P53MVA and Pembrolizumab in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
Phase: PHASE2
Conditions: Recurrent Platinum-Resistant Fallopian Tube Carcinoma, Recurrent Platinum-Resistant Ovarian Carcinoma, Recurrent Platinum-Resistant Primary Peritoneal Carcinoma
Sponsor: City of Hope Medical Center

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IRB Protocol #16448 
 
Protocol Date:    February 08, 2023     
Packet:  18 
 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF MEDICAL ONCOLOGY 
 
 
TITLE:  P53MVA AND PEMBROLIZUMAB IN TREATING PATIENTS WITH RECURRENT OVARIAN, 
PRIMARY PERITONEAL, OR FALLOPIAN TUBE  CANCER 
 
CITY OF HOPE PROTOCOL NUMBER: IRB# 16448 
PROTOCOL DATED:  02/08/23 
COH Amendment                                          DATE(S) OF AMENDMENT(S)/REVISION(S) 
COH Amendment  01                                    Protocol Dated 04/18/17  (FDA Amend)                             Version 01                       
COH Amendment  02                                    Protocol Dated 12/06/17                                                       Version 02 
COH Amendment  03                                    Protocol Dated 01/18/18                        
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COH Amendment  04                                    Protocol Dated 05/14/18  (Merck Amend)                         Version 04 
COH Amendment  05                                    Protocol Dated 04/12/19  (Merck Amend)                         Version 05 
COH Amendment  06                                    Protocol Dated 04/15/19   
 
 
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COH Amendment  07                                    Protocol Dated 05/09/19  (Merck Amend)                         Version 07 
COH Amendment  08                                    Protocol Dated 05/15/19   
 
 
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COH Amendment  09                                    Protocol Dated 07/19/19   
 
 
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COH Amendment  10                                    Protocol Dated 09/10/19   
 
 
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COH Amendment  12                                    Protocol Dated 11/13/20   
 
 
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COH Amendment  13                                    Protocol Dated 11/13/20  Title Page 
 
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COH Amendment 14 
 
          Protocol Dated 03/04/21 
 
 
               Packet  14 
COH Amendment 15 
 
          Protocol Dated 04/15/21 
 
 
               Packet  15 
COH Amendment 16 
 
          Protocol Dated 11/02/21 
 
 
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COH Amendment 17 at Continuation 
Protocol Dated 11/02/21 (tp) 
 
 
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COH Amendment 18 
                          Protocol Dated 02/08/23 
 
 
 
Packet 18 
 
SPONSOR/IND NUMBER: COH/IND 14716 
DISEASE SITE:  
STAGE (if applicable):  
MODALITY: IV and SC 

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IRB Protocol #16448 
 
Protocol Date:    February 08, 2023     
Packet:  18 
PHASE/TYPE: Phase II  
 
PRINCIPAL INVESTIGATOR: 
 
Thanh Dellinger, M.D.      
Department of Medical Oncology, City of Hope 
Comprehensive Cancer Center  
COLLABORATING INVESTIGATOR(S): 
Division of Translational Vaccine 
Research   
 
                                          
Don J Diamond, Ph.D    
Ferdynand Kos, Ph.D    
Michael Tran, M.D. 
Alex Jung, M.D. Department of Diagnostic Radiology 
 
 
 
 PARTICIPATING CLINICIANS: 
 
                                       
 
                                        
Vincent Chung, M.D.        Department of Medical Oncology  
Christine Wei, M.D.     Department of Pathology 
 
STUDY STATISTICIAN: 
Paul Frankel, Ph.D.  Department of Biostatistics 
 
PARTICIPATING SITES: 
City of Hope Comprehensive Cancer Center  
 
 
STUDY SPONSOR AND MONITOR: 
City of Hope 
 AGENT NSC# AND IND#: 
p53MVA: COH-IND 14716 
Pembrolizumab (Keytruda): NDC 0006-3029-02 
COORDINATING CENTER:                         City of Hope                                      
 
 
 

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SPONSOR: CITY OF HOPE 
 
TITLE:  P53MVA AND PEMBROLIZUMAB IN TREATING PATIENTS WITH 
RECURRENT OVARIAN, PRIMARY PERIOTONEAL, OR FALLOPIAN TUBE CANCER 
 
 
IND NUMBER: p53MVA vaccine COH/IND 14716 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 6 
2.0 
TRIAL DESIGN.......................................................................................................... 6 
2.1 
Trial Design ............................................................................................................. 6 
2.2 
Trial Diagram .......................................................................................................... 7 
3.0 
OBJECTIVES &HYPOTHESES .............................................................................. 8 
3.1 
Primary Objective & Hypothesis .......................................................................... 8 
3.2 
Secondary Objectives & Hypotheses ..................................................................... 8 
3.3 
Exploratory Objective ............................................................................................ 8 
4.0 
BACKGROUND & RATIONALE ............................................................................ 8 
4.1 
Background ............................................................................................................. 8 
4.1.1 Pharmaceutical and Therapeutic Background....................................................... 9 
4.1.2 Preclinical and Clinical Trial Data ........................................................................ 9 
4.2 
Rationale .................................................................................................................. 9 
4.2.1 Rationale for the Trial and Selected Population ................................................. 14 
4.2.2 Justification for Dose .......................................................................................... 15 
4.2.3 Rationale for Endpoints ...................................................................................... 16 
5.0 
METHODOLOGY ................................................................................................... 17 
5.1 
Study Population ................................................................................................... 17 
5.1.1 Participant Inclusion Criteria .............................................................................. 17 
5.1.2 Participant Exclusion Criteria ............................................................................. 19 
5.1.3 Lifestyle Restrictions .......................................................................................... 22 
5.1.4 Pregnancy ............................................................................................................ 22 
5.2 
Trial Treatments ................................................................................................... 23 
5.2.1 Timing of Dose Administration ............................................................................. 23 

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5.2.2 Dose Modification and toxicity management for immune-related AEs associated 
with pembrolizumab ........................................................................................... 24 
5.2.3 Second Course * ................................................................................................. 30 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 31 
5.3.1 Acceptable Concomitant Medications ................................................................ 31 
5.3.2 Prohibited Concomitant Medications/Therapy ................................................... 31 
5.3.3 Rescue Medications & Supportive Care ............................................................. 32 
5.4 
Participant Withdrawal/Discontinuation Criteria ............................................ 33 
5.5 
Participant Replacement Strategy ...................................................................... 34 
5.6 
Clinical Criteria for Early Trial Termination ................................................... 34 
6.0 
TRIAL FLOW CHART ........................................................................................... 35 
6.1 
Study Flow Chart .................................................................................................. 35 
7.0 
TRIAL PROCEDURES ........................................................................................... 36 
7.1 
Trial Procedures ................................................................................................... 36 
7.1.1 Administrative Procedures .................................................................................. 36 
7.1.2 Clinical Assessments .......................................................................................... 38 
7.1.3 Laboratory Procedures/Assessments................................................................... 43 
7.1.4 Other Procedures ................................................................................................. 44 
7.1.5 Visit Requirements .............................................................................................. 44 
7.2 
City of Hope Data and Safety Monitoring .......................................................... 46 
7.3 
Merck requirements for Assessing and Recording Adverse Events ................ 49 
7.3.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck ......................................................................................... 51 
7.3.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck ................. 51 
7.3.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck.............. 52 
7.3.4 Evaluating Adverse Events ................................................................................. 54 

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7.3.5 Sponsor Responsibility for Reporting Adverse Events ...................................... 58 
8.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 58 
8.1 
Statistical Analysis Plan Summary ..................................................................... 58 
8.2 
Statistical Analysis Plan ....................................................................................... 58 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 59 
9.1 
Investigational Product ........................................................................................ 59 
9.2 
Packaging and Labeling Information ................................................................. 59 
9.3 
Clinical Supplies Disclosure ................................................................................. 59 
9.4 
Storage and Handling Requirements .................................................................. 60 
9.5 
Returns and Reconciliation .................................................................................. 61 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 62 
10.1 
Institutional Review Board .................................................................................. 62 
10.2 
Recruitment of Subjects ....................................................................................... 62 
10.3 
Advertisements ...................................................................................................... 62 
10.4 
Study location and Performance Sites ................................................................ 62 
10.5 
Confidentiality ....................................................................................................... 62 
10.6 
Financial Obligations and Compensation........................................................... 63 
10.7 
Informed Consent Processes ................................................................................ 63 
11.0 
References .................................................................................................................. 64 
12.0 
APPENDICES ........................................................................................................... 68 
Appendix 1: ECOG Performance Status ........................................................................ 68 
Appendix 2: Common Terminology Criteria for Adverse Events V5.0 (CTCAE) ..... 68 
Appendix 3: Contraceptive Guidance and Pregnancy Testing .................................... 69 
Contraception Requirements ........................................................................................... 69 

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Pregnancy Testing ........................................................................................................... 70 
 
 
 
 
 
 
 
 
 
 
 

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1.0 TRIAL SUMMARY 
Abbreviated Title 
Combined Immunotherapy for Ovarian Cancer 
Trial Phase 
II 
Clinical Indication 
Platinum Refractory Ovarian Cancer 
Trial Type 
Therapeutic 
Type of control 
Immunotherapy 
Route of administration 
p53MVA (SC) and Pembrolizumab (IV) 
Trial Blinding 
Not applicable 
Treatment Groups 
1 
Number of trial participants 
16-28 
Estimated enrollment period 
12 months 
Estimated duration of trial 
24 months 
Duration of Participation 
Maximum of 24 months 
Estimated average length of treatment per patient 
6-12 months 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a Phase II, single center study enrolling 16-28 patients. Patients will be initially enrolled at 
a single dose level and dose de-escalation of p53MVA will be employed if necessary. 
Single arm: p53MVA (dose 5.0 x108 pfu) + pembrolizumab (anti-PD1 mAb flat dose: 200 mg) 
p53MVA and pembrolizumab will be given concurrently in accordance with previous studies that 
show potential for checkpoint inhibitors in combination with vaccines. The aim is to use 
pembrolizumab to enhance the activity of the p53MVA vaccine to deliver clinical benefit: 
Treatment Schedule: 
Week  1 (day 1): p53MVA  + pembrolizumab 
Week  4:   p53MVA +  pembrolizumab 
Week  7:   p53MVA +  pembrolizumab 
Week 10:  pembrolizumab 
Week 13:  pembrolizumab 
Week 16:  pembrolizumab continuing every 3 weeks up to 35 cycles (105 weeks)* 

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(Pembrolizumab treatment may be extended beyond 49 weeks if a second course is indicated, see 
Section 5.2.3) 
2.2 
Trial Diagram 
 
 
Enrollment complete 
Final Data analysis  n=28 
17 
17 
11 

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3.0 OBJECTIVES &HYPOTHESES 
3.1 
Primary Objective & Hypothesis 
(1) Objective: to assess response rate (complete responses and partial responses) after treatment 
with p53MVA and Pembrolizumab.  
Hypothesis: combined treatment with p53MVA and Pembrolizumab will result in a higher 
response rate than observed with single agent Pembrolizumab in this patient population (8% 
with acceptable toxicity. 
3.2 
Secondary Objectives & Hypotheses 
(1) Objective:  Secondary objectives are to assess median PFS, clinical benefit (complete 
response, partial response lasting >6 months), overall survival (OS), safety and tolerability.  
Hypothesis:  median PFS, clinical benefit (complete response, partial response lasting >6 
months) and OS will be superior to that reported with single agent Pembrolizumab in this 
patient population, with acceptable toxicity. 
3.3 
Exploratory Objective 
(1) 
Objective: Biological/immunological correlates which be exploratory in nature.  We will 
evaluate if the CD8+ T cell signal exceeds that detected in the single agent p53MVA trial. In 
the prior single agent study the p53-reactive CD8+ T cells increased above baseline after the 
first immunization but did not expand further with subsequent immunization. We 
hypothesize that the CD8+ T cell response will be enhanced by pembrolizumab, resulting in 
larger or more durable increases in the CD8+ T cell response. 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-
L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda®(pembrolizumab) is indicated for the treatment of patients across a number of 
indications because of its mechanism of action to bind the PD-1 receptor on the T cell.  For more 
details on specific indications refer to the Investigator brochure. 
 

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4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such as 
melanoma [2, 3]. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily 
member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2)[4, 5]. 
The structure of murine PD-1 has been resolved [6].  PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-
based inhibition motif, and an immunoreceptor tyrosine-based switch motif.  Following T-cell 
stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor 
tyrosine-based switch motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-
associated protein kinase (ZAP70), which are involved in the CD3 T-cell signaling cascade [5, 7-
9].  The mechanism by which PD-1 down-modulates T-cell responses is similar to, but distinct 
from, that of CTLA-4, because both molecules regulate an overlapping set of signaling proteins 
[10, 11].  As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic 
intervention in platinum resistant ovarian cancer. 
 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Merck Investigator’s Brochure for Preclinical and Clinical data on Pembrolizumab. 
4.2 
Rationale 
p53 Immunotherapy: A promising approach to cancer immunotherapy involves the use of vaccines 
which target defined tumor associated antigens.  An ideal and widely expressed target for the 
cellular immune response is the p53 gene product.  The p53 protein maintains normal cell division 
and about 40-60% of solid tumors have p53 mutations [12].  Mutations of p53, which abrogate its 
function as a suppresser of cell division, are associated with high intracellular concentration of the 

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p53 protein.  This makes p53 an attractive target for immunotherapy, since the intracellular 
concentration of wild type p53 in healthy tissue is low. Cells expressing normal p53 at low levels 
will escape an enhanced immune response to over-expressed mutant p53. In addition, there is 
considerable evidence that p53 mutation is associated with aggressive disease and metastasis. 
Antibodies against human p53 are demonstrable in a notable proportion of patients with breast, lung, 
colorectal, gastric, esophageal, ovarian, pancreatic, and prostate cancer. Furthermore, the presence 
of T cell responses to p53 has been demonstrated in peripheral blood mononuclear cells (PBMC) 
from patients with colon [13] and ovarian cancer [14].  
It is possible that mutations in the p53 gene give rise to true tumor associated antigens. However, 
in order to have widespread application, p53 immunotherapy targets the wild type epitopes of p53. 
Since p53 is a partially tolerized autoantigen, breaking immunological tolerance to p53 is required 
for successful immunotherapy targeting this antigen. Dr Diamond’s group at COH, and others, 
have generated human CTL in vitro capable of lytic activity against human tumor cells 
overexpressing p53 protein[15-17].   
Clinical Trials of p53 Vaccines:  Administration of the canarypox virus ALVAC to a group of 
patients with unresectable colorectal cancer demonstrated that 2 out of 5 patients receiving the 
highest vaccine dose developed p53 specific responses [18].  Ad-p53 pulsed dendritic cells have 
been evaluated in Phase I and Phase II clinical trials in cancer patients with advanced malignancies 
[19].  The majority of patients generated potent p53-specific immunity and evidence of clinical 
benefit was demonstrated. Leffers et al reported that a p53-synthetic long peptide vaccine was 
well-tolerated and induced p53-specific T cell responses in patients with recurrent ovarian cancer 
[20]. When the vaccine was combined with cyclophosphamide, a reduction in Tregs was observed 
and 2/10 patients showed stable disease [21]. This was followed by a Phase 1/2 study combining 
gemcitabine, Pegintron and p53 SLP vaccine in patients with platinum-resistant ovarian cancer. 
The combination of gemcitabine and Pegintron stimulated higher frequencies of circulating 
proliferating CD4+ and CD8+ T-cells but not regulatory T-cells. All vaccinated patients showed 
strong vaccine-induced p53-specific T-cell response, but clinical responses were disappointing 
[22]. No autoimmunity or serious adverse events were reported in these trials.  p53MVA has 
advantages over vaccines comprised of selected epitopes, since a wider range of CD4+ and CD8+ 
T cells epitopes can be generated by antigen processing of the entire p53 protein.  
However, p53 clinical vaccines tested to date are limited to patients with certain tissue types, or 
require individual manufacturing for each patient thus making it costly and laborious to produce. 
City of Hope (COH) has developed a strategy using the genetically engineered virus MVA 
(modified vaccinia Ankara) to immunize patients with the wild type p53 antigen. 
The p53MVA vector expresses the full-length wild type human p53 gene. This vaccine was well-
tolerated in a first-in-human study conducted at City of Hope. This first-in-human study of 
p53MVA as a single agent in a cohort of 12 patients was found to be well-tolerated and 
immunogenic but clinical responses were not observed[23]. 
MVA Vectors: Attenuated poxviruses are being developed as vaccines in numerous diseases, 
including influenza, HIV, malaria and tuberculosis. Modified Vaccinia virus Ankara (MVA) is an 
attenuated, replication deficient vaccinia virus strain which is highly immunogenic. The lack of 
productive viral replication gives MVA a good safety profile, due to minimal potential for 

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reversion to virulent forms, even when used in immunocompromised individuals. Despite its 
inability to replicate in most mammalian cells, MVA can still efficiently express viral and 
recombinant genes making it a potent antigen delivery platform. Furthermore, due to the 
inactivation of immune evasion genes, MVA vectors demonstrate useful adjuvant properties [24]. 
MVA vectors are taken up by antigen presenting cells such as dendritic cells, allowing cross 
presentation of transgene encoded antigens and priming of specific T cell responses [24]. 
MVA has a superlative safety record, being used in numerous clinical trials with only mild side-
effects. MVA was administered as a smallpox vaccine to over 120,000 individuals in Europe 
during the 1970s.  No serious adverse events were reported, and no reports of systemic infection 
occurred.  Recombinant MVA vaccines have been evaluated in over 15 clinical trials in the United 
States and Europe and no serious adverse events have been reported. Minor adverse events include 
mild injection site discomfort and erythema and transient influenza like symptoms. In patients with 
cancer, administration of 5 x 108 pfu of recombinant MVA was well tolerated and resulted in 
recombinant protein specific immunogenicity and evidence of clinical cancer response [25, 26]. 
Multiple phase 2 studies of single-agent immune checkpoint blockade in epithelial ovarian cancer 
have been reported [27-29]. These studies varied in terms of patient population, PD-L1 
requirement and assays for defining PD-L1 positivity. 
In ovarian cancer, the link between PD-L1 expression and response to check point inhibitors, 
remains controversial, with mixed correlations in clinical reports. In a large study of avelumab, 
conducted in ovarian cancer, the ORR was 12.3% for PD-L1 positive cancers (i.e. >1% threshold 
in tumor cells) versus 5.9% of PD-L1negative cancers. However, the ORR difference, the median 
PFS and median OS, were not statistically significant [27]. KEYNOTE-100, a phase 2 study that 
evaluated the activity and safety of pembrolizumab in recurrent ovarian cancer, is the largest study 
to date of single-agent immune checkpoint in this disease [30]. In this study, PD-L1 expression 
was measured as combined positive score (CPS) and higher PD-L1 expression CPS of ≥10 resulted 
in a higher ORR compared to a CPS score of ≥1 or <1. 
Combined p53MVA Vaccine and PD-1 Blockade: By immunizing mice with an MVA vaccine 
expressing p53, it has been possible to generate wild type (wt) p53 specific cytotoxic T 
lymphocytes (CTL) capable of lysing p53 overexpressing tumor cells.  In addition, p53MVA 
vaccination of mice resulted in rejection of established tumors and lasting systemic anti-tumor 
immunity [31].  This effect was potentiated by depletion of Tregs, resulting in enhanced antigen 
specific immunity and tumor rejection in two different strains of mice [32].  In other studies, 
conducted at City of Hope, PBMC from patients with a variety of solid tumors were stimulated in 
vitro with p53MVA infected antigen presenting cells.  The majority of cancer patients evaluated 
developed p53 specific CTL responses directed against a variety of p53 derived epitopes [33]. 
Evidence from murine studies indicate that inhibition of the PD-1/PDL-1 checkpoint pathway with 
blocking antibodies can enhance the effects of cancer vaccines [34-37]. Our pre-clinical data with 
a murine equivalent of pembrolizumab has shown dramatic success in a metastatic model of 
pancreatic cancer that is resistant to the chemotherapy agent Gemzar™ and Abraxane™ 
combinations. Anti-murine PD1 mAb induced regression in an immunocompetent syngeneic 
orthotopic murine KPC (Kras and p53 mutant), PD-L1+ pancreatic tumor model. Mice with 13 

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day established tumors received treatment on days 13 and 20 and showed dramatic regressions of 
both small and large tumors [38]. 
P53MVA and the PD-1/PDL-1 barrier: The first in human Phase I trial of the p53MVA vaccine 
conducted at COH was well-tolerated at two doses. Three patients were treated with 3 vaccinations 
of 1 x108 pfu and 9 patients were treated with 3 vaccinations of 5.6 x108 pfu, with only low grade 
adverse events reported [23]. Since evidence of strong T cell and neutralizing antibody responses 
to the MVA backbone were demonstrated [23] it is likely that immune responses are the major 
mechanism of clearance of p53MVA in vivo. p53MVA is well-tolerated and capable of elevating 
anti-p53 CD8+ T cell responses in patients with advanced, refractory colon and pancreatic cancer. 
However, despite the detection of immunological responses to the vaccine, clinical responses were 
not apparent [23]. One possible explanation for this is that the elevation of p53-reactivity was not 
sustained and expanded by successive vaccination (see below). 
 
 
Immunosuppression in cancer patients, both systemic and within the tumor microenvironment is 
now considered a major barrier to effective immunotherapy. This is mediated by suppressive 
cytokines such as TGF-beta and suppressive cell types including Tregs and MDSC. The ligands 
for programmed cell death 1 (PD-1), an immuno inhibitory receptor belonging to CD28/cytotoxic 
T lymphocyte antigen 4 family, are PD-1 ligand 1 and 2 (PD-Ls). Recent reports suggest that the 
aberrant expression of PD-Ls on tumor cells impairs antitumor immunity, resulting in the immune 
evasion of the tumor cells. in vitro studies with human PBMC have shown that PD-1ligation 
dramatically shifts the dose-response curve, making T cells less sensitive to T-cell receptor-
generated signals. Hence, even low levels of PD-1 expression can inhibit functions such as 
cytokine release and T cell expansion [39]. 
 
-2
0
2
4
6
8
10
pre vac
post vac 1
post vac 2
post vac 3
% CD137+ cells  in CD8+ gate
% p53-reactive CD8+ T cells (means of 9 patients)

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High frequencies of PD-1+ T cells were detected in participants of the first-in human, single agent 
p53MVA trial when compared to healthy donors [40]. Therefore, it was not surprising to find a 
significant inverse correlation relationship between the frequency of PD1+ T cells and anti-p53 
CD8+ T cell response in the trial participants. Further investigation showed that antibody blockade 
of PD-1 in vitro increased the p53 immune responses detected after the second or third 
immunizations (shown below). 
 
 
These findings suggested that combination treatment with p53MVA and PD-1 blockade could help 
sustain the anti-p53 immune response and lead to enhanced clinical benefit. Thus, we believe that 
a logical strategy is to combine the p53MVA vaccine with checkpoint inhibition therapy.  
Published reports of trials combing cancer vaccines and PD-1 blockade are limited to date. A multi 
peptide vaccine administered in combination with Nivolumab showed immunologic activity and 
-10
0
10
20
30
40
50
60
70
pre-vaccine
post vac 1
post vac 2
post vac 3
healthy
controls
% PD-1+ T cells in CD8+ gate

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promising survival in high-risk resected melanoma [41]. Currently there are 12 clinical trials listed 
on ClinicalTrials.Gov combining peptide or cell based cancer vaccines with nivolumab or 
pembrolizumab. 
 
4.2.1 Rationale for the Trial and Selected Population 
Ovarian cancer is an aggressive malignancy with a very poor prognosis due to intrinsic and 
acquired chemotherapy resistance. Around 60-80% of patients initially respond to platinum-based 
chemotherapy (cisplatin/carboplatin) in combination with paclitaxel, however the vast majority 
later relapse with chemoresistant disease. Hence, new treatments such as immunotherapy are being 
actively pursued. However, myeloid derived suppressor cells (MDSC) and T regulatory cells 
(Tregs) are known to accumulate in the ovarian cancer microenvironment [42-46] and are a major 
barrier to effective immunotherapy. 
Ovarian Cancer patients with higher expression of PD-L1 have been shown to have a significantly 
poorer prognosis than patients with lower expression. Although patients with higher expression of 
PD-L 2, also had a poorer prognosis, the difference was not statistically significant. In addition, a 
significant inverse correlation was observed between PD-L1 expression and the intraepithelial 
CD8+ T lymphocyte count, suggesting that PD-L1 on tumor cells directly suppresses antitumor 
CD8(+) T cells. Multivariate analysis showed the expression of PD-L1 on tumor cells and 
intraepithelial CD8(+) T lymphocyte count are independent prognostic factors. Hence it follows 
that the PD-1/PD-L pathway is a good target for restoring antitumor immunity in ovarian cancer 
[47]. 
 
In a trial of a high-affinity, fully human monoclonal anti-PDL-1 antibody (BMS-936559), in 
patients with selected advanced cancers, only one of 17 patients with ovarian cancer showed an 
objective clinical response, compared to 9 of 52 melanoma patients treated [48]. The largest study 
conducted to date of anti-PDL-1 antibody (Avelumab), reported 123 ovarian cancer patients 
treated as of October 2015. ORR was 9.7% based on 12 partial responses, of which 6 were ongoing. 
Stable disease was observed in 55 patients (44%), and the disease control rate was 54.0%. Median 
OS was 10.8 months [49]. 
More encouraging results were achieved with the anti-PD-1 antibody, Nivolumab. Twenty patients 
with platinum-resistant ovarian cancer were treated with an intravenous infusion of nivolumab 
every 2 weeks at a dose of 1 or 3 mg/kg.  The best overall response was 15%, which included two 
patients with durable complete responses (in the 3-mg/kg cohort). The disease control rate in all 
20 patients was 45%, median PFS was 3.5 months (95% CI, 1.7 to 3.9 months) and median OS 
was 20.0 months (95% CI, 7.0 months to not reached) at study termination. However, grade 3 and 
higher AEs were observed in around 40% of patients [28]. 
Another ongoing study of PD-1 blockade in ovarian cancer combines Pembrolizumab with weekly 
paclitaxel (NCT02440425). Paclitaxel induces proinflammatory cytokine secretion and immune 
cell activation[50]. Another study of Pembrolizumab in ovarian cancer (NCT02054806) reported 
the following at ASCO 2015: of 26 patients treated, there was one complete response, 2 partial 
responses and 6 patients with stable disease[51]. 

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This study will evaluate the p53MVA vaccine in combination with a checkpoint inhibitor, 
pembrolizumab. Subjects must have recurrent, platinum refractory ovarian cancer, with evidence 
of p53 over expression to be eligible. Patients will receive injections of p53MVA vaccine, for a 
total of three injections.  Patients will be evaluated for toxicity through the first cycle of therapy.   
Pembrolizumab will be administered at a standard dose of 200 mg every 3 weeks, for 
approximately two years (35 cycles). In the case of grade 3 vaccine related toxicity, the dose of 
p53MVA will be decreased. In the case of pembrolizumab induced immune-mediated adverse 
events, treatment will be held or permanently discontinued according to the package insert. 
Pembrolizumab treatment may be extended beyond 49 weeks (17 cycles) if a second course is 
indicated (see Section 5.2.3). This study will be conducted in compliance with the protocol, Good 
Clinical Practice (GCP) and the applicable regulatory requirements. 
 
4.2.2 Justification for Dose 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab for adults across all indications and regardless of tumor type.  As outlined 
below, this dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and non-small cell lung cancer (NSCLC), covering different disease settings (treatment 
naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment settings 
(monotherapy and in combination with chemotherapy).  Five studies compared 2 mg/kg Q3W 
versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 
3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 
and KN006).  All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied representing an approximate 5- to 7.5-fold difference in exposure.  The 2 
mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses studied.  
Subsequently, flat dose-exposure-response relationships were also observed in other tumor types 
including head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, 
confirming 200 mg Q3W as the appropriate dose independent of the tumor type.  These findings 
are consistent with the mechanism of action of pembrolizumab, which acts by interaction with 
immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 

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saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression.  This evaluation concluded that pembrolizumab at 200 mg Q3W 
achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported 
by these PK characteristics and given that fixed-dose has advantages of reduced dosing complexity 
and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for evaluation 
across all pembrolizumab protocols. 
 
4.2.3 Rationale for Endpoints 
 
4.2.3.1 Efficacy Endpoints 
Measurement of efficacy (primary endpoint) in this trial will be response rate (CR+PR).  
Secondary endpoints will include median PFS, median OS and clinical benefit (CR+PR+SD 
lasting >6 months) and safety and tolerability. CR, PR and SD will be assessed according to 
irRECIST criteria (see Section 7.1.2.5) 
A phase I trial of p53MVA was completed in patients with colorectal or pancreatic cancer. Patients 
with unresectable and chemotherapy resistant disease with over expression of p53 were eligible.  
The highest dose tested (5.6 x108 pfu) was well tolerated. A robust CD8+ T cell responses against 
p53 were detected in the majority of patients after vaccination, but no clinical responses were 
apparent. We characterized patient peripheral blood T cells for expression of the Programmed 
Death 1(PD-1) receptor and found frequencies significantly higher than healthy controls. 
Furthermore, the percentage of PD1+ T cells and peak p53 response showed an inverse, statistically 
significant correlation in the CD8+ compartment. In light of our findings regarding PD-1 
expression, in vitro blockade and p53 response, we believe that combining the vaccine with 
pembrolizumab is the logical next step in the optimization of p53MVA therapy for cancer. We 
therefore propose a phase II study to evaluate the efficacy and safety of pembrolizumab combined 
with the p53MVA vaccine in advanced ovarian cancer patients. The primary endpoint in this trial 
will be response rate (CR+PR). Secondary endpoints include median PFS, clinical benefit 
(CR+PR+SD>6 months), overall survival, safety and tolerability, and biological correlates which 
remain exploratory in nature 

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5.0 METHODOLOGY 
5.1 
Study Population 
5.1.1 Participant Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Female participants who are at least 18 years of age on the day of signing informed consent 
with histologically or cytologically confirmed diagnosis of epithelial ovarian, primary 
peritoneal or fallopian tube cancer will be enrolled in this study. Patients must have 
experienced recurrence or progression within 6 months after completion of platinum based 
chemotherapy (by RECIST 1.1 criteria). 
 
2. A patient is eligible to participate if she is not pregnant (see Appendix 3), not breast- 
feeding, 
and 
at 
least 
one 
of 
the 
following 
conditions 
applies:  
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR  
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the 
treatment period and for at least 30 days after the last dose of study treatment. 
 
3. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial.   
 
4. Have measurable disease based on RECIST 1.1, or detectable disease. Lesions situated in 
a previously irradiated area are considered measurable if progression has been 
demonstrated in such lesions. 
a) Measurable disease is defined as at least one lesion that can be accurately measured in 
at least one dimension (longest dimension to be recorded).  Each lesion must be greater 
than or equal to 10 mm when measured by CT, PET/CT or MRI. Lymph nodes must be 
greater than or equal to 15 mm in short axis when measured by CT, PET/CT or MRI. 
-Detectable disease in a patient is defined as one who does not have measurable disease, 
but has at least one of the following conditions: 
* 
Baseline values of CA-125 at least 2 X ULN  
* 
Ascites and/ or pleural effusion attributed to tumor 
* 
Solid and/ or cystic abnormalities on radiographic imaging that do not meet 
modified RECIST criteria, immune-related response criteria (irRC) for target lesions.  
 
b) Platinum Resistance 
• 
Patients whose ovarian cancer recurs/progresses within 0-6 months following 
platinum-based chemotherapy have platinum resistant or refractory disease. These patients 
are not considered to benefit from additional platinum-based therapy and are treated with 
other sequential single agents.  Such patients are eligible for this trial. 
• 
Patients with documented disease recurrence/progression within 6-12 months of 
completing platinum-based therapy, are considered to have ‘borderline' platinum 
sensitivity. These patients will not be eligible for this trial. 

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• 
Patients who relapse more than 12 months after completion of platinum-based 
treatment are considered ‘platinum sensitive’ and will not be eligible for this trial, since 
they have a favorable (33-59%) chance of responding to further rounds of platinum based 
chemotherapy.  
 
5. Patients with confirmed p53 mutation by molecular analysis and/or evidence of p53 
overexpression by immunohistochemistry (≥10% of cells within the tumor staining 
positive) will be eligible. This will be assessed semi-quantitatively by a CLIA approved 
Pathology Core Pathologist, using CLIA approved mutational analysis or immuno-
histochemistry techniques on formalin-fixed paraffin-embedded tissue. In the case of 
equivocal IHC results, p53 involvement may be confirmed by detection of p53 molecular 
analysis on tumor DNA. Patients on whom molecular analysis of p53 mutations is already 
available, will not require ICH analysis. Molecular analysis may be performed as an 
additional research procedure at the end of the study (distinct from eligibility 
determination) if the PI deems it of scientific value and research funding is available to 
cover the cost. Patients are not required to have PD-L1 positive ovarian tumors and PD-L1 
testing is not mandatory on this study. However, we will collect the data on PD-L1 testing 
when available. 
 
6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 
(Karnofsky ≥60%) and a life expectancy of at least 3 months.  
 
7. Up to 4 prior chemotherapy regimens for recurrent disease are allowed. Adjuvant 
chemotherapy and maintenance Taxol after completion of six cycles of adjuvant 
Carboplatin – Taxol will not be counted as a “prior chemotherapy regimen” for the purpose 
of this study. Treatment with targeted agents or hormones would not be considered as a 
systemic chemotherapy regimen. Eligible Patients are those with documented disease 
recurrence/progression within 0-6 months of completing platinum-based chemotherapy. 
Patients should not have received any non-oncology, viral vaccines within 30 days prior to 
starting protocol treatment. 
 
8. Have adequate organ function as defined in the following table (Table 1).  Specimens must 
be collected within 14 days prior to the start of study treatment. 
 
 
 
 
 
 

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Table 1  Adequate Organ Function Values 
 
5.1.2 Participant Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
System 
Adequate Organ Function (Laboratory Value) 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine 
clearance (GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 × ULN OR 
≥50 mL/min for participant with creatinine levels 
>1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases) 
Coagulation 
 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated 
partial 
thromboplastin 
time 
(aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants 
Cardiac 
left ventricle ejection fraction (LVEF) 
≥55% 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit 
of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion 
within last 2 weeks. 
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of specific 
chemotherapies. 

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1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to study treatment 
start (see Appendix 3).  If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. 
 
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, 
CD137). 
 
3. Has received prior systemic anti-cancer therapy including investigational agents within 
4 weeks prior to treatment start. 
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 
or baseline. Participants with ≤Grade 2 neuropathy may be eligible. 
Note: If participant received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting study treatment. 
 
4. Has received prior radiotherapy within 3 weeks of start of study treatment.  Participants 
must have recovered from all radiation-related toxicities, not require corticosteroids, and 
not have had radiation pneumonitis.  A 1-week washout is permitted for palliative radiation 
(≤2 weeks of radiotherapy) to non-CNS disease. 
 
5. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples 
of live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed. 
 
6. Is currently participating in or has participated in a study of an investigational agent or has 
used an investigational device within 4 weeks prior to the first dose of study treatment. 
Note:  Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous investigational 
agent.  
 
7. Has a diagnosis of immunodeficiency (including organ grafts and HIV), or is receiving 
systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of study drug 
(exceptions: nasal corticosteroids, inhaled steroids, adrenal replacement steroids and 
steroid creams are allowed). 
 
 
8. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.  Note:  Participants with basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin, superficial bladder cancer or any carcinoma in situ (e.g. breast 

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carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not 
excluded. 
 
9. Has known active CNS metastases and/or carcinomatous meningitis.  Participants with 
previously treated brain metastases may participate provided they are radiologically stable, 
i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the 
repeat imaging should be performed during study screening),  clinically stable and without 
requirement of steroid treatment for at least 14 days prior to first dose of study treatment. 
 
10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
 
11. Has 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 (eg. thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
  
12. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis. 
 
13. Has an active infection requiring systemic therapy. 
 
14. Has a known history of Human Immunodeficiency Virus (HIV). 
   
15. Has active infection with Hepatitis A (as determined by an acute hepatitis panel), a known 
history of Hepatitis B (Hepatitis B surface Ag reactive), or active Hepatitis C virus 
(qualitative HCV RNA detectable). 
 
16. Active TB (Bacillus Tuberculosis) infection (as determined by Quantiferron Test).  
 
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the subject’s participation for the 
full duration of the study, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator.   
 
18. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
 
19. Is pregnant or breastfeeding, or expecting to conceive children within the projected 
duration of the study, starting with the screening visit through 120 days after the last dose 
of trial treatment. 
 
20. Patients with a history of cardiac disease are excluded: myocardial infarction or arterial 
thromboembolic events within 6 months prior to baseline, severe or unstable angina, New 
York Heart Association Class III or IV disease, QTCB (corrected according to Bazett's 
formula) interval >470 msec, serious uncontrolled hypertension (systolic >150 and/or 

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diastolic >100 mm Hg).Baseline electrocardiography, echocardiography and assessment of 
serum troponin (I ) are included in the screening exams. Subjects in whom these assays are 
abnormal (EKG excluding 1st degree branch block, sinus brachycardia, sinus tachycardia 
or non-specific T wave changes, serum troponin ≥ grade 2) are ineligible. 
 
21. Patients with a family history or Li-Fraumeni syndrome will not be eligible. 
 
22. History of severe environmental allergies or allergy to egg proteins. 
 
5.1.3 Lifestyle Restrictions 
5.1.3.1 Meals and Dietary Restrictions 
Participants should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
5.1.3.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Refer to Appendix 3 for approved 
methods of contraception. 
5.1.4 Pregnancy 
5.1.4.1 Female participants: 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female participant occurring after the participant receives the first dose of 
protocol therapy up to 120 days post-last dose of pembrolizumab are considered immediately 
reportable events or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier. Protocol therapy is to be discontinued immediately. The 
pregnancy, suspected pregnancy, or positive pregnancy test must be reported to the Study 
PI and the DCC immediately within 24 hours of awareness. The female subject may be referred 
to an obstetrician-gynecologist (preferably one with reproductive toxicity experience) or another 
appropriate healthcare professional for further evaluation. 
The Investigator should make every effort to follow the female participant until completion of the 
pregnancy per institutional policies, and should notify the Study PI.  
Abnormal pregnancy outcomes and neonatal deaths that occur within 28 days of birth should be 
reported as an SAE per expedited reporting guidelines. 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study treatment.  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to Merck within 2 
working days if the outcome is a serious adverse experience (eg, death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).  The study 

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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 Merck. 
5.1.4.1.1 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing infant, 
participants who are breast-feeding are not eligible for enrollment.  The Sponsor must report any 
potential infant exposure through lactation within 10 calendar days of sponsor’s awareness to 
Merck. 
5.1.4.2 Male participants: 
If a female partner of a male participant becomes pregnant within 120 days post last dose of 
pembrolizumab, the male participant should notify the Investigator, and the pregnant female 
partner should be advised to call their healthcare provider immediately.  
The Investigator should make every effort to follow the outcome of the pregnancy per institutional 
policies and should notify the Study PI. 
 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2. 
Table 1  Trial Treatment 
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 
p53MVA 
5.0 x 108 pfu  
Q3W 
injection into 
subcutaneous 
tissue of the 
upper arm 
(over deltoid 
muscle) 
every 3 weeks for a 
total of 3 
vaccinations 
Experimental 
 
5.2.1 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be 
administered up to 5 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. All trial treatments will be administered on an outpatient basis. Pembrolizumab 200 mg 
will be administered as a 30 minute IV infusion every 3 weeks.  Sites should make every effort to 
target infusion timing to be as close to 30 minutes as possible.  However, given the variability of 

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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 Merck Pharmacy Manual contains specific 
instructions for the preparation of the pembrolizumab infusion fluid and administration of infusion 
solution. Section 9.0 of this protocol contains instructions for preparation and handling of the 
p53MVA vaccine. 
5.2.2 Dose Modification and toxicity management for immune-related AEs associated 
with pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last 
dose of pembrolizumab treatment and may affect more than on body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications.  Based 
on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive care. 
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes.  
In order to monitor for immune mediated hyperthyroidism and hypothyroidism, patients will be 
assessed for thyroid function (TSH) at baseline. TSH testing will be repeated during/after the 
treatment phase if clinical signs and symptoms of thyroid disorders are observed. Additional 
procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the 
evaluation. Based on the severity of irAEs, withhold or permanently discontinue pembrolizumab 
and administer corticosteroids. Dose modification and toxicity management guidelines for irAEs 
associated with pembrolizumab are provided in Table 3.

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Table 3 Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to 
≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-
related AEs 
Toxicity grade 
or conditions 
(CTCAEv5.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
• 
Monitor participants for 
signs and symptoms of 
pneumonitis 
• 
Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate corticosteroid 
treatment 
• 
Add prophylactic 
antibiotics for 
opportunistic infections 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
discontinue 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
• Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
• 
Monitor participants for 
signs and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 
bowel perforation 
(ie, peritoneal signs and 
ileus). 
• 
Participants with ≥ Grade 
2 diarrhea suspecting 
colitis should consider GI 
consultation and 

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Grade 4 
Permanently 
discontinue 
performing endoscopy to 
rule out colitis.  
• 
Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids.  
If sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted via 
IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer 
corticosteroids (initial 
dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper 
• 
Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 
enzyme value returned to 
baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglyce
mia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure 
Withhold 
• Initiate insulin 
replacement therapy for 
participants with T1DM  
• Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
 
• 
Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes. 
Hypophysiti
s 
Grade 2 
Withhold 
• Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.   
 
• 
Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4  
Withhold or 
permanently 
discontinue1 
Hyperthyroi
dism  
Grade 2 
Continue  
• Treat with non-selective 
beta-blockers (eg, 
propranolol) or 
thionamides as 
appropriate  
• 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroid
ism 
Grade 2-4 
Continue  
• Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
• 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 

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liothyroinine) per 
standard of care 
Nephritis 
and Renal 
dysfunction 
Grade 2 
Withhold  
• Administer 
corticosteroids 
(prednisone 1-2 mg/kg 
or equivalent) followed 
by taper. 
• 
Monitor changes of renal 
function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer 
corticosteroids 
• 
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-
related AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
• Based on type and 
severity of AE 
administer 
corticosteroids  
• 
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the 
type of event.  
Events that 
require 
discontinuation 
include and not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is 
required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal 
replacement therapy or achieved metabolic control (in case of T1DM).   
 
 
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated infusion 
reaction are provided in Table 4.  
 
 
 

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Table 4A Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hrs 
Stop Infusion. 
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 participant is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 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 participant 
should be premedicated for the next scheduled 
dose. 
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
drug treatment 
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to 
infusion of _____ with: 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
analgesic). 
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: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Participant is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period 
of drug administration. For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 
(CTCAE) at http://ctep.cancer.gov 

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Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants 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. 
 
Precautions and Dose modification and toxicity management of reactions related to 
p53MVA vaccine 
Precautions: All subjects will be monitored for one hour in the clinic after each immunization. 
Notation will be made of the subject’s temperature and of any local reaction at the injection 
site.  The subjects will be contacted by telephone or e-mail approximately 24 and 48 hours 
after each immunization to evaluate vaccine related complications. If there is any clinical 
evidence to suggest myopericarditis, patients will receive a full cardiac evaluation, including 
EKG, serial troponins, echocardiography and consultation by a cardiologist. p53MVA 
vaccination will be withheld in patients showing ≥Grade 2 hepatitis.  
 
Dose Reductions: In the first-in-human, single agent study, p53MVA vaccination was well-
tolerated in 9 patients receiving a dose of 5.6 x 108 pfu. The highest level AE recorded was 
grade 2. Hence, we do not anticipate the need for p53MVA dose reductions. However if 
required, intra-patient dose reductions will be carried out as follows: 
 
Table 4B  p53MVA Vaccine Dose modification and Treatment Guidelines 
                 Toxicity 
Management 
Grade ≥2 hepatitis related or 
unrelated to p53MVA 
Grade ≥3 allergic reactions 
possibly related to p53MVA 
Skip and follow the patient weekly or as needed until 
the toxicity improves to < Grade 2.  May resume 
p53MVA in the next cycle at 2.8 x 108 pfu 
Grade 
3 
non- 
hematologic 
toxicity, unrelated to p53MVA 
Skip and follow the patient weekly or as needed until the 
toxicity improves to < Grade 2.  Resume p53MVA at 2.8 
x 108 pfu 
Grade 
4 
non- 
hematologic 
toxicity (even if unrelated to 
p53MVA) 
Cease all study agents 
 

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5.2.3 Second Course * 
All participants who stop study treatment with SD or better may be eligible for up to an 
additional 17 cycles (approximately 1 year) of pembrolizumab treatment if they progress after 
stopping study treatment from the initial treatment phase.  This retreatment is termed the 
Second Course Phase of this study and is only available if the study remains open and the 
participant meets the following conditions: 
Either 
• Stopped initial treatment with study treatment after attaining an 
investigator-determined confirmed CR based on RECIST 1.1, and 
o Was treated with at least 8 cycles of study treatment before discontinuing 
treatment, and 
o Received at least 2 treatments with pembrolizumab beyond the date when the 
initial CR was declared 
OR 
• Had SD, PR, or CR and stopped study treatment after completion of 
35 administrations (approximately 2 years) of study treatment for reasons other than 
disease progression or intolerability 
AND 
• Experienced an investigator-determined radiographic disease progression by 
irRECIST 1.1 after stopping initial treatment, and 
o No new anticancer treatment was administered after the last dose of study 
treatment, and 
o The participant 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 participant will not be counted as an event for the primary analysis of either endpoint in this 
study. 
*Note: patients must have measurable disease at the start of protocol treatment to be eligible 
for this provision. 
 
 

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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 final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant's primary physician.  
 
5.3.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’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 case report form (CRF) 
including all prescription, over-the-counter (OTC), 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 after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2. 
 
5.3.2 Prohibited Concomitant Medications/Therapy 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy (radiation therapy to a symptomatic solitary lesion or to the brain 
may be allowed at the investigator’s discretion).   
• Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are 
live attenuated vaccines and are not allowed.  

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• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  All 
treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination may 
be required.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to continue the 
participant on study treatment requires the mutual agreement of the investigator, the Sponsor 
and the participant. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.3.3 Rescue Medications & Supportive Care 
Participants 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 along with the dose modification guidelines in 
Section 5.2.2, [Table 3].  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 of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance.  Refer to [Table 3] in Section 
5.2.2 for guidelines regarding dose modification and supportive care.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
 

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5.4 
Participant Withdrawal/Discontinuation Criteria 
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 7.1.4 – Other Procedures. 
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons: 
• The participant or participant’s legally acceptable representative requests to 
discontinue study treatment 
• Confirmed radiographic disease progression, according to irRECIST criteria (outlined 
in Section 7.1.2.6) 
• Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment 
• Unacceptable adverse experiences as described in Section 5.2.2. 
• The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or sponsor, placed the participant at unnecessary risk 
from continued administration of study treatment. 
• The participant has a confirmed positive serum pregnancy test 
• Noncompliance with study treatment or procedure requirements 
• Recurrent Grade 2 pneumonitis 
• Discontinuation of treatment may be considered for participants who have attained a 
confirmed complete response (CR), at the PI's discretion. These participants may be 
eligible for second course treatment described in Section 5.2.3. 
• The participant is lost to follow-up 
• Completion of 35 treatments with pembrolizumab 
Note: The number of treatments is calculated starting with the first dose.  Participants who 
stop will stop pembrolizumab after receiving 17 doses on study. Patients may be eligible 
for retreatment if they progress after stopping study treatment provided they meet the 
requirements detailed in Section 5.2.3. Participants may be retreated in the Second Course 
Phase (Retreatment) for up to an additional 17 cycles (approximately 1 year). 
• Administrative reasons 
 

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5.5 
Participant Replacement Strategy 
5.6 
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 participants 
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 participant treatment can be made. 
 
 

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6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening Phase 
Treatment Cycles 
treatment 
end 
Treatment Cycle/Title: 
Pre study 
  
screening 
(Visit 2) 
1 
2  
3 
4 
to be repeated until week 
105 
Safety 
Follow-
up 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-14 to -1 
 
± 5 
± 5 
± 5 
± 5 
± 5 
± 5 
± 5 
d7-21 
days post 
discon 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics and Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
prior/concomitant medication 
review 
X 
 
 
 
 
 
 
 
 
 
 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
 
X 
X 
X 
X 
X----as per standard of care------X 
 
Vital Signs and Weight 
 
X 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test (if indicated) 
 
X 
 
 
 
 
 
 
 
 
 
HIV, active TB and acute 
hepatitis panel (if indicated) 
 
X 
 
 
 
 
 
 
 
 
 
PT/PTT 
 
X 
 
 
 
 
 
 
 
 
 
CBC with Differential 
 
X 
X 
X 
X 
X------as per standard of care----X 
 
Comprehensive Serum 
Chemistry Panel 
 
X 
X 
X 
X 
X------as per standard of care-----X 
 
T3, FT4 and TSH 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Cardiac function (EKG/ECG) 
 
X 
 
 
 
 
 
 
 
 
 
Serum Troponin I, BNP 
 
X 
 
X 
 
 
 
 
 
 
 
Pembrolizumab 
 
 
X 
X 
X 
Xc 
X 
X 
X 
X 
 
p53MVA 
 
 
X 
X 
X 
 
 
 
 
 
 
Tumor Imaging (CT or PET/CT) 
X 
 
 
 
X 
 
 
X--every 9 weeks--X 
 
CA-125 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Immunologic Blood Collectionb 
 
 
X 
X 
X 
X 
 
 
*X 
*X 
*X 
Study Chart Notes: Baseline evaluations must be conducted no more than 14 days before treatment start, except imaging 
which are permissible up to 30 days prior to initiation of therapy. All treatments/evaluations during/after the treatment 
phase may be +/- 5 days. *At the discretion of the PI. aImaging scans must be obtained prior to cycle 4 of therapy +/- 5 
days. Subsequent restaging scans will be obtained after every 3 cycles of treatment. +/- 5 days.  bAll blood specimens to 
be collected prior to administration of study agents. Patients with a hemoglobin (Hgb) level < 9g/dL will not undergo 
further immunologic phlebotomy until the Hgb level has been documented to rise above 9g/dL.  cAfter completion of the 
three combined doses of p53MVA + PEM, continued administration of PEM as a single agent may continue up to week 
49 (first course). dPatients completing Week 49 treatment will have an end of study visit, 1-3 weeks after the last dose of 
PEM. See Section 5.2.3. on 'Second course' of Pembrolizumab. 
 

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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 participant 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 participant.  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 participant prior to 
participating in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the participant’s dated signature or by the participant’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 participant before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the participant must receive the IRB approval in advance 
of use.  The participant or his/her legally acceptable representative should be informed in a 
timely manner if new information becomes available that may be relevant to the participant’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 participant’s dated signature or by the participant’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 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 participant 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 participant 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 participant 
within 28 days before starting the trial.  Treatment for the disease for which the participant 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 participant 
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 Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a participant initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before 
the first dose of the new therapy.  Once new anti-cancer therapy has been initiated the 
participant will move into survival follow-up, according to COH standard practice.  

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7.1.1.6 Patient Registration  
Eligible subjects must be registered with the Clinical Trials Office (CTO) prior to start of 
protocol therapy.  Issues that would cause treatment delays should be discussed with the 
Principal Investigator. If a subject does not receive protocol therapy following registration, the 
subject’s registration on the study may be canceled after discussion with the PI. The CTO 
should be notified of cancellations as soon as possible. 
Once a patient has been identified, the signed informed consent has been obtained, all 
pretreatment evaluations have been performed, and subject’s eligibility has been confirmed, a 
subject will be registered on study. 
To register a subject, the treating physician should contact the protocol nurse or the responsible 
Clinical Research Coordinator (CRC) in the Clinical Trial Office (CTO) to complete the 
eligibility checklist.  
The protocol nurse or CRC will complete eligibility and enroll patient to trial. 
7.1.2 Clinical Assessments 
The following laboratory tests will be conducted at baseline and during the treatment phase 
according to the study chart:  
a. 
Complete blood count with platelet count and differential 
b. 
Comprehensive metabolic panel  
 
c. 
Urine for pregnancy test where appropriate  
d. 
Blood for immune studies which will be processed and stored by Dr Don Diamond's 
Lab. PBMC will be separated from heparinized blood by standard density gradient 
centrifugation and analyzed immediately, or cryopreserved for future analysis. 
e. 
Serum Troponin (I) and B-type natriuretic peptide (BNP) 
f. 
Immuno-histochemistry staining for the primary ligand of PD-1 (PDL-1)  
g. 
CA-125 tumor marker  
 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee be responsible for determining the event name, assessing 
the severity (i.e., grade), expectedness, and attribution of all adverse events as applicable per 
the City of Hope Clinical Research Adverse Event and Unanticipated Problem policy.  Adverse 
events will be characterized using the descriptions and grading scales found in the most recent 
version of the NCI CTCAE Version 5.0 (see Appendix 2).  Toxicities will be characterized in 
terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  

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Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs. 
7.1.2.2 Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during the study according to standard of 
care.  
7.1.2.3 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix 1) during 
eligibility screening.  
7.1.2.5 Tumor Imaging and Assessment of Disease 
Clinical response will be assessed by modified irRECIST criteria.  Conventional RECIST 
criteria for measuring responses to cytotoxic agents are not optimal for immunotherapies which 
do not act directly on the tumor, and reductions in disease burden may take many months to 
occur. Therefore improved overall survival (OS) can result without improved progression free 
survival/time to progression (PFS/TTP).  Hence, we will employ Immune-related response 
criteria (irRECIST, irRC) which are adapted from WHO response criteria are being employed 
for immunotherapy trials [52], shown below: 
 

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New, measurable lesions 
 (i.e., ≥5 × 5 mm)  
Incorporated into tumor burden  
New, non measurable lesions  
(i.e., <5 × 5 mm)  
Do not define progression (but preclude irCR)  
Non-index lesions  
Contribute to defining irCR (complete disappearance required)  
CR  
Disappearance of all lesions, 2 consecutive observations, ≥ 4 wks apart  
PR  
≥50% decrease in tumor burden from baseline, 2 consecutive observations, 
≥ 4 wks apart  
SD  
50% decrease in tumor burden from baseline cannot be established, nor 25% 
increase compared with nadir  
PD  
At least 25% increase in tumor burden compared with nadir (at any single 
time point) in two consecutive observations at least 4 wk apart  
 
Decreased tumor volume will be assessed relative to baseline, including measurable lesions  >5 × 
5 mm.  Only index and measurable new lesions are taken into account in irRC (in contrast to 
conventional WHO criteria which do not require the measurement of new lesions, nor do they 
include new lesion measurements in the characterization of evolving tumor burden).  
At the baseline tumor assessment, the sum of the products of the two largest perpendicular 
diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions and five 
cutaneous index lesions) is calculated. At each subsequent tumor assessment the SPD of the index 
lesions and of new, measurable lesions (≥5 × 5 mm; up to 5 new lesions per organ: 5 new cutaneous 
lesions and 10 visceral lesions) are added together to provide the total tumor burden: Tumor Burden 
= SPD index lesions + SPD new, measurable lesions 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative 
of all involved organs, should be identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis 

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for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. 
If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
Percentage changes in tumor burden per assessment time point describe the size and growth kinetics 
of both conventional and new, measurable lesions as they appear. At each tumor assessment, the 
response in index and new, measurable lesions is defined based on the change in tumor burden 
(after ruling out irPD). Decreases in tumor burden must be assessed relative to baseline 
measurements (i.e. the SPD of all index lesions at screening). 
Non-Target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 target 
lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or unequivocal 
progression of each should be noted throughout follow-up. 
Metastatic Bone Lesions 
Disease progression is considered if a minimum of 2 new lesions is observed on bone scan. New 
lesions seen by the end of the first response assessment (with the first re-staging bone scan) may 
represent disease that was not detected on the pre-study scan, and a confirmatory scan will be 
required at the next scheduled re-staging bone scan unless clinically not indicated. If confirmed, 
progression should be dated by the initial time when the lesions are first detected. If new lesions 
are seen after the first assessment, but no additional lesions are seen on confirmatory scans, the 
scans from post-first assessment would serve as the baseline scan to evaluate for disease 
progression. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are superficial e.g. palpable lymph 
nodes. 
Measurable Disease 
All measurements will be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations will be performed as close as possible to the beginning of treatment. The same 
method of assessment will be used to characterize each identified and reported lesion at baseline 
and during follow-up. Imaging-based evaluation is preferable unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Duration of Response 
The duration of overall response will be measured from the time measurement criteria are met for 
CR, PR or SD until the first date that recurrent or progressive disease is documented.  
Progression-Free Survival (PFS) 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
Overall Survival (OS) 

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OS will be determined for each patient with time origin at the start of the treatment until death. 
Every effort will be made to follow patients for survival after they discontinue the study. 
 
Conventional CT and PET/CT: both CT and PET/CT will be acceptable for measuring baseline and 
post treatment disease burden.  
 
7.1.2.6 Correlative Studies Blood Sampling 
In addition to tolerability and clinical response, immune responses to the vaccine will be 
determined from in vitro analysis of blood draws collected pre-study and during according to 
the study calendar. All immune correlates will be assessed in a research laboratory rather than 
in a CLIA-approved laboratory, since they are secondary endpoints. In order to assure 
reproducibility, SOPs will be followed for all assays. The Department of Experimental 
Therapeutics at City of Hope has extensive experience using these assays to analyze the 
immune response of gastric cancer patients on the first-in-human trial of p53MVA as a single 
agent. We are qualified to conduct the proposed research in compliance with Good Laboratory 
Practices (GLP) and to comply with all legal and regulatory requirements. Experimental 
procedures for correlative studies are detailed below: 
 
Correlate 
Assay 
Methodology 
p53-specific T 
cell response  
T cell activation 
assay 
peripheral blood CD3+ T cells are tested for reactivity to a p53 
peptide library by flow cytometric detection of the T cell activation 
marker CD137.  
This provides a marker of anti p53 reactivity post vaccination i.e. 
an indicator of p53MVA vaccine activity.  
Immuno 
phenotyping 
Multi color flow 
cytometry 
The frequency of MDSC, Tregs and checkpoint molecules such as 
PD-1 and PDL-1 will be quantified using commercially available 
fluorescently labeled antibodies. Cells are washed and incubated 
with antibody in the presence of 1 % FBS for 30 mins at room 
temperature, in the dark. Matched isotype controls are included for 
each sample. In the case of Treg analysis, a permeabilization step, 
using the BD Cytofix/Cytoperm kit, is incorporated into the 
protocol to allow detection of the intracellular marker FOXP-3. 
Analysis will be carried out using a Gallios cytometer (Beckman 
Coulter).  
 

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7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5. 
 
Table 5 Laboratory Tests 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Urine pregnancy 
test † 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase (ALP) 
 
 
Platelet count 
Alanine aminotransferase 
(ALT) 
 
PT/PTT 
WBC (total and 
differential) 
Aspartate aminotransferase 
(AST) 
 
Total thriiodothyronine (T3) 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
 
Free tyroxine (T4) 
Absolute Neutrophil 
Count 
Carbon Dioxide ‡ 
 
Thyroid stimulating hormone 
(TSH) 
Absolute Lymphocyte 
Count 
(CO2 or bicarbonate) 
 
PK 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
 
 
Phosphorus 
 
 
 
Potassium   
 
 
 
Sodium 
 
 
 
Magnesium 
 
 
 
Total Bilirubin 
 
 
 
Direct Bilirubin (If total 
bilirubin is elevated above the 
upper limit of normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a 
serum pregnancy test will be required.   
 
Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 14 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  

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7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a participant discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events 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.  Participants who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet 
the criteria specified in Section 5.2.3.  After discontinuing treatment following assessment of 
CR, these participants should return to the site for a Safety Follow-up Visit (described in 
Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study (described in Section 
7.1.5.3.2). 
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 Screening 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
will be done only after obtaining written informed consent.  Studies or procedures that were 
for clinical indications (not exclusively to determine study eligibility) may be used for baseline 
values, even if the studies were done before informed consent was obtained.  All clinical 
laboratory tests and blood draw volumes will be performed at a COH CLIA approved lab for 
both inpatients and outpatients, and as specified in the Study Flow Chart. All test results and 
assessments required to establish pre-eligibility of a recipient subject (related or unrelated) 
must be obtained prior to enrollment. The following “Eligibility Check List” is required at the 
screening visit: 
 
• Signed ICF/disclosure authorization form 
• Medical history 
• Physical exam including vital signs, height and weight 
• HIV antibody if appropriate 
• Acute Hepatitis panel 
• Quantiferron test for active TB infection 
• Comprehensive metabolic panel (CMP) CBC with differential 
• Cardiac function tests: electrocardiography, echocardiography, serum troponin (I) and 
BNP (B-type natriuretic peptide)  
• Pregnancy test if appropriate 
• Review of concomitant medications  
• Assessment of inclusion/exclusion criteria 
• Enrollment  

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*Complete metabolic panel (CMP) CLIA approved lab, including the following: glucose, BUN 
(blood urea nitrogen), creatinine, total protein, albumin, calcium, sodium, potassium, chloride, 
total carbon dioxide, total bilirubin, alkaline phosphatase, ALT (alanine transaminase) and 
AST (aspartate aminotransferase). 
 
7.1.5.2 Treatment Period 
Treatment will be administered on an out-patient basis. At weeks 1, 4 and 7 Pembrolizumab 
and p53MVA will be administered at the same study visit. Pembrolizumab will be 
administered first followed by p53MVA at least 30 minutes later.   
 
Patients showing progressive disease by imaging (according to irRECIST criteria) will receive 
no further study agents. 
Patients completing combination therapy (p53MVA+PEM on weeks 1, 4 and 7) may be treated 
with doses of pembrolizumab (PEM) alone every 3 weeks, up to 35 cycles. The intended 
function of pembrolizumab in this setting is to enhance the activity of the p53MVA vaccine to 
clinically beneficial levels. Pembrolizumab treatment may be extended beyond 49 weeks (17 
cycles) if a second course is indicated (see Section 5.2.3). 
Treatment delays due to adverse events of less than 3 weeks are allowable on this protocol. 
7.1.5.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 1-3 weeks after 
the last dose of study treatment or before the initiation of a new anti-cancer treatment, 
whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded.  Participants with an AE of Grade > 1 will be followed until the resolution of the AE 
to Grade 0-1 or until the beginning of a new anti-cancer therapy, whichever occurs first.  SAEs 
that occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.  Participants who are eligible for retreatment 

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with pembrolizumab (as described in Section 5.2.3) may have up to two safety follow-up visits, 
one after the Initial Treatment Period and one after the Second Course Treatment. 
7.1.5.3.2 Follow-up Visits 
Participants who discontinue study treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 12 weeks (42 ± 7 days) by 
radiologic imaging to monitor disease status, as per standard of care.  Every effort should be 
made to collect information regarding disease status until the start of new anti-cancer therapy, 
disease progression, death, end of the study or if the participant begins retreatment with 
pembrolizumab as detailed in Section 5.2.3.  Information regarding post-study anti-cancer 
treatment will be collected if new treatment is initiated. 
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 5.2.3 will move from the follow-up phase to the Second Course Phase when 
they experience disease progression.   
7.1.5.3.3 Survival Follow-up 
Participants who experience confirmed disease progression or start a new anticancer therapy, 
will move 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 trial, 
whichever occurs first.  
 
7.2 
City of Hope Data and Safety Monitoring 
7.2.1 Risk Determination 
This is a high risk study, as defined in the City of Hope Institutional DSMP.  This determination 
was made because the study involves a COH held IND for p53MVA and off label use of a 
commercially available product, Pembrolizumab. This is a combined immunotherapy study of 
vaccine and antibody. As p53MVA does not integrate into host DNA, this study is NOT 
classified as gene therapy. p53MVA has already been tested in 20 human subjects at COH 
(IRB#10105 and IRB#13373). Pembrolizumab is FDA approved for two indications. A study 
testing the combination of p53MVA and Pembrolizumab is underway at COH (IRB#15002). 
This will be the second study testing the two agents in combination.  
7.2.2 City of Hope Data and Safety Monitoring Committee 
The COH Data and Safety Monitoring Committee (DSMC) will review and monitor study 
progress, compliance, toxicity, safety, and accrual data from this trial via the PMT Progress 
Report (submitted by the Study Principal Investigator according to the frequency outlined in 
the City of Hope Institutional DSMP). The DSMC is composed of clinical specialists who have 
no direct relationship with the study. Information that raises any questions about participant 
safety will be addressed with the Protocol Management Team. 

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7.2.3 All Investigator Responsibilities 
An investigator is responsible for ensuring that an investigation is conducted according to the 
signed investigator statement, the investigational plan, and applicable regulations; for 
protecting the rights, safety, and welfare of subjects under the investigator's care; and for the 
control of drugs under investigation. 
7.2.4 Study Principal Investigator Responsibilities 
The Study Principal Investigator is responsible for the conduct of the clinical trial, including 
overseeing that sponsor responsibilities are executed in accordance with federal regulations. 
 
7.2.5 Protocol Management Team (PMT) 
The Protocol Management Team (PMT), minimally consisting of the study PI, collaborating 
investigator, research nurse, clinical research associate/coordinator, and the study 
biostatistician, is responsible for ongoing monitoring the data and safety of this study, 
including implementation of the stopping rules for safety/toxicity. 
The PMT is recommended to meet (in person or via teleconference) to review study status. 
The meeting is a forum to discuss study related issues including accrual, SAE/AE/UPs 
experienced, study response, deviations/violations, and study management issues. The 
appropriateness of further subject enrollment and the specific intervention for subsequent 
subject enrollment are addressed.  
7.2.6 Quality Assurance 
Clinical site monitoring is conducted to ensure that the rights of human subjects are protected, 
that the study is implemented in accordance with the protocol and regulatory requirements, 
and that the quality and integrity of study data and data collection methods are maintained.  
Monitoring for this study will be performed by the City of Hope Office of Clinical Trials 
Monitoring (OCTM), within City of Hope’s Office for Safety and Data Quality.  
Details of clinical site monitoring are documented in the OCTM SOP and the Risk Based 
Monitoring (RBM) plan. These documents specify the frequency of monitoring, monitoring 
procedures, the amount of subject data to be reviewed, and the distribution of monitoring 
reports to the study team and the COH DSMC.  
7.2.7 Adverse Events and Unanticipated Problems 
The research team is responsible for classifying adverse events (AE) and unanticipated 
problems (UP) as defined in the relevant regulations and reporting to all applicable parties, 
including but not limited to the COH IRB, DSMC, Food and Drug Administration (FDA), 
National Institutes of Health (NIH) and other collaborators, e.g., pharmaceutical companies. 
The research team is responsible for the continued monitoring and tracking of all AEs in order 
to ensure non-reportable events are reviewed and monitored and do not rise to a reporting level. 

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7.2.8 Assessment of Adverse Events 
The PI will be responsible for determining the event name, and assessing the severity (i.e. 
grade), expectedness, and attribution of all adverse events as applicable per the City of Hope 
Clinical Research Adverse Event and Unanticipated Problem policy. Adverse events will be 
characterized using the descriptions and grading scales found in NCI CTCAE v5.0. A copy of 
the scale can be found at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm.  
The following definitions will be used to determine the causality (attribution) of the event to 
the study agent or study procedure. 
• Unrelated – The event is clearly NOT related to study treatment, and is clearly related 
to other factors such as the participant’s clinical state, other therapeutic interventions, 
or concomitant medications administered to the participant. 
• Unlikely – The event is unlikely related to the study treatment, and is most likely 
related to other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs. 
• Possible – The event may be related to study treatment, as it follows a reasonable 
temporal sequence from the time of drug administration, but could have been produced 
by other factors such as the participant’s clinical state, other therapeutic interventions, 
or concomitant drugs.  
• Probable – The event is most likely related to the study treatment, as it follows a 
reasonable temporal sequence from the time of drug administration and a known 
response pattern to the study drug, and is unlikely related to the participant’s clinical 
state, other therapeutic interventions, or concomitant drugs.  
• Definite – The event is clearly related to the study treatment, as it follows a reasonable 
temporal sequence from the time of drug administration and a known response pattern 
to the study drug, and is not reasonably explained by other factors such as the 
participant’s condition, therapeutic interventions, or concomitant drugs. 
 
7.2.9 Reporting of Adverse Events 
AEs will be collected from the signing of informed consent until ending study participation. 
Routine AE reporting will occur via data entry into the study eCRF. AEs will be monitored by 
the Protocol Management Team (PMT). AEs reported through expedited processes (e.g., 
reported to the IRB, FDA, etc.) must also be reported in routine study data submissions. 
7.2.10 Expedited Reporting Requirements of SAEs and UPs to the COH Regulatory 
Committees 
Adverse events that meet the criteria of serious OR are unanticipated problems will be reported 
according to the approved City of Hope Clinical Research Adverse Event and Unanticipated 
Problem policy. Reporting of SAEs will begin once the patient undergoes study intervention 

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and must be followed until the event is resolved, stabilized, or determined to be irreversible by 
the investigator.  Follow-up SAE reports must be submitted for all events that require expedited 
reporting when the status of the event changes and until the resolution or stabilization of the 
event. 
 
7.2.11 Reporting to the FDA 
The study PI (or designee) will be responsible for contacting the Office of IND Development 
and Regulatory Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the 
FDA.  OIDRA will assist the PI with the preparation of the report and submit the report to the 
FDA in accordance with the City of Hope Clinical Research Adverse Event and Unanticipated 
Problem policy.  
Serious Adverse Events meeting the requirements for expedited reporting to the Food and Drug 
Administration (FDA), as defined in 21 CFR 312.32, will be reported as an IND safety report 
using the MedWatch Form FDA 3500A for Mandatory Reporting. 
The criteria that require reporting using the Medwatch 3500A are: 
• 
Any unexpected fatal or life threatening adverse experience associated with use of 
the drug must be reported to the FDA no later than 7 calendar days after initial 
receipt of the information [21 CFR 312.32(c)(2)] 
• 
Any adverse experience associated with use of the drug that is both serious and 
unexpected must be submitted no later than 15 calendar days after initial receipt 
of the information [21 CFR 312.32(c)(1)] 
• 
Any follow-up information to a study report shall be reported as soon as the 
relevant information becomes available. [21 CFR 312.32(d)(3)] 
 
In addition, the study PI will submit annually within 60 days (via COH OIDRA) of the 
anniversary date of when the IND went into effect, an annual report to the FDA which is to 
include a narrative summary and analysis of the information of all FDA reports within the 
reporting interval, a summary report of adverse drug experiences, and history of actions taken 
since the last report because of adverse drug experiences. 
 
7.2.12 Adherence to the Protocol & Reporting of Protocol Deviations 
 
Deviations from the protocol should be avoided, except when necessary to eliminate immediate 
hazard(s) for the protection, safety, and well-being of a research participant. As a result of 
deviations, corrective actions are to be developed by the study staff and implemented promptly. 
All protocol deviations and planned protocol deviations will be reported in accordance with 
the City of Hope Clinical Research Protocol Deviation policy. 
 
7.3 
Merck requirements for Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product and which does not 

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necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), 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 
use of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials, or 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse 
and from withdrawal. 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before treatment starts, must be reported by the investigator if the participant is receiving  
run-in treatment, if the event causes the participant to be excluded from the study, or is the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, or a procedure.  
● All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study treatment must be reported by the investigator.  
● All AEs meeting serious criteria, from the time of treatment start through 90 days following 
cessation of study treatment, or 30 days following cessation of study treatment if the participant 
initiates new anticancer therapy, whichever is earlier must be reported by the investigator.  
● All pregnancies and exposure during breastfeeding, from the time of treatment start through 
120 days following cessation of study treatment, or 30 days following cessation of study 
treatment if the participant initiates new anticancer therapy must be reported by the 
investigator.  
●Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately by the investigator if the event is 
considered to be drug-related. 
Investigators are not obligated to actively seek AE or SAE or other reportable safety events in 
former study participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she considers the 

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event to be reasonably related to the study treatment or study participation, the investigator 
must promptly notify Merck. 
 
7.3.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this study, 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 overdose of pembrolizumab. In the event of overdose, the participant should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product 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 Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229). 
 
7.3.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and infant exposure during breast feeding are not considered adverse 
events, it is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a participant (spontaneously reported to them) that occurs during the study. 
Pregnancies and infant exposures during breast feeding that occur after the consent form is 
signed but before treatment  must be reported by the investigator if they cause the participant 
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, or a procedure.   
Pregnancies and infant exposures during breast feeding that occur from the time of treatment 
start through 120 days following cessation of Sponsor’s product, or 30 days following 
cessation of treatment if the participant 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. 

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Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety (Attn: Worldwide Product Safety; FAX 215-661-6229). 
 
7.3.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.3.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• causes another important medical event  
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per 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. 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose. 
 
Refer to Table 7 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause that occurs to any participant must be reported within 24 
hours to the Sponsor and within 2 working days to Merck Global Safety if it causes the 
participant 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. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the participant initiates 
new anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a 
serious adverse event, including death due to any cause whether or not related to the Merck 
product, must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product 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 

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in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to Merck Global Safety. 
All participants with serious adverse events 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:  +1-215-661-6229 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or 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 215-661-6229) at the time of submission to FDA. 
 
7.3.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229). 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any participant must 
be reported within 2 working days to Merck Global Safety if it causes the participant 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. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the participant initiates 
new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not 
related to Merck product, must be reported within 2 working days to Merck Global Safety. 
 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.4.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor and to Merck, 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 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 

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*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.  
 
7.3.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 5.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
This Phase II study is based on prior experience of the combination of p53MVA and 
pembrolizumab, and overlapping toxicities are not expected.  However, we will monitor 
closely for toxicity. If there are more than 2 serious adverse events related to treatment on 
protocol in the first 9 subjects, the study will hold for toxicity review. 

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Table 7 Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
CTCAE V5.0 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 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 serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the participant, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event 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 serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of participant 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 adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to 
Merck within 2 working days. 

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Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the participant 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 adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck product caused the adverse event 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 test drug and the adverse event based upon the available 
information. 
The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the participant was actually exposed to Merck product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), 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 
Merck 
product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
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 
 

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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
Product 
(continued)  
Dechallenge 
Was 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 participant re-exposed to 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 ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCTPOSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE PARTICIPANT, 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 Merck product or drug class pharmacology or 
toxicology? 
The assessment of relationship will be reported on the case report forms /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 Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is reasonable.  
The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Participant did not receive the Merck product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable 
OR the AE is more likely explained by another cause than the Merck product.  (Also entered for a participant with overdose without an associated 
AE.) 

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7.3.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events 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 
This is a phase II study to evaluate the efficacy and safety of pembrolizumab+p53MVA 
vaccine in advanced ovarian cancer who have progressed after at least one line of 
chemotherapy for advanced disease and are resistant to platinum therapy.  
The primary endpoint in this trial will be response rate (CR+PR).  
Secondary endpoints include median PFS, median OS and clinical benefit (CR+PR+SD>6 
months), safety and tolerability, and biological correlates which remain exploratory in nature.  
Median PFS and OS will be reported in months. Clinical benefit will be calculated as the % of 
patients experiencing CR or PR or SD in total. Response rate, clinical benefit, PFS, and OS 
will also be summarized by PDL-1 expression.  
8.2 
Statistical Analysis Plan 
Sample Size Accrual Rate  
Study size is based on our therapeutic target of achieving with acceptable toxicity a 
considerable improvement in the response rate observed with single agent pembrolizumab in 
this patient population, previously reported as 8% (KEYNOTE-100).  Specifically, we seek to 
have good power to detect an improvement in the response rate to 25%.  To achieve this, 
Simon’s MiniMax two-stage design is employed  to have 85% power to detect a true promising 
response rate of 25%, with a type I error of 8% for declaring a true discouraging response rate 
of 8% as worthy of further consideration:  Initially, 17 patients will be enrolled for the first 
stage.  If 2 or more patients experience a response during the first stage, accrual will continue 
to 28 patients.  With a total of 28 patients, at least 5 responders (18%) is the minimum to 
determine the combination worthy of further consideration. This design has a 60% chance of 
early stopping if the true response rate is 8%.  Final determination of promise will be based on 
the totality of the clinical endpoints and consideration of the profile of patients’ PDL-1 
expression, where a different accrual pattern when compared to KEYNOTE-100 may require 
a higher or lower threshold for the final decision. Expected accrual rate is approximately one 
patient every one and ½ months. 
Analysis of Biological Correlates 
Peripheral blood samples will be collected pre- and post-immunization for assessment of anti-
p53 T cell responses and immunophenotyping.  Immunosuppresive cell types (MDSC, Tregs) 
and other selected lymphocyte subsets and markers including PD-1, PDL-1 and PDL-2 will be 
quantified. Secondary endpoints will be clinical responses and T cell reactivity to p53. These 

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secondary endpoints are exploratory in nature. We will evaluate if the CD8+ T cell signal 
exceeds that detected in the single agent p53MVA trial. In the prior single agent study the p53-
reactive CD8+ T cells increased above baseline after the first immunization, but did not expand 
further with subsequent immunization. We hypothesize that the CD8+ T cell response will be 
enhanced by pembrolizumab, resulting in larger or more durable increases in the CD8+ T cell 
response. The total area under the curve (AUC) of the CD8+ T cell reactivity over three 
injections (minus the baseline) provides a metric for this requirement.  We have approximately 
84% power to detect a 2.1-fold increase in AUC with a type I error of 22%. Empirically, this 
is associated with a cut-off of a 55% increase in AUC.  These estimates use the Wilcoxon rank-
sum test, and are based on residual re-sampling simulations based on historical AUC values 
(subtracting baseline) and a hypothesized increase in that AUC. 
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 product in accordance with the protocol and any applicable laws and 
regulations. 
Pembrolizumab will be provided by Merck as summarized in Table 8. 
Table 8 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Supplies will be labeled in accordance with regulatory requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the participant, the trial site personnel, the 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. 
 
 
 
 

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9.4 
Storage and Handling Requirements 
PEMBROLIZUMAB 
Clinical supplies 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. Clinical supplies may not be used for any purpose 
other than that stated in the protocol. 
Preparation: Add 2.3 mL of Sterile Water for Injection, USP by injecting the water along the 
walls of the vial (not directly on the lyophilized powder), resulting in a concentration 25 mg/ml. 
Slowly swirl the vial. Allow up to 5 minutes for the bubbles to clear. Do not shake the vial. 
Visually inspect the reconstituted solution for particulate matter and discoloration prior to 
administration. Reconstituted pembrolizumab is a clear to slightly opalescent, colorless to 
slightly yellow solution. Discard reconstituted vial if extraneous particulate matter other than 
translucent to white proteinaceous particles is observed. Alternatively, pembrolizumab 
solution provided at 100mg/4mL (25mg/mL) will be used. 
 
Withdraw the required volume from the vial(s) of pembrolizumab and transfer into an 
intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP. Mix diluted solution 
by gentle inversion. The final concentration of the diluted solution should be 1 mg/mL - 10 
mg/mL and administered IV over 30 minutes, through an intravenous line containing a sterile, 
non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter.  
 
Storage of Reconstituted and Diluted Solutions: pembrolizumab contains no preservative, 
hence reconstituted, diluted solutions should not be stored at room temperature for more than 
6 hours after preparation. This includes storage of reconstituted vials, storage of infusion 
solutions in the IV bag and the duration of infusion. Under refrigeration (2°C - 8°C) diluted 
solutions should not be stored for more than 24 hours from the time of preparation. If 
refrigerated, allow the diluted solution to come to room temperature prior to administration. 
Do not freeze. Caution should be exercised in handling pembrolizumab solutions. The use of 
gloves and gowns is recommended. If the product comes into contact skin or mucosa, the skin 
should be washed thoroughly with soap and water and mucosa irrigated with copious amounts 
of water.  
 
Disposal: Unused and residual drug should be put into a plastic bag and disposed of in a 
chemical waste container. 
 
p53MVA Vaccine (IND#14716)  
p53MVA is a Modified Vaccina Ankara Virus based vaccine expressing the full length, wild 
type human p53 gene. The p53MVA vaccine was evaluated in an FDA directed toxicology 
study in mice.  p53MVA was administered doses 50 fold higher, in a mg/kg basis, than the 
proposed starting clinical dose. There was no obvious toxicity seen in the animals in terms of 
weight, physical appearance, activity level, chemical or hematologic parameters.  Histologic 
evaluation of organs at necropsy revealed no evidence of toxicity.  p53MVA was cleared from 
the skin injection site within 60 days of administration and from all other tissues including 
blood within 2 weeks of administration. In the first in human study conducted at COH, the 

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p53MVA vaccine was been well-tolerated at doses of 1 x108 pfu and 5.6 x108 pfu with only 
low grade toxicity being reported. 
p53MVA has been manufactured using GMP-grade materials at The Center for Biomedicine 
and Genetics (CBG) at City of Hope. The final product is diluted in PBS with 7.5% lactose 
and vialed at 1.2ml per vial. The concentration is 4.5 x 108 pfu/ml.  The vaccine is expected to 
remain stable at room temperature for a minimum of 4 hours, as determined in recently 
completed stability study stipulated by the FDA.  Patients will receive injections of 1.1ml for 
dose level 1. In the event of de-escalation to dose level -1, patients will receive an injection 
volume of 0.5ml, giving a dose of 2.2 x 108 pfu.  
Preparation: p53MVA will be stored in a -80 C freezer with restricted access. Variations in 
temperature between -60 C to -90 C will be acceptable and will maintain MVA virus stability. 
Vaccine preparations will be dispensed by the City of Hope Investigational Drug Service 
(IDS). Vials will be thawed at room temperature. Administration of the vaccine must occur 
within 4 hours after vial is removed from freezer. The vial will be vortexed for 60 seconds at 
the highest setting followed by visual inspection for clumps. If clumps are observed, a further 
vortex of 60 seconds will be performed. The time at which vortexing is completed will be 
recorded in the log and the vaccine dispensed, even if clumping is still visible. One dose of 
vaccine preparation will be drawn into a 3ml sterile syringe (dose level 1) or 1ml sterile syringe 
(dose level -1), approximately 1.1ml of solution, dose volume not to exceed 1.1ml. After 
labeling appropriately, the syringe will be placed in a sealable plastic bag and placed on ice for 
transport to the clinic for administration. The research nurse will attach a needle to the syringe 
containing the vaccine and the dose of p53MVA will be administered by a single injection into 
subcutaneous tissue of the upper arm (over deltoid muscle). There is no available data on 
potential drug interactions of p53MVA in humans. 
Caution should be exercised in handling and preparing p53MVA vaccine solution. The use of 
gloves and gowns is recommended. If vaccine comes into contact with skin or mucosa, skin 
should be washed thoroughly with soap and water and mucosa irrigated with copious amounts 
of water. Unused and residual p53MVA should be put into a plastic biohazard bag and disposed 
of in a biological waste container. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the participants and the 
amount remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used investigational 
product from Merck 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 provided that appropriate records of disposal are 
kept. 

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All unused (unopened) vials of p53MVA vaccine will be stored at COH IDS, or returned to 
the CBG, as per the PI direction. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Institutional Review Board 
In accordance with City of Hope policies, an Institutional Review Board (IRB) that complies 
with the federal regulations at 45 CFR 46 and 21 CFR 50, 56 and State of California Health 
and Safety code, Title 17, must review and approve this protocol and the informed consent 
form prior to initiation of the study.  All institutional, NCI, Federal, and State of California 
regulations must be fulfilled. 
10.2 Recruitment of Subjects 
Individuals who satisfy the inclusion criteria will be identified through the individual 
practitioners in the Departments of General & Oncologic Surgery and Medical Oncology and 
Therapeutics Research at COH.  Written informed consent will be obtained from the 
participant.   
10.3 Advertisements 
A lay summary to be posted on City of Hope’s public Clinical Trials On-LineSM website and 
Clinicaltrials.gov will be reviewed and approved by the IRB prior to their use to recruit 
potential study subjects. 
10.4 Study location and Performance Sites 
This study will be performed at the City of Hope National Medical Center.  All study 
interventions will be performed at this site by a study nurse under the direction of Dr. Thanh 
Dellinger or her designee at the Clinical Research Unit (Phase I unit) at COH.  The laboratory 
analysis will take place in the Department of Experimental Therapeutics, Fox South, Room 
1002 under the direction of Dr. Don Diamond. 
10.5 Confidentiality 
This research will be conducted in compliance with federal and state of California requirements 
relating to protected health information (PHI).  The study will record individual immunological 
response to the vaccine and any side effects, and this will be linked to the subject’s identity 
using a coded study number.  The principal investigator, co-investigators, and laboratory 
technicians will have access to this information, but all information will be treated 
confidentially.  No identifiers will be used in any subsequent publication of these results. 
Clinical information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA or NIH. 

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10.6 Financial Obligations and Compensation 
The investigational agents, p53MVA and pembrolizumab, will be provided free of charge by 
COH according to the protocol.   
Standard of care drugs and procedures will be the responsibility of the research participant and/or 
the insurance carrier.  The research participant will be responsible for all copayments, 
deductibles, and other costs of treatment and diagnostic procedures as set forth by the insurance 
carrier.  The research participant and/or the insurance carrier will be billed for the costs of 
treatment and diagnostic procedures in the same way as if the research participant were not in 
a research study.  However, neither the research participant nor the insurance carrier will be 
responsible for the research procedures related to this study. 
In the event of physical injury to a research participant, resulting from research procedures, 
appropriate medical treatment will be available at the City of Hope to the injured research 
participant, however financial compensation will not be available. The research participant will 
not be paid for taking part in this study. 
10.7 Informed Consent Processes 
The Principal Investigator or IRB approved named designate will explain the nature, duration, 
purpose of the study, potential risks, alternatives and potential benefits, and all other 
information contained in the informed consent document.  In addition, they will review the 
experimental subject’s bill of rights and the HIPAA research authorization form.  Research 
subjects will be informed that they may withdraw from the study at any time and for any reason 
without prejudice, including as applicable, their current or future care or employment at City 
of Hope or any relationship they have with City of Hope.  Research subjects will be afforded 
sufficient time to consider whether or not to participate in the research. 
Before signing the study consent form, HIPAA authorization form and the Experimental 
Subject’s Bill of Rights, research subjects will undergo an assessment of their comprehension 
of the study by the Research Subject Advocate.  Should sufficient doubt be raised regarding 
the adequacy of comprehension, further clarifications will be made and the questionnaire 
repeated until a satisfactory result is obtained.  Prospective research subjects who cannot 
adequately comprehend the fundamental aspects of the research study with a reasonable 
amount of discussion, education and proctoring will be ineligible for enrollment.  For those 
subjects who do comprehend the fundamental aspects of the study, consent will be obtained 
and documented, followed by eligibility testing.  The research team will review the results of 
eligibility testing and determine if the subject is a candidate for study enrollment.  
 
 
 

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12.0 APPENDICES 
Appendix 1: ECOG Performance Status 
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. 
* As published in Am. J. Clin. Oncol.:Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J ClinOncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
 
Appendix 2: Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm) 
 
 
 
 
 
 
 

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Appendix 3: Contraceptive Guidance and Pregnancy Testing 
 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
▪ 
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 (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.  
○ Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
 
Contraception Requirements 
 
Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception that has a low user dependency consistently and 
correctly as described in Table 9 during the treatment phase and for 30 days after cessation of 
therapy.   
 
 

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Table 9 
Highly Effective Contraceptive Methods That Have Low User Dependency 
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen-only contraceptive implant a 
● Intrauterine hormone-releasing system (IUS) 
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant. 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies. 
 
a) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive implants are limited to those which inhibit ovulation. 
 
 
Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test. Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.