Phase I/II Trial of Combination Immunotherapy in Subjects With Advanced HPV Associated Malignancies
Phase: PHASE1
Conditions: Cervical Cancer, HPV Cancers, Anal Cancer, Oropharyngeal Cancer, Vulvar, Vaginal, Penile, Rectal Cancer
Sponsor: National Cancer Institute (NCI)

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Abbreviated Title: Combo Immunotx in HPV Cancers
Version Date: 04.03.2025
Abbreviated Title: Combo Immunotx in HPV Cancers 
NIH Protocol #: 20C0045
Version Date:  April 3, 2025
NCT Number: NCT04287868 
RSC Number: 2744
Title: Phase I/II Trial of Combination Immunotherapy in Subjects with Advanced HPV 
Associated Malignancies
NCI Principal Investigator: Charalampos Floudas, MD, DMSc, MS  
Center for Immuno-Oncology (CIO)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
10 Center Drive 
Building 10, Room 7N240A 
Bethesda, MD 20892 
Phone: 240-858-3032 
Email: charalampos.floudas@nih.gov 
Drug Name:
PDS0101
MSB0011359C
(M7824)
M9241 (also named 
PDS01ADC)
IND Number:
019267
019267
019267
Sponsor:
Center for Cancer 
Research, NCI
Center for Cancer 
Research, NCI
Center for Cancer 
Research, NCI
Manufacturer:
PDS Biotechnology
EMD Serono, Inc.
PDS Biotechnology
Supplier:
PDS Biotechnology
EMD Serono, Inc.
PDS Biotechnology
Commercial Agents: None

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PRÉCIS
Background:
•
Metastatic or refractory/recurrent HPV associated malignancies (cervical, anal, 
oropharyngeal cancers etc.) are poorly palliated by standard therapies. There is an unmet 
need for active treatments for these tumors.
•
In a phase I trial of M7824 (NCT02517398) 15 out of 43 (34.9%) participants with HPV 
associated malignancies had radiographic tumor responses according to RECIST 1.1 or 
iRECIST.
•
While the response rate observed with M7824 appears to be higher than single agent    
PD-1 inhibitors alone (15-20%), the majority of patients with these diseases still do not 
seem to benefit from immunotherapy.
•
Preclinical studies suggest that the use of a combination of multiple immunotherapy 
agents may have improved anti-tumor efficacy. 
o
Specifically, preclinical studies have shown that the combination of three 
immunotherapy agents (1) a therapeutic vaccine against HPV positive cancers 
(PDS0101), (2) a bifunctional fusion protein targeting PD-L1 and TGF beta 
(M7824), and (3) a tumor targeted immunocytokine (PDS01ADC) produces 
greater anti-tumor activity than any single or dual combination of these agents.  
Objectives:
•
To evaluate the objective response rate (ORR) according to Response Evaluation 
Criteria (RECIST 1.1) of the combination of (1) a therapeutic vaccine against HPV 
positive cancers (PDS0101), (2) a tumor targeted immunocytokine (PDS01ADC) and 
(3) a bifunctional fusion protein targeting PD-L1 and TGF beta (M7824) in subjects 
with checkpoint naïve advanced HPV associated malignancies.   
Eligibility:
•
Age > 18 years old.
•
Subjects with cytologically or histologically confirmed locally advanced or metastatic 
HPV associated malignancies:
o
Cervical cancers;  
o
P16+ Oropharyngeal cancers; 
o
Anal cancers; 
o
Vulvar, vaginal, penile, and squamous cell rectal cancers;
o
Other locally advanced or metastatic solid tumors (e.g., lung, esophagus) that are 
known HPV+. 
•
Prior first line systemic therapy is required unless the participant declines standard 
treatment after appropriate counseling has been provided.
•
Subjects must have measurable disease.

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Design:
•
This is a phase I/II trial of combination immunotherapy. 
•
The trial will be conducted using a Simon optimal two-stage design. 
•
Participants will receive HPV vaccine + PDS01ADC + M7824. 
•
The first six participants will be evaluable for dose limiting toxicities (DLTs) and accrual 
will only continue to 8 participants who have not been treated with checkpoint inhibitors 
if less than 2 out of the first 6 participants experience a DLT. 
•
If three or more out of eight participants who have not been treated with checkpoint 
inhibitors have objective responses accrual will be expanded to enroll 20 evaluable 
participants.  
•
Patients with cervical cancer with prior pelvic radiation and boost brachytherapy will be 
enrolled in a separate cohort to evaluate safety and preliminary evidence of efficacy.

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TABLE OF CONTENTS 
PRÉCIS...........................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ................................................................................................7
1.
INTRODUCTION ...................................................................................................................7
1.1
Study Objectives ...............................................................................................................7
1.2
Background and Rationale................................................................................................8
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................30
2.1
Eligibility Criteria ...........................................................................................................30
2.2
Screening Evaluation ......................................................................................................32
2.3
Participant Registration and Status Update Procedures..................................................34
2.4
Baseline Evaluation.........................................................................................................35
3
STUDY IMPLEMENTATION .............................................................................................35
3.1
Study Design...................................................................................................................35
3.2
Drug Administration .......................................................................................................39
3.3
Study Intervention Compliance ......................................................................................40
3.4
Dose Modifications.........................................................................................................40
3.5
Study Calendar................................................................................................................51
3.6
Cost and Compensation ..................................................................................................53
3.7
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................53
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................54
4.1
The Following Treatments Should Not Be Administered During the Trial ...................54
5
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES ..........55
5.1
Biospecimen Collection ..................................................................................................55
5.2
Samples for Genetic/Genomic Analysis .........................................................................58
5.3
Storage Use and Sharing of Specimens and Data (Including for Secondary Research)
Error! Bookmark not defined.
6
DATA COLLECTION AND EVALUATION .....................................................................61
6.1
Data Collection ...............................................................................................................61
6.2
Data Sharing Plans..........................................................................................................62
6.3
Response Criteria ............................................................................................................62
6.4
Toxicity Criteria..............................................................................................................69

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7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN...69
7.1
Definitions.......................................................................................................................69
7.2
OHSRP Office of Compliance and Training / IRB Reporting........................................69
7.3
NIH Required Data and Safety Monitoring Plan............................................................70
8
SPONSOR PROTOCOL/SAFETY REPORTING................................................................70
8.1
Definitions.......................................................................................................................70
8.2
Assessment of Safety Events ..........................................................................................72
8.3
Reporting of Serious Adverse Events .............................................................................72
8.4
Waiver of expedited reporting to CCR ...........................................................................73
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborators......................................73
8.6
Reporting Pregnancy.......................................................................................................73
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND...................73
8.8
Sponsor Protocol Deviation Reporting ...........................................................................74
8.9
Data Safety Monitoring Board (DSMB) (OSRO)...........................................................74
9
CLINICAL MONITORING PLAN ......................................................................................75
10
STATISTICAL CONSIDERATIONS ...............................................................................76
10.1
Statistical Hypothesis ..................................................................................................76
10.2
Sample Size Determination.........................................................................................76
10.3
Populations for Analyses.............................................................................................77
10.4
Statistical Analyses......................................................................................................77
11
COLLABORATIVE AGREEMENTS...............................................................................79
11.1
Cooperative Research and Development Agreement (CRADA)................................79
12
HUMAN SUBJECTS PROTECTIONS.............................................................................79
12.1
Rationale For Subject Selection ..................................................................................79
12.2
Participation of Children .............................................................................................79
12.3
Participation of Subjects Unable to Give Consent ......................................................79
12.4
Risks/Benefit Assessment ...........................................................................................80
12.5
Consent Process and Documentation ..........................................................................82
13
REGULATORY AND OPERATIONAL CONSIDERATIONS.......................................83
13.1
Study Discontinuation and Closure.............................................................................83
13.2
Quality Assurance and Quality Control ......................................................................84
13.3
Conflict of Interest Policy ...........................................................................................84

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13.4
Confidentiality and Privacy.........................................................................................84
14
PHARMACEUTICAL INFORMATION ..........................................................................85
14.1
PDS0101 (IND # 019267)...........................................................................................85
14.2
M7824 (MSB0011359C) (IND # 019267)..................................................................87
14.3
PDS01ADC (IND # 019267) ......................................................................................90
15
REFERENCES ...................................................................................................................91
16
APPENDICIES...................................................................................................................96
16.1
Appendix A Performance Status Criteria....................................................................96

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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council for Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1. INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
•
To evaluate the objective response rate (ORR) according to Response Evaluation Criteria 
(RECIST 1.1) of the combination of (1) a therapeutic vaccine against HPV positive 
cancers (PDS0101), (2) a tumor targeted immunocytokine PDS01ADC (NHS-IL12, 
M9241) and (3) a bifunctional fusion protein targeting PD-L1 and TGF beta (M7824) in 
subjects with checkpoint naïve advanced HPV associated malignancies.   
1.1.2
Secondary Objectives
•
To evaluate the safety of the combination of (1) a therapeutic vaccine against HPV 
positive cancers (PDS0101), (2) a tumor targeted immunocytokine PDS01ADC (NHS-
IL12, M9241) and (3) a bifunctional fusion protein targeting PD-L1 and TGF beta 
(M7824) in subjects with advanced HPV associated malignancies.   
•
To assess progression-free survival time (PFS) according to RECIST 1.1. 
•
To assess overall survival (OS). 
•
To assess duration of response and ratio of participants that are hospitalized because of 
adverse events attributed to disease progression.
•
To evaluate the safety of the combination at a reduced dose level in patients with cervical 
cancer with prior pelvic radiation and boost brachytherapy where a potential higher risk 
of grade 3 hematuria may exist with the full starting doses of both M7824 and 
PDS01ADC.
1.1.3
Exploratory Objectives
•
To conduct exploratory immunologic studies to understand and improve the administered 
treatment, including:

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o
peripheral immune subset analysis before and on treatment;
o
soluble factors circulation (e.g., sCD27 and sCD40 ligand) before and on 
treatment;
o
tumor tissue immune infiltration before and after treatment.
•
To assess responses to therapy using iRECIST. 
•
To assess responses to therapy by HPV serotype or PD-L1 expression.
•
To assess correlation between circulating tumor DNA and response to therapy
•
To assess response to therapy in checkpoint refractory disease
•
To assess response to therapy by HLA type
•
To assess response using reduced doses of PDS01ADC or M7824
1.2
BACKGROUND AND RATIONALE
1.2.1
HPV Associated Malignancies  
In the United States, there are more than 30,000 cases of HPV associated cancer annually [1] 
(Table 1). Metastatic HPV associated malignancies (cervical, anal, oropharyngeal cancers etc.) 
are often incurable and poorly palliated by standard therapies. Responses to chemotherapy are 
variable but generally short-lived with median PFS around 3 to 7 months [2-5]. In a Gynecologic 
Oncology Group randomized trial comparing four cisplatin-based doublets as first line therapy for 
cervical cancer the response rates were 22-29% and median PFS was 4 to 6 months with median 
OS 10 to 13 months [6]. The addition of bevacizumab to combination chemotherapy has been 
reported to increase OS by 3.7 months, but virtually all patients die of their disease within 2 years 
[7]. Randomized trials of second line therapy are lacking but response rates for single agents are 
generally reported to be less than 20% [8]. Early evidence suggests that immune checkpoint 
therapy also has a low response rate in this disease with a phase 1b trial (KEYSTONE 028) 
showing a 12.5% response rate (3/24 patients) and a phase II study showing a response rate of 
13.3% (13/98 patients) to pembrolizumab in patients with recurrent or metastatic cervical cancer 
[9].  
Table 1:  Estimated annual incidence of HPV associated cancers in the US
Site
Incidence of HPV associated cancers 
Cases attributed to HPV (%)
Oropharyngeal
15,738 
11,000 (70.1%)
Cervix
11,771
10,700 (90.6%)
Vulvar
3554
2400 (68.8%)
Vaginal
802
600 (75%)
Penis
1168
700 (63.3%)

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Site
Incidence of HPV associated cancers 
Cases attributed to HPV (%)
Rectal (squamous 
cell)
750
700 (91.1%)
Anus
5,010
4,600 (91.1%)
Total
38,793
30,700 (79.1%)
For oropharyngeal cancer, the best estimates of the chemotherapy responsiveness are inferred from 
looking at the oropharyngeal site in subset analyses from clinical trials for head and neck cancers. 
In a pivotal clinical trial that established platinum, 5-fluorouracil (5-FU), plus cetuximab as first 
line therapy in head and neck cancer, patients with oropharyngeal tumors experienced PFS of 4 to 
6 months and OS of 8 to 11 months [3]. Immune checkpoint therapy has become the standard 
second line therapy for metastatic oropharyngeal cancer but response rates are still low with this 
therapy. As an example, the phase 1b trial (KEYNOTE-012) of pembrolizumab which led to its 
FDA approval for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) as 
second line therapy had a 17.7% response rate (34/192 patients). Response rates were slightly 
better in HPV positive HNSCC (21.9%) [10], but still occurred in only a minority of the patients. 
In regard to metastatic anal cancer, only a handful of randomized trials have been performed in the 
last 30 years. In the metastatic setting, most of the evidence is limited to small phase II trials, 
retrospective series, and case reports. A recent retrospective series looking at 77 patients, 44 (55%) 
of whom received 5-FU in combination with cisplatin, 24 (31%) of whom received carboplatin + 
paclitaxel, and 11 (14%) of whom received another regimen showed a median PFS of 7 months 
and median OS of 22 months [5]. As with HNSCC, recent early phase trials evaluating immune 
checkpoint therapy in this disease have shown that responses here too are limited to around 20% 
of patients treated. A recent phase II trial of nivolumab for metastatic squamous cell anal cancer 
showed a 21% response rate (7/33 patients) and a recent phase IB trial (KEYNOTE-028) of 
pembrolizumab showed a 20% response rate (5/25 patients) [11]. In a recently published phase II 
trial, Massarelli et al. evaluated the combination of a therapeutic HPV vaccine and Nivolumab 
[12]. In contrast to previous single therapy immune checkpoint inhibitor trials, they found an 
overall response rate of 33% showing the potential benefit of Immuno-Oncology (I/O) 
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Table 2 Response in patients treated with ISA101 and Nivolumab (Massarelli JAMA Oncol 
Sept 27, 2018)
Unfortunately, little data exists evaluating immunotherapy for rarer HPV associated malignancies 
including metastatic vulvar, vaginal, penile, squamous cell rectal or neuroendocrine cervical 
cancer.  
1.2.2
Rationale for Combination of I/O Agents
Preclinical studies are now revealing that an effective immuno-oncology strategy for enhancing 
anti-tumor responses is the use of multiple immune-mediating agents, each targeting different 
components of the immune system. These include: (a) induction of an immune response via 
vaccination directed against tumor-associated antigens, (b) reduction of immunosuppressive 
entities in the TME by the use of anti-PD1/PDL1 MAb checkpoint inhibitors, and/or reduction of 
immunosuppressive cytokines such as TGF-β with the use of a bifunctional anti-PDL1/TGF-β2 
“Trap” designated M7824, and (c) potentiation of the immune response in the TME by the use of 
the tumor targeting NHS-IL12 immunocytokine.  
The CIO, in collaboration with the GMB, has been able to develop and/or co-develop these agents 
via a series of CRADAs. Each has been interrogated in a series of preclinical studies and in Phase 
I/II clinical studies in the CCR as well as by other investigators. Preclinical studies and early 
clinical studies are demonstrating the relative lack of additional toxicities with enhanced clinical 
benefit employing combinations of 2 of these agents. Preclinical studies are now demonstrating 
that the combined use of agents from each of the immune-mediating categories described above 
elicits the most immune-mediated anti-tumor activities.
1.2.2.1
HPV Vaccine
PDS0101 is a novel nanoparticle-based immunotherapy (therapeutic vaccine) developed to treat 
genital cancers such as anal, cervical, vulvar cancer etc. and their precancers (late-stage 
dysplasia/neoplasia), as well as head and neck cancers caused by infection with the human 
papilloma virus (HPV). PDS0101 is a subcutaneously administered therapy consisting of two 
vialed components mixed by the investigator at the time of administration. The immunotherapy is 
composed of liposomal nanoparticles of the pure immunologically active R enantiomer of the 

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cationic (positively charged) lipid DOTAP (dioleoyl-trimethylammonium propane) mixed with 6 
lipidated antigenic peptides derived from the HPV-16 E6 and E7 proteins. 
In-vivo and in-vitro studies performed in normal and transgenic mouse models as well as in-vitro 
studies using human lymphocytes in culture demonstrated potent immune modulating effects by 
R-DOTAP. The pure R stereoisomer of DOTAP acts as a potent activator of the MAP kinase 
signaling pathway leading to activation and maturation of dendritic cells and subsequent induction 
of the production and release of cytokines and chemokines critical for promotion of an effective 
immune response. The positive charge on the surface of R-DOTAP liposomes facilitates their 
uptake by the dendritic cell. This in turn facilitates uptake of the HPV peptide antigen micelles and 
the antigenic processing and presentation by dendritic cells to T-cells. The ability of cationic 
liposomes to destabilize endosomes facilitates antigen delivery into the cytoplasm of the dendritic 
cells and other antigen presenting cells [13].  Effective induction of cytotoxic T-lymphocyte (CTL) 
responses and tumor regression has been demonstrated in the pre-clinical studies. 
Figure 1. Anti-tumor efficacy of DOTAP/E7 vs. CpG-E7 and CFA-E7 in C57BL/6J mice 
bearing TC-1 HPV+ tumors.  
Toxicology studies of R-DOTAP and a prototype R-DOTAP/HPV16-E7 single peptide 
formulation were evaluated in rats and in non-human primates (monkeys). No deaths or clinical 
signs related to treatment were observed in any of the studies. No treatment effects on body weight 
were noted. No treatment-related and/or toxicologically significant effects for any clinical 
chemistry parameters evaluated were noted during any of the studies. All hematology parameters, 
red blood cell counts, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin and 
mean corpuscular hemoglobin concentration remained normal.  
Toxicology 
of 
the 
PDS0101 
clinical 
formulation 
(6-peptide 
HPVmix 
and 
ImmunoMAPKRDOTAP) was evaluated in humanized transgenic mice.  The transgenic mice 
expressed the human HLA-A2 antigen recognition and presentation molecule, and their antigen 
presenting cells were therefore capable of recognizing and responding to the HPV A2 epitope 
human peptide antigens in the drug formulation. Similar to toxicology studies in rats and monkeys 

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with the prototype drug formulation, few clinically relevant toxicological effects were observed at 
any dose level in the transgenic humanized mice. However, for the clinical PDS0101 formulation 
mean hematocrit was decreased in the low R-DOTAP + HPVmix and high R-DOTAP + HPV mix 
groups by approximately 3% and 5%, respectively; and although minimal, may be related to 
treatment. No treatment-related toxicological findings were observed during gross necropsy. 
Microscopic histopathologic findings (minimal fibrosis) considered related to treatment with the 
test article were limited to the skin at the injection site in 3 out of 8 in the high R-DOTAP + HPV 
mix group only. 
In 2014-2016, a Phase I/IIA human clinical trial was performed at 3 sites in the US in 12 subjects 
with high-risk HPV infection and biopsy-proven cervical intraepithelial neoplasia (CIN1) to study 
the safety and immunogenicity of PDS0101.The study initiated with Cohort 1 and progressed 
through Cohort 3, with each subsequent cohort receiving a higher dose of PDS0101 (i.e., 1.0, 3.0, 
and 10.0 mg R-DOTAP); 3 in Cohort 1 (1-mg R-DOTAP dose), 3 in Cohort 2 (3 mg R-DOTAP 
dose), and 6 in Cohort 3 (10-mg RDOTAP dose). Successive cohorts received a constant dose of 
2.4 mg HPV-16 E6 and E7 peptides (400 μg/peptide) with 1 of 3 escalating doses of R-DOTAP. 
All subjects received 3 doses of vaccine given SC, approximately 21 days apart.  10/12 subjects 
had a positive vaccine-induced response (a ≥3-fold increase over baseline at ≥1 of the 4 post-
vaccination visits by either the IFN-γ or granzyme B ELISpot assays, with background counts 
subtracted). Individual subject results from both the IFN-γ and the granzyme B assays showed that 
all doses of RDOTAP were effective in inducing HPV-specific T-cell responses (Figure 2A). IFN-
γ (all T-cells) and the granzyme B (CD8+ T-cells) responses were elicited in both HPV-16+ and 
HPV-16- subjects, and in subjects with various HLA types. 
Administration of PDS0101 was also well tolerated. The majority of AEs were due to 
administration site reactions. Most administration site reactions were mild or moderate in severity. 
Some more severe administration site reactions including swelling and redness were reported in 
the 3- and 10-mg R-DOTAP cohorts. Most administration site reactions resolved the same day or 
within a few days. Per the subject symptoms diary, administration site reactions were more severe 
and of longer duration in subjects in the 10-mg R-DOTAP cohort. No clinically significant 
differences in the types and pattern of TEAEs were observed between Vaccinations 1, 2, or 3. No 
DLTs were observed; thus, the MTD was the 10-mg R-DOTAP dose. No serious adverse events 
(SAEs), study discontinuations due to adverse events, or deaths occurred. No clinically relevant 
abnormal hematology, blood chemistry, urinalysis, or physical findings were observed. Regression 
of CIN was noted in a number of patients (Figure 2B). Regression was seen in CIN related to a 
variety of HPV types including HPV-16, HPV-18 as well as other high-risk HPV types. The 3-mg 
R-DOTAP PDS0101 dose (containing 2.7 mg HPV-16 E6 & E7 antigens) has been chosen for 
further evaluation in larger Phase II trials given it seems to afford the best combination of safety 
and potency.  The original dose of HPV-16 E6 & E7 antigens has been minimally increased from 
2.4 mg to 2.7 mg for planned phase II studies. This was done due to some concern with possible 
oxidation of one of the peptides at the original lower dose. For simplicity the dose of all peptides 
has been minimally increased.   

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Figure 2 A (top). ELISpot responses in patients treated with PDS0101. B (bottom). CIN 
Regression in patients treated with PDS0101 [14].
Avelumab (anti-PD-L1) and M7824 (anti-PD-L1/TGF- βR2)
Studies in the LITB were the first to describe [15, 16] avelumab, a fully human anti-PD-L1 IgG1 
MAb, and its ability to mediate ADCC for a range of human carcinoma cells employing NK cells 
as effectors. Avelumab (Bavencio) has since been approved by the FDA for the therapy of Merkel 
cell carcinoma (the first drug approved for this indication) and second line urothelial carcinomas. 
We have also shown that endogenous IL-12 will enhance avelumab-mediated NK lysis, thus 

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forming the basis for the combined use of avelumab or M7824 with NHS-IL12. The first-in-human 
clinical study of avelumab with over 1,700 patients was led by Gulley with the dose escalation and 
initial PK and PD done entirely within the CCR [16]. Because of the activity this study was 
amended to include multiple expansion cohorts internationally. Because PD-L1 is also expressed 
on some immune cell subsets, our finding [17] that there were no adverse events in the patients 
treated with avelumab above that seen with other anti-PD-L/PD-L1 MAbs was important for 
planning further studies with avelumab or M7824.
TGF-β is a well-known inhibitor of immune cell function, especially in the TME [18-23]. Prior 
studies have indicated the advantage in the use of a TGF-β inhibitor in combination with 
checkpoint therapy [24, 25] In collaboration with our CRADA partner EMD Serono, we have 
supported the development of a bifunctional fusion protein aimed at bringing a TGF-β TRAP to 
tumor cells via binding to PD-L1. M7824 is a novel fusion protein consisting of anti PD-L1 
antibody linked to the extracellular domain of two TGF-βR2 (serving as a TGF-β TRAP) (Figure 
3). 
Figure 3. Schematic drawings of Avelumab and M7824.
We were the first to report [26, 27] that M7824 (a) mediates ADCC, (b) increases tumor cell gene 
expression of molecules involved in T-cell trafficking to the tumor, (c) enhances TRAIL- and 
antigen-specific CD8+ T-cell lysis of tumor cells, and (d) reduces TGF-β‒induced 
immunosuppressive activity. We have also recently demonstrated [28] in in vivo preclinical 
murine carcinoma models (Figure 4A and B) that M7824 has the ability to decrease TGF-β‒ 
induced signaling in the TME. Specifically, phosphorylation of SMAD2 was significantly 
decreased in tumors following M7824 treatment, and not with an M7824(mut) molecule, devoid 
of the PD-L1 binding site (Figure 4C). In both breast and colon carcinoma murine models, M7824 
decreased tumor burden and increased survival, which required both CD8+ and NK cell activity 
(Figure 4D). 

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Figure 4 (A) Comparison of anti-tumor activity of M7824, and M7824(mut) devoid of PD-L1 
binding site in the EMT6 breast cancer model. (B) Accumulation of M7824 in the TME 
resulting in reduction of SMAD2 signaling (C) and increased T- and NK-cell activation 
(D). Knudson …Schlom J. OncoImmunology. 2018:e1426519. 
Two recent studies [29, 30] demonstrated the advantage in anti-tumor activity in the use of the 
bifunctional agent vs. the use of a PD- 1/PD-L1 checkpoint in combination with a systemic TGF-
β inhibitor. TGF-β is also known to alter human carcinoma cells from a more epithelial to a more 
mesenchymal phenotype and such tumor cells are more resistant to a range of therapies (Figure 
5). In LTIB studies, TGF-β‒induced mesenchymalization of carcinoma cells was shown [31] to be 
reversed by M7824, rendering tumor cells more susceptible to chemotherapy and immune-
mediated killing [26, 28, 31] 
The first-in-human trial of M7824 (anti-PD-L1/TGF-βR2) was conducted at the CCR [32]. 
Nineteen heavily pretreated patients with solid tumors (non-melanoma) were treated; the MTD 
was not reached. M7824 was shown to saturate peripheral PD-L1 and sequester all released (acid 
released) plasma TGFβ1, -β2, and -β3 throughout the dosing period at >1 mg/kg (recommended 
phase 2 dose is 1200 mg or about 10 mg/kg). There were signs of clinical efficacy across all dose 
levels (Figure 6 and Figure 7), including one ongoing CR (cervical cancer), two durable PRs 
(pancreatic and anal cancers), one near PR (cervical) and two cases of prolonged stable disease. 

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Figure 5. Functions of M7824.

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Figure 6. Phase I trial of M7824, spider plot of tumor responses and reduction of serum levels of 
TGF1.

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Figure 7. M7824 Phase I, responses in two patients.
In the Phase I study [32] 15/43 (34.9%) of patients with checkpoint naïve HPV associated 
malignancies had radiographic tumor responses according to RECIST 1.1 or iRECIST with M7824 
(anti-PD-L1/TGF-βR2) therapy. Prior studies by others have shown approximately a 15% 
objective response in this population employing checkpoint inhibition therapy. In an ongoing 
phase II study (NCT03427411) 3/22 (13.6%) patients with checkpoint refractory advanced HPV 
associated malignancies have had responses to M7824 which compares well to the less than 5% 
response rate seen in the literature with further checkpoint therapy. 
Sufficient peripheral blood mononuclear cells were available from 12 patients on the phase I trial 
to test for HPV-specific T-cell responses before and after M7824 treatment. Considering all post-
therapy timepoints examined, 7 of 12 patients (58%) had an increase in HPV-specific T cells post- 
vs pre-M7824 therapy. Immune responses after 1 and 3 cycles of M7824 were compared between 
patients who developed a clinical response of stable disease or better vs those with progressive 
disease (Figure 8). In clinical responders, HPV-specific T cells developed in 3 of 4 patients (75%) 
after 1 cycle of M7824 and in 4 of 4 patients (100%) after 3 cycles. On the other hand, in patients 
with progressive disease, HPV-specific T cells developed in only 1 of 5 patients (20%) after 1 
cycle of M7824 and in 1 of 4 patients (25%) after 3 cycles (Supplementary Table 3). There was 
also an increased magnitude of HPV-specific T cells generated in clinical responders vs 
nonresponders: clinical responders had on average 12- to 27-fold more HPV-specific T cells 

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Abbreviated Title: Combo Immunotx in HPV Cancers
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producing cytokines or positive for CD107a (LAMP1, a functional marker of T and NK cell 
activity) after 1 and 3 cycles of M7824 compared with nonresponders (Figure 3A).
Another observation worth noting is that 2 of the 3 patients with HPV+ cancer who received prior 
lymphodepleting chemotherapy (e.g., cyclophosphamide, fludarabine) were assessed for immune 
responses post- vs pre-M7824 therapy, and neither had evidence of an HPV T-cell‒specific 
immune response. In contrast, in patients with HPV+ cancer who did not receive prior 
lymphodepleting chemotherapy, 6 of 9 (67%) had a positive T-cell‒specific immune response.
Figure 8. Immune responses in HPV+ patients with disease control (BOR of SD, PR, or CR) vs 
nonresponders (BOR of PD) to M7824 therapy by intracellular cytokine staining 
following in vitro stimulation with a mixture of overlapping 15-mer peptide pools 
encoding HPV-16 E6 and E7, as previously described.21

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PDS01ADC Immunocytokine (NHS-IL12, M9241)
PDS01ADC (previously called NHS-IL12 or M9241) is a tumor targeting immunocytokine that 
binds to DNA-histone in necrotic areas of tumor. Studies by others have shown the ability of 
radiolabeled NHS-IL12 to target murine and human tumors (Figure 9). Prior studies in the LTIB 
have shown the ability of this agent to elicit anti-tumor activity in multiple murine models, and in 
combination with anti-PD-L1 and with radiation and chemotherapy [33]. Gulley (GMB, CCR) and 
the LTIB conducted the Phase I dose escalation trial of the NHS-IL12 immunocytokine [34]. Due 
to known prior toxicities using a rec. 
Figure 9. NHS-IL12 Immunocytokine.  (A) NHS76 is a fully human 2
nd generation TNT antibody 
bound to 2 murine IL-12 (p70) molecules. (B) a: Specific tumor targeting of transplanted lung 
carcinoma by the MAb NHS-IL12(mu). Control MAb BC1-IL12(mu). b: NHS-IL12 tumor 
targeting of nuclear DNA histones.
IL-12 protein, multiple ascending dose levels were employed and the agent was administered every 
4 weeks. Time-dependent increase in serum IFN-γ and subsequent rise in IL-10 increased with 
dose and varied greatly among patients (Figure 10A). Increases in TCR diversity and TIL density 
in the TME following NHS-IL12 dosing were observed in those patients with elevation IFN-γ 
serum levels (Figure 10B). Toxicity was acceptable with an MTD of 16.8 mcg/kg and this total 
dose was also found to be safe when given split in half on an every 2 week schedule. Although no 
objective tumor responses were seen, of 30 patients with measurable disease, 15 had stable disease, 
with some durable (from 6‒30+ months).

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Figure 10. (A) Diversity of IFN-γ spikes in sera among patients 3 days post-NHS-IL12 treatment 
for cycles 1 (C1) and 2 (C2): as examples, 2 patients with high (pts 1 and 2, red and 
blue) and low (pts 3 and 4, green and orange) levels are shown. (B) Changes in TCR 
clonal diversity in the tumor biopsy correlate with serum IFN-g responses post-NHS-
IL12 treatment. (C) # of clones in tumor comprising the top 25% of the repertoire of 
patient 1 pre- and post-NHS-IL12, demonstrating an increase in TCR diversity in a 
high IFN-g responder after therapy.

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Our recent preclinical studies have also shown the enhanced anti-tumor effect of avelumab when 
used in combination with NHS-IL12 in syngeneic mice bearing an intravesical bladder tumor 
(Figure 11, left panel) and that this effect is mediated via an IFN-γ‒dependent mechanism. 
Studies in NSG-β2m‒/‒ mice bearing HTB1, a human bladder carcinoma, and reconstituted with 
human PBMC, also showed the enhanced anti-tumor effect of the combination that coincided with 
increased NK and CD8+ in the TME (Figure 11, right panel).
Figure 11. Anti-tumor activity of NHS-IL12 + anti-PD-L1 in NSG-β2m‒/‒ mice bearing human 
bladder cancer (HTB1).
This further provided the rationale for an ongoing CCR led clinical study of avelumab in 
combination with NHS-IL12 (NCT02994953), currently evaluating safety of the combination. In 
addition, to the combination being found to be safe and well-tolerated, evidence of radiographic 
tumor responses has been observed. As an example, a patient with checkpoint refractory metastatic 
urothelial cancer with a large sacral mass and retroperitoneal adenopathy at enrollment has had an 
ongoing complete response for 18+ months. 
Combination Immunotherapies
In addition to harnessing the potential multi-functionality of M7824, we have conducted several 
combination studies employing this agent with other immune modulating agents. We have 
previously shown [27] enhanced anti-tumor activity when M7824 was combined with vaccine in 
EMT6, a metastatic breast carcinoma murine model (Figure 12). 

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Figure 12. Combined effect of Ad-Twist vaccine and M7824 in EMT6 breast carcinoma model 
(Knudson, 2018)
Furthermore, combining M7824 with NHS-IL12 also greatly enhanced anti-tumor activity in the 
EMT6 breast carcinoma model (Figure 13). Tumor challenge studies showed the presence of 
immune memory in mice that received the combination of M7824 and NHS-IL12, which conferred 
protection against re-challenge with tumor. Similar results were also seen in the MB38-CEA 
murine colorectal carcinoma model.
Multimodal therapies were also carried out in mice bearing HPV+ tumors. The combination of 
PDS0101 vaccine and M7824 showed significant anti-tumor efficacy in the NSG 2m-/- humanized 
mouse model reconstituted with human PBMC and bearing human cervical HPV+ cancer (SiHa) 
subcutaneously (Figure 14). 
Figure 13. Anti-tumor effect of M7824 + NHS-IL12 combination treatment in EMT6.

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Abbreviated Title: Combo Immunotx in HPV Cancers
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Figure 14. Tumor growth in humanized mice bearing SiHa (human HPV+ cervical cancer) and 
treated with PBS control, PDS0101 vaccine, M7824, or PDS0101+M7824.
In contrast to the previous clinical trials, where we saw anti-tumor efficacy of M7824 or PDS0101 
alone in HPV-associated tumors, in this model there was no single therapy effect of M7824 or 
PDS0101, but the combination significantly decreased tumor burden. Furthermore, in C57BL/6J 
mice bearing TC-1 (a murine lung carcinoma line transfected with HPV16 E6 and E7 
oncoproteins), which is a very aggressive model of HPV+ carcinoma, the combination of PDS0101 
vaccine, M7824 and NHS-IL12 resulted in the greatest level of anti-tumor activity compared to 
the use of individual agents or dual combinations (Figure 15). The use of the combination of 
PDS0101 vaccine, M7824 and NHS-IL12 also resulted in an intense influx of CD4+ and CD8+ T 
cells in tumors (Figure 16, upper panels and Figure 17), increased activation and proliferation 
of T-cells (Figure 16, lower panels), as well as an enhanced HPV specific T cell response 
measured by ELISpot not seen with lesser combinations (Figure 18).  
-10
-5
0
5
10
15
20
25
0
50
100
150
200
250
Days Post PBMC Instillation
Tumor Volume (mm3)
PDS0101 + M7824
PDS0101
M7824
PBS Control
*
Statistics: Two-Way ANOVA of repeated measures p= 0.0119
PDS0101 + M7824 in hNSG SiHa (Cervical) Model
Treatment
Tumor volume 
>200  mm3
PBS Control
6/12
M7824
4/12
PDS0101
5/12
PDS0101+M7824
1/12

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Figure 15 A. Tumor growth in C57BL/6J mice bearing TC-1 HPV+ tumors, and treated with 
combinations of PDS0101, M7824, and PDS01ADC.
Figure 15 B. Tumor control (low volume) in C57BL/6J mice bearing TC-1 HPV+ tumors, and 
treated with combinations of PDS0101, M7824, and NHS-IL12.
0
5
10
15
20
25
0
100
200
300
400
500
600
700
1000
2000
Days Post Tumor Implantation
Tumor Volume (mm3)
PDS0101+NHS
0
5
10
15
20
25
0
100
200
300
400
500
600
700
1000
2000
Days Post Tumor Implantation
Tumor Volume (mm3)
PDS0101+M7824
0
5
10
15
20
25
0
100
200
300
400
500
600
700
1000
2000
Days Post Tumor Implantation
Tumor Volume (mm3)
M7824+NHS
0
5
10
15
20
25
0
100
200
300
400
500
600
700
1000
2000
Days Post Tumor Implantation
Tumor Volume (mm3)
PDS0101+M7824+NHS
Treatment
Tumor Volume 
<300mm3
PBS Control
0/16
DOTAP
0/8
M7824
0/16
PDS0101
3/16
NHS
6/16
M7824+NHS
8/16
PDS0101+NHS
10/16
PDS0101+M7824
5/16
PDS0101+M7824+NHS
13/17

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Figure 16. Increased T-cell infiltration by tumor weight, and increased T-cell activation and 
proliferation in combination treated mice. (Rumfield et al; unpublished)
PBS Control
DOTAP
PDS0101
M7824
NHS
PDS0101 + M7824
PDS0101 + NHS
M7824 + NHS
PDS0101 + M7824 + NHS
0
20
40
60
80
Cell Number
CD8+/Ki67+/CD44+/mg tumor
PBS Control
DOTAP
PDS0101
M7824
NHS
PDS0101 + M7824
PDS0101 + NHS
M7824 + NHS
PDS0101 + M7824 + NHS
0
20
40
60
80
Cell Number
CD4+/Ki67+/CD44+/mg tumor
PBS Control
DOTAP
PDS0101
M7824
NHS
PDS0101 + M7824
PDS0101 + NHS
M7824 + NHS
PDS0101 + M7824 + NHS
0
100
200
300
400
500
Cell Number
#CD8+/mg Tumor
PBS Control
DOTAP
PDS0101
M7824
NHS
PDS0101 + M7824
PDS0101 + NHS
M7824 + NHS
PDS0101 + M7824 + NHS
0
100
200
300
400
500
Cell Number
#CD4+/mg Tumor
*
*
*
*

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Figure 17. Immunohistochemistry shows increased T-cell infiltration in C57BL/6J mice bearing 
TC-1 HPV+ tumors, and treated with the combination of PDS0101, M7824, and NHS-
IL12.

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Figure 18. PDS0101 generated HPV-specific T-cells, as measured by ELISpot. Table shows a 
summary of tumor volume and E7-specific IFN ELISpot for C57BL/6J mice bearing 
TC-1 HPV+ tumors, and treated with combinations of PDS0101, M7824, and NHS-
IL12
1.2.3
Safety and Efficacy of I/O Combinations in Humans
Table 3: Previously evaluated combinations of I/O agents demonstrating an acceptable safety 
profile.
Avelumab (anti-PD-L1) + NHS-IL12
NCT02994953
CEA/ MUC1 vaccine + M7824
NCT03315871
Dose Rationale: In the phase I dose escalation trial of combination Avelumab (anti-PD-L1) + 
NHS-IL12, escalating doses of NHS-IL12 were evaluated at 8,12, and 16.8 mcg/kg given every 4 
weeks in combination with standard dosing of Avelumab. The combination including NHS-IL12 
at the highest dose evaluated (16.8 mcg/kg given every 4 weeks) was found to be well tolerated. 
The only DLT observed on the trial was a transient grade 3 AST/ALT elevation at NHS-IL12 at 
12 mcg/kg but otherwise no other DLT was observed and the MTD was not reached. Therefore, 
Treatment
Tumor Volume 
<300mm3
E7 ELISpot
PBS Control
0/16
-
DOTAP
0/8
-
M7824
0/16
-
PDS0101
3/16
+
NHS
6/16
-
M7824+NHS
8/16
-
PDS0101+NHS
10/16
+
PDS0101+M7824
5/16
+
PDS0101+M7824+NHS
13/17
-
IFN+ Spots per 2.5 x
*
*
*
*
PBS Control
DOTAP
PDS0101
M7824
NHS
PDS0101 + M7824
PDS0101 + NHS
M7824 + NHS
PDS0101 + M7824 + NHS
0
200
400
600
HPV 16 E7 15-mer

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for this protocol, NHS-IL12 was originally used at a dose of 16.8 mcg/kg every 4 weeks in 
combination with the standard phase II dose of M7824 of 1200 mg given every two weeks. While 
we observed no DLTs with the combination of NHSIL12 at 16.8 mcg/kg along with M7824 and 
PDS0101 in the six participant lead in safety cohort, after treating 19 participants on protocol we  
observed that the majority of participants (11/19; 57.9%) needed dose reductions of NHSIL12 
when given in combination with PDS0101 and M7824 due mostly to grade 2 fever and flu like 
symptoms. 
At this point (with Protocol Amendment Version 12.11.2020) we lowered the starting dose of 
NHS-IL12 in this protocol from 16.8 mcg/kg to 8 mcg/kg to try and minimize toxicity. After 
evaluating a total of 39 patients on this protocol including 21 with starting dose of 16.8 mcg/kg 
and 18 patients with starting dose of 8 mcg/kg we observed what looks to be reduced efficacy in 
patients receiving 8 mcg/kg as a starting dose with only 3/18 patients responding with the 8 mcg/kg 
starting dose as compared to 11/21 with the 16.8 mcg/kg starting dose. Therefore, based on this 
observation that the possibility that a lowering starting dose of NHS-IL12 may reduce efficacy we 
are amending to allow treatment (effective with Protocol Amendment Version 09.20.2021) with a 
limited number of doses of NHS-IL12 at 16.8 mcg/kg (four doses total), followed by dosing at 8 
mcg/kg every 4 weeks thereafter. This is based upon responding patients in the first 21 patients 
which received anywhere between 1-4 doses of NHS-IL12 at 16.8 mcg/kg before dose reductions.  
1.2.4
Immune Assays
Multiple immune assays have been developed in the LTIB to better define the mechanism(s) 
involved in the use of specific novel agents, as monotherapy or in combination therapies, both for 
preclinical and clinical studies. In addition to analyses of biopsies, analyses of the peripheral 
immunome can provide valuable information in that multiple samples can be analyzed over the 
course of a given therapy vs. pre-therapy. The LTIB has now developed and employed [15, 16, 31, 
35] a flow cytometry‒based assay that can analyze 123 immune cell subsets in human PBMC from 
one vial of processed PBMC (approximately 107 cells). This assay will be used in this clinical trial 
to detect multiple (n=32) subsets of CD4+ T cells, CD8+ T cells (n=29), Tregs (n=7), B cells 
(n=5), NK (n=20), NKT (n=4), DC (n=10), and MDSC (n=16) to better understand the role of each 
agent. We also plan to evaluate changes in TCR clonal diversity both in biopsies and the periphery. 
One example involves an ongoing first-in-human trial of the NHS-IL12 tumor-targeting 
immunocytokine. TCR diversity increased 6-14‒fold in biopsies of patients with a high or 
intermediate IFN-γ response but were unchanged or decreased with a low IFN-γ response. These 
findings also correlated with TIL in biopsies. We are also currently employing NanoString 
analyses to identify a gene signature in biopsies and PBMC, pre- and post-treatment. The GMB 
will conduct multiplexed, multispectral imaging of FFPE tissue to evaluate multiple immune 
parameters within the TME before and after treatment in patients with available tissue.
1.2.5
Summary
•
We are proposing a novel I/O combination to help overcome multiple barriers in an 
effective anti-tumor immune response. 
o
(1) HPV therapeutic vaccine targeting tumor associated antigens to prime an anti-
tumor immune response
o
 (2) PDS01ADC and M7824 to enable activated immune cells to work better in 
the TME

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Abbreviated Title: Combo Immunotx in HPV Cancers
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•
Preclinical studies have shown that treatment with the combination of an HPV 
therapeutic vaccine, M7824 and PDS01ADC leads to greater anti-tumor activity than any 
single or double combination of these agents
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Subjects with cytologically or histologically confirmed locally advanced or metastatic 
HPV associated malignancies:
•
Cervical cancers;  
•
P16+ Oropharyngeal cancers; 
•
Anal cancers; 
•
Vulvar, vaginal, penile, and squamous cell rectal cancers;
•
Other locally advanced or metastatic solid tumors (e.g., lung, esophagus) that are 
known HPV+. 
2.1.1.2
Subjects must have measurable disease, per RECIST 1.1. See Section 6.3 for the 
evaluation of measurable disease.
2.1.1.3
Subjects must have received one prior line of systemic chemotherapy as well as 
checkpoint therapy if checkpoint therapy is FDA approved for that specific tumor type 
(e.g., HNSCC and PDL1+ cervical cancer). Prior checkpoint therapy is not needed 
where checkpoint therapy has not been FDA approved for that specific tumor type (e.g. 
anal, vaginal, vulvar, penile, PDL1 negative cervical). Exceptions to the above include 
participant who are not eligible to receive the above therapies or who decline these 
standard treatment options after appropriate counseling has been provided. 
2.1.1.4
Age >18 years. 
2.1.1.5
ECOG performance status < 2.
2.1.1.6
Adequate hematologic function at screening, as follows:
•
Absolute neutrophil count (ANC) ≥1 x 109/L; 
•
Hemoglobin ≥ 9 g/dL; 
•
Platelets ≥ 75,000/microliter. 
2.1.1.7
 Adequate renal and hepatic function at screening, as follows:
•
Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR 
Measured or calculated creatinine clearance ≥ 40 mL/min for participant with 
creatinine levels > 1.5 X institutional ULN (GFR can also be used in place of 
creatinine or CrCl);
•
Bilirubin ≤ 1.5 x ULN OR in subjects with Gilbert’s syndrome, a total bilirubin ≤ 3.0 
x ULN;
•
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN, 
unless liver metastases are present, then values must be ≤ 3 x ULN).
2.1.1.8
The effects of the immunotherapies on the developing human fetus are unknown. For this 
reason and because immunotherapeutic agents as well as other therapeutic agents used in 

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this trial are known to be teratogenic, individuals of child-bearing potential and 
individuals able to father children must agree to use highly effective contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for two 
months after study treatment. 
2.1.1.9
Participants serologically positive for HIV, Hep B, Hep C are eligible as long as the viral 
loads are undetectable by quantitative PCR. HIV positive participants must have CD4 
count ≥ 200 cells per cubic millimeter at enrollment, be on stable antiretroviral therapy 
for at least 4 weeks and have no reported opportunistic infections or Castleman’s disease 
within 12 months prior to enrollment.
2.1.1.10 Ability of subject to understand and the willingness to sign a written informed consent 
document.
2.1.2
Exclusion Criteria
2.1.2.1
Participants with prior investigational drug, chemotherapy, immunotherapy or any prior 
radiotherapy (except for palliative bone directed therapy) within the past 28 days prior to 
the first drug administration except if the investigator has assessed that all residual 
treatment-related toxicities have resolved or are minimal and feel the participant is 
otherwise suitable for enrollment. Participants may continue adjuvant hormonal therapy 
in the setting of a definitively treated cancer (e.g., breast cancer).
2.1.2.2
Known intolerance to or life threatening side effects resulting from prior checkpoint 
inhibitor therapy.
2.1.2.3
Major surgery within 28 days prior to the first drug administration (minimally invasive 
procedures such as diagnostic biopsies are permitted). 
2.1.2.4
Known active brain or central nervous system metastasis (less than a month out from 
definitive radiotherapy or surgery), seizures requiring anticonvulsant treatment (<3 
months) or clinically significant cerebrovascular accident (<3 months). In order to be 
eligible participants must have repeat CNS imaging at least a month after definitive 
treatment showing stable CNS disease. Participants with evidence of intratumoral or 
peritumoral hemorrhage on baseline imaging are also excluded unless the hemorrhage is 
grade ≤ 1 and has been shown to be stable on two consecutive imaging scans.    
2.1.2.5
Pregnant individuals are excluded from this study because these drugs have not been 
tested in pregnant individuals and there is potential for teratogenic or abortifacient effects.  
Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with these immunotherapies, nursing should be 
discontinued if the mother is treated on this protocol.
2.1.2.6
Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent with exception of: 
•
Diabetes type I, eczema, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease or 
other mild autoimmune disorders not requiring immunosuppressive treatment; 
•
Subjects requiring hormone replacement with corticosteroids are eligible if the 
steroids are administered only for the purpose of hormonal replacement and at doses 
≤ 10 mg of prednisone or equivalent per day;

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•
Administration of steroids for other conditions through a route known to result in a 
minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is 
acceptable; 
•
Subjects on systemic intravenous or oral corticosteroid therapy with the exception of 
physiologic doses of corticosteroids (≤ the equivalent of prednisone 10 mg/day) or 
other immunosuppressives such as azathioprine or cyclosporin A are excluded on the 
basis of potential immune suppression. For these subjects these excluded treatments 
must be discontinued at least 1 weeks prior to enrollment for recent short course use 
(≤ 14 days) or discontinued at least 4 weeks prior to enrollment for long term use (> 
14 days). In addition, the use of corticosteroids as premedication for contrast-enhanced 
studies is allowed prior to enrollment and on study.
2.1.2.7
Subjects with a history of serious intercurrent chronic or acute illness, such as cardiac or 
pulmonary disease, hepatic disease, bleeding diathesis or recent (within 3 months) 
clinically significant bleeding events, or other illness considered by the Investigator as 
high risk for investigational drug treatment. 
2.1.2.8
Subjects unwilling to accept blood products as medically indicated.
2.1.2.9
History of non-HPV associated second malignancy within 3 years of enrollment except 
localized malignancy which has been adequately treated or malignancy which does not 
require active systemic treatment (e.g., low risk CCL). Patients taking adjuvant hormonal 
therapy for definitively treated cancers (e.g. breast cancer) are eligible. 
2.1.2.10 Subjects with a known severe hypersensitivity reaction to a monoclonal antibodies (grade 
>/= 3 NCI-CTCAE v5) will be evaluated by the allergy/immunology team prior to 
enrollment. 
2.1.2.11 Receipt of prior lymphodepleting chemotherapy (e.g. cyclophosphamide, fludarabine) or 
any organ transplantation requiring ongoing immunosuppression.   
2.1.3
Recruitment Strategies
This study will be posted on www.clinicaltrials.gov, NIH websites and on NIH social media 
forums. After IRB approval of the recruitment material, this study may be advertised at national 
conferences including AACR and ASCO and may also be shared with the HPV and Anal Cancer 
Foundation who may advertise it further. 
Participants will be recruited from the current participant population at NIH. Participants with 
HPV related cancers are currently being treated on another trial through CIO, CCR, NIH, where 
2-3 participants per month are being screening and enrolled. Some of these participants come from 
established community networks, some of these participants are self-referrals, and some of these 
participants are referred by another group (Dr. Hinrichs’s group, ETIB, CCR, NIH) who also have 
a large referral base for HPV related cancers.
2.2
SCREENING EVALUATION
2.2.1
Screening activities prior to the obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 
•
Email, written, in person or telephone communications with prospective subjects 

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Abbreviated Title: Combo Immunotx in HPV Cancers
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•
Review of existing medical records to include H&P, laboratory studies, etc.  
•
Review of existing MRI, x-ray, or CT images
•
Review of existing photographs or videos
•
Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
2.2.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the study consent or 
the consent for study # 01C0129 (provided the procedure(s) are permitted on that study) on which 
screening activities will be performed. Assessments performed at outside facilities or on another 
NIH protocol within these timeframes below may also be used to determine eligibility once a 
participant has signed the consent. 
Within 28 days prior to enrollment, unless otherwise specified:
•
Complete medical history and physical examination (including height, weight, vital signs, 
and ECOG performance status).
•
CT of chest, abdomen and pelvis.
•
A brain CT scan in participants with known CNS disease as described in Section 2.1.2.4.
•
For skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion.
•
EKG
•
Clinical laboratory tests (within 16 days prior to enrollment).

Chemistry: sodium, potassium, chloride, bicarbonate, calcium, glucose, BUN, 
creatinine, ALT, AST, alkaline phosphatase, total protein, albumin, and total and 
direct bilirubin.

Hematology: complete blood count (CBC) with differential.

CD4 (if clinically indicated).

HLA typing (where feasible)
•
Urine or serum pregnancy test (β-HCG) for individuals of childbearing-potential and 
individuals < 12 months since the onset of menopause (within 16 days prior to 
enrollment). 
•
Urinalysis.
•
HBV, HCV, HIV testing including viral load if clinically indicated (within 3 months prior 
to enrollment).
•
Histologic confirmation (at any time point prior to enrollment). If there is no available 
tumor sample or pathology report, a biopsy will be performed to confirm the diagnosis.

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2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at: https://nih.sharepoint.com/sites/NCI-CCR-OCD-
Communications/SitePages/OEC-Administrative---Clinical-Research-(ADCR).aspx?Mode=Edit.
2.3.1
Screen Failure
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a 
transient lab abnormality may be rescreened. 
2.3.2
Treatment Assignment Procedures
Cohorts
Number
Name
Description
1
Cohort 1
Subjects with HPV associated malignancies
2
Cohort 2
Subjects with cervical cancer with prior pelvic radiation 
and boost brachytherapy
        2                                      
Arms
Number
Name
Description
1
Arm 1
HPV vaccine + PDS01ADC + M7824 
2        Arm 2       
HPV vaccine + PDS01ADC + M7824 at reduced doses
Arm Assignment
Participants in Cohort 1 will be assigned to Arm 1, and patients in Cohort 2 will be assigned to 
Arm 2. If more than three of eight patients have an objective response then accrual will be 
expanded to enroll 20 evaluable participants for cohort 1, while cohort 2 may enroll up to 12 
patients for a safety evaluation and up to 12 additional patients for preliminary evaluation of 
efficacy as well as further evaluation of safety

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2.4
BASELINE EVALUATION
All subjects are required to complete baseline evaluations within one week prior to the first planned 
dosing of the study drug (any screening evaluation done within this time period can also serve for 
the baseline evaluation):
•
Physical exam including weight, ECOG performance status and vital signs. 
•
Concomitant Medications and Baseline Signs and Symptoms evaluation.
•
Urine or serum pregnancy test (β-HCG) for individuals of childbearing-potential and 
individuals < 12 months since the onset of menopause.
•
Chemistry: sodium, potassium, chloride, bicarbonate, calcium, glucose, BUN, 
creatinine, ALT, AST, alkaline phosphatase, total protein, albumin, and total and direct 
bilirubin.
•
ACTH, TSH, reflex free T4, lipase, amylase, CRP
•
Hematology: CBC with differential 
•
Coagulation panel: PT, INR, and PTT
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
•
This is a phase I/II trial of combination immunotherapy. 
•
The trial will be conducted using a Simon optimal two-stage design. 
•
Participants will receive HPV vaccine + PDS01ADC + M7824 (Figure 19).
o
The first six participants will be evaluable for dose limiting toxicities (DLTs) and 
accrual will continue to 8 participants if less than 2 out of the first 6 participants 
experience a DLT.
If three or more out of eight patients have objective responses then accrual will be expanded to 
enroll 20 evaluable participants (Figure 20).  Additional patients will be enrolled in the cohort 
with prior pelvic radiation and boost brachytherapy: up to 12 for safety and dose finding and up 
to 12 for an exploratory evaluation of efficacy.
•
There will be a minimum of six days between the first and second participant. The third 
through sixth participant may enroll no sooner than 48 hours after the most recent enrollee. 
Once six participants have enrolled and been found to be safe further participants may 
enroll at any time.
•
Although positive HPV testing will not be required prior to enrolling, HPV testing will be 
offered as an exploratory endpoint and participants testing negative for HPV after enrolling 
or whose HPV status cannot be confirmed may be replaced with other participants for the 
primary efficacy analysis. Participants testing negative for HPV after enrolling or whose 
HPV status cannot be confirmed may continue to receive treatment on study. 
•
The combination of PDS0101+ PDS01ADC+ M7824 will be evaluated in all HPV 
serotypes given the clinical remissions PDS Biotechnology has observed in CIN studies 
with PDS0101 in non-HPV 16 serotypes. However, if it is found that the ORR with non-

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HPV-16 serotypes is noticeably less than the ORR observed with HPV 16 serotypes than 
participants having disease related to non-HPV-16 serotypes may be replaced with 
participants having disease related to the HPV-16 serotype for the first and second stage of 
the primary efficacy analyses.
•
In addition, while the primary focus of this protocol is to evaluate the response rate of this 
I/O combination in participants with a wide array of HPV associated malignancies, if the 
I/O combination in not deemed to be promising in this larger population (less than three 
out of eight evaluable participants have a response) than the study will be amended to 
evaluate this I/O combination specifically in participants with cervical cancer (and 
participants who have already been enrolled with non-cervical cancers may be replaced 
with cervical cancer participants for the first stage of the primary efficacy analyses).
•
While checkpoint refractory participants will be eligible to enroll, the primary objective of 
response rate will be determined among the checkpoint naïve participants and the response 
rate among checkpoint refractory participants will be an exploratory objective. 

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Figure 19.
Figure 20.

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3.1.1
Dose Limiting Toxicity
DLT for first 6 participants: 
Dose-limiting toxicity (DLT) will be defined as any one of the following adverse events, 
possibly attributable to study drugs, that occur within 28 days of the start of therapy:
•
Any Grade 4 or higher adverse drug reactions (ADRs) as defined by CTCAE v5.0 and 
assessed as possibly related to that agent by the Investigator, except for laboratory values 
that are asymptomatic or resolve to Grade ≤ 1 or baseline grade within 7 days without 
medical intervention. 
•
Any Grade 3 ADRs possibly attributed to an agent except for any of the following:
o
Grade 3 flu-like symptoms or fever, as well as associated symptoms of fatigue, 
headaches, nausea, emesis which can be controlled with conservative medical 
management.  
o
Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites 
of known or suspected tumor.
o
Grade 3 Hgb decrease (< 8.0 g/dL) that is clinically manageable with blood 
transfusions or erythroid growth factor use does not require treatment 
discontinuation. 
o
Grade 3 laboratory values that are asymptomatic or resolve to Grade ≤ 1 or baseline 
grade within 14 days.
o
Keratoacanthoma and squamous cell carcinoma of the skin. 
o
Any endocrinopathy that can be medically managed with hormone replacement
o
Any grade 3 adverse drug reaction which can be medically managed with minimal 
risk to the participant (e.g., placement of a pleural catheter for recurrent 
inflammatory pleural effusions) and resolves to at least grade one or baseline 
grade within 14 days. 
Criteria are based on the NCI Common Terminology Criteria for Adverse Events, Version 5.
Where clinically appropriate subjects will receive one year of treatment during which subjects will 
be followed with surveillance scans every 6-12 weeks. On a case by case basis treatment beyond 
a year is allowed per investigator discretion. 
Patents might be taken off treatment for disease progression prior to completing one year of 
treatment, but where clinically appropriate, treatment beyond radiographic progression is allowed 
if in the opinion of the investigator the subject is benefiting from treatment.
Subjects will be taken off treatment if unacceptable toxicity occurs and is attributed to all 
therapeutic agents. If a single agent is tolerated that agent may be continued.  
This trial will be conducted using a Simon two-stage phase II trial design in which 8 evaluable 
participants will enroll and if 3 or more of the 8 have an objective response, then accrual would 
continue until a total of 20 evaluable participants have been treated. If there are 9 or more of 20 
(45.0%) who experience a response, this would be sufficiently interesting to warrant further study. 
In the event that a participant develops a response (>30% decrease in target lesions as compared 
with baseline scan) following initial progression or “pseudo-progression”, this response will be 
considered as an objective response in the determination to expand accrual.

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3.2
DRUG ADMINISTRATION
General Rule: 
A window of +/- 14 days for a scheduled treatment is allowed in the event of scheduling issues 
(i.e., holiday, bad weather or other scheduling issues). The minimum time between administrations 
of a similar agent is 11 days. Where feasible PDS0101 should be administered first, followed by 
PDS01ADC (when given), followed by M7824.
3.2.1
PDS0101
PDS0101 will be administered every 4 weeks for 6 doses followed by every three months (i.e. 
every 12 weeks) for an additional two doses.
Dosage Form:  
Sterile injectable liquid 
Number of vials: 
2-vial formulation 
Preparation: 
1:1 v/v mixture of the 2 vial formulation.  0.6mL of vial #1, 
ImmunoMAPK-RDOTAP added to vial# 2, HPVmix (0.6 
mL) 
Total Administered 
dose: 
2.7 mg of total peptide and 3 mg of R-DOTAP 
Total Injection Volume: 
1.0mL (administered as two individual 0.5mL injections)
Injection route: 
 
Subcutaneous 
•
0.6 ml will be drawn up from each vial (Vial #1 Immuno MAPK-RDOTAP, Vial #2 HPV 
mix) and mixed (total = 1.2ml for the PDS0101 admixture). Two separate 0.5 ml doses will 
be injected into the participant. These should preferably be given ~6cm apart in the same 
limb. Each subsequent vaccination should preferably be administered alternating between 
limbs (e.g., L arm  R thigh). 
3.2.2
M7824
Subjects will receive M7824 via IV infusion over 1 hour (-10 minutes / +20 minutes, that is, over 
50 to 80 minutes) once every 2 weeks. M7824 will be administered as a "flat" dose of 1,200 mg 
independent of body weight. However lower doses may also be used as per Section 3.4.3. M7824 
is administered as an intravenous infusion with a mandatory 0.2 micron in-line filter.
In order to mitigate potential infusion-related reactions, premedication with an antihistamine and 
with acetaminophen (for example, 25-50 mg diphenhydramine and 500-650 mg acetaminophen) 
within approximately 30 to 60 minutes prior to dosing of M7824 is optional and at the discretion 
of the Investigator. 
3.2.3
PDS01ADC
PDS01ADC will be administered at as dose of 16.8mcg/kg by SC injection every 4 weeks for up 
to 4 consecutive doses then 8mcg/kg every 4 weeks thereafter. However lower doses may also be 
used as per Section 3.4.3. The dose of PDS01ADC will be calculated based on the weight of the 

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subject determined within 2 weeks prior to the day of drug administration. The dose of PDS01ADC 
used for the previous administration can be repeated if the change in the subject’s weight is 10% 
or less than the weight used for the last dose calculation.
3.3
STUDY INTERVENTION COMPLIANCE
All study interventions will be given at NIH and documented in the electronic medical record.
3.4
DOSE MODIFICATIONS
3.4.1
Discontinuation
Treatment with individual agents will be discontinued in the case of:
•
Any Grade 4 or higher adverse drug reactions (ADRs) as defined by CTCAE v5.0 and 
assessed as possibly related to that agent by the Investigator, except for laboratory values 
that are asymptomatic or resolve to Grade ≤ 1 or baseline grade within 7 days 
•
Any Grade 3 ADRs possibly attributed to an agent except for any of the following:
o
Grade 3 flu-like symptoms or fever, as well as associated symptoms of fatigue, 
headaches, nausea, emesis which can be controlled with conservative medical 
management.  
o
Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor.
o
Grade 3 Hgb decrease (< 8.0 g/dL) that is clinically manageable with blood transfusions 
or erythroid growth factor use does not require treatment discontinuation. 
o
Grade 3 laboratory values that are asymptomatic or resolve to Grade ≤ 1 or baseline 
grade within 14 days. 
o
Keratoacanthoma and squamous cell carcinoma of the skin. 
o
Any endocrinopathy that can be medically managed with hormone replacement
o
Any grade 3 adverse drug reaction which can be medically managed with minimal risk 
to the participant (e.g., placement of a pleural catheter for recurrent inflammatory pleural 
effusions) and resolves to at least grade one or baseline grade within 14 days. 
3.4.2
Dose Delay
Individual agents should be withheld for any Grade 2 or 3 ADR possibly attributed to that agent 
until resolution to Grade ≤ 1 unless the ADR in the opinion of the investigator is not clinically 
relevant or can be medically managed with minimal risk to the participant. PDS01ADC  may be 
restarted at any scheduled visit as long as there is at least 11 days between doses of this agent. 
Should a clinically relevant grade 2 or 3 ADR persist for more than 4 weeks, consideration should 
be given to discontinuing treatment with that individual agent at the discretion of the investigator. 
For non-medical logistical reasons, unrelated acute illnesses, or palliative radiation, scheduled 
assessments and dosing can be delayed up to 2 months. Where at all possible, dosing should be 
restarted to keep in line with the original treatment schedule.     
3.4.3
Dose Modification 
Participants with dose modifications or skipped doses within DLT period for reasons other than a 
DLT (e.g., logistical reasons) who do not experience a DLT within the DLT window will not be 
evaluable for DLTs and will be replaced for the six-participant lead in DLT assessment.  

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Participants who have dose modifications or skipped doses within the DLT period for logistical 
reasons and nevertheless experience a DLT within the DLT period will be considered DLT 
evaluable.  
PDS0101 HPV vaccine: Vaccine doses will not be modified but doses may be skipped per 
investigator discretion. For example, PDS0101 (which targets HPV 16 specifically) may be held 
for non-HPV 16 tumors per investigator discretion.  
M7824: Doses (including starting doses) may be reduced to a 300 or 600 mg flat dose or doses 
may be skipped. 
PDS01ADC: All patients, except patients with cervical cancer and prior pelvic radiation and 
brachytherapy (described in the next paragraph), will receive PDS01ADC at a starting dose of 16.8 
mcg/kg for up to a total of 4 consecutive doses at which time the dose will be reduced to 8 mcg/kg 
thereafter. Doses may be reduced to 8 mcg/kg at any time after the first dose for grade ≥ 2 flu-like 
symptoms, fever, or other PDS01ADC related toxicities. Additionally, doses may be skipped or 
further dose-reduced to 4 or 6 mcg/kg. For patients who have already received initial starting doses 
of PDS01ADC at 8 mcg/kg they may receive PDS01ADC at 16.8 mcg/kg for up to a total of 4 
consecutive doses. In select participants receiving doses of 8 mcg/kg or lower, consideration may 
be given to every 2 week dosing of this agent. 
In patients with cervical cancer with prior pelvic radiation and boost brachytherapy where a 
potential higher risk of grade 3 hematuria may exist with the full starting doses of M7824 at 1200 
mg and PDS01ADC at 16.8 mcg/kg, a staring dose of M7824 at 600 mg and PDS01ADC at 4 
mcg/kg will be used instead. If grade 3 or greater hematuria occurs in ≥ 2 out of four of these 
patients then the starting dose for these patients will be lowered to M7824 at 300 mg and 
PDS01ADC at 4 mcg/kg. If grade 3 or greater hematuria occurs in ≥ 2 out of four of these patients 
when given M7824 at 300 mg and PDS01ADC at 4 mcg/kg then these patients will no longer to 
be eligible to enroll on this protocol. On the other hand, if < 2 patients out of four have grade 3 or 
greater bleeding events when given M7824 at 600 mg and PDS01ADC at 4 mcg/kg but objective 
responses are also observed in < 2 out of these four patients then a dose of M7824 at 1200 mg in 
combination with PDS01ADC at 4 mcg/kg will be evaluated in these patients. If ≥ 2 patients out 
of four have grade 3 or greater bleeding events or < 2 out of four patients have objective responses 
when given M7824 at 1200 mg and PDS01ADC at 4 mcg/kg then the combination of M7824 at 
600 mg and PDS01ADC at 6 mcg/kg may be evaluated. 
Stopping Rule: If more than one third of enrolled patients have permanently discontinued one or 
more study agents due to grade 3 or 4 toxicity per guidelines in Section 3.4.1 or any death has 
occurred which is at least possibly related to study regimen this will prompt a suspension of accrual 
and reassessment of available safety information prior to reopening study to accrual.

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3.4.4
Guidelines for Management of Infusion Reactions
NCI-CTCAE Grade
Treatment Modification for Infused Agent 
(M7824)
Grade 1 – mild
Mild transient reaction; infusion interruption 
not indicated; intervention not indicated.
Consider decreasing the infusion rate of the 
particular agent by 50% and monitoring 
closely for any worsening.
Grade 2 – moderate
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDs, narcotics, i.v. 
fluids); prophylactic medications indicated for 
≤ 24 hours.
Consider temporarily discontinuing infusion 
of the particular agent.
Consider resuming infusion of the particular 
agent at 50% of previous rate once infusion 
related reaction has resolved or decreased to 
at least Grade 1 in severity, and monitor 
closely for any worsening.
Grade 3 or Grade 4 – severe or life-
threatening
Grade 3: Prolonged (e.g., not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); hospitalization 
indicated for clinical sequelae.
Grade 4: Life-threatening consequences; 
urgent intervention indicated.
Stop the infusion immediately and disconnect 
infusion tubing from the subject.
For grade 3 events:  Consider withdrawing 
immediately from treatment with that 
particular agent and not offering any further 
treatment with that agent based upon if the 
clinical condition can be safely managed.
For grade 4 events: Withdraw immediately 
from treatment and do not offer further 
treatment with that agent. 
If the infusion rate of M7824 has been decreased by 50% or interrupted due to an infusion reaction, 
keep it decreased for the next scheduled infusion. If no infusion reaction is observed in the next 
scheduled infusion, the infusion rate may be returned to baseline at the subsequent infusions based 
on investigator’s medical judgment. 
If hypersensitivity reaction occurs, the subject should be treated according to the best available 
medical practice.
3.4.5
Guidelines for Management of Immune-Mediated Adverse Reactions
(In addition to the below guidelines, investigators may also use NCCN, ASCO, SITC or FDA 
guidelines for Immune Related Adverse Events) 

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Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Diarrhea: < 4 stools/day over Baseline
Colitis: asymptomatic 
Consider continuing M7824 
Symptomatic treatment (e.g. 
loperamide)
Consider close monitoring for 
worsening symptoms
Consider educating subject to 
report worsening immediately
If worsens:
Treat as Grade 2, 3 or 4. 
Grade 2 
Diarrhea: 4 to 6 stools per day over 
Baseline; IV fluids indicated < 24 
hours; not interfering with ADL
Colitis: abdominal pain; blood in stool 
Consider withholding M7824 
Symptomatic treatment
If improves to Grade ≤ 1: 
Consider resuming therapy
If persists > 7 days or recurs:
Consider treating as Grade 3 or 4.
Grade 3 to 4
Diarrhea (Grade 3): ≥ 7 stools per day 
over Baseline; incontinence; IV fluids 
≥ 24 h; interfering with ADL
Colitis (Grade 3): severe abdominal 
pain, medical intervention indicated, 
peritoneal signs
Grade 4: life-threatening, perforation
Consider withholding or permanently 
discontinuing M7824 for Grade 3 
events based upon if the clinical 
condition can be safely managed. For 
grade 4 events permanently 
discontinue treatment.
Consider 1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent
Consider adding prophylactic 
antibiotics for opportunistic 
infections 
Consider lower endoscopy 
If improves: 
Consider continuing steroids 
until Grade ≤ 1, then tapering 
over at least 1 month; consider 
resuming therapy following 
steroids taper (for initial Grade 
3). 
If worsens, persists > 7 days, or 
recurs after improvement:
Consider adding infliximab 
5mg/kg (if no contraindication). 
Note: infliximab should not be 
used in cases of perforation or 
sepsis. 

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Dermatological irAEs
Grade of Rash
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1 to 2 
Covering ≤ 30% body surface area 
Consider continuing M7824 
Consider symptomatic therapy (for 
example, antihistamines, topical 
steroids) 
If persists > 1 to 2 weeks or 
recurs: 
Consider withholding M7824 
therapy 
Consider skin biopsy 
Consider 0.5-1.0 mg/kg/day 
prednisone or equivalent. Once 
improving, consider tapering 
steroids over at least 1 month, 
consider prophylactic antibiotics 
for opportunistic infections, and 
consider resuming M7824 
therapy following steroids taper.
If worsens: 
Consider treating as Grade 3 to 4. 
Grade 3 to 4
Grade 3: Covering > 30% body 
surface area; 
Grade 4: Life threatening 
consequences 
Consider withholding or permanently 
discontinuing M7824 for Grade 3 
events based upon if the clinical 
condition can be safely managed. For 
grade 4 events permanently 
discontinue treatment.
Consider skin biopsy 
Consider dermatology consult 
Consider 1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Consider adding prophylactic 
antibiotics for opportunistic 
infections 
If improves to Grade ≤ 1: 
Consider tapering steroids over at 
least 1 month; consider resuming 
therapy following steroids taper 
(for initial Grade 3).
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Radiographic changes only 
Consider withholding M7824 
Consider Pulmonary and Infectious 
Disease consults 
Consider re-assessing at least 
every 3 weeks
If worsens: 
Consider treating as Grade 2 or 
Grade 3 to 4. 
Grade 2
Mild to moderate new symptoms 
Consider withholding M7824 
If improves: 

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Consider pulmonary and Infectious 
Disease consults
Consider monitoring symptoms 
daily; consider hospitalization 
Consider 1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Consider adding prophylactic 
antibiotics for opportunistic 
infections 
Consider bronchoscopy, lung biopsy 
When symptoms return to Grade 
≤ 1, consider tapering steroids 
over at least 1 month, and then 
consider resuming therapy 
following steroids taper 
If not improving after 2 weeks or 
worsening: 
Consider treating as Grade 3 to 4. 
Grade 3 to 4
Grade 3: Severe new symptoms; 
New/worsening hypoxia;
Grade 4: Life-threatening 
Consider withholding or permanently 
discontinuing M7824 for Grade 3 
events based upon if the clinical 
condition can be safely managed. For 
grade 4 events permanently 
discontinue treatment.
Consider hospitalization.
Consider pulmonary and Infectious 
Disease consults.
Consider 1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Consider adding prophylactic 
antibiotics for opportunistic 
infections 
Consider bronchoscopy, lung biopsy 
If improves to Grade ≤ 1: 
Consider tapering steroids over at 
least 1 month 
If not improving after 48 hours or 
worsening: 
Consider adding additional 
immunosuppression (for 
example, infliximab, 
cyclophosphamide, IV 
immunoglobulin, or 
mycophenolate mofetil) 
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Grade 1 AST or ALT > ULN to 3.0 x 
ULN and/or Total bilirubin > ULN to 
1.5 x ULN 
Consider continuing M7824 
Consider continued liver function 
monitoring 
If worsens: 
 Consider treating as Grade 2 or 3 
to 4. 
Grade 2
AST or ALT > 3.0 to ≤ 5 x ULN 
and/or total bilirubin > 1.5 to ≤ 3 x 
ULN 
Consider withholding M7824 
If returns to Grade ≤ 1:
Consider resuming therapy.
If elevation persists > 7 days or 
worsens: 
Consider treating as Grade 3 to 4.
Grade 3 to 4
AST or ALT > 5 x ULN and/or total 
bilirubin > 3 x ULN 
Consider withholding or permanently 
discontinuing M7824 for Grade 3 
events based upon if the clinical 
condition can be safely managed. For 
grade 4 events permanently 
discontinue treatment. 
If returns to Grade ≤ 1: 
Consider tapering steroids over at 
least 1 month 
If does not improve in > 7 days, 
worsens or rebounds: 

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Consider 1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Consider adding prophylactic 
antibiotics for opportunistic 
infections 
Consider consulting 
gastroenterologist/ hepatologist
Consider obtaining MRI/CT scan of 
liver and liver biopsy if clinically 
warranted 
Consider adding mycophenolate 
mofetil 1 gram (g) twice daily 
If no response within an 
additional 7 days, consider other 
immunosuppressants per local 
guidelines.
Renal irAEs
Grade of Creatinine Increased 
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Creatinine increased > ULN to 1.5 x 
ULN
Consider continuing M7824 
Continue renal function monitoring
If worsens:
Consider treating as Grade 2 to 3 or 
4.
Grade 2 
Creatinine increased > 1.5 and ≤ 6 x 
ULN
Consider withholding M7824 
Consider 1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Consider adding prophylactic 
antibiotics for opportunistic infections
Consider renal biopsy
If returns to Grade ≤1:
Consider tapering steroids over at 
least 1 month, and consider 
resuming therapy following 
steroids taper.
If worsens: 
Treat as Grade 4.
Grade 3-4
Creatinine increased > 6 x ULN
Consider withholding or permanently 
discontinuing M7824 for Grade 3 
events based upon if the clinical 
condition can be safely managed. For 
grade 4 events permanently 
discontinue treatment.
Consider 1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Consider adding prophylactic 
antibiotics for opportunistic infections
Consider renal biopsy
Consider Nephrology consult
If returns to Grade ≤1:
Consider tapering steroids over at 
least 1 month.

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Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations (e.g. 
troponin, CK-MB, BNP) or cardiac 
imaging abnormalities suggestive of 
myocarditis. 
Consider withholding or permanently 
discontinuing M7824 based upon if 
the clinical condition can be safely 
managed.
Consider hospitalization
In the presence of life threatening 
cardiac decompensation, consider 
transfer to a facility experienced in 
advanced heart failure and 
arrhythmia management.
Consider cardiology consult to 
establish etiology and rule-out 
immune-mediated myocarditis. 
Consider myocardial biopsy if 
recommended per cardiology consult.
If symptoms improve and 
immune-mediated etiology is 
ruled out, consider re-starting 
therapy.
If symptoms do not 
improve/worsen, viral 
myocarditis is excluded, and 
immune-mediated etiology is 
suspected or confirmed following 
cardiology consult, consider 
managing as immune-mediated 
myocarditis.
Immune-mediated myocarditis
Consider withholding or permanently 
discontinuing M7824 based upon if 
the clinical condition can be safely 
managed.
Consider guideline based supportive 
treatment as appropriate as per 
cardiology consult.
Consider 1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Consider adding prophylactic 
antibiotics for opportunistic 
infections.
Once improving, consider 
tapering steroids over at least 1 
month.
If no improvement or worsening, 
consider additional 
immunosuppressants (e.g. 
azathioprine, cyclosporine A).
*Local guidelines, or eg. ESC or AHA guidelines 
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management
Grade 1 or Grade 2 
endocrinopathies (hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Consider continuing M7824 
Consider endocrinology consult if 
needed
Consider continuing hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate.

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Consider starting thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for Type I 
diabetes mellitus) as appropriate. 
Consider ruling-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis)
Grade 3 or Grade 4 
endocrinopathies (hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Consider withholding or 
permanently discontinuing M7824 
for Grade 3-4 events based upon if 
the clinical condition can be safely 
managed. 
Consider hospitalization
Consider endocrinology consult
Consider starting thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for type I 
diabetes mellitus) as appropriate. 
Consider ruling-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis)
Consider resuming therapy once 
symptoms and/or laboratory tests 
improve to Grade ≤ 1 (with or 
without hormone 
replacement/suppression).
Consider continuing hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate. 
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)
If secondary thyroid and/or adrenal 
insufficiency is confirmed (i.e. 
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately 
low ACTH):
•
Consider referring to 
endocrinologist for dynamic 
testing as indicated and 
measurement of other hormones 
(FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens 
in women) 
•
Consider hormone 
replacement/suppressive therapy 
as appropriate 
•
Consider performing pituitary 
MRI and visual field 
examination as indicated
If hypophysitis confirmed:
Consider resuming therapy once 
symptoms and hormone tests 
improve to Grade ≤ 1 (with or 
without hormone replacement).
In addition, for hypophysitis 
with abnormal MRI, consider 
resuming M7824 only once 
shrinkage of the pituitary gland 
on MRI/CT scan is documented. 
Consider continuing hormone 
replacement/suppression therapy 
as appropriate.

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•
Continue M7824 if mild 
symptoms 
•
Consider withholding M7824 
and if moderate, severe or life-
threatening symptoms of 
hypophysitis. Consider 
hospitalization. Consider 
initiating corticosteroids (1 to 2 
mg/kg/day prednisone or 
equivalent) followed by 
corticosteroids taper during at 
least 1 month.
•
Consider adding prophylactic 
antibiotics for opportunistic 
infections.
Other irAEs (not described above)
Grade of other irAEs 
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical signs or 
symptoms suggestive of a potential 
irAE
Consider withholding M7824 
pending clinical investigation
If irAE is ruled out, consider 
managing as appropriate 
according to the diagnosis and 
consider re-starting therapy
If irAE is confirmed, consider 
treating as Grade 2 or 3 irAE.
Grade 2 irAE or first occurrence of 
Grade 3 irAE
Consider withholding M7824 based 
upon if the clinical condition can be 
safely managed.
Consider 1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Consider adding prophylactic 
antibiotics for opportunistic 
infections 
Specialty consult as appropriate
If improves to Grade ≤ 1: 
Consider tapering steroids over 
at least 1 month and resuming 
therapy following steroids taper.
Recurrence of same Grade 3 irAEs
Consider permanently discontinuing 
M7824 based upon if the clinical 
condition can be safely managed; 
Consider
1.0 to 2.0 mg/kg/day
prednisone or equivalent
Consider adding prophylactic 
antibiotics for opportunistic 
infections 
Specialty consult as appropriate
If improves to Grade ≤ 1: 
Consider tapering steroids over 
at least 1 month.

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Grade 4 
Permanently discontinue M7824 
Consider to 2.0 mg/kg/day
prednisone or equivalent and/or 
other immunosuppressant as needed
Consider adding prophylactic 
antibiotics for opportunistic 
infections 
Consider specialty consult as 
appropriate
If improves to Grade ≤ 1: 
Consider tapering steroids over 
at least 1 month
Requirement for 10 mg per day or 
greater prednisone or equivalent 
for more than 12 weeks for reasons 
other than hormonal replacement 
for adrenal insufficiency
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer
Consider permanently discontinuing 
M7824 
Consider specialty consult as 
appropriate 
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BNP=B-type natriuretic 
peptide; CK-MB=creatine kinase MB; CT= computed tomography; FSH=follicle-stimulating 
hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; irAE=immune related 
adverse event; IV=intravenous; LH=luteinizing hormone; MRI=magnetic resonance imaging; 
NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; 
PRL=prolactin;T4=thyroxine; TSH=thyroid stimulating hormone; ULN=upper limit of normal

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3.5
STUDY CALENDAR
Procedure
Screening1
Baseline / 
Week 12
Week 
(2N+1)3
EOT4
Safety 
follow 
up5
Long 
Term 
follow up6
Treatment3 
X
X
NIH Advance Directives Form7
X
Medical History
X
Height
X
Physical exam, weight, vital 
signs, ECOG 
X
X
X
X
X
HIV, HCV, HepB
X
EKG
X
X
X
CBC with differential
X
X
X
X
X
Biochemical profile8
X
X
X
X
X
Tumor Markers9
X
X
X
CD4 10
X
HLA typing
X
ACTH, TSH, reflex Free T4, 
lipase, amylase, CRP
X
X11
Urinalysis 
X
Urine or serum pregnancy 
testing in individuals of 
childbearing potential 
X
X
X
PT, INR, aPTT
X
Tumor evaluation (CT Scan)12
X
X
X
Brain CT 13
X
Concomitant Medications
X
X
X
X
Adverse events
X
X
X
X
Optional biopsy for immune 
analysis 14
X
X
Research Blood 15
X
X
X
Telephone Follow Up
X
X

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1. Screening evaluations performed within 28 days prior to the first drug administration, unless specified in Section 
2.2.
2. Baseline evaluations performed within 1 week prior to first drug administration.
3. Schedule of therapeutic agents administered will be as outlined in Section 3.1, Figure 19.. PDS01ADC will be 
given every 4 weeks, M7824 infusion will be every two weeks and HPV vaccine will be given every 4 weeks for the 
first 6 doses followed by every 12 weeks thereafter. (The first administration of HPV vaccine should preferably be 
given 1-2 weeks before the first administration of PDS01ADC and M7824.) Administration of study agents and 
indicated evaluations can be done up to 14 days earlier or delayed up to 14 days due to holidays, inclement weather, 
conflicts, or similar reasons. The timing of subsequent administrations is adjusted to maintain a minimum of 11 days 
between treatments of similar agents. 
4. EOT – End of treatment visit: Where feasible, on the day of or within 7 days of the decision to discontinue treatment 
prematurely before completion of one year of treatment. Does not need to be completed if drug is withheld after one 
year of treatment.
5. 28 days (+/- 7 days) after last treatment. If subjects are not willing to come to NIH to FU visit, they will be contacted 
by phone to assess adverse events. 
6. Participants who have come off treatment for disease progression will be followed by phone annually for survival. 
Participants who have not progressed on treatment will continue to be followed and scanned per investigator discretion 
until progression. Initial and follow up courses of treatment may extend beyond a year per investigator discretion. 
7. As indicated in Section 12.3, all subjects will be offered the opportunity to complete an NIH advanced directives 
form. This should be done preferably at baseline but can be done at any time during the study as long as the capacity 
to do so is retained. The completion of the form is strongly recommended, but is not required.
8. Biochemical profile: mineral panel, sodium, potassium, chloride, bicarbonate, calcium, glucose, BUN, creatinine, 
ALT, AST, alkaline phosphatase, total protein, albumin, and total and direct bilirubin. Note: the mineral panel will 
start from baseline onward. 
9. Evaluate CEA, CA19-9, CA125 and CA15-3 at baseline and follow elevated values thereafter.
10. In HIV positive participants.  
11. Every 8 weeks.
12. Every 8 weeks. In the event of a PR or CR tumor imaging assessments may be performed every 3 months (+/- 2 
weeks) at the discretion of the investigator. Tumor assessment should be continued beyond end of treatment in 
participants who have not experienced PD until they experience PD in order to assess PFS. MRI will be used when 
CT scan is not an option to follow the disease clinically. Gadolinium will be used only for clinically indicated MRIs. 
Bone scans and other imaging assessments may also be performed as clinically indicated.
13. In participants with known CNS disease as described in Section 2.1.2.4. MRIs may be performed as clinically 
indicated in this population.
14. Optional biopsies at baseline and as close as possible to first imaging restaging.
15. Where feasible, research blood for study assessments (see Section 5) will be collected at baseline, 3 days and 1 
week after the first M7824 + PDS01ADC dose) as well as at weeks 3 and 7 and at restaging visits in selected 
participants, per PI discretion.

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3.6
COST AND COMPENSATION 
3.6.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs if they are 
not covered by an insurance company. Medicines that are not part of the study treatment will not 
be provided or paid for by the NIH Clinical Center.    
3.6.2
Compensation
There will be no compensation provided on this study.
3.6.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation. Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate. The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.  
3.7
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Regardless of reason for removal from study therapy, participants will be asked to have a 28 day 
follow up safety visit. Participants who refuse to return for this visit will be asked to review any 
safety concerns by phone within this time period.  
3.7.1
Criteria for Removal from Protocol Therapy
•
Clinical or radiographic progression of disease except when the investigator feels the 
subject is still benefiting from treatment. (It is generally preferable for participants to 
remain on treatment past initial radiographic progression in case there is pseudo -
progression, except when the investigator feels that the clinical picture warrants 
changing therapy at initial progression).
•
Unacceptable Toxicity possibly attributed to all active therapies. 
•
Participant requests to be withdrawn from active therapy.
•
Start of another systemic anticancer treatment or participation in another 
investigational therapeutic trial. Focal palliative radiotherapy, ablation, or surgery to a 
site of disease will not necessitate removal from protocol therapy.  
•
Investigator discretion.
•
Positive pregnancy test.
3.7.2
Off-Study Criteria
•
Screen failure.
•
PI decision to end the study.
•
Participant requests to be withdrawn from study. 
•
Participant lost to follow up.

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•
Investigator discretion. 
•
Death.
3.7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for 4 scheduled visits 
and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:
•
The site will attempt to contact the participant and reschedule the missed visit for within 
the next 2 weeks and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain if the participant wishes to and/or should continue in the study.
•
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, an IRB approved certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record or study file. 
•
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
Any medications (other than those excluded by the clinical trial protocol) that are considered 
necessary to protect subject welfare or alleviate symptoms and will not interfere with the trial 
medication may be given at the Investigator’s discretion.
Palliative radiotherapy delivered in a normal organ-spearing technique may be administered during 
the trial. The assessment of PD will not be based on the necessity for palliative radiotherapy.
4.1
THE FOLLOWING TREATMENTS SHOULD NOT BE ADMINISTERED DURING THE TRIAL 
•
Other immunotherapies or immunosuppressive drugs (for example, chemotherapy or 
systemic corticosteroids except for prophylaxis or treatment of allergic reactions, 
endocrine replacement therapy at low dose prednisone [≤ 10 mg daily] or equivalent, for 
the treatment of irAEs, or for short courses (≤ 14 days) as appropriate medical therapy for 
unrelated medical conditions (e.g., asthma).  Steroids with no or minimal systemic effect 
(topical, inhalation) are allowed.
•
Prophylactic use of corticosteroids for infusion related reactions. Corticosteroid 
administration prior to CT scans in participants with intravenous contrast allergy is 
allowed.
•
Any live vaccine therapies for the prevention of infectious disease. Administration of 
inactivated vaccines is allowed (for example, inactivated influenza vaccines or locally 
approved COVID vaccines).
•
Systemic anticancer treatment.

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5
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 
5.1
BIOSPECIMEN COLLECTION 
Test/assay
Volume 
(approx.) per 
Timepoint
Type of 
tubea
Collection point 
Location of 
specimen 
analysisb,*
Standard and 123 
immune cell 
subsets by FACS
CIO
Functional 
Analysis of 
immune cell 
subsets by FACS, 
scATAC-Seq, 
scRNASeq
CIO and NCI 
Frederick 
Genomic Core 
Facility
Antigen Specific 
Immune Response 
by cytokine 
staining assay
CIO
T cell clonality by 
immunseq 
platform
CIO and NCI 
Frederick 
Genomic Core 
Facility
RNA expression 
level of 770 genes
60-80 mL 
blood for 
PBMCs
Sodium 
heparin 
(green top) 
tubes
CIO and NCI 
Frederick 
Genomic Core 
Facility
Soluble Factors 
(to include sCD27 
and sCD40 
ligand) by ELISA 
16 mL blood 
for serum
SST
CIO and Jones 
Lab
Immune Markers 
by IHC
Tumor 
samples
N/A
See study calendar 
3.5
GMB TIME Lab

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Test/assay
Volume 
(approx.) per 
Timepoint
Type of 
tubea
Collection point 
Location of 
specimen 
analysisb,*
RNA expression 
level of 770 genes
Tumor 
samples
N/A
CIO and NCI 
Frederick 
Genomic Core 
Facility
HPV status by 
PCR of DNA
Tumor 
samples
N/A
Dr. Hinrich’s Lab
Circulating tumor 
DNA (ctDNA) by 
PCR system
Plasma
EDTA 
(lavender 
top)
CIO and NIH 
Core Facility
T cell clonality by 
immunoseq 
platform
Tumor 
samples
N/A
CIO and NCI 
Frederick 
Genomic Core 
Facility
a Please note that tubes and media may be substituted based on availability with the permission of 
the PI or laboratory investigator.
b The location of specimen processing or analysis may be adjusted with the permission of the PI or 
laboratory investigator
*Research blood samples will be sent to the Clinical Services Program – Leidos Biomedical 
Research, Inc. (CSP) (Section 5.3.1) for barcoding, initial processing and storage. Tissue will be 
sent to the Laboratory of Pathology as described in Section 5.3.2. From these facilities, coded, 
linked samples will be sent to the designated labs for analysis upon request.
Note: Platforms and procedures for analysis may be adjusted based upon current technology 
and/or collaborations in place at the time of actual analyses.
5.1.1
Immune Phenotyping
Exploratory immunologic studies will be conducted to evaluate the study drug’s effect on the 
immune response before and after treatment, to gain insight into potential biomarkers, and help 
improve the administered therapy. Blood will be collected as per Study Calendar 3.5. The 
following immune assays may be performed at the Center for Immuno-Oncology (CIO) at the 
NCI’s Center for Cancer Research (CCR) in select participants where adequate samples are 
available:
1. PBMCs may be analyzed for changes in standard immune cell types (CD4 and CD8 T cells, 
natural killer [NK] cells, regulatory T cells [Tregs], myeloid-derived suppressor cells [MDSCs], 
and dendritic cells) as well as 123 immune cell subsets, using multi-color flow cytometry, 
scATAC-Seq and scRNA-Seq.

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2. PBMCs from selected subjects may be analyzed for function of specific immune cell subsets, 
including CD4 and CD8 T cells, NK cells, Tregs, and MDSCs using flow-based assays.
3. PBMCs may be analyzed for tumor antigen-specific immune responses using an intracellular 
cytokine staining assay. PBMCs will be stimulated in vitro with overlapping 15-mer peptide pools 
encoding the tumor-associated antigens such as CEA, MUC-1 and Brachyury; control peptide 
pools will involve the use of human leukocyte antigen peptide as a negative control and CEFT 
peptide mix as a positive control. CEFT is a mixture of peptides of CMV, Epstein-Barr virus, 
influenza, and tetanus toxin. Post-stimulation analyses of CD4 and CD8 T cells will involve the 
production of IFN-γ, IL-2, TNF, and the degranulation marker CD107a. If sufficient PBMCs are 
available, assays may also be performed for the development of T cells to other tumor-associated 
antigens.
5.1.2
Soluble Factors
Samples for soluble factor analysis will be collected as per Study Calendar 3.5. 
-Sera may be analyzed pre- and post-therapy for the following soluble factors: sCD27, sCD40 
ligand using commercial ELISA kits.
-Sera may be analyzed for changes in cytokines (IFN-γ, IL-10, IL-12, IL-2, IL-4, etc.), 
chemokines, antibodies, tumor-associated antigens, and/or other markers using ELISA or 
multiplexed assays (e.g., Mesoscale, Luminex, cytokine bead array).
-Sera may also be evaluated by Jones Lab (1 mL of serum at baseline and on-treatment timepoints 
as available) for extracellular vesicle (exosome) - associated surface markers (including CD63, 
CD9, CD81, CD9, CD40, HLA, CD31, CD44, CD45, CD14, and CD2) to evaluate changes in the 
repertoire of shed vesicles from tumor, immune, and endothelial cells (e.g. Miltenyi Biotec, 
MACSplex EV Kit IO, human). Magnetic bead-based separation methods developed in the Jones 
Lab will be used to further isolate extracellular vesicle subsets for further cargo analysis in the 
Jones Lab, including cytokine analysis as described above, and RNA analysis. For the RNA 
analysis, following separation of specific EV subsets, as described above, EV subset total RNAseq 
may be performed. Where possible, total RNA will be isolated from magnetically separated EVs 
(Norgen Exosome Total RNA Isolation Kit), and cDNA libraries generated from EV Subset RNA 
and bulk (unfractionated) EV RNA with Takara Smarter Stranded Pico libraries (Jones Lab and 
NCI Frederic RNAseq Core). These analyses will be used to gauge whether soluble cell fragments 
in the form of extracellular vesicles reveal tumor, immune, and vascular responses to treatment. 
The "ESCAPE" RNAseq pipeline we will use has been custom developed by the Jones Lab and 
NCI CCBR to include identification of human RNA and viral RNA, so we will also interrogate 
whether treatment responses correlate with shedding of HPV viral elements as RNA fragments in 
EV subsets. Where possible, fragmented extracellular DNA cargo from EVs (not whole genomic 
DNA) will be quantified and analyzed to evaluate correlation with tumor characteristics and 
response to treatment.
5.1.3
Analyses of Tumor Tissue for Immune Markers
Study of immune infiltration as well as PD-L1 status within the tumor microenvironment pre vs. 
post treatment by IHC and/or multiplex immunofluorescence may be performed by the GMB 
TIME Lab. Where available, archival tumor samples will be requested (preferably tissue samples 
from the last 6 months). For participants with lesions amenable to biopsy, two optional biopsies 

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may be performed at baseline and at first restaging. Tumor samples will be sent to the Laboratory 
of Pathology for disease evaluation; remaining samples will be used for research. Tissue samples 
for research may also be stored in CSP as described in Section 5.3.1. 
5.1.4
Assessment of HPV status
In participants with available tumor tissue (either archival or by optional biopsy), HPV testing will 
be performed using the Roche Cobas or Becton Dickinson HPV PCR based DNA assay, if no prior 
HPV testing of the tumor has been performed. This will be done through collaboration with Dr. 
Hinrich’s Lab.
5.1.5
Circulating tumor DNA 
If sufficient plasma is available, selected participant samples may be analyzed for circulating 
tumor DNA (CIO and NIH Core Facility).  Plasma DNA will be isolated with an automated 
purification system by Promega Corp using a system-attached bar-code reader to track samples 
and DNA products.  The circulating tumor/HPV DNA will be quantified with a digital droplet 
PCR system from Bio-Rad to obtain precise quantification. This is just quantification by PCR. 
There is no DNA sequencing. 
5.1.6
Biospecimen Sharing on Protocol
We may share existing identifiable data and blood and tissue samples with and obtain existing 
identifiable data and blood and tissue samples from NCI protocols 18C0056 Phase II Trial of 
M7824 in Subjects with HPV Associated Malignancies and 20C0104 Phase I/II Trial of HPV 
Vaccine PRGN-2009 Alone or in Combination with Anti-PD-L1/TGF-β trap (M7824) in Subjects 
with HPV Associated Cancers in order to allow for parallel processing of correlatives and potential 
integrative analysis.
5.2
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.2.1
Description of the scope of genetic/genomic analysis
5.2.1.1
RNA and T-cell Receptor Clonality Analysis of Blood and Tumor Tissue
Where possible, RNA expression and T-cell receptor clonality analysis will be done on the 
peripheral blood as well as archived tumor tissue or optional biopsies to help further evaluate 
changes in immune response and RNA expression levels with treatment as well as to determine 
tumor and infiltrating lymphocyte characteristics which may be predictive of response to 
treatment. In addition, these analyses will also be used to gauge resistance mechanisms and 
additional targets for future therapy. Coded, linked samples may be analyzed for RNA expression 
levels using the Nanostring platform and T-cell receptor clonality using the ImmunoSeq platform 
(CIO and NCI Frederick Genomic Core Facility).
NCI Fredrick Genomic Core Facility:
Leidos Biomedical Research, Inc:
Dr. Xiaolin Wu 
ATRF, Rm C3016
8560 Progress Drive
Frederick, MD 21701
Ph. 301-846-7677

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5.2.1.2
scRNA-Seq and scATAC-Seq 
Where possible, scRNA-Seq (single cell transcriptome assessment) and scATAC-Seq (single cell 
genome-wide chromatin accessibility assessment) will be performed on PBMCs to further 
evaluate the results of PBMC immune phenotyping (5.1.1) and study effects of the treatment on 
gene expression and epigenomic regulation of gene expression. 
5.2.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized
Confidentiality for genetic samples will be maintained as described (Section 5.3.1 and 5.3.2).
5.2.3
Management of Results
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the 
American College of Medical Genetics and Genomics recommendations for the return of 
incidental findings that is current at the time of primary analysis. Subjects will be contacted at 
this time with a request to provide a blood sample to be sent to a CLIA certified laboratory. If 
the research findings are verified in the CLIA certified lab, the subject will be offered the 
opportunity to come to NIH (at our expense) to have genetic education and counseling to explain 
this result. If the subject does not want to come to NIH, a referral to a local genetic healthcare 
provider will be provided (at their expense).
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis.
5.3
SAMPLE STORAGE, TRACKING AND DISPOSITION
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  Samples 
will not be sent outside the National Institutes for Health (NIH) appropriate approvals and/or 
agreements, if required.
5.3.1
Sample Management and Storage at Clinical Services Program – Leidos Biomedical 
Research, Inc. (CSP)
Clinical Services Program - Leidos Biomedical Research, Inc.
Attn: Theresa Burks 
1050 Boyles Street
Bldg. 496/Room 121
Frederick, MD 21702
On days samples are drawn, Jen Bangh at CSP (part of NCI Frederick Central Repositories) should 
be notified (phone: [301] 846-5893; fax [301] 846-6222). She will arrange same-day courier 
delivery of the specimens.
All data associated with the participant samples is protected by using a secure database. All 
Clinical Support Laboratory Staff receive annual training in maintaining records’ confidentiality. 
All samples drawn at the NIH Clinical Center will be transported to the Clinical Support 
Laboratory at the Frederick National Laboratory for Cancer Research by couriers.

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Samples will be tracked and managed by Central Repository database, where there is no link to 
personal identifiable information. All samples will be stored in either a -80ºC freezer or vapor 
phase liquid nitrogen. These freezers are located at NCI Frederick Central Repository in Frederick, 
Maryland.
NCI Frederick Central Repositories (managed under a subcontract) store, among other things, 
biological specimens in support of NIH clinical studies. All specimens are stored in secure, 
limited-access facilities with sufficient security, backup, and emergency support capability and 
monitoring to ensure long-term integrity of the specimens for research. 
Specimens are stored in accordance with applicable HHS and FDA Protection of Human Subjects 
Regulations in accordance with the subcontractor’s Federal-wide Assurance. The subcontractor’s 
role limited to clinical research databases and repositories containing participant specimens. The 
subcontractor does not conduct or have any vested interest in research on human subjects, but does 
provide services and support the efforts of its customers, many of which are involved in research 
on human subjects. 
It is the intent and purpose of the subcontractor to accept only coded, linked samples and sample 
information. To the limit of our ability, every effort will be made to ensure that protected 
information is not sent electronically or by hard copy or on vial labels. 
Sample data is stored in the BioSpecimen Inventory System II (BSI). This inventory tracking 
system is used to manage the storage and retrieval of specimens as well as to maintain specimen 
data. BSI is designed for controlled, concurrent access. It provides a real-time, multi-user 
environment for tracking millions of specimens. The system controls how and in what order 
database updates and searches are performed. This control prevents deadlocks and race conditions. 
For security, BSI has user password access, 3 types of user access levels, and 36 user permissions 
(levels of access) that can be set to control access to the system functions. BSI provides audit 
tracking for processes that are done to specimens including shipping, returning to inventory, 
aliquoting, thawing, additives, and other processes. BSI tracks the ancestry of specimens as they 
are aliquoted, as well as discrepancies and discrepancy resolution for specimens received by the 
repository. If a specimen goes out of the inventory, the system maintains data associated with the 
withdrawal request. Vials are labeled with a unique BSI ID which is printed in both eye-readable 
and bar-coded format. No participant -specific information is encoded in this ID. 
Investigators are granted view, input, and withdrawal authority only for their specimens. They may 
not view specimen data or access specimens for which they have not been authorized. Access to 
specimen storage is confined to repository staff. Visitors to the repositories are escorted by 
repository staff at all times.
5.3.2
Procedures for Storage of Tissue Specimens in the Laboratory of Pathology
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation. Unutilized excess tissues are stored for up to 
three months, in accordance with College of American Pathologists/Joint Commission on 
Accreditation of Healthcare Organizations (CAP/JCAHO) guidelines, and then discarded. 
Following completion of the diagnostic workup, the slides and tissue blocks are stored indefinitely 
in the LP’s clinical archives. All specimens are catalogued and retrieved utilizing the clinical 

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laboratory information systems, in accordance with CAP/JCAHO regulations. The use of any 
stored specimens for research purposes is only allowed when the appropriate IRB approval has 
been obtained. In some cases, this approval has been obtained via the original protocol on which 
the participant was enrolled.
5.3.3
Protocol Completion/Sample Destruction
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are 
remaining at the completion of the protocol will be stored in the conditions described above. The 
study will remain open so long as sample or data analysis continues. Samples from consenting 
subjects will be stored until they are no longer of scientific value or if a subject withdraws consent 
for their continued use, at which time they will be destroyed. The PI will report any loss or 
unanticipated destruction of samples per Section 7.2.1. If the patient withdraws consent the 
participant’s data will be excluded from future distributions, but data that have already been 
distributed for approved research use will not be able to be retrieved.
Samples will also be reported as lost if they are lost in transit between facilities or misplaced by a 
researcher. Freezer problems, lost samples, or other problems associated with samples that meet 
expedited reporting requirements (see Section 7.2.1 ) will also be reported.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and timeliness. 
The principal investigator, associate investigators/research nurses and/or a contracted data 
manager will assist with the data management efforts. Primary and final analyzed data will have 
identifiers so that research data can be attributed to an individual human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
Document AEs from the first study drug administration, Study Day 1 through 28 days after 
removal from study treatment or until off-study, whichever comes first. Adverse events that are 
serious need to be recorded through 28 days after the last intervention. Beyond 28 days after the 
last intervention and through long term follow up (survival of subject), only adverse events which 
are serious and related to the study intervention need to be recorded.
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:
•
Results in discontinuation from the study
•
Is associated with clinical signs or symptoms 
•
Requires treatment or any other therapeutic intervention
•
Is associated with death or another serious adverse event, including hospitalization. 
•
Is judged by the Investigator to be of significant clinical impact

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•
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the 
participant’s outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in Section 7.2.1. 
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:
•
Coded, linked data in an NIH-funded or approved public repository.
•
Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
•
Identified or coded, linked data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through:
•
An NIH-funded or approved public repository: clinicaltrials.gov
•
BTRIS (automatic for activities in the Clinical Center).
•
Approved outside collaborators under appropriate individual agreements.
•
Publication and/or public presentations.
When will the data be shared? 
•
Before publication.
•
At the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.
6.3
RESPONSE CRITERIA
6.3.1
Antitumor Response
Tumor assessments may include the following evaluations: physical examination (with photograph 
and measurement of skin lesions, as applicable); cross-sectional imaging using computed 
tomography (CT) or magnetic resonance imaging (MRI) scan of the chest, abdomen, and pelvis 
(pelvis scan is optional unless known pelvic disease is present at baseline); nuclear bone scan for 
subjects with known/suspected bone lesions; and CT or MRI scan of the brain (only as clinically 
warranted based on symptoms/findings). The preferred method of disease assessment is CT with 

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contrast. If CT with contrast is contraindicated, CT of the chest without contrast and MRI scan of 
the abdomen/pelvis is preferred. 
At baseline, tumor lesions will be selected and categorized as target or non-target lesions. Target 
lesions include those lesions that can be accurately measured in at least 1 dimension as ≥ 20 mm 
with conventional techniques or ≥ 10 mm with CT scan. Malignant lymph nodes with a short axis 
diameter ≥ 15 mm can be considered target lesions. Up to a maximum of 2 target lesions per organ 
and 5 target lesions in total will be identified at baseline. These lesions should be representative of 
all involved organs and selected based on their size (those with the longest diameter) and their 
suitability for accurate repeated measurements. A sum of the longest lesion diameter (LLD) for all 
target lesions will be calculated and reported as the baseline sum LLD. For malignant lymph nodes 
identified as target lesions, the short axis diameter will be used in the sum of LLD calculation. All 
other lesions (or sites of disease) should be identified as non-target lesions (including bone 
lesions).
All post-baseline response assessments should follow the same lesions identified at baseline. The 
same mode of assessment (e.g., CT) used to identify/evaluate lesions at baseline should be used 
throughout the course of the study unless subject safety necessitates a change (e.g., allergic 
reaction to contrast media).
For the primary endpoint antitumor activity will be evaluated with target and/or non-target lesions 
according to RECIST Version 1.1.
6.3.2
Disease Parameters
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as: 
•
By chest x-ray: > 20 mm; 
•
By CT scan: 
o
Scan slice thickness 5 mm or under: as > 10 mm
o
Scan slice thickness > 5 mm: double the slice thickness 
•
With calipers on clinical exam: > 10 mm.
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node 
must be > 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed.
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable.

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Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same participant, these are preferred for selection as target 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, on occasion, 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 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.
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 
in rare cases unequivocal progression of each should be noted throughout follow-up. 
6.3.3
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g., for body scans).
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 

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quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible.
6.3.4
Response Criteria
All the scans performed at Baseline and other imaging performed as clinically required (other 
supportive imaging) need to be repeated at subsequent visits. In general, lesions detected at 
Baseline need to be followed using the same imaging methodology and preferably the same 
imaging equipment at subsequent tumor evaluation visits.
Brain CT / MRI scan should be performed, if clinically indicated by development of new specific 
symptoms or on the discretion of the Principal Investigator. For each subject, the Investigator will 
designate 1 or more of the following measures of tumor status to follow for determining response: 
CT or MRI images of primary and / or metastatic tumor masses, physical examination findings, 
and the results of other assessments. All available images collected during the trial period will be 
considered. The most appropriate measures to evaluate the tumor status of a subject should be 
used. The measure(s) to be chosen for sequential evaluation during the trial have to correspond to 
the measures used to document the progressive tumor status that qualifies the subject for 
enrollment. The tumor response assessment will be assessed and listed according to the Study 
Calendar 3.5.
The foreseen treatment duration is until disease progression verified by a scan subsequent to the 
initial documentation of PD, unacceptable toxicity, or any criterion for withdrawal from the trial 
occurs (see Section 6.3). Before stopping the treatment, progressive disease should be confirmed 
by imaging 4 to 6 weeks (preferably 6 weeks, but not later) after progression has been diagnosed 
according to RECIST 1.1 [36]. If progression is based on the occurrence of a new lesion in an area 
not scanned at Baseline, a further on-study scan 6 weeks later should be considered before 
performing the 28-Day Safety Follow-up visit. Treatment may be continued despite progression 
according to RECIST 1.1 at any time if:
•
There are no new or concerning symptoms.
•
There is no decrease in ECOG PS.
•
The Investigator does not consider it necessary to administer a salvage therapy. 
The treatment should be stopped immediately, if the subject does not tolerate M7824 or if 
therapeutic failure occurs, which requires urgent treatment with an additional drug or results in 
clinically significant progression / deterioration. 
Tumor responses to treatment will be assigned based on the evaluation of the response of target, 
non-target, and new lesions according to RECIST 1.1 (all measurements should be recorded in 
metric notation).

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•To assess objective response, the tumor burden at baseline will be estimated and used for 
comparison with subsequent measurements. At baseline, tumor lesions will be categorized in target 
and non-target lesions according to RECIST 1.1.
Results for these evaluations will be recorded with as much specificity as possible so that pre-and 
post-treatment results will provide the best opportunity for evaluating tumor response. 
Any CR or PR should be confirmed according to RECIST 1.1. In the case of a PR or CR, a 
confirmatory CT or MRI scan should be done no sooner than 4 weeks (preferably at the scheduled 
6-week interval). 
The Investigator may perform scans in addition to a scheduled trial scan for medical reasons or if 
the Investigator suspects PD.
As an exploratory endpoint antitumor activity will also be evaluated according to iRECIST [37].
Using iRECIST criteria the following will be incorporated into assessment:
1. An increase in the sum of target lesions of more than 20%, unequivocal increase in non-
target lesions or new lesions result in iUPD (unconfirmed progressive disease); iUPD can 
be assigned multiple times as long as iCPD (confirmed progressive disease) is not confirmed 
at the next assessment.
2. Progression is confirmed in the target lesion category if the next imaging assessment after 
iUPD (4–8 weeks later) confirms a further increase in sum of measures of target disease 
from iUPD, with an increase of at least 5 mm. Progression is confirmed in the non-target 
lesion category if subsequent imaging, done 4–8 weeks after iUPD, shows a further 
unequivocal increase in non-target lesions. Progression is confirmed in the new lesions 
category if at next assessment additional new lesions appear or an increase in size of 
previously seen new lesions is seen (≥5 mm for sum of new lesion target).
3. However, the criteria for iCPD (after iUPD) are not considered to have been met if 
complete response, partial response, or stable disease criteria (compared with baseline and 
as defined by RECIST 1.1) are met at the next assessment after iUPD. The status is reset 
(unlike RECIST 1.1, in which any progression precludes later complete response, partial 
response, or stable disease). iCR, iPR, or iSD should then be assigned; and if no change is 
detected, then the timepoint response is iUPD.
6.3.5
Response Criteria by RECIST 1.1
6.3.5.1
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum of diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progressions).

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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study.
6.3.5.2
Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
participants to be considered in complete clinical response.
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion increase.
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator).
6.3.5.3
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The participant's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.
For Participants with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks. Confirmation**
CR
Non-
CR/Non-PD
No
PR
CR
Not 
evaluated
No
PR
PR
Non-
CR/Non-
PD/not 
evaluated
No
PR
>4 wks. Confirmation**
SD
Non-
CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks. from baseline**

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Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
PD
Any
Yes or 
No
PD
Any
PD***
Yes or 
No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
*
See RECIST 1.1 manuscript for further details on what is evidence of a 
new lesion.
**
Only for non-randomized trials with response as primary endpoint.
***
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression.
Note: Participants with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment.
For Participants with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials 
so to assign this category when no lesions can be measured is not advised
6.3.5.4
Duration of Response
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).

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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
6.3.5.5
Progression-Free Survival
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first.
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
participants while on the study. The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at:  
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 
Non-Compliance 
Human 
Subjects 
Research 
found 
at:https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance
-800Series-ComplianceandResearchEventReportingRequirements.
Note: Only IND Safety Reports that meet the definition of an unanticipated problem or present 
new information that might affect the willingness of participants to enroll or remain on the study 
will need to be reported per these policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found 
at:https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance
-800Series-ComplianceandResearchEventReportingRequirements.
7.2.3
NCI Clinical Director Reporting
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.

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In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.3
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.3.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular basis (approximately weekly) when participants 
are being actively treated on the trial to discuss each participant. Decisions about dose level 
enrollment and dose escalation if applicable will be made based on the toxicity data from prior 
participants. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in Section 
7.2.2 will be submitted within the appropriate timeline. 
The principal investigator will review adverse event and response data on each participant to 
ensure safety and data accuracy. The principal investigator will personally conduct or supervise 
the investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
8
SPONSOR PROTOCOL/SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2)).
8.1.2
Adverse Event of Special Interest (AESI)
Mucosal bleeding events which are at least possibly related to study drug (M7824) will be captured 
as AESIs. These events will not require expedited reporting to the study sponsor unless they also 
meet SAE criteria. 
8.1.3
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
•
Death;
•
A life-threatening adverse event (see Section 8.1.4);
•
Inpatient hospitalization or prolongation of existing hospitalization 

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o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient convenience) is not considered a serious adverse event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.
•
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions;
•
A congenital anomaly/birth defect;
•
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.4
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death (21CFR312.32).
8.1.5
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0.
8.1.6
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  
•
Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.
•
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.1.7
Adverse Events of Special Interest (AESI)
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product(s) and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. The 
rapid reporting of AESIs allows ongoing surveillance of these events to characterize and 
understand them in association with the use of these investigational products. 

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Only AESIs that match the definition of SAE will be reported as other SAEs within 24 hours from 
the knowledge of event. 
The following adverse events, regardless of site, will be collected as an AESI to enable evaluation 
of potential risk factors, such as site/past radiation/associated infection at site/recent 
instrumentation and other variables such as time to onset, exposure history, grade of bleeding, 
anatomical sites, etc. can be collected.
•
Mucosal Bleeding possibly due to TGFβ inhibition.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity and 
relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship. AEs will be followed through resolution.
SAEs will be:
•
Assessed for severity and relationship to study product and alternate etiology (if not related 
to study product) by a licensed study physician listed on the Form FDA 1572 as the site 
principal investigator or sub-investigator.
•
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.
•
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to Section 6.1. All serious adverse events 
recorded must be reported to the sponsor. All serious adverse events recorded from the time of 
first investigational product administration must be reported to the sponsor with the exception of 
any listed in section 8.4. 
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited 
reporting requirements are found in section 8.4.
All SAE reporting must include the elements described in Section 8.1.7.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and 
instructions 
can 
be 
found 
at: 
https://nih.sharepoint.com/:u:/r/sites/NCI-CCR-OCD-
Communications/SitePages/Forms-and-Instructions.aspx?csf=1&web=1&e=uWBXtI. 

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Following the assessment of the SAE by OSRO, other supporting documentation of the event may 
be requested by the OSRO Safety and should be provided as soon as possible.
8.4
WAIVER OF EXPEDITED REPORTING TO CCR 
As overall survival, which includes death due to disease progression and hospitalization due to 
disease progression are part of the study objectives, and captured as an endpoint in this study, 
death/hospitalization due to disease progression will not be reported in expedited manner to the 
sponsor. However, if there is evidence suggesting a causal relationship between the study drug and 
the event, report the event in an expedited manner according to Section 8.3.
8.5
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
Reporting will be per the collaborative agreement. 
8.6
REPORTING PREGNANCY 
All 
required 
pregnancy 
reports/follow-up 
to 
OSRO 
will 
be 
submitted 
to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions can 
be 
found 
here: 
https://nih.sharepoint.com/:u:/r/sites/NCI-CCR-OCD-
Communications/SitePages/Forms-and-Instructions.aspx?csf=1&web=1&e=uWBXtI. 
8.6.1
Maternal exposure
If a participant becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor. The potential risk of 
exposure of the fetus to the investigational agent(s) or chemotherapy agents (s) should be 
documented in box B5 of the MedWatch form “Describe Event or Problem”.
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (Section 8.1.3) should be reported as SAEs. 
The outcome of all pregnancies should be followed up and documented.
8.6.2
Paternal exposure
Participants should refrain from fathering a child or donating sperm during the study and for 2 
months after the last dose of M7824.
Pregnancy of the participant’s partner is not considered to be an AE. The outcome of all 
pregnancies occurring from the date of the first dose until 2 months after the last dose should, if 
possible, be followed up and documented. Pregnant partners may be offered the opportunity to 
participate in an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry 
study) to provide data about the outcome of the pregnancy for safety reporting purposes.
8.7
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected in expedited manner to the FDA in accordance 
to 21 CFR 31.2.32. CCR will report an AE as a suspected adverse reaction only if there is evidence 
to suggest a causal relationship between the study product and the adverse event. CCR will notify 
FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing 
drug under its INDs or under any investigator’s IND) in an IND safety report of potential serious 

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risks from clinical trials or any other source, as soon as possible, in accordance to 21 CFR Part 
312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
8.8
SPONSOR PROTOCOL DEVIATION REPORTING
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual of 
Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial.
It is the responsibility of the study Staff to document any protocol deviation identified by the Staff 
or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online application. 
The entries into the PDTS online application should be timely, complete, and maintained per CCR 
PDTS user requirements. 
In addition, any deviation to the protocol should be documented in the participant’s source records 
and reported to the reviewing IRB per their guidelines. OSRO required protocol deviation 
reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 Compliance 
with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol deviations.
8.9
DATA SAFETY MONITORING BOARD (DSMB) (OSRO)
The safety oversight for this protocol will be under the direction of a DSMB composed of 
individuals with the appropriate expertise, including a biostatistician experienced in statistical 
methods for clinical trials and a clinician with relevant expertise. Members of the DSMB should 
be independent from the study conduct and free of conflict of interest, or measures should be in 
place to minimize perceived conflict of interest. The DSMB will operate according to the charter 
which is reviewed and approved as part of the initial DSMB meeting. The charter will define the 
DSMB reviews for this protocol including the frequency of cumulative data reviews. 
Types of DSMB reviews include:
•
Initial review for a new protocol:
Review of the Protocol, ICF, presentation from the PI/designee, study-related documents, halting 
rules, statistical methods, set triggers for data review or analyses, establish guidelines for 
monitoring, and finalize Report formats.
•
Cumulative data review, at least once a year but may be more frequent.
•
Ad hoc review as described in the protocol when:
o
Clinical trial halting criteria are met.
o
Occurrence of a specific time point, or event described in the protocol (e.g., interim 
analysis, dose escalation criteria are not met resulting in a halt in enrollment) 
o
At the request of the Sponsor due to a safety concern or clinical trial conduct issue 

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•
Final review meeting at the end of the clinical trial.  Additional meetings are not required 
unless the Sponsor requests consultation by the committee, or a potential safety concern or 
study-related issue arises.
Following each DSMB review, the DSMB will provide its recommendations to the Sponsor. The 
recommendations signed by the Committee Chair and the Sponsor determination on the 
recommendations signed by the OSRO Director, will be distributed to the PI for the protocol 
under review. 
9
CLINICAL MONITORING PLAN
Clinical site monitoring is conducted to ensure: 
•
that the rights of the participants are protected; 
•
that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and,  
•
the quality and integrity of study data and data collection methods are maintained.  
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) Good 
Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable regulatory 
requirements.
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates.
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will occur at the study site.  
Monitoring visit reports will describe visit activities, observations, and associated action items or 
follow-up required for resolution of any issues, discrepancies, or deviations.  Monitoring reports 
will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, coordinating 
center (if applicable), and the OSRO regulatory file.
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol 
Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per 
institutional and IRB guidance.

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10 STATISTICAL CONSIDERATIONS
10.1 STATISTICAL HYPOTHESIS
The primary objective of this trial is to determine the objective response rate of combination 
immunotherapy in participants with HPV associated malignancies. A secondary hypothesis 
(objective) will be to obtain preliminary data on duration of response, PFS, OS and ratio of 
participants that are hospitalized because of adverse events attributed to disease progression. An 
exploratory hypothesis (objective) will be to evaluate exploratory immunologic studies to 
understand and improve the administered treatment. 
In patients with cervical cancer with prior pelvic radiation and boost brachytherapy, a key 
secondary objective is to evaluate the safety of the combination at a reduced dose level in these 
patients where a potential higher risk of grade 3 hematuria may exist with the full starting doses 
of M7824 at 1200 mg and PDS01ADC at 16.8 mcg/kg.
10.2 SAMPLE SIZE DETERMINATION
Data from the ongoing trial indicates that a response rate for M7824 may be approximately 30%. 
In the main study cohort (Cohort 1), this trial will try to demonstrate if the proposed combination 
therapies may be associated with an improved response rate.
The trial will treat participants with HPV related cancers with HPV vaccine + M7824 + 
PDS01ADC. The objective is to determine if this treatment can be associated with an acceptable 
response rate. To establish the efficacy of this combination treatment, the primary objective would 
be to determine if using the proposed agents would rule out a 30% response rate and result in a 
response rate consistent with 60%. As such, this trial in participants with HPV associated 
malignancies will be conducted using a Simon optimal two-stage phase II trial design (Simon R, 
Controlled Clinical Trials 10:1-10, 1989) to rule out an unacceptably low PR+CR rate of 30% 
(p0=0.30) in favor of an improved response rate of 60% (p1=0.60). With alpha=0.10 (probability 
of accepting a poor treatment=0.10) and beta = 0.10 (probability of rejecting a good 
treatment=0.10), the first stage will enroll 8 evaluable checkpoint naïve participants, and if 0 to 2 
of the 8 have a clinical response, then no further participants will be accrued. If 3 or more of the 
first 8 checkpoint naïve participants have a response, then accrual would continue until a total of 
20 evaluable checkpoint naïve participants have been treated. As it may take up to several months 
to determine if a patient has experienced a response, a temporary pause in the accrual may be 
necessary to ensure that enrollment to the second stage is warranted. If there are 3 to 8 checkpoint 
naïve participants with a response out of 20 participants, this would be an uninterestingly low 
response rate. If there were 9 or more of 20 (45.0%) checkpoint naïve patients who experienced 
a response, this would be sufficiently interesting to warrant possible further study of the 
combination in later trials in this disease type; decisions about future use of the combination will 
incorporate response as well as toxicity profile information. Under the null hypothesis (30% 
response rate), the probability of early termination is 55.2%.
In the cohort with patients with cervical cancer with prior pelvic radiation and boost brachytherapy 
where a potential higher risk of grade 3 hematuria may exist with the full starting doses of M7824 
at 1200 mg and PDS01ADC at 16.8 mcg/kg, the safety evaluation may require up to 12 patients 
as outlined in Section 3.4.3, and if there are preliminary hints of efficacy within these 12 patients, 

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up to 12 additional patients may be enrolled at the dose found to be safe for these patients to further 
explore the safety as well as the potential response rate in a small number of patients.
It is expected that if 2 participants per month enroll on the trial, in order to enroll up to a total of 
20 evaluable participants with checkpoint naïve disease in the main cohort, and 12+12=24 
maximum in the patients in cohort 2, up to 3 years may be required. To allow for several 
inevaluable participants for the primary objective and potential replacements based on HPV status 
the accrual ceiling will be set at 56 participants. If additional patients are required to enroll on the 
trial to account for screen failures and inevaluable patients, the ceiling increase will be 
incorporated in an amendment.
10.3 POPULATIONS FOR ANALYSES
All participants who receive any investigational treatment will be evaluable for safety and toxicity 
evaluations. All participants will be evaluable for toxicity from the time of their first treatment 
with any agent. 
For efficacy, a modified intention to treat population will be used. Only those participants who 
have measurable disease present at baseline and have had their disease re-evaluated will be 
considered evaluable for response. (Note: Participants who exhibit objective disease progression 
prior to the end of cycle 1 will also be considered evaluable.)
10.4 STATISTICAL ANALYSES
10.4.1 General Approach
Participants will be evaluated with respect to the grades and types of toxicities obtained. The results 
will be presented descriptively and tabled if appropriate. Further planned analyses are described 
below.
10.4.2 Analysis of the Primary Endpoints
The percentage of checkpoint naïve subjects whose initial doses of study drugs are not modified 
that achieve an objective confirmed complete or partial overall tumor response using RECIST 
Version 1.1 will be evaluated. If anti-tumor responses are observed, the 95% confidence interval 
of the response rate will be evaluated.   
10.4.3 Analysis of the Secondary Endpoints
Data will be obtained on duration of response, PFS, OS and ratio of participants that are 
hospitalized because of adverse events attributed to disease progression. In addition, patients in 
cohort 2 will have their safety evaluated based on the description in Section 3.4.3.
10.4.3.1 Duration of Response
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that PD is objectively documented and is 
evaluated using the Kaplan-Meier method.
10.4.3.2 Progression-Free Survival
PFS will be evaluated using Kaplan-Meier methods. PFS will be defined as the time from the date 
of first treatment to the date of disease progression or death (any cause) whichever occurs first. 

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Subjects who do not have disease progression or have not died at the end of follow up will be 
censored at the last known date the subject was progression free.
10.4.3.3 Objective Response
Objective response is a complete or partial radiographic response as defined by RECIST 1.1 
(Section 6.3.5).
10.4.3.4 Overall Survival
OS will be evaluated using Kaplan-Meier methods. OS will be defined as the time from the date 
of first treatment to the date of death (any cause). Subjects who are alive at the end of follow up 
will be censored at the last known date alive.
10.4.4 Safety Analyses
Safety endpoints will be analyzed as summary statistics during treatment and/or as change scores 
from baseline assessments.  AEs will be coded as defined in the Medical Dictionary for Regulatory 
Activities (MedDRA). All AEs will be recorded and tabulated following each treatment. AEs will 
be recorded by severity, frequency, and relationship to the study intervention and will be presented 
by System Organ Class (SOC) designations and preferred term groupings. Information on each 
AE will include start date, stop date, severity, relationship, expectedness, outcome, and duration. 
Adverse events leading to premature discontinuation from the study intervention and serious 
treatment-emergent AEs will be presented either in a Table or a Listing. 
In addition, overall safety will be assessed by descriptive analyses using tabulated frequencies of 
AEs by grade using CTCAE Version 5 within dose cohorts and for the overall study population in 
terms of treatment-emergent AEs, SAEs, and clinically significant changes in safety laboratory 
tests, physical examinations, ECGs, and vital signs.
Patients in cohort 2 will have their safety evaluated as detailed in Section 3.4.3, with up to 12 
patients, with further evaluation focusing on bleeding events in the maximum of 12 patients 
enrolled at the dose considered safe among the patients in this cohort also being enrolled for an 
exploratory evaluation of efficacy.
10.4.5 Baseline Descriptive Statistics
Baseline Characteristics will be described. 
10.4.6 Planned Interim Analyses
Interim assessment of efficacy will be made according to the Simon two stage phase II designs of 
each cohort described in Section 10.4.6.
10.4.7 Tabulation of Individual Participant Data
Individual responses in a cohort may be depicted within a larger group using a waterfall plot or 
spider diagram. 
10.4.8 Exploratory Analyses 
10.4.8.1 Exploratory Analyses: Immune Responses
Where feasible exploratory immune analyses will be conducted to evaluate anti-tumor immune 
responses. Immune response will be assessed among all subjects treated in each cohort. The 
magnitude of immune responses will be described. A subject will be considered evaluable for 

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immune response if they receive at least one dose of treatment. The percentage of subjects with a 
positive immune response will be evaluated by cohort. For flow cytometry analyses on PBMC 
samples, Student T tests or Kruskal-Wallis and Wilcoxon rank sum tests as appropriate will be 
performed on percentages of TNF- and/or IFN- expressing cells among the different cohorts to 
determine any significant differences in cell populations. For antigen specific T cell responses, a 
positive immune response is defined by CMI reactivity in ex vivo stimulation using a flow 
cytometric readout (cytokine production or CD107 expression). Antigen-specific peptide 
challenge assays require a readout of >250 reactive T-cells/million cells above the background 
[38]. 
10.4.8.2 Exploratory Analyses: Preliminary Activity in Patients Receiving Lower Doses
In patients who receive reduced initial doses of therapy as per Section 3.4.3, both in the dose 
seeking portion as well as in a small group of patients treated at the safe dose, the percentage of 
subjects who achieve an objective confirmed complete or partial overall tumor response using 
RECIST Version 1.1 for a specific initial dose will be evaluated. If anti-tumor responses are 
observed, the 95% confidence interval of the response rate will be evaluated.  
11 COLLABORATIVE AGREEMENTS
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
A CRADA (02666) is in place with EMD Serono for the supply of M7824.
A CRADA (03279) is in place with PDS Biotechnology for the supply of PDS0101 and 
PDS01ADC.
12 HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION
Subjects from all racial/ethnic groups are eligible for this study if they meet the eligibility criteria. 
Efforts will be made to extend accrual to a representative population. Due to impaired cellular 
immunity which may affect the efficacy of treatment, patients with poorly controlled HIV as well 
as patents with detectable viral loads of hepatitis B and C will be excluded. 
Participants who do not accept blood transfusions will be excluded. As there is a risk of severe 
bleeding with this study drug, participants must be willing to receive blood transfusions if 
medically necessary for their own safety. Participants must be able to receive blood transfusions 
in order to minimize the risks of receiving M7824.
12.2 PARTICIPATION OF CHILDREN
Individuals under the age of 18 will not be eligible to participate in this study because of unknown 
toxicities in pediatric patients.
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to provide consent are excluded from enrolling in the protocol. However, it is 
possible that subjects enrolled in the protocol may permanently lose the capacity to consent for 
themselves during the course of this study.  In the event this occurs, the subjects will remain in the 
study because there is a prospect of direct benefit from research participation. All subjects ≥ age 

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18 will be offered the opportunity to fill in their wishes for research and care, and assign a 
substitute decision maker on the “NIH Advance Directive for Health Care and Medical Research 
Participation” form so that another person can make decisions about their medical care in the event 
that they become incapacitated or cognitively impaired during the course of the study. 
Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for 
evaluation to assess ongoing capacity of the subjects and to identify an LAR, as needed.
Please see Section 12.5.1 for consent procedure.
12.4 RISKS/BENEFIT ASSESSMENT
Participants will receive evaluation of their disease at the National Cancer Institute’s Clinical 
Center.  The potential benefit to a participant that goes onto study is a reduction in the bulk of their 
tumor which may or may not have a favorable impact on symptoms and/or survival.
Potential adverse reactions attributable to the administration of the study drug utilized in this trial 
are discussed in Section 14. All care will be taken to minimize side effects, but they can be 
unpredictable in nature and severity. Participants will be examined and evaluated prior to 
enrollment. All evaluations to monitor the treatment of participants will be recorded in the medical 
record. If participants suffer any physical injury as a result of the participation in this study, 
immediate medical treatment is available at the Clinical Center, National Cancer Institute, 
Bethesda, Maryland.
Although no compensation is available, any injury will be evaluated and treated in keeping with 
the benefits or care to which participants are entitled under applicable regulations. 
12.4.1 Risks
Some of the procedures performed on this study are not known to be associated with risk. These 
include urine tests and EKGs. Below are a list of procedures and study interventions that are 
associated with risk.
12.4.1.1 Study Drug Risks
Risks include the possible occurrence of any of a range of side effects which are listed in the 
Consent Document.
Participants may be harmed from being in this study by toxicity due to the drug or combination 
of drugs given during this study. M7824 is similar to immune check point inhibitors. There are 
preliminary data to suggest that not all patients benefit from immune check point inhibitors nor 
M7824. Additionally, there are preliminary data to suggest that an unexpectedly rapid 
progression of disease occurs in some patients receiving immunotherapy such as immune 
checkpoint inhibitors.
12.4.1.2 Risk of Optional Biopsies
All care will be taken to minimize risks that may be incurred by tumor sampling. However, there 
are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained 
fully during informed consent.

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12.4.1.3 Risks of Exposure to Ionizing Radiation
This research study involves the possibility of 7 CT CAP scans, 1 brain CT scan, and 2 CT guided 
biopsies collected for research purposes. 
The amount of radiation exposure you will receive from these procedures is equal to approximately 
9.4 rem. The CT scans and CT guided biopsies in this study will expose the research participant to 
31.3 years’ worth of background radiation. This level of exposure results in an increased risk of 
cancer. 
12.4.1.4 Additional Risks of CT Scans
In addition to the radiation risks addressed above, CT scans that employ contrast may cause allergic 
reactions, injection site reactions abdominal discomfort and fainting.
12.4.1.5 Research Blood Collection Risks
Risks of blood draws include pain and bruising in the area where the needle is placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop. 
12.4.1.6 Other Risks
Risks include the possible occurrence of any of a range of side effects which are listed in the 
Consent Document or this protocol document. Frequent monitoring for adverse effects will help 
to minimize the risks associated with administration of the study agents.
12.4.2 Benefits
The potential benefit to a patient that goes onto study is a reduction in the bulk of their tumor 
which may or may not have favorable impact on symptoms and/or survival.
12.4.3 Assessment of Potential Risks and Benefits
Metastatic or refractory/recurrent HPV associated malignancies (cervical, anal, oropharyngeal 
cancers, etc.) are in need of improved therapy options. Preclinical studies suggest that the use of a 
combination of multiple immunotherapy agents may have improved anti-tumor efficacy. 
A number of clinically appropriate strategies to minimize risks to participants have been built into 
the protocol through the means of inclusion/exclusion criteria, monitoring strategies, and 
management guidelines. Overall, there is direct potential benefit of the combination of a 
therapeutic vaccine against HPV positive cancers (PDS0101), a tumor targeted immunocytokine 
(PDS01ADC) and a bifunctional fusion protein targeting PD-L1 and TGF beta (M7824) in subjects 
with advanced HPV associated malignancies for participants retaining the ability to consent and 
those who lose capacity to consent during the course of the trial with this combination 
immunotherapy proposed in this study.
The potential benefit to a participant that goes onto this study is a reduction in the bulk of their 
tumor which may or may not have favorable impact on symptoms and/or survival.
Potential adverse reactions attributable to the administration of the study drug utilized in this trial 
are discussed in Section 14. All care will be taken to minimize side effects, but they can be 
unpredictable in nature and severity.

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12.5 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) as applicable for review prior to consenting. A designated study 
investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant/consent designee(s).  Whether in person or remote, the privacy of 
the subject will be maintained. Consenting investigators (and participant/consent designee, when 
in person) will be located in a private area (e.g., clinic consult room). When consent is conducted 
remotely, the participant/consent designee will be informed of the private nature of the discussion 
and will be encouraged to relocate to a more private setting if needed.  
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document. When required, witness signature will be 
obtained similarly as described for the investigator and participant.
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent 
at the NIH Clinical Center, this study will use the following to obtain the required signatures: 
•
Adobe platform (which is not 21 CFR Part 11 compliant); or, 
•
iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the 
same screen may be used when at the same location, but is not required.
Both the investigator and the subject will sign the document using a finger, stylus or mouse.
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent 
Process for additional information (e.g., verification of participant identity when obtaining 
consent 
remotely) 
found 
at 
https://nih.sharepoint.com/sites/NCI-CCR-OCD-
Communications/SitePages/OEC-Administrative---Clinical-Research-
(ADCR).aspx?Mode=Edit.
As there is an optional biopsy for research in this protocol, the participant will be asked to sign a 
separate consent at the time of the procedure. If the participant refuses the optional biopsy at that 
time, the refusal will be documented in the medical record and in the research record.
12.5.1 Consent Process for Participants Who Decline Other Treatment Options
Participants who are eligible because they decline the treatment options described in the

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eligibility criteria (see Section 2.1) will have consent obtained in the presence of an independent 
consent monitor from the Bioethics department or Human Subjects Protection Unit (HSPU).
12.5.2 Consent Process for Adults Who Lack Capacity to Consent to Research Participation
For participants addressed in Section 12.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 12.5. 
12.5.3 Request for Waiver of Consent for use of Data from Protocols 18C0056 and 20C0104
To allow for integrative analysis of research samples across studies 18C0056, 20C0045 and 
20C0104 we request a waiver of informed consent for these participants. 
Requirements for Waiver of Consent consistent with 45 CFR 46.116 (f):
(1) The research involves no more than minimal risk to the subjects.
a. Analysis of samples and data from these studies involves no additional risks to participants.
(2) The waiver or alteration will not adversely affect the rights and welfare of the participants.
a. Further use of this data has no impact on the rights and welfare of the participants as the 
consent signed for 18C0056 and 20C0104 includes all analyses proposed under the current study. 
The consent does not specify the inability for reuse of these data by this PI and his research team. 
(3) The research could not practicably be carried out without the waiver or alteration.
a. Many 18C0056 and 20C0104 participants are off-study, or have died and so cannot be 
practicably reconsented; however, although these participants are unreachable, their data remain 
essential.  
(4) The research could not practicably be carried out without using such information or 
biospecimens in an identifiable format
a. The relevant 18C0056 and 20C0104 data for these analyses will need to remain identifiable 
(instead of coded, linked data) as 20C0045, 20C0104 and 18C0056 are under the same PI and 
study team, and are therefore inherently unable to be completely deidentified due to a likely 
potential for accidental identification by the PI or study team researchers (i.e., the PI and study 
team know  the specific details of each of these participants in their entirety as they are the team 
performing all of the research protocols).   
(5) Whenever appropriate, the subjects will be provided with additional pertinent information 
after participation.
a. As no new participant specific data will be generated from the comparison, it is not anticipated 
that pertinent data will be generated.
13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, the Investigational New Drug (IND) and regulatory authorities.  If the study is 

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prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study 
participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for 
the termination or suspension.  Study participants will be contacted, as applicable, and be informed 
of changes to study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Demonstration of efficacy that would warrant stopping   
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted, and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Council for Harmonisation 
Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial. The study leadership in conjunction with the National Cancer Institute has established 
policies and procedures for all study group members to disclose all conflicts of interest and will 
establish a mechanism for the management of all reported dualities of interest.
13.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 

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samples and genetic tests in addition to the clinical information relating to participants. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records.
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be stored at the NCI CCR. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by the 
clinical site and by NCI CCR research staff will be secured and password protected. At the end of 
the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants.
14 PHARMACEUTICAL INFORMATION
PDS0101 (IND # 019267)
14.1.1 Source / Acquisition and Accountability
PDS0101 will be provided by PDS Biotechnology through a CRADA.
R-DOTAP and HPVmix will be provided to the clinical trial site by the manufacturer. The 
investigator or designee (e.g., pharmacist) will maintain an ongoing inventory of the 
investigational product supply according to standard site procedures. The investigational product 
will be dispensed at the direction of an investigator for administration to a study participant 
enrolled on the clinical trial. Disposal of expired or unused product will be returned to the 
manufacturer or disposed of according to standard site procedures based on agreement between 
the manufacturer and the site.

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14.1.2 Toxicity 
In 2014-2016, a Phase I/IIA human clinical trial was performed at 3 sites in the US in 12 subjects 
with high-risk HPV infection and biopsy-proven CIN1 to study the safety and immunogenicity of 
PDS0101. Administration of PDS0101 was well tolerated. The majority of AEs were due to 
administration site reactions. Most administration site reactions were mild or moderate in severity. 
Some more severe administration site reactions including swelling and redness were reported in 
the 3- and 10-mg R-DOTAP cohorts. Most administration site reactions resolved the same day or 
within a few days. Per the subject symptom diary, administration site reactions were more severe 
and of longer duration in subjects in the 10-mg R-DOTAP cohort. No clinically significant 
differences in the types and pattern of TEAEs were observed between Vaccinations 1, 2, or 3. No 
DLTs were observed; thus, the MTD was the 10-mg R-DOTAP dose. No serious adverse events 
(SAEs), study discontinuations due to adverse events, or deaths occurred. No clinically relevant 
abnormal hematology, blood chemistry, urinalysis, or physical findings were observed.
14.1.3 Formulation and Preparation 
PDS0101 is a 2-vial formulation which is mixed 1:1 v/v just prior to administration.   
Vial #1 (ImmunoMAPK-RDOTAP): is a sterile, turbid pharmaceutical suspension of liposomal 
nanoparticles composed of the pure R-enantiomer of the cationic (positively charged) lipid 
DOTAP (dioleoyl-trimethylammonium propane). The particle size is between 100-200nm.  
RDOTAP is a novel immune modulator which induces the production of important cytokines and 
chemokines and also enhances the cytolytic T-Lymphocyte response when combined with the 
antigenic peptides. ImmunoMAPK-RDOTAP is has been evaluated at 3 dose levels, 1.0, 3.0 and 
10.0mg.   
Vial #2 (HPVmix): is a sterile, clear and slightly viscous suspension consisting of 6 nononcogenic 
lipidated peptides selected from immunogenic regions of the human papillomavirus strain 16 E6 
and E7 proteins. The peptides exist in a mixed micellar particulate state.  The HPVmix formulation 
contains 20% by volume of dimethyl sulfoxide (DMSO).  HPVmix is being evaluated at a single 
dose level of 2.7 mg. 
The 1:1 mixture of R-DOTAP and HPVmix (antigens) yields a mixture of liposomes and peptide 
mixed micelles in 10% DMSO. The nanoparticulate vaccine induces antigen specific T-cell 
therapeutic responses. 
14.1.4 Stability and Storage 
ImmunoMAPK-RDOTAP (Vial #1) and HPV Mix (Vial #2)
Storage:  
 
Store at -70oC ± 10oC.  
Shipping: 
Shipped on dry ice in insulated container.  Always check the 
temperature monitoring device to ensure maintenance of required 
storage condition during shipment.  
R-DOTAP Thawing: Place at room temperature for a minimum of 90 minutes (1.5 hours) 
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HPVmix Thawing: 
Remove from freezer at least 60 minutes (1 hour) after removal of 
RDOTAP. Place at room temperature for a minimum of 30 minutes 
(0.5 hours) and a maximum of 90 minutes (1.5 hours) prior to mixing 
with RDOTAP. 
Mixture: 
PDS0101 should not be administered if held in vial for more than 
120 minutes (2 hours) at ambient temperature after mixing.
14.1.5 Administration Procedures
Subcutaneous administration in a limb. Each subsequent vaccination should preferably be 
administered alternating between limbs (e.g., L arm  R arm). 
Two separate 0.5mL injections preferably ~ 6 cm apart of vaccine in the same extremity
Total Dose:  3.0mg R-DOTAP/2.7 mg HPV Peptides
14.1.6 Incompatibilities
Not available. 
14.2 M7824 (MSB0011359C) (IND # 019267)
14.2.1 Source / Acquisition and Accountability
M7824 is manufactured and supplied for the trial by EMD Serono Research and Development 
Institute.
M7824 will be provided to the clinical trial site by the manufacturer. The investigator or designee 
(e.g., pharmacist) will maintain an ongoing inventory of the investigational product supply 
according to standard site procedures. The investigational product will be dispensed at the 
direction of an investigator for administration to a study participant enrolled on the clinical trial. 
Disposal of expired or unused product will be returned to the manufacturer or disposed of 
according to standard site procedures based on agreement between the manufacturer and the site.
14.2.2 Toxicity 
The immunoglobulin portion of M7824 molecule is identical to avelumab (Bavencio). Respective 
warnings and precautions for grade 2 or higher immune-mediated pneumonitis, immune-mediated 
colitis, immune-mediated endocrinopathies, immune-mediated hepatitis) and infusion reactions 
are included in the prescribing for Bavencio (bavencio.com). Participants will be pre-medicated to 
prophylax against infusions reactions. The following additionally significant immune-mediated 
adverse reactions have occurred in less than 1% of 1738 participants treated with BAVENCIO: 
myocarditis with fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema 
multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic 
inflammatory response. The above irAEs are all considered an anticipated risk of treatment with 
M7824 and thus will not be considered DLTs.
In a phase 1, open-label 3+3 dose-escalation study of M7824 in 16 participants, 3 participants 
experienced grade 3 drug-related adverse events including skin infection secondary to grade 2 
bullous pemphigoid, lipase increased, and colitis with associated anemia. There were no grade 4 – 
5 treatment related adverse events. Please see table below for details.

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Treatment-related adverse events
3 mg/kg (n = 
3)
10 mg/kg (n = 3)
20 mg/kg (n = 7)
Total (n = 16)
Any 
Grade
Grade 
3
Any 
Grade
Grade 
3
Any 
Grade
Grade 
3
Any 
Grade
Grade 
3
Participants with 
any event**
2 
(66.7)
1 
(33.3)
1 
(33.3)
0 (0.0)
4 
(57.1)
2 
(28.6)
7 
(43.8)
3 
(18.8)
Anemia
1 
(14.3)
1 
(14.3)
1 (6.3)
1 (6.3)
Bullous 
pemphigoid 
1 
(33.3)
1 (6.3)
Colitis
1 
(14.3)
1 
(14.3)
1 (6.3)
1 (6.3)
Dermatitis 
acneiform
1 
(33.3)
1 (6.3)
Dyspnea 
exertional***
1 
(14.3)
1 (6.3)
Hyperthyroidism
1 
(14.3)
1 (6.3)
Hypophosphatemia
1 
(14.3)
1 (6.3)
Hypothyroidism
1 
(33.3)
1 
(14.3)
2 
(12.5)
Infusion-related 
reaction
1 
(14.3)
1 (6.3)
Keratoacanthoma
1 
(14.3)
1 (6.3)
Lipase increase
1 
(14.3)
1 
(14.3)
1 (6.3)
1 (6.3)
Nausea
1 
(33.3)
1 (6.3)
Pruritus
1 
(33.3)
1 (6.3)
Rash maculo-
papular
1 
(33.3)
1 
(33.3)
2 
(12.5)
Skin infection
1 
(33.3)
1 
(33.3)
1 (6.3)
1 (6.3)
Vomiting
1 
(33.3)
1 (6.3)
**There were no treatment-related AEs in the 3 participants treated with 1 mg/kg M7824.
***The differential for this dyspnea was pneumonitis vs. lymphangitic spread of disease (disease 
progression).

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As of August 2017, > 500 participants have been treated with M7824 across multiple solid tumor 
expansion cohorts. The safety profile is consistent with other monotherapy checkpoint inhibitors, 
with the exception of keratoacanthomas and cutaneous squamous cell carcinomas which have 
occurred in approximately 3-5% of participants and are well managed with surgical excision. 
These lesions have not been a criterion for treatment discontinuation, but thus far have all 
spontaneously regressed following treatment discontinuation.
In addition, after discussion among NCI investigators on multiple protocols using M7824, multiple 
bleeding events ranging from low grade gingival bleeding and epistaxis to more serious 
hemoptysis, GI bleeding, and hematuria have been observed. Some of these events can be 
attributed to bleeding events related to cancer. However, there remains the possibility that M7824 
may increase the overall risk of bleeding in ways that may not be directly related to direct tumor 
bleeding or inflammatory bleeding events described with checkpoint inhibitors like M7824. It is 
hypothesized that this possible increased bleeding risk may be due to TGF beta inhibition which 
has an effect on angiogenesis. Accordingly, participants will be notified of the same possible risk 
in the informed consent document for this study (e.g., gum bleeding, nose bleeds, coughing up 
blood, blood in their urine, or blood in the stool).
At least 2 instances of nodular regenerative hyperplasia have been observed with the use of this 
agent.
14.2.2.1 Hemophagocytic lymphohistiocytosis (HLH)
HLH/MAS is an inflammatory response which may be related to immune therapy, but the 
mechanism is poorly understood. This may present with liver function test abnormalities, low 
blood cell counts, fevers, elevated ferritin and/or elevated triglycerides. HLH may be acquired 
(secondary), but in the setting of immune therapy we believe it is acquired. This can spontaneously 
resolve or be treated with steroids or other immune suppressive therapies.
14.2.3 Formulation and Preparation 
M7824 is provided as a sterile liquid formulation and packaged at a 10 mg/mL concentration in 
USP/ Ph Eur type I 50R vials that are filled with drug product solution to allow an extractable 
volume of 60 mL (600 mg/60 mL). The vials are closed with rubber stoppers in serum format 
complying with USP and Ph Eur with an aluminum crimp seal closure. Each single-use vial 
contains 600mg of M7824, formulated as 10mg/mL of active, 6% (w/v) Trehalose, 40 mM NaCl, 
5 mM Methionine, 0.05% (w/v) Tween 20, 10 mM L-Histidine at pH 5.5. 
The liquid formulation is diluted directly with 0.9% sodium chloride solution for injection. The 
estimated volumes of delivery are anticipated to be no more than 250mL. The verified 
concentration range in the infusion solution is 0.16 mg/mL to 9.6 mg/mL. 
14.2.4 Stability and Storage 
M7824 must be stored at 2℃ to 8℃ until use. Product stored at room temperature for extended 
periods of time might be subject to degradation. M7824 must not be frozen. Rough shaking of the 
reconstituted solution must be avoided. 
The chemical and physical in-use stability for the infusion solution of M7824 in 0.9% sodium 
chloride for injection has been demonstrated for a total of 72 hours at room temperature; however, 
from a microbiological point of view, the diluted solution should be used immediately and is not 

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intended to be stored unless dilution has taken place in controlled and validated aseptic conditions. 
No other drugs should be added to the infusion containers containing M7824. See Manual of 
Preparation of approved ancillary supplies. 
14.2.5 Administration Procedures
See Section 3.2. 
14.2.6 Incompatibilities
Not available. 
14.3 PDS01ADC (IND # 019267)
Note: The study drug M9241 (or NHS-IL12), was acquired by PDS Biotechnology Corporation 
from Merck KGaA in late 2024 and renamed to PDS01ADC. The drug supply for this study was 
and may continue to be manufactured by Merck through agreements with PDS Biotechnology 
Corp.  Until such time that all drug labels, prescribing information, and associated documents 
(e.g., Investigator’s Brochure) may be updated to the new name (PDS01ADC), this protocol will 
retain a references to both M9241 and PDS01ADC.
14.3.1 Source / Acquisition and Accountability
PDS01ADC (previously known as M9241 or NHS-IL12) is manufactured and supplied by PDS 
Biotechnology Corporation. The drug was previously manufactured by Merck KGaA, but was 
transferred to PDS Biotechnology through a License Agreement.
PDS01ADC will be provided to the clinical trial site by the supplier. The investigator or designee 
(e.g., pharmacist) will maintain an ongoing inventory of the investigational product supply 
according to standard site procedures. The investigational product will be dispensed at the 
direction of an investigator for administration to a study participant enrolled on the clinical trial. 
Disposal of expired or unused product will be returned to the manufacturer or disposed of 
according to standard site procedures based on agreement between the manufacturer and the site.
14.3.2 Toxicity 
Subjects (n=59) were treated subcutaneously with PDS01ADC in a single ascending dose cohort 
followed by a multiple ascending dose cohort (n=37 with every 4-week dosing). The primary 
objective of this trial was to determine MTD as defined by the number of DLTs. None of the 
subjects treated with single or multiple doses up to 12.0 µg/kg experienced a DLT. At 16.8 µg/kg, 
1/6 subjects had a DLT (grade 3 increase in alanine transaminase [ALT]). At 21.8 µg/kg, 2/6 
subjects had a DLT (grade 3 increase in aspartate transaminase [AST] and ALT; grade 3 increase 
in lipase without clinical signs of pancreatitis). MTD was 16.8 µg/kg. The most frequently 
observed treatment-related adverse event (TRAE) was decreased lymphocyte count (27/59 
subjects; 45.8%). Other TRAEs included decreased white blood cells (WBCs) (24/59; 40.7%), 
fever and elevated AST (21 each; 35.6%), elevated ALT (20; 3.9%), and anemia and flu-like 
symptoms (18 each; 30.5%) (Table 2; Supplemental Figure 5). Among the cohort receiving 16.8 
µg/kg, the most frequently reported TRAEs were elevated AST (75%), decreased WBCs and 
elevated ALT (68.8% each), and decreased lymphocyte count and fever (62.5% each). At least one 
grade ≥ 3 TRAE was seen in 12/59 subjects (20.3%). These included decreased lymphocyte count 
(5; 8.5%), decreased neutrophil count (4; 6.8%), elevated ALT (3; 5.1%), decreased WBCs (2; 

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3.4%), and hypokalemia, hyperhidrosis, elevated alkaline phosphatase, AST, and lipase (1 each; 
1.7%). All grade ≥ 3 TRAEs were transient; only hyperhidrosis was symptomatic. One grade 4 
TRAE was observed (asymptomatic decreased lymphocyte count); no grade 5 TRAE was 
observed. 
14.3.3 Formulation and Preparation 
PDS01ADC is formulated as a 1.5 mg/mL solution and is supplied by the Sponsor in single-use 
glass vials with a rubber stopper and sealed with an aluminum Flip Off® crimp seal closure. 
The contents of the PDS01ADC vials are sterile and nonpyrogenic, and do not contain 
bacteriostatic preservatives. Any spills that occur should be cleaned up using the facility’s standard 
cleanup procedures for biologic products. 
Rough shaking of the solution must be avoided. 
PDS01ADC drug product will be administered undiluted (1500mcg/mL) for doses ≥ 300mcg. 
However, for doses below 300 g, PDS01ADC drug product must be diluted with 0.9% saline 
solution (sodium chloride injection). Doses 100 to 299 mcg will be administered as a 500mcg/mL 
solution and doses 30 to 99 mcg will be administered as a 150 mcg/mL solution. Detailed 
information on medical devices to be used for the preparation and administration of PDS01ADC 
will be provided in the Investigator Brochure. 
Any unused portion of the solution should be discarded in biohazard waste disposal with final 
disposal by accepted local and national standards of incineration.
14.3.4 Stability and Storage 
PDS01ADC drug product must be stored at 2°C to 8°C until use, with a temperature log maintained 
daily. All medication boxes supplied to the study site must be stored carefully, safely, and 
separately from other drugs. 
The chemical and physical in-use stability of PDS01ADC diluted and undiluted solution in 
syringes has been demonstrated for 24 hours at 25°C. However, to reduce the risk of microbial 
contamination, the solution should be used immediately unless medication preparation has been 
performed in controlled and validated aseptic conditions. Rough shaking of the solution must be 
avoided. 
14.3.5 Administration Procedures
PDS01ADC is administered subcutaneously. It can be given in the arm, leg or abdomen. Where 
feasible it should be given in a different limb than the vaccine. 
14.3.6 Incompatibilities
Not available. 
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16 APPENDICIES
16.1 APPENDIX A PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; 
some signs or symptoms of 
disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
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.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours.
30
Severely disabled, 
hospitalization indicated.  Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.