Conditions: Metastatic Non-small Cell Lung Cancer Metastatic Triple-negative Breast Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 57
Healthy volunteers: no

Brief summary:
This is a Phase II trial to determine the efficacy and safety of stereotactic body radiation therapy (SBRT) and in situ oncolytic virus therapy used as a window of opportunity treatment before pembrolizumab in patients with metastatic triple negative breast cancer (TNBC) and metastatic non-small cell lung cancer (NSCLC). In situ oncolytic virus therapy will consist of adenovirus-mediated expression of herpes simplex virus thymidine kinase (ADV/HSV-tk) plus valacyclovir therapy.

Detailed description:
This is a Phase II trial to determine the efficacy and safety of stereotactic body radiation therapy (SBRT) and in situ oncolytic virus therapy used as a window of opportunity treatment before pembrolizumab in patients with metastatic triple negative breast cancer (TNBC) and metastatic non-small cell lung cancer (NSCLC). In situ oncolytic virus therapy will consist of adenovirus-mediated expression of herpes simplex virus thymidine kinase (ADV/HSV-tk) plus valacyclovir. Male and female patients aged ≥ 18 years with histologically confirmed locally advanced or metastatic TNBC that has relapsed on or is refractory to 1 or more lines of standard of care therapy or histologically or cytologically confirmed metastatic NSCLC that is immunotherapy and chemotherapy naïve or previously treated with 1 cycle of platinum-containing chemotherapy are eligible to participate in the study. ADV/HSV-tk (5 x 1011 viral particles) in a 2-mL total volume will be injected intratumorally on Day 0 of the study. Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days. Valacyclovir treatment will be administered 24 hours after the gene vector injection from Day 1 to Day 15 of the study. SBRT of 30 gray (Gy; 6 Gy X 5 fractions) will be administered over 2 weeks from Day 2 to Day 16 of the study. Pembrolizumab (200 mg) will be administered intravenously over 30 minutes every 3 weeks starting on Day 17 of the study and continuing until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. The primary endpoint will be the objective response rate of ADV/HSV-tk + valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before pembrolizumab in patients with metastatic TNBC and metastatic NSCLC. RECIST 1.1 will be used to assess treatment response. Secondary endpoints will include a) clinical benefit rate; b) duration of response; c) overall survival and progression-free survival rates; d) toxicity (toxicity will be defined as any treatment-related death or any ≥ grade 3 toxicity excluding alopecia and constitutional symptoms as assessed by the NCI CTCAE v4.03); and e) antitumor activity of ADV/HSV-tk plus valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before pembrolizumab.

Arms:
arm 1: ADV/HSV-tk (5 x 1011 virus particles) in a 2-mL total volume will be injected intratumorally on Day 0.

Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days from Day 1 to Day 15.

SBRT of 30 Gy (6 Gy X 5 fractions) will be administered over 2 weeks from Day 2 to Day 16.

Pembrolizumab (200 mg) will be administered intravenously over 30 minutes every 3 weeks starting on Day 17 and continuing until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Interventions: intervention 1: ADV/HSV-tk intervention 2: Valacyclovir intervention 3: SBRT intervention 4: Pembrolizumab
Intervention descriptions: intervention 1: Replication-defective recombinant adenovirus vector intervention 2: Prodrug of the antiviral drug acyclovir intervention 3: Low-dose SBRT intervention 4: Humanized immunoglobulin G4 anti-programmed death-1 (PD-1) monoclonal antibody

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
SPONSOR: Houston Methodist Cancer Center & Houston Methodist Research Institute 
 
TITLE: Phase II Window of Opportunity Trial of Stereotactic Body Radiation Therapy and In 
Situ Oncolytic Virus Therapy in Metastatic Triple Negative Breast Cancer and Metastatic Non-
Small Cell Lung Cancer Followed by Pembrolizumab (STOMP) 
 
SHORT TITLE: SBRT and Oncolytic Virus Therapy Before Pembrolizumab for Metastatic 
TNBC and NSCLC (STOMP) 
 
 
 
PRINCIPAL INVESTIGATOR: 
 
Jenny Chang, M.D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
IND NUMBER: 
 
 
 
17200 
 
IRB NUMBER: 
 
 
 
Pro00015649 
 
ClinicalTrials.gov Identifier:  
 
NCT03004183 
 
 
VERSION NUMBER: 
 
 
16 
 
DATE:  
 
 
 
 
9-25-2020 
 
 
 


PI: Chang/IND17200/5.2019 (v15.0) 
 
 
1
 
 
 
SPONSOR: Houston Methodist Cancer Center & Houston Methodist Research Institute 
 
TITLE: Phase II Window of Opportunity Trial of Stereotactic Body Radiation Therapy and 
In Situ Oncolytic Virus Therapy in Metastatic Triple Negative Breast Cancer and Metastatic 
Non-Small Cell Lung Cancer Followed by Pembrolizumab (STOMP) 
 
PRINCIPAL INVESTIGATOR: 
 
Jenny Chang, M.D. 
 
SUB-INVESTIGATORS: 
 
 
Eric Bernicker, M.D. 
Brian Butler, M.D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
IND NUMBER: 
 
 
 
17200 
 
IRB NUMBER: 
 
 
 
Pro00015649 
 
 
VERSION NUMBER: 
 
 
16 
 
DATE:  
 
 
 
 
9-25-2020 
 


PI: Chang/IND17200/5.2019 (v15.0) 
 
 
2
1.0 TRIAL SUMMARY 
Abbreviated Title 
Stereotactic Body Radiation Therapy and In Situ Oncolytic Virus Therapy 
in Metastatic Triple Negative Breast Cancer and Metastatic Non-Small Cell 
Lung Cancer Followed by Pembrolizumab 
Trial Phase 
II 
Clinical Indication 
Metastatic triple negative breast cancer (TNBC) and metastatic non-small 
cell lung cancer (NSCLC)  
Trial Type 
Window of opportunity 
Type of control 
None 
Route of administration 
Pembrolizumab, intravenous infusion; oncolytic virus therapy (adenovirus-
mediated expression of herpes simplex virus thymidine kinase [ADV/HSV-
tk], intratumoral injection; valacyclovir, oral 
Trial Blinding 
None 
Treatment Groups  
1 
Number of trial subjects 
57 (TNBC, 28; NSCLC, 29) 
Estimated enrollment period 
18–24 months 
Estimated duration of trial 
36 months 
Duration of Participation 
Continuing until disease progression, unacceptable toxicity, or up to 24 
months in subjects without disease progression  
Estimated average length of 
treatment per patient 
Continuing until disease progression, unacceptable toxicity, or up to 24 
months in subjects without disease progression 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a Phase II window of opportunity study evaluating the efficacy and toxicity of 
stereotactic body radiation (SBRT) and in situ oncolytic virus therapy (adenovirus-mediated 
expression of herpes simplex virus thymidine kinase [ADV/HSV-tk]) followed by 
pembrolizumab in patients with metastatic triple negative breast cancer (TNBC) and metastatic 
non-small cell lung cancer (NSCLC). 
 
 
 
 
 
 
 


PI: Chang/IND17200/5.2019 (v15.0) 
 
 
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2.2 
Trial Diagram 
vp = viral particle; t.i.d. = three times daily; IV = intravenously; Q3W = every 3 weeks. 
 
3.0 OBJECTIVES  
3.1 
Primary Objective  
Objective: To determine the objective response rate (ORR) of ADV/HSV-tk plus (+) 
valacyclovir therapy in combination with SBRT used as a window of opportunity treatment 
before pembrolizumab in patients with metastatic TNBC and metastatic NSCLC. Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be used to assess treatment response. 
Modified immune-related response criteria (irRC; derived from RECIST 1.1) will also be 
documented. 
 
3.2 
Secondary Objectives  
Objectives:   
(1)  
To determine the duration of response (DoR) of ADV/HSV-tk + valacyclovir therapy 
in combination with SBRT used as a window of opportunity treatment before pembrolizumab 
in patients with metastatic TNBC and metastatic NSCLC.  


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4
 
(2)  
To determine the overall survival (OS) rate of ADV/HSV-tk + valacyclovir therapy in 
combination with SBRT used as a window of opportunity treatment before pembrolizumab in 
patients with metastatic TNBC and metastatic NSCLC.  
 
(3)  
To determine the progression-free survival (PFS) rate of ADV/HSV-tk + valacyclovir 
therapy in combination with SBRT used as a window of opportunity treatment before 
pembrolizumab in patients with metastatic TNBC and metastatic NSCLC.  
 
(4)  
To document the toxicities associated with ADV/HSV-tk + valacyclovir therapy in 
combination with SBRT used as a window of opportunity treatment before pembrolizumab in 
patients with metastatic TNBC and metastatic NSCLC. Toxicity will be defined as any 
treatment-related death or any ≥ Grade 3 hematological toxicity excluding alopecia and 
constitutional symptoms, as assessed by the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) v4.03. 
 
(5)  
To document the antitumor activity of ADV/HSV-tk + valacyclovir therapy in 
combination with SBRT used as a window of opportunity treatment before pembrolizumab in 
patients with metastatic TNBC and metastatic NSCLC, as assessed by the RECIST 1.1.  
Modified irRC will also be documented. 
 
(6) 
To estimate the clinical benefit rate (CBR) of ADV/HSV-tk + valacyclovir therapy in 
combination with SBRT used as a window of opportunity treatment before pembrolizumab in 
patients with metastatic TNBC and metastatic NSCLC. 
 
 
3.3 
Exploratory Objectives 
Objectives:  
(1) 
To determine the abscopal effect of ADV/HSV-tk + valacyclovir therapy in 
combination with SBRT followed by pembrolizumab. The primary criterion for abscopal effect 
evaluation will be computed tomography (CT)-based response assessment (RECIST 1.1) of a 
non-target lesion. The secondary criterion will be immune parameters including programmed 
death-1 (PD-1) and programmed death-ligand 1 (PD-L1) expression, immune infiltrates, and 
cytokine expression (interleukin [IL]-1, IL-2, IL-6, IL-12, interferon [IFN]-c, tumor necrosis 
factor-α [TNF-α], and granulocyte macrophage colony-stimulating factor [GM-CSF]). 
 
(2) 
To measure the immune response to ADV/HSV-tk + valacyclovir therapy in 
combination with SBRT followed by pembrolizumab in patients with metastatic TNBC and 
metastatic NSCLC.  
 
(3) 
To explore correlative tissue and blood-based biomarkers including but not limited to 
T-cell cytokine profiles (IL-1, IL-2, IL-6, IL-12, [IFN-c, TNF-α, and GM-CSF), tumor-
infiltrating lymphocytes (TILs), PD-1 and PD-L1 expression, effector and suppressor 
immunocyte populations, and mutation load. 


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4.0 
BACKGROUND & RATIONALE 
4.1 
Background 
Despite the significant advances in our understanding of breast cancer biology, limited 
progress has been made in the treatment of advanced breast cancer. There has been little change 
in the OS of women with treatment-resistant metastatic breast cancer over the last several 
decades.1 Notably, approximately 40,000 women with metastatic breast cancer die each year 
primarily due to treatment resistance and failure. TNBC is a mutationally complex breast 
cancer subtype with poor prognosis and no current targeted therapy options. Compared with 
other intrinsic breast cancer subtypes, TNBC has higher expression levels of PD-L1 and its 
receptor PD-1, which may hinder antitumor T cell responses. Immunotherapy has 
demonstrated promising efficacy in pretreated metastatic TNBC and appears to be one of future 
treatment choices for resistant cancers.2  
 
Lung cancer is the leading cause of cancer death in the United States. Lung cancer is expected 
to account for an estimated 224,390 new cases (117,920 in men and 106,470 in women) and 
158,080 deaths (85,920 in men and 72,160 in women) in 2016.1 Only 16.8% of lung cancer 
patients are alive for 5 years or more after their diagnosis. NSCLC accounts for over 85% of 
all lung cancer cases. Most patients are diagnosed with advanced or metastatic (stage IIIB/IV) 
disease,3 and current first-line treatment options for these patients are limited. In patients with 
advanced NSCLC, first-line platinum-based doublet chemotherapy yields 1-year OS rates of 
only 30–40% and can cause significant toxicities that may complicate treatment.3 However, 
much progress has recently been made in the diagnosis and treatment of lung cancer including 
screening methods, minimally invasive techniques for diagnosis and treatment, and advances 
in radiation therapy (RT) including SBRT, targeted therapies, and immunotherapies.4-8  
 
Cancer immunotherapy harnesses and boosts the innate powers of the immune system to fight 
cancer and represents the most promising new cancer treatment approach since the 
development of chemotherapeutic agents in the late 1940s. Because of the extraordinary 
memory and specificity of the immune system, immunotherapy has the potential to achieve 
complete, long-lasting remissions with few or no side effects in cancer patients, regardless of 
their cancer type. Immunotherapies targeting PD-1 have shown unprecedented rates of durable 
clinical responses in patients with various cancer types.9-13 Upregulation of PD-L1 and its 
ligation to PD-1 on antigen-specific CD8+ T-cells (termed adaptive immune resistance) 
represents a major mechanism by which cancer tissues limit the host immune response.14, 15 
Under healthy conditions, PD-1, expressed on the cell surface of activated T-cells, functions 
to downmodulate unwanted or excessive immune responses, including autoimmune reactions. 
PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily member related to 
CD28 and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) that has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2). The structure of murine PD-1 has been resolved.  PD-1 and its family members are 
type I transmembrane glycoproteins containing an Ig variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains two tyrosine-based signaling motifs, an 


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6
immunoreceptor tyrosine-based inhibition motif and immunoreceptor tyrosine-based switch 
motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases Src 
homology phosphatase (SHP)-1 and SHP-2 to the ITSM motif within its cytoplasmic tail. This 
leads to the dephosphorylation of effector molecules such as CD3ζ, protein kinase-θ, and 
ZAP70, which are involved in the CD3 T-cell signaling cascade. The mechanism by which 
PD-1 downmodulates T-cell responses is similar to but distinct from that of CTLA-4, as both 
molecules regulate an overlapping set of signaling proteins. PD-1 was shown to be expressed 
on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, regulatory T 
cells (Tregs), and natural killer (NK) cells. PD-1 expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells (DCs). The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed 
or can be induced in a variety of cell types, including non-hematopoietic tissues and various 
tumors. Both ligands are type I transmembrane receptors containing both IgV- and Ig constant-
like domains in the extracellular region and contain short cytoplasmic regions with no known 
signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered 
through the T-cell receptor. PD-L1 is expressed at low levels on various non-hematopoietic 
tissues, most notably on vascular endothelium, whereas PD-L2 protein is only detectably 
expressed on antigen-presenting cells found in lymphoid tissue and chronic inflammatory 
environments. PD-L2 is thought to control immune T-cell activation in lymphoid organs, 
whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues. Although 
healthy organs express little (if any) PD-L1, a variety of cancers have been demonstrated to 
express abundant levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor-
specific T-cell expansion in subjects with melanoma. This suggests that the PD-1/PD-L1 
pathway plays a critical role in tumor immune evasion and should be considered an attractive 
target for therapeutic intervention. 
 
Clinical trials have demonstrated the therapeutic potential of PD-1 blockade therapy. Brahmer 
et al. demonstrated that, among patients with previously treated advanced squamous NSCLC, 
OS, response, and PFS rates were significantly better with the PD-1 inhibitor nivolumab than 
with docetaxel regardless of PD-L1 expression level. The confirmed ORR was significantly 
higher with nivolumab than with docetaxel (20% [95% confidence interval (CI): 14–28] vs. 
9% [95% CI: 5–15]; P = 0.008).16 Herbst et al. found that treatment with MPDL3280A, a PD-
L1-specific monoclonal antibody (mAb), induces therapeutic responses in patients with 
advanced NSCLC, renal cell cancer, and melanoma.17 Powles et al. showed that the same 
antibody can be used to treat urothelial bladder cancer. Among patients with a minimum of 6 
weeks of follow-up, ORRs were 43% (13/30; 95% CI: 26–63) for those with tumor PD-L1 
immunohistochemical (IHC) expression scores of 2 or 3 (2/3) and 11% (4/35; 95% CI: 4–26) 
for those with tumor PD-L1 IHC expression scores of 0 or 1 (0/1). In the tumor PD-L1 IHC 
expression 2/3 score group, the ORR included a 7% complete response (CR) rate (2/30). 
Among patients with a tumor PD-L1 IHC expression score of 2/3 and a minimum of 12 weeks 
of follow-up, an ORR of 52% (13/25; 95% CI: 32–70) was achieved. Sixteen of the 17 
responders had ongoing responses, and all 17 responders continued on MPDL3280A treatment 
until the data cutoff. One patient who initially responded at the first response assessment later 
presented with new lesions, including a bladder mass thought to be consistent with pseudo-
progression.18 Anti-PD-L1 immunotherapy has also shown promising results in TNBC.2 The 


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7
latest data analysis of a Phase I clinical trial of MPDL3280A in TNBC revealed a 24-week 
PFS rate of 27% and ORR rate of 19%, with three of four responses ongoing. This data is 
encouraging, because longer responses do not typically occur in metastatic TNBC patients 
treated with chemotherapy, the standard of care for this population.2 Together, these studies 
demonstrate the durable responses and low toxicity rates of anti-PD-1 immunotherapy. This is 
particularly important as high-grade adverse effects have limited the use of immunotherapy for 
cancer treatment in the past. PD-L1/PD-1 expression in cancer cells is an obvious candidate 
biomarker for immunotherapy response, as PD-L1/PD-1 can directly turn off the immune 
response by inhibiting the activity of tumor-infiltrating cytotoxic T-lymphocytes (CTLs). 
However, PD-L1 and PD-1 expression in tumor cells has been shown to have little predictive 
power. On the other hand, Herbst et al. reported that PD-L1 expression in immune cells is a 
good biomarker of response to immunotherapy.17 The finding that the complexity of the T-cell 
population in the tumor infiltrate can predict good response to checkpoint blockade therapy 
highlights the importance of identifying tumor antigens that can elicit an effective antitumor 
immune response. Previous studies have suggested that tumors with a high load of somatic 
mutations are more likely to respond to immunotherapy, as in theory these tumors would have 
a higher diversity of neoantigens that can trigger an immune response when CTLA-4/PD-1 
inhibition is bypassed. 
 
Pembrolizumab (MK-3475) is a potent and highly selective humanized mAb of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2. Antibody-mediated PD-1 blockade with pembrolizumab and other similar 
agents reinvigorates the immune system, allowing for cancer cell targeting and destruction. 
Pembrolizumab is one of a number of closely related therapies dubbed immune checkpoint 
blockade.19 On September 4, 2014, KeytrudaTM (pembrolizumab) was approved by the United 
States Food and Drug Administration (FDA) for the treatment of patients with unresectable or 
metastatic melanoma and disease progression following ipilumumab and, if BRAF V600 
mutation positive, a BRAF inhibitor. On October 2, 2015, KeytrudaTM (pembrolizumab) 
received accelerated FDA approval for the treatment of patients with metastatic PD-L1-
positive NSCLC whose disease has progressed on or after platinum-containing chemotherapy 
or targeted therapy against anaplastic lymphoma kinase (ALK) or epidermal growth factor 
receptor (EGFR), if appropriate. KeytrudaTM is approved for use with a companion diagnostic, 
the PD-L1 IHC 22C3 pharmDx test, the first test designed to detect PD-L1 expression in 
NSCLC tumors. FDA approval for both disease indications was based on the results from the 
open label, first-in-human Phase Ib KEYNOTE-001 study (NCT01295827) of pembrolizumab 
in patients with progressive locally advanced or metastatic carcinomas. The melanoma cohort 
included patients with advanced disease previously treated with ipilimumab or ipilimumab in 
combination with a BRAF inhibitor (for BRAF mutation carriers).20 After mandatory biopsy, 
patients were treated with one of three doses of pembrolizumab for 12 weeks; responders 
continued on treatment until disease progression. Among 173 patients treated with the 
recommended 2-mg/kg pembrolizumab dose, the overall response rate was 24%, with a DoR 
of 1.4 to 8.5 months. The NSCLC cohort included 550 patients with metastatic disease.21 The 
ORR in the efficacy population, which comprised 61 patients with PD-L1 strongly positive 
tumors, was 41% (95% CI: 28.6–54.3); all were partial responses (PRs). At the time of the 
analysis, responses were ongoing in 21 of 25 (85%) patients, with 11 (44%) patients having a 


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8
DoR of ≥ 6 months. The most commonly occurring (≥ 20%) adverse events (AEs) included 
fatigue, decreased appetite, dyspnea, and cough. The most frequent (≥ 2%) serious AEs (SAEs) 
were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. Immune-
mediated AEs occurred in 13% of patients and included pneumonitis, colitis, hypophysitis, and 
thyroid disorders. Multiple ongoing clinical trials in all phases (NCT02551432, 
NCT02520154, 
NCT02530502, 
NCT02446457, 
NCT02306850, 
NCT02402920, 
NCT02298959, and NCT02560636) are evaluating pembrolizumab monotherapy and 
combination therapies for the treatment of all stages of liquid and solid malignancies, including 
TNBC. The KEYNOTE-086 study (NCT02447003) is a Phase II trial of pembrolizumab 
monotherapy in metastatic TNBC patients. The KEYNOTE-119 study (NCT02555657) is an 
open label, randomized Phase III study of single-agent pembrolizumab versus single-agent 
chemotherapy per physician's choice for metastatic TNBC. The KEYNOTE-173 study 
(NCT02622074) is a Phase Ib study to evaluate the safety and clinical activity of 
pembrolizumab in combination with chemotherapy as neoadjuvant treatment for TNBC. 
Together, these studies will pave the way for expanding the indications for pembrolizumab. 
 
RT is proven to provide local tumor control. RT has traditionally been thought to mediate 
tumor regression through direct cytotoxic effects. However, it is now known that RT also alters 
the local tumor microenvironment to affect both local and systemic antitumor immune 
responses. There is growing evidence that the rational integration of RT with the expanding 
armamentarium of clinically approved immunotherapeutics can yield potent antitumor 
responses exceeding those of either therapy alone.22 The beneficial effects of RT in cancer 
patients extend beyond direct tumor cell cytotoxicity. Delivery of localized radiation to tumors 
often leads to systemic responses at distant sites, a phenomenon known as the abscopal effect, 
which has been attributed to the induction and enhancement of endogenous antitumor innate 
and adaptive immune responses. The mechanisms surrounding the abscopal effect are diverse 
and include trafficking of lymphocytes into the tumor microenvironment, enhanced tumor 
recognition and killing via upregulation of tumor antigens and antigen-presenting machinery, 
and induction of positive immunomodulatory pathways.23 Cytokines play an important role in 
the abscopal effect. In one case, a Japanese patient receiving RT for thoracic vertebral bone 
metastasis experienced spontaneous regression of an unrelated hepatocellular carcinoma. Pre- 
and post-analyses of serum cytokine levels revealed a marked elevation in TNF-α following 
RT, suggesting that abscopal-mediated regression may involve such cytokines as part of the 
host immune response.24 RT-induced IFN-β has been shown to enhance T-cell-dependent 
tumor regression by increasing the cross-priming capacity of tumor-infiltrating DCs in vivo. 
This effect can be mimicked by exogenous IFN-β delivery to tumor tissues.25 Immune cell 
mediation of the abscopal effect is supported by the observation that exogenous administration 
of chemokines following local RT enhances tumor cell killing at distal sites. This abscopal 
effect was tumor-type independent and involved the infiltration of CD8+ and CD4+ 
lymphocytes and NK1.1+ NK cells into the tumor sites of mice.26 The abscopal effect remains 
an active area of investigation in the immunotherapy field. CTLA-4, a negative regulator of 
cytotoxic CD8+ T-cells, has been targeted as a means to activate antitumor immune CTLs. 
CTLA-4 blockade has been shown to decrease the threshold of activation of endogenous 
tumor-reactive T-cells in mouse xenografts.27 Local RT and CTLA-4 blockade have recently 
been shown to significantly reduce the motility of TILs at tumor sites, thereby allowing TILs 


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9
to engage in stable interactions with tumor targets.28 The NK group 2, member D (NKG2D) 
ligand retinoic acid early inducible-1 is upregulated in irradiated neoplastic cells; interaction 
with its receptor, NKG2D, on CTLs costimulates and enhances tumor cell killing. T-cell 
receptor, NKG2D, and CTLA-4-transduced signals contribute to the stability of the 
immunological synapse. Their association appears to be mediated in part by increased antibody 
responses to the multiple tumor antigens released after RT.29 
 
Multiple factors contribute to the development of an abscopal effect. The abscopal effect 
involves the interplay of irradiation and induction of adaptive immune responses leading to 
tumor cell elimination at distant sites. Antitumor CTL responses, which represent the outcome 
of an abscopal effect primed by irradiated tumor cells, seem to play a significant role in RT-
induced antigen-specific immunity.30 Further evidence that antigen-specific T cells are elicited 
after RT is borne out by studies demonstrating a significant CD8+ T-cell-mediated reduction 
in systemic tumor burden after local ablative RT.31 T-cell priming following RT-mediated 
tumor cell death has been postulated to occur through DC cross presentation of released tumor 
antigens in draining lymph nodes, leading to primary or metastatic tumor rejection.  
 
Antigen presentation by DCs seems to be crucial to RT-induced CD8+ T cell-dependent 
antitumor immunity. Antigens can be endogenously or exogenously loaded onto major 
histocompatibility complex (MHC) class I molecules. RT seems to differentially affect these 
two antigen presentation pathways. Presentation of endogenous antigens is blocked in 
irradiated DCs, whereas presentation of exogenously pulsed peptide antigens is enhanced in 
irradiated DCs, leading to favorable antitumor T-cell responses.32 RT dose-dependently 
facilitates cell surface expression of MHC class I molecules by three different mechanisms: 
(1) induction of protein unfolding and degradation to increase the intracellular peptide pool; 
(2) enhancement of protein synthesis to increase the intracellular peptide pool; and (3) 
generation of radiation-specific peptide antigens to increase the diversity of the intracellular 
peptide pool. By increasing the quantity and/or diversity of the peptide pool, RT leads to an 
overall increase in the number and density of surface peptide/MHC class I complexes 
expressed on murine DCs.33 In some cases, RT upregulates cancer-testis antigens, a class of 
potentially immunogenic tumor rejection antigens, which can be targeted with adoptive T-cell 
therapy and other antigen-specific immune-based approaches.34 One significant hurdle faced 
by T-cell-based immunotherapies is downregulation of MHC genes, which may represent an 
important mechanism by which tumor cells, especially those breaching the interface between 
normal and malignant tissues, evade host immune surveillance. 
 
It is generally believed that Tregs are more radioresistant than conventional effector T-cells35 
and may be over-represented in RT-treated patients compared with RT-naïve patients.36 
Radiation has been shown to upregulate transforming growth factor-β and adenosine A2A in 
head and neck squamous cell carcinoma patients.37 This can provide both a growth and survival 
advantage to Tregs38, thereby suppressing the potential beneficial antitumor effects of RT. 
Strategies to eliminate or suppress the number and activity of Tregs such as adjusting RT dose 
and schedule would enhance RT-induced antitumor responses.  
 


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Abscopal effects have been mainly observed in patients with lymphoid malignancies wherein 
radiation or treatment of local disease led to regression in distant unirradiated sites.39-41 
However, notable cases have been observed in Merkel cell carcinoma,42 advanced uterine 
cervical carcinoma,43 and hepatocellular carcinoma. Irradiation of affected lymphoid sites may 
be more likely to incite systemic immunity because of the higher likelihood of immune 
effectors trafficking through these regions and encountering released antigen. However, 
irradiation of affected visceral sites including bone, skin, and parenchyma has also been shown 
to induce abscopal effects.43, 44 In cancer therapies, some notions of metastasis and recurrence 
may be explained using oligometastases and oligo-recurrence. Oligometastases is the state 
capable of achieving long-term survival or cure with local therapy despite active primary 
legions. On the other hand, oligo-recurrence is the notion that metastatic and recurrent lesions 
could be treated with local therapy since the primary lesions have been controlled.45-47 SBRT 
provides a treatment option for oligometastases by enabling the delivery of high-dose (HD) 
oligo-fractionated radiation to deep-seated tumors while minimizing damage to normal 
tissues.48 This HD ablative RT can also be employed in combination strategies such as adoptive 
cell and anti-CTLA-4 therapies. Administration of autologous DCs, produced ex vivo through 
autologous leukapheresis-derived monocytes, can also boost immune responses presumably 
by facilitating the presentation of tumor antigens released during RT.49 In clinical trials, the 
addition of SBRT to HD IL-2 has been shown to be highly effective in patients with metastatic 
melanoma and renal cell cancer and represents a clinically tenable strategy given that HD IL-
2 is approved for use in these malignancies. The presence of an elevated effector memory 
CD4+ T-cell population in the peripheral blood was associated with a clinical response in these 
patients.50 
 
Viral vectors have also been shown to induce antitumor immune responses. Completed and 
ongoing clinical trials have shown that ADV/HSV-tk followed by ganciclovir (GCV) therapy 
(ADV/HSV-tk + GCV) has a favorable toxicity profile and antitumor activity in prostate 
cancer. Furthermore, this system has been shown to direct systemic antitumor activity in 
several experimental cancer models, including prostate cancer, and thus may serve as the basis 
for in situ immunomodulatory gene therapy. In a mouse model of prostate cancer, NK cells 
were shown to mediate the antimetastatic activity of ADV/HSV-tk + GCV. To enhance its 
antitumor activity, ADV/HSV-tk + GCV has been combined with ADV/IL-12. IL-12 increases 
NK cell proliferation and cytotoxicity. ADV/HSV-tk + GCV + ADV/IL-12 combination 
therapy demonstrated superior local and systemic growth suppression compared with either 
therapy alone. Importantly, when the metastatic tumor burden was increased to an extent that 
negated the growth-suppressive activity directed by ADV/HSV-tk + GCV or ADV/IL-12 
alone, the combination therapy continued to demonstrate significant growth suppression. 
Examination of TILs showed enhanced NK lytic activity with the combination therapy.51 
Suicide gene therapy using HSV-tk + GCV therapy is being explored for the treatment of a 
wide variety of cancers. HSV-tk phosphorylates GCV, converting it to a non-diffusible 
nucleoside analog that terminates DNA synthesis, causing cell death.52 However, gene therapy 
approaches for metastatic cancer are divided between those that deliver genes hematogenously 
to disseminated lesions, requiring methods of tissue-restricted gene expression or specific 
tissue targeting by the delivery vector, and those that manifest systemic antitumor capabilities 
following local gene expression, such as gene-modified immunotherapy.53 With regard to the 


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HSV-tk system, the generation of immunologic activity has been suggested by numerous 
investigators to be an important aspect of therapy that may be exploited in the treatment of 
disseminated tumor lesions. 
 
Several avenues of study have demonstrated the immunologic activity of HSV-tk therapy. 
HSV-tk + GCV-treated tumors contain areas of necrosis highlighted by infiltration of 
macrophages and CD4+ and CD8+ T-cells.54-57 Furthermore, within treated tumors are 
detectable levels of the cytokines IL-1, IL-2, IL-6, IL-12, IFN-c, TNF-α, and GM-CSF in a 
fashion consistent with a Th1 (cellular based) response profile.57,  Functional antitumor roles 
for these immune effectors have been suggested to impact within a treated tumor in the form 
of a local bystander effect and on synchronously growing non-transduced tumors or challenge 
tumor cell injections in the form of a distant bystander effect.54, 58-61 Further supportive 
evidence has noted a significant loss of growth suppression in immunocompromised hosts.55, 
58, 59 HSV-tk + GCV may induce immune-related activities through necrosis-mediated 
exposure of putative tumor antigens to the cytokine-stimulated lymphocytic infiltrate. 
However, for the most part, direct demonstration of effector cell induction and its relevance to 
in vivo responses is lacking. In an orthotopic model of mouse prostate cancer, injection of 
ADV/HSV-tk + GCV therapy was found not only to inhibit local tumor growth but also to 
suppress spontaneous metastatic activity.60 Furthermore, following surgical removal of a 
treated subcutaneous tumor, systemic activity against a tumor cell challenge injection of 
parental cells via the tail vein was induced by ADV/HSV-tk + GCV treatment of the primary 
tumor. Direct evidence of HSV-tk + GCV-mediated induction of antitumor lymphocytes was 
provided by a serial assay demonstrating the lytic activity of TILs isolated from HSV-tk + 
GCV-treated orthotopic tumors against parental tumor cells in vitro.61 These studies 
demonstrated the induction of NK cells by ADV/HSV-tk + GCV treatment. Gene therapy 
performed in the absence of NK cells, but not T-cells, resulted in a modest but significant loss 
of HSV-tk + GCV-directed growth suppression within the primary tumor and complete 
abrogation of systemic activities.61 Therefore, HSV-tk + GCV therapy appears to induce NK 
cells to impact local and remote tumor growth. Enhancement of NK cell activity may improve 
therapeutic response to ADV/HSV-tk + GCV. 
Viral vectors have been increasingly studied as potential antitumor therapeutic agents. With 
their ability to invade and replicate within target cells, viruses have been utilized as oncolytic 
agents to directly lyse tumor cells. Viruses can also deliver their genetic payload into infected 
cells, allowing for the repair of defective tumor suppressor genes, disruption of oncogenic 
pathways, and production of cytokines that activate the immune system. Furthermore, viruses 
encoding tumor-associated antigens can infect DCs to trigger tumor-specific immune 
responses. The ability to engineer viruses with high levels of tumor specificity and efficient 
rates of infection has enhanced the safety profile of these agents, making viral vector-mediated 
gene therapy, either alone or in conjunction with more conventional therapies, a viable option 
for cancer therapy.62 
4.1.1 Preclinical and Clinical Trial Data 
4.1.1.1 Pembrolizumab Preclinical Pharmacology63 
 


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Pembrolizumab binds to human and Cynomolgus monkey PD-1 with comparable affinity and 
blocks the binding of human and Cynomolgus monkey PD-1 to PD-L1 and PD-L2 with 
comparable potency. Pembrolizumab does not cross-react with dog, rat, or mouse PD-1. 
Pembrolizumab does not bind Ig superfamily members CD28, CTLA-4, or inducible T-cell 
costimulator. 
 
Pembrolizumab strongly enhances T-lymphocyte immune responses in cultured blood cells 
from healthy human donors, cancer subjects, and non-human primates. In T-cell activation 
assays using human donor blood cells, the half-maximal effective concentration has been 
approximately 0.1 to 0.3 nM. Pembrolizumab was found to modulate the levels of IL-2, TNF-
α, IFN-γ, and other cytokines. Pembrolizumab potentiates existing immune responses only in 
the presence of antigen and does not non-specifically activate T-cells. In in vitro peripheral 
blood mononuclear cell and whole blood cytokine release assays, the cytokine levels induced 
by pembrolizumab were low and comparable to those induced by trastuzumab. Pembrolizumab 
does not induce antibody-dependent cell-mediated cytotoxicity or complement-dependent 
cytotoxicity. 
 
4.1.1.2 Pembrolizumab Preclinical Pharmacokinetics63 
The pharmacokinetics (PK) of pembrolizumab were evaluated in a non-Good Laboratory 
Practices (GLP) single-dose PK study and two GLP repeat-dose toxicokinetic studies (1 month 
and 6 month) in Cynomolgus monkeys.  
 
After single-dose intravenous (IV) administration at 0.3, 3, or 30 mg/kg in Cynomolgus 
monkeys, decline of serum concentration followed multiphasic kinetics. Anti–drug antibodies 
(ADAs) were detected in most of the treated animals. Clearance (CL) and terminal half-life 
(t1/2) appeared to be dose-dependent in the dose range tested, with t1/2 varying from 4 to 10 
days. 
 
In the 1-month repeat-dose (once weekly) GLP toxicity study at 6, 40, or 200 mg/kg in 
Cynomolgus monkeys, ADAs were detected in most of the low-dose (6 mg/kg) treated animals. 
The systemic exposure (area under the curve [AUC]) over the 7-day dosing interval was sex 
independent and increased with increasing dose. The mean t1/2 values in individual ADA-
negative animals ranged from 15.7 to 22.3 days across doses. 
 
In the 6-month repeat-dose (every other week) GLP toxicity study at 6, 40, or 200 mg/kg in 
Cynomolgus monkeys, ADAs were detected in most of the low-dose (6 mg/kg) treated animals. 
The systemic exposure to pembrolizumab was independent of sex and was approximately dose 
proportional across all doses. The mean t1/2 values in individual ADA-negative animals 
ranged from 21 to 22 days across doses. 
 
4.1.1.3 Pembrolizumab Preclinical Safety Pharmacology/Toxicology63 
The potential for systemic toxicity of pembrolizumab was assessed in a 1-month repeat-dose 
toxicity study with a 4-month recovery and a 6-month repeat-dose toxicity study with a 4-
month recovery period in Cynomolgus monkeys. In the 1-month toxicity study, Cynomolgus 
monkeys were administered an IV dose of 6, 40, or 200 mg/kg once weekly for a total of 5 


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13
doses. Four monkeys/sex/group were euthanized during Week 5. The remaining 2 
monkeys/sex/group were euthanized during Week 23, after a 4-month post-dose period. In this 
study, pembrolizumab was well tolerated in monkeys, with the systemic exposure (AUC) up 
to approximately 170,000 µg·day/mL over the course of the study. There was no test article–
related mortality, and test article–related changes were limited to an increased incidence of 
inguinal swelling and increased splenic weights in males receiving 200 mg/kg. Both of these 
findings were not considered adverse and there was no histopathologic correlation. Splenic 
weights were normal at the post-dose necropsy. Anti-pembrolizumab antibodies were detected 
in 7 out of 8 animals in the 6 mg/kg dose group and 1 out of 8 animals in the 40 mg/kg dose 
group and were associated with an apparent increase in pembrolizumab CL. The presence of 
ADA in monkeys in the low-dose group and in 1 monkey in the mid-dose group did not impact 
the pharmacodynamic response, as sufficient target engagement was demonstrated for the 
duration of the study (with the exception of 1 low-dose monkey). Additionally, anti-
pembrolizumab antibodies were not detected in any monkeys in the high-dose group, 
suggesting that potential toxicity has been evaluated at the highest exposure levels in the study. 
Based on the lack of adverse test article-related findings in this study, the no observed adverse 
effect level (NOAEL) was ≥ 200 mg/kg. 
 
In the 6-month toxicity study, the potential for systemic toxicity was assessed in Cynomolgus 
monkeys administered an IV dose of 6, 40, or 200 mg/kg once every other week for 
approximately 6 months (a total of 12 doses) followed by a 4-month treatment-free period. 
Three animals/sex/group were designated for interim necropsy at the end of the 6-month dosing 
phase (3 days after receiving the last dose in Week 23); the remaining monkeys were 
designated for final necropsy following the 4-month treatment-free period. Pembrolizumab 
was well tolerated at all dose levels. There were no test article-related antemortem findings, 
electrocardiographic or ophthalmic findings, changes at injection sites, gross observations, or 
organ weight changes at the interim or final necropsy. As there were no test article-related 
histomorphologic findings at interim necropsy, histomorphologic evaluation of tissues 
collected at final necropsy was not conducted. The presence of ADA was observed in 5 out of 
10 animals in the 6 mg/kg/dose group during the dosing phase, which correlated with an 
apparent increased rate of pembrolizumab elimination in these animals. No anti–
pembrolizumab antibodies were detected in the 40 or 200 mg/kg/dose groups during the dosing 
phase, and no pembrolizumab serum concentration profiles in these 2 groups suggested an 
effect of ADA on pembrolizumab elimination rate. During the treatment-free period, anti–
pembrolizumab antibodies were detected in 2 animals in the 6 mg/kg/dose group, which 
already had ADA present during the dosing phase, and in 2 additional animals (1 in the 6 
mg/kg/dose group and 1 in the 200 mg/kg/dose group), which were ADA-negative during the 
dosing phase. The detection of anti-pembrolizumab antibodies had a minimal effect on the 
mean group systemic exposure to pembrolizumab during the study and did not impact the 
evaluation of potential toxicity of pembrolizumab for the duration of the 6-month study, 
because there were no test article-related effects on any of the parameters examined and no 
monkey in the mid- and high-dose groups developed ADA during the dosing phase. In 
conclusion, pembrolizumab administered once every other week over a 6-month duration to 
Cynomolgus monkeys was well tolerated and the NOAEL was ≥ 200 mg/kg/dose (the highest 
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4.1.1.4 Pembrolizumab Clinical Trial Data63 
 
4.1.1.4.1 Ongoing Studies 
KEYNOTE-001 (NCT01295827) is an open label, first-in-human Phase I study of 
pembrolizumab in subjects with progressive locally advanced or metastatic carcinomas, 
especially melanoma or NSCLC. This study is active, but not recruiting patients. Part A of the 
study involved dose escalation that used a traditional 3+3 design. Cohorts of 3 to 6 subjects 
were enrolled sequentially at escalating doses of 1, 3, or 10 mg/kg administered every 2 weeks 
(Q2W). Once the dose escalation was completed, additional subjects were enrolled into Parts 
A1 and A2 to further characterize the PK and pharmacodynamics of pembrolizumab. In Parts 
B and D, subjects with metastatic melanoma were enrolled to assess the safety and antitumor 
activity of pembrolizumab. Additionally, Part B explored 3 different dose regimens in subjects 
with metastatic melanoma: 10 mg/kg Q2W, 10 mg/kg every 3 weeks (Q3W), and 2 mg/kg 
Q3W. In Part C, subjects with NSCLC (with prior systemic therapy) were enrolled at 10 mg/kg 
Q3W to assess the tolerability, safety, and antitumor activity of pembrolizumab. Part D 
explored the low and high doses of pembrolizumab identified in Parts A and B in subjects with 
advanced or metastatic melanoma. In Part F, non-previously treated (Cohort F-1) and 
previously treated (Cohort F-2) subjects with NSCLC whose tumors expressed PD-L1 were 
enrolled at 10 mg/kg Q2W and 10 mg/kg Q3W to characterize the tolerability, safety, and 
antitumor activity of pembrolizumab. A small cohort of previously treated (at least 2 lines of 
systemic therapy) subjects with NSCLC whose tumors did not express PD-L1 were enrolled 
and treated at a dose of 10 mg/kg Q2W (Cohort F-2). In Cohort F-3, previously treated subjects 
with NSCLC whose tumors expressed PD-L1 were enrolled at 2 mg/kg Q3W to better 
characterize the efficacy, safety, and antitumor activity of pembrolizumab. Each of the 2 
disease-specific cohorts (melanoma and NSCLC) were enrolled to confirm tolerability and 
evaluate tumor response to pembrolizumab. The overall response rate and disease control rate 
for 655 melanoma subjects who received pembrolizumab were 31% and 51%, respectively. 
The ORR was 19.4%, and the median DoR was 12.5 months for 495 NSCLC patients who 
received pembrolizumab at a dose of 2 mg/kg Q3W, 10 mg/kg Q3W, or 10 mg/kg Q2W.64 
Median PFS and OS were 3.7 months and 12 months, respectively.  
 
KEYNOTE-002 (NCT01704287) is a partially blinded, randomized Phase II study designed 
to evaluate 2 doses of pembrolizumab versus a chemotherapy control arm in subjects with 
ipilimumab-refractory metastatic melanoma.65 Subjects (n = 540) were randomized to receive 
pembrolizumab 2 mg/kg Q3W (n = 180), pembrolizumab 10 mg/kg Q3W (n = 181), or 
chemotherapy (according to current clinical practice; n = 179) for the treatment of melanoma. 
Subjects assigned to the control chemotherapy arm could cross over to the experimental 
pembrolizumab arm once progression was confirmed (approximately ≥ Week 12). Based on 
410 PFS events, PFS was improved in the pembrolizumab 2 mg/kg (hazard ratio [HR]: 0.57; 
95% CI: 0.45–0.73; P < 0.0001) and pembrolizumab 10 mg/kg groups (HR: 0.50; CI: 0.39–
0.64; P < 0.0001) compared with the chemotherapy group. The 6-month PFS rate was 34% 
(95% CI: 27–41) in the pembrolizumab 2 mg/kg group, 38% (95% CI: 31–45) in the 
pembrolizumab 10 mg/kg group, and 16% (95% CI: 10–22) in the chemotherapy group. Grade 
3–4 treatment-related AEs occurred in 20 (11%) patients in the pembrolizumab 2 mg/kg group, 


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25 (14%) patients in the pembrolizumab 10 mg/kg group, and 45 (26%) patients in the 
chemotherapy group. The most common Grade 3–4 treatment-related AE in the 
pembrolizumab groups was fatigue (2 [1%] of 178 patients in the 2 mg/kg group and 1 [<1%] 
of 179 patients in the pembrolizumab 10 mg/kg group compared with 8 [5%] of 171 patients 
in the chemotherapy group). Other Grade 3–4 treatment-related AEs included generalized 
edema and myalgia (each in 2 [1%] patients) in the pembrolizumab 2 mg/kg group; 
hypopituitarism, colitis, diarrhea, decreased appetite, hyponatremia, and pneumonitis (each in 
2 [1%] patients) in the pembrolizumab 10 mg/kg group; and anemia (9 [5%] patients), fatigue 
(8 [5%] patients), neutropenia (6 [4%] patients), and leucopenia (6 [4%] patients) in the 
chemotherapy group. 
 
KEYNOTE-011 (NCT01840579) is an open label, non-randomized, multicenter Phase I study 
of pembrolizumab monotherapy in Japanese subjects with advanced solid tumors and in 
combination with cisplatin/pemetrexed and carboplatin/paclitaxel in subjects with advanced 
NSCLC in Japan. This study is active, but not recruiting patients. In Part A (monotherapy, 3+3 
design), subjects with advanced solid tumors received escalating doses of pembrolizumab 
(dose level 1, 2 mg/kg Q2W; dose level 2, 10 mg/kg Q2W). Three patients received 
pembrolizumab at 2.0 mg/kg and 7 patients received pembrolizumab at 10 mg/kg. No dose-
limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-
related AEs (DRAEs; mostly Grade 1 or 2); the most common DRAEs were nausea, malaise, 
pyrexia, and aspartate aminotransferase (AST)/alanine transaminase (ALT) increased (n = 2 
each). No Grade 4 or 5 DRAEs occurred. Immune-related AEs comprised Grade 3 ALT 
increased (n = 1), Grade 3 AST increased (n = 1), Grade 1 pneumonitis (n = 1), and Grade 1 
thyroid-stimulating hormone increased (n = 1). A partial tumor response was observed in one 
patient with NSCLC and in one patient with melanoma.66 In Part B (combination, 3+6 design), 
subjects with advanced NSCLC receive pembrolizumab 10 mg/kg Q3W in combination with 
either cisplatin/pemetrexed (Cohort 1) or carboplatin/paclitaxel (Cohort 2).  
 
KEYNOTE-012 (NCT01848834) is a multicenter, non-randomized, multicohort Phase Ib trial 
of pembrolizumab in subjects with PD-L1-positive advanced solid tumors. This study is active, 
but not recruiting patients. All subjects received pembrolizumab 10 mg/kg Q2W. Cohort A 
enrolled subjects with TNBC; Cohorts B and B2 enrolled subjects with squamous cell 
carcinoma of the head and neck; Cohort C enrolled subjects with urothelial tract cancer of the 
renal pelvis, ureter, bladder, or urethra; and Cohort D enrolled subjects with adenocarcinoma 
of the stomach or gastroesophageal junction.  
 
KEYNOTE-013 (NCT01953692) is an open label, multicenter Phase Ib trial of pembrolizumab 
in subjects with hematologic malignancies. This study is recruiting patients. All subjects 
receive pembrolizumab at 10 mg/kg Q2W. Cohort 1 is enrolling subjects with intermediate-1, 
intermediate-2, or high-risk myelodysplastic syndrome who have failed at least 4 cycles of 
hypomethylating agent treatment. Cohort 2 is enrolling subjects with relapsed/refractory 
multiple myeloma. Cohort 3 is enrolling subjects with relapsed/refractory Hodgkin lymphoma 
who are ineligible for or refused a stem cell transplant and whose disease has relapsed after 
treatment with or failed to respond to brentuximab vedotin. Cohort 4a is enrolling subjects with 
relapsed/refractory mediastinal large B cell lymphoma who are ineligible for or refused a stem 


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cell transplant, and Cohort 4b is enrolling subjects with any other positive PD-L1-positive 
relapsed/refractory non-Hodgkin lymphoma who are ineligible for or refused a stem cell 
transplant.  
 
KEYNOTE-021 (NCT02039674) is an open label, multicenter Phase I/II study of 
pembrolizumab at 2 dosing schedules in combination with chemotherapy or immunotherapy 
in subjects with locally advanced or metastatic NSCLC. This study is recruiting patients. The 
study is composed of 2 parts. The objective of Part 1 is to determine the recommended Phase 
II dose (RP2D) for pembrolizumab in combination with different chemotherapy and/or 
immunotherapy regimens: 
• Cohort A – 1:1 randomization to carboplatin and paclitaxel plus either pembrolizumab 
2 mg/kg or pembrolizumab 10 mg/kg 
• Cohort B – 1:1 randomization to carboplatin, paclitaxel, and bevacizumab plus either 
pembrolizumab 2 mg/kg or pembrolizumab 10 mg/kg 
• Cohort C – 1:1 randomization to carboplatin and pemetrexed plus either pembrolizumab 
2 mg/kg or pembrolizumab 10 mg/kg 
• Cohort D – ipilimumab plus pembrolizumab 
• Cohort E – erlotinib plus pembrolizumab 
• Cohort F – gefitinib plus pembrolizumab 
The objective of Part 2 is to evaluate the antitumor activity of pembrolizumab in combination 
with chemotherapy or immunotherapy. Part 2 includes a randomized comparison of 
chemotherapy ± pembrolizumab based on the doses defined in Part 1, as well as a cohort 
expanding the ipilimumab cohort from Part 1: 
• Cohort G – 1:1 randomization to carboplatin and pemetrexed with or without pembrolizumab 
200 mg 
• Cohort H – ipilimumab (RP2D from Part 1 Cohort D) plus pembrolizumab followed by 
pembrolizumab monotherapy 
 
KEYNOTE-023 (NCT02036502) is an open label, multicenter Phase I trial of pembrolizumab 
in combination with lenalidomide (Len) and dexamethasone (Dex) or pembrolizumab and Len 
in subjects with relapsed/refractory multiple myeloma who have failed at least 2 lines of prior 
therapy, including a proteasome inhibitor (e.g., bortezomib or carfilzomib) and an 
immunomodulary derivative (thalidomide, pomalidomide, lenalidomide). This study is 
recruiting patients. The trial uses a modified 3+3 design for dose determination, followed by 
dose confirmation and expansion, a further evaluation of safety, and a preliminary assessment 
of efficacy. During dose determination, cohorts of approximately 3 to 6 subjects are enrolled 
and receive pembrolizumab 2 mg/kg or 1 mg/kg IV Q2W in each 28-day cycle in combination 
with Dex 40 mg QW and/or Len 25 mg or 10 mg on Days 1 to 21. After a preliminary maximum 
tolerated dose (MTD)/maximum administered dose (MAD) is identified, additional subjects 
are enrolled at a fixed dose of pembrolizumab 200 mg or 100 mg in combination with Len/Dex 
to confirm the MTD/MAD.  
 
KEYNOTE-28 (NCT02054806) is an open label, non-randomized, multicenter, multicohort 
Phase Ib trial of pembrolizumab in subjects with PD-L1-positive advanced solid tumors. This 
study is active, but not recruiting patients. Subjects were enrolled into 1 of the following 20 


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solid tumor cohorts: A1, colon or rectal adenocarcinoma; A2, anal canal squamous cell 
carcinoma; A3, pancreas adenocarcinoma; A4, esophageal squamous cell carcinoma or 
adenocarcinoma (including gastroesophageal junction); A5, biliary tract adenocarcinoma 
(gallbladder and biliary tree but excluding ampulla of Vater cancers); A6, carcinoid tumors; 
A7, neuroendocrine carcinomas (well or moderately differentiated pancreatic neuroendocrine 
tumor); B1, estrogen receptor-positive human epidermal growth factor receptor 2-negative 
breast cancer; B2, ovarian epithelial, fallopian tube, or primary peritoneal carcinoma; B3 
endometrial carcinoma; B4, cervical squamous cell cancer; B5, vulvar squamous cell 
carcinoma; C1, small cell lung cancer; C2, mesothelioma (malignant pleural mesothelioma); 
D1, thyroid cancer (papillary or follicular subtype); D2, salivary gland carcinoma; D3, 
nasopharyngeal carcinoma; E1, glioblastoma multiforme; E2, leiomyosarcoma; and E3, 
prostate adenocarcinoma. All subjects received pembrolizumab 10 mg/kg Q2W.  
 
4.1.1.4.2 Summary of Pharmacokinetics Data63 
PK samples have been obtained in the ongoing studies KEYNOTE-001, KEYNOTE-002, 
KEYNOTE-012, KEYNOTE-013, and KEYNOTE-023 from subjects with solid tumors 
(KEYNOTE-001 Part A); subjects with advanced melanoma (KEYNOTE-001 Parts B and D, 
KEYNOTE-002); subjects with NSCLC (KEYNOTE-001 Parts C and F); subjects with 
advanced solid tumors which include breast cancer (TNBC) and head and neck cancer, 
urothelial tract cancer, and gastric cancer (KEYNOTE-012); and subjects with hematological 
cancers (KEYNOTE-013 and KEYNOTE-023). Pre-dose and post-dose samples have been 
obtained in various cycles: cycles 1, 2, 5, and 6 for KEYNOTE-001 melanoma; cycles 1 and 6 
for KEYNOTE-001 NSCLC; and cycles 1 and 2 for KEYNOTE-002, KEYNOTE-012, 
KEYNOTE-013, and KEYNOTE-023. Pre-dose samples only were drawn every 3 to 8 cycles 
thereafter. In KEYNOTE-001 Part A, extensive blood sampling was applied during cycles 1 
and 2 for detailed PK analysis. Pre-dose minimum serum concentration (Ctrough) and post-dose 
serum concentration (Cmax) levels were consistent and in good agreement across the different 
studies. There is no meaningful difference between the pre-dose or post-dose concentration 
values per time point for the different indications.  
 
The PK profile of pembrolizumab was investigated in Part A of the ongoing study KEYNOTE-
001. Results have been obtained following a single dose at 1, 3, and 10 mg/kg pembrolizumab 
to 17 subjects with solid tumors in cycle 1 (Part A and A-1). The observed PK profile of 
pembrolizumab was typical of those observed for other IgG mAbs, with a t1/2 of 
approximately 2 to 3 weeks. There was no indication of dose dependency of t1/2 in the 3 dose 
groups. A dose-related increase in exposure was observed from 1 to 10 mg/kg. The long t1/2 
supports a dosing interval of Q2W or Q3W. 
 
Consistent with the 5-fold higher dose, pre-dose or post-dose concentrations of the 10 mg/kg 
Q3W regimens are approximately 5 times higher than those of the 2 mg/kg Q3W regimen, 
confirming dose proportionality of pembrolizumab exposure in this dose range. The overall 
geometric mean 24-week pre-dose serum concentration values from subjects treated with 10 
mg/kg Q2W (N = 128 [N = 89 melanoma subjects and N = 39 subjects other cancer types]) 
across all studies and indications is 231 μg/mL (range, 191–296 μg/mL), which is on average 
30% higher than the week 24 pre-dose concentration (155 μg/mL) from subjects treated with 


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10 mg/kg Q3W (range, 154–156 μg/mL; N = 168 [N = 161 melanoma subjects and N = 7 
NSCLC subjects]). 
 
In summary, the PK profile of pembrolizumab, with low CL and limited volume of distribution, 
is typical for therapeutic antibodies. Exposure to pembrolizumab is approximately linear in the 
dose range of clinical relevance (1 to 10 mg/kg). 
 
4.1.1.4.3 Summary of Immunogenicity Data63 
Data for immunogenicity assessment are available from subjects with advanced melanoma 
(KEYNOTE-001, Parts B and D, and KEYNOTE-002) and from subjects with NSCLC 
(KEYNOTE-001, Parts C and F). For the subjects with advanced melanoma, the observed 
incidence of treatment-emergent ADAs in evaluable subjects was 0.4% (1 out of 268 subjects), 
based on 1 subject with a confirmed treatment-emergent positive status compared with all 
evaluable subjects including 3 with a non-treatment-emergent positive status and 264 with a 
negative immunogenicity status. A subset analysis of subjects treated with pembrolizumab 2 
mg/kg Q3W was performed. In this analysis, none of the 220 evaluable subjects treated with 2 
mg/kg Q3W tested positive for treatment-emergent anti-pembrolizumab antibodies. None of 
the subjects with NSCLC were classified as treatment-emergent or non-treatment-emergent 
positive. To this point, only 6 of the 290 assessable subjects were treated with 2 mg/kg. Due 
to the majority of subjects receiving the high dose, only 16 subjects had a drug concentration 
with the last sample below the drug tolerance level (DTL) and could be classified as 
conclusively negative. The other 274 subjects were classified as inconclusive because the last 
sample had a drug concentration above the DTL. Thus, to date, the occurrence of treatment-
emergent ADA has been observed in 1 subject or less than 1% of the subjects evaluable for 
immunogenicity assessment, indicating a low potential of pembrolizumab to elicit the 
formation of ADA. No impact of ADA on pembrolizumab exposure, efficacy, or safety has 
been observed. 
 
4.1.1.4.4 Summary of Efficacy Data63 
The overall response rate obtained in KEYNOTE-001 demonstrated the antitumor activity of 
pembrolizumab in subjects with melanoma (ipilimumab-naïve and previously treated with 
ipilimumab). The KEYNOTE-002 study demonstrated superior PFS for both pembrolizumab 
treatment arms compared with the chemotherapy control arm. In KEYNOTE-002, treatment 
with pembrolizumab lead to an overall response rate that was > 4 fold higher than the response 
rate of the chemotherapy control arm. This difference was highly statistically significant. The 
overall response rates for pembrolizumab treatment in KEYNOTE-001 and KEYNOTE-002 
compared favorably to historical response rates for available treatments for melanoma, 
particularly in subjects who have progressed after multiple prior therapies. 
 
4.1.1.4.5 Summary of Adverse Event Data63 
In the pembrolizumab monotherapy trials (KEYNOTE-001, KEYNOTE-002, KEYNOTE-
012, KEYNOTE-013, KEYNOTE-28, and KEYNOTE-011 [monotherapy arm]), the overall 
incidence of AEs ranged from 83.0% (73 of 88 subjects in KEYNOTE-012) to 100% (10 of 
10 subjects in KEYNOTE-011). The most commonly reported AEs included fatigue, diarrhea, 
decreased appetite, nausea, and anemia. The incidence of DRAEs ranged from 39.8% (35 of 


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19
88 subjects in KEYNOTE-013) to 80.0% (8 of 10 subjects in KEYNOTE-011). The most 
commonly reported DRAEs across all studies were nausea, fatigue, and diarrhea. The 
incidence of Grade 3–5 DRAEs across studies ranged from 6.8% (6 of 88 in KEYNOTE-013) 
to 12.0% (187 of 1562 subjects in KEYNOTE-001/002). The most commonly reported Grade 
3–5 DRAEs were anemia, ALT increased, and AST increased. Most subjects who experienced 
an AE continued in the study, with the incidence of AEs leading to discontinuation ranging 
from 1.9% (8 of 430 subjects in KEYNOTE-28) to 12.3% (192 of 1562 subjects in KEYNOTE-
001/002). The majority of AEs leading to discontinuation were not considered drug related. 
Discontinuations due to a DRAE were infrequent and ranged from 0% (no subjects in 
KEYNOTE-011) to 4.5% (4 of 88 subjects in KEYNOTE-013). The most commonly reported 
DRAEs leading to discontinuation were pneumonitis, ALT increased, and AST increased. The 
overall pattern of AEs observed in melanoma subjects enrolled in KEYNOTE-002 
demonstrates the favorable safety profile of pembrolizumab compared with chemotherapy. 
Consistent with prior observations from randomized comparisons of the 2 mg/kg and 10 mg/kg 
dose levels when given Q3W, there are no important differences in the safety profile of 
pembrolizumab at these 2 dose levels, and both doses appear to have a favorable safety profile 
compared with chemotherapy. 
 
In the combination therapy trials KEYNOTE-021 and KEYNOTE-023, the overall incidence 
of AEs was 95.4% (62 of 65 subjects) and 80% (8 of 10 subjects), respectively. In KEYNOTE-
021, the most commonly reported AEs across the dose regimens were fatigue (49.2%), 
constipation and nausea (26.2% each), decreased appetite (23.1%), diarrhea (18.5%), and 
anemia and alopecia (15.4% each). In KEYNOTE-023, the most commonly reported AEs 
across the dose regimens were neutropenia and thrombocytopenia (50.0% each), followed by 
anemia, respiratory tract infection, and back pain (30.0% each). The incidence of DRAEs was 
86.2% (56 of 65 subjects) in KEYNOTE-021 and 60.0% (6 of 10 subjects) in KEYNOTE-023. 
In KEYNOTE-021, the most commonly reported DRAEs across the dose regimens were 
fatigue (35.4%); nausea, decreased appetite, and alopecia (13.8% each); diarrhea (12.3%); and 
constipation and AST increased (10.8% each). In KEYNOTE-023, the most commonly 
reported DRAEs across the dose regimens were neutropenia and thrombocytopenia (50.0% 
each); anemia (30.0%); and dysphonia, hiccups, and pruritis (20.0% each). 
 
Grade 3–5 DRAEs were reported in 23.1% (15 of 65 subjects) in KEYNOTE-021 and 50.0% 
(5 of 10 subjects) in KEYNOTE-023. In KEYNOTE-021, the most common Grade 3–5 
DRAEs across dose regimens were AST increased (6.2%) and anemia and ALT increased 
(4.6% each). In KEYNOTE-023, the only Grade 3–5 DRAEs that occurred in more than 1 
subject across dose regimens were neutropenia (40.0%) and anemia (20.0%). 
 
In KEYNOTE-021, most subjects continued treatment despite AEs, and only 4.6% of subjects 
discontinued study treatment due to an AE. Only 3.1% of subjects discontinued study treatment 
due to an AE that was considered related to the study treatment by investigators. AEs resulting 
in discontinuation were reported in 3.1% of subjects (2 of 65 subjects). Interstitial lung disease, 
dermatitis allergic, and drug eruption were the only AEs resulting in discontinuation and were 
reported in 1 subject each (1.5%). In KEYNOTE-023, no subjects discontinued study treatment 
due to an AE. 


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20
 
In general, the incidence of drug-related SAEs (DRSAEs) was low. Many of the events 
occurred in 1 subject each and/or < 1.0% each. In the pembrolizumab monotherapy trials, the 
most commonly reported DRSAEs (those that occurred in 3 or more subjects overall in at least 
1 study) were pneumonitis (range, 0.7%–1.3% of subjects); colitis (range, 0.3%–0.9% of 
subjects), pyrexia (range, 0.3%–0.5% of subjects); diarrhea (range, 0.2%–0.4% of subjects); 
hepatitis (0.7% of subjects); nausea, adrenal insufficiency, hyponatremia, hyperthyroidism, 
hypophysitis, vomiting, and dyspnea (0.3% of subjects each); and dehydration, generalized 
edema, hypothyroidism, renal failure acute, and pericardial effusion (0.2% of subjects each). 
The remaining DRSAEs occurred in 1 or 2 subjects each per study. In the combination therapy 
trials, all DRSAEs were reported in 1 subject each. In KEYNOTE-021, 8 subjects experienced 
DRSAEs; the DRSAEs were as follows: anemia, febrile neutropenia, atrial fibrillation, colitis, 
pyrexia, hypersensitivity, ALT increased, AST increased, drug eruption, rash, and urticaria. In 
KEYNOTE-023, 2 subjects experienced DRSAEs; 1 subject had an event of pneumonia and 
the other had an event of tumor lysis syndrome. Due to the fact that KEYNOTE-021 and 
KEYNOTE-023 were combination studies and also were of small sample size, comparative 
evaluation of the AE profile of pembrolizumab combination therapy from those protocols to 
pembrolizumab monotherapy or to chemotherapy monotherapy in other studies cannot be 
made. 
 
Among KEYNOTE-001 and KEYNOTE-002 studies, the incidence of AEs of special interest 
(AEOSI) was 16.1%. Overall, the most commonly reported AEOSI included hypothyroidism 
(7.2%), pneumonitis (2.9%), infusion reaction (2.5%), and hyperthyroidism (2.2%). The 
incidences of the remaining AEOSI were low (range, 0.1%–1.3%). The overall incidence of 
drug-related AEOSI was 14.3%. Overall, 2.6% of subjects discontinued treatment due to an 
AEOSI, and the most commonly reported drug-related AEOSI leading to discontinuation was 
pneumonitis (1.3%). Only one subject died of AEOSI (pneumonitis, 0.1% of subjects). 
Corticosteroids were not used to manage myositis, pericarditis, thyroiditis, type 1 diabetes 
mellitus (T1DM), uveitis, or vasculitis. 
 
4.1.1.5 HSV-tk Preclinical and Clinical Trial Data 
Many laboratories have shown the in vitro susceptibility of mouse and human prostate cancer 
cells to HSV-tk/prodrug treatment. Our group has evaluated the effects of ADV-tk + GCV on 
in vivo tumor growth and survival in mouse prostate cancer models.67  An adenoviral vector 
carrying the HSV-tk gene under the control of the Rous sarcoma virus promoter was 
administered by direct intratumoral injection.67-69 Tumor growth was significantly delayed in 
the ADV-tk + GCV group compared with the control groups (ADV-tk  + saline and ADV-β-
galactosidase [control vector] + saline or GCV).67 Tumor volume in the ADV-tk + GCV-
treated group was 16% of that in the combined control groups. However, with longer follow-
up, ADV-tk + GCV-treated tumors began to grow at a rate similar to control tumors. Mean 
survival was 14.2 ± 0.6 days for the combined control groups and 21.2 ± 1.3 days for the 
treatment group (P < 0.001 by Mantel-Cox log-rank analysis). Animal studies have also shown 
that ADV-tk treatment can protect against metastases. In an orthotopic model, the spontaneous 
metastasis rate was significantly lower for the ADV-tk + GCV treatment group compared with 
the pooled control groups (12.5% [2/16] vs. 71.4% [10/14]; P = 0.0032 by Fisher's Exact test).70 


PI: Chang/IND17200/5.2019 (v15.0) 
 
 
21
Similar results were obtained in experimental metastasis models (i.e., tail vein injection of 
tumor cells). HSV-tk/GCV gene therapy in combination with radiation significantly prolonged 
survival compared with either therapy alone and sham treatment (22.9 ± 1.34 days vs. 16.9 ± 
0.84 days and 11.3 ± 0.77 days, respectively; P < 0.001 by log-rank and Wilcoxon tests).70  
Based on extensive efficacy and toxicity studies in mice, cotton rats, and non-human 
primates,68, 71 our group designed a dose escalation Phase I clinical study to evaluate the 
potential toxicity of ADV/HSV-tk in humans (Regulatory Affairs Certification [RAC] protocol 
# 9601-144). The study was evaluated and approved by the local institutional review board 
[IRB] and institutional biosafety committee and national (RAC and FDA) regulatory bodies. 
Subjects included men with locally recurrent prostate cancer after RT. Vector particles (2 x 
109 to 2 x 1012) were administered in a single intratumoral injection guided by ultrasound 
imaging. Three patients achieved PRs, and only occasional transient toxicities were observed 
(Phase I Study of Adenoviral Vector Delivery of the HSV-tk Gene and the Intravenous 
Administration of Ganciclovir in Men with Local Recurrence of Prostate Cancer after 
Radiation Therapy, National Institutes of Health-Office of Recombinant DNA Activities # 
9601-144).71 
Based on our favorable preclinical and clinical trial data, a Phase I/II study was designed to 
analyze the efficacy and toxicity of HSV-tk gene therapy in combination with RT in prostate 
cancer patients.72 In this study, intravenous GCV was replaced with valacyclovir (Valtrex, 
Glaxo Wellcome), an orally administered medication that is rapidly and almost completely 
metabolized in the liver to acyclovir. The trial consisted of 3 treatment arms: Arm A, low-risk 
patients treated with HSV-tk/valacyclovir + RT; Arm B, high-risk patients treated with the 
same regimen as Arm A with the addition of hormonal therapy; and Arm C, patients with stage 
D1 (positive pelvic lymph nodes) who received the same regimen as Arm B with the addition 
of 45 Gy to the pelvic lymphatics. Fifty-nine patients (29 in Arm A, 26 in Arm B, and 4 in 
Arm C) completed the trial. The median age was 68 years (range, 39–85 years). The median 
follow-up for the entire group was 13.5 months (range, 1.4–27.8 months). Only Arm A patients 
were observed to have an increase in prostate specific antigen (PSA) on day 14, which then 
declined appropriately. All patients in Arm A (median follow-up, 13.4 months) and Arm B 
(median follow-up, 13.9 months) had biochemical control at last follow-up. Three patients in 
Arm C (with pretreatment PSA of 335, 19.6, and 2.5 ng/mL and a combined Gleason score of 
8, 9, and 9 involving all biopsy cores) had biochemical failure at 3, 3, and 7.7 months. Two 
patients had distant failure in bone and 1 patient in the para-aortic lymph nodes outside the 
radiation portal. Six to twelve prostate biopsies performed in these 3 patients revealed no 
evidence of residual carcinoma. In Arm A, biopsy showed no evidence of carcinoma in 66.7% 
(18/27), 92.3% (24/26), 91.7% (11/12), 100% (8/8), and 100% (6/6) of patients at 6 weeks, 4 
months, 12 months, 18 months, and 24 months after treatment, respectively. In Arm B, biopsy 
showed no evidence of carcinoma in 96% (24/25), 90.5% (19/21), 100% (14/14), 100% (7/7), 
and 100% (2/2) of patients at 6 weeks, 4 months, 12 months, 18 months, and 24 months after 
treatment, respectively. This was the first reported trial of its kind in the field of prostate cancer 
that aimed to expand the therapeutic index of RT by combining it with in situ gene therapy.73  


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22
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
The PD-1 pathway represents a major tumoral immune resistance mechanism. Viral vector-
based gene therapy such as ADV/HSV-tk + GCV has also been shown to induce antitumor 
immune activity by several mechanisms including enhancing NK proliferation and 
cytotoxicity, boosting cytokine stimulatory activity, and increasing lymphocytic infiltrate. The 
therapeutic potential of HSV-tk gene therapy is greatly enhanced by a “bystander effect” in 
which cytotoxicity is conferred to non-transduced neighboring cells. RT has been shown to 
augment endogenous antitumor innate and adaptive immune responses. The beneficial effects 
of RT in cancer patients extend beyond direct tumor cell cytotoxicity. Delivery of localized 
radiation to tumors often leads to systemic responses at distant sites, a phenomenon known as 
the abscopal effect, which has been attributed to the induction and enhancement of endogenous 
antitumor innate and adaptive immune responses. The mechanisms surrounding the abscopal 
effect are diverse and include trafficking of lymphocytes into the tumor microenvironment, 
enhanced tumor recognition and killing via upregulation of tumor antigens and antigen-
presenting machinery, and induction of positive immunomodulatory pathways. Thus, RT in 
combination with immunomodulators can produce significant local control and induce 
antitumor responses at distant sites by triggering and amplifying endogenous cellular immune 
responses. Here, we propose a rational combination of ADV/HSV-tk in situ gene therapy plus 
SBRT followed by immunomodulatory therapy with pembrolizumab for the treatment of 
metastatic TNBC and metastatic NSCLC.   
 
TNBC is an aggressive, difficult-to-treat disease with poor prognosis and no current targeted 
therapy options. Compared with other intrinsic breast cancer subtypes, TNBC has higher 
expression levels of PD-L1 and its receptor PD-1, which may hinder antitumor T cell 
responses. Lung cancer remains the leading cause of cancer-related deaths worldwide. NSCLC 
accounts for over 85% of all lung cancer cases. Most patients are diagnosed with advanced or 
metastatic (stage IIIB/IV) disease, and current first-line treatment options for these patients are 
limited. In patients with advanced NSCLC, first-line platinum-based doublet chemotherapy 
yields 1-year OS rates of only 30–40% and can cause significant toxicities that may complicate 
treatment.3 Pembrolizumab has demonstrated promising efficacy in TNBC and NSCLC.64, 74 
In a Phase Ib study, 18.5% of 27 evaluable patients with heavily pretreated recurrent or 
metastatic TNBC responded to pembrolizumab (10 mg/kg Q2W).74 One patient had a CR, 4 
patients had a PR, 7 patients had stable disease (SD), and 12 patients had progressive disease 
(PD). Results of an ongoing Phase Ib study have demonstrated the antitumor activity and 
acceptable side effect profile of pembrolizumab in patients with advanced NSCLC. These 
study results have led to FDA accelerated approval of KeytrudaTM (pembrolizumab) for the 
treatment of patients with metastatic PD-L1-positive NSCLC whose disease has progressed on 
or after platinum-containing chemotherapy or targeted therapy against ALK or EGFR, if 
appropriate. Use of ADV/HSV-tk in situ gene therapy plus SBRT before pembrolizumab may 
represent a window of opportunity to enhance pembrolizumab efficacy in patients with 
metastatic TNBC and metastatic NSCLC. 
 
 


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23
4.2.2 Rationale for Dose Selection  
An open label Phase I trial (KEYNOTE-001) is being conducted to evaluate the safety and 
clinical activity of single-agent pembrolizumab. The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered Q2W in subjects 
with advanced solid tumors. All three dose levels were well tolerated and no dose-limiting 
toxicities were observed. This first-in-human study of pembrolizumab showed evidence of 
target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 
3 mg/kg, and 10 mg/kg Q2W). No MTD has been identified to date. Ten mg/kg Q2W, the 
highest dose tested in KEYNOTE-001, will be the dose and schedule utilized in Cohorts A, B, 
C, and D of this protocol to test for initial tumor activity. Recent data from other clinical studies 
within the pembrolizumab program has shown that a lower dose of pembrolizumab and a less 
frequent schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life.63 Pharmacodynamic data 
suggested that peripheral target engagement is durable (> 21 days). This early PK and 
pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing 
schedule.   
 
A population PK analysis has been performed using serum concentration time data from 476 
patients. Within the resulting population PK model, CL and volume parameters of 
pembrolizumab were found to be dependent on body weight. The relationship between CL and 
body weight, with an allometric exponent of 0.59, is within the range observed for other 
antibodies and would support both body weight normalized dosing or a fixed dose across all 
body weights. Pembrolizumab has been found to have a wide therapeutic range based on the 
melanoma indication. The differences in exposure for a 200 mg fixed-dose regimen relative to 
a 2 mg/kg Q3W body weight-based regimen are anticipated to remain well within the 
established exposure margins of 0.5–5.0 for pembrolizumab in the melanoma indication. The 
exposure margins are based on the notion of similar efficacy and safety in melanoma at 10 
mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e., 5-fold higher dose and 
exposure). The population PK evaluation revealed a lack of significant impact of tumor burden 
on exposure. In addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients; 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W; 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model); and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg Q3W will provide exposures that 1) are optimally consistent with those 
obtained with 2 mg/kg dose Q3W; 2) will maintain individual patient exposures in the exposure 


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24
range established in melanoma as associated with maximal efficacy response; and 3) will 
maintain individual patients exposure in the exposure range established in melanoma that are 
well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and reduce potential dosing errors. A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
ADV/HSV-tk will be administered intratumorally (single-site injection) at 5 x 1011 virus 
particles (vp) on Day 0. This dose is based on the toxicity results from the Phase I/II study of 
ADV-tk oncolytic virus therapy in combination with chemoradiation in patients with 
pancreatic adenocarcinoma.75  
The dose of valacyclovir to be used in this study is 2 g orally three times daily (t.i.d.) for 14 
days (Day 1 to Day 15). This dose has been calculated to give a similar AUC as 10 mg/kg of 
IV acyclovir administered every 8 hours. This is the same dose regimen used in a previous 
Phase I clinical trial of ADV/HSV-tk + acyclovir and topotecan in patients with recurrent 
ovarian cancer.76   
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
The primary efficacy endpoint will be the ORR of ADV/HSV-tk + valacyclovir therapy and 
SBRT followed by pembrolizumab in patients with metastatic TNBC and metastatic NSCLC. 
Secondary efficacy endpoints are antitumor activity (RECIST 1.1 in addition to modified 
irRC), DoR, OS rate, PFS rate, and CBR.  
 
4.2.3.2 Biomarker Research 
Blood and tissue-based markers associated with response to the study treatment will be 
evaluated, including but not limited to T-cell cytokine profiles (IL-1, IL-2, IL-6, IL-12, IFN-
c, TNF-α, and GM-CSF), TILs, PD-1 and PD-L1 expression, effector and suppressor 
immunocyte populations, and mutation load.  
 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
The TNBC cohort will be comprised of patients with histologically confirmed locally advanced 
or metastatic TNBC that has relapsed on or is refractory to 1 or more lines of standard of care 
therapy. Patients must have received no more than one prior line of cytotoxic therapy for 
metastatic disease. Taxane and anthracycline-based chemotherapy must have been received, 
unless contraindicated. The NSCLC cohort will be comprised of male and female patients aged 
≥ 18 years with histologically or cytologically confirmed metastatic NSCLC that is 


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25
immunotherapy naïve or previously treated with a maximum of 1 immunotherapy regimen 
AND chemotherapy naïve or previously treated with 1 cycle of platinum-containing 
chemotherapy. Patients will be screened for EGFR and ALK mutation. EGFR/ALK mutation-
negative patients and patients with EGFR or ALK genomic tumor aberrations that have failed 
FDA-approved targeted therapy for these aberrations will be eligible for enrollment in the 
study. Written informed consent is required before performing any study-specific tests or 
procedures. Signing of the Informed Consent Form can occur outside the 28-day screening 
period. All screening evaluations must be completed and reviewed to confirm that patients 
meet all eligibility criteria before study entry. Results of standard-of-care tests or examinations 
performed prior to obtaining informed consent and within 28 days prior to study entry (except 
where otherwise specified) may be used for screening assessments rather than repeating such 
tests. The investigator will maintain a screening log to record details of all patients screened 
and to confirm eligibility or record reasons for screening failure, as applicable. 
5.1.2 Subject Inclusion Criteria 
Subjects must meet all the following inclusion criteria in order to be eligible for participation 
in this trial: 
1. Willing and able to provide written informed consent/assent for the trial. 
2. Male or female ≥ 18 years of age on the day of informed consent signing. 
3. Histologically confirmed locally advanced or metastatic TNBC that has relapsed on or 
is refractory to standard of care therapy. TNBC is defined as estrogen receptor (ER), 
progesterone receptor, and human epidermal growth factor receptor 2 (HER2) negative. 
ER and progesterone receptor negativity are defined as <10% IHC staining. HER2 test 
result is negative if a single test (or both tests) performed show: 
- 
IHC 1+ or 0  
- 
In situ hybridization negative based on 
o Single-probe average HER2 copy number < 4.0 signals/cell 
o Dual-probe HER2/CEP17 ratio < 2 with an average HER2 copy 
number < 4.0 signals/cell  
OR histologically or cytologically confirmed metastatic NSCLC that is 
immunotherapy naïve or previously treated with a maximum of 1 immunotherapy 
regimen AND chemotherapy naïve or previously treated with 1 cycle of platinum-
containing chemotherapy. EGFR/ALK mutation-negative NSCLC patients and NSCLC 
patients with EGFR or ALK genomic tumor aberrations that have failed FDA-approved 
targeted therapy for these aberrations will be eligible for enrollment in the study.  
4. Measurable disease based on RECIST 1.1, a target lesion of suitable diameter (at least 
1 cm) for SBRT with the exception of a primary breast tumor, and a non-target lesion 
(visceral metastatic lesion) at least 1 cm in diameter for abscopal effect evaluation.   
5. Willing to provide biopsy tissues as required by the study. 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
7. Adequate organ function as defined in Table 1. All screening labs should be performed 
within 28 days of trial treatment initiation.   
Table 1 Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 


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26
Absolute 
neutrophil 
count 
(ANC) 
≥1,500/µL (without granulocyte colony stimulating factor support within 14 
days of assessment) 
Platelets 
≥100,000/µL 
Hemoglobin 
≥8 g/dL without transfusion or erythropoietin dependency (within 7 days of 
assessment) 
White blood cell count (WBC) 
>2,500/µL and <15,000/µL 
Lymphocyte count 
≥500/µL 
Renal 
 
Serum creatinine  
<2 X upper limit of normal (ULN)  
Hepatic 
 
Serum total bilirubin 
≤1.0 X ULN (Subjects with known Gilbert’s disease who have serum 
bilirubin level ≤3 X ULN may be enrolled)  
 
 
Aspartate transaminase (AST) 
and Alanine transaminase 
(ALT) 
≤2.5 X ULN with normal alkaline phosphatase  
(≤5 X ULN for subjects with liver metastases) OR ≤1.5 X ULN in 
conjunction with alkaline phosphatase >2.5 X ULN 
Albumin 
>2.5 mg/dL 
Coagulation 
International normalized ratio 
(INR) or prothrombin time (PT) 
 
Activated partial thromboplastin 
time (aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or aPTT is within therapeutic range of intended use of 
anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or aPTT is within therapeutic range of intended use of 
anticoagulants 
aCrCl should be calculated per institutional standard. 
 
8. Life expectancy ≥ 6 months. 
9. ≥ 4 weeks since any major surgery. 
10.  A 2-week washout period post any prior systemic anticancer therapy, RT, targeted 
anticancer therapy or mAb, and/or investigational therapy is required prior to trial 
entry. Subject should be recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to a 
previously administered therapy. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
11. Female subjects of childbearing potential should have a negative serum pregnancy (β-
human chorionic gonadotropin [β-HCG]) within 7 days prior to receiving the first dose 
of the trial treatment and should not be lactating.   
12. Female subjects of childbearing potential (Section 5.5.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.5.2 – Contraception, for the 
course of the study through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
13. Male subjects of childbearing potential (Section 5.5.2) must agree to use an adequate 
method of contraception as outlined in Section 5.5.2 – Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
 


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27
5.1.3 Subject Exclusion Criteria 
Subjects meeting any of the following exclusion criteria must be excluded from participating 
in the trial: 
1.  Unwilling or unable to comply with the study protocol. 
2. Subjects for who bone metastases are the only available non-target lesions for abscopal 
effect evaluation. 
3.  Subjects with tumors for which SBRT is not considered appropriate standard therapy 
with the exception of subjects with a primary breast tumor. This includes subjects with 
target lesions less than 1 cm in diameter and those with large central lung lesions. 
4. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
5. Known history of active tuberculosis (Bacillus Tuberculosis). 
6. Known or suspected hypersensitivity to pembrolizumab or any of its excipients or any 
component of the proposed regimen (gene vector/valacyclovir). 
7. Known gallbladder or bile duct disease (i.e., infection or cholecystitis) or acute or 
chronic pancreatitis. 
8. ECOG performance status of ≥2 or oxygen dependence (e.g., advanced chronic 
obstructive pulmonary disease). 
9. Inability to swallow food or any condition of the upper gastrointestinal tract that 
precludes administration of oral medications (valacyclovir). 
10. Congestive heart failure: New York Association class III or IV heart failure or unstable 
angina (see Section 12.4). 
11. Sustained or clinically significant cardiac arrhythmias including sustained ventricular 
tachycardia, ventricular fibrillation, clinically significant bradycardia, advanced heart 
block (Mobitz II or higher atrioventricular nodal block), prolonged corrected QT 
interval (longer than 470 milliseconds), or history of acute myocardial infarction. 
12. Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused 
by diabetes or Parkinson’s disease), human immunodeficiency virus (HIV), cirrhosis, 
uncontrolled hypothyroidism, or cardiac failure. 
13. History of syncope or family history of idiopathic sudden death. 
14. Known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
15. Known active central nervous system metastases and/or carcinomatous meningitis.  
Subjects with previously treated brain metastases may participate provided they are 
stable (without evidence of progression by imaging for at least 4 weeks prior to the first 
dose of trial treatment and any neurologic symptoms have returned to baseline), have 
no evidence of new or enlarging brain metastases, and are not using steroids for at least 
7 days prior to trial treatment. This exception does not include carcinomatous 
meningitis, which is excluded regardless of clinical stability.   
16. Active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 


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28
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
17. History of (non-infectious) pneumonitis that required steroids or current pneumonitis. 
18. Active infection requiring systemic therapy. 
19. History or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the 
full duration of the trial, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator.   
20. Known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
21. Pregnant or breastfeeding, expecting to conceive or father children within the projected 
duration of the trial, starting with the prescreening or screening visit through 120 days 
after the last dose of trial treatment, or is unwilling to practice an effective method of 
birth control. Women of childbearing potential must have a negative serum pregnancy 
test within 7 days prior to administration of trial treatment.  
22. Prior treatment with gene vector therapy. 
23. Prior treatment with immunomodulatory therapy or immunotherapy (TNBC cohort 
only) 
24. Prior treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (TNBC cohort 
only). 
25. Known history of HIV (HIV 1/2 antibodies). 
26. History of liver disease such as cirrhosis or known active hepatitis B (e.g., hepatitis B 
surface antigen reactive) or hepatitis C (e.g., hepatitis C virus RNA [qualitative] is 
detected). 
27. History of or current alcohol misuse/abuse within the past 12 months. 
28. Major surgery within 4 weeks prior to study enrollment. 
29. Received a live vaccine within 30 days of planned start of trial therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines and are not allowed. 
 
5.2 
Trial Treatments 
The treatments to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatments 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
ADV/HSV-tk 
5 x 1011 vp in 2-
mL volume  
Once  
Intratumorally 
Day 0 
Experimental 
Valacyclovir 
2 g 
t.i.d. for 14 
days 
Orally 
Day 1 - Day 15 
Experimental 
SBRT* 
30 Gy 
6 Gy X 5 
fractions over 
14 days 
- 
Day 2 - Day 16 
Experimental 


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29
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab** 
200 mg 
Q3W 
IV infusion 
Day 1 of each 3-week 
cycle  
Experimental 
 
vp = viral particles; t.i.d. = three times daily; Q3W = every 3 weeks; IV = intravenous. 
*Primary breast tumors will be treated with three-dimensional RT (short course of 5−8 fractions). 
**Pembrolizumab will continue until disease progression, unacceptable toxicity, or up to 24 months (35 cycles) in subjects 
without disease progression. All subjects who stop pembrolizumab treatment with complete response may be eligible for up 
to an additional 12 months (17 cycles) of pembrolizumab treatment if they progress after stopping pembrolizumab from the 
initial treatment phase. The subject must meet the conditions outlined in Section 5.2.3. 
 
ADV/HSV-tk 
The tumor will be identified by positron emission tomography (PET)/CT by the radiation 
oncologist. ADV/HSV-tk will be administered intratumorally as a single injection using a 21-
gauge needle. For nodal, lung, and liver lesions, ADV/HSV-tk will be administered after 
fiducial placement for SBRT. For primary lung tumors, ADV/HSV-tk will be administered 
under endobronchial ultrasound (EBUS) guidance. In cases where the tumor cannot be 
accessed by EBUS, a CT-guided injection will be performed. For primary breast tumors, 
ADV/HSV-tk will be administered under ultrasound guidance. For liver and lung metastatic 
lesions, ultrasound or CT-guided injection of ADV/HSV-tk will be performed. EBUS will be 
performed with the patient under sedation. Patients will be monitored until the sedation has 
worn off. For CT-guided injections, local anesthesia will be used and patients will be 
monitored for several hours after the procedure. 
SBRT 
Primary lung tumors and metastatic lesions (breast and lung) will be treated with SBRT (6 Gy 
X 5 fractions over 2 weeks). Primary breast tumors will be treated with three-dimensional (3D) 
RT (short course of 5−8 fractions over 2 weeks). Tumor target will be decided by PET/CT 
scan. For the planned dosing regimen, SBRT simulation will be done before treatment. For 
subjects with multiple tumors, the largest tumor will be selected. Sedation is not necessary for 
SBRT. 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   


PI: Chang/IND17200/5.2019 (v15.0) 
 
 
30
5.2.1.2 Dose Modification 
Pembrolizumab: AEs (both non-serious and serious) associated with pembrolizumab 
exposure may represent an immunologic etiology.  These AEs may occur shortly after the first 
dose or several months after the last treatment dose. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 3 below. See Section 5.4 for 
supportive care guidelines, including use of corticosteroids. 
Table 3 Dose Modification Guidelines for Pembrolizumab-Related AEs 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks 
4 
Permanently discontinue 
Permanently discontinue 
Increased AST, 
ALT, or Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 Diabetes 
Mellitus (T1DM; 
if new onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new 
onset T1DM or Grade 3-4 
hyperglycemia associated with 
evidence of beta cell failure 
Resume pembrolizumab when patients are clinically 
and metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab can 
be continued while endocrine 
replacement therapy is instituted 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can 
be continued while thyroid 
replacement therapy is instituted 
Therapy with pembrolizumab can be continued while 
thyroid replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite 
adequate premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks 
4 
Permanently discontinue 
Permanently discontinue 


PI: Chang/IND17200/5.2019 (v15.0) 
 
 
31
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 
50% relative to baseline and lasts for at least 1 week then patients should be discontinued from treatment. 
b 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. Refer to Table 4 – Infusion Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently 
discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held that do not recover 
to Grade 0-1 within 12 weeks of the last dose. 
 
ADV/HSV-tk oncolytic virus therapy: Significant toxicity has not been observed with the 
administration of ADV/HSV-tk oncolytic virus therapy alone or in combination with RT or 
chemotherapy in previous clinical trials.71, 73, 75, 76 Fever may occur due to the local 
inflammatory and immune response to ADV-tk, which will be treated with acetaminophen as 
necessary. If local inflammation is extensive or infection develops, valacyclovir will be 
stopped and antibiotics and/or anti-inflammatory therapy will be given as appropriate.  
In both the TNBC and NSCLC cohorts, ADV/HSV-tk dose will be de-escalated to 5 x 109 vp 
if unacceptable toxicity occurs with the planned dose of ADV/HSV-tk. If toxicity occurs with 
this dose modification, the dose will be further de-escalated to 5 x 106 vp. 
Dosing interruptions for pembrolizumab and SBRT/3D RT 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). Subjects should be placed back 
on study therapy within 3 weeks of the scheduled interruption, unless otherwise discussed with 
the Sponsor. The reason for interruption should be documented in the patient's study record. 
Patients whose treatment is interrupted or permanently discontinued due to an AE including 
abnormal laboratory value must be followed at least once a week for 4 weeks and subsequently 
at 4-week intervals until resolution or stabilization of the event, whichever comes first. Dose 
interruptions should be reported on the appropriate Dosage Administration case report form 
(CRF). The maximum time allowed for toxicity-related treatment interruption is 21 days (3 
weeks) from the intended dosing day. If interruption is > 3 weeks, the patient must be 
discontinued from the study treatment. However, the patient will continue to be followed for 
toxicity. 
Valacyclovir: For patients with serum creatinine level of 1.6−2.0 × ULN, valacyclovir dose 
will be reduced 50% (i.e., 1 g t.i.d.). 
5.2.2 Timing of Dose Administration 
All trial treatments will be administered on an outpatient basis. 
ADV/HSV-tk (5 x 1011 vp) in a 2-mL total volume will be injected intratumorally on Day 0 of 
the study. For nodal, lung, and liver lesions, ADV/HSV-tk will be administered after fiducial 
placement for SBRT. 


PI: Chang/IND17200/5.2019 (v15.0) 
 
 
32
Valacyclovir will be orally administered at a dose of 2 g t.i.d. for 14 days from Day 1 to Day 
15 of the study.  
 
Primary lung tumors and metastatic lesions (breast and lung) will be treated with SBRT (30 
Gy; 6 Gy X 5 fractions). Primary breast tumors will be treated with a short course (5−8 
fractions) of 3D RT. SBRT and 3D RT will be administered over 2 weeks from Day 2 to Day 
16 of the study. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion Q3W (± 1 day).  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
5.2.3 Second Course 
All subjects who stop pembrolizumab treatment with CR may be eligible for up to an additional 
12 months (17 cycles) of pembrolizumab treatment if they progress after stopping 
pembrolizumab from the initial treatment phase. This retreatment is termed the Second Course 
Phase of this trial and is only available if the trial remains open and the subject meets the 
following conditions: 
Either 
• Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR based on the RECIST 1.1, and 
o Was treated with at least 8 cycles of pembrolizumab before discontinuing 
treatment, and 
o Received at least 2 cycles of pembrolizumab beyond the date when the initial CR 
was declared 
OR 
• Had CR and stopped pembrolizumab treatment after completion of 24 months (35 
cycles) of pembrolizumab for reasons other than disease progression or intolerability 
AND 
• Experienced an investigator-determined radiographic disease progression by the 
RECIST 1.1 after stopping initial pembrolizumab treatment, and 
o No new anticancer treatment was administered after the last dose of 
pembrolizumab, and 


PI: Chang/IND17200/5.2019 (v15.0) 
 
 
33
o The subject meets all of the safety parameters listed in the inclusion criteria and 
none of the safety parameters listed in the exclusion criteria, and 
o The study is ongoing 
An objective response or disease progression that occurs during the Second Course Phase for 
a subject will not be counted as an event for the primary analysis of either endpoint in this trial. 
 
5.2.4 Trial Blinding/Masking 
This is an open label trial; therefore, the Sponsor, investigator, and subject will know the 
treatment administered. 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The investigator should discuss any questions regarding this with 
the Merck Clinical team. The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the subject's primary physician.  
5.3.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the CRF including all 
prescription, over-the-counter, herbal supplements, and IV medications and fluids.  If changes 
occur during the trial period, documentation of drug dosage, frequency, route, and date may 
also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered 30 days after the last dose of trial treatment should be recorded for SAEs and 
events of clinical interest (ECIs) as defined in Section 7.2. 
5.3.2 Prohibited Concomitant Medications/Therapies 
Subjects are prohibited from receiving the following until disease progression is 
documented per modified irRC and RECIST 1.1: 
• Antineoplastic systemic chemotherapy, hormone therapy, or targeted/biological 
therapy.  
• Immunotherapy not specified in this protocol. 
• RT not specified in this protocol. 


PI: Chang/IND17200/5.2019 (v15.0) 
 
 
34
NOTE: Patients are allowed to have palliative radiotherapy to a painful site if they are 
otherwise benefitting from the trial treatment per the treating physician’s judgment and and 
it is not the target index lesion for tumor response assessment. 
• Investigational agents other than pembrolizumab and ADV/HSV-tk. 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in the trial.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, bacillus Calmette-Guérin, 
and typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
ECI of suspected immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications that are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.4 
Rescue Medications & Supportive Care 
5.4.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined below. Where appropriate, these guidelines 
include the use of oral or IV 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.  
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 5.2.1.2 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
• Pneumonitis:  


PI: Chang/IND17200/5.2019 (v15.0) 
 
 
35
o For Grade 2 events, 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. 
o For Grade 3–4 events, immediately treat with IV steroids. Administer 
additional anti-inflammatory measures as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
• Diarrhea/Colitis:  
Subjects 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).   
o All subjects 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 gastrointestinal consultation and endoscopy to confirm or 
rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with IV steroids followed by HD oral 
steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• T1DM if new onset (including diabetic ketoacidosis) or ≥ Grade 3 hyperglycemia 
if associated with ketosis (ketonuria) or metabolic acidosis 
o For T1DM or Grade 3–4 Hyperglycemia 
 Insulin replacement therapy is recommended for T1DM and for Grade 
3–4 hyperglycemia associated with metabolic acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
• Hypophysitis: 
o For Grade 2 events, treat with 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. 
o For Grade 3–4 events, treat with an initial dose of IV corticosteroids 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. 


PI: Chang/IND17200/5.2019 (v15.0) 
 
 
36
• 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. 
o Grade 2 hyperthyroidism events (and Grade 2–4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g., propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy with 
levothyroxine or liothyroinine is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 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. 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3–4 events, treat with IV corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o 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.  
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of infusion 
completion.  
Table 4 shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
Table 4 Infusion Reaction Treatment Guidelines 


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37
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 subject 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 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
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. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5 hr (± 
30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg p.o. (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg p.o. (or 
equivalent dose of antipyretic). 
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. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
IV = intravenous; NSAID = nonsteroidal anti-inflammatory drug; p.o. = orally. 
 
5.5 
Diet/Activity/Other Considerations 
5.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting. 


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38
5.5.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age, a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the absence 
of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or 
bilateral tubal ligation/occlusion at least 6 weeks prior to screening;  
OR  
(3) have a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study treatment and for 120 days after 
the last dose of study treatment by complying with one of the following:  
  
(1) practice abstinence† from heterosexual activity;  
 
OR  
 
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
 
Acceptable methods of contraception are‡: 
 Single method (one of the following is acceptable): 
• intrauterine device 
• vasectomy of a female subject’s male partner  
• contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
• diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• cervical cap with spermicide (nulliparous women only)   
• contraceptive sponge (nulliparous women only)  


PI: Chang/IND17200/5.2019 (v15.0) 
 
 
39
• male condom or female condom (cannot be used together) 
• hormonal contraceptive: contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
 
 †Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and Ethic Review Committees (ERCs)/IRBs.  Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception.  
Subjects should be informed that the trial therapy may involve unknown risks to the fetus 
(unborn baby) if pregnancy were to occur during the study.  In order to participate in the study, 
subjects of childbearing potential must adhere to the contraception requirement (described 
above) from the day of trial therapy initiation throughout the study period up to 120 days after 
the last dose of trial therapy. If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
5.5.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on the study treatment, the subject will 
immediately be removed from the study. The site will contact the subject at least monthly and 
document the subject’s status until the pregnancy has been completed or terminated. The 
outcome of the pregnancy will be reported to the Sponsor and to Merck without delay and 
within 24 hours to the Sponsor and within 2 working days to Merck if the outcome is a serious 
adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor. If a male subject 
impregnates his female partner, the study personnel at the site must be informed immediately 
and the pregnancy reported to the Sponsor and to Merck and followed as described above and 
in Section 7.2.2. 
5.5.4 Use in Nursing Women 
It is unknown whether pembrolizumab and valacyclovir are excreted in human milk. It is 
known, however, that among women taking valacyclovir, concentrations of valacyclovir in 
breast milk are about four times higher than in the mother's blood. The safety of valacyclovir 
in breastfeeding infants has not been established. Since many drugs are excreted in human 
milk, and because of the potential for serious adverse reactions in the nursing infant, subjects 
who are breastfeeding are not eligible for enrollment. 


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40
5.6 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or Sponsor if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons. Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
• Dose interruption that exceeds 21 days 
• Unacceptable adverse experiences  
• Any Grade 4 or greater AE 
• Severe (Grade 3) or life-threatening (Grade 4) immune-mediated complication 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Death 
• Administrative reasons 
• Discontinuation of pembrolizumab treatment may be considered for subjects who have 
attained a confirmed CR and have been treated for at least 8 cycles (at least 24 weeks) 
of pembrolizumab and have received at least 2 cycles of pembrolizumab beyond the 
date when the initial CR was declared. These subjects may be eligible for second course 
treatment as described in Section 5.2.3. 
• Completion of 24 months (35 cycles) of pembrolizumab 
 
NOTE: Subjects who stop pembrolizumab after completion of 24 months (35 cycles) may be 
eligible for retreatment if they progress after stopping pembrolizumab provided they meet the 
requirements detailed in Section 5.2.3. Subjects may be retreated in the Second Course Phase 
(Retreatment) for up to an additional 12 months (17 cycles [calculated starting with the first 
dose]). 
 
The End of Treatment and Follow-up visit procedures are listed in Section 7.1.5 (Visit 
Requirements). At the end of treatment (EOT), each subject will be followed for 30 days for 
AE monitoring (SAEs will be collected for 90 days after EOT as described in Section 7.2.3.1).  
Subjects who discontinue for reasons other than PD will have post-treatment follow-up for 
disease status until disease progression, initiating a non-study cancer treatment, withdrawing 
consent, or becoming lost to follow-up. After documented disease progression each subject 
will be followed by telephone for OS until death, withdrawal of consent, or the end of the 
study, whichever occurs first. 


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41
5.7 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 
6.0 TRIAL FLOW CHART 
6.1 
Trial Flow Chart 


Product:  Pembrolizumab 
42 
Protocol/Amendment No.:   
 
 
 
 
 
 
Visit 
Screeninga 
Baselineb 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10* 
EOT 
 
Day 
-28 to -1 
-7 to -1 
0±5 
2±5 
4±5 
7±5 
9±5 
11±5 
17±5 
38±5 
59±5 
80*±5 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examc 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
12-Lead ECG and MUGA Scan or 
Echocardiogramd 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Concomitant Therapies 
Continuous from screening period 
 
Hematologye 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Clinical Chemistrye 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Urinalysisf 
X 
 
Serum Pregnancy (β-hCG )g 
X 
 
Tumor Assessments (modified irRC 
and RECIST 1:1)h 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Brain MRI (NSCLC patients only)i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biopsy j 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Correlative Studies Blood Collectionk 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
AEs and SAEs 
 
 
From informed consent signing up to 30 days after the last treatment dosem 
 
ADV/HSV-tk    Administrationl 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Valacyclovir   Administrationl 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
SBRT Administrationl 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Pembrolizumab Administrationl 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 


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Protocol/Amendment No.:   
 
 
 
 
 
 
Abbreviations:  AE = adverse event; ALT = alanine transaminase; ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; AST = 
aspartate transaminase; β-hCG, beta-human chorionic gonadotropin; BUN = blood urea nitrogen; CBC = complete blood count; CT = computed tomography; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; GM-CSF = granulocyte macrophage colony-stimulating 
factor; IFN = interferon; IL = interleukin; INR = international normalized ratio; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; MUGA = 
multigated acquisition; Q3W = every 3 weeks; PD-1 = programmed death-1; PD-L1 = programmed death-ligand 1; PET = positron emission tomography; p.o. 
= orally; PT = prothrombin; RT = radiation therapy; SAE = serious adverse event; T3 = triiodothyronine; T4 = thyroxine; Th1 = T-helper; t.i.d. = three times 
daily; TIL = tumor-infiltrating lymphocyte; TNF = tumor necrosis factor; TSH = thyroid-stimulating hormone; vp = viral particles; WBC = white blood cell. A 
window of ± 5 days is allowed for visits and study assessments (except as otherwise specified).  
a.  Within 28 days prior to Day 0 of ADV/HSV-tk.   
b.  Within 7 days prior to Day 0 of ADV/HSV-tk. Only screening procedures not performed within 7 days of ADV/HSV-tk dosing are required at baseline.  
c. The baseline symptom-medical history and physical examination are not required if the screening medical history and physical examination were conducted 
within 7 to 28 days prior to Day 0 of ADV/HSV-tk. Vital sign (blood pressure, respiratory rate, pulse, and oral temperature) measurements will be performed at 
each physical exam. 
d. A 12-lead ECG will be performed at screening, at EOT, and when clinically indicated.  MUGA scan or echocardiogram will be performed only if clinically 
indicated. 
e. A blood sample for CBC with platelet count and differential WBC count will be obtained at screening, on Days 0 and 17, every 3 weeks thereafter until 
completion of the protocol-specified treatment, at EOT, and when clinically indicated. 
If a patient is found to have an ANC <1.5 x 10^9/L, platelet count < 100 x 10^9/L, or both, the CBC with differential should be repeated at least every other day 
until the ANC and platelet count have exceeded these values.   
A blood sample for clinical chemistry panel (albumin, glucose, sodium, potassium, carbon dioxide, chloride, calcium, BUN, creatinine, total bilirubin, total 
protein, alkaline phosphatase, AST, and ALT) and evaluation of phosphorus, magnesium, and LDH will be obtained at screening, on Days 0 and 17, every 3 
weeks thereafter until completion of the protocol-specified treatment, at EOT, and when clinically indicated. PT/INR and aPTT will be tested at screening and  
on Day 17. TSH, free T4, and total T3 will be tested at screening and when clinically indicated. 
f. Urinalysis (blood, glucose, protein, specific gravity) will be performed at screening and when clinically indicated. 
g. For women of childbearing potential, the results of a serum β-hCG pregnancy test must be negative within 7 days before the first treatment dose is administered.  
If the screening serum β-hCG pregnancy test is performed more than 7 days before ADV/HSV-tk dosing, it must be repeated at baseline, with results known to 
be negative prior to the first dose of the study treatment. Testing is to be repeated as clinically indicated. 
h. For tumor assessments, CT scan of the chest, abdomen, and pelvis will be performed at screening, every 8 weeks thereafter and/or at the discretion of the 
treating physician, when clinically indicated, and 30 days after the last dose of pembrolizumab. For patients with equivocal CT scan results, PET scan will be 
performed. For abscopal effect evaluation, CT-based response assessment of non-target lesions will be performed at screening, every 8 weeks thereafter, and 30 
days after the last dose of pembrolizumab. 
i. Brain MRI will be performed on NSCLC patients only at screening. 
j. In patients with accessible tumor, biopsies will be conducted at Day 0 and 3 (± 2) days after the first dose of pembrolizumab. Patients whose disease progresses 
while on treatment will also undergo biopsy before they start their new treatment. Banked tumor tissue obtained as part of the patient’s standard care and 
additional biopsy tissues will be evaluated for correlative biomarkers including cytokine expression (IL-1, IL-2, IL-6, IL-12, IFN-c, TNF-α, and GM-CSF), 
TILs, PD-1 and PD-L1 expression, and mutation load. Cytokine expression, TILs, and PD-1 and PD-L1 expression will also be analyzed for abscopal effect 
evaluation. 
k. Blood samples for correlative studies will be collected at screening, 3 (± 2) days after the first dose of pembrolizumab, and end of Cycle 2 of pembrolizumab. 
An additional sample will be collected from patients whose disease progresses while on treatment. Blood will be collected into standard vacutainer tubes (3 
green top tubes). 
l. ADV/HSV-tk (5 x 10 11 vp) in a 2-mL total volume will be injected intratumorally (single-site injection) on Day 0 of the study.  The study coordinator will 
dispense the 14-day quantity of valacyclovir to the patient on Day 0. The patient will be instructed to take valacyclovir (2 g) p.o. t.i.d. for 14 days (from Day 1 
to Day 15 of the study). Primary lung tumors and metastatic lesions (breast and lung) will be treated with SBRT of 30 Gy (6 Gy X 5 fractions).  Primary breast 


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Protocol/Amendment No.:   
 
 
 
 
 
 
 
 
 
 
 
 
tumors will be treated with a short course (5-8 fractions) of three-dimensional RT. SBRT and three-dimensional RT will be administered over 2 weeks from Day 
2 to Day 16 of the study. Pembrolizumab at a dose of 200 mg will be intravenously infused over 30 min Q3W (± 1 day) starting on Day 17 (± 1 day) of the study 
and continuing until disease progression, unacceptable toxicity, or up to 24 months (35 cycles) in subjects without disease progression. All subjects who stop 
pembrolizumab treatment with complete response may be eligible for up to an additional 12 months (17 cycles) of pembrolizumab treatment if they progress 
after stopping pembrolizumab from the initial treatment phase. The subject must meet the conditions outlined in Section 5.2.3. 
m. AEs and SAEs will be captured from the time of informed consent signing up to 30 days after the final dose of pembrolizumab. Study treatment-related SAEs 
and any study patient death occurring beyond 30 days after the last dose of pembrolizumab should also be reported.  
*Patients will be treated until disease progression, unacceptable toxicity, or up to 24 months in subjects without disease progression. 
 


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7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit. Individual trial procedures are described in detail below. It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, hepatitis C, etc.) and thus, local regulations may 
require that additional informed consent be obtained from the subject. In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form, and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use. The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial. The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations, 
and Sponsor requirements. 
 


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7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the investigator. Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial. Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2.  
 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation, and surgeries. 
7.1.1.5.3 Subsequent Anticancer Therapy Status 
The investigator or qualified designee will review all new antineoplastic therapy initiated after 
the last dose of trial treatment. If a subject initiates a new anticancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 


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Protocol/Amendment No.:   
 
 
 
 
 
 
first dose of the new therapy. Once new anticancer therapy has been initiated, the subject will 
move into survival follow-up.  
7.1.2 Clinical Procedures/Assessments 
A visit window of ±5 days is allowed for study visits and assessments (except as otherwise 
specified). 
7.1.2.1 Adverse Event Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to the NCI CTCAE v4.03 (see Section 12.2). Toxicities will be 
characterized in terms of seriousness, causality, toxicity grading, and action taken with regard 
to trial treatment.  
For both the TNBC and NSCLC cohorts, a safety run-in period will be implemented for the 
initial subjects enrolled onto the study. An initial cohort of 3 patients will be followed for 
toxicity through the first cycle of pembrolizumab. The PI will submit a status update for the 
first 3 patients after each individual is enrolled onto this trial via a Reportable Event 
application.  
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs and Section 8.0 for detailed information regarding the run-in cohorts.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam at baseline, on 
Days 0 and 17, every 3 weeks thereafter until completion of the protocol-specified treatment, 
and at EOT. Vital signs including temperature, pulse, respiratory rate, and blood pressure will 
be measured at each physical exam. Height will be measured at screening only. Weight will be 
measured at screening, on Days 0 and 17, every 3 weeks thereafter until completion of the 
protocol-specified treatment, at EOT, and when clinically indicated.  
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
7.1.2.4 ECOG Performance Scale 
The investigator or qualified designee will assess ECOG performance status (see Section 12.1) 
at screening, on Days 0 and 17, every 3 weeks thereafter until completion of the protocol-
specified treatment, and at EOT.   


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7.1.2.5 Electrocardiogram/Multigated Acquisition Scan/Echocardiogram 
A 12-lead electrocardiogram ECG will be performed at screening, at EOT, and when clinically 
indicated. Multigated acquisition scan or echocardiogram will only be performed when 
clinically indicated. 
 
7.1.2.6 Brain Magnetic Resonance Imaging 
Brain magnetic resonance imaging will be performed on NSCLC patients only at screening. 
7.1.2.7 Tumor Imaging and Assessment of Disease and Abscopal Effect Evaluation 
Tumor assessments will be performed at screening, every 8 weeks thereafter until completion 
of the protocol-specified study treatment and/or at the discretion of the treating physician, 
when clinically indicated, and 30 days after the last dose of pembrolizumab. Tumor imaging 
will consist of CT scan of the chest, abdomen, and pelvis. Disease status will be assessed using 
RECIST 1.1 in addition to modified irRC (see Section 12). For patients with equivocal CT 
scan results, PET scan will be performed. For abscopal effect evaluation, CT-based response 
assessment (RECIST 1.1) of a non-target lesion will be performed at screening, every 8 weeks 
thereafter until completion of the protocol-specified study treatment, and 30 days after the last 
dose of pembrolizumab. 
 
Modified irRC is based on recent cancer immunotherapy clinical studies showing that 
immunotherapy-mediated tumor regressions or stabilizations may only become evident or 
prominent over time. For this trial, the concepts of the irRC77 are combined with RECIST 1.1 
to come up with the modified irRC, which uses unidimensional measurements. For modified 
irRC, only target and measurable lesions are taken into account. In contrast to the RECIST 1.1, 
the modified irRC (a) require confirmation of both progression and response by imaging at 8 
weeks after initial imaging and (b) do not necessarily score the appearance of new lesions as 
PD if the sum of lesion diameters of target lesions (minimum of 10 mm per lesion, maximum 
of 5 target lesions, maximum of 2 per organ) and measurable new lesions does not increase by 
≥ 20%. All measurements should be recorded in metric notation. The modified irRC based on 
RECIST 1.1 are defined as follows: 
• New measurable lesions: incorporated into tumor burden. 
• New non-measurable lesions: do not define progression but precludes immune-related CR 
(irCR). 
• Overall irCR: complete disappearance of all lesions (whether measurable or not) and no 
new lesions. All measurable lymph nodes must also have a reduction in short axis to 10 
mm or less. 
• Overall immune-related PR (irPR): ≥ 30% decrease in the sum of the longest diameters of 
target and new measurable lesions. 
• Overall immune-related SD (irSD): Sum of the longest diameters of target and new 
measurable lesions neither irCR, irPR, (compared to baseline), or immune-related PD 
(irPD) (compared to nadir). 


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Protocol/Amendment No.:   
 
 
 
 
 
 
• Overall irPD: ≥ 20% increase in the sum of the longest diameters of target and new 
measurable lesions (compared to nadir), confirmed by repeat, consecutive observations at 
least 4 weeks (normally it should be done at 6 weeks) from the date first documented. 
Documentation of irPD (based on the modified irRC) does not mandate discontinuation of the 
study treatment even after irPD is confirmed with CT scan 8 weeks after the initial observation 
of irPD. 
RECIST 1.1 are defined as follows: 
Target Lesions (Main Tumor) 
• CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < 10 mm. 
• PR: At least a 30% decrease in the sum of the diameters of target lesions, using the baseline 
sum diameters as the reference. 
• PD: At least a 20% increase in the sum of the diameters of target lesions, using the smallest 
sum on study (includes the baseline sum) as the reference.  In addition to the relative 20% 
increase, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:  the 
appearance of one or more new lesions is also considered progression) 
• SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
using the smallest sum diameters while on study as the reference. 
 
Non-Target Lesions  
• CR: Disappearance of all non-target lesions and normalization of tumor marker levels. All 
lymph nodes must be non-pathological in size (< 10 mm short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for 
a patient to be considered in complete clinical response. 
• Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker levels above the normal limits. 
• PD: Appearance of one or more new lesions and/or unequivocal progression of existing 
non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion 
increase.     
• Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or investigator). 
 
7.1.2.7.1 Second Course (Retreatment) Tumor Imaging 
Tumor imaging must be performed within 4 weeks prior to restarting treatment with 
pembrolizumab. The first on-study imaging assessment should be performed at 8 weeks (± 7 
days) after the restart of treatment. Subsequent tumor imaging should be performed every 8 
weeks (± 7 days) or more frequently, if clinically indicated.  


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Protocol/Amendment No.:   
 
 
 
 
 
 
7.1.2.8 Tumor Tissue and Blood Collection and Correlative Studies  
In patients with accessible tumor, biopsies will be conducted at Day 0 and 3 (± 2) days after 
the first dose of pembrolizumab. Subjects whose disease progresses while on treatment will 
undergo an additional biopsy before starting their new treatment. Banked tumor tissue obtained 
as part of the subject’s standard of care and collected biopsy tissues will be evaluated for Th1 
response by cytokine expression (IL-1, IL-2, IL-6, IL-12, IFN-c, TNF-α, and GM-CSF); TILs; 
PD-1 and PD-L1 expression; and mutation load. PD-1 and PD-L1 expression, immune 
infiltrates, and cytokine expression will also be analyzed for abscopal effect evaluation. 
 
Blood samples for correlative studies will be collected at screening, 3 (± 2) days after the first 
dose of pembrolizumab, and end of Cycle 2 of pembrolizumab. An additional sample will be 
collected from subjects whose disease progresses while on treatment. Blood samples will be 
collected into standard vacutainer tubes (2 green top tubes). Samples will be evaluated for 
profile of circulating suppressor and effector immunocytes and cytokines. 
 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below 
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)  
A blood sample for clinical chemistry panel (sodium, potassium, carbon dioxide, chloride, 
calcium, glucose, albumin, blood urea nitrogen, creatinine, total bilirubin, total protein, 
alkaline phosphatase, AST, and ALT) and evaluation of phosphorus, magnesium, and lactate 
dehydrogenase will be obtained at screening, on Days 0 and 17, and every 3 weeks thereafter 
until completion of the protocol-specified treatment, at EOT, and when clinically indicated. 
PT/INR and aPTT will be tested at screening and on Day 17. Thyroid-stimulating hormone, 
free thyroxine, and total thriiodothyronine will be tested at screening and when clinically 
indicated. A blood sample for complete blood count (CBC) with platelet count and differential 
WBC count will be obtained at screening, on Days 0 and 17, every 3 weeks thereafter until 
completion of the protocol-specified treatment, at EOT, and when clinically indicated. If a 
patient is found to have an ANC < 1.5 x 10^9/L, platelet count < 100 x 10^9/L, or both, the 
CBC with differential should be repeated at least every other day until the ANC and platelet 
count have exceeded these values. For women of childbearing potential, the results of a serum 
β-hCG pregnancy test must be negative within 7 days before the administration of the first 
dose of trial treatment. If the screening serum β-hCG pregnancy test is performed more than 7 
days before ADV/HSV-tk dosing, it must be repeated at baseline. Pregnancy testing is to be 
repeated as clinically indicated. Urinalysis (blood, glucose, protein, specific gravity) will be 
performed at screening and when clinically indicated. Laboratory tests for hematology, 
chemistry, urinalysis, and others are specified in Table 5.  
 
Table 5 Laboratory Tests 


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Protocol/Amendment No.:   
 
 
 
 
 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hemoglobin 
Platelet count 
WBC count (total 
and differential) 
ANC 
 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Lactate dehydrogenase 
Carbon dioxide  
Creatinine 
Calcium 
Chloride 
Glucose 
Phosphorus 
Potassium   
Sodium 
Magnesium 
Total bilirubin 
Total protein 
Blood urea nitrogen 
Blood 
Glucose 
Protein 
Specific gravity  
Microscopic exam (If 
abnormal)  
results are noted 
Serum β- hCG† 
PT  (INR) 
aPTT 
Total thriiodothyronine  
Free thyroxine  
Thyroid-stimulating hormone  
  
  
  
  
  
  
†Perform on women of childbearing potential only.  
 
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation. Any AEs 
which are present at the time of discontinuation/withdrawal should be followed in accordance 
with the safety requirements outlined in Section 7.2 - Assessing and Recording Adverse 
Events.   
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Post-Treatment Visits 
7.1.5.1.1 Safety Follow-Up Visit 
 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anticancer treatment, whichever 
comes first. All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0–
1 or the beginning of a new antineoplastic therapy, whichever occurs first. SAEs that occur 


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Protocol/Amendment No.:   
 
 
 
 
 
 
within 90 days of EOT or before initiation of a new anticancer treatment should also be 
followed and recorded.   
 
7.1.5.1.2 Follow-up Visits 
 
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed every 6 weeks (42 ± 7 days) by radiologic 
imaging to monitor disease status. After 1 year, the imaging time point will occur every 9 
weeks (± 7 days). Every effort should be made to collect information regarding disease status 
until the start of new antineoplastic therapy, disease progression, death, or end of the study.   
7.1.5.1.3 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anticancer therapy, 
the subject moves into the Survival Follow-up Phase and should be contacted by telephone 
every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of 
the study, whichever occurs first.  
7.2 
Assessing and Recording Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can, therefore, be any unfavorable and 
unintended sign (e.g., abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product or protocol-specified procedure, whether or not 
considered related to the medicinal product or protocol-specified procedure. Any worsening 
(i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting 
condition that is temporally associated with the study treatment is also an AE. Progression of 
the cancer under study is not considered an AE.  
All AEs that occur after informed consent form signing must be reported by the investigator if 
they cause the subject to be excluded from the trial or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment, or a procedure.  
 
From the time of informed consent signing through 30 days following cessation of treatment, 
all AEs must be reported by the investigator. AE reporting will be performed according to 21 
CFR 312.32. AEs will be recorded at each examination on the Adverse Event 
CRFs/worksheets. AEs (including lab abnormalities that constitute AEs) should be described 
using a diagnosis whenever possible, rather than individual underlying signs and symptoms. 
When a clear diagnosis cannot be identified, each sign or symptom should be reported as a 
separate AE. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the subject’s CRF. The reporting timeframe for AEs 
meeting any serious criteria is described in section 7.2.3.1. The investigator will make every 
attempt to follow all subjects with non-SAEs for outcome. 


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Protocol/Amendment No.:   
 
 
 
 
 
 
AEs will not be collected for subjects during the prescreening period as long as that subject 
has not undergone any protocol-specified procedure or intervention. If the subject requires a 
blood draw, fresh tumor biopsy etc., the subject is first required to provide consent to the main 
study and AEs will be captured according to guidelines for standard AE reporting.  
The occurrence of AEs should be sought by non-directive questioning of the patient at each 
study visit. AEs may also be detected when they are volunteered by the patient during or 
between visits or through physical examination, laboratory test, or other assessments. As far 
as possible, each AE should be evaluated to determine: 
 
1. Severity grade (CTCAE Grade 1–4) 
2. Duration (Start and end dates or if continuing at the Safety Follow-up Visit) 
3. Relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)  
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, hospitalized, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown) 
7. Whether it is serious, where a SAE is defined as in Section 7.2.3.1. 
 
All AEs should be treated appropriately. Such treatment may include changes in study 
treatment including possible interruption or discontinuation, starting or stopping concomitant 
treatments, changes in the frequency or nature of assessments, hospitalization, or any other 
medically required intervention. Once an AE is detected, it should be followed until its 
resolution, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome.  
 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥ 5 times the indicated dose). No specific information is available on the 
treatment of pembrolizumab overdose. Appropriate supportive treatment should be provided 
if clinically indicated. In the event of overdose, the subject should be observed closely for signs 
of toxicity. Appropriate supportive treatment should be provided if clinically indicated. 
If an AE(s) is associated with (“results from”) pembrolizumab overdose, the AE(s) is reported 
as a SAE, even if no other seriousness criteria are met. 
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious ECI, using the terminology “accidental or intentional overdose without adverse effect.” 


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Protocol/Amendment No.:   
 
 
 
 
 
 
For valacyclovir overdose, activated charcoal may be administered to aid in the removal of 
unabsorbed drug. General supportive measures are recommended. Acute renal failure and 
neurological 
symptoms, 
including 
confusion, 
hallucinations, 
agitation, 
decreased 
consciousness and coma, and nausea and vomiting may occur. Caution is required to prevent 
inadvertent overdose. Many of the reported cases involved renally impaired and geriatric 
patients receiving repeated overdoses due to lack of appropriate dosage reduction. 
All reports of overdose with and without an AE must be reported within 24 hours to the 
Sponsor (hmccsaereports@houstonmethodist.org; FAX 713-790-5106) and within 2 working 
days hours to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 993-1220). 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered AEs, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after informed consent form signing must be reported 
by the investigator if they cause the subject to be excluded from the trial or are the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment, or a procedure.   
Pregnancies and lactations that occur from the time of informed consent signing through 120 
days following cessation of treatment or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, must be reported by the investigator.  
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
Such 
events 
must 
be 
reported 
within 
24 
hours 
to 
the 
Sponsor 
(hmccsaereports@houstonmethodist.org; FAX 713-790-5106) and within 2 working days to 
Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 993-1220). 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A SAE is any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization, unless hospitalization is for: 
o routine treatment or monitoring of the studied indication and not associated 
with any deterioration in condition 


Product:   Pembrolizumab 
55 
Protocol/Amendment No.:   
 
 
 
 
 
 
o elective or preplanned treatment for a preexisting condition that is unrelated to 
the indication under study and has not worsened since the start of study drug 
o treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of a SAE given above and not resulting in hospital admission 
o social reasons and respite care in the absence of any deterioration in the 
subject’s general condition; 
• Is a congenital anomaly/birth defect; 
• Is another important medical event. This refers to an AE that may not result in death, 
be immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent one of the outcomes listed above, or 
involves suspected transmission via a medicinal product of an infectious agent.  
• Note: In addition to the above criteria, AEs meeting either of the below criteria, 
although not serious per International Conference on Harmonisation (ICH) definition, 
are reportable to the Merck in the same timeframe as SAEs to meet certain local 
requirements. Therefore, these events are considered serious by Merck for collection 
purposes. 
o Is a new cancer (that is not a condition of the study); 
o Is associated with an overdose. 
Refer to Table 6 for additional details regarding each of the above criteria. 
From the time of informed consent form signing, any SAE or follow up to a SAE, including 
death due to any cause other than progression of the cancer under study (reference Section 
7.2.3.1 for additional details), that occurs to any subject must be reported within 24 hours to 
the Sponsor (hmccsaereports@houstonmethodist.org; FAX 713-790-5106) and within 2 
working days to Merck Global Safety if it causes the subject to be excluded from the trial or is 
the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment, or a procedure. 
From the time of informed consent form signing through 90 days following cessation of 
treatment or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any SAE or follow up to a SAE, including death due to any cause 
other than progression of the cancer under study (reference Section 7.2.3.1 for additional 
details), whether or not related to the study treatment, must be reported within 24 hours to the 
Sponsor and within 2 working days to Merck Global Safety. 
Additionally, any SAE considered by an investigator who is a qualified physician to be related 
to the study treatment that is brought to the attention of the investigator at any time following 
consent through the end of the specified safety follow-up period specified in the paragraph 
above or at any time outside of the time period specified in the previous paragraph also must 
be reported immediately to the Sponsor and to Merck Global Safety. 
All subjects with SAEs must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 


Product:   Pembrolizumab 
56 
Protocol/Amendment No.:   
 
 
 
 
 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by the 
FDA, European Union, Pharmaceutical and Medical Devices agency, and other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission. 
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to the FDA. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious AEs are also known as ECI and must be reported within 24 
hours to the Sponsor (hmccsaereports@houstonmethodist.org; FAX 713-790-5106) and within 
2 working days to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 993-
1220). 
From the time of informed consent form signing, any ECI or follow up to an ECI that occurs 
to any subject must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety if it causes the subject to be excluded from the trial or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment, or a procedure. 
From the time of informed consent form signing through 90 days following cessation of 
treatment or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any ECI or follow up to an ECI, whether or not related to the 
study treatment, must be reported within 24 hours to the Sponsor and within 24 hours to Merck 
Global Safety. 
ECIs for this trial include: 
1.  an overdose of pembrolizumab, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3 X ULN and an elevated 
total bilirubin lab value that is greater than or equal to 2 X ULN and, at the same time, an 
alkaline phosphatase lab value that is less than 2 X ULN, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  
 
7.2.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.2.3- Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless 
there is evidence suggesting a causal relationship between the study treatment and the event. 
Any such event will be submitted to the Sponsor within 24 hours and to Merck Global Safety 
within 2 working days either by electronic or paper media. 
 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
 


Product:   Pembrolizumab 
57 
Protocol/Amendment No.:   
 
 
 
 
 
 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression of the cancer under 
study. 
 
Hospitalization related to convenience (e.g., transportation issues, etc.) will not be considered 
a SAE. 
 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all AEs according to the NCI 
CTCAE v4.03. Any AE which changes CTCAE grade over the course of a given episode will 
have each change of grade recorded on the Adverse Event CRFs/worksheets. 
 
All AEs regardless of CTCAE grade must also be evaluated for seriousness. 


58 
 
  
 
 
 
Table 6 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all AEs as to: 
V4.03 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL). 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; disabling; 
limiting self-care ADL. 
 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A SAE is any untoward medical occurrence that at any dose: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an AE 
that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a SAE.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of the study treatment and is documented in the subject’s 
medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis); or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any AE associated with an overdose is considered a SAE for collection purposes. An overdose that is not associated 
with an AE is considered a non-serious ECI and must be reported within 24 hours to the Sponsor and to Merck within 2 working days. 


59 
 
  
 
 
 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a SAE when, based upon 
appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed previously 
(designated above by a †). 
Duration 
Record the start and stop dates of the AE. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the AE cause the study treatment to be discontinued? 
Relationship to 
the study 
treatment  
Did the study treatment cause the AE? The determination of the likelihood that the study treatment caused the AE will be provided by an investigator who is a qualified 
physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a medically 
qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended as reference 
guidelines to assist the investigator in assessing the likelihood of a relationship between the study treatment and the AE based upon the available information. 
The following components are to be used to assess the relationship between the study treatment and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study treatment caused the AE: 
 
Exposure 
Is there evidence that the subject was actually exposed to the study treatment such as: reliable history, acceptable compliance assessment, expected 
pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
study 
treatment?  
Is the time of onset of the AE compatible with a drug-induced effect? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 
 


60 
 
  
 
 
 
Relationship 
The following components are to be used to assess the relationship between Merck product and the AE: (continued) 
to Merck 
Product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
Sponsor’s product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE 
MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE 
SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE MODIFICATION 
GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology or 
toxicology? 
The assessment of relationship will be reported on the CRFs/worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including consideration 
of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product is 
reasonable. The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not reasonable 
OR the AE is more likely explained by another cause than the Merck product.  (Also entered for a subject with overdose without an associated AE.) 


61 
 
  
 
 
7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All AEs will be reported to regulatory authorities, IRB/IECs, and investigators in accordance 
with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
Sample Size: For the TNBC cohort, the null and alternate hypotheses are 19% ORR78 and 39% 
ORR, respectively. For the NSCLC cohort, the null and alternate hypotheses are 20% ORR79 
and 40% ORR, respectively. For the TNBC cohort, the target response rate is 39%.  With a 
sample size of 28 patients, if the observed number of responders is 11 (39.3%); the 95% CI 
estimate will have a margin of error of 18.1 percentage points (i.e., 21.2% to 57.4%) based on 
the normal approximation.  For the NSCLC cohort, the target response rate is 40%.  With a 
sample size of 29 patients, if the observed number of responders is 12 (41.4%); the 95% CI 
estimate will have a margin of error of 17.9 percentage points (i.e., 23.5% to 59.3%) based on 
the normal approximation. For both the TNBC and NSCLC cohorts, we will implement a safety 
run-in period for the initial subjects enrolled onto the study. An initial cohort of 3 patients will 
be followed for toxicity through the first cycle of pembrolizumab. The PI will submit a status 
update for the first 3 patients after each individual is enrolled onto this trial via a 
Reportable Event application. If only 1 of 3 patients experience toxicity, then 3 more patients 
will be enrolled. If no more than 1 of 6 patients experience toxicity, then the trial will be fully 
opened. The staggering interval will be 5 weeks for the run-in cohort. 
Statistical Analysis: DoR, OS rate, PFS rate, and CBR will be analyzed. Safety profiles will 
also be assessed through summaries of AEs, SAEs, AEs leading to treatment discontinuation, 
and treatment-related death. The safety analysis will report the frequency of all AEs and 
laboratory abnormalities as well as the frequency of dose interruptions and toxicity-related 
treatment discontinuation. Toxicity rates will be presented using the worst NCI CTCAE grade 
per patient.  
9.0 LABELING, PACKAGING, STORAGE, AND RETURN OF CLINICAL SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of 
investigational products in accordance with the protocol and any applicable laws and 
regulations. 
Pembrolizumab will be provided by Merck as summarized in Table 7. 
Table 7 Product Descriptions 


62 
 
  
 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/4 mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Investigational products will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Investigational Product Disclosure 
This trial is open label; therefore, the subject, trial site personnel, Sponsor, and/or designee are 
not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Investigational products must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
Investigational products may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the investigational product 
received from Merck or designee, the amount dispensed to and returned by the subjects, and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
products will be destroyed at the site per institutional policy. It is the investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures and that appropriate records of disposal are kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the FDA Modernization Act and FDA Amendments Act, the Sponsor of the 
trial is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. 


63 
 
  
 
 
Information posted will allow subjects to identify potentially appropriate trials for their disease 
conditions and pursue participation by calling a central contact number for further information 
on appropriate trial locations and trial site contact information.     
10.2 Data Management  
CRFs will be designed and utilized to capture all patient data. An electronic database will be 
designed to store patient CRFs. Data quality control will be performed regularly by the research 
coordinator/research nurse to ensure timely, accurate, and complete patient data collection. 
Queries will be generated and resolved prior to the generation of interim and final summary 
reports.    
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12.0 APPENDICES 
12.1 ECOG Performance Status Scale 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982;5:649-55.  
 
12.2 Common Terminology Criteria for Adverse Events V4.03 
The descriptions and grading scales found in the revised NCI CTCAE version 4.03 will be 
utilized for AE reporting. (http://evs.nci.nih.gov/ftp1/CTCAE/About.html)


69 
 
  
 
 
12.3 Modified irRC (derived from RECIST 1.1)  
Overall responses derived from changes in index, non-index, and new lesions 
Measurable Response 
Non-Measurable Response 
Overall Response Using 
Modified irRC 
 
Index and New, 
Measurable 
Lesions (Tumor 
Burden) 
 
Non-Index 
Lesions 
New, Non- 
Measurable 
Lesions 
 
 
Decrease 100%  
Absent 
Absent 
irCR* 
Decrease 100%  
Stable 
Any 
irPR* 
Decrease 100%  
Unequivocal 
progression 
Any 
irPR* 
Decrease ≥ 30%  
Absent / Stable 
Any 
irPR* 
Decrease ≥ 30%  
Unequivocal 
progression 
Any 
irPR* 
Decrease < 30% to 
increase < 20% 
Absent / Stable 
Any 
irSD 
Decrease < 30% to 
increase < 20% 
Unequivocal 
progression 
Any 
irSD 
Increase ≥ 20% 
Any 
Any 
irPD 
*Assuming that the response (irCR and irPR) and progression (irPD) are confirmed by a 
second, consecutive assessment at least 4 weeks apart. 
irCR, immune-related complete response; irPR, immune-related partial response; irSD, 
immune-related stable disease; irPD, immune-related progressive disease. 


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12.4 New York Heart Association Functional Classifications  
 
Class 
Description 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results 
in fatigue, palpitation, dyspnea, or anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary physical 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on physical 
activity without discomfort. Symptoms of cardiac insufficiency or of 
angina syndrome may be present at rest. If any physical activity is 
undertaken, discomfort is increased.