Conditions: Melanoma Merkel Cell Carcinoma Other Solid Tumors
Keywords: T-VEC (Talimogene Laherparepvec) Radiotherapy 16-224
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 19
Healthy volunteers: no

Brief summary:
The purpose of this phase II clinical study is to test the good and bad effects of T-VEC (talimogene laherparepvec) with or without hypofractionated radiotherapy on people with melanoma, Merkel cell carcinoma, or other solid tumors with skin metastasis.

Detailed description:

Arms:
arm 1: Patients will receive 3 radiotherapy treatments (one treatment every 3-5 days) during weeks 3 and 4. The first treatment will occur 6 (+/- 2) hours after the Talimogene Laherparepvec administration at week 3.Talimogene Laherparepvec will be administered at weeks 0, 3, 5, 7, 9, 11, 13 and 15. The first dose of Talimogene Laherparepvec will be 10\^6 plaque forming units (PFU)/mL, followed three weeks later by a dose of 10\^8 pfu/mL. arm 2: Patients will receive Talimogene Laherparepvec alone, as described above, without radiotherapy.

Interventions: intervention 1: TALIMOGENE LAHERPAREPVEC (TVEC) intervention 2: Hypofractionated Radiotherapy
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 1 of 36 
 
 
A Phase II Randomized Trial of Intralesional Talimogene Laherparepvec 
(TALIMOGENE LAHERPAREPVEC) with or without Hypofractionated Radiotherapy 
for Cutaneous Melanoma, Merkel Cell Carcinoma, or Other Solid Tumors 
PROTOCOL FACE PAGE FOR 
MSK THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal Investigator/Department: 
Christopher Barker, MD 
Radiation Oncology 
Co-Principal 
Investigator(s)/Department: 
Simon N. Powell, MD, PhD 
Charlotte E. Ariyan, MD, PhD 
Radiation Oncology 
Surgery 
Investigator(s)/Department: 
Nancy Lee, MD 
Sean McBride, MD 
Nadeem Riaz, MD 
Boris Mueller, MD 
Borys Mychalczak, MD 
Daphna Gelblum, MD 
Melissa Zinovoy, MD 
Michael Bernstein, MD 
Atif Khan, MD 
Lior Braunstein, MD 
Carla Hajj, MD 
David Guttmann, MDDhwani 
Parikh, MD 
Justin Mann, MD 
Ariel Marciscano, MD 
Yao Yu, MD 
Neeta Pandit-Taskar, MD 
Sandra D’Angelo, MD 
Chrisann Kyi, MD 
Mario Lacouture, MD 
Susan Seo, MD 
Dmitriy Zamarin, MD, PhD 
Alexander N. Shoushtari, MD 
Paul B. Chapman, MD 
Michael Postow, MD 
Margaret Callahan, MD 
Jedd D. Wolchok, MD, PhD 
Parisa Momtaz, MD 
James Harding, MD 
Mimma Errante, NP 
Nana Prempeh-Keteku, NP 
Zhigang Zhang, PhD 
Dina Boulos, RPh 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation OncologyRadiation 
Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiology 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Epidemiology and Biostatistics 
Pharmacy 
Consenting 
Professional(s)/Department: 
Christopher Barker, MD 
Simon N. Powell, MD, PhD 
Nancy Lee, MD 
Sean McBride, MD 
Nadeem Riaz, MD 
Boris Mueller, MD 
Borys Mychalczak, MD 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 2 of 36 
 
 
 
Daphna Gelblum, MD 
Melissa Zinovoy, MD 
Michael Bernstein, MD 
Chiaojung Jillian Tsai, MD, PhD 
Tzu-I Jonathan Yang, MD 
Oren Cahlon, MD 
Beryl McCormick, MD 
Lior Braunstein, MD 
Atif Khan, MD 
Carla Hajj, MD 
David Guttmann, MD 
Dhwani Parikh, MD 
Justin Mann, MD 
Ariel Marciscano, MD 
Yao Yu, MD 
Sandra D’Angelo, MD 
Chrisann Kyi, MD 
Mario Lacouture, MD 
Susan Seo, MD 
Dmitriy Zamarin, MD, PhD 
Alexander N. Shoushtari, MD 
Paul B. Chapman, MD 
Jedd D. Wolchok, MD, PhD 
Michael A. Postow, MD 
Margaret K. Callahan, MD, PhD 
Parisa Momtaz, MD 
James Harding, MD 
Charlotte E. Ariyan, MD, PhD 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Surgery 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
OneMSK Sites 
Manhattan 
Westchester 
Monmouth, NJ 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 3 of 36 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 5 
3.0 
BACKGROUND AND RATIONALE .................................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .......................................................... 10 
4.1 
Design ........................................................................................................................... 10 
4.2 
Intervention .................................................................................................................... 10 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS.......................................................................... 11 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .......................................................................... 11 
6.1 
Subject Inclusion Criteria ............................................................................................... 11 
6.2 
Subject Exclusion Criteria .............................................................................................. 12 
7.0 
RECRUITMENT PLAN ..................................................................................................... 12 
8.0 
PRETREATMENT EVALUATION..................................................................................... 13 
9.0 
TREATMENT/INTERVENTION PLAN .............................................................................. 13 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION................................................... 17 
11.0 
TOXICITIES/SIDE EFFECTS ............................................................................................ 18 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...................... 21 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ...................................................................... 22 
14.0 
BIOSTATISTICS ............................................................................................................... 22 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 23 
15.1 
Research Participant Registration .................................................................................. 23 
15.2 
Randomization............................................................................................................... 24 
16.0 
DAT A M ANAGEMENT ISSUES ....................................................................................... 24 
16.1 
Quality Assurance ......................................................................................................... 26 
16.2 
Data and Safety Monitoring............................................................................................ 27 
17.0 
PROTECTION OF HUMAN SUBJECTS ........................................................................... 26 
17.1 
Privacy .......................................................................................................................... 27 
17.2 
Serious Adverse Event (SAE) Reporting ........................................................................ 27 
17.2.1 
 28 
18.0 
INFORMED CONSENT PROCEDURES ........................................................................... 28 
19.0 
REFERENCES ................................................................................................................. 29 
20.0 
APPENDICES ................................................................................................................... 31 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 4 of 36 
 
 
\ 
Arm B: 
Intralesional TALIMOGENE 
LAHERPAREPVEC without radiotherapy 
Arm A: 
Intralesional TALIMOGENE 
LAHERPAREPVEC with radiotherapy 
Randomize 1:1 
 
Stratify by disease (melanoma, Merkel cell carcinoma, or other solid tumor malignancy) 
Patients with melanoma, Merkel cell carcinoma, or other solid tumor malignancy with cutaneous, 
superficial subcutaneous soft tissue or lymphatic metastases 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This is a randomized phase II study entitled “A Phase II Randomized Trial of Intralesional 
Talimogene Laherparepvec with or without Hypofractionated Radiotherapy for Cutaneous 
Melanoma or Merkel Cell Carcinoma, or Other Solid Tumors.” Patients with cutaneous 
metastases from melanoma, Merkel cell carcinoma, and other solid tumor malignancies will 
be studied. Patients must have at least one cutaneous metastasis amenable to intralesional 
oncolytic immunotherapy with Talimogene Laherparepvec and radiotherapy and one 
metastasis amenable to observation. 
The primary objective of the study is to characterize the systemic response of metastases 
not injected or irradiated in patients treated with Talimogene Laherparepvec with or without 
radiotherapy. 
The secondary objectives of the study are to characterize the clinical efficacy, safety, patient 
reported quality of life, duration of response, time to response onset, progression free and 
overall survival associated with the treatment of patients with Talimogene Laherparepvec 
with or without radiotherapy. 
The exploratory objective of the study is to characterize the immunologic response 
associated with the treatment of patients with Talimogene Laherparepvec with or without 
radiotherapy. 
It is estimated that a minimum of 18 and a maximum of 34 patients will be enrolled over a 
minimum of 2 and a maximum of 3 years to complete the study over a minimum of 3 and a 
maximum of 4-year time period. 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary Objectives: 
 
1. 
To assess the systemic efficacy of Talimogene Laherparepvec with or without 
radiotherapy in patients with cutaneous metastases from melanoma, Merkel cell 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 5 of 36 
 
 
carcinoma, or other solid tumor malignancy. Systemic efficacy will be measured by 
the subject level modified WHO (mWHO) defined response of a metastasis not 
injected with Talimogene Laherparepvec or irradiated 16 weeks after initiation of 
therapy. A systemic response rate of ≤ 7.5% is unacceptable and a rate of ≥ 27% is 
acceptable (for both arms). 
Secondary Objectives: 
 
1. 
To assess the clinical efficacy of Talimogene Laherparepvec with or without 
radiotherapy in patients with cutaneous metastases from melanoma, Merkel cell 
carcinoma, or other solid tumor malignancy. Clinical efficacy will be measured by 
determining the objective response rate (ORR) defined as patients achieving 
complete response or partial response defined by the modified World Health 
Organization (mWHO) criteria. Response will be assessed approximately 16 weeks 
after the first treatment. Among patients randomized to receive Talimogene 
Laherparepvec, we expect ORRs to be comparable to previous studies (26.4% 95% 
CI 21.4-31.5%). Patients randomized to receive Talimogene Laherparepvec and 
radiotherapy are expected to have ORRs higher than previously published studies of 
Talimogene Laherparepvec alone. 
2. 
To assess the safety of Talimogene Laherparepvec with or without radiotherapy in 
patients with cutaneous metastases from melanoma, Merkel cell carcinoma, or other 
solid tumor malignancy as measured by the frequency of adverse events (grade 2-5 
adverse events). The window for adverse event assessment will include the 20 week 
time period from first treatment until 5 weeks after last treatment. We expect that 
frequency and grade of adverse events in patients receiving Talimogene 
Laherparepvec will be similar to previous studies of Talimogene Laherparepvec 
alone, and that radiotherapy will increase the frequency and grade of adverse events. 
3. 
To evaluate the patient reported quality of life following Talimogene Laherparepvec 
with or without radiotherapy in patients with cutaneous metastases from melanoma, 
Merkel cell carcinoma, or other solid tumor malignancies treated with Talimogene 
Laherparepvec with or without hypofractionated radiotherapy. It is expected that 
quality of life (described further in section 12.0) will improve after Talimogene 
Laherparepvec with or without radiotherapy. 
4. 
To assess the duration of response (DOR) in patients achieving a partial or complete 
response. DOR will be defined as the duration of time from occurrence of partial or 
complete response until first occurrence of progression or date of death if the patient 
dies due to any causes before progression. 
5. 
To assess the time to response onset in following Talimogene Laherparepvec with or 
without radiotherapy. It is expected that the time to response onset in patients 
randomized to receive Talimogene Laherparepvec will be similar to previous studies 
of Talimogene Laherparepvec alone (median 4.1 months, range 1.2-16.9 months). It 
is anticipated that the time to response onset in patients receiving Talimogene 
Laherparepvec and radiotherapy will be earlier than prior studies of Talimogene 
Laherparepvec alone. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 6 of 36 
 
 
6. 
To estimate progression free and overall survival in patients receiving Talimogene 
Laherparepvec with or without radiotherapy for cutaneous metastases from 
melanoma and Merkel cell carcinoma. Progression free survival will be defined as 
the time elapsed from start of protocol treatment until progression (according to 
mWHO criteria) or death. 
Exploratory Objectives: 
 
1. 
To characterize the immunologic response to Talimogene Laherparepvec with or 
without radiotherapy in patients with cutaneous metastases from melanoma, Merkel 
cell carcinoma, or other solid malignancies. Tumor biopsies and peripheral blood 
specimens will be used to characterize immunologic effects of treatment such as 
tumor infiltrating lymphocytes and peripheral blood immunophenotype, serum 
antibody titers and cytokine array analyses. 
3.0 
BACKGROUND AND RATIONALE 
Cutaneous metastases. Secondary malignant neoplasms of the skin (also referred to as 
cutaneous metastases) are not infrequently encountered in patients with advanced cancer. 
According to one study, 5.3% of patients with solid tumors develop cutaneous metastases 
(Krathen RA South Med J 2003). Practically, the anatomic compartment of “cutaneous 
metastases” includes the skin (cutis) and superficial subcutaneous soft tissues and 
lymphatics (in-transit channels as well as lymph nodes). The disorder is especially common 
in high-risk skin malignancies, including melanoma and Merkel cell carcinoma. Cutaneous 
metastases can lead to problems such as infection, hemorrhage, and discomfort. One study 
demonstrated that the presence of cutaneous metastases was the single most deleterious 
factor in patient quality of life (Shimozuma K Surg Today 1995). Surgical excision may be a 
simple and effective means of dealing with cutaneous metastasis, but is not always possible 
because of patient comorbidities or extent of the cutaneous metastases. System ic therapy 
alone often has limited efficacy for cutaneous metastases (Richtig E Br J Dermatol 2005). 
We have recently reported on the efficacy of a variety of skin-directed therapies (such as 
radiation therapy and intralesional therapy) for cutaneous metastases, and found that 
treatment is well-tolerated, associated with improvements in quality of life, and frequently 
leads to reduction in size of the treated tumor (Spratt DE J Clin Oncol 2014). The systemic 
efficacy of skin-directed therapy on non-treated metastases has not been well-characterized. 
Radiotherapy for cutaneous metastases. Radiotherapy has been used for many years as 
a palliative treatment for cutaneous metastases. Our recent meta-analysis of skin-directed 
therapies for cutaneous metastases demonstrated that radiotherapy yields a complete 
response in 62.7% (95% CI 22.8-90.5%), and an objective response in 83.8% (95% CI 37.9- 
97.8%). Moreover, studies that combined radiotherapy with other skin-directed therapies 
(intralesional therapy or topical therapy) demonstrated even higher overall response rates 
(Spratt DE J Clin Oncol 2014). As noted above, the systemic efficacy to skin-directed 
radiotherapy has not been well-characterized. However, studies from our group and others 
have suggested that radiotherapy may augment immunologic response to produce systemic 
responses in non-irradiated metastases (Postow M N Engl J Med 2011, Barker CA Cancer 
Immunol Res 2013, Teulings H Br J Derm 2013). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 7 of 36 
 
 
Talimogene laherparepvec (TALIMOGENE LAHERPAREPVEC) for cutaneous 
metastases. Talimogene laherparepvec (TALIMOGENE LAHERPAREPVEC) is an 
intralesional oncolytic immunotherapy consisting of a modified type-1 herpes simplex virus 
that selectively replicates in malignant cells and stimulates an immune response. A phase I 
trial of Talimogene Laherparepvec (formerly OncoVEXGM-CSF) in 30 patients with cutaneous 
or subcutaneous metastases from a variety of malignancies (breast, head and neck, 
melanoma, gastrointestinal) who had failed prior therapy demonstrated the safety of this 
approach (Hu JC Clin Cancer Res 2006). A subsequent phase II study of 50 patients with 
cutaneous metastases from melanoma demonstrated an overall response rate of 26%, an 
revealed responses of metastases that were not injected (Senzer NN J Clin Oncol 2009). 
Correlative analyses suggested that response in metastases that were not injected were due 
to immunologic effects of Talimogene Laherparepvec (Kaufman HL Ann Surg Oncol 2010). 
Preliminary results of a phase III study of Talimogene Laherparepvec versus granulocyte 
monocyte colony stimulating factor (GM-CSF) for patients with unresectable stage IIIB-IV 
melanoma have been presented, and demonstrated an overall response rate of 26.4% (95% 
CI 2.7-29.2%), with a trend toward improved overall survival (Andtbacka RHI ASCO 2013). 
Responses were seen most often at the site of the injected cutaneous metastasis (64.3%), 
but also in non-injected cutaneous metastases (33.7%), and non-injected visceral 
metastases (15.2%). Importantly, the median time to response was 16 weeks, therefore 
approximately 7.5% of patients are expected to have response in uninjected metastases at 
this time point (Andtbacka RHI HemOnc Today Melanoma and Cutaneous Malignancies 
Meeting 2014). Increasing the response rate by combining Talimogene Laherparepvec with 
other therapies is an active area of study. 
Preclinical rationale for combining TALIMOGENE LAHERPAREPVEC with 
radiotherapy. As previously reviewed, there is an abundance of preclinical literature to 
suggest that combining oncolytic immunotherapy (such as TALIMOGENE 
LAHERPAREPVEC) with radiotherapy can increase the antineoplastic effects of each 
treatment modality (Touchefeu Y Rad Onc 2011, Advani S IJROBP 2006). Irradiation of 
cancer cells can increase viral uptake, replication, gene expression and the induction of host 
cell death, thereby enhancing the effects of oncolytic immunotherapy (see Figure 1). 
Conversely, viral proteins can inhibit components of the DNA damage response pathway, 
thereby sensitizing cancer cells to the effects of radiation therapy (see Figure 2). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
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Page 8 of 36 
 
 
 
 
 
Clinical experience combining TALIMOGENE LAHERPAREPVEC and 
radiotherapy. Several studies have investigated the combination of oncolytic 
immunotherapy (such as TALIMOGENE LAHERPAREPVEC) and radiotherapy. Most 
relevant to the current protocol is a phase I/II trial of Talimogene Laherparepvec (formerly 
OncoVEXGM-CSF) and chemoradiation therapy that was reported in 2010 (Harrington KJ Clin 
Cancer Res 2010). Seventeen patients with locally advanced mucosal squamous cell 
carcinoma of the head and neck (mSCCHN) underwent high dose radiotherapy (70 Gy in 35 
fractions), with concomitant cisplatin chemotherapy (100 mg/m^2) and escalating doses 
(10^6 – 10^8 plaque forming units (pfu)/mL) of intralesional Talimogene Laherparepvec 
during radiotherapy (day 1, 22, 43 and 64, see Figure 3). Escalating doses of Talimogene 
Laherparepvec were delivered without observation of dose limiting toxicities. Adverse events 
(AEs) were consistent with those normally observed during standard chemoradiation therapy 
for locally advanced mSCCHN), and grade 3 or 4 observed in ≥2 patients were unrelated to 
Talimogene Laherparepvec dose. The recommended dose of Talimogene Laherparepvec 
for concomitant administration with radiotherapy in future studies of mSCCHN was 10^6 
followed by 10^8. This dosing schedule is consistent with previous and ongoing studies in 
melanoma, and other diseases (Figure 3). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Mechanisms through which 
ionizing radiation may enhance 
oncolytic immunotherapy. From 
Touchefeu Y Radiother Oncol 2011. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. Mechanisms through 
which oncolytic immunotherapy may 
enhance radiotherapy. From 
Touchefeu Y Radiother Oncol 2011. 


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IRB Number: 16-224 A(11) 
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The efficacy of this combination was promising. At a median follow-up of 29 months, 100% 
of patients achieved locoregional disease control, and 76.5% of patients were relapse-free. 
Notably, no patient participating in this study had measurable metastases that were not 
irradiated or injected with Talimogene Laherparepvec (Harrington KJ Clin Cancer Res 2010). 
Therefore, the systemic efficacy of this therapeutic combination was not assessed. 
Combining immunotherapy and radiotherapy. We have previously reviewed and reported 
on the combinations of radiotherapy and immunotherapy (Barker and Postow IJROBP 
2014). Of particular interest is the ability of the radiotherapy to augment the systemic 
response to immunotherapy. Evidence of this phenomenon is demonstrated by the abscopal 
effect, or regression of a non-irradiated tumor after radiotherapy. Investigators have 
previously found that the combination of granulocyte-monocyte colony stimulating factor 
(GM-CSF) and radiotherapy can produce an abscopal effect in 27% of patients. In the 
OPTiM trial described above, patients treated with GM-CSF demonstrated a non-injected 
visceral response rate of <5%, while those treated with Talimogene Laherparepvec 
demonstrated a non-injected visceral metastasis response rate of 15.2%. Whether 
radiotherapy combined with Talimogene Laherparepvec can increase the response rate 
among non-injected visceral metastases is unknown. Given that systemic response of 
visceral metastases that have not been injected or irradiated is a sign of successful 
immunotherapy, it is this endpoint that is of considerable interest for investigation. 
To our knowledge, a study of Talimogene Laherparepvec and radiotherapy to characterize 
the systemic efficacy of this therapeutic combination has never been performed, and has not 
been initiated elsewhere. The present study will provide information for society regarding the 
potential benefit of this therapeutic combination. For patients with cutaneous metastases 
from melanoma, Merkel cell carcinoma, or other solid tumor malignancy this study may 
provide valuable therapeutic benefit from treatment using 2 active agents. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3. Schedule of concurrent T-VEC and chemoradiotherapy in a previously 
reported phase I/II clinical trial. From Harrington KJ Clin Cancer Res 2010. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 10 of 36 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a prospective, single site phase II randomized trial examining the systemic efficacy 
(primary objective), clinical efficacy, safety, quality of life effects, duration of response, time 
to response, progression-free and overall survival (secondary objectives) of patients of 
Talimogene Laherparepvec with or without radiotherapy in patients with cutaneous 
metastases from melanoma, Merkel cell carcinoma, or other solid tumor malignancies. 
4.2 
Intervention 
Patients with cutaneous metastases from melanoma, Merkel cell carcinoma or other solid 
tumor malignancy will be screened for eligibility. If a patient is found to have anything other 
than cutaneous metastases from melanoma, Merkel cell carcinoma or other solid tumor 
malignancy, appropriate clinical management will be undertaken. 
If eligible, patients will undergo baseline PET/CT imaging, quality of life assessment, followed 
by intralesional Talimogene Laherparepvec with or without radiotherapy. 
Talimogene Laherparepvec will be administered at weeks 0, 3, 5, 7, 9, 11, 13 and 15. The 
first dose of Talimogene Laherparepvec will be 10^6 plaque forming units (PFU)/mL, followed 
three weeks later by a dose of 10^8 pfu/mL. Up to 4 mL will be injected at each treatment. 
Metastases will be injected, beginning with the largest tumor first, with volumes indicated 
below, until a maximum of 4 mL has been used. 
 
Tumor size 
(longest dimension) 
Talimogene laherparepvec 
(TVEC) 
injection volume 
Dose concentration 
>5 cm 
≤4 mL 
10^6 PFU/mL at week 0, 
10^8 PFU/mL thereafter 
2.6-5 cm 
≤2 mL 
10^6 PFU/mL at week 0, 
10^8 PFU/mL thereafter 
1.6-2.5 cm 
≤1 mL 
10^6 PFU/mL at week 0, 
10^8 PFU/mL thereafter 
0.6-1.5 cm 
≤0.5 mL 
10^6 PFU/mL at week 0, 
10^8 PFU/mL thereafter 
≤0.5 cm 
≤0.1 mL 
10^6 PFU/mL at week 0, 
10^8 PFU/mL thereafter 
Table 1. TALIMOGENE LAHERPAREPVEC injection volume and concentration based on 
tumor size. 
Patients randomized to Arm A will receive 3 radiotherapy treatments (one treatment every 3- 
6 days) during weeks 3 and 4. The first treatment will occur 6 (+/- 2) hours after the 
Talimogene Laherparepvec administration at week 3. 
Patients randomized to Arm B will receive Talimogene Laherparepvec alone, as described 
above, without radiotherapy. 


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Page 11 of 36 
 
 
Patients will undergo disease re-evaluation with PET/CT and quality of life assessment at 
week 16. 
Patients with potential for clinical benefit may continue Talimogene Laherparepvec every 2 
weeks, after week 15, for up to 24 weeks. This will be determined by the treating clinician. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
Please see Investigational Product Information – Talimogene Laherparepvec (AMG 678). 
The agent is under review by the FDA for use in patients with melanoma and will be used 
under a cross-referenced IND for use in other diseases. 
External beam radiation therapy is a standard, non-investigational treatment for cutaneous 
metastasis. 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
• 
Man or woman ≥ 18 years old 
• 
Life expectancy > 4 months 
• 
Histopathologically confirmed melanoma, Merkel cell carcinoma or other solid tumor 
malignancy 
• 
Cutaneous, subcutaneous soft tissue, or superficial lymphatic metastasis not suitable 
for surgical resection 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 
• 
Cutaneous, subcutaneous soft tissue, or superficial lymphatic metastasis that is 
amenable to injection and irradiation and > 10 mm in longest dimension 
o Cutaneous metastasis in a region of previous radiation therapy is amenable to 
radiation therapy as part of this protocol if at least 6 months has elapsed since 
prior radiotherapy and the dose of radiotherapy previously administered did 
not exceed an equivalent dose of 60 Gy in 2 Gy equivalent fractions at the 
skin surface (using linear-quadratic modeling with alpha/beta=11.5) 
• 
Metastasis that is > 10 mm in longest dimension or exhibits radiotracer uptake 
consistent with metastasis on PET/CT 
• 
Adequate coagulation function (platelet count >50 k/mcL, international normalized 
ratio of < 1.5) 
• 
Resolution or stabilization of clinically significant adverse events from prior therapy 
• 
Able to provide valid written informed consent 
6.2 
Subject Exclusion Criteria 
• 
Active herpetic skin lesions or prior complications of HSV-1 infection (such as 
herpetic keratitis, herpetic encephalitis) 
• 
Receipt of a therapeutic anticoagulant 
• 
Receipt of live vaccine within 28 days of planned first dose of TVEC 


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• 
Receipt of another cancer therapy (targeted therapy, chemotherapy, investigational 
therapy, immunotherapy, radiotherapy or surgery) which is yielding an overall 
response (by response criteria in this study) 
o Patients with stable or progressing disease (as determined by at least 2 
consecutive assessments at 6-week interval) can continue to receive the 
same therapy during treatment as part of this protocol 
• 
History of symptomatic autoimmune disease (such as lupus, scleroderma, Crohn’s 
disease, ulcerative colitis) requiring systemic treatment (for example corticosteroids or 
immunosuppressants); replacement therapy (for example, thyroxine, insulin) is not 
considered a systemic treatment 
• 
History of high grade (CTCAE > Grade 3) immune mediated adverse event from prior 
cancer immunotherapy 
• 
History of CTCAE > Grade 2 immune mediated endocrinopathy from prior cancer 
immunotherapy 
• 
Intermittent or chronic use of oral or intravenous antiherpetic drug (such as acyclovir) 
• 
Active or chronic hepatitis B or C infection 
o Previously infected with evidence of immunity and no evidence of active 
hepatitis is not an exclusion criterion 
• 
Known human immunodeficiency virus (HIV) infection 
• 
Known leukemia or lymphoma 
• 
Common variable immunodeficiency 
• 
Patients requiring chronic high dose immunosuppressants including steroids 
(prednisone daily equivalent of ≥ 10 mg) 
• 
Known severe congenital or acquired cellular or humoral immunodeficient or 
immunocompromised patients (as noted in Investigators Brochure and 
Developmental Core Safety Information) 
• 
High likelihood of protocol non-compliance (in opinion of investigator) 
• 
Woman of childbearing potential unwilling to use effective contraception during 
protocol treatment and for 3 months after last dose of Talimogene Laherparepvec 
• 
Woman of childbearing potential that is pregnant or breast-feeding, or planning to 
become pregnant or breast-feed during protocol treatment and for 3 months after last 
dose of Talimogene Laherparepvec 
7.0 
RECRUITMENT PLAN 
Investigators and their research teams will serve as the primary recruiters for this study. 
Potential research subjects will be identified by a member of the patient’s treatment team, the 
protocol investigator, or the research team. If the investigator is a member of the treatment 
team, s/he will screen the patient’s records for suitable research study criteria and discuss 
the study and the potential for enrolling in the research study. Potential subjects contacted 
by their treating physician will be referred to the investigator/research staff of the study. 
Women and minorities will be identified in this same manner. 
During the initial contact between the investigator/research staff and the patient, the patient 
may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process. The investigator/research staff may also review portions of the patients 


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medical records at MSKCC to further assess eligibility. They will use the information 
provided by the patient and/or medical record to confirm that the patient is eligible and to 
contact the patient regarding study enrollment. If the patient is ineligible for enrollment in the 
research study, the research staff will destroy all information collected on the patient during 
the initial conversation and medical records review, except for any information that must be 
maintained for screening log purposes. 
In most cases, the initial contact with the prospective subject will be by a member of the 
treatment team, investigator or research staff working in consultation with the treatment 
team. The recruitment process outlined presents no more than minimal risk to the privacy of 
the patients who are screened and minimal PHI will be maintained as part of the screening 
log. For these reasons, we seek a (partial) limited waiver of authorization for purposes of (1) 
(2) handling of PHI contained within those records and provided by potential subjects; and 
(3) maintaining information in a screening log of patients approached (if applicable). 
This limited waiver will apply only to MSKCC for the purpose of maintaining screening logs. 
The study will not be advertised. Subjects will not be reimbursed for participation. 
We plan to accrue 18 - 34 patients at our center over 2 – 3 years. 
8.0 
PRETREATMENT EVALUATION 
The following tests and procedures are required prior to protocol registration. These 
procedures are standard of care. 
Within 4 weeks prior to registration 
• 
Physical examination 
• 
ECOG performance status 
• 
Vital signs (weight, heart rate, blood pressure, respiratory rate, oxygen saturation) will 
be assessed in clinic 
• 
Complete blood count (CBC) 
• 
Comprehensive metabolic profile (CMP) 
• 
Hepatitis B and C panels (Hepatitis B Surface Antigen, Hepatitis B Core Antibody 
(total), Hepatitis B Surface Antibody, Hepatitis C Antibody), and possible additional 
testing, depending on serological testing 
• 
Prothrombin and activated partial thromboplastin time test (PT&APTT) 
• 
Clinical review of the MSK histopathology report confirming cancer 
• 
Quality of life assessment (Skindex -16, Appendix B) will be completed by subjects 
• 
Pregnancy test for women of childbearing potential (by either blood or urine) 
• 
Digital photography will be performed to document the location and size of cutaneous 
metastases. 
• 
PET/CT (IV or oral contrast is not required, but is permissible if clinically indicated.) 
 
9.0 
TREATMENT/INTERVENTION PLAN 
Study Assessments and Procedures 
During Treatment 
Weeks 0, 3, 5, 7, 11 and 15 (+ 1 week) 


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• 
Physical examination 
• 
ECOG performance status 
• 
Vital signs (weight, heart rate, blood pressure, respiratory rate, oxygen saturation) will 
be assessed in clinic 
• 
Complete blood count (CBC) 
• 
Basic metabolic profile (BMP) 
• 
Prothrombin and activated partial thromboplastin time test (PT&APTT) 
• 
Pregnancy test for women of childbearing potential, by blood or urine (at weeks 3, 7, 
11 and 15 only) 
• 
Research blood test 
• 
Research skin tumor biopsy (at weeks 0, 7 and 15 only) 
Weeks 0-15 (+ 1 week) 
• 
Administration of Talimogene Laherparepvec (T-VEC) 
* Patients with potential for clinical benefit may continue TALIMOGENE 
LAHERPAREPVEC after week 15 every 2 weeks for up to 24 weeks (to be 
determined by treating clinician) 
• 
Radiation therapy for patients randomized into Arm A; first fraction given 6 (+/-2) 
hours after week 3 Talimogene Laherparepvec administration; 2nd and 3rd fraction 
given every 3-6 days over next 14 days 
• 
Adverse event review (including NCI PRO-CTCAE v1.0, Appendix C) 
End of Treatment 
 
Week 16 (+ 1 week) or when TVEC is discontinued prior to week 15 
• 
Physical examination 
• 
ECOG performance status 
• 
Vital signs (weight, heart rate, blood pressure, respiratory rate, oxygen saturation) will 
be assessed in clinic 
• 
Adverse event review (including NCI PRO-CTCAE v1.0, Appendix C) 
• 
Complete blood count (CBC) 
• 
Comprehensive metabolic profile (CMP) 
• 
Prothrombin and activated partial thromboplastin time test (PT&APTT) 
• 
Research blood test (If TVEC stopped before week 15) 
• 
Pregnancy test for women of childbearing potential (by either blood or urine) 
• 
Research skin tumor biopsy (If TVEC stopped before week 15) 
• 
Quality of life assessment (Skindex -16, Appendix B) to be completed by subjects 
• 
Digital photography 
• 
PET/CT (IV or oral contrast is not required, but is permissible if clinically indicated.) 
 
Follow-Up 
 
Week 20 (+ 1 week) or 4 weeks after last TVEC dose 
• 
Adverse event review (including NCI PRO-CTCAE v1.0, Appendix C) 
 
 
9.1 Oncolytic immunotherapy by Talimogene Laherparepvec (TALIMOGENE 
LAHERPAREPVEC) administration 


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Intralesional administration of Talimogene Laherparepvec will be performed in a private room 
in the outpatient clinic area. 
Intralesional therapy for cutaneous metastasis is a standard procedure, but Talimogene 
Laherparepvec is an investigational agent. 
The selection of cutaneous metastasis for Talimogene Laherparepvec injection will be based 
on lesion size. Injections will begin with the largest metastasis, and then will proceed to the 
next largest metastasis, until all the cutaneous metastases have been injected, or the 
maximum volume of Talimogene Laherparepvec (4 mL) has been used for that treatment 
cycle. The injection of all of the cutaneous metastases is expected to take no more than 20 
minutes. 
Visceral metastases will not be injected with Talimogene Laherparepvec during the protocol 
therapy. 
During the course of Talimogene Laherparepvec administration, patients will be clinically 
evaluated every 2-3 weeks (as indicated in section 10.0), for any symptoms or signs of 
toxicity. If a patient experiences a grade 2 or higher immune mediated adverse event, 
Talimogene Laherparepvec administration will be delayed until the adverse event is grade 1 
or less in severity. Non-immune related adverse events grade 3 or greater will also lead to a 
delay in Talimogene Laherparepvec administration, until they have resolved to grade 1 or 
less. In the event of a dose limiting toxicity, as described in section 11.1.3, Talimogene 
Laherparepvec administration will be discontinued indefinitely. 
9.2 External beam radiation therapy 
Radiation therapy will be administered in the Department of Radiation Oncology, in a 
treatment suite in the outpatient clinic area. The largest cutaneous metastasis amenable to 
radiation therapy (see section 6.1 for criteria) will be targeted. This metastasis will also be 
injected with Talimogene Laherparepvec before and after radiation therapy. Other cutaneous 
metastases causing symptoms may also be targeted with radiation therapy at the discretion 
of the radiation oncologist. 
Radiation therapy will be simulated prior to the initiation of radiation therapy. The patient will 
be positioned comfortably in a manner that facilitates the delivery of radiation therapy. 
Generally, this will be lying supine, recumbent on a dedicated treatment couch for radiation 
therapy. Immobilization equipment will be created and alignment markings generated to 
ensure setup reproducibility. A CT scan of the region being treated with radiation therapy will 
be performed with the patient in the treatment position. The simulation process takes 
approximately 1 hour. 
Radiation therapy will be planned by delineating the grossly evident tumor (the gross tumor 
volume, or GTV) on the simulation CT, and creating a margin around this to account for the 
setup uncertainty and organ motion. An isotropic volumetric expansion of 1 cm will be 
performed to generate the planning target volume (PTV). The radiation dose will be 
prescribed so that the ≥ 95% of the PTV receives the prescription dose (27 Gy in 3 fractions 
over 7-9 days). Custom shielding and bolus will be created and beam type (megavoltage 
photons or electrons) and energy will be selected to ensure that the irradiated volume is as 


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small as possible, but able to deliver an adequate dose to the PTV. The irradiated skin 
surface receiving the prescription dose of radiation (27 Gy) will be limited to 65 cm 2 
(equivalent to a round field with diameter of 9 cm, or a square field 8x8 cm). The process of 
target delineation and shielding creation is expected to take 20 minutes, but will be 
performed offline, and does require the patient to be present. 
Simulation will be scheduled prior to radiation therapy. 
The first dose of radiation will be delivered 6 (+/- 2) hours after the second dose of 
Talimogene Laherparepvec. Preclinical studies have demonstrated this sequence of therapy 
and interval of time is necessary to yield synergistic effects of oncolytic immunotherapy and 
radiotherapy. The subsequent two doses of radiation therapy will occur every 3-6 days, over 
no more than 14 days. 
During the course of radiation therapy patients will be clinically evaluated at least once a 
week, for any symptoms or signs of toxicity. 
9.3 Cutaneous metastasis biopsy 
Punch biopsy will be obtained for immunologic correlative analyses. Local anesthesia will be 
provided by intradermal injection of lidocaine 1% mixed with epinephrine at 1:100,000 by a 
30 gauge needle. After allowing 5 minutes for adequate anesthesia, a 3 mm punch biopsy 
will be obtained. The biopsy site will be closed with cuticular sutures or steri-strips. Patients 
will be instructed to keep the biopsy site clean after the procedure. This procedure will be 
done as an outpatient. The biopsy is expected to take no longer than 15 minutes and will be 
performed on the day of (but prior to first dose) of oncolytic immunotherapy. The biopsy will 
be repeated around 7 and 15 weeks after the first dose, at the site of the prior biopsy, and at 
up to two other sites (if present): (1) the site of another cutaneous metastasis that was not 
injected or irradiated (if present), (2) the site of another cutaneous metastasis that was 
injected but not irradiated (if present). 
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Study Timeline 
Pre- 
Treatment 
Treatment 
End of 
Treatment6 
Follow- 
Up7 
Week 
(+/-) 
-4 to 0 
0 
(1) 
3 
(1) 
5 
(1) 
7 
(1)4 
9 
(1) 
11 
(1) 
13 
(1) 
15 
(1) 
16 
(1) 
20 
(1) 
Assessments 
Pathology Review 
X 
PET/CT (with or 
without contrast) 
X 
X 
Quality of life 
questionnaires 
X 
X 
Digital photography 
X 
X 
Adverse event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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review1 
ECOG performance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (weight, 
heart rate, blood 
pressure, 
respiratory rate, 
oxygen saturation) 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
Complete medical 
history 
X 
Hepatitis B Surface 
Antigen, Hepatitis B 
Core Antibody 
(total), hepatitis B 
surface Antibody, 
Hepatitis C 
Antibody5 
X 
Comprehensive 
metabolic profile 
X 
X 
Basic metabolic 
profile 
X 
X 
X 
X 
X 
X 
Complete blood 
count 
X 
X 
X 
X 
X 
X 
X 
PT&APTT 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testing 
(blood or urine); 
WOCBP only 
X2 
X 
X 
X 
X 
Research blood 
test3 
X 
X 
X 
X 
X 
X 
Research skin 
punch biopsy4 
X 
X 
X 
Treatment 
TALIMOGENE 
LAHERPAREPVEC 
X 
X 
X 
X 
X 
X 
X 
X† 
Radiation therapy 
X* 
†Patients with potential for clinical benefit may continue TALIMOGENE LAHERPAREPVEC after week 15 every 2 
weeks for up to 24 weeks (as determined bytreating clinician) 
*Only for Arm A; first fraction given 6 (+/-2) hours after week 3 TALIMOGENE LAHERPAREPVEC administration; 
2nd and 3rd fraction given every 3-6 days over no more than 14 days 
1Including Appendix C, “NCI PRO-CTCAE v1.0” 
2Within 2 weeks of starting Talimogene Laherparepvec treatment 
3 Research bloods will be 3 tubes (3 CPT) at each time point; stored at immune monitoring core facility for up to 1 
year after completion of study 
4One lavender top (EDTA) tube of blood will be drawn on the same day as the research skin punch biopsy; 
window for biopsywill be +/- 3 weeks 
5Additional testing to evaluate for hepatitis maybe required depending on the serological results 
6For patients that discontinue TVEC before week 16, the End of Treatment visit occurs after last dose of TVEC 
7Follow-Up at week 20 or 4 weeks after last TVEC dose 


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11.0 
TOXICITIES/SIDE EFFECTS 
The study will use the Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 for assessing toxicity related to oncolytic immunotherapy and radiotherapy. 
Overall, toxicities grade 2-5 will be identified, graded and scored using “Common Toxicity 
Criteria for Adverse Events, version 4.0, grading criteria and definitions”. 
11.1 
TALIMOGENE LAHERPAREPVEC 
Side effects of Talimogene Laherparepvec for cutaneous metastasis are listed below. Also 
see Investigators Brochure, Developmental Core Safety Information, Toxicity Management 
Guidelines for studies with Talimogene Laherparepvec [AMG 678] and Core Informed 
Consent Form Risks and Discomforts Section. 
11.1.1.0 
Important Identified Risks 
 
• 
Disseminated herpetic infection in severely immunocompromised 
individuals (those with any severe congenital or acquired cellular and/or 
humoral immune deficiency) 
• 
Accidental exposure of healthcare providers (HCPs) to talimogene 
laherparepvec 
• 
Cellulitis at site of injection 
11.1.1.1 
Important Potential Risks 
 
• 
Disseminated herpetic infection in immunocompromised patients (such as 
those with HIV/AIDS, leukemia, lymphoma, common variable 
immunodeficiency, or those who require high dose steroids or other 
immunosuppressive agents) 
• 
Symptomatic talimogene laherparepvec infection in non-tumor tissue in 
treated patients 
• 
Transmission of talimogene laherparepvec from patient to close contacts 
or HCPs via direct contact with injected lesions or body fluids resulting in 
symptomatic infection (primary or reactivation) 
• 
Symptomatic herpetic infection due to latency and reactivation of 
talimogene laherparepvec or wild type HSV-1 
• 
Immune-mediated adverse events 
• 
Plasmacytoma at the injection site 
• 
Impaired wound healing at the injection site 
• 
Talimogene laherparepvec mediated anti GM-CSF antibody response 
 
 
11.1.2.0 
Adverse Drug Reactions (ADRs) 
 
Adverse drug reactions observed in talimogene laherparepvec clinical trials are listed below 
in Table 2. Consult the current Investigator’s Brochure for the full information on ADRs. 


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System Organ Class 
Preferred Term 
CIOMS Frequency 
Very Common: ≥10% 
Common: 1%-<10% 
Uncommon: <1% 
General disorders and administration site conditions 
Fatigue 
Very Common 
Chills 
Very Common 
Pyrexia 
Very Common 
Influenza like illness 
Very Common 
Malaise 
Common 
Axillary pain 
Common 
Injection site reactions* 
Very Common 
Gastrointestinal disorders 
Nausea 
Very Common 
Vomiting 
Very Common 
Diarrhea 
Very Common 
Constipation 
Very Common 
Abdominal pain 
Common 
Abdominal discomfort 
Common 
Musculoskeletal and connective tissue disorders 
Myalgia 
Very Common 
Arthralgia 
Very Common 
Pain in extremity 
Very Common 
Groin pain 
Common 
Skin and subcutaneous tissue disorders 
Vitiligo 
Common 
Rash 
Common 
Dermatitis 
Common 
Infections and infestations 
Cellulitis 
Common 
Oral herpes 
Common 
Incision site infection 
Uncommon 
Nervous system disorders 
Headache 
Very Common 
Dizziness 
Common 
Eye disorders 
Herpetic keratitis 
Uncommon 
Respiratory, thoracic and mediastinal disorders 
Oropharyngeal pain 
Common 
Obstructive airway disorder 
Uncommon 
Metabolism and nutrition disorders 
Dehydration 
Common 
Injury, poisoning and procedural complications 
Contusion 
Common 
Procedural pain 
Common 
Wound complication 
Common 
Wound secretion 
Common 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) 


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System Organ Class 
Preferred Term 
CIOMS Frequency 
Very Common: ≥10% 
Common: 1%-<10% 
Uncommon: <1% 
Tumor pain 
Common 
Infected neoplasm 
Common 
Plasmacytoma at the injection site 
Uncommon 
Investigations 
Weight decreased 
Common 
Vascular disorders 
Deep vein thrombosis 
Common 
Flushing 
Common 
Blood and lymphatic system disorders 
Anemia 
Common 
Immune system disorders 
Worsening psoriasis 
Uncommon 
Pneumonitis 
Uncommon 
Glomerulonephritis 
Uncommon 
Vasculitis 
Uncommon 
* Injection site reactions include: very common term of injection site pain, common terms of 
injection site erythema, injection site hemorrhage, injection site swelling, injection site 
reaction, injection site inflammation, secretion discharge, injection site discharge, uncommon 
term of injection site warmth. 
Table 2. ADRs Observed in Talimogene Laherparepvec Clinical Trials 
11.1.3.0 
Dose Limiting Toxicities (DLTs) 
 
Dose limiting toxicities (DLTs) are defined below. 
11.1.3.1 
Definitions of Dose Limiting Toxicity 
Toxicity should be evaluated according to CTCAE version 4.0, and should 
only include events assessed as related to talimogene laherparepvec during 
treatment and up to 30 days after the last talimogene laherparepvec injection. 
The following herpetic events should be considered as DLTs: 
• 
Serious herpetic events such as herpetic encephalitis, encephalomyelitis 
or disseminated herpetic infection 
• 
Any herpetic events confirmed due to talimogene laherparepvec that 
require treatment with acyclovir or similar anti-viral agent. Talimogene 
laherparepvec treatment should be suspended if treatment is required with 
systemic acyclovir or other anti-virals. If ongoing anti-viral treatment is 
required, talimogene laherparepvec treatment should be permanently 
discontinued 


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Consider also including the following as DLTs: 
• 
Grade 3 or greater immune-mediated adverse events 
• 
Any grade plasmacytoma at or near the injection site or evidence of 
impaired wound healing at the injection site 
• 
Grade 3 or greater allergic reactions considered at least possibly related to 
talimogene laherparepvec 
• 
Grade 4 non-hematologic toxicity 
• 
Grade 3 non-hematologic toxicity lasting > 3 days despite optimal 
supportive care 
- 
Grade 3 fatigue will not be classified as DLT, irrespective of duration 
• 
Any grade 3 or higher non-hematologic laboratory value if the abnormality: 
- 
fails to respond to medical intervention, or 
- 
leads to hospitalization, or 
- 
persists for > 1 week unless deemed not clinically important per both 
investigator and sponsor 
• 
Grade 3 or 4 febrile neutropenia 
• 
Grade 4 thrombocytopenia associated with a bleeding event deemed at 
least possibly related to talimogene laherparepvec and requiring 
intervention 
• 
Any other intolerable toxicity leading to permanent discontinuation of 
talimogene laherparepvec 
• 
Grade 5 toxicity (ie. Death) 
If an unexpected DLT deemed at least possibly related to talimogene 
laherparepvec occurs, talimogene laherparepvec administration should be 
delayed until the DLT has resolved to at least CTCAE (v. 4.0) Grade 1. 
If talimogene laherparepvec dosing is delayed by more than 6 weeks from the 
date of the planned dose due to the occurrence of an adverse event that is 
considered related to talimogene laherparepvec, the subject must be 
permanently taken off talimogene laherparepvec treatment. 
11.1.3 
Dose Reductions 
Dose reductions with regards to changes in the concentrations of talimogene 
laherparepvec are not permitted. However, patients may require a reduction in 
the volume injected due to a disease response (defined in dosing section) or 
due to local toxicity at the injection site. However, if in the course of 
administration of talimogene laherparepvec the subject cannot tolerate the full 
dose due to an injection-related adverse event such as pain, the total volume 
given should be recorded, and the reason for intolerance should be 
documented as an adverse event. 
11.1.4 
Talimogene Laherparepvec Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent Discontinuation 


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If talimogene laherparepvec treatment was delayed by > 2 weeks, that dose will 
be deemed to have been missed and the subject will proceed to the next 
scheduled treatment visit. Dose reductions of talimogene laherparepvec is not 
permitted, other than a reduction in the volume injected due to a disease 
response. 
If a subject experiences any of the following treatment-related toxicities, 
talimogene laherparepvec administration should be delayed until the toxicity has 
resolved to at least CTCAR grade 1 or baseline: 
• 
Grade 2 or greater immune-mediated adverse events, with the exception 
of vitiligo 
• 
Grade 2 or greater allergic reactions 
• 
Any other grade 3 or greater hematologic or non-hematologic toxicity 
Subjects who are receiving talimogene laherparepvec may not receive systemic 
antiherpetic drugs (eg, acyclovir, valacyclovir, famciclovir), but may receive a 
topically administered antiherpetic drug more than 20 cm from a talimogene 
laherparepvec injection site. Dosing should be permanently discontinued if, in 
the opinion of the investigator, the subject develops clinical evidence of any 
systemic herpes infection (such as encephalitis or disseminated infection). If the 
subject requires corticosteroid dosing of > 10 mg prednisone daily (or equivalent) 
for related toxicities, talimogene laherparepvec dosing must be withheld until the 
corticosteroid dose has decreased to < 10 mg prednisone daily (or equivalent). 
Talimogene laherparepvec treatment should be continued based on the potential 
benefit/risk assessment of the subject. If talimogene laherparepvec dosing is 
delayed by more than 4 weeks from the date of the planned dose (ie, 
approximately 6 weeks or 7 weeks depending whether the patient is receiving 
Q2W or Q3W dosing from the previous dose) due to the occurrence of an 
adverse event that is considered related to talimogene laherparepvec, the 
subject must be permanently withdrawn from talimogene laherparepvec 
treatment. 
Talimogene laherparepvec is to be permanently discontinued for subjects 
meeting any of the following criteria: 
• 
The subject, for any reason, requires treatment with another anticancer 
therapeutic agent for treatment of the study disease. In this case, 
discontinuation from the treatment occurs immediately upon introduction 
of the new agent. 
• 
Confirmed PD 
• 
A grade 2 or greater immune-mediated adverse event (with the exception 
of vitiligo) or allergic reactions attributed to talimogene laherparepvec 
that would require a dose delay of greater than 4 weeks from the date of 
the planned dose (ie, approximately 6 weeks from the previous dose). 
Note: immune-mediated glomerulonephritis, vasculitis, and pneumonitis 
and exacerbation of psoriasis have been observed in subjects receiving 


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talimogene laherparepvec in clinical trials. Most of these subjects had a 
history of other autoimmune disease and/or prior treatment with agents 
that offered plausible alternative etiologies, however, immune-mediated 
adverse events can potentially involve any organ system 
• 
Any other talimogene laherparepvec-related non-hematologic or 
hematologic toxicities grade 3 or greater occur that, in the opinion of the 
investigator, would require a dose delay of greater than 4 weeks from the 
date of the planned dose (ie, approximately 6 weeks from the previous 
dose) 
• 
The subject develops clinical evidence of any systemic herpes infection 
(such as encephalitis or disseminated infection) 
• 
A female subject becomes pregnant or fails to use acceptable method(s) 
of affective contraception (for those subjects who are able to conceive) 
• 
Concurrent medical illness that, in the judgment of the investigator, would 
make continued treatment with talimogene laherparepvec dangerous for 
the subject 
For additional information related to special warnings and precautions for the use of 
talimogene laherparepvec, please refer to the latest version of the Investigator’s 
Brochure. 
11.2 
Side effects of radiation therapy for cutaneous metastasis are listed below. 
 
Common Terminology Criteria 
Adverse Event 
Grade 1 
frequency 
Grade 2 
frequency 
Grade 3 
frequency 
Grade 4 
frequency 
Radiation dermatitis 
100% 
50% 
10% 
<2% 
Pruritis 
50% 
10% 
Pain of skin 
50% 
10% 
<2% 
Skin ulceration 
50% 
10% 
<2% 
Alopecia 
100% 
10% 
Skin hyperpigmentation 
50% 
10% 
<2% 
Skin hypopigmentation 
100% 
10% 
Telangiectasia 
50% 
10% 
Skin atrophy 
100% 
10% 
<2% 
Skin induration 
100% 
10% 
<2% 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
The primary endpoint for systemic efficacy is the week 16 response of the largest metastasis 
not injected with Talimogene Laherparepvec or irradiated. Overall subject level response is 
defined as partial or complete (>50% or greater decrease in largest lesion) by the modified 
World Health Organization (mWHO) criteria, and will include measurements of tumor size by 
CT component of PET/CT, by standard uptake value (SUV) by PET component of PET/CT, 
and clinically by digital photography. Please see Appendix A for complete radiographic 
assessment details and the mWHO response criteria. 


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Study radiologists will be specifically informed which lesion is the target for response 
assessment. A separate calculation of response within and outside the irradiated volume will 
be determined. Study radiologists will be blinded, however, as to which treatment arm the 
patient has been assigned. 
Radiographic imaging evaluations are considered standard of care for patients treated for 
cutaneous metastases. 
Patients are considered evaluable for the primary endpoint if they: 
• 
Receive one dose of Talimogene Laherparepvec, and for patients enrolled on Arm A, 
one dose of RT, as well as a baseline and at least one post-baseline disease 
assessment 
• 
Discontinue the study due to symptomatic progression, death, or toxicity at any point, 
even if they have not received one dose of Talimogene Laherparepvec and one dose 
of RT 
Patients who discontinue the study and do not meet evaluable criteria above are replaceable. 
In this event, the replacement patient will be assigned to the same treatment arm that lost a 
patient. 
Patient reported health-related quality of life outcomes will be assessed using the Skindex-16 
(Appendix B). The Skindex-16 is a 1 page instrument consisting of 16 items with responses 
provided on a 7-point Likert scale based on experience over the last week. Responses are 
categorized in 3 subscales: emotions, functioning, and symptoms, with combined subscale 
scores yielding an overall score ranging from 0 (best) to 100 (worst). Of the 16 items in the 
instrument, 7 contribute to symptoms, 4 contribute to emotion, and 5 contribute to 
functioning. In a psychometric analysis, subscales have a high degree of internal 
consistency reliability (Cronbach’s alpha = 0.86, 0.93, 0.92 for symptoms, emotions and 
functioning). The subscale scores were also highly reproducible after 72 hours (r= 0.90, 
0.89, and 0.88 for symptoms, emotions and functioning) (Chren MM J Cutan Med Surg 
2001). 
13.0 
CRITERIAFOR REMOVAL FROM STUDY 
Consent for participation in the study may be withdrawn by the patient or patient’s health 
care proxy at any time. 
If at any time, the patient develops clinically significant progressive disease, s/he will be 
withdrawn from the study and referred for alternative therapy. 
If at any time the patient is found to be ineligible for the protocol as designated in the section 
on Criteria for Subject Eligibility (i.e., a change in diagnosis), the patient will be removed from 
the study. 
If at any time, the protocol therapy jeopardizes the safety of the patient, s/he may be 
withdrawn from the study. 
14.0 
BIOSTATISTICS 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 25 of 36 
 
 
Patients will be randomized into two separate arms (stratified by disease type), each of which 
will use a Simon’s optimal two-stage design to assess the primary endpoint of systemic 
response (defined as patients achieving partial response or complete response) of a 
metastasis that was not injected or irradiated. The single largest measureable metastatic 
disease site will be used for this assessment 16 weeks after the first dose of Talimogene 
Laherparepvec. For each arm, a 7.5% or lower response rate is considered not promising, a 
27% or higher response rate is considered promising, and the probabilities of a type I error 
(falsely accepting a non-promising therapy) and type II error (falsely rejecting a promising 
therapy) are set to 0.10 and 0.20, respectively. 
In the first stage, 9 evaluable patients will be accrued to each arm. If at least 1 patient 
achieves response among these 9 patients, then an additional 6 patients will be accrued to 
that arm in the second stage. If no patients achieve response then that arm will be closed to 
further accrual and declared negative. At the end of the trial if 3 or more patients achieve 
response out of 15 then that treatment arm will be considered worthy of further 
investigation. This design has an early stopping probability of 0.06 if the true response rate is 
at least 27% and 0.50 if the true response rate is at most 7.5%. Although a comparison will 
be done between the two arms by a two-sample proportion test on response rates, this 
sample size may not have enough power to distinguish the two arms. Thus if both treatment 
arms are declared worthy of further investigation compared to historical control rate, the 
treatment arm with the higher observed response rate will be selected as the preferred 
treatment modality for future studies. The probabilities of selecting correctly the arm with the 
true higher response rate are given below. The maximum number of patients needed is 30, 
for which we expect to enroll in 36 months. 
 
True response rates for the two arms 
27% 
vs 
35% 
27% 
vs 
40% 
27% 
vs 
45% 
30% 
vs 
35% 
30% 
vs 
40% 
35% 
vs 
40% 
35% 
vs 
45% 
35% 
vs 
50% 
Probability of picking the correct arm 
(i.e., the one with the higher response 
rate) 
0.61 
0.72 
0.80 
0.54 0.65 
0.54 
0.65 
0.74 
 
Note that in the above, all patients are assumed evaluable. However, it might happen that 
some patients are not evaluable due to various reasons such as withdrawal or loss to follow- 
up, etc. Such inevaluable patients will be replaced. We expect that about 13% of patients 
might need to be replaced. In other words, we expect to enroll up to 34 patients in total. The 
clinical efficacy of Talimogene Laherparepvec will be measured by the ORR and summarized 
by the sample proportion for each of the two arms. A comparison will be done between the 
two arms. Safety of Talimogene Laherparepvec will be summarized and compared similarly. 
QOL total and subscale scores will be summarized numerically and graphically, and trends 
will be observed and reported per arm. Wilcoxon rank sum tests will also be used to compare 
the QOL scores between the two arms for each assessment time point. DOR will be 
assessed using actuarial curves based on patients who achieved response and compared 
between the two arms using a stratified log-rank test. Time to response onset, progression 
free and overall survival will be analyzed in a similar way but will be based on all patients. 
Immunologic response data will be summarized descriptively, with mean, median and 
standard deviations calculated. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 26 of 36 
 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility Checklist 
is confirming that the participant is eligible to enroll in the study. Study staff are responsible 
for ensuring that all institutional requirements necessary to enroll a participant to the study 
have been completed. See related Clinical Research Policy and Procedure #401 (Protocol 
Participant Registration). 
15.2 
Randomization 
 
Patients will be randomized into two separate arms (stratified by disease type). Once the 
participant’s eligibility is established, the registration will be finalized and the participants will 
be randomized using the Clinical Research Database (CRDB). Randomization will be 
accomplished by the method of random permuted block, and will be stratified by disease 
type. After treatment arm is determined by randomization, RSAs at MSKCC will notify the 
physicians at MSKCC of the treatment arm and participant ID via email within 24 hours of 
randomization. 
16.0 
DATA MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned to this study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordination of the activities 
of the protocol study team. 
The data collected for this study will be entered into the Clinical Research Database (CRDB). 
Source documentation will be available to support the computerized patient record. 
Data 
 
Standardized Case Report Forms (CRFs) will not be used for this study. Data will be entered 
directly into the CRDB. The study RSA will ensure data is populated in the CRDB accurately 
and in a timely manner. 
Source Documentation 
Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. Source documentation should be 
consistent with data entered into CRDB. 
16.1 
Quality Assurance 
 
Monthly registration reports will be generated to monitor patient accrual and completeness of 
registration data. Routine data-quality reports will be generated to assess missing data an 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 27 of 36 
 
 
inconsistencies. Accrual rates, and extent and accuracy of evaluations and follow-up, will be 
monitored periodically and potential problems will be brought to the attention of the study 
team for discussion and reaction. 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, with the first audit occurring after the 3rd patient is 
registered, and then more frequently if indicated. The audit will include a review of source 
documentation to evaluate compliance for: 
• 
Informed consent documents and procedures 
• 
Adherence to eligibility criteria 
• 
Protocol defined treatment 
• 
Required baseline, on study and follow-up protocol testing 
• 
IRB documents (submitted amendments, annual continuing review reports, SAEs) 
After the audit is complete, a summary will be sent to the PI and research team. The 
summarized findings will generate specific recommendations for correcting shortcomings or 
inadequately performed tasks. The audit report and any corrective plans will be submitted to 
the IRB/PB, CRQA and maintained in the department’s protocol regulatory binder. 
16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in 2001. The plans address the new policies 
set forth by the NCI in the document entitled “Policy of the National Cancer Institute for Data 
Safety and Monitoring of Clinical Trials” which can be found at: 
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1 
The DSM Plans at MSKCC were established and are monitored by the Office of Clinical 
Research. The MSKCC Data and Safety Monitoring Plans can be found on the MSKCC 
Intranet at: 
http://smskpsps9/dept/ocrOCR%20Website%20Documents/Clinical%20Research%20Quality 
%20Assurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20Plan.pdf 
There are several different mechanisms whereby clinical trials are monitored for data, safety, 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research quality assurance) and departmental procedures for quality 
control, plus there are two institutional committees that are responsible for monitoring the 
activities of our clinical trials programs. The committees, Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinical trials, report to the Center’s Research Council and 
Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., National 
Institutes of Health sponsored, in-house sponsored, industrial sponsored, National Cancer 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 28 of 36 
 
 
Institute cooperative group, etc.) will be addressed and the monitoring procedures will be 
established at the time of protocol activation. 
16.3 
Regulatory Documentation 
 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSKCC Institutional Review Board/Privacy Board (IRB/PB). 
16.3.1 Amendments 
 
Each change to the protocol document must be organized and documented by MSKCC and 
first approved by the MSKCC IRB/PB. 
16.3.2 Additional IRB Correspondence 
Prospective and Retrospective Deviations 
A protocol deviation Is any change or departure from an IRB approved research protocol 
and/or the MSK IRB Standard Operating Procedures (SOPs). Deviation may be either 
prospective or retrospective. 
 
A prospective deviation is one that requires IRB approval piror to implementing the proposed 
change. As per IRB SOP RR-407, only specific events require a prospective deviation 
request. These include requests to treat a research participant who does not meet all 
eligibility criteria, who requires alteration in their treatment plan or requires a change in the 
informed consent procedures outlines in the IRB SOP. 
A retrospective deviation is a deviation that has already occurred. Any retrospective 
deviations that do not meet the definition of an unanticipated problem must be reported to the 
Human Research Protection Program (HRPP) Office within 10 business days of identification 
by the MSK PI or study team. These deviations will be reviewed and approved by the HRPP 
staff and escalated to the IRB Chair/Associate Chairs, as appropriate. 
16.3.3 Document Maintenance 
 
The MSKCC PI will maintain adequate and accurate records to enable the implementation of 
the protocol to be fully documented and the data to be subsequently verified. 
A regulatory binder will be maintained at MSKCC; this binder will be electronic. 
After study closure, study related documents and CRFs will be retained for 3 years. 
17.0 
PROTECTION OF HUMAN SUBJECTS 
This protocol does not involve children, because children do not develop cutaneous 
metastases from melanoma, Merkel cell carcinoma or other solid malignancies often, and 
radiation therapy is preferable for adult patients. This statement is based on exclusion 4B of 
the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research 
Involving Human Subjects. In conformity with the NIH Revitalization Act of 1993, every effort 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 29 of 36 
 
 
will be made to include participation of all ethnicities. There will be no restrictions based on 
racial/ethic background. The risk of participating in this protocol is related to the risk of skin 
injury from radiation (radiation dermatitis, pruritis, pain of skin, skin ulceration, alopecia, skin 
hyperpigmentation, skin hypopigmentation, telangiectasia, skin atrophy, skin induration), 
and/or the risk of undertreating the cutaneous metastasis. These risks are low, and the 
relative risk/benefit is favorable, compared with other treatment options. Alternative options 
for management include observation, topical or systemic chemical or immunologic therapy. 
 
Subjects will be responsible for all charges associated with the items that are part of the 
routine clinical care, including diagnostic evaluations as well as the intralesional injections 
and radiation therapy procedures. The subjects will not be compensated for their 
participation. If a patient is injured as a result of being in this study, emergency care, 
hospitalization, and outpatient care will be made available by the hospital and billed to the 
patient and his/her insurance company as part of his/her medical expenses. 
The exams, tests or procedures in the study are part of regular cancer care. The patient 
and/or health plan/insurance company will need to pay for the following tests in the study: 
• 
Pathology review 
• 
Physical exam 
• 
Blood tests 
• 
Imaging tests 
• 
Intralesional drug administration 
• 
Radiation therapy 
17.1 
Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
17.2 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
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 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 30 of 36 
 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is 
required for 30-days after the participant’s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious 
Adverse Events’, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org. All other 
reports should be sent to sae@mskcc.org. 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject’s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
The PI’s signature and the date it was signed are required on the completed report. 
17.2.1 Sponsor Reporting 
17.2.1.1 Safety Reporting to Amgen 
 
The Sponsor/Investigator is responsible for compliance with expedited reporting 
requirements for serious, unexpected and related adverse events (SUSARs), for generation 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 31 of 36 
 
 
of SAE reports including narratives, and for periodic reporting to Amgen of SAEs are outlined 
in Table 3 and Table 4 below. Individual safety reports (table 3) should be accompanied by 
the Fax Cover Form provided and sent to Amgen Global Safety, utilizing the fax or email 
information provided on the cover page. Aggregate safety reporting (table 4) including 
listings, tabulations and summary reports should be scanned and accompanied by the Fax 
Cover Form provided and sent to Amgen NASCR, utilizing the email information provided on 
the cover page. 
In addition to the requirements outlined in Table 3 and 4 Sponsor/Investigators are required 
to report direct exposures to talimogene laherparepvec (e.g., needle stick, splash back) of 
herpetic illness and all suspected herpetic events (refer to Section 17.2.1.2 ‘Accidental 
Exposures to Talimogene Laherparepvic and Herpetic Event Reporting’). 
Table 3 Reporting Requirements for Interventional Studies 
 
Safety Data 
Timeframe for Submission to Amgen 
Suspected Unexpected Serious Adverse Reaction 
(SUSARs) 
Individual reports sent to Amgen at time 
of expedited reporting to IRB 
Serious Adverse Events (SAEs) (related) 
Individual reports sent to Amgen at time 
of expedited reporting to IRB 
Pregnancy/Lactation 
Individual reports sent within 10 days of 
Sponsor/Investigator awareness 
Individual reports should be faxed to 1-888-814-8653 or scanned and sent via email to svc- 
ags-in-us@amgen.com 
Table 4. Aggregate Reports 
 
Safety Data 
Timeframe for submission to Amgen 
Adverse events (all serious and non-serious 
adverse events, regardless of relatedness) 
Line listing and summary tabulation of all 
adverse events sent annually AND at end of 
study 
US IND Annual Safety Report 
Annually 
Other Aggregate Analyses 
(any report containing safety data generated 
during the course of the study) 
At time of ISS sponsor submission to any 
body governing research conduct (e.g., RA, 
IRB, etc.) 
Final (End of Study) Report, including: 
• 
Unblinding data for blinded studies 
• 
Reports of unauthorized use of a 
marketed product 
At time of ISS sponsor submission to any 
body governing research conduct (e.g., RA, 
IRB, etc.) but not later than 1 calendar year 
after study completion 
Aggregate reports should be submitted via email to the Amgen NASCR manager, 
accompanied by the Fax Cover Form 
17.2.1.2 Accidental Exposures to Talimogene Laherparepvec and Herpetic 
Event Reporting 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 32 of 36 
 
 
In order to better assess and understand the potential risks to treated patients and/or 
third parties following the treatment of clinical trial subjects with talimogene 
laherparepvec, special reporting procedures apply for accident exposures to 
talimogene laherparepvec and for suspected herpetic events. See Table 5 below 
“Accidental Exposure and Herpetic Event Reporting Requirement Summary”. 
Clinicians should review the lmlygic package insert (available online) for additional 
information on the safe handling of talimogene laherparepvec. 
17.2.1.2.1 Accidental Exposure of HCPs to Talimogene Laherparepvec 
 
HCPs involved in your clinical trial who were directly exposed to talimigene 
laherparepvec (e.g., needle stick, splash back) but who are without signs or 
symptoms of herpetic illness should be reported to Amgen at 1-855-IMLYGIC 
(1-855-465-9442). 
17.2.1.2.2 Suspected Herpetic Events 
Suspected herpetic events must be reported to Amgen within 24 hours of 
awareness. 
Reporting is required for: (1) suspected herpetic events in treated patients; (2) 
suspected herpetic events in at risk HCPs with direct or indirect exposure and (3) 
suspected herpetic events in treated patient’s close contacts. 
In addition to reporting these events, suspected herpetic lesions should be swabbed 
and submitted for qPCR testing for the detection of talimogene laherparepvec. 
Samples should be collected using appropriate technique and a flocked swab from 
site supplies. This test is likely to be more reliable if performed within the first three 
days of symptom appearance. However, all lesions should be swabbed, regardless 
of the timing of presentation. Amgen does not require qPCR or other testing for wide 
type HSV-1. 
o Reporting Process for ISS Treated Patients: 
▪ 
Any suspected herpetic lesion should be reported to Amgen at 1-855- 
IMLYGIC (1-855-465-9442), evaluated by the Sponsor/Investigator 
and swabbed for qPCR testing 
▪ 
Once an initial report has been made, additional materials will be 
provided, including reporting forms and supplies needed for shipment 
of swab samples. Amgen will require patient consent for qPCR testing, 
which must be obtained prior to swabbing. 
o Reporting Process for HCPs and Close Contacs: 
▪ 
Sponsor/Investigator should advise any HCPs and/or Close Contacts 
with suspected herpetic lesions to contact their personal physician to 
facilitate reporting to Amgen. Suspected herpetic lesions should be 
reported by the Sponsor/Investigator, personal physician or exposed 
individual to Amgen at 1-855-IMLYGIC (1-855-465-9442). Once an 
initial report has been made, additional materials will be provided, 
including reporting forms and supplies needed for the shipment of 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 33 of 36 
 
 
swab samples. Amgen will require patient consent for qPCR testing, 
which must be obtained prior to swabbing. 
 
 
Table 5. 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 
Sw abbing 
qPCR Test 
Result 
Distributio 
n* 
Treated 
Patients 
w ith 
suspected 
herpetic 
lesions 
Sponsor / 
Investigator 
Within 24 
hours of 
Sponsor / 
Investigator 
aw areness 
Contact Amgen 
at 1-855- 
IMLYGIC (1- 
855-465-9442) 
to report event 
Collect sw abs 
fromsuspected 
lesions (ideally 
w ithin 3 days of 
appearance of 
symptoms) 
Yes, if 
consent 
obtained 
Sponsor / 
Investigator 
Sponsor / 
Investigator 
and Amgen 
HCP directly 
exposed to 
product 
(e.g., needle 
stick, splash 
back) 
w ithout 
signs or 
symptoms of 
herpetic 
illness 
HCP’s Personal 
Physician or 
impacted person 
Within 24 
hours of 
Reporter 
aw areness 
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 w ith 
suspected 
herpetic 
lesions 
HCP’s Personal 
Physician or 
impacted person 
Within 24 
hours of 
Reporter 
aw areness 
Contact Amgen 
at 1-855- 
IMLYGIC (1- 
855-465-9442) 
to report event 
Collect sw abs 
fromsuspected 
lesions (ideally 
w ithin 3 days of 
appearance of 
symptoms) 
Yes, if 
consent 
obtained 
HCP or 
HCP’s 
Personal 
Physician 
HCP’s 
Personal 
Physician 
and Amgen 
Close 
Contact (eg 
caregiver, 
spouse, 
child) w ith 
suspected 
herpetic 
lesions 
Sponsor/ 
Investigator, 
Close Contact’s 
Personal 
Physician or 
Close Contact 
Within 24 
hours of 
Reporter 
aw areness 
Contact Amgen 
at 1-855- 
IMLYGIC (1- 
855-465-9442) 
to report event 
Collect sw abs 
fromsuspected 
lesions (ideally 
w ithin 3 days of 
appearance of 
symptoms) 
Yes, if 
consent 
obtained 
Sponsor/ 
Investigator, 
Close 
Contact’s 
Personal 
Physician 
Sponsor/ 
Investigator 
, Close 
Contact’s 
Personal 
Physician 
and Amgen 
*The lab conducting the qPCR testing on behalf of Amgen is Viracor. 
 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 34 of 36 
 
 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
19.0 
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IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
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Memorial Sloan Kettering Cancer Center 
IRB Number: 16-224 A(11) 
Approval date: 10-Sep-2019 
Page 36 of 36 
 
 
 
 
20.0 
APPENDICES 
Appendix A. Radiographic assessment details and the mWHO response criteria 
Appendix B. Skindex-16 
Appendix C. NCI PRO-CTCAE v1.0