 
i. 
How Supplied 
 
1. 
Amgen 
supplies 
talimogene 
laherparepvec 
(T-VEC) 
and 
the 
Pharmaceutical Management Branch distributes.   
 
There are two nominal vials concentrations:  
x 1 x 106 PFU/mL packaged as 10 vials per box  
x 1 x 108 PFU/mL packaged as 20 vials per box 
 
2. 
Both vial strengths contain 1 mL extractable volume (with approximately 
0.1 mL overfill volume) of talimogene laherparepvec solution consisting of 
disodium hydrogen phosphate dehydrate, sodium dihydrogen phosphate 
dehydrate, sodium chloride, sorbitol, myo-inositol and Water for Injection. 
T-VEC is a sterile, semi-translucent to opaque suspension, practically free 
from particles, preservative free frozen liquid packaged in a single-use 2 
mL Crystal Zenith Resin vial. Each vial is sealed with a gray stopper (latex-
free) and is Fluorotec-coated on the product side.  
 

 
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3. 
Current supplies of talimogene laherparepvec are provided as a 
preservative-free solution in a single-use vial without a clear copolyester 
plastic sleeve. 
 
In early 2019, talimogene laherparepvec vials will change in appearance 
only. Supplies will be transitioned to single-use vials permanently inserted 
into a clear copolyester plastic sleeve. The product label will be found on 
the vial sleeve. Talimogene laherparepvec vial is compatible with the 
Closed System Transfer Device (CSTD), PhaSeal CSTD. 
 
j. 
Storage, Preparation and Stability 
1. 
Storage:  
 
Talimogene laherparepvec intact vials are stable between -90°C and -
70°C, protect from light. [Note: Frost-free, auto defrosts freezers must not 
be used since they cycle to warmer temperatures several times a day.]  
 
Freezer Set Point  
Acceptable Range 
-80°C 
-90°C to -70°C 
 
Stability: Shelf-life surveillance of the intact vials is on-going. 
 
If a storage temperature excursion is identified, promptly store talimogene 
laherparepvec to between -90°C and -700C and quarantine the supplies.  
Provide a detailed report of the excursion (including documentation of 
temperature 
monitoring 
and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
2. 
Preparation  
 
a. 
Special handling and precautions:  
 
1. 
Talimogene laherparepvec (T-VEC) is a live attenuated 
HSV-1. 
When 
preparing, 
follow local institutional 
guidelines for handling, personal protective equipment, 
accidental spills, and waste disposal of biohazard 
material. 
 
2. 
Healthcare providers who are immunocompromised or 
pregnant should not prepare talimogene laherparepvec 
(T-VEC). 
 
3. 
Wear personal protective equipment including gown, 
gloves, mask and safety glasses or face shield.   
 
4. 
Avoid accidental exposure to talimogene laherparepvec 
(T-VEC), especially contact with skin, eyes, and mucous 
membranes. 
 
5. 
Cover any exposed wounds before handling. 
 
6. 
In the event of an accidental occupational exposure (e.g., 
through a splash to the eyes or mucous membranes), 
flush with clean water for at least 15 minutes. 

 
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7. 
In the event of exposure to broken skin or needle stick, 
clean the affected area thoroughly with soap and water 
and/or a virucidal disinfectant such as 1% sodium 
hypochlorite or Virkon®. 
 
8. 
Seek healthcare provider for signs of systemic (fever, 
aches, nausea, and malaise) or local (fever, pain, redness 
and swelling) infection. 
 
9. 
Treat all talimogene laherparepvec (T-VEC) spills with a 
virucidal agent such as 1% sodium hypochlorite and blot 
using absorbent materials. 
 
10. 
Dispose of all materials that may have come in contact 
with talimogene laherparepvec (T-VEC) 
(e.g., vial, 
syringe, needle, cotton gauze, gloves, masks, or 
dressings) in accordance with institution biohazard 
procedure. 
 
11. 
In the event of a secondary exposure (e.g., leakage 
through occlusive dressing to subject or contacts) to 
talimogene laherparepvec 
(T-VEC), 
clean the site 
thoroughly with soap and water or a virucidal disinfectant. 
Seek healthcare provider for signs of systemic (fever, 
aches, nausea, and malaise) or local (fever, pain, redness 
and swelling) infection. 
 
b. 
Patient Care Implications:  
 
1. 
Advise patients on the potential for secondary exposure, 
e.g., broken skin.  Advise patients on careful wound 
care. 
 
2. 
Necrotic or ulcerating lesions may occur and may be 
predisposed to local and/or systemic infections such as 
cellulitis, bacteremia, etc.  Advise patients on careful 
wound care. Infection precautions are recommended for 
tumor necrosis that results in open wounds.   
 
3. 
There is a potential risk for exposure of talimogene 
laherparepvec (T-VEC) from patients to anyone in direct 
contact with the patient.  Individual with open skin lesions 
and immunosuppressant should not come in contact with 
talimogene laherparepvec (T-VEC) injection site or its 
protective dressing.  
 
4. 
An Information Sheet about talimogene laherparepvec (T-
VEC) and the risk of transmission and accidental 
exposure should be provided to patient’s Health Care 
Providers and Close Contacts (see Sections 18.4 and 
18.5) 
 

 
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c. 
Thawing of talimogene laherparepvec (T-VEC): 
1. 
Remove frozen agent vial from freezer  
 
2. 
Determine the total volume required for injection. 
 
3. 
Thaw frozen vials at room temperature, 15ºC to 30ºC 
(59ºF to 86ºF) until liquid (approximately 30 minutes). Do 
not expose vial to higher temperatures. Protect vial from 
light during the thaw process.  
 
4. 
DO NOT shake vial 
5. 
Gently swirl for completion of thaw. 
 
6. 
Carefully check the vial for cracks 
 
7. 
DO NOT re-freeze thawed vial. 
 
d. 
After Thawing: 
1. 
Gently swirl the vial to ensure the contents are mixed to a 
homogeneous solution free of ice. 
 
2. 
Carefully check the vial for damage (e.g., cracks).  
Dispose of damaged vial(s) according to the institutional 
policy 
and 
guidelines 
and 
notify 
PMB 
at 
pmbafterhours@mail.nih.gov.  
 
3. 
Draw required dose volume according to tumor size 
injection volume (see below) into a syringe that is properly 
labeled.  
 
4. 
Administer to patient as soon as possible. 
 
Stability at 2°C to 8°C (360 F to 460 F) 
Thawed vial stability 
Prepared syringe stability 
1 x 106 
PFU/mL 
1 x 108 
PFU/ mL 
1x 106 
PFU/mL 
1x 108 
PFU/ mL 
12 hours 
(inclusive of 4 
hours 
maximum in 
the syringe) 
48 hours 
(inclusive of 
8 hours 
maximum 
in syringe) 
4 hours 
8 hours 
 
Stability up to 27°C (800 F) 
Thawed vial stability 
Prepared syringe stability 
1x 106 
PFU/mL 
1x 108 
PFU/ mL 
1x 106 
PFU/mL 
1x 108 
PFU/mL 
4 hours 
(inclusive of 2 
hours 
maximum in 
the syringe) 
4 hours 
(inclusive of 
4 hours 
maximum 
in the 
syringe) 
2 hours 
4 hours 

 
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3. Stability: 
 
Shelf-life surveillance of the intact vials is on-going. 
 
NOTE:  Upon receipt of the agent supplies, the site has 90 seconds to 
verify the contents and place the agent supplies in the -80° (+/- 100C) 
freezer once the inner shipping container lid is opened and the supply 
exposed to room temperature. See Section 18.9 and Section 18.10. 
 
k. 
Drug Ordering and Accountability 
 
1. Drug Ordering  
 
Starter supplies will not be provided. NCI supplied agents may be 
requested by the responsible Investigator (or their authorized designee) at 
each participating institution. Pharmaceutical Management Branch (PMB) 
policy requires that drug be shipped directly to the institution where the 
patient is to be treated. PMB does not permit the transfer of agents 
between institutions (unless prior approval from PMB is obtained). The 
CTEP assigned protocol number (S1607) must be used for ordering all 
CTEP supplied investigational agents. The responsible investigator at 
each participating institution must be registered with CTEP, DCTD through 
an annual submission of FDA Form 1572, Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF) and a CV. If there are several 
participating investigators at one institution, CTEP-supplied investigational 
agents for the study should be ordered under the name of one lead 
investigator at that institution.  Active CTEP-registered investigators and 
investigator-designated shipping designees and ordering designees can 
submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application.  Access to OAOP requires the establishment of a 
CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status and a “current” password. For 
questions about drug orders, transfers, returns, or accountability, call or 
email PMB any time. Refer to the PMB’s website for specific policies and 
guidelines related to agent management.  
 
Initial agent supplies may be requested only when subject enrollment onto 
the study is confirmed. There will be NO next day delivery of Talimogene 
laherparepvec requests available. Sites must plan agent ordering and 
study subject treatment accordingly.  
 
Agent order requests received on Monday, Tuesday, or Wednesday of 
the week, will be shipped on Tuesday, Wednesday and Thursday, 
respectively. Agent order requests received on Thursday or Friday of the 
week will be shipped on Monday of the following week. There will be no 
exceptions to this planned schedule. Sites should also consider planned 
Federal Government holidays when submitting agent requests and 
scheduling study subject treatment. 
 
Talimogene laherparepvec will be shipped on dry ice.  Only one strength 
of the agent will be in a single shipping container. You may receive multiple 
shipping containers for a single strength depending on the number vials 
being shipped. Upon receipt of the agent supplies, the site has 90 seconds 
to verify the contents and place the agent supplies in the 800 C (+/- 100 C) 
freezer (see Section 18.9) once the inner shipping container lid is opened 

 
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and the supply exposed to room temperature.  Record exposure time in 
the temperature exposure tracking log (see Section 18.10). The log must 
be retained with your study records. If exposure time exceeds 90 seconds, 
quarantine the agent supplies in the 800 C (+/- 100 C) freezer and call PMB 
immediately at 240/276-6575 for guidance. 
 
2. 
Drug Handling and Accountability (NCI logs or other) 
 
The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page.  Store and maintain separate NCI Investigational 
Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
 
3. 
Drug return and/or disposition instruction  
 
a. 
Drug disposition: All undispensed drug supplies should be 
returned to the PMB. When it is necessary to return study drug 
(e.g., sealed bottles remaining when PMB sends a stock recovery 
letter), investigators should return the study drug to the PMB using 
the NCI Return Agent Form available on the NCI home page 
(http://ctep.cancer.gov).  
b. 
Drug Expiration:  Stability testing is ongoing. PMB will send a 
stock recovery letter when notified that the agent is no longer 
suitable for use. 
4. 
Contact Information 
 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/  
 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov   
 
PMB policies and guidelines:  
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP  
 
CTEP 
Identity 
and 
Access 
Management 
(IAM) 
account: 
https://ctepcore.nci.nih.gov/iam/  
 
CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov   
 
IB Coordinator: IBCoordinator@mail.nih.gov   
 
PMB email:  PMBAfterHours@mail.nih.gov  
 
 
 

 
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4.0 
STAGING CRITERIA 
 
All patients will be staged using the AJCC 7th edition, 2009 
 
STAGE III 
 
Any T                ≥ N1                 M0 
 
Stage IV 
 
Any T                Any N               M1 
 
Primary Tumor (T) 
 
TX 
Primary tumor cannot be assessed (e.g., curettaged or severely regressed melanoma) 
T0 
No evidence of primary tumor 
Tis 
Melanoma in situ 
T1 
Melanomas 1.0 mm or less in thickness 
T2 
Melanomas 1.01 – 2.0 mm 
T3 
Melanomas 2.01 – 4.0 mm 
T4 
Melanomas more than 4.0 mm 
 
Regional Lymph Nodes (N) 
 
NX 
Patients in whom the regional nodes cannot be assessed (e.g., previously removed for 
another reason) 
N0 
No regional metastases detected 
N1-3 
Regional metastases based upon the number of metastatic nodes and presence or 
absence of intralymphatic metastases (in transit or satellite metastases) 
 
Distant Metastasis (M) 
 
M0 
No detectable evidence of distant metastases 
M1a 
Metastases to skin, subcutaneous or distant lymph nodes 
M1b 
Metastases to lung 
M1c 
Metastases to all other visceral sites or distant metastases to any site combined with an 
elevated serum LDH 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration.  For each criterion requiring test results and dates, please record this information on the 
Onstudy Form and submit via Medidata Rave® (see Section 14.0).  Any potential eligibility issues should 
be addressed to the Data Operations Center in Seattle at 206/652-2267 or melanomaquestion@crab.org 
prior to registration. 
 
In calculating days of tests and measurements, the day a test or measurement is done is considered Day 
0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later would be considered Day 28.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Day 14, 28, 42, or 56 falls on a 
weekend or holiday, the limit may be extended to the next working day. 
 
 

 
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5.1 
Disease Related Criteria 
 
a. 
Patients must have pathologically confirmed Stage IV or unresectable Stage III 
melanoma (see Section 4.0).  Patients must not have disease that is suitable for 
local therapy, administered with curative intent. 
 
b. 
Patients must have measurable disease per RECIST 1.1 (see Section 10.1). 
Contrast-enhanced CT scans of the chest, abdomen and pelvis are required. A 
whole body PET/CT scan with diagnostic quality images and intravenous iodinated 
contrast may be used in lieu of a contrast enhanced CT of the chest, abdomen and 
pelvis. Imaging of the head and neck, or the limbs is required only if the patient 
has a lesion(s) in these areas. Contrast may be omitted if the treating investigator 
believes that exposure to contrast poses an excessive risk to the patient. If skin 
lesions are being followed as measurable disease, photograph with a ruler 
included and physician’s measurements, must be kept in the patients chart as 
source documentation. All measurable lesions must be assessed within 28 days 
prior to registration. Tests to assess non-measurable disease must be performed 
within 42 days prior to registration. All disease must be assessed and documented 
on the Baseline Tumor Assessment Form (RECIST 1.1).  
 
c. 
Cohort A: Patients must have at least one measurable visceral lesion (per RECIST 
1.1). A visceral lesion is any solid organ except for skin, lymph node, and 
musculoskeletal tissue. At least one of these visceral lesions must be measurable 
per RECIST 1.1.  
 
Cohort B: Patients must not have any visceral lesions. 
 
d. 
Patients must, in the opinion of the treating physician, be candidates for 
intralesional administration into cutaneous, subcutaneous, or nodal lesions.  
 
e. 
Patients may have brain metastases if all lesions have been treated with 
stereotactic radiation therapy, craniotomy, or gamma knife therapy and have not 
required steroids for at least 14 days prior to registration. 
 
5.2 
Prior/Concurrent Therapy Criteria 
 
a. 
Patient must have had prior treatment with anti-PD-1 or anti-PD-L1 agents  and 
have documented disease progression on these agents prior to registration (see 
Section 18.1 for a list of these agents). Patients who have progressed after 
adjuvant anti-PD1/L1 agents are eligible. 
 
b. 
Patients must not have had surgery, biologic therapy, or hormonal therapy within 
14 days prior to registration. Patients must not have had chemotherapy, targeted 
small molecule therapy, or radiation therapy within 14 days prior to registration. 
Patients must not have had a monoclonal antibody for cancer treatment, except 
anti-PD1/L1 antibodies, within 28 days prior to registration. 
 
x 
Patients must have recovered from all adverse events due to prior anti-
cancer therapy (residual toxicity ≤ Grade 1) prior to registration, with the 
exception of patients with ≤ Grade 2 neuropathy, ≤ Grade 2 
hypothyroidism, or ≤ Grade 2 alopecia.  
x 
If patients received major surgery, they must have recovered adequately 
from toxicity and/or complications from the intervention prior to 
registration. 
 

 
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c. 
Patients must not have received prior treatment with talimogene laherparepvec (T-
VEC). Prior treatment with T-VEC is defined as receiving at least one injection with 
1 x 108 pfu. 
 
d. 
Patients must not have received any live vaccine within 30 days prior to 
registration. Seasonal flu vaccines that do not contain live virus are permitted. 
 
e. 
Patients must not be planning to receive other biologic therapy, radiation therapy, 
hormonal therapy, chemotherapy, surgery, or other therapy while on this protocol. 
Palliative radiation therapy or surgery can be considered for symptomatic non-
target lesions after discussions with the study team. 
 
5.3 
Clinical/Laboratory Criteria 
 
a. 
Patients must be ≥ 18 years of age. 
 
b. 
Patients must have Zubrod Performance Status ≤ 2. (see Section 10.4). 
 
c. 
Patients must have adequate hematologic function as evidenced by all of the 
following within 28 days prior to registration: ANC ≥ 1,500/mcL; hemoglobin ≥ 8 
g/dL; platelets ≥ 100,000/mcL. 
 
d. 
Patients must have adequate hepatic function as evidenced by all of the following 
within 28 days prior to registration: albumin ≥ 2.5 g/dL, total bilirubin ≤ 1.5 x 
Institutional Upper Limit of Normal (IULN) except patients with documented 
Gilbert’s Syndrome (≤ 3 x IULN is eligible); AST and ALT both ≤ 3 x IULN. 
 
e. 
Patients must have LDH obtained prior to registration. 
 
f. 
Patients must have complete physical examination and medical history obtained 
within 28 days prior to registration. 
 
g. 
Patients must not require use of systemic corticosteroid within 14 days prior to 
registration or during protocol treatment. Patients with preexisting severe 
autoimmune 
disease 
requiring 
systemic 
corticosteroids 
or 
ongoing 
immunosuppression are not eligible.  
 
h. 
Patients must not have known history of hepatitis B, hepatitis C, or HIV due to 
contraindication of talimogene laherparepvec (T-VEC) in immune-compromised 
patients and that administration of talimogene laherparepvec (T-VEC) has not 
been tested in HIV-positive patients. The 
use of physiologic doses of 
corticosteroids may be approved after consultation with the Study Chair. 
 
i. 
Patients must not have a history of (non-infectious) pneumonitis that required 
steroids or current pneumonitis. 
 
j. 
Patients must not have an active infection requiring systemic therapy nor a viral 
infection requiring intermittent treatment with an antiherpetic drug, other than 
intermittent topical use. 
 
k. 
Patients must not have active herpetic skin lesions or prior complications of 
herpetic infection (e.g., herpetic keratitis or encephalitis) which requires 
intermittent or chronic treatment with an anti-herpetic drug other than intermittent 
topical use. 
 
l. 
Patients must not have organ allografts.  

 
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m. 
Patients must not have an uncontrolled intercurrent illness or whose control may 
be jeopardized by the treatment with the study therapy, or psychiatric illness/social 
situations which would limit compliance with study requirements. 
 
n. 
Patients must not have active autoimmune disease (e.g., pneumonitis, 
glomerulonephritis, vasculitis, or other) that requires systemic treatment (i.e., use 
of corticosteroids, immunosuppressive drugs or biological agents used for 
treatment of autoimmune diseases) in the past 2 years. Replacement therapy (e.g., 
thyroxine for hypothyroidism, insulin for diabetes or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a form 
of systemic treatment for autoimmune disease. 
 
o. 
Patient must not have evidence of any clinically significant immunosuppression 
such as the following: 
 
1. 
Primary 
immunodeficiency 
state 
such 
as 
Severe 
Combined 
Immunodeficiency Disease; 
2. 
Concurrent opportunistic infection; 
3. 
Receiving systemic immunosuppressive therapy (>2 weeks) including oral 
steroid doses >10 mg/day of prednisone or equivalent within 2 weeks prior 
to enrollment. 
 
p. 
Patients must not have any other malignancy that requires active treatment. 
 
q. 
Patients must not be pregnant or nursing due to risk of fetal or nursing infant 
harm.  Women of reproductive potential must have a negative serum pregnancy 
test within 7 days prior to registration. Women/men of reproductive potential must 
have agreed to use an effective contraceptive method while on study and for 120 
days after last study treatment.  A woman is considered to be of "reproductive 
potential" if she has had menses at any time in the preceding 12 consecutive 
months.  In 
addition 
to 
routine 
contraceptive 
methods, 
"effective 
contraception" also includes heterosexual celibacy and surgery intended to 
prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a 
hysterectomy, bilateral oophorectomy or bilateral tubal ligation.  However, if at any 
point a previously celibate patient chooses to become heterosexually active during 
the time period for use of contraceptive measures outlined in the protocol, he/she 
is responsible for beginning contraceptive measures. 
 
5.4 
Specimen Submission Criteria 
 
Patients must be offered the opportunity to submit archival tissue for translational medicine 
as described in Section 15.1. Patients must also be willing to undergo biopsies and submit 
tissue and blood for translational medicine as described in Section 15.1. With patients 
consent, any remaining specimens will be banked for future use. 
 
5.5 
Regulatory Criteria 
 
a. 
Patients must be informed of the investigational nature of this study and must sign 
and give written informed consent in accordance with institutional and federal 
guidelines. 
 
b. 
As a part of the OPEN registration process (see Sections 13.3 and 13.4 for OPEN 
access instructions) the treating institution's identity is provided in order to ensure 
that the current (within 365 days) date of institutional review board approval for this 
study has been entered in the system. 

 
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6.0 
STRATIFICATION FACTORS 
 
Patients will be stratified into two cohorts. 
 
Cohort A: Patients with at least one visceral lesion (at least one must be measurable). 
 
Cohort B: Patients with no evidence of visceral lesions.  
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Dr. Hu-Lieskovan at 801/585-0308 
(or siwen.hu-lieskovan@hci.utah.edu)   For dosing principles or questions, please consult the 
SWOG Policy #38 "Dosing Principles for Patients on Clinical Trials" at http://swog.org (see Policy 
#38 under the Policies & Procedures link in the “About” dropdown). 
 
7.1 
Treatment 
 
Patients will receive the following treatment for up to two years or until meeting one of the 
criteria in Section 7.4. 
 
Agent 
Dose 
Route 
Day 
Schedule a 
 
T-VECf 
up to 4 ml of  
Intralesional 
1 
Cycle 1 
 
1 million PFU/mL d 
 
(106 PFU/mL) 
 
T-VECf 
up to 4 ml of 
Intralesional 
1 
Cycles 2-36  
 
100 million PFU/mL d 
 
 
 
 
(108 PFU/mL) 
 
 
Pembrolizumab 
200 mg* 
IV over 30 min e 1 
Cycles 1-36 c* 
(MK-3475) 
 
a 
Note: One cycle = 21 days; Maximum of 36 cycles, 
b 
All planned doses of pembrolizumab (MK-3475) must be administered. Missed doses must be 
made up. 
c 
Please see Table 1: Injection Volume Per Lesion below. 
d 
pembrolizumab (MK-3475) infusion timing should be as close to 30 minutes as possible; 
however, a window of -5 and +10 minutes is permitted (i.e., 25-40 minutes). 
e    pembrolizumab (MK-3475) infusion timing should be as close to 30 minutes as 
possible; however, a window of -5 and +10 minutes is permitted (i.e., 25-40 minutes). 
f 
If patient has a confirmed complete response in the injectable lesions, as defined in 
section 10.3.a, with stable disease or better in all other sites of disease, contact the 
study chair for permission to permanently discontinue the administration of T-VEC. 
Patient must continue on pembrolizumab (MK-3475) per protocol.  
 
a. 
Administration of talimogene laherparepvec (T-VEC)  
 
All reasonably injectable lesions (cutaneous, subcutaneous, and nodal lesions with 
or without image ultrasound guidance) should be injected with the maximum 
dosing volume available on an individual dosing occasion. If the patient has more 
than one injectable lesion, one lesion must be left un-injected prior to the Day 28 
biopsy for Cohort B (see Section 15.1) Talimogene laherparepvec (T-VEC) must 

 
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not be administered into visceral organ metastases. On each treatment day, 
prioritization of injections is recommended as follows: 
 
x 
Any new injectable tumor that has appeared since the last injection 
x 
By tumor size, beginning with the largest tumor 
x 
Any previously un-injectable tumor(s) that is now injectable 
 
Within the injection volume guidelines in the table below, it is recommended that 
each lesion receive the maximum amount possible at each visit before moving 
onto the next lesion, subject to tumor-specific limitations (such as inability to inject 
the full amount into the lesion). Prescribe the estimated total volume by rounding 
up to the nearest 1 mL. 
 
Lesions should be injected until the maximum volume per day (4 mL) has been 
reached or there are no further injectable lesions, whichever comes first. The 
TOTAL maximum dose in any one treatment is 4 mL for all lesions combined.  Use 
the maximum amount whenever lesions allow.  
 
Table 1: Injection Volume Per Lesion 
 
Tumor Size (longest dimension) 
Maximum Injection Volume 
PER Lesion 
> 5 cm 
4 mL 
> 2.5 cm to 5cm 
2 mL 
> 1.5 cm to 2.5 cm 
1 mL 
> 0.5 cm to 1.5 cm 
0.5 mL 
≤ 0.5 cm 
0.1 mL 
 
b. 
Injection Site Care 
 
After administration of talimogene laherparepvec (T-VEC) the injected lesions will 
be covered with a watertight dressing which allows for air exchange and it may 
also include an absorbent pad underneath covering the lesion. These dressings 
are like the dressings that are placed on skin when intravenous lines are placed to 
deliver medicine. The dressing can be removed 7 days after the last talimogene 
laherparepvec (T-VEC) injection. See also Section 18.6: Instructions for 
talimogene laherparepvec (T-VEC) Site Care and Section 18.7: Information 
Related to Exposure to talimogene laherparepvec (T-VEC). 
 
c. 
Administration of pembrolizumab (MK-3475)  
 
Pembrolizumab (MK-3475) treatment will be administered on Day 1 of each 3-
week treatment cycle, after all procedures and assessments have been completed.  
Pembrolizumab (MK-3475) treatment may be administered up to 3 days before or 
after the protocol-specified Q 3 weeks due to administrative reasons. 
 
Pembrolizumab (MK-3475) will be administered as a 30 minute IV infusion. 
Infusion timing should be as close to 30 minutes as possible; however, a window 
of -5 minutes and +10 minutes is permitted (i.e., infusion time is 25-40 minutes). 
 
Dosing interruptions are permitted in the case of medical / surgical events or 
logistical reasons not related to study therapy (e.g., elective surgery, unrelated 
medical events, patient vacation, and/or holidays). Patients should be back on 

 
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study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the study chair. The reason for interruption should be documented 
in the patient’s study record. 
 
All planned doses must be administered. Missed doses must be made up. 
 
7.2 
Full CDUS Reporting Requirement 
 
Because this study contains an investigational drug for which CTEP holds the IND, it falls 
under CTEP requirements for full reporting.  This involves required submission of cycle-
specific toxicity and dose information (see Section 14.4, the S1607 Treatment Form, and 
the S1607 Adverse Event Form).  A cycle is defined as 21 days.  
 
7.3 
Prohibited and Cautionary Concomitant Medications 
 
Patients should not receive the following therapies during this trial: 
x 
Antineoplastic systemic chemotherapy or biological therapy. 
x 
Immunotherapy not specified in this protocol. 
x 
Any non-study anti-cancer agent (investigational or non-investigational). 
x 
Investigational agents other than pembrolizumab (MK-3475) and talimogene 
laherparepvec (T-VEC). 
x 
Radiation therapy 
o 
Note:  Administration of palliative radiation therapy to non-targeted lesions 
is allowed. 
x 
Anti-viral agents, unless approved after consultation with the study chairs. 
x 
Live vaccines: Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, 
Bacillus Calmette-Guérin (BCG), and typhoid (oral) vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed; however, 
intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are 
not allowed. 
x 
Systemic glucocorticoids for any purpose other than to modulate symptoms from 
an event of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Study Chairs. 
 
Patients who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from protocol 
treatment. Patients may receive other medications that the investigator deems to be 
medically necessary. 
 
Any steroid use other than emergency situations must be discussed with the study chair. 
 
7.4 
Criteria for Removal from Protocol Treatment 
 
a. 
Completion of protocol treatment (36 cycles) 
 
b. 
Progression of disease or symptomatic deterioration (as defined in Section 10.2). 
 
1. 
A minority of subjects treated with immunotherapy may derive clinical 
benefit either delayed responses, stable disease, or increased overall 
survival despite initial evidence of progressive disease (PD). 
 
 

 
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Patients may be permitted to continue treatment beyond initial RECIST 
1.1-defined PD as long as they meet the following criteria: 
x 
Patients must be clinically stable with no change in performance 
status due to disease progression. 
x 
No indication for immediate alternative treatment. 
x 
Patient shows clinical benefit and tolerates study drug, as 
determined by the investigator.  The assessment of clinical benefit 
should take into account whether the subject is clinically stable or 
deteriorating and likely or unlikely to receive further benefit from 
continued treatment. 
x 
The time of progression is noted from the first assessment that 
meets criteria as defined in Section 10.2d 
 
Note: Patients who continue beyond initial RECIST-defined PD must have 
repeat scans every12 weeks to ensure that treatment continuation criteria 
are still met. 
 
c. 
Unacceptable toxicity. 
 
d. 
T-VEC treatment delay > 12 weeks for any reason other than a confirmed CR in 
the injectable lesions.  
 
e. 
Positive pregnancy test. 
 
f. 
The patient may withdraw from the study at any time for any reason. 
 
7.5 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice. 
 
7.6 
Follow-Up Period 
 
All patients will be followed, as indicated in Section 9.0, until 5 years after registration or 
death, whichever occurs first. Subsequently, patients will be asked to provide contact 
information for survival status follow-up (via phone) until 10 years after registration, for 
compliance with NIH OSP guidelines for long-term follow-up. 
 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
Two different versions of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be used on this study. 
 
a. 
Serious Adverse Event (SAE) reporting 
 
The CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 
will be utilized for SAE reporting only. The CTCAE Version 5.0 can be 
downloaded from the CTEP home page (https://ctep.cancer.gov).  All appropriate 
treatment areas should have access to a copy of the CTCAE Version 5.0. 
 
 

 
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b. 
Routine toxicity reporting 
 
This study will utilize the CTCAE Version 4.0 for routine toxicity reporting.  A copy 
of the CTCAE Version 4.0 can be downloaded from the CTEP home page 
(https://ctep.cancer.gov).  All appropriate treatment areas should have access to a 
copy of the CTCAE Version 4.0. 
 
8.2 
Dose Modifications  
 
a. 
General Pembrolizumab (MK-3475) Dose Modifications 
 
1. 
Missed doses of pembrolizumab (MK-3475) must be made up. 
 
2. 
Adverse events (both non-serious and serious) associated with 
pembrolizumab (MK-3475) exposure may represent an immunologic 
etiology.  These adverse events may occur shortly after the first dose or 
several months after the last dose of treatment.  pembrolizumab (MK-
3475) must be withheld for drug-related toxicities and severe or life-
threatening AEs as per Table 1 below. See Section 8.2b for supportive 
care guidelines, including use of corticosteroids. 
 
3. 
If pembrolizumab (MK-3475) must be permanently discontinued, patient 
may continue to receive talimogene laherparepvec (T-VEC).  
 
NOTE: Due to the possible effect of treatment with pembrolizumab (MK-3475) on 
the immunologic response to infectious disease vaccines, patients must not have 
had any infectious disease vaccination (e.g., standard influenza, H1N1 influenza, 
pneumococcal, meningiococcal, tetanus toxoid) 1 week before or after any dose 
of pembrolizumab (MK-3475). 
 
Table 1 Dose Modification Guidelines for Drug-Related Adverse Events related to 
pembrolizumab (MK-3475)  
 
General instructions: 
1. 
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral 
steroids. Other immunosuppressive treatment should begin if the irAEs are not controlled by 
corticosteroids.  
2. 
Pembrolizumab must be permanently discontinued if the irAE does not resolve or the 
corticosteroid dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab treatment.  
3. 
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 
weeks. 
4. 
If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to 
≤ Grade 1 after corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or 
other therapies  
Monitoring and 
follow-up  
Pneumonitis  
Grade 2 
Withhold  
x  Administer 
corticosteroids 
(initial dose of 
x  Monitor 
participants for 
signs and 

 
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Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
x  Add prophylactic 
antibiotics for 
opportunistic 
infections 
symptoms of 
pneumonitis 
x  Evaluate 
participants 
with suspected 
pneumonitis 
with 
radiographic 
imaging and 
initiate 
corticosteroid 
treatment 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
x  Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
x  Monitor 
participants for 
signs and 
symptoms of 
enterocolitis 
(ie, diarrhea, 
abdominal 
pain, blood or 
mucus in stool 
with or without 
fever) and of 
bowel 
perforation (ie, 
peritoneal 
signs and 
ileus) 
x  Participants 
with ≥Grade 2 
diarrhea 
suspecting 
colitis should 
consider GI 
consultation 
and performing 
endoscopy to 
rule out colitis 
x  Participants 
with 
diarrhea/colitis 
should be 
advised to 
drink liberal 
quantities of 
clear fluids. If 
sufficient oral 
fluid intake is 
not feasible, 
fluid and 
electrolytes 
should be 
substituted via 
IV infusion 
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue 

 
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AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
x  Administer 
corticosteroids 
(initial dose of 
0.5 - 1 mg/kg 
prednisone or 
equivalent) 
followed by taper 
x  Monitor with 
liver function 
tests (consider 
weekly or more 
frequently until 
liver enzyme 
value returned 
to baseline or 
is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
x  Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
New onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
E-cell failure 
Withhold d 
x  Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 
x  Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 
x  Monitor 
participants for 
hyperglycemia 
or other signs 
and symptoms 
of diabetes 
Hypophysitis 
Grade 2 
Withhold 
x  Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically indicated 
x  Monitor for 
signs and 
symptoms of 
hypophysitis 
(including 
hypopituitarism 
and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism  
Grade 2 
Continue 
x  Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate 
x  Monitor for 
signs and 
symptoms of 
thyroid 
disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3, 4 
Continue 
x  Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care 
x  Monitor for 
signs and 
symptoms of 
thyroid 
disorders 
Nephritis: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold 
x  Administer 
corticosteroids 
(prednisone 
1 – 2 mg/kg or 
equivalent) 
followed by taper 
x  Monitor 
changes of 
renal function 
Grade 3 or 4 
Permanently 
discontinue 

 
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Myocarditis 
Grade 1 or 2 
Withhold 
x  Based on severity 
of AE administer 
corticosteroids 
x  Ensure 
adequate 
evaluation to 
confirm 
etiology and/or 
exclude other 
causes 
Grade 3 or 4 
Permanently 
discontinue 
All Other 
immune-related 
AEs 
Persistent 
Grade 2 
Withhold 
x  Based on severity 
of AE administer 
corticosteroids 
x  Ensure 
adequate 
evaluation to 
confirm 
etiology or 
exclude other 
causes 
Grade 3 
Withhold or 
discontinue 
based on the 
event e  
Recurrent 
Grade 3 or 
Grade 4  
Permanently 
discontinue 
a  AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 - 3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal 
b  AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; 
bilirubin:>3.0 - 10.0 x ULN if baseline normal; >3.0 - 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d  The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the 
investigator or treating physician. If control achieved or ≤ Grade 2, pembrolizumab may be 
resumed. 
e  Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, 
encephalitis, Stevens-Johnson Syndrome and toxic epidermal necrolysis. 
 
Dosing interruptions are permitted in the case of medical/surgical events or 
logistical reasons not related to study therapy (e.g., elective surgery, unrelated 
medical events, patient vacation, and/or holidays). Patients should be placed back 
on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Study Chair. The reason for interruption should be documented 
in the patient's study record. 
 
b. 
Talimogene laherparepvec (T-VEC) Dose Delay and Treatment Discontinuation 
Guidelines AEs that are considered 
“Dose Limiting” for talimogene 
laherparepvec (T-VEC) Treatment Modification Guidelines 
1. 
Herpetic events that should be considered DLTs: 
x 
Serious herpetic events such as herpetic encephalitis, 
encephalomyelitis or disseminated herpetic infection. 
x 
Any herpetic events confirmed due to talimogene laherparepvec 
(T-VEC) that require treatment with acyclovir or similar anti-viral 
agent.  
Talimogene laherparepvec (T-VEC) treatment should be held if 
systemic acyclovir or other anti-viral is indicated.  If ongoing anti-viral 
treatment is required, talimogene laherparepvec (T-VEC) treatment 
should be permanently discontinued. 
*  
Herpetic events due to wild-type HSV-1 or wild-type HSV-2 
which require acyclovir and are not due to talimogene 
laherparepvec (T-VEC) (as confirmed by PCR testing) should not 

 
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be considered as DLTs caused by talimogene laherparepvec (T-
VEC). 
2. 
DLT will also be defined as any of the following talimogene laherparepvec 
(T-VEC)-related toxicity: 
x 
Grade 3 or greater immune-mediated AEs. 
x 
Grade 3 or greater allergic reactions. 
x 
Any grade plasmacytoma 
x 
Any other Grade 3 or greater hematologic or non-hematologic 
toxicity, with the exceptions of:  
x 
Any grade of alopecia, 
x Grade 3 arthralgia or myalgia,  
x Grade 3 fatigue, that improved to Grade 0-1 within 2 cycles, 
x Grade 3 fever,  
x Grade 3 diarrhea or vomiting responding to supportive care. 
  
Dose Reductions/delay:  
x 
Dose reductions with regards to changes in the concentrations of 
talimogene laherparepvec (T-VEC) are not permitted. However, patients 
may require a reduction in the volume injected due to a disease response 
(defined in dosing Section 7.1a) or due to local toxicity at the injection site. 
x 
If talimogene laherparepvec (T-VEC) treatment was delayed due to AEs 
or other reasons by >1 week, that dose will be deemed to have been 
missed and the patient will proceed to the next scheduled treatment visit.  
x 
If DLTs occur, talimogene laherparepvec (T-VEC) administration should 
be delayed until the DLT has resolved to at least CTCAE version 4.0 Grade 
1.  (AEs less than DLT may also require talimogene laherparepvec (T-
VEC) dose delay.  See instructions in Table 2 below) 
x 
If talimogene laherparepvec (T-VEC) dosing is delayed by more than 4 
weeks (approximately 7 weeks from the previous dose) due to treatment 
related AEs, talimogene laherparepvec (T-VEC) should be permanently 
discontinued.   
x 
If talimogene laherparepvec (T-VEC) dosing is delayed by more than 4 
weeks (approximately 7 weeks from the previous dose) for reasons other 
than treatment-related toxicity, the case must be reviewed by the sponsor 
of the study (CTEP) to determine if the patient can resume talimogene 
laherparepvec (T-VEC) therapy. 
x 
If talimogene laherparepvec (T-VEC) has to be permanently discontinued 
for any reason other than a complete response, patient will be removed 
from further treatment with  pembrolizumab (MK-3475) and will come off 
study. 
 
 

 
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Table 2: Treatment delays and discontinuation due to Specific AEs 
related to T-VEC 
Condition 
Grade 
Talimogene laherparepvec (T-VEC) 
modification 
x Injection site reactions 
Any 
grade 
Volume of talimogene laherparepvec 
(T-VEC) injection may be adjusted 
and should be held based on the 
degree of local toxicities 
x Active herpetic 
cutaneous or mucosal 
lesions, herpes labialis, 
or active dermatoses in 
the region of the injected 
tumors  
Any 
grade 
Mild: continue talimogene 
laherparepvec (T-VEC) 
If requiring systemic acyclovir or 
similar anti-viral agents: Hold 
talimogene laherparepvec (T-VEC).   
x Serious herpetic events 
such as herpetic 
encephalitis, 
encephalomyelitis or 
disseminated herpetic 
infection  
Any 
grade  
Discontinue talimogene laherparepvec 
(T-VEC) 
x Any condition requiring 
corticosteroid dosing of 
>10 mg prednisone daily 
(or equivalent) and/or 
other 
immunosuppressive 
medication for related 
toxicities 
N/A 
Hold talimogene laherparepvec (T-
VEC) dosing until corticosteroid dose 
has decreased to <10 mg prednisone 
daily (or equivalent) and the other 
immunosuppressive medication has 
been stopped. 
x Plasmacytoma   
Any 
grade 
Permanently discontinue talimogene 
laherparepvec (T-VEC) 
x Immune-mediated AEs 
(These may include 
pauci-immune 
glomerulonephritis, 
vasculitis, and 
pneumonitis, but may 
involve any organ 
system)  
Grade 
2 or 
greater 
Hold talimogene laherparepvec (T-
VEC) (with the exception of vitiligo).  If 
delay is > 12 weeks, discontinue 
talimogene laherparepvec (T-VEC) 
x Allergic reactions, or 
urticaria   
Grade 
2 or 
greater 
Hold talimogene laherparepvec (T-
VEC).  If delay is > 12 weeks, 
permanently discontinue talimogene 
laherparepvec (T-VEC) 
x Other talimogene 
laherparepvec (T-VEC) 
related grade 3+ AEs or 
intolerable grade 2 AEs 
(Except brief grade 3 
fever, fatigue, pain, or 
nausea/vomiting 
responding to supportive 
care) 
 
Hold talimogene laherparepvec (T-
VEC) until AE is grade 0-1.   
x If delay is > 12 weeks, discontinue 
talimogene laherparepvec (T-VEC) 
x If the AE was grade 4, decision to 
resume talimogene laherparepvec 
(T-VEC) upon recovery should be 
reviewed with the sponsor (CTEP) 

 
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c. 
Concomitant Medication/Supportive Care Guidelines for pembrolizumab (MK-
3475). 
Medications or vaccinations specifically prohibited in Section 5.2 (eligibility criteria) 
are not allowed during the ongoing trial). 
 
Patients should receive appropriate supportive care measures as deemed 
necessary by the treating investigator.  Suggested supportive care measures for 
the management of adverse events with potential immunologic etiology are 
outlined below. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory 
agents if symptoms do not improve with administration of corticosteroids.   Note 
that several courses of steroid tapering may be necessary as symptoms may 
worsen when the steroid dose is decreased. For each disorder, attempts should 
be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines 
are intended to be applied when the investigator determines the events to be 
related to pembrolizumab (MK-3475). 
 
Note: If after the evaluation the event is determined not to be related, the 
investigator does not need to follow the treatment guidance (as outlined below). 
Refer to Section 8.2a for dose modifications.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event.  
 
1. 
Pneumonitis:  
x 
For Grade 2 events: 
o 
Treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
x 
For Grade 3-4 events:  
o 
Immediately treat with intravenous steroids. Administer additional 
anti-inflammatory measures, as needed. 
o 
Add prophylactic antibiotics for opportunistic infections in the case 
of prolonged steroid administration. 
 
2. 
Diarrhea/Colitis:  
 
Patients should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, 
with or without fever) and of bowel perforation (such as peritoneal signs 
and ileus). 
x 
All patients who experience diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids.  If sufficient oral fluid intake 
is not feasible, fluid and electrolytes should be substituted via IV 
infusion.  For Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis 
x 
For Grade 2 - 3 diarrhea/colitis: 
o 
Administer oral corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks  
x 
For Grade 4 diarrhea/colitis: 
o 
Treat with intravenous steroids followed by high dose oral 
steroids.   

 
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o 
When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. 
 
3. 
Type 
1 diabetes 
mellitus (if new 
onset, 
including diabetic 
ketoacidosis [DKA]) or ≥ Grade 3 Hyperglycemia, if associated with 
ketosis (ketonuria) or metabolic acidosis (DKA) 
x 
For T1DM (onset) or Grade 3-4 hyperglycemia 
o 
Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with 
metabolic acidosis or ketonuria.  
o 
Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
4. 
Hypophysitis: 
x 
For Grade 2 events:  
o 
Treat with corticosteroids.  
o 
When symptoms improve to Grade 1 or less, steroid taper should 
be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose 
is tapered. 
x 
For Grade 3-4 events:  
o 
Treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids.  
o 
When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as 
the steroid dose is tapered. 
 
5. 
Hyperthyroidism or Hypothyroidism:  
 
Thyroid disorders can occur at any time during treatment. Monitor 
patients for changes in thyroid function (at the start of treatment, 
periodically during treatment, and as indicated based on clinical 
evaluation) and for clinical signs and symptoms of thyroid disorders. 
x 
Grade 
2 
hyperthyroidism 
events 
(and 
Grade 
2-4 
hypothyroidism): 
o 
In 
hyperthyroidism, treatment 
with non-selective beta-
blockers (e.g. propranolol) is suggested as initial therapy.  
o 
In hypothyroidism, treat with thyroid hormone replacement 
therapy (levothyroxine or liothyroinine) as indicated per 
standard of care. 
 
x 
Grade 3-4 hyperthyroidism  
o 
Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less 
than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 
 
6. 
Hepatic: 
x 
For Grade 2 events:  
o 
Monitor liver function tests more frequently until returned to 
baseline values (consider weekly).  
o 
Treat with IV or oral corticosteroids. 
x 
For Grade 3-4 events:  
o 
Treat with intravenous corticosteroids for 24 to 48 hours.  

 
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o 
When symptoms improve to Grade 1 or less, a steroid taper 
should be started and continued over no less than 4 weeks. 
 
7. 
Renal Failure or Nephritis: 
x 
For Grade 2 events, treat with corticosteroids. 
x 
For Grade 3-4 events, treat with systemic corticosteroids. 
o 
When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. 
 
8. 
Skin-only Toxicity: 
x 
Treat with systemic corticosteroids.   
o 
When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. 
 
9. 
Management of Infusion Reactions: Signs and symptoms usually 
develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion.  
 
Table 3 Infusion Reaction Treatment Guidelines below shows treatment 
guidelines for patients who experience an infusion reaction associated 
with administration of pembrolizumab (MK-3475). 
 
d. 
Table 3 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the patient 
is deemed medically stable in the 
opinion of the investigator. 
 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for ≤ 24 
hrs 
x 
Stop Infusion and monitor 
symptoms. 
x 
Additional appropriate 
medical therapy may include 
but is not limited to: 
o 
IV fluids 
o 
Antihistamines 
o 
NSAIDS 
o 
Acetaminophen 
o 
Narcotics 
x 
Increase monitoring of vital 
signs as medically indicated 
until the patient is deemed 
medically stable in the 
opinion of the investigator. 
x 
If symptoms resolve within 
one hour of stopping drug 
infusion, the infusion may be 
restarted at 50% of the 
original infusion rate (e.g., 
from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held 
until symptoms resolve and 
the subject should be 
premedicated for the next 
scheduled dose. 
Patient may be 
premedicated 1.5h 
(± 30 minutes) prior 
to infusion of 
pembrolizumab 
(MK-3475) with: 
 
Diphenhydramine 
50 mg PO (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 
500-1000 mg PO (or 
equivalent dose of 
antipyretic). 

 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Please Note: Prior to re-
starting the infusion, 
confirm that the 4-hour room 
temperature stability from the 
time of the IV bag preparation 
will not be exceeded. 
Otherwise, dosing will be 
held until symptoms resolve 
and the patient should be 
premedicated for the next 
scheduled dose. 
 
Patients who develop Grade 2 
toxicity upon re-challenge, 
despite adequate premedication, 
must be permanently 
discontinued from protocol 
treatment. 
 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
x 
Additional appropriate 
medical therapy may include 
but is not limited to: 
o 
IV fluids 
o 
Antihistamines 
o 
NSAIDS 
o 
Acetaminophen 
o 
Narcotics 
o 
Oxygen 
o 
Pressors 
o 
Corticosteroids 
o 
Epinephrine 
 
x 
Increase monitoring of vital 
signs as medically indicated 
until the patient is deemed 
medically stable in the 
opinion of the investigator. 
x 
Hospitalization may be 
indicated. 
x 
Patient is permanently 
discontinued from protocol 
treatment. 
No subsequent 
dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration. 
 
 
e. 
Concomitant Medication Considerations for talimogene laherparepvec (T-VEC) 
 
Talimogene laherparepvec (T-VEC) is sensitive to acyclovir and other antiherpetic 
viral drugs and would be rendered ineffective.  Thus, if systemic anti-herpetic 
medication is indicated, talimogene laherparepvec (T-VEC) must be discontinued. 
 
 

 
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8.3 
White blood Cell Growth Factors 
 
If used, white blood cell growth factors, including biosimilars, must be used per ASCO 
guidelines (http://jco.ascopubs.org/content/24/19/3187.full) and 
NCCN 
Guidelines® 
Myeloid Growth Factors  
(http://www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf ).  
 
8.4 
Dose Modification Contacts 
 
For treatment or dose modification questions, please contact Dr. Hu-Lieskovan at 801/585-
0308 (or Siwen.Hu-Lieskovan@hci.utah.edu) or Dr. Ribas at 310/206-3928. 
 
8.5 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 
 
 

 
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9.0 
STUDY CALENDAR 
 
 
  Cycle 1   
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6-36 f 
 
 
 
REQUIRED STUDIES 
  
Pre 
Study 
W 
1 
W 
2 
W 
3 
W 
4 
W 
5 
W 
6 
W 
7 
W 
8 
W 
9 
W 
10 
W 
11 
W 
12 
W 
13 
W 
14 
W 
15 
W 
16 
W 
17 
W 
18 
At 
Prog 
Pre-
Prog 
Off 
Treat 
F/U 
Post-
Prog Off 
Treat 
F/U g 
PHYSICAL  a 
History & Physical (w/ 
BSA, BP, Height & 
Weight) b 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
X 
PS & Toxicity Notation 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
  
Disease Assessment 
X 
  
  
  
  
  
  
  
  
X 
  
  
Xd 
  
  
  
  
  
X 
X 
  
Baseline Abnormalities 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Skin Exam  
X 
  
  
  
  
  
  
  
  
X 
  
  
 
Xd 
  
  
  
  
  
  
  
  
LABORATORY  a 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ANC, hemoglobin, 
platelets 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
CBC, Na, K, CO3, BUN, 
Ca, fasting glucose, 
alkaline phosphatase, 
albumin 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
Total and direct bilirubin J 
X  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
AST and ALT 
X  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
Serum Creatinine 
X  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
LDH 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
TFTs (TSH, totalT3, free 
T4) h  
X 
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
X 
  
  
Pregnancy Test c 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
 X 
Calendar continued on next page.  Click here for Footnotes. 
 
 

 
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Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6-36 f 
  
Pre- 
Study 
W 
1 
W 
2 
W 
3 
W 
4 
W 
5 
W 
6 
W 
7 
W 
8 
W 
9 
W 
10 
W 
11 
W 
12 
W 
13 
W 
14 
W 
15 
W 
16 
W 
17 
W 
18 
At 
Prog 
Pre-
Prog 
Off 
Treat 
F/U 
Post-
Prog 
Off 
Treat 
F/U g 
X-RAYS AND SCANS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Tumor Measurements 
(CT/MRI) d 
X 
  
  
  
  
  
  
  
 
X 
  
  
Xd 
  
  
  
  
  
 X 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPECIMENS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Tissue biopsy e 
X 
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
Archival tissue i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Specimen 
Submission (20 ml) e 
X 
  
X 
  
X 
  
  
  
  
 
X 
  
  
  
  
  
  
  
  
X 
  
  
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Talimogene 
laherparepvec (T-VEC) 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
Pembrolizumab (MK-
3475)  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X  
  
  
  
  
  
Click here for Footnotes. 
 
NOTE: Forms are found on the protocol abstract page on the SWOG website (www.swog.org). Forms submission guidelines are found  in Section 14.0. 
 
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for continuous treatment, 
disease 
assessment, 
specimen 
collection, 
and 
follow-up 
activities) 
must 
follow 
the 
established 
SWOG 
guidelines 
as 
outlined 
in 
https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. 
 
 

 
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FOOTNOTES:  
a The following exams & labs are performed prior to receiving first dose & prior to all other infusions until end of protocol treatment: physical (w/BSA, BP, & WT), 
performance status (PS), toxicity notation, ANC, hemoglobin, platelets, total and direct bilirubin, AST and ALT, serum creatinine, fasting glucose, LDH, alkaline 
phosphatase, albumin. The following are recommended for good medical practice: CBC, Na, K, CO3, BUN, and Ca. Adverse Event Assessments on the study 
will continue for all patients until resolution of adverse effects. Patients with ongoing toxicities should be seen more often as clinically indicated. 
b History prior to each treatment initiation to include a menstrual, sexual, and contraceptive use history, including date of l ast menstrual period (for women of 
childbearing potential) which will help determine the need for pregnancy testing. Similar questions regarding contraceptive use to be asked of men who are 
sexually active with women of childbearing potential. 
c Women of child bearing potential must have a negative serum or urine pregnancy test at screening within 7 days prior to regis tration. Following registration, 
serum or urine pregnancy tests are required within 72 hours prior to the first dose of study treatment, then according to institutional practice during therapy, tests 
should coincide with clinic visits for blood work and ending with discontinuation of study treatment. At discontinuation, a n egative pregnancy test within the 
preceding 6 weeks is sufficient. A pregnancy test should be done at any time there are clinical concerns for possible pregnancy. 
d Disease assessments by CT, MRI, or skin measurement will be performed initially at weeks 9 (+/- 1 week) followed by confirmatory scan/skin measurement at 
week 13 (+/- 1 week), thereafter every 12 weeks (+/- 2 weeks) until disease progression. Patients who remain on protocol treatment following initial disease 
progression (see Section 7.4b)  must continue this same disease assessment schedule until removal from protocol treatment. The same measurement modality 
as used at pre-study for disease assessment must be used throughout the trial. 
e See Section 15.1 for additional information. To be performed on or prior to Day 1 and on Day 21-35 (Day 28 +/- 7 days). If it is not feasible to obtain the first 
biopsy, tissue that was collected at any timepoint since demonstrated progression on PD-1 or PD-L1 therapy may be substituted provided that at least 20 
unstained slides are available. NOTE: If any blood collection timepoint was missed, sites must draw blood at the next patient visit for lab work.  
f 
Protocol treatment and parameters will continue at these intervals for 36 cycles of treatment until progression of disease or until patient has met any of the 
guidelines in Section 7.4. Patients who progress but meet the criteria in section 7.4.b.1 for staying on protocol treatment for clinical benefit shoul d continue 
follow-up as indicated by this column. 
g Follow-up visits should occur at least every 6 months (+/- 1 week) through 1 year after completion of treatment and then annually (+/- 1 month) until 5 years 
from registration or death (whichever occurs first). 
h Patients must be monitored for changes in thyroid function and for clinical signs/symptoms of thyroid disorders (as clinically indicated) 
I 
Collected prior to previous anti-PD-1 or anti-PD-L1 treatment. 
J To be performed as clinically indicated. 
 

 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
10.1 
Measurability of Lesions 
 
a. 
Measurable disease: Measurable disease is defined differently for lymph nodes 
compared with other disease and will be addressed in a separate section below. 
1. 
Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 2.0 cm by chest x-ray, by ≥ 1.0 cm 
with CT or MRI scans, or ≥ 1.0 cm with calipers by clinical exam. All tumor 
measurements must be recorded in decimal fractions of centimeters (or 
millimeters). 
 
The defined measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 0.5 cm or less.  If CT scans have 
slice thickness greater than 0.5 cm, the minimum size for a measurable 
lesion should be twice the slice thickness. 
 
2. 
Malignant lymph nodes are to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 
perpendicular to the long axis of the lymph node) when assessed by scan 
(CT scan slice recommended being no greater than 0.5 cm). 
 
b. 
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter < 1.0 cm or pathologic lymph nodes with ≥ 1.0 cm to < 
1.5 cm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered non-measurable as are previously radiated 
lesions that have not progressed 
 
c. 
Notes on measurability 
 
1. 
For CT and MRIs, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  Body scans should by performed with breath-hold scanning 
techniques, if possible. 
 
2. 
PET-CT:  At present, the low dose or attenuation correction CT portion of 
a PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT, then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT. 
 
3. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. 
 
4. 
Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable 
nor non-measurable) since they are, by definition simple cysts. 
 
5. 
If a target lesion becomes very small some radiologists indicate that it is 
too small to measure.  If the lesion is actually still present, a default 
measurement of 0.5 cm should be applied.  If the radiologist believes the 
lesion has gone, a default measurement of 0.0cm should be recorded. 

 
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10.2 
Objective Status at Each Disease Evaluation 
 
Objective Status is to be recorded at each evaluation.  All measurable lesions up to a 
maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, 
should be identified as target lesions at baseline.  All other lesions (or sites of disease) 
including any measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions.  Measurements must be provided for target measurable lesions, 
while presence or absence must be noted for non-target measurable and non-measurable 
disease. 
 
For studies that use disease progression as an endpoint, whole body scanning at specific 
intervals is necessary to determine that progression is NOT present outside of the “target” 
areas.  Therefore, in these studies it is not acceptable to image only the “target” areas of 
the body in follow-up scans.  For study-specific imaging requirements, see the Study 
Calendar in Section 9.0. 
 
a. 
Complete Response (CR):  Complete disappearance of all target and non-target 
lesions (with the exception of lymph nodes mentioned below).  No new lesions.  
No disease related symptoms.  Any lymph nodes (whether target or non-target) 
must have reduction in short axis to < 1.0 cm.  All disease must be assessed using 
the same technique as baseline. 
 
b. 
Partial Response (PR):  Applies only to patients with at least one measurable 
lesion.  Greater than or equal to 30% decrease under baseline of the sum of 
appropriate diameters of all target measurable lesions.  No unequivocal 
progression of non-measurable disease.  No new lesions.  All target measurable 
lesions must be assessed using the same techniques as baseline. 
 
c. 
Stable:  Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as 
baseline. 
 
d. 
Progression:  One or more of the following must occur:  20% increase in the sum 
of appropriate diameters of target measurable lesions over smallest sum observed 
(over baseline if no decrease during therapy) using the same techniques as 
baseline, as well as an absolute increase of at least 0.5 cm.  Unequivocal 
progression of non-measurable disease in the opinion of the treating physician (an 
explanation must be provided).  Appearance of any new lesion/site.  Death due to 
disease without prior documentation of progression and without symptomatic 
deterioration (see Section 10.2e). 
 
NOTE: Any initial documentation of progression at the Week 9 assessment (or 
earlier) must be confirmed by a second determination of progression at the Week 
13 assessment. If the Week 13 assessment documents an absence of 
progression, the patient’s disease is assumed not to have progressed. If the Week 
13 assessment is inadequate and there are no subsequent assessments 
documenting absence of progression, the initial documentation of progression will 
be considered definitive. After the disease assessment at Week 13, the 
documentation of any of the criteria in the paragraph above will be counted as 
disease progression. 
 
 
Notes regarding new lesions:  FDG-PET imaging can complement regular scans 
in identifying new lesions according to the following algorithm. 
 
1. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of progression based on a new lesion. 
 

 
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2. 
No FDG-PET at baseline and a positive FDG-PET at follow-up 
corresponding to a potential new site of disease must have a confirmation 
by anatomical assessment (e.g., CT, MRI, x-ray) as new site of disease to 
be considered progressive disease.  In such a case, the date of progressive 
disease will be the date of the initial abnormal FDG-PET. 
 
e. 
Symptomatic deterioration:  Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  Efforts 
should be made to obtain objective evidence of progression after discontinuation. 
 
f. 
Assessment 
inadequate, 
objective 
status 
unknown. 
 Progression or 
symptomatic deterioration has not been documented, and one or more target 
measurable lesions have not been assessed or inconsistent assessment methods 
were used. 
 
g. 
Objective status notes: 
 
1. 
Non-measurable and non-target measurable disease do not affect 
Objective Status in determination of CR (must be absent--a patient who 
otherwise has a CR, but who has non-measurable or non-target 
measurable disease present or not assessed, will be classified as having 
a PR).  However, non-measurable and non-target lesions are included in 
determination of progression (if new sites of disease develop or if 
unequivocal progression occurs in the opinion of the treating physician). 
 
2. 
An objective status of PR or stable cannot follow one of CR.  Stable can 
follow PR only in the rare case that tumor increases too little to qualify as 
progression, but enough that a previously documented 30% decrease no 
longer holds. 
 
3. 
In cases for which initial flare reaction is possible (hypercalcemia, 
increased bone pain, erythema of skin lesions), objective status is not 
progression unless either symptoms persist beyond 4 weeks or there is 
additional evidence of progression. 
 
4. 
Lesions that appear to increase in size due to presence of necrotic tissue 
will not be considered to have progressed. 
 
5. 
For bone disease documented on bone scan only, increased uptake does 
not constitute unequivocal progression.  However, increase in the soft 
tissue component of a lesion as measured by CT or MRI would constitute 
progression. 
 
6. 
Appearance of new pleural effusions does not constitute unequivocal 
progression unless cytologically proven of neoplastic origin, since some 
effusions are a toxicity related to therapy or other medical conditions.  
Increase in the size of an existing effusion does not constitute unequivocal 
progression, since the fluid status of the patient could alter the size of the 
effusion. 
 
7. 
If CR determination depends on a lesion for which the status is unclear by 
the required tests, it is recommended the residual lesion be investigated 
with biopsy or fine needle aspirate. 
 
 

 
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10.3 
Best Response 
 
This is calculated from the sequence of objective statuses. Best response should be 
documented for as long as the patient remains on protocol treatment. 
 
a. 
CR:  Two or more consecutive objective statuses of CR a minimum of four weeks 
apart. 
 
b. 
PR:  Two or more  consecutive objective statuses of PR or better a minimum of 
four weeks apart but not qualifying as CR. 
 
c. 
Unconfirmed CR:  One objective status of CR but not qualifying as CR or PR. 
 
d. 
Unconfirmed PR:  One objective status of PR but not qualifying as CR, PR or 
unconfirmed CR. 
 
e. 
Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration, but not qualifying as anything else 
above. 
 
f. 
Increasing disease:  Objective status of progression within 13 weeks of 
registration, not qualifying as anything else above. 
 
g. 
Symptomatic deterioration:  Objective status of symptomatic deterioration within 
13 weeks of registration, not qualifying as anything else above. 
 
Inadequate assessment, response unknown:  Progression or symptomatic deterioration 
greater than 13 weeks after registration and no other response category applies. 
 
10.4 
Performance Status 
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light 
housework, office work. 
 
2 
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours. 
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours. 
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair. 
 
 

 
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10.5 
Progression-Free Survival 
 
From date of registration to date of first documentation of progression (see note in Section 
10.2d), or death due to any cause.  Patients last known to be alive without report of 
progression are censored at date of last contact. 
 
10.6 
Time to Death 
 
From date of registration to date of death due to any cause.  Patients last known to be alive 
are censored at date of last contact. 
 
10.7 
Durable Response Rate  
 
Complete or partial response per RECIST 1.1 with no evidence of disease progression for 
at least 180 days from the initial documentation of CR/PR. Patients last known to have an 
objective response but who are lost to follow-up before 180 days will be considered to have 
inadequate disease assessments. Patients known to have an objective response who have 
an objective response at the following disease assessment will be considered to have 
continued objective response in the interim, regardless of duration between disease 
assessments. 
 
10.8 
Response in the Injected Lesions 
 
Best response of CR, UCR, PR or UPR as specified in Section 10.3 taking into 
consideration only lesions deemed injectable at any time prior to progression as defined in 
Section 10.2d. All other disease must be stable or better. No new visceral or otherwise 
uninjectable lesions. 
 
10.9 
Response in visceral lesions 
 
Best response of CR, UCR, PR or UPR as specified in Section 10.3 taking into 
consideration only visceral lesions present at baseline. All other disease must be stable or 
better. No new lesions. 
     
10.10 
Response in non-injected (non-visceral) lesions 
 
Best response of CR, UCR, PR or UPR as specified in Section 10.3 taking into 
consideration only lesions that were not injected at Cycle 1, Week 1. All other disease must 
be stable or better. No new lesions. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Cohort A: Patients who have injectable lesions and measurable visceral diseases 
 
a. 
Cohort A will use a 2-stage design with an accrual goal of 17 eligible patients in 
total. This includes 9 eligible patients in the first stage and 8 eligible patients in the 
second stage. The anticipated accrual rate for Cohort A is 1 patient per month. 
Assuming an ineligibility rate of 10%, we will accrue 19 total patients (10 patients 
in the first stage and 9 patients in the second stage) to enroll 17 eligible patients. 
 
b. 
Primary Endpoint: The primary endpoint for Cohort A is objective response 
(confirmed CR or PR) rate (ORR).  
 
We propose a two-stage design with the assumption that a true ORR of 5% or 
lower indicates that the treatment will not be of further interest and that a true ORR 
of 25% or more would be of considerable interest. The alternative hypothesis of 

 
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25% ORR is what is felt to be a clinically significant antitumor activity of adding 
talimogene laherparepvec (T-VEC) to anti-PD-1 for a population of patients who 
are already progressing on prior anti-PD-1 therapy. 
 
Initially, 9 eligible patients would be entered. If necessary, Cohort A may be 
temporarily closed to accrual while the data mature.  If zero objective responses 
(confirmed PR/CR) are observed among these 9 patients, then Cohort A would be 
closed and the treatment determined to be inactive in this population. If one or 
more objective responses (confirmed PR/CR) are observed, then 8 more eligible 
patients would be accrued, for a total sample size of 17 eligible patients. Two or 
more objective responses (confirmed PR/CR) out of 17 patients would be 
considered evidence that the treatment warrants further study, provided other 
factors such as toxicity and overall survival also appear favorable. This design has 
an alpha of 17.2% (i.e. probability of declaring the regimen warrants further study 
when the true ORR is 5%) and a power of 90.2% (probability of declaring the 
regimen warrants further study when the true ORR is 25%). 
 
c. 
Secondary Endpoints:  
We will estimate the durable response rate. For Cohort A, with a total of 17 eligible 
patients, we will be able to estimate the durable response rate to within 23.7% 
(95% CI). 
 
We will estimate the response rate (complete and partial, confirmed and 
unconfirmed responses) by three different methods. RECIST 1.1 will be applied, 
but with the following restrictions:  1) considering only the injected lesions as target 
lesions, 2) considering only the non-injected lesions as target lesions,3) 
considering only the visceral lesions as target lesions and 4) across all lesions per 
RECIST guidelines. We will construct 95% confidence intervals for the estimated 
rates.  For Cohort A, with a total of 17 eligible patients, assuming all 17 patients 
have both injected and non-injected measurable lesions, we will be able to 
estimate each of these response rates to within 23.7% (95% CI). 
 
We will estimate the median PFS and median OS and construct 95% Brookmeyer-
Crowley Confidence intervals.  For Cohort A, with a total of 17 eligible patients, we 
will be able to estimate the PFS, OS, and DR rates at a particular time point (e.g., 
6 months) to within 23.7% (95% CI).   
 
To assess the association between objective response rate and CD8 T-cell 
infiltration in the injected tumors, we will use a two-sample t-test to test for 
difference in mean quantitative CD8 expression between patients who have an 
objective response and patients who do not have an objective response.  We will 
control the type I error at the two-sided 0.05 level.  For Cohort A, assuming 17 
eligible patients and an ORR of 25%, then we anticipate 80% power to detect a 
mean difference in CD8 expression of 1.68 standard deviations. If the distributions 
are far from normal or subject to influential points, then instead of t-tests, we will 
use robust, rank based or non-parametric alternatives such as the Wilcoxon test.  
We will repeat the analysis to assess the association between durable response 
rate and CD8 T-cell infiltration in the non-injected tumors. 
 
We will assess whether ctDNA fraction at baseline and Day 28 is associated with 
ORR using a two-sample t-test at the two-sided 0.05 level. For Cohort A, with 17 
eligible patients and assuming 25% of patients have a response, we anticipate 
80% power to detect a difference in mean ctDNA fraction of 1.68 standard 
deviations. 
 
11.2 
Cohort B: Patients who have injectable lesions and no visceral lesions 
 

 
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a. 
Cohort B will use a 2-stage design with an accrual goal of 25 eligible patients in 
total.  This includes 16 patients in the first stage and 9 patients in the second stage.  
Assuming an ineligibility rate of 10%, we will accrue 28 total patients to enroll 25 
eligible patients. 
 
b. 
Primary Endpoint: 
 
The primary endpoint for Cohort B is objective response (confirmed PR or CR) 
rate (ORR).  
 
We propose a two-stage design with the assumption that a true ORR of 10% or 
lower indicates that the treatment will not be of further interest and that a true ORR 
of 30% or more would be of considerable interest. The alternative hypothesis of 
30% ORR is what is felt to be a clinically significant antitumor activity of adding 
talimogene laherparepvec (T-VEC) to anti-PD-1 for a population of patients who 
are already progressing on prior anti-PD-1 therapy. 
 
Initially, 16 patients would be entered. Cohort B may be temporarily closed to 
accrual while the data mature. If one or fewer objective responses (confirmed 
PR/CR) are observed among these 16 patients, then cohort B would be closed 
and the treatment determined to be inactive in this population. If two or more 
objective responses (confirmed PR/CR) are observed, then 9 more patients would 
be accrued, for a total sample size of 25 patients.  
 
Five or more objective responses out of 25 eligible patients would be considered 
evidence that the treatment warrants further study, provided other factors such as 
toxicity and overall survival also appear favorable.  This design has an alpha of 
10% (i.e. probability of declaring the regimen warrants further study when the true 
ORR is 10%) and a power of 90% (probability of declaring the regimen warrants 
further study when the true ORR is 30%). 
 
c. 
Secondary Objectives:  
We will estimate the durable response rate. For Cohort B, with a total of 25 eligible 
patients, we will be able to estimate the durable response rate to within 19.6% 
(95% CI). 
 
We will estimate the ORR, in injected lesions, in non-injected lesions, across all 
lesions and construct 95% confidence intervals for the estimated rates.  For Cohort 
B, with a total of 25 eligible patients, we will be able to estimate the ORR in injected 
lesions, in non-injected lesions, across all lesions to within 19.6%.   
 
We will estimate the median PFS and median OS and construct 95% Brookmeyer-
Crowley Confidence intervals. For Cohort B, with a total of 25 eligible patients, we 
will be able to estimate the PFS, OS, and DR rates at a particular time point to 
within 19.6% (95% CI).   
 
To assess the association between objective response rate and CD8 T-cell 
infiltration in the injected tumors, we will use a two-sample t-test to test for 
difference in mean quantitative CD8 expression between patients who have a 
objective response and patients who do not have an objective response.  We will 
control the type I error at the two-sided 0.05 level.   For Cohort B, assuming 25 
eligible patients and a ORR of 30%, then we anticipate 80% power to detect a 
mean difference in CD8 expression of 1.28 standard deviations.  If the distributions 
are far from normal or subject to influential points, then instead of t-tests, we will 
use robust, rank based or non-parametric alternatives such as the Wilcoxon test.  

 
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We will repeat the analysis to assess the association between durable response 
rate and CD8 T-cell infiltration in the non-injected tumor. 
 
We will assess whether ctDNA fraction at baseline and Day 28 is associated with 
ORR using a two-sample t-test at the two-sided 0.05 level. For Cohort B, with 25 
eligible patients and assuming 30% of patients have a response, we anticipate 
80% power to detect a difference in mean ctDNA fraction of 1.28 standard 
deviations. 
 
11.3 
Data and Safety Monitoring 
 
There is no formal data and safety monitoring committee for single arm Phase II studies.  
Toxicity and accrual monitoring are done routinely by the Study Chair, study Statistician 
and the Disease Committee Chair.  Endpoint monitoring is done by the study Statistician 
and Study Coordinator.  Accrual reports are generated weekly and formal toxicity reports 
are generated every 6 months.  In addition, the Statistical Center, Adverse Event 
Coordinator at the Operations Office, SAE Physician Reviewer, and Study Coordinator 
monitor toxicities on an ongoing basis. 
 
 
12.0 
DISCIPLINE REVIEW 
 
Discipline review is not necessary for this study. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Patients must be registered prior to initiation of treatment (no more than 7 calendar days 
prior to planned start of treatment).   
 
13.2 
 Investigator/Site Registration 
 
For patient enrollment at participating sites:  Local Institutional Biosafety Committee (IBC) 
approval is required before a site can enroll patients to T-VEC protocols. 
 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a Cooperative Group.  Each investigator must have an NCI investigator number and 
must maintain an “active” investigator registration status through the annual submission of 
a complete investigator registration packet to CTEP. 
 
a. 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all investigators participating in any NCI-sponsored clinical trial 
to register and to renew their registration annually. 
 
Registration requires the submission of: 
 
x 
a completed Statement of Investigator Form (FDA Form 1572) with an 
original signature 
x 
a current Curriculum Vitae (CV) 
x 
a completed and signed Supplemental Investigator Data Form (IDF) 
x 
a completed Financial Disclosure Form (FDF) with an original signature 
 

 
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Fillable PDF forms and additional information can be found on the CTEP website 
at http://ctep.cancer.gov/investigatorResources/investigator_registration.htm.    
 
For questions, please contact the CTEP Investigator Registration Help Desk by 
email at pmbregpend@ctep.nci.nih.gov.  
 
b. 
CTEP Associate Registration Procedures 
The 
Cancer 
Therapy 
Evaluation Program (CTEP) 
Identity and Access 
Management (IAM) application is a web-based application intended for use by both 
Investigators (i.e., all physicians involved in the conduct of NCI-sponsored clinical 
trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored 
clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration 
and annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering 
with CTEP as an Investigator, which must be completed before a CTEP-IAM 
account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU 
members’ website. 
 
Additional information can be found on the CTEP website at  
http://ctep.cancer.gov/branches/pmb/associate_registration.htm.  For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
ctepreghelp@ctep.nci.nih.gov.  
 
c. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
1. 
IRB Approval:   
 
Each investigator or group of investigators at a clinical site must obtain 
IRB approval for this protocol and submit IRB approval and supporting 
documentation to the CTSU Regulatory Office before they can be 
approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a 
determination of whether a site has fulfilled all regulatory criteria including 
but not limited to: an active Federal Wide Assurance (FWA) number, an 
active roster affiliation with the Lead Network or a participating 
organization, a valid IRB approval, and compliance with all protocol 
specific requirements. 
 
Sites participating on the NCI CIRB initiative that are approved by the 
CIRB for this study are not required to submit IRB approval documentation 
to the CTSU Regulatory Office. For sites using the CIRB, IRB approval 
information is received from the CIRB and applied to the RSS in an 
automated process. Signatory Institutions must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB via IRBManager to 
indicate their intent to open the study locally.  The CIRB’s approval of the 
SSW is then communicated to the CTSU Regulatory Office.  In order for 
the SSW approval to be processed, the Signatory Institution must inform 

 
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the CTSU which CIRB-approved institutions aligned with the Signatory 
Institution are participating in the study. 
 
2. 
Downloading Site Registration Documents:   
 
Site registration forms may be downloaded from the S1607 protocol page 
located on the CTSU members’ website.   
x 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
x 
Click on the Protocols tab in the upper left of your screen 
x 
Either enter the protocol # in the search field at the top of the 
protocol tree, or 
x 
Click on the By Lead Organization folder to expand 
x 
Click on the SWOG link to expand, then select trial protocol S1607 
x 
Click on LPO Documents, select the Site Registration documents 
link, and download and complete the forms provided.   
 
3. 
Requirements For S1607 Site Registration: 
 
x 
CTSU Transmittal Sheet (optional)  
x 
IRB approval (For sites not participating via the NCI CIRB; local 
IRB documentation, an IRB-signed CTSU IRB Certification Form, 
Protocol of Human 
Subjects Assurance 
Identification/IRB 
Certification/Declaration of Exemption Form, or combination is 
accepted) 
 
Special Protocol Specific Requirements (PSRs) for protocols utilizing T-
VEC:   
x 
For patient enrollment at protocol initiation: The Principle 
Investigator should submit a document confirming Approval from 
the local Institutional Biosafety Committee (IBC) at the initial site 
(PI’s or the coordinating site) 
x 
For patient enrollment at additional participating sites: Local IBC 
approval is required before members site can enroll patients to T-
VEC protocols. 
x 
Additional information can be found in protocol appendix Section 
18.3. 
 
4. 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office, 
where they will be entered and tracked in the CTSU RSS.  
 
ONLINE:  
www.ctsu.org (members’ section)  
Æ Regulatory Submission Portal 
 
EMAIL:  
CTSURegulatory@ctsu.coccg.org 
(for 
regulatory 
document submission only) 
 
FAX:   
215/569-0206 
 
MAIL:   
CTSU Regulatory Office 
       
 
1818 Market Street, Suite 1100 
      
  
Philadelphia, PA 19103 
 
 

 
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5. 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the 
CTSU website.   
 
x 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
x 
Click on the Regulatory tab at the top of your screen 
x 
Click on the Site Registration tab 
x 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation 
and institutional compliance with protocol-specific requirements as 
outlined by the Lead Network. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, 
the 
site 
user 
must 
have 
an 
active 
CTEP-IAM 
account 
(check 
at 
https://ctepcore.nci.nih.gov/iam/) and a 'Registrar' role on either the LPO or participating 
organization roster. 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
i. 
Country of Residence 
 
j. 
ZIP Code 
 
k. 
Gender (select one): 
x 
Female Gender 
x 
Male Gender 
 

 
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l. 
Ethnicity (select one): 
x 
Hispanic or Latino 
x 
Not Hispanic or Latino 
x 
Unknown 
 
m. 
Method of Payment (select one): 
x 
Private Insurance 
x 
Medicare 
x 
Medicare and Private Insurance 
x 
Medicaid 
x 
Medicaid and Medicare 
x 
Military or Veterans Sponsored NOS 
x 
Military Sponsored (Including Champus & Tricare) 
x 
Veterans Sponsored 
x 
Self Pay (No Insurance) 
x 
No Means of Payment (No Insurance) 
x 
Other 
x 
Unknown 
 
n. 
Race (select all that apply): 
x 
American Indian or Alaska Native 
x 
Asian 
x 
Black or African American 
x 
Native Hawaiian or other Pacific Islander 
x 
White 
x 
Unknown 
 
13.4 
Registration Procedures 
 
a. 
All site staff will use OPEN to enroll patients to this study.  OPEN is integrated with 
the CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient in the Rave database.  OPEN can be accessed at 
https://open.ctsu.org, from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on the 
SWOG CRA Workbench. 
b. 
Prior to accessing OPEN site staff should verify the following: 
x 
All eligibility criteria have been met within the protocol stated timeframes 
and the affirmation of eligibility on the Registration Worksheet has been 
signed 
by 
the 
registering 
investigator 
or 
another 
investigator 
designate. Site staff should refer to Section 5.0 to verify eligibility. 
 
x 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
c. 
The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.  Please print this confirmation for your records. 
 
d. 
Further instructional information is provided on the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org or at https://open.ctsu.org. 
For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com.    
 
 

 
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13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 
Data must be submitted according to the protocol requirements for ALL patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible. 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see Section 14.3a for details. 
 
14.3 
Data Submission Procedures 
 
a. 
Data collection for this study will be done exclusively through the Medidata Rave® 
clinical data management system. Access to the trial in Rave is granted through 
the iMedidata application to all persons with the appropriate roles assigned in 
Regulatory Support System (RSS). To access Rave via iMedidata, you must have 
an active CTEP-IAM account (check at https://ctepcore.nci.nih.gov/iam/) and the 
appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on either the LPO 
or participating organization roster at the enrolling site. 
Upon initial site registration approval for the study in RSS, all persons with Rave 
roles assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata. To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings) and can be accessed by clicking on 
the link in the upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time 
of initial registration approval for the study in RSS will also receive a separate 
invitation from iMedidata to activate their account. Account activation instructions 
are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ website under 
the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com.  
 

 
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b. 
You may also access Rave® via the SWOG CRA Workbench.  Go to the SWOG 
web site (http://swog.org) and logon to the Members Area using your SWOG 
Roster ID Number and password. After you have logged on, click on Workbenches, 
then CRA Workbench to access the home page for the CRA Workbench and follow 
the link to Rave® provided in the left-hand navigation panel. 
To access the CRA Workbench the following must be done (in order): 
 
1. 
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number, 
2. 
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed, 
3. 
Your Web User Administrator has added you as a web user and has given 
you the appropriate system permissions to view data for that institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  For 
point 3, contact your local Web User Administrator (refer to the "Who is my Web 
User Administrator?" function on the swog.org Members logon page). 
 
For difficulties with the CRA Workbench, please email  
technicalquestion@crab.org.  
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU) please 
refer to the CTSU Participation Table. 
 
14.4 
Data Submission Overview and Timepoints 
 
a. 
WITHIN 7 DAYS OF REGISTRATION:   
 
S1607 Onstudy Form 
 
S1607 Baseline Abnormalities Form 
 
S1607 Baseline Tumor Assessment Form 
 
Pathology report documenting histologic confirmation of melanoma* 
 
Radiology reports from all scans performed to assess disease at baseline* 
 
Physician report documenting any measurement of skin lesions made during a 
physical examination* 
 
*NOTE: Upload reports via the Source Documentation: Baseline form in Rave®. 
 
b. 
WITHIN 7 DAYS AFTER EACH CYCLE OF TREATMENT (1 cycle =21 days)  
 
Submit the following: 
 
S1607 Treatment Form 
 
S1607 Adverse Event Form 
 
 
c. 
WITHIN 
14 DAYS AFTER EACH DISEASE ASSESSMENT (SEE STUDY 
CALENDAR FOR SCHEDULE): 
 
Submit the following: 

 
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S1607 Follow-Up Tumor Assessment Form 
 
Radiology reports from all scans performed to assess disease*.  
 
Physician report documenting any measurements of skin lesions made during a 
physical examination.* 
 
*NOTE: Upload reports via the Source Documentation: Follow-Up form in Rave®. 
 
d. 
WITHIN 14 DAYS OF DISCONTINUATION OF TREATMENT: 
Submit the following: 
 
Off Treatment Notice 
 
S1607 Treatment Form 
 
S1607 Adverse Event Form 
 
e. 
WITHIN 14 DAYS OF PROGRESSION/RELAPSE: 
S1607 Follow-Up Tumor Assessment Form 
 
Radiology reports from all scans performed to assess disease*. Physician must 
note tumor measurement in patient records. 
 
Physician report documenting any measurements of skin lesions made during a 
physical examination.* 
 
If patient is going to discontinue protocol treatment at the time of progression, also 
submit the materials specified in Section 14.4d. 
 
See Section 15.0 for specimen submission requirements. 
 
*NOTE: Upload reports via the Source Documentation: Follow-Up form in Rave®. 
 
f. 
EVERY 6 MONTHS FOR THE FIRST YEAR AFTER REGISTRATION YEAR AND 
THEN ANNUALLY UNTIL 5 YEARS FROM REGISTRATION 
OR DEATH 
(whichever occurs first): 
Submit the following: 
 
Advanced Melanoma Follow Up Form 
 
Late Effects Form (if prior to treatment for progression or relapse or a second 
primary, and prior to non-protocol treatment, the patient experiences any severe 
[Grade ≥ 3] long term toxicity that has not been previously reported) 
 
 

 
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g. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
Submit the following:  
 
Notice of Death  
 
Advanced Melanoma Follow Up Form, or if patient was on treatment at the time of 
death, the materials specified in Section 14.4d. 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Translational Medicine  
 
Specimens for Translational Medicine (required for patient): 
 
a. 
Specimens must be submitted at the time points listed below.  Collection 
instructions are outlined in Section 15.1c and submission instructions are outlined 
in Section 15.1e. 
 
b. 
Specimens must be submitted at the following times (see Section 9.0): 
 
1. 
Tumor Samples 
 
Archival Tissue (collected before the previous anti-PD-1 or anti-PD-L1 
therapy): If available, please submit 30 unstained slides (or maximum 
amount that can be submitted per availability or institutional policy) x 4 um 
each***. 
 
Fresh Biopsy: At least 2 passes/cores from 14-gauge coring needle, 3 
passes/cores from 18-gauge coring needle, or equivalent volume via other 
techniques, from each biopsied lesion. While cores may be formalin fixed 
in the same container, each core should be embedded in a separate 
paraffin block. Tissue from each block should be submitted.  If no block 
can be shipped, submit 30 unstained slides (or maximum amount that can 
be submitted per availability or institutional policy) x 4 um each, from each 
block. Tissue must be collected prior to Day 1 of protocol treatment* and 
again 28 calendar days (+/- 7 calendar days) after starting protocol 
treatment**.    
 
 
Baseline 
(mandatory) 
Day 28 
(mandatory) 
Progression 
(optional) 
Cohort A (with visceral lesions) 
x 
Injected 
skin/nodal lesion 
 
x 
Site of 
progression (the 
fastest growing 
lesion) 
x 
Un-injected 
skin/nodal lesion 
x 
 
x 
Visceral lesion 
 
x 
Cohort B (no visceral lesions) 
x 
Injected 
skin/nodal lesion 
 
x 
Site of 
progression 
(the fastest 
growing lesion) 
x 
Un-injected 
skin/nodal lesion 
x 
x 
*  
Biopsy on or prior to Day 1 should be performed prior to Day 1. If it is 
not feasible to prospectively obtain this biopsy, tissue collected at any 

 
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time since demonstrated progression on PD-1 or PD-L1 therapy may 
be substituted provided that 30 unstained slides are available. 
** 
The tissue samples may be batch shipped after collection of tissue 
from Day 28 (+/- 7 calendar days) biopsy. Tissue blocks/slides should 
be stored at 4oC before shipping. 
*** If archival tissue is not available for submission, proceed as usual per 
directed time points for biopsy collection. Archival tissue is required if 
available and patient consents.  
 
With patient consent, remaining specimens will be banked for future 
use. 
 
2. 
Blood Samples: 
 
20 mL of peripheral blood for PBMCs collected in purple-top EDTA tube(s) 
at:  
x 
Baseline (after registration but prior to starting treatment on Day 1 
within 7 days prior to starting treatment per Section 13.1.) 
x 
Week 2  
x 
Week 4   
x 
Week 10 
x 
Progression  
 
Whole blood must be sent via overnight courier (e.g. FedEx) within 
24 hours of collection. Specimens may be shipped Monday through 
Thursday using only overnight delivery to arrive Monday through 
Friday. No blood should be collected or shipped on Friday or right 
before a holiday.  Additionally, since blood must be logged and 
shipped the day of collection, blood should not be collected prior 
to subject registration. 
 
With patient consent, remaining specimens will be banked for 
future use. 
 
NOTE: If any blood collection timepoint was missed, sites must 
draw blood at the next patient visit for lab work. 
 
c. 
Specimen Collection Instructions 
1. 
Standard collection of Paraffin Embedded Tissue Block. 
x 
Place the fresh tissue in formalin. Do Not Exceed 24 hours fixation 
time. 
x 
Fixed tissue must be paraffin embedded within 24 hours. 
x 
Send H & E (Hematoxylin and Eosin) stained section if it is routine 
practice for the site.  Otherwise, sending the block without the 
H&E slide is adequate. 
 
2. 
Standard Instructions for Shipping Paraffin Embedded Tissues: 
x 
Include in shipment: 
i. 
Tissue as outlined above. Please indicate the location of 
the biopsied lesions (skin, lymph node, lung, liver, etc.) 
ii. 
A copy of the packing/shipping list produced by the 
SWOG Online Specimen Tracking System. 
x 
Ship paraffin embedded tissue according to the shipping 
guidelines for ambient specimens in the General Specimen 
Submission Instructions below. 
 

 
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NOTE: Paraffin tissue blocks will NOT be returned to the submitting institution 
unless it is required for patient care. If the block is needed for patient care, a 
written request must be submitted to the Study Chair with a rationale for the 
return.  
 
3. 
Standard Instructions for Collecting and Shipping Fresh Whole Blood 
Specimens. 
x 
Use 10 ml vacutainer tubes with EDTA to collect whole blood. 
i. 
If your site does not have the recommended size of 
vacutainer tubes required by the treatment protocol, other 
sized tubes may be used to collect the required/requested 
amount of blood. 
ii. 
Avoid using < 3mL collection tubes. 
iii. 
Pre-label vacutainer tube(s) according to specimen 
labeling requirements indicated in the General Specimen 
Submission Instructions. 
x 
Use aseptic techniques and draw blood from the patient into the 
vacutainer tube(s). The amount of blood required will vary per 
protocol. 
x 
Immediately after the blood is drawn, thoroughly mix the blood 
with the anticoagulant by gently inverting the vacutainer tube(s) 
multiple times. 
x 
Store whole blood prior to shipping at room temperature. Do not 
freeze the whole blood. Storage time longer than 24 hours should 
be noted on the specimen shipping form. 
x 
Whole blood should be shipped the same day (day of collection) 
preferably using Federal Express, Priority Overnight service. Use 
of other courier services may delay package receipt. 
i. 
Specimens may be shipped Monday through Thursday using 
only overnight delivery to arrive Monday through Friday. No 
blood should be collected or shipped on Friday or right before 
a holiday.  
ii. 
During the months of April-September, ship fresh specimens 
on a cold pack. During the months of October-March, insulate 
fresh specimens to keep from freezing due to weather (ex. 
wrap specimen in bubble wrap). 
 
For packaging instructions, refer to the shipping guidelines for ambient 
specimens in the General Specimen Submission Instructions outlined above. 
 
d. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 

 
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e. 
SHIPPING SAMPLES 
1. 
SWOG Specimen Tracking System (STS) 
All specimen submissions for this study must be entered and tracked using 
the SWOG online Specimen Tracking system. SWOG members may log 
on the online system via the CRA Workbench. To access the CRA 
Workbench, go to the SWOG Web site (http://swog.org) and logon to the 
Members Area. After you have logged on using your SWOG roster ID 
number and password, click on the CRA Workbench link to access the 
home page for CRA Workbench website. Non- SWOG users may log into 
SpecTrack using their CTSU UserID and password on the SpecTrack login 
page located at  
https://crawb.crab.org/SpecTrack/Logon.aspx (select the option “SWOG – 
SWOG – CTSU”).  SpecTrack start-up instructions (both written and 
demo) are available after signing in to SpecTrack.  
 
A copy of the Shipment Packing List produced by the online Specimen 
Tracking system should be printed and placed in the pocket of the 
specimen bag if it has one, or in a separate resealable bag. The Specimen 
Submission Form is NOT required when the online system is used. 
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE 
NO EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as database 
errors 
or 
connectivity 
issues, 
please 
send 
an 
email 
to 
technicalquestion@crab.org. For procedural help with logging and 
shipping specimens, there is an introduction to the system on the 
Specimen Tracking main page 
(http://dnet.crab.org/SpecTrack/Documents/Instructions.pdf); or contact 
the Data Operations Center at 206/652-2267 to be routed to the Data 
Coordinator for further assistance. 
 
In the online specimen tracking system, the appropriate SWOG laboratory 
for submission of tissue and blood samples for SWOG Repository 
Submission and testing is identified as follows: 
 
Lab #224: The Ribas Laboratory 
Attention: Agustin Vega-Crespo 
Medical Receiving – Study S1607 
CHS 54-200 
650 CHARLES E YOUNG DR S  
UCLA Medical Center 
Los Angeles, CA 90095 
Phone: 310-825-2676 
Fax: 310-825-2493  
 
Contacts:   
Beata Berent-Maoz 
E-mail: BBerent@mednet.ucla.edu 
Agustin Vega-Crespo  
Email: avegacrespo@mednet.ucla.edu 
 
 

 
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2. 
Federal guidelines for the shipment of blood products: 
a.  
The tube must be wrapped in an absorbent material. 
b.  
The tube must then be placed in an AIRTIGHT container (like a 
resealable bag). 
c.  
Pack the resealable bag and tube in a Styrofoam shipping 
container. 
d.  
Pack the Styrofoam shipping container in a cardboard box. 
e.  
Mark the box "Biohazard". 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice:  
 
Informed Consent 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
This study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the 
Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46). 
 
Drug Accountability 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312.  
 
Publication and Industry Contact 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between Merck and Amgen (hereinafter referred 
to as "Collaborator(s)") and the NCI Division of Cancer Treatment and Diagnosis.  Therefore, the 
following obligations/guidelines in addition to the provisions in the "Intellectual Property Option to 
Collaborator"  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award apply to the use of the Agent in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators.  The protocol documents for studies 
utilizing Agents contain confidential information and should not be shared or distributed 
without the permission of the NCI.  If a copy of this protocol is requested by a patient or 
patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different Collaborative Agreements, 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data"): 
 

 
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a. 
NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NCI, the design 
of the proposed combination protocol, and the existence of any obligations which 
would tend to restrict NCI's participation in the proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-
Party Data solely for development, regulatory approval, and commercialization of 
its own Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative  
Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as described 
in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  Additionally, all 
Clinical Data and Results and Raw Data will be collected, used and disclosed consistent 
with all applicable federal statutes and regulations for the protection o f human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. 
Any data provided to the Collaborator(s) for Phase III studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there 
is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days from 
the date of receipt for review.  Collaborator shall have the right to request that publication 
be delayed for up to an additional 30 days in order to ensure that Collaborator's confidential 
and proprietary data, in addition to the Collaborator(s)'s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) 
for courtesy review as soon as possible and preferably at least three (3) days prior to 
submission, but in any case, prior to presentation at the meeting or publication in the 
proceedings.  Press releases and other media presentations must also be forwarded to 
CTEP prior to release.  Copies of any manuscript, abstract and/or press release/media 
presentation should be sent to: 
 
E-mail:  ncicteppubbs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to the Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of the 
Collaborator's confidential/proprietary information. 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data.  Reports are due January 31, April 30, 
July 31, and October 31.  Instructions for submitting data using the CDUS can be found on 
the CTEP Web site  

 
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(http://ctep.cancer.gov/reporting/cdus.html). 
 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events 
(both routine and expedited) that have occurred on the study and meet the mandatory 
CDUS reporting guidelines must be reported via the monitoring method identified above.  
If your study has been assigned to CDUS-Abbreviated reporting, no adverse event 
reporting (routine or expedited) is required to be reported via CDUS, but expedited adverse 
events are still required to be submitted via CTEP-AERS. 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are due January 31, 
April 30, July 31 and October 31. 
 
Confidentiality 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
Adverse Event Reporting Requirements  
 
a. 
Purpose 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as well 
as those who will enroll in future studies using similar agents. Adverse events are 
reported in a routine manner at scheduled times during a trial. (Directions for 
routine reporting are provided in Section 14.0.) Additionally, certain adverse events 
must be reported in an expedited manner to allow for more timely monitoring of 
patient safety and care. The following guidelines prescribe expedited adverse 
event reporting for this protocol.  
 
b. 
Reporting method 
This study requires that expedited adverse events be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS).  
CTEP's guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted to the SWOG Operations Office 
electronically via the CTEP-AERS Web-based application located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_eve
nts.htm   
 
c. 
When to report an event in an expedited manner 
Some adverse events require 24-hour notification (refer to Table 16.1) via CTEP-
AERS.  
 
In the rare event when internet connectivity is disrupted a 24-hour notification is 
made to NCI by telephone at 301-897-7497.  An electronic report MUST be 
submitted immediately upon re-establishment of internet connection.   
 
When the adverse event requires expedited reporting, submit the report within the 
number of calendar days of learning of the event specified in Table 16.1.  
 
 

 
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Any supporting documentation should be submitted to CTEP per NCI guidelines 
for AE reporting located at:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pd   
 
d. 
Other recipients of adverse event reports 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures. 
 
e. 
Expedited reporting for investigational agents 
Expedited reporting is required if the patient has received at least one dose of the 
investigational agent(s) as part of the trial. Reporting requirements are provided in 
Table 16.1. The investigational agents used in this study are  pembrolizumab (MK-
3475) and talimogene laherparepvec (T-VEC). If there is any question about the 
reportability of an adverse event or if on-line CTEP-AERS cannot be used, please 
telephone or email the SAE Specialist at the Operations Office, 210/614-8808 or 
adr@swog.org, before preparing the report. 

 
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Table 16.1 
Phase I and Early Phase II Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under a CTEP IND within 30 Days of the Last Administration of the 
Investigational Agents/Intervention1 pembrolizumab (MK-3475) and talimogene laherparepvec 
(T-VEC) 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 
An adverse event is considered serious if it results in ANY of the following outcomes:   
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). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR or Section 
16.1f.   
 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24 -
hour report. 
 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious 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: 
x All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
May 5, 2011 
 

 
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f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Phase I and Early Phase II Studies Utilizing an Agent under a 
CTEP IND: 
 
1. 
Group-specific instructions 
Submission of the on-line CTEP-AERS report plus any necessary 
amendments generally completes the reporting requirements.  In 
addition, you may be asked to submit supporting clinical data to the 
Operations Offices in order to complete the evaluation of the event.  If 
requested, the supporting data should be sent within 5 calendar days 
by fax to 210-614-0006.  Supporting clinical data submitted should 
include: 
x 
Printed copy of the first page of the CTEP-AERS Report. 
x 
Copies of clinical sourced documentation of the event. 
x 
If applicable, and they have not yet been submitted to the 
SWOG Data Operations Center copies of Off Treatment 
Notice and/or Notice of Death. 
 
g. 
Accidental talimogene laherparepvec (T-VEC) exposure and suspected infection 
in study patients receiving talimogene laherparepvec (T-VEC):   
If the patient receiving talimogene laherparepvec (T-VEC) on study has 
developed signs or symptoms of herpetic infection, the event must be reported 
to Amgen AND CTEP-AERS and patient should be followed up by the study 
team for viral assays: Report to CTEP-AERS as SAE.  
NOTE:  Refer to Section 18.3 for Additional Reporting Requirements 
 
h. 
Reporting Secondary Malignancy, including AML/ALL/MDS 
 
1. 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 
 
CTEP requires all secondary malignancies that occur following 
treatment with an agent under an NCI IND to be reported via CTEP -
AERS.  Three options are available to describe the event. 
 
x 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
x 
Myelodysplastic syndrome (MDS) 
x 
Treatment-related secondary malignancy 
 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
Second Malignancy: A second malignancy is one unrelated to the 
treatment of a prior malignancy (and is NOT a metastasis from the 
initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/d
ocs/aeguidelines.pdf  
 
 

 
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2. 
Any supporting documentation should be submitted to CTEP per NCI 
guidelines for AE reporting located at  
http://ctep.cancer.gov/protocoldevelopment/electronic_applications/do
cs/aeguidelines.pdf    
 
A copy of the report and the following supporting documentation must 
also be submitted to SWOG Operations Office within 30 days by fax to 
210-614-0006 or mail to the address below: 
 
x 
a copy of the pathology report confirming the AML/ALL 
/MDS diagnosis 
x 
(if available) a copy of the cytogenetics report   
 
SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 
San Antonio, Texas 78229 
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial. 
 
i. 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
 
1. 
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – Other 
(pregnancy)” 
under the Pregnancy, 
puerperium and perinatal 
conditions SOC.   
 
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
2. 
Fetal Death Fetal Death defined in CTCAE as “A disorder characterized 
by death in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation” should be 
reported expeditiously as Grade 4 “pregnancy, puerperium and 
perinatal conditions – Other (pregnancy loss)” under the Pregnancy, 
puerperium and perinatal conditions SOC.   
 
3. 
Death Neonatal Neonatal death, defined in CTCAE as “A disorder 
characterized by cessation of life occurring during the first 28 days of life” 
that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention should be reported expeditiously.   
 
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration – Other (neonatal loss)” under the 
General disorders and administration SOC. 
 
Fetal death and neonatal death should NOT be reported as a Grade 5 event.  If 
reported as such, the CTEP-AERS interprets this as a death of the patient being 
treated. 
 
 

 
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NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed and 
faxed with any additional medical information to 301-230-0159.  The potential risk 
of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section of the CTEP-AERS 
report. 
 
The Pregnancy Information Form is available at:  
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm    
 
j. 
Additional Reporting Requirements for T-VEC-associated adverse events and 
biosafety incidents. 
Please see Appendix 18.3. 

 
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17.0 
BIBLIOGRAPHY 
 
1  
Keir ME, Butte MJ, Freeman GJ, et al: PD-1 and its ligands in tolerance and immunity. Annu Rev 
Immunol 26:677-704, 2008. 
 
2   
Okazaki T, Chikuma S, Iwai Y, et al: A rheostat for immune responses: the unique properties of 
PD-1 and their advantages for clinical application. Nat Immunol 14(12):1212-8, 2013. 
 
3   
Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 
12(4):252-64, 2012. 
 
4   
Keir ME, Butte MJ, Freeman GJ, et al: PD-1 and its ligands in tolerance and immunity. Annu Rev 
Immunol 26:677-704, 2008. 
 
5   
Tumeh PC, Harview CL, Yearley JH, et al: PD-1 blockade induces responses by inhibiting adaptive 
immune resistance. Nature 515(7528):568-71, 2014. 
 
6   
Tumeh PC, Harview CL, Yearley JH, et al: PD-1 blockade induces responses by inhibiting adaptive 
immune resistance. Nature 515(7528):568-71, 2014. 
 
7  
Andtbacka, R.H., et al., Talimogene Laherparepvec Improves Durable Response Rate in Patients 
With Advanced Melanoma. J Clin Oncol, 33(25): p. 2780-8, 2015.. 
 
8   
Puzanov, I., et al., Talimogene Laherparepvec in Combination With Ipilimumab in Previously 
Untreated, Unresectable Stage IIIB-IV Melanoma. J Clin Oncol, 34(22): p. 2619-26, 2016.. 
 
9   
Hodi FS, O'Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with 
metastatic melanoma. N Engl J Med 363(8):711-23, 2010. 
 
10  
Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated 
metastatic melanoma. N Engl J Med 364:2517-26, 2011. 
 
11   
Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. N Engl J Med 366(26):2443-54, 2012. 
 
12  
Brahmer JR, Tykodi SS, Chow LQ, et al: Safety and activity of anti-PD-L1 antibody in patients with 
advanced cancer. N Engl J Med 366(26):2455-65, 2012. 
 
13   
Hamid O, Robert C, Daud A, et al: Safety and tumor responses with lambrolizumab (anti-PD-1) in 
melanoma. N Engl J Med 369(2):134-44, 2013.  
 
14  
Andtbacka, R.H.I., et al., Patterns of Clinical Response with Talimogene Laherparepvec (T-VEC) 
in Patients with Melanoma Treated in the OPTiM Phase III Clinical Trial. Annals of Surgical 
Oncology, 23(13): p. 4169-4177, 2016.  
 
 
 
 

 
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18.0 
APPENDIX 
 
18.1 
Anti-PD-1 and Anti-PD-L1 Agents 
 
18.2 
Translational Medicine Methods 
 
18.3 
Site Requirements Based on Guidelines from the NIH OSP (Adapted for CTEP-
sponsored T-VEC Protocols) 
 
18.4 
Additional Reporting Requirements for talimogene laherparepvec (T-VEC) associated 
adverse events, biosafety incidents, and accidental exposure of Health Care Providers 
(HCPs) to talimogene laherparepvec (T-VEC)  
 
18.5 
Information Sheet for Caregivers, Family Members, and Other Close Contacts to Clinical 
Trial Participants Being Given talimogene laherparepvec (T-VEC) 
 
18.6 
Information Sheet for Patients Receiving Talimogene Laherparepvec (T-VEC) 
 
18.7 
Instructions for Talimogene Laherparepvec (T-VEC) Injection Site Care 
 
18.8 
Information Related to Exposure to Talimogene Laherparepvec (T-VEC) 
 
18.9 
Receiving Instructions for NCI-supplied Talimogene laherparepvec (NSC 785349) 
 
18.10 
NCI Temperature Exposure Log Talimogene laherparepvec (NSC 785349) 

 
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18.1 
Anti-PD-1 and Anti-PD-L1 Agents 
 
x 
Atezolizumab 
x 
Avelulmab 
x 
Durvalumab 
x 
Nivolumab 
x 
Pembrolizumab (MK-3475)  
 
 
 

 
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18.2 
Translational Medicine Methods 
 
1. 
Data 
storage 
and computational 
infrastructure: 
To optimally perform 
computational analysis on the large amount of genomic and imaging data to be 
generated from this study, it is expected that appropriate cloud computing 
infrastructure with the necessary analysis pipeline is required for the storage and  
computation of these data. One such computational infrastructure and resource 
available for this study is through the collaboration with the Parker Institute for 
Cancer Immunotherapy. 
 
2. 
Quantitative analysis of T-cell infiltration: Given local virus replication and GM-
CSF release, we anticipate increased CD8+ Tcell infiltration in the tumors after 
combination of intratumoral injection of talimogene laherparepvec (T-VEC) and 
PD-1 blockade starts. Slides taken from standard formalin-fixed paraffin-
embedded (FFPE) tissue blocks obtained from baseline, Day 28 (on treatment), 
and upon progression to determine the presence of CD8+ T-cells inside tumors 
and in the invasive margin. Slides will be analyzed using quantitative digital 
pathology following the methods described. (1) 
All slides will be 
scanned 
at 
an 
absolute 
magnification 
of 
X200 
(resolution 
of 0.5 mm/pixel). 
An algorithm was 
designed 
based 
on 
pattern 
recognition 
that 
quantified immune 
cells within S100-
positive 
areas 
(tumor) and S100-
negative 
areas 
(invasive margin). 
Image 
analysis 
based 
on 
RGB 
(red, green, blue) 
spectra will be used to detect all cells by counterstaining with haemotoxylin (blue), 
and DAB or fast red. CD8 expression is determined using two read-outs that are 
independent of each other to account for tumor heterogeneity: cell density (number 
of positive cells /mm2) and percentage cellularity (number of positive cells/number 
of nucleated cells) using Indica Labs Halo platform. 
 
3. 
Analysis of TCR clonality in tumors and in blood: To answer the question  
whether the T-cell response is targeting specific tumor antigen (mono-clonal) or a 
non-specific process (poly-clonal) in both the tumors and in the peripheral blood, 
we will analyze TCR clonality by deep sequencing the TCR Vβ CDR region using 
the ImmunoSeq assay from Adaptive Biotech as described. (2)   PBMC from blood 
and thick slides from FFPE tissues taken at baseline and Day 28 after initiation of 
treatments, will be used to isolate DNA for TCR Vβ sequencing. This analysis will 
provide information about the clonality or diversity of T-cells infiltrating tumors and 
circulating in the blood. DNA analysis will be performed by the UCLA 
Immunogenetics core laboratory (CLIA approved lab). 
 
 
Figure 2: Proposed mechanism of action of T-VEC. 
 
 

 
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DNA will be isolated from FFPE thick cuts or PBMC followed by extraction using a 
DNeasy kit (Qiagen). Melanin will be removed from visibly pigmented melanoma 
samples using a PCR Inhibitor Removal kit (ZymoResearch). TCR Vβ CDR3 
regions will be amplified and sequenced using the survey ImmunoSeq assay in a 
multiplexed PCR method using 45 forward primers specific to TCR Vβ gene 
segments and 13 reverse primers specific to TCR Vβ gene segments (Adaptive 
Biotechnologies). Reads of length 87bp will be obtained using the Illumina HiSeq 
System. For each sample, Shannon entropy will be calculated on the clonal 
abundance of all productive TCR sequences in the data set. Shannon entropy will 
be normalized to the range by dividing Shannon entropy by the logarithm of the 
number of unique productive TCR sequences in the data set. This normalized 
entropy value will be then inverted (normalized entropy) to produce our clonality 
metric. 
 
4. 
Analysis of tumor immune microenvironment: Local viral replication and 
antigen presentation, as well as GM-CSF release, will attract dendritic cell 
infiltration, and change the global tumor immune microenvironment in favor of 
activating the immune system to target the tumor. In addition, interferon produced 
by inflammatory cells in an attempt to eradicate the viral infection, can up -regulate 
PD-L1 expression, providing rationale for synergy of talimogene laherparepvec (T-
VEC) with PD-1 blockade.  
 
Slides taken from standard FFPE tissue blocks obtained from baseline, the on-
treatment biopsy (Day 28) and upon progression will be stained by IHC for PD-L1 
(SP142, Spring Bioscience), PD-1, dendritic cell markers (CD80, CD86), immune 
suppressive cell markers 
(anti-FoxP3 for Treg, anti-CD68 
antibody for 
macrophage, clone PG-M1, DAKO, anti-CD14 
for monocyte, CD15 for 
granulocytes), or other immune related functional expression and biomarkers. 
Slides will be analyzed using quantitative multiplexed digital pathology. (3, 4) 
 
Immunostaining of the rest of the targets will be performed at the UCLA Anatomic 
Pathology IHC Laboratory (CLIA approved lab) on Leica Bond III autostainers 
using Leica Bond ancillary reagents and REFINE polymer DAB detection system. 
All stained slides will be evaluated in a blinded fashion by one dermatopathologist 
and one investigator trained to identify the features of melanoma, and the presence 
of positive stained targets within the tumor parenchyma (tumor) and the connective 
tissue surrounding the tumor (invasive margin).  
 
Analysis of mRNA expression by Nanostring allowed demonstrating that an 
interferon gamma signature is predictive of response with pembrolizumab (5), 
which is logical as it is an indirect measure of a pre-existing infiltrate by T cell with 
specificity to tumor antigens leading to the production of interferon gamma and the 
adaptive expression of PD-L1. 
Further 
analyses 
of mRNA 
expression 
demonstrated a dominant set of genes in patients whose tumors did not respond 
to anti-PD-1, which we termed innate PD-1 resistance signature (IPRES). (6)  We 
will consider to extract total RNA from FFPE samples and do nanostring analysis 
for global evaluation of immune activation. With these studies we anticipate to 
obtain a comprehensive view of the effects of the combined therapy of T-VEC and 
pembrolizumab to reverse resistance to single agent anti-PD-1 therapy. 
 
5. 
Analysis of mutational load by whole exome sequencing:  
It is currently unknown which antigens are being recognized by T-cells attacking 
tumors after release of PD-1 blockade. But evidence from studies with other 
immunotherapies suggests that most of these antigens are neoepitopes resultant 
from somatic mutations. In a recent experience, whole exome sequencing was 
performed on tumors and matching blood of patients treated with CTLA4 blockade 

 
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with ipilimumab or tremelimumab. (7)  Neoantigen peptides were tested for the 
ability to activate lymphocytes from ipilimumab-treated patients. Mutational load 
was associated with clinical benefit (p=0.01), but alone was not sufficient to predict 
benefit.  Using genome-wide somatic neoepitope analysis and patient-specific 
HLA typing, the authors identified candidate tumor neoantigens for each patient. 
Recently, a correlation of tumor mutational load and response to PD-1 antibody 
therapy was also reported in NSCLC patients treated with pembrolizumab (MK-
3475). (8) We want to evaluate whether tumor mutational load and circulating tumor 
DNA (ctDNA) profile are associated with response to talimogene laherparepvec 
(T-VEC) + pembrolizumab (MK-3475) combination in this anti-PD1 refractory 
melanoma population. In addition, since the IFN pathway is critically important for 
the efficacy of the talimogene laherparepvec (T-VEC) oncolytic viral therapy, we 
want to evaluate mutations in the IFN signaling pathway and the correlation with 
tumor specific immune response of the talimogene laherparepvec (T-VEC) + 
pembrolizumab (MK-3475) combination therapy. 
 
DNA will be isolated from thick slides of FFPE tissues and *PBMC via commercial 
kit (i.e. Qiagen AllPrep DNA/RNA FFPE kit, cat 80234). Whole exome sequencing 
(WES), including probe-based exon capture, library preparation, and high 
throughput 100bp paired-end sequencing on the Illumina HiSeq2500 platform will 
be performed at the UCLA Immunogenetics core laboratory. DNA from the same 
patient’s PBMC (preferably) or other non-cancerous tissue will be isolated and 
sequenced for baseline comparison and differentiation of germline SNPs from true 
somatic mutations. Read mapping and data preprocessing will be performed 
according to the Broad Institute Best Practices Guidelines for the Genome Analysis 
Toolkit (version 3), and mutation detection will require a consensus call among 
several published programs (Varscan2, 
MuTect, GATK HaplotypeCaller). 
Mutational load will be quantified as the number of nonsynonymous somatic 
mutations per MB. Circulating tumor DNA profiling from patient-matched baseline 
and on-treatment plasma samples will be performed to determine the amount or 
fraction of ctDNA corresponding to the genetic profile of the patient tumor biopsies.   
Taken together, this will evaluate whether tumor mutational load and circulating 
tumor DNA (ctDNA) profile are associated with response to talimogene 
laherparepvec (T-VEC) + pembrolizumab (MK-3475) combination in this anti-PD1 
refractory melanoma population. 
 
Translational Medicine Objectives 
 
a. 
For all analyses, if the distributions are far from normal or subject to 
influential points, then we will use robust, rank based or non-parametric 
approaches such as the Wilcoxon test.  Similarly, we will conduct adjusted 
analyses to accommodate any potential confounders that may arise, e.g. 
technical batch. 
 
To assess whether there is a change in T-cell infiltration from baseline to 
Day 28, we compare CD8 expression levels between baseline and week 
2 using a paired t-test.  We will control type I error at the two-sided 
alpha=0.05 level. For Cohort A, with 17 eligible patients, we anticipate 80% 
power to detect a change in mean CD8 expression from baseline to Day 
28 of 0.72 standard deviations. Among patients that progress, we will 
repeat the analysis to compare CD8 expression at progression to baseline 
with the understanding that there is potentially informative missingness in 
that patients who do not progress may have higher infiltration. 
 
We will further assess whether increased T-cell infiltration from baseline 
to Day 28 is associated with higher ORR.  Specifically, we will compute 
the change in CD8 expression between Day 28 and baseline and compare 
the change in CD8 expression between objective responders and non-

 
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objective responders using a two-sample t-test at the two-sided 0.05 level.  
For Cohort A, with 17 eligible patients and assuming 25% of patients have 
a response, we anticipate 80% power to detect a difference in mean 
change in CD8 expression of 1.68 standard deviations. Subsequently, to 
assess the hypothesis that TCR clonality is higher in patients who respond 
to the combination therapy, suggesting that the T-cells are targeting the 
tumor, we will compute the clonality metric as the normalized Shannon 
entropy for all patients at baseline and Day 28.  We will then compute the 
change in clonality metric from baseline to Day 28.  The change in clonality 
will be compared between responders and non-responders using a two-
sample t-test with significance determined at the two-sided alpha=0.05 
level.  For Cohort A, assuming that 25% of patients respond, then we 
anticipate 80% power to detect a difference in clonality change of 1.68 
standard deviations. We will repeat the analyses examining TCR clonality 
in peripheral blood.  Finally, we will assess whether ctDNA fraction at 
baseline and Day 28 is associated with ORR using a two-sample t-test at 
the two-sided 0.05 level. For Cohort A, with 17 eligible patients and 
assuming 25% of patients have a response, we anticipate 80% power to 
detect a difference in mean ctDNA fraction of 1.68 standard deviations. 
 
To assess whether the tumor microenvironment is improved by injection 
with talimogene laherparepvec (T-VEC), we will examine the expression 
of approximately 10 candidate immune markers: PD-L1, PD-1, dendritic 
cell markers (CD80, CD86), immune suppressive cell markers (anti-FoxP3 
for Treg, anti-CD68 antibody for macrophage, clone PG-M1, DAKO, anti-
CD14 for monocyte, and CD15 for granulocytes).  For each marker, we 
will test for a difference in expression between baseline and the Day 
28using paired t-tests at the alpha = 0.005 level to accommodate multiple 
comparisons.  We will subsequently test the association between change 
in expression level of each marker (from baseline to Day 28) with response 
using a two-sample t-test at the alpha = 0.005 level. For Cohort A, in 
comparing expression at baseline to Day 28, with 17 eligible patients, we 
anticipate 80% power to detect a change in mean expression of 1.0 
standard deviations.  In comparing change in expression between 
responders and non- responders, assuming 25% of patients respond 
durably, then we anticipate 80% power to detect a difference in mean 
change in expression of 2.3 standard deviations. 
 
To assess the hypothesis that higher mutational load at baseline or at Day 
28 is associated with durable response rate, we will assess the association 
between overall mutational load at each time point, separately, and 
durable response rate.  Specifically, we will use logistic regression to 
regress response status on the mutation rates (at baseline or at Day 28) 
and use a 1-df test to obtain a p-value for the association between durable 
response and mutation rate.  We will control the type I error at the two-
sided alpha=0.10 level. If logistic regression behaves poorly, e.g. due to 
low response rates, we will consider using robust or flexible alternatives.  
 
b. 
For all analyses, if the distributions are far from normal or subject to 
influential points, then we will use robust, rank based or non-parametric 
approaches such as the Wilcoxon test.  Similarly, we will conduct adjusted 
analyses to accommodate any potential confounders that may arise, e.g. 
technical batch. 
 
 

 
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To assess whether there is a change in T-cell infiltration from baseline to 
Day 28, we compare CD8 expression levels between baseline and Day 28 
using a paired t-test.  We will control type I error at the two-sided 
alpha=0.05 level.  For Cohort B, with 25 eligible patients, we anticipate 
80% power to detect a change in mean CD8 expression from baseline to 
Day 28 of 0.58 standard deviations. Among patients that progress, we will 
repeat the analysis to compare CD8 expression at progression to baseline 
with the understanding that there is potentially informative missingness in 
that patients who do not progress may have higher infiltration.   
 
We will further assess whether increased T-cell infiltration from baseline 
to Day 28 is associated with higher ORR.  Specifically, we will compute 
the change in CD8 expression between Day 28 and baseline and compare 
the change in CD8 expression between responders and non-responders 
using a two-sample t-test at the two-sided 0.05 level.  For Cohort B, with 
25 eligible patients and assuming 30% of patients have a response, we 
anticipate 80% power to detect a difference in mean change in CD8 
expression of 1.28 standard deviations. 
 
We will first assess whether TCR clonality within the tumor increases 
following treatment with combination therapy.  Specifically, we will test for 
difference in mean normalized Shannon entropy for all patients between 
baseline and Day 28.  For Cohort B, with 25 eligible patients, we anticipate 
80% power to detect a change in mean normalized Shannon entropy from 
baseline to Day 28 of 0.58 standard deviations. We will repeat the analysis 
to compare TCR clonality at progression to baseline among patients who 
progress. Subsequently, to assess the hypothesis that TCR clonality is 
higher in patients who respond to the combination therapy, suggesting that 
the T-cells are targeting the tumor, we will compute the clonality metric as 
the normalized Shannon entropy for all patients at baseline and Day 28.  
We will then compute the change in clonality metric from baseline to Day 
28.  The change in clonality will be compared between responders and 
non- responders using a two-sample t-test with significance determined at 
the two-sided alpha=0.05 level. For Cohort B, assuming that 30% of 
patients respond, then we anticipate 80% power to detect a difference in 
clonality change of 1.28 standard deviations. We will repeat the analyses 
examining TCR clonality in peripheral blood.  Finally, we will assess 
whether ctDNA fraction at baseline and Day 28 is associated with ORR 
using a two-sample t-test at the two-sided 0.05 level. For Cohort B, with 
25 eligible patients and assuming 30% of patients have a response, we 
anticipate 80% power to detect a difference in mean ctDNA fraction of 1.28 
standard deviations. 
 
To assess whether the tumor microenvironment is improved by injection 
with talimogene laherparepvec (T-VEC), we will examine the expression 
of approximately 10 candidate immune markers: PD-L1, PD-1, dendritic 
cell markers (CD80, CD86), immune suppressive cell markers (anti-FoxP3 
for Treg, anti-CD68 antibody for macrophage, clone PG-M1, DAKO, anti-
CD14 for monocyte, and CD15 for granulocytes).  For each marker, we 
will test for a difference in expression between baseline and the Day 28 
using paired t-tests at the alpha = 0.005 level to accommodate multiple 
comparisons.  We will subsequently test the association between change 
in expression level of each marker (from baseline to Day 28) with response 
using a two-sample t-test at the alpha = 0.005 level. For Cohort B, in 

 
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comparing expression at baseline to Day 28, with 25 eligible patients, we 
anticipate 80% power to detect a change in mean expression of 0.80 
standard deviations.  In comparing change in expression between 
responders and non-responders, assuming 30% of patients respond, then 
we anticipate 80% power to detect a difference in mean change in 
expression of 1.73 standard deviations. 
 
To assess the hypothesis that higher mutational load at baseline or at Day 
28 is associated with response rate, we will assess the association 
between overall mutational load at each time point, separately, and 
response rate.  Specifically, we will use logistic regression to regress 
response status on the mutation rates (at baseline or at Day 28) and use 
a 1-df test to obtain a p-value for the association between response and 
mutation rate.  We will control the type I error at the two-sided alpha=0.10 
level. If logistic regression behaves poorly, e.g. due to low response rates, 
we will consider using robust or flexible alternatives. 
 
 

 
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6. 
References:  
 
1.  
Tumeh PC, Harview CL, Yearley JH, et al: PD-1 blockade induces 
responses by inhibiting adaptive immune resistance. Nature 
515(7528):568-71, 2014.2. 
2. 
Tumeh PC, Harview CL, Yearley JH, et al: PD-1 blockade induces 
responses by inhibiting adaptive immune resistance. Nature 
515(7528):568-71, 2014.2. 
3. 
Tumeh PC, Harview CL, Yearley JH, et al: PD-1 blockade induces 
responses by inhibiting adaptive immune resistance. Nature 
515(7528):568-71, 2014.2. 
4  
Angelo M, Bendall SC, Finck R, Hale MB, Hitzman C, Borowsky AD, 
Levenson RM, Lowe JB, Liu SD, Zhao S, Natkunam Y, Nolan GP. 
Multiplexed ion beam imaging of human breast tumors. Nat Med. 2014 
Apr;20(4):436-42. doi: 10.1038/nm.3488. Epub 2014 Mar 2. PMID: 
24584119; PMCID: PMC4110905. 
 
5.  
Ribas, A., et al., Association of response to programmed death receptor 
(PD-1) blockade with pembrolizumab (MK-3475) with an interferon-
inflammatory immune gene signature. Journal of Clinical Oncology, 
33(suppl.): p. abstr 3001, 2015. 
6.  
Hugo, W., et al., Genomic and Transcriptomic Features of Response to 
Anti-PD-1 Therapy in Metastatic Melanoma. Cell, 65(1): p. 35-44, 2016. 
7.  
Snyder, A., et al., Genetic basis for clinical response to CTLA-4 blockade 
in melanoma. N Engl J Med, 371(23): p. 2189-99, 2014. 
8.  
Rizvi, N.A., et al., Cancer immunology. Mutational landscape determines 
sensitivity to PD-1 blockade in non-small cell lung cancer. Science, 
348(6230): p. 124-8, 2015. 
 
 
 

 
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18.3 
Site Requirements Based on Guidelines from the NIH Office of Scientific Policy (OSP) 
(Adapted for CTEP-sponsored T-VEC Protocols) 
 
Because talimogene laherparepvec (T-VEC) is a gene transfer agent, all protocols should 
follow the NIH Office of Scientific Policy (OSP) guidelines, including protocol submission, 
AE reporting and Annual Reports to OSP. Compliance with the OSP requirements is the 
responsibility of the Principle and Participating.  Investigators should review the OSP 
website  
(http://osp.od.nih.gov/sites/default/files/resources/NIH_Guidelines_PRN_1-sided.pdf) for 
complete instructions.  In addition, all participating sites should follow the guidelines of local 
Institutional Biosafety Committee (IBC).   
Key (but not all) OSP requirements are outlined below: 
 
1) 
Registration of protocol with OSP: (Appendix M-I-A and M-I-B of the OSP 
guidelines   
https://osp.od.nih.gov/wp-content/uploads/NIH_Guidelines.html#_Toc446948494 
 
The Principle Investigator or coordinating site IBC should submit the following to 
OSP via email at HGTprotocols@mail.nih.gov no less than 10 days before the 
anticipated 
protocol 
activation. 
 
(CTEP 
Protocol 
Information 
Office, 
pio@ctep.nci.nih.gov should be copied on this submission)  
x 
The proposed protocol and Inform Consent Form (these documents do not 
have to be the final, IRB-approved version) 
x 
Institutional Biosafety Committee (IBC)’s review or letter  
Additional contact information is also available 
on the 
OSP website 
http://www.osp.od.nih.gov/about/contact-us/  
 
An NIH OSP acknowledgement that the protocol registration process is complete 
will occur within the 10 working days prior to the anticipated date of 
enrollment.  Final IBC approval may then be granted 
 
2) 
Reporting of Initiation of the Clinical Investigation (Appendix M-I-C-1 Packet 
of OSP guidelines  
https://osp.od.nih.gov/wp-
content/uploads/NIH_Guidelines.html#_Toc446948494):  
 
The Principle Investigator of the protocol should submit the following documents 
to NIH OSP, no later than 30 working days after the first patient enrollment to the 
trial. (CTEP Protocol Information Office, pio@ctep.nci.nih.gov   should be copied 
on this submission)   
x 
A cover letter with the following information:  
o 
applicable NIH grant number(s) 
o 
the FDA IND number 
o 
any modifications to the protocol as required by FDA 
o 
the date of the initiation of the trial.  
x 
A copy of the protocol approved by the local Institutional Biosafety Committee 
(IBC) and IRB;  
x 
A copy of the informed consent document (ICD) approved by the Institutional 
Review Board (IRB);  
x 
A copy of the final IBC approval from the clinical trial site, 
x 
A copy of the final IRB approval;  
  
 
 

 
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3) 
Requirement for all Participating Institutions (Appendix M-I-C-2 Packet of OSP 
guidelines  
https://osp.od.nih.gov/wp-
content/uploads/NIH_Guidelines.html#_Toc446948494) 
 
(CTEP 
Information 
Office, Protocol pio@ctep.nci.nih.gov should be copied on this submission)  
x 
For patient enrollment, all participating sites should obtain approval from the 
local IBC before patients can be enrolled at the site.    Local IBC guidelines 
such as safety reporting requirements should also be followed.   
x 
The following should be submitted to OSP within 30 days of the first patient 
enrollment at the site: 
o 
IBC approval from the participating site;  
o 
IRB approval (if CIRB is used, submit CIRB approval);  
o 
IRB-approved informed consent document (ICD); 
o 
NIH grant number(s) if applicable. 
 
4) 
Annual Reports (Appendix M-I-C-3 Annual Report  
https://osp.od.nih.gov/wp-
content/uploads/NIH_Guidelines.html#_Toc446948494– by Principle Investigator 
or delegate  
 
Within 60 days after the one-year anniversary of the date on which the 
investigational new drug (IND) application went into effect, and after each 
subsequent anniversary until the trial is completed, CTEP as the sponsor will 
submit the Annual Reports (for all T-VEC trials under the CTEP IND) containing 
information set forth in (a), (b), and (c) (see Appendix M-I-C-3 in the link above), 
which shall include Clinical Trial Information, Progress Reports and Analysis, and 
Updated Protocol.   
 
5) 
Reporting of SAEs  
 
CTEP as the sponsor will submit SAEs that are serious, unexpected and related 
(i.e. IND Safety Reports) to OSP at the same timeline as for FDA reporting.   
SAEs or other AEs should be reported to local IBC per local IBC guidelines. 
 
6) 
Site Registration (see section 13.2 for more information) 
 
Special requirements for T-VEC protocols:   
x 
For patient enrollment for protocol initiation: The Principle Investigator should 
submit Approval from the local IBC of the initial site (PI’s or the coordinating 
site) 
x 
For patient enrollment at additional participating sites: Local Institutional 
Biosafety Committee (IBC) approval is required before a site can enroll 
patients to T-VEC protocols. 
 
 
 
 

 
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18.4 
Additional Reporting Requirements for talimogene laherparepvec (T-VEC) associated 
adverse events, biosafety incidents, and accidental exposure of Health Care Providers 
(HCPs) to talimogene laherparepvec (T-VEC)  
 
a. 
Talimogene laherparepvec (T-VEC) Specific Reporting Guidelines for Amgen 
Reporting is required for: (1) suspected herpetic events in treated patients; (2) 
suspected herpetic events in at-risk HCPs with direct or indirect exposure to 
talimogene laherparepvec (T-VEC); and 3) suspected herpetic events in the 
treated patient’s close contacts.  The mechanism, timing, and follow-up procedures 
are summarized in the table below and described below, in bullet (b) (for treated 
patients) and (c) (HCPs and close contacts). 
 
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 
Investigator 
Within 24 
hours of 
Investigator 
awareness 
Contact 
Amgen at 1-
855-IMLYGIC 
(1-855-465-
9442) 
AND 
Report to 
CTEP through 
CTEP-AERS 
See Section 
16.1 
Collect swabs 
from 
suspected 
lesions within 
3 days of 
appearance 
of symptoms 
Yes, if 
consent 
obtained 
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 
herpetic 
lesions 
HCP’s 
Personal 
Physician or 
impacted 
person 
Within 24 
hours of 
Reporter 
awareness 
Contact 
Amgen at 1-
855-IMLYGIC 
(1-855-465-
9442) to 
report event 
Collect swabs 
from 
suspected 
lesions within 
3 days of 
appearance of 
symptoms 
Yes, if 
consent 
obtained 
HCP or 
HCP’s 
Personal 
Physician 
HCP’s 
Personal 
Physician and 
Amgen 
Close Contact 
(e.g., 
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 within 
3 days of 
appearance of 
symptoms 
Yes, if 
consent 
obtained 
Close 
Contact’s 
Personal 
Physician 
Close 
Contact’s 
Personal 
Physician and 
Amgen 
 
 
 

 
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b. 
Accidental talimogene laherparepvec (T-VEC) exposure and suspected infection 
in study patients receiving talimogene laherparepvec (T-VEC):   
If the patient receiving talimogene laherparepvec (T-VEC) on study has developed 
signs or symptoms of herpetic infection, the event must be reported to Amgen AND 
CTEP-AERS (See Section 16.1) and patient should be followed up by the study 
team for viral assays:  
 
Notify Amgen immediately (within 24 hours) upon knowledge of suspected 
infection).  Contact the Amgen Call Center at 1-855-IMLYGIC (1-855-465-
9442). 
 
• 
Patient should be seen by the study physician.  The herpetic lesions should 
be tested for DNA specific to talimogene laherparepvec (T-VEC).  This 
testing must occur within three days of the appearance of the symptoms:  
• 
Swabs of cold sore, vesicles or any other lesions suspected to be herpetic 
in origin should be obtained. 
• 
Amgen will provide the qPCR test manual for sample collection and 
shipment to Viracor  
• 
qPCR or other testing for wild type HSV-1 is not required.  A commercially 
available test should be ordered if the investigator believes it is clinically 
indicated. 
 
c. 
Accidental Exposure of Health Care Provider (HCP) to talimogene laherparepvec 
(T-VEC) without herpetic symptoms and signs:  
If the HCP is suspected to have been exposed to talimogene laherparepvec (T-
VEC) (direct exposure, e.g. needle sticks, splash) without signs or symptoms of 
herpetic infection, the event must be reported to Amgen.   
 
1. 
Report to Amgen by calling Amgen Call Center at 1-855-IMLYGIC (1-855-
465-9442). 
  
d. 
Accidental Exposure and Secondary Transmission of talimogene laherparepvec 
(T-VEC) to Close Contacts or Health Care Provider (HCP) with symptoms/signs of 
herpetic infection:  
If a close contact or HCP is suspected to have been exposed to talimogene 
laherparepvec (T-VEC) (with signs or symptoms of herpetic infection, the event 
must be reported to Amgen.  Amgen will provide instructions regarding follow up 
with physicians and talimogene laherparepvec (T-VEC) testing. 
 
1. 
Report to Amgen immediately (within 24 hours) as symptoms or signs are 
observed.  Contact the Amgen Call Center at 1-855-IMLYGIC (1-855-465-
9442).  
 
• 
Amgen will provide close contacts/HPC with instructions to see 
physicians 
for 
management 
and 
evaluation 
of 
talimogene 
laherparepvec (T-VEC) DNA.  This testing must occur within three 
days of the appearance of the symptoms. 
 
• 
The physicians of HCP or Close Contacts will be responsible for 
obtaining the swab of herpetic lesions and submitting it to talimogene 
laherparepvec (T-VEC) testing, per instructions from Amgen.  
 
2. 
Also refer to instructions in the Information Sheet for Close Contacts. 
  
*NOTE:  Close contacts in regions where talimogene laherparepvec (T-

 
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VEC) is commercially available should contact their HCP to evaluate the 
lesions.  In the US, suspected herpetic lesions should be reported to 
Amgen as instructed above.  Close contacts have the option of follow-up 
testing for further characterization of the infection.  This test is likely to be 
more reliable if it can be performed within the first three days of symptoms 
appearing. 
 
*NOTE:  Close contacts in regions where talimogene laherparepvec (T-
VEC) is not commercially available (e.g. Canada) may contact their HCP 
for evaluation and appropriate treatment.  They should come to the study 
site for sample collections for qPCR testing for suspected herpetic lesions.  
This test is likely to be more reliable if it can be performed in the first three 
days of symptoms appearing. 
 
e. 
NIH Office of Science Policy (OSP) Reporting of Human Gene Transfer 
(talimogene laherparepvec (T-VEC)) Adverse Events (known or suspected), 
Associated Adverse Events and BioSafety Incidents 
 
1. 
Any serious adverse event that is both unexpected and associated with 
the use of T-VEC (ie, there is a reasonable possibility that the event may 
have been caused by the use of T-VEC) must be clearly labeled as a 
Safety Report and reported to SWOG by fax to 210-614-0006 and the 
Institutional Biosafety Committee (IBC) (via local institutional procedures) 
within 7 days of site knowledge of the event, using the form below (in 
addition to CTEP-AERS serious adverse event reporting. See Section 
16.1). 
 
PROTOCOL AND EVENT TYPE 
NIH/OBA (RAC) Protocol Number  
S1607 
FDA IND number 
 
Date this report completed: 
 
Seriousness of the AE (choose one) 
Death      
Life-threatening      
Initial or prolonged hospitalization 
Disability 
Congenital anomaly 
Required intervention to prevent 
permanent impairment/damage 
Other medically important condition 
Non-serious 
Severity of Event 
Minimal          
Moderate        
Severe   
Life- Threatening       
Fatal 
Was this event expected in terms of its 
severity? 
Yes          
No             
Was this event expected in terms of its 
specificity? 
Yes          
No             
Relationship of Event to gene transfer 
product 
Unrelated           
Unlikely           
Possible       
Probable           

 
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PROTOCOL AND EVENT TYPE 
NIH/OBA (RAC) Protocol Number  
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Definite 
Attribution of AE 
 
Attribution of AE, continued 
 
Concomitant medication 
Product 
Intervention 
Underlying disease 
Route of administration 
Other suspected cause (describe) 
_______________________________ 
Type of report 
Initial         
Follow-up 
DEMOGRAPHICS 
PI Name 
 
 
Name of Clinical Trial Site/Organization 
 
PI Telephone Number 
 
PI E-mail Address 
 
Reporter name  
 
Reporter Telephone number 
 
Reporter E-mail address 
 
Research Participant’s study 
identification number 
 
Research Participant’s gender 
 
Research Participant’s date of birth 
 
Research Participant’s date of death 
 
Research Participant’s weight in kgs 
 
Research Participant’s height in cms 
 
Which Arm/Cohort/treatment group was 
the patient assigned to? 
 
Was patient dosed? 
Yes           
No           
Information Not Available 
What study agent was received: 
IND agent      
Placebo     
Blinded Study Agent 
Were there any Protocol 
Deviations/Violations/Exceptions for this 
participant?   
Yes:____________________________ 
 
No    
 
 

 
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DETAILED ADVERSE EVENT INFORMATION 
ADVERSE EVENT DATE 
 
Description of Event 
 
 
 
Relevant tests (e.g. x-rays) and results 
 
 
 
Treatment (s) of Adverse Event  
(Include medications used to treat this 
event.) 
 
 
 
 
Name of Concomitant Medications 
(Do not include medications used to 
treat this event.) 
 
 
 
 
Pre-existing conditions/  
relevant clinical history  
(if this is an oncology trial, please 
designate primary disease, e.g. ovarian 
cancer) 
 
 
 
 
Date(s) of treatment(s) of the adverse 
event 
 
 
Outcome of the event 
Recovered/resolved 
Recovering/resolving 
Not recovered/not resolved 
Recovered/resolved with sequelae 
Fatal 
Unknown 
Documentation accompanying the 
report 
(e.g., H& P, Progress Notes, Discharge 
Summary, Lab Reports, Other, etc.)  
 
Description of any “other” 
documentation 
 
 
 
 

 
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PRODUCT AND DOSING INFORMATION 
Name of gene transfer product 
 
Vector type (e.g. adenovirus) 
 
Vector sub-type (e.g. type 5, also 
include relevant deletions) 
 
Lot number 
  
Was the agent manufactured at an 
NGVL? 
 
Route of administration 
 
Site of administration 
 
Did patient receive the dose specified in 
the protocol? 
 
If not, what dose was given? 
 
Date of first exposure to study agent? 
 
Date of most recent exposure to study 
agent? 
 
Total dose received prior to this event? 
 
Total dose quantity administered to 
patient to date 
 
Unit of measure for a single dose 
 
Dose quantity in a single administration 
 
If courses used, how many were given 
prior to this event? 
 
How many doses on the last course 
were given? 
 
Was the administration of this product 
stopped because of this adverse event? 
 
Name of other treatment (s) 
(medications, radiation, surgery) 
received by research participant as 
required by the protocol 
 
 
 
 
2. 
Any significant problems, violations of the NIH Guidelines, or any 
significant research-related accidents and illnesses must be reported to 
SWOG by fax to 210-614-0006 and the Institutional Biosafety Committee 
(IBC) (via local institutional procedures) within 7 days of site knowledge of 
the event along with the requested narrative below. Reports to SWOG 
must be submitted on the Form below by fax to 210-614-0006. This 
includes any spill, skin puncture, or accident involving T-VEC.  Spills or 
accidents, resulting in an overt exposure must be immediately reported 
to 
the 
NIH 
Office 
of 
Biotechnology 
Activities 
at: 
HGTprotocols@mail.nih.gov, SWOG and the Institutional IBC, at the 
contact information below. 
 
 

 
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Does this incident involve 
research patient to the NIH 
Guidelines? 
 
                  
܆YES           ܆NO 
 
If no, this incident does not require reporting to 
OSP 
 
Institution Name: 
 
 
 
Date of Report: 
 
 
 
Reporter name and position: 
 
 
 
Telephone number:  
 
 
 
Email address: 
 
 
 
Reporter mailing address: 
 
 
 
 
 
 
Date of incident: 
 
 
 
Name of Principal 
Investigator: 
 
 
 
 
Is this an NIH-funded 
project? 
 
܆YES            ܆NO 
 
If yes, please provide the following information 
(if known) 
 
NIH grant of contract number: 
NIH funding institute or center: 
NIH program officer (name, email address): 
 
 
 

 
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What was the nature of the 
incident? 
 
 
܆Failure to follow approved containment 
conditions 
܆Failure to obtain IBC approval 
܆Incomplete inactivation 
܆Loss of containment 
܆Loss of a transgenic animal 
܆Personnel exposure 
܆Spill 
܆Other (please describe): 
 
 
Did the Institutional 
Biosafety Committee (IBC) 
approve this research? 
 
 
܆YES            ܆NO 
 
If yes, date of approval:  
 
What was the approved 
biosafety level of the 
research? 
 
܆BL1 
܆BL2         ܆BL2+                
܆BL3         ܆BL3+  
܆BL4 
 
What section(s) of the NIH 
Guidelines is the research 
subject to? 
 
 
 
Has a report of this incident 
been made to other 
agencies?  If so, please 
indicate 
 
܆CDC                          ܆Funding 
agency/sponsor 
 
܆USDA                        ܆State or local Public 
Health 
 
܆FDA                           ܆Law enforcement 
 
܆EPA                           ܆Other (please 
describe): 
 
܆OSHA 
 
Nature of recombinant or 
synthetic material involved 
in incident (strain, 
attenuation, etc.) 
 
 
 

 
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Please provide a narrative of the incident including a timeline of events. The 
incident should be described in sufficient detail to allow for an understanding of the 
nature and consequences of the incident. Include the following information as 
applicable. 
 
A description of: 
 
x 
The incident/violation location (e.g. laboratory biosafety level, vivarium, non-
laboratory space) 
 
x 
Who was involved in the incident/violation, including others present at the 
incident location?  
 
Note – please do not identify individuals by name. Provide only gender 
and position titles (e.g., graduate student, post doc, animal care worker, 
facility maintenance worker) 
 
x 
Actions taken immediately following the incident/violation, and by whom, to 
limit any health or environmental consequences of the event 
 
x 
The training received by the individual(s) involved and the date(s) the training 
was conducted 
 
x 
The institutional or laboratory standard operating procedures (SOPs) for the 
research and whether there was any deviation from these SOPS at the time of 
the incident/violation 
 
x 
Any deviation from the IBC approved containment level or other IBC approval 
conditions at the time of the incident/violation  
 
x 
The personal protective equipment in use at the time of the incident/violation 
 
x 
The occupational health requirements for laboratory personnel involved in the 
research 
 
x 
Any medical surveillance provided or recommended after the incident 
 
x 
Any injury or illness associated with the incident 
 
x 
Equipment failures 
 
DESCRIPTION OF INCIDENT: (use additional space as necessary) 
 
Has the IBC reviewed this 
incident? 
 
                  
܆YES           ܆NO 
 
 
 
Please describe the root cause 
of this incident: 
 
 
 

 
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Describe measures taken by the institution to mitigate any problems identified.  For measures identified 
but not yet taken, please include a timeline for their implementation (use additional space as necessary):  
x 
Additional information may be requested by NIH OSP after review of this report depending 
on the nature of the incident. 
 
x 
Submitting this completed template to NIH OSP does NOT fulfill the reporting 
requirements of other agencies.  You should verify with the other parties to whom you 
must report whether the use of this template is acceptable. 
 
 

 
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18.5 
Information Sheet for Caregivers, Family Members, and Other Close Contacts to Clinical 
Trial Participants Being Given talimogene laherparepvec (T-VEC) and for Non-Study 
Health Care Providers (HCP) 
 
 
 
Study Title: _____________________________________________________    
NCI protocol #:_____________                        Amgen Tracking #:_________________ 
 
The patient ____________________________ is enrolled on the clinical trial above using 
the experimental drug Talimogene laherparepvec (talimogene laherparepvec (T-VEC)).  
This clinical trial is sponsored by the National Cancer Institute.   
 
The PI Name: ________________ and PI contact # _____________________ 
 
______________________________________________________________________ 
 
Dear Family Members, Caregivers, other Close Contacts and non-study Healthcare 
Providers: 
This Information Sheet is being provided to patients who has been enrolled in a clinical trial 
of Talimogene Laherparepvec (T-VEC), and their close contacts and Healthcare Providers 
not involved in the trial.   A close contact is considered a person that lives with the Patient 
(household member), care-giver, sex partner, or shares a bed with the Patient or conducts 
other activities that could involve exchange of bodily fluids through close physical contact.  
Non-study HCP are HCPs not involved in the talimogene laherparepvec (T-VEC) clinical 
trials but are seeing patients receiving talimogene laherparepvec (T-VEC) or their close 
contacts. 
The purpose of this Sheet is to inform you of 1) Potential risk of exposure to talimogene 
laherparepvec (T-VEC), 2) Precautions and 3) Instructions in the case of talimogene 
laherparepvec (T-VEC) transmission.  In the end of this document, Additional information 
about talimogene laherparepvec (T-VEC) for Healthcare Providers who are not involved in 
this trial 
 
I. 
What is the Study Drug, Talimogene Laherparepvec (T-VEC)? 
Talimogene laherparepvec (T-VEC) is an investigational drug that is being studied 
for the treatment of certain types of cancer. Talimogene laherparepvec (T-VEC) 
contains a weakened form of the Herpes Simplex Virus Type 1 (the “cold sore” 
virus or “HSV-1”).  
 
II. 
Can talimogene laherparepvec (T-VEC) be spread to family members or other 
close contacts? 
Talimogene laherparepvec (T-VEC) could potentially be spread to family or people 
who have close physical or intimate contact with the Patient after tumor(s) are 
injected with the study drug.  So far there have been no reported cases in clinical 
trial participants who have received talimogene laherparepvec (T-VEC) of 
spreading talimogene laherparepvec (T-VEC) to family members or other close 
contacts.  In clinical trials so far, no talimogene laherparepvec (T-VEC) has been 
detected outside of the dressing that is placed on top of the site where it was 
injected.   
The naturally occurring herpes simplex virus is not transmitted through the air or 
water droplets (such as when coughing or sneezing).  Spreading occurs through 
direct contact from one person to another, particularly if a cold sore or genital sore 
is present (for example, through kissing or having sexual intercourse or other 

 
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intimate contact). It may also be spread by sharing a razor, towel, dish that has 
come in contact with a sore or bodily fluids.  
Spreading (transmission) of talimogene laherparepvec (T-VEC) may be similar to 
spreading of the naturally occurring herpes simplex virus, and spreading may be 
more likely if you have a break in your skin or a mucous membrane comes into 
contact with an injection site or body fluids of a treated patient.  Unlike the naturally 
occurring virus, however, talimogene laherparepvec (T-VEC) is administered into 
tumor lesions and is not expected to be able to replicate effectively in other 
noncancerous tissues.  There have been no cases of spreading of talimogene 
laherparepvec (T-VEC) to close contacts reported in clinical studies to date.   
Small amounts of talimogene laherparepvec (T-VEC) have been detected in 
patients’ blood and urine for up to 1 week after injection. In patients treated with 
talimogene laherparepvec (T-VEC) in clinical trials, talimogene laherparepvec (T-
VEC) has been found on the surface of the injected tumors, into the second week 
after the injection, but not on the outside of the dressings that covered these 
injection sites. Close contacts should avoid direct contact with the injection sites. 
It is not known if talimogene laherparepvec (T-VEC) virus can appear in mucous 
membranes of the lips and mouth or genitals of treated patients. A clinical study is 
ongoing to determine if talimogene laherparepvec (T-VEC) can be detected in the 
mouth area and genital area of treated patients.  
To reduce the risk of exposure to and transmission of talimogene 
laherparepvec (T-VEC), please read carefully the Instructions below.   
 
III. 
Who Should Not Have Contact with talimogene laherparepvec (T-VEC)? 
Persons with weakened immune systems, newborns and pregnant women should 
not come in contact with the lesions that have been injected with talimogene 
laherparepvec (T-VEC) or body fluids of treated patients.   
 
Close contacts or family members who are pregnant or have weakened immune 
systems should not touch injection sites, change dressings or clean injection sites. 
Newborns should not come into contact with the injection sites. Used dressings 
and cleaning materials should be kept away from pregnant women, newborns and 
those with weakened immune systems. 
 
IV. 
What Precautions Should Be Taken to Avoid Being Exposed to talimogene 
laherparepvec (T-VEC)? 
 
x 
Avoid direct contact with the treated patient’s injection sites and body fluids. 
x 
Wear gloves if changing dressings which cover the treated patient’s injection 
sites. 
x 
Place all used dressings and cleaning materials in a sealed, plastic bag, and 
throw them away as household waste or return to the study site for disposal 
depending on local guidance. 
x 
The patient should avoid touching or scratching the injection site. 
x 
The injection sites should be covered for at least 7 days after the last injection 
with watertight dressings which allow for air exchange. If the dressing comes 
loose or falls off prior to 7 days after the injection, it should be replaced right 
away with a clean dressing. However, you may need to keep the dressing on 
longer if the lesions at the injection sites are weeping or oozing.  (please also 
refer to Instructions for talimogene laherparepvec (T-VEC) Injection Site 
Care) 
x 
Observe proper hygiene (wash hands with warm water and soap after touching 
the injected lesions or handling the dressings) to avoid spreading talimogene 

 
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laherparepvec (T-VEC) to other persons.  If there is direct contact with the 
injected sites, you should clean the affected area on your body with soap and 
water and/or a disinfectant.  
x 
If the treated patient develops any mouth or genital herpetic lesions (for 
example a painful fluid filled blister) during treatment with talimogene 
laherparepvec (T-VEC) or during the follow-up period of the clinical trial, they 
should avoid activities that could increase the possibility of transmission such 
as sharing straws, drinking glasses or engaging in sexual activity until the 
lesions fully resolve.    
x 
The naturally occurring herpes simplex virus (HSV-1) can be transmitted 
through sexual contact. It is not known if talimogene laherparepvec (T-VEC) 
will behave the same way, thus treated patients or their partners should use a 
latex condom when engaging in sexual activity to prevent possible 
transmission of talimogene laherparepvec (T-VEC) during the treatment with 
talimogene laherparepvec (T-VEC) and until 4 months after the end of 
treatment. For those with latex allergies, polyurethane condoms may be used . 
 
V. 
What Can Happen if Family Members or Close Contacts are Exposed to 
talimogene laherparepvec (T-VEC)?  
The naturally occurring type of HSV can cause a variety of symptoms. Due to the 
changes in talimogene laherparepvec (T-VEC) that make it different from the 
naturally occurring HSV, the chance of developing a herpes type infection is low, 
but you should know how to recognize these symptoms.   
If talimogene laherparepvec (T-VEC) were transmitted from a talimogene 
laherparepvec (T-VEC) treated patients to a third party, the potential symptoms 
might be similar to those of the naturally occurring herpes simplex virus such as:  
x 
Sores around the mouth (“cold sore”, “fever blister”) or genitals (“genital 
sore”).   
x 
Blisters may develop on the fingers, ears or face. 
x 
Eye infection (herpetic keratitis) with eye pain, light sensitivity, discharge 
from the eyes or blurry vision. 
x 
Abdominal pain and infections, and inflammation inside the abdomen 
(infrequently). 
x 
Rarely, serious infections of the brain (encephalitis) or spinal cord causing 
paralysis (unable to move) have been reported. Signs may include fever, 
confusion or other behavior changes, headache, numbness and pain in 
the legs, constipation or difficulty with urination. 
x 
Life-threatening infections (disseminated herpes) can develop in people 
with a weakened immune system. 
x 
In addition, after the acute infection, the naturally occurring herpes virus 
may travel to spinal nerve roots.  The virus can reactivate from the nerve 
roots and cause recurrent cold sores or other signs of infection as 
described above. Stress, other illness, or menstruation are common 
triggers for reactivation of the naturally occurring herpes simplex virus.   
 
Persons should seek a healthcare provider for signs of systems suggestive 
of herpes infection occur.  talimogene laherparepvec (T-VEC) is sensitive to 
the antiviral drug acyclovir and any possible infection may be treated with 
this drug in its usual doses by your doctor.   
 
VI. 
INSTRUCTIONS for Reporting of Suspected talimogene laherparepvec (T-
VEC) Exposure or Infection: 
 
1) 
Instructions 
for Close 
Contact 
with suspected 
exposure 
to 
talimogene laherparepvec (T-VEC):  If a close contact or non-study HCP 

 
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is suspected to have been exposed to talimogene laherparepvec (T-VEC) 
(e.g. symptoms suggestive of herpes infection or contact of open 
skin/mucosa with talimogene laherparepvec (T-VEC)), you should 
inform the individuals below and seek medical attention.  Your doctor 
may want to determine if talimogene laherparepvec (T-VEC) is present, 
depending on the symptoms observed.  For example if a cold sore 
appears, a swab may be taken for analysis.  These tests will be most 
reliable if done within the first 3 days of symptoms occurring, but you 
should report to your health care provider at any time symptoms appear.  
Before any samples or information about your health or symptoms is 
collected your authorization will be requested in writing. 
 
1. 
Call the Amgen Call Center at 1-855-IMLYGIC (1-855-465-
9442) 
immediately when 
the close contacts/HCP noticed 
symptoms/signs of herpes infection, as testing of the virus must 
occur within 3 days.   
x 
Amgen will provide close contacts/HPC with instructions 
to seek medical consultations for management and 
potentially for talimogene laherparepvec (T-VEC) DNA 
test.  The talimogene laherparepvec (T-VEC) DNA test 
must be done within three days of the appearance of the 
symptoms. 
x 
The physicians of Close Contacts will be responsible for 
obtaining the swab of herpetic lesions submit it to 
talimogene 
laherparepvec 
(T-VEC) 
testing, 
per 
instructions from Amgen.   
x 
The Amgen Call Center is open 24 hours a day, 7 days a 
week (24/7).  Please have this Information Sheet handy 
when you call Amgen.   
2. 
Also inform the talimogene laherparepvec (T-VEC) clinical 
trial doctor of the incident by contacting: <<insert study site 
contact>>.  
3. 
When seeing a doctor for your symptom or talimogene 
laherparepvec (T-VEC) exposure, please give this Information 
Sheet to the Doctor. 
 
 
 

 
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18.6 
Information Sheet for Patients Receiving Talimogene Laherparepvec (T-VEC) 
 
Study Title: ______________________________________________________    
NCI protocol #:___________   Amgen Tracking #:_______________________ 
 
The patient ____________________________ is enrolled on the clinical trial above using 
the experimental drug Talimogene laherparepvec (T-VEC).  This clinical trial is sponsored 
by the National Cancer Institute.   
 
The PI Name: __________________ and PI contact # __________________ 
 
________________________________________________________________ 
This form is addressed to the patient, but includes important information for others who 
care for this patient.  
 
Dear Patient: 
 
This Information Sheet is being provided to patients who has been enrolled in a clinical trial 
of Talimogene Laherparepvec (T-VEC).  A separate Information Sheet is also being 
provided for you close contacts and Healthcare Providers not involved in the trial.   A close 
contact is considered a person that lives with the Patient (household member), care-giver, 
sex partner, or shares a bed with the Patient or conducts other activities that could involve 
exchange of bodily fluids through close physical contact. 
 
The purpose of this Sheet is to inform you of 1) Potential risk of exposure to talimogene 
laherparepvec (T-VEC), 2) Precautions and 3) Instructions in the case of talimogene 
laherparepvec (T-VEC) transmission.  In the end of this document, additional information 
is also provided for Instructions for talimogene laherparepvec (T-VEC) injected sites 
care. 
 
I. 
What is the Study Drug, Talimogene Laherparepvec (T-VEC)? 
talimogene laherparepvec (T-VEC) is an investigational drug that is being studied 
for the treatment of certain types of cancer. talimogene laherparepvec (T-VEC) 
contains a weakened form of the Herpes Simplex Virus Type 1 (the “cold sore” 
virus or “HSV-1”).  
 
II. 
Can talimogene laherparepvec (T-VEC) be spread to family members or other 
close contacts? 
talimogene laherparepvec (T-VEC) could potentially be spread to family or people 
who have close physical or intimate contact with the Patient after tumor(s) are 
injected with the study drug.  So far there have been no reported cases in clinical 
trial participants who have received talimogene laherparepvec (T-VEC) of 
spreading talimogene laherparepvec (T-VEC) to family members or other close 
contacts.  In clinical trials so far, no talimogene laherparepvec (T-VEC) has been 
detected outside of the dressing that is placed on top of the site where it was 
injected.   
 
The naturally occurring herpes simplex virus is not transmitted through the air or 
water droplets (such as when coughing or sneezing).  Spreading occurs through 
direct contact from one person to another, particularly if a cold sore or genital sore 
is present (for example, through kissing or having sexual intercourse or other 
intimate contact). It may also be spread by sharing a razor, towel, dish that has 
come in contact with a sore or bodily fluids.   
 

 
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Spreading (transmission) of talimogene laherparepvec (T-VEC) may be similar to 
spreading of the naturally occurring herpes simplex virus, and spreading may be 
more likely if you have a break in your skin or a mucous membrane comes into 
contact with an injection site or body fluids of a treated patient.  Unlike the naturally 
occurring virus, however, talimogene laherparepvec (T-VEC) is administered into 
tumor lesions and is not expected to be able to replicate effectively in other 
noncancerous tissues.  There have been no cases of spreading of talimogene 
laherparepvec (T-VEC) to close contacts reported in clinical studies to date.   
 
Small amounts of talimogene laherparepvec (T-VEC) have been detected in 
patients’ blood and urine for up to 1 week after injection. In patients treated with 
talimogene laherparepvec (T-VEC) in clinical trials, talimogene laherparepvec (T-
VEC) has been found on the surface of the injected tumors, into the second week 
after the injection, but not on the outside of the dressings that covered these 
injection sites. Close contacts should avoid direct contact with the injection sites. 
 
It is not known if talimogene laherparepvec (T-VEC) virus can appear in mucous 
membranes of the lips and mouth or genitals of treated patients. A clinical study is 
ongoing to determine if talimogene laherparepvec (T-VEC) can be detected in the 
mouth area and genital area of treated patients.  
 
To reduce the risk of exposure to and transmission of talimogene 
laherparepvec (T-VEC), please read carefully the Instructions below.   
 
III. 
Who Should Not Have Contact with talimogene laherparepvec (T-VEC)? 
 
Persons with weakened immune systems, newborns and pregnant women should 
not come in contact with the lesions that have been injected with talimogene 
laherparepvec (T-VEC) or body fluids of treated patients.   
 
Close contacts or family members who are pregnant or have weakened immune 
systems should not touch injection sites, change dressings or clean injection sites. 
Newborns should not come into contact with the injection sites. Used dressings 
and cleaning materials should be kept away from pregnant women, newborns and 
those with weakened immune systems. 
 
IV. 
What Precautions Should Be Taken to Avoid Being Exposed to talimogene 
laherparepvec (T-VEC)? 
 
x 
Avoid direct contact with the treated patient’s injection sites and body fluids. 
x 
Wear gloves if changing dressings which cover the treated patient’s injection 
sites. 
x 
Place all used dressings and cleaning materials in a sealed, plastic bag, and 
throw them away as household waste or return to the study site for disposal 
depending on local guidance. 
x 
The patient should avoid touching or scratching the injection site. 
x 
The injection sites should be covered for at least 7 days after the last injection 
with watertight dressings which allow for air exchange. If the dressing comes 
loose or falls off prior to 7 days after the injection, it should be replaced right 
away with a clean dressing. However, you may need to keep the dressing on 
longer if the lesions at the injection sites are weeping or oozing.  (please also 
refer to Instructions for talimogene laherparepvec (T-VEC) Injection Site 
Care) 
x 
Observe proper hygiene (wash hands with warm water and soap after touching 
the injected lesions or handling the dressings) to avoid spreading talimogene 
laherparepvec (T-VEC) to other persons.  If there is direct contact with the 
injected sites, you should clean the affected area on your body with soap and 
water and/or a disinfectant.  

 
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x 
If the treated patient develops any mouth or genital herpetic lesions (for 
example a painful fluid filled blister) during treatment with talimogene 
laherparepvec (T-VEC) or during the follow-up period of the clinical trial, they 
should avoid activities that could increase the possibility of transmission such 
as sharing straws, drinking glasses or engaging in sexual activity until the 
lesions fully resolve.    
x 
The naturally occurring herpes simplex virus (HSV-1) can be transmitted 
through sexual contact. It is not known if talimogene laherparepvec (T-VEC) 
will behave the same way, thus treated patients or their partners should use a 
latex condom when engaging in sexual activity to prevent possible 
transmission of talimogene laherparepvec (T-VEC) during the treatment with 
talimogene laherparepvec (T-VEC) and until 4 months after the end of 
treatment. For those with latex allergies, polyurethane condoms may be used . 
 
V. 
What Can Happen if Family Members or Close Contacts are Exposed to talimogene 
laherparepvec (T-VEC)?  
 
The naturally occurring type of HSV can cause a variety of symptoms. Due to the 
changes in talimogene laherparepvec (T-VEC) that make it different from the 
naturally occurring HSV, the chance of developing a herpes type infection is low, 
but you should know how to recognize these symptoms.   
If talimogene laherparepvec (T-VEC) were transmitted from a talimogene 
laherparepvec (T-VEC) treated patients to a third party, the potential symptoms 
might be similar to those of the naturally occurring herpes simplex virus such as:  
x 
Sores around the mouth (“cold sore”, “fever blister”) or genitals (“genital sore”).   
x 
Blisters may develop on the fingers, ears or face. 
x 
Eye infection (herpetic keratitis) with eye pain, light sensitivity, discharge from 
the eyes or blurry vision. 
x 
Abdominal pain and infections, and inflammation inside the abdomen 
(infrequently). 
x 
Rarely, serious infections of the brain (encephalitis) or spinal cord causing 
paralysis (unable to move) have been reported. Signs may include fever, 
confusion or other behavior changes, headache, numbness and pain in the 
legs, constipation or difficulty with urination. 
x 
Life-threatening infections (disseminated herpes) can develop in people with 
a weakened immune system. 
 
In addition, after the acute infection, the naturally occurring herpes virus may travel 
to spinal nerve roots.  The virus can reactivate from the nerve roots and cause 
recurrent cold sores or other signs of infection as described above. Stress, other 
illness, or menstruation are common triggers for reactivation of the naturally 
occurring herpes simplex virus.   
 
Persons should seek a healthcare provider for signs of systems suggestive 
of herpes infection occur.  talimogene laherparepvec (T-VEC) is sensitive to 
the antiviral drug acyclovir and any possible infection may be treated with 
this drug in its usual doses by your doctor.   
 
VI. 
INSTRUCTIONS for Reporting of Suspected talimogene laherparepvec (T-VEC) 
Exposure or Infection: 
 
1) Instructions for patients treated with talimogene laherparepvec (T-VEC): 
If you develop symptoms of herpes infection:    
 
x 
IMMEDIATELY inform the talimogene laherparepvec (T-VEC) trial doctor 
by contacting: <<insert study site contact>>.  The talimogene 
laherparepvec (T-VEC) trial doctor will provide further instructions for 

 
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management and evaluation.   You doctor may need to obtain test for the 
virus within 3 days of your notification of the symptoms 
x 
If you are seeing a doctor who is not part of the clinical trial, please give 
this information sheet to the Doctor and have them contact the talimogene 
laherparepvec (T-VEC) trial staff: <<insert study site contact>>. 
2) Instructions for Close Contact or non-study Healthcare providers with suspected 
exposure to talimogene laherparepvec (T-VEC):  
x 
Please refer to the Information Sheet for Close Contacts.    
 
 

 
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18.7 
Instructions for Talimogene Laherparepvec (T-VEC) Injection Site Care 
 
After administration of talimogene laherparepvec (T-VEC) the injected lesions will be 
covered with a watertight dressing which allows for air exchange and it may also include 
an absorbent pad underneath covering the lesion. These dressings are like the dressings 
that are placed on skin when intravenous lines are placed to deliver medicine.  
The dressing can be removed 7 days after the last talimogene laherparepvec (T-VEC) 
injection. However, you may need to keep the dressing on longer if the lesions at the 
injection sites are weeping or oozing.  Patients and/or caregivers must be instructed to 
change the dressings properly, and they should be provided with all necessary materials 
including disposable gloves, dressings, and plastic containers or bags.  When you remove 
the dressing follow the instructions below: 
1) 
Wash your hands thoroughly with soap and water. 
2) 
Put on the disposable gloves, gently remove the dressing and place the soiled 
dressing in the disposal bag provided.  
3) 
Take the disposable gloves off by turning inside out and put them in the disposal 
bag.  Seal the plastic bag and throw away as household waste or return to the 
study site for disposal depending on local guidance. 
4) 
Wash your hands thoroughly with soap and warm water. 
If the dressing becomes loose or comes off altogether prior to 7 days from the injection 
site, you will need to change the dressing.  You will be provided with extra dressings.  You 
may need a relative or friend to help change the dressing.  When you change the dressing, 
follow the instructions below: 
1) 
Lay out all the necessary supplies, such as, alcohol swabs, new dressing and a 
plastic bag to place the soiled dressing.  
2) 
Wash hands thoroughly with soap and warm water, and put on the disposable 
gloves prior to changing the dressing.  
3) 
Remove the soiled dressing and place it into the plastic bag or container. 
4) 
Before placing a new dressing, change gloves by turning them inside out and put 
them into the disposal bag. 
5) 
Next, put on a fresh pair of gloves 
6) 
Apply the new dressing as instructed. Try to avoid touching the injection site while 
applying the new dressing.   
7) 
Wipe down the outside of the dressing with an alcohol swab to further minimize 
any cross contamination.  
8) 
Take off the gloves and place all soiled materials in the disposal bag. 
9) 
Seal the plastic bag and dispose as household waste or return to the study site for 
disposal depending on local guidance. 
10) 
Wash your hands thoroughly with soap and warm water.  

 
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If your close contact (household members, care-givers, sex partners, or someone you 
share a bed with) is pregnant or has a weakened immune system, they should not touch 
injection sites, change your dressings or clean your injection sites.  Newborns (babies who 
are one month or less in age) should not come into contact with the injection sites.  Keep 
used dressings and cleaning materials away from pregnant women, newborns, and those 
with weakened immune systems. 
IMPORTANT 
x 
Reactions at or near the area of the injection have been seen in people administered 
talimogene laherparepvec (T-VEC). Symptoms include bleeding, redness, swelling 
and inflammation at the injection site.  Skin infection caused by bacteria at the site of 
injection which may require hospitalization for antibiotic treatment have also been 
reported.  Other symptoms may include warmth at the injection site or 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, such as those mentioned above, at the injection site(s), you should contact 
the study doctor or his/her staff immediately. 
x 
If there are signs that the skin (under the dressing but that was not injected and is in 
contact with the adhesive) is becoming irritated/red, please contact the study site.  A 
different dressing type may need to be applied or you may have a cream applied that 
helps prevent irritation.  
Do Not: 
x 
Don’t put salves or ointments on the injection site. 
x 
Don’t scratch or pick at the injection site 
x 
Avoid directly touching (with bare hands) uncovered skin that has been injected with 
the study drug.  
Infections: Tumor necrosis may be seen with the use of talimogene laherparepvec (T-
VEC).  The presence of necrotic or ulcerating lesions may pre-dispose the patient to local 
and/or systemic infections such as cellulitis, bacteremia, etc.  Careful wound care and 
infection precautions are recommended if tumor necrosis results in open wounds.  Patients 
should avoid touching or scratching injection sites or their occlusive dressings, as doing so 
could lead to inadvertent transfer of IMLYGIC to other areas of the body.   
 

 
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18.8 
Information Related to Exposure to Talimogene Laherparepvec (T-VEC) 
 
Accidental Occupational Exposure:  
Accidental exposure may lead to transmission of talimogene laherparepvec (T-VEC) and 
herpetic infection.  Nurses and other study staff (e.g., pharmacists) with open skin wounds 
should not come into direct contact with talimogene laherparepvec (T-VEC).  HCP who are 
immunocompromised or pregnant should not prepare or administer talimogene 
laherparepvec (T-VEC). All personnel handling the virus or material contaminated with 
talimogene laherparepvec (T-VEC) must observe safety precautions (e.g., wear a 
laboratory coat, safety glasses, and gloves).   
x 
In the event of an accidental occupational exposure through a splash to the eyes or 
mucous membranes, flush with clean water for at least 15 minutes.  In the event of 
exposure to broken skin or needle stick, clean the site thoroughly with soap and water 
or a virucidal disinfectant such as 1% sodium hypochlorite or Virkon®.   
Exposure of Non-treated Individuals to talimogene laherparepvec (T-VEC):  
As there is a potential risk for exposure of talimogene laherparepvec (T-VEC) from patients 
to anyone in direct contact with the patient, persons with open skin lesions or who are 
immunosuppressed, pregnant women and newborns should avoid direct contact with the 
injected lesions, dressings or body fluids of the treated patients.   
x 
In the event of a secondary exposure (e.g., leakage through occlusive dressing to 
patient or contacts) to talimogene laherparepvec (T-VEC), clean the site thoroughly 
with soap and water or a virucidal disinfectant such as 1% sodium hypochlorite or 
Virkon®.   
Persons should seek a healthcare provider for signs of systemic (fever, aches, nausea, 
and malaise) or local (fever, pain, redness and swelling) infection.  talimogene 
laherparepvec (T-VEC) is sensitive to acyclovir which may be administered, if clinically 
indicated.   
Accidental Spills:  
Spills should be treated with a virucidal agent.  All disposable materials contaminated with 
talimogene laherparepvec (T-VEC) must be destroyed and disposed of in compliance with 
local institutional guidelines. 
 

 
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18.9 
Receiving Instructions for NCI-supplied Talimogene laherparepvec (NSC 785349) 
 
IMPORTANT: READ THE ENTIRE INSTRUCTIONS BEFORE OPENING 
THE INNER SHIPPING CONTAINER 
 
Step 1: 
Verify all shipment documents are present: 
o 
NCI Shipment Record of Clinical Drug Request 
o 
Temperature Exposure Log 
 
Step 2: 
Transfer Talimogene laherparepvec vials to -80oC (+/- 100 C) freezer 
 
You have 90 seconds to verify the contents of the shipping container and place the 
agent supplies in the -80oC (+/- 100 C) freezer once the inner container lid is opened 
and the supply exposed to room temperature. 
x 
Place the shipping container near the -80oC (+/- 100 C) freezer 
x 
Don gloves per your institutional procedures for handling dry ice 
x 
Open the lid of the inner shipping container 
x 
A second person should record the start time on the temperature exposure log once 
the lid of inner shipping container is removed 
x 
Open the payload box sleeve and remove the payload box containing the carton(s) of 
Talimogene laherparepvec  
x 
Open the payload box and remove carton(s) of Talimogene laherparepvec 
o 
Verify agent, strength, quantity and lot number received against NCI Shipment 
Record of Clinical Drug Request 
x 
Place carton(s) of Talimogene laherparepvec in the -80oC (+/- 100 C) freezer and 
close the freezer door 
x 
Record the stop time on the temperature exposure log 
 
Step 3:  
Complete documentation 
x 
Confirm the time difference from start time to stop time does not exceed 90 seconds 
x 
Complete remainder for temperature exposure log and retain with your study records 
x 
If exposure time exceeds 90 seconds, quarantine the agent supplies in the -80oC (+/- 
100 C) freezer and call PMB immediately at 240-276-6575 for guidance. 
 

 
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18.10 
NCI Temperature Exposure Log Talimogene laherparepvec (NSC 785349) 
 
NCI Protocol Number: _____________________ 
PMB Order Number: ______________________ (obtain from Shipment Record) 
Date Received: ______________ 
Maximum exposure time: 90 Seconds 
Exposure Time 
Start Time = time inner shipping container lid is removed 
Stop Time = time -80oC (+/- 100 C) freezer door is closed 
 
Start Time: _____:_____:_____ (hour:minute:second - example: 09:50:01) 
Stop Time: _____:_____:_____ (hour:minute:second - example: 09:50:58) 
 
Confirm time difference from start time to stop time does not exceed 90 seconds: 
□     YES 
 
□     NO 
 
Comments: ______________________________________________________ 
 
Name: _______________________________ Date: ____________ 
 
Complete one log for each shipping container received. 
 
Retain log with your study records. If exposure time exceeds 90 seconds, quarantine the 
agent supplies in the -80oC (+/- 100 C) freezer and call PMB immediately at 240-276-6575 
for guidance.