Phase I/II Trial of HPV Vaccine PRGN-2009 Alone or in Combination With Anti-PD-L1/TGF-Beta Trap (M7824) in Subjects With HPV Positive Cancers
Phase: PHASE1
Conditions: HPV Positive Cancer, Vulvar, Vaginal, Penile, Rectal Cancer, Anal Cancer, Oropharyngeal Cancer, Cervical Cancer
Sponsor: National Cancer Institute (NCI)

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Abbreviated Title: Combo Immunotx in HPV OPSCC
Version Date: 09.20.2023
Abbreviated Title: Combo Immunotx in HPV OPSCC 
NIH Protocol #: 20C0104
Version Date: September 20, 2023
NCT Number: NCT04432597
IBC Registration: RD-20-V-22
RSC Number: 2763
Title: 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
NCI Principal Investigator: 
Charalampos Floudas, MD, DMSc, MS
Center for Immuno-Oncology (CIO)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
Building 10, Room 7N240A 
Bethesda, MD 20892 
Phone: 240-858- 3032 
Email: charalampos.floudas@nih.gov
Drug Name:
PRGN-2009
 M7824
IND Number:
19628
19628
Sponsor:
CCR, NCI
CCR, NCI
Manufacturer:
Precigen, Inc. 
EMD Serono, Inc.
Supplier
Precigen, Inc. 
EMD Serono, Inc.
Commercial Agents: None

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PRÉCIS
Background

Metastatic HPV associated malignancies (cervical, anal, oropharyngeal cancers, etc.) are 
often incurable and poorly palliated by standard therapies.

HPV-positive (p16+) oropharyngeal cancers are the most common HPV-associated 
malignancy in the United States and are increasing in incidence. 

Stage II and III HPV-positive oropharyngeal cancer is primarily treated with definitive 
therapy. 

Although the prognosis for stage I HPV+ oropharyngeal cancer is favorable, about 20 
percent of patients with stage II disease and 35 percent of patients with stage III disease 
will die within four years.

Attempts to de-intensify treatment of HPV-positive oropharyngeal cancer by replacing 
high-dose cisplatin with cetuximab concurrent with radiotherapy have failed.

Induction and neoadjuvant immunotherapy are an area of active study in this type of cancer. 
The aims of induction immunotherapy are to induce antigen-specific immunity prior to 
definitive therapy and to reduce the risk of disease relapse for patients with stage II and III 
disease. 

Therapeutic vaccines targeting HPV alone or in combination with M7824 (dual PD-L1 and 
TGF beta inhibitor) have demonstrated induction of HPV antigen-specific responses and 
tumor growth inhibition in multiple pre-clinical models of HPV-positive malignancy.

In clinical studies done in the CCR, M7824 as monotherapy has produced a notable 
objective response rate (35-40%) for metastatic HPV + cancers including Oropharyngeal 
Squamous Cell Carcinoma (OPSCC) and preclinical studies support the addition of an 
investigational HPV vaccine with therapeutic intent (PRGN-2009, a gorilla adenoviral 
based vaccine) to further increase anti-tumor efficacy.
Objectives:
Phase I in participants with recurrent/metastatic HPV positive cancer:

Primary objective: To determine the safety and recommended phase II dose (RP2D) of 
PRGN-2009 (HPV vaccine) alone or in combination with M7824 administered at RP2D of 
1200 mg q2w.
Phase II in participants with newly diagnosed stage I (T1,T2 N1)/II/III p16-positive oropharyngeal 
cancer and patients with newly diagnosed operable stage II/III/IVA/IVB HPV+ sinonasal 
squamous cell cancer:

Primary objective: To determine if HPV vaccine alone (Arm 2A) is able to result in a  2-
fold increase in CD3+ tumor infiltrating T cells post treatment compared with pre-
treatment in p16-positive oropharyngeal cancer.
Eligibility:
Phase I: 

Men or women of age > 18 years old.

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
Subjects with cytologically or histologically confirmed locally advanced not amenable to 
potentially curative local therapies 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.
Phase II: 

Men or women of age > 18 years old.

Subjects with newly diagnosed stage I (T1,T2 N1), II or III p16-positive oropharyngeal 
squamous cell carcinoma (OPSCC) or stage II/III/IVA/IVB HPV-SNSCC planned for 
definitive therapy.
Design:
Phase I: Recurrent/metastatic HPV associated cancer:

A 3+3 dose escalation design will be used which will evaluate PRGN-2009 (HPV vaccine) 
at two dose levels (1x1011 and 5x1011 viral particle (VP) units) given as monotherapy 
followed by a third dose level evaluating the RP2D dose of PRGN-2009 in combination 
with 1200 mg (RP2D) of M7824. In addition, the combination of PRGN-2009 at RP2D 
with 1200 mg of M7824 will be expanded to a total of 10 evaluable participants to gauge 
the preliminary efficacy of the combination of PRGN-2009 and M7824 in participants with 
advanced disease.

There will be a 4-week DLT evaluation period for each dose level.

It is expected that up to 22 participants may enroll.
Phase II: 

Newly diagnosed p16-positive oropharyngeal cancer:

Evaluation of HPV vaccine alone (Arm 2A: Stage I (T1,T2 N1)/II/III) as neoadjuvant/ 
induction therapy before definitive standard of care therapy.

Participants will receive neoadjuvant/ induction immunotherapy at NIH Clinical Center 
and then be referred back to their home institution for definitive standard of care 
therapy.

It is expected that up to 20 participants may enroll. 

Newly diagnosed stage II/III/IVA/IVB HPV-SNSCC: 

Enrollment and treatment will occur similarly as participants with p16+ oropharyngeal 
cancer for exploratory correlates to advise possible future trials. Up to 2 participants 
may enroll in this group. 

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TABLE OF CONTENTS
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ................................................................................................7
1
INTRODUCTION ...................................................................................................................8
1.1
Study Objectives ...............................................................................................................8
1.2
Background and Rationale................................................................................................9
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................20
2.1
Eligibility Criteria ...........................................................................................................20
2.2
Screening Evaluation ......................................................................................................23
2.3
Participant Registration and Status Update Procedures..................................................24
2.4
Baseline Evaluation.........................................................................................................25
3
STUDY IMPLEMENTATION .............................................................................................27
3.1
Study Design...................................................................................................................27
3.2
Drug Administration .......................................................................................................29
3.3
Dose Modifications.........................................................................................................30
3.4
Study Calendar................................................................................................................39
3.5
Cost and Compensation ..................................................................................................45
3.6
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................45
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................46
4.1
Permitted Medications ....................................................................................................46
4.2
Prohibited Medications ...................................................................................................46
5
CORRELATIVE STUDIES FOR RESEARCH ...................................................................48
5.1
Biospecimen Collection ..................................................................................................48
5.2
Sample Storage, Tracking and Disposition.....................................................................52
6
DATA COLLECTION AND EVALUATION .....................................................................55
6.1
Data Collection ...............................................................................................................55
6.2
Data Sharing Plans..........................................................................................................56
6.3
Response Criteria ............................................................................................................56
6.4
Toxicity Criteria..............................................................................................................63
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN...63
7.1
Definitions.......................................................................................................................63

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7.2
OHSRP Office of Compliance and Training / IRB Reporting........................................63
7.3
NCI Clinical Director Reporting.....................................................................................64
7.4
Institutional Biosafety Committee (IBC) Reporting Criteria..........................................64
7.5
NIH Required Data and Safety Monitoring Plan............................................................65
8
SPONSOR PROTOCOL / SAFETY REPORTING..............................................................66
8.1
Definitions.......................................................................................................................66
8.2
Assessment of Safety Events ..........................................................................................67
8.3
Reporting of Serious Adverse Events .............................................................................68
8.4
Waiver of Expedited Reporting to CCR .........................................................................68
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborators......................................68
8.6
Reporting Pregnancy.......................................................................................................68
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND...................69
8.8
Sponsor Protocol Deviation Reporting ...........................................................................69
9
CLINICAL MONITORING..................................................................................................70
10
STATISTICAL CONSIDERATIONS ..................................................................................70
10.1
Statistical Hypothesis ..................................................................................................70
10.2
Sample Size Determination.........................................................................................71
10.3
Populations for Analyses.............................................................................................72
10.4
Statistical Analyses......................................................................................................72
11
COLLABORATIVE AGREEMENTS..................................................................................74
11.1
Cooperative Research and Development Agreement (CRADA)................................74
12
HUMAN SUBJECTS PROTECTIONS................................................................................74
12.1
Rationale For Subject Selection ..................................................................................74
12.2
Participation of Children .............................................................................................74
12.3
Participation of Subjects Unable to Give Consent ......................................................74
12.4
Risk/Benefit Assessment.............................................................................................75
12.5
Consent Process and Documentation ..........................................................................77
13
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................78
13.1
Study Discontinuation and Closure.............................................................................78
13.2
Quality Assurance and Quality Control ......................................................................79
13.3
Conflict of Interest Policy ...........................................................................................79
13.4
Confidentiality and Privacy.........................................................................................79

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14
PHARMACEUTICAL INFORMATION .............................................................................80
14.1
PRGN-2009 (IND #19628) .........................................................................................80
14.2
M7824 (IND #19628 ).................................................................................................85
15
REFERENCES ......................................................................................................................89
16
APPENDIX A: Performance Status Criteria .........................................................................94

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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council on 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.

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1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objectives
Phase I in participants with recurrent/metastatic HPV positive cancer:

Primary objective: To determine the safety and recommended phase II dose (RP2D) 
of PRGN-2009 (HPV vaccine) alone or in combination with M7824 administered at 
RP2D of 1200 mg q2w.
Phase II in participants with newly diagnosed stage I (T1,2 N1)/II/III p16-positive 
oropharyngeal cancer (OPSCC) cancer:

Primary objective: To determine if HPV vaccine alone (Arm 2A) is able to result in a 
 2-fold increase in CD3+ tumor infiltrating T cells post treatment compared with pre-
treatment in p16-positive oropharyngeal cancer. 
1.1.2
Secondary Objectives
Phase I in participants with recurrent/metastatic HPV positive cancer:

To assess overall response rate (ORR) according to RECIST 1.1.    

To assess progression-free survival time (PFS). 

To assess overall survival (OS).

To assess duration of response.

To assess ratio of participants that are hospitalized because of adverse events attributed 
to disease progression.
Phase II in participants with newly diagnosed stage I (T1,2 N1)/II/III p16-positive 
oropharyngeal cancer (OPSCC) cancer:

To determine if the use of PRGN-2009 alone results in significantly prolonged survival 
as compared to the expected 80% three-year historical survival for this population.

To determine the 3-year overall and relapse-free survival rate for PRGN-2009 alone 
(Arm 2A) as neoadjuvant/ induction therapy before definitive standard of care therapy 
for this population.

To assess the safety of the recommended phase II dose (RP2D) of PRGN-2009 (HPV 
vaccine) alone in this participant population. 
1.1.3
Exploratory Objectives
Phase I and Phase II

To conduct exploratory immunologic studies to understand and improve the administered 
treatment, including:
o
To examine the pharmacokinetics of bintrafusp alfa while on treatment. 
o
To determine the ORR per RECIST v1.1 of combination of PRGN-2009 and 
M7824 in participants with advanced HPV associated malignancies

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
Precigen, Inc. may analyze samples to be used for additional exploratory analyses, to 
further investigate:
o
HPV 16/18 -specific immune responses, activation status of the immune system, 
anti-tumor specific immune responses induced by the exposure to PRGN-2009.
Phase II only

To determine the rate of objective response following neoadjuvant/induction 
immunotherapy alone per RECIST 1.1.

To assess changes in salivary HPV DNA from pre-treatment and compared to during 
neoadjuvant/induction therapy with PRGN-2009 (HPV vaccine) alone in participants with 
HPV-OPC. 

To determine the feasibility and safety of neoadjuvant treatment therapy with PRGN-2009 
(HPV vaccine) alone in participants with HPV-SNSCC.

To assess the differences in CD3+ tumor infiltrating lymphocytes following neoadjuvant 
therapy with PRGN-2009 (HPV vaccine) alone in participants with HPV-SNSCC.

To determine the objective response rate following neoadjuvant therapy with PRGN-2009 
(HPV vaccine) alone in participants with HPV-SNSCC.
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 
metastatic 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 (KEYNOTE 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%)

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Site
Incidence of HPV associated cancers 
Cases attributed to HPV (%)
Vaginal
802
600 (75%)
Penis
1168
700 (63.3%)
Rectal (squamous 
cell)
750
700 (91.1%)
Anus
5,010
4,600 (91.1%)
Total
38,793
30,700 (79.1%)
For metastatic 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. More recently pembrolizumab had been FDA approved as first line 
therapy for metastatic PD-L1 expressing HNSCC but the response rate for pembrolizumab alone 
in this setting is still only 16.9%. 
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) 
combination therapy for these diseases. 
Human papilloma virus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) now 
represents the most common HPV-associated malignancy in the United States and the incidence 
is rising (13, 14). Over 80% of OPSCC is HPV-positive, and nearly all HPV-positive OPSCC are 
caused by HPV 16 or 18. Definitive standard-of-care treatment for patients with stage II/III HPV-
positive oropharyngeal head and neck squamous cell carcinoma most commonly includes multi-

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modality treatment consisting of concurrent chemotherapy and radiation (CRT) (15). Surgery is 
rarely utilized due to the morbidity associated with resection of oropharyngeal tissues. Despite 
maximum treatment, 20% of patients with stage II and 35% of patients with stage III disease will 
die within 4 years of diagnosis (Figure 1)(16). In patients cured of their disease, treatment often 
results in dysfunctional swallowing, taste, and speech as well as in extensive tissue fibrosis and 
pain (17). Patients with HPV-positive OPSCC are diagnosed at a younger age, making the long-
term morbidity associated with concurrent CRT particularly concerning. Induction treatment 
strategies that have the goals of both decreasing disease recurrence and increasing survival permit 
the future study of definitive treatment de-intensification (18). Attempts to de-intensify treatment 
of HPV-positive OPSCC by replacing cisplatin chemotherapy with the EGFR monoclonal 
antibody (mAb) cetuximab have failed (15). Stage I (AJCC 8th edition) includes patients with T0-2 
and N0-1 disease. Treatment within Stage I is not uniform. Recommended treatment for T1-2 N0 
disease is definitive radiotherapy or surgical resection with or without ipsilateral/bilateral neck 
lymph node dissection and risk-stratified adjuvant treatment. Recommended treatment for T1-2 
N1 with 1 lymph node (ipsilateral) not larger than 3 cm is definitive chemoradiotherapy or 
radiotherapy or surgical resection with or without ipsilateral/bilateral neck lymph node dissection 
and risk-stratified adjuvant treatment. Recommended treatment for T1-2 N1 with 1 lymph node 
(ipsilateral) larger than 3 cm or 2 or more ipsilateral lymph nodes none larger than 6 cm follows 
the paradigm of Stage II disease, with definitive chemoradiotherapy or resection plus adjuvant 
treatment. Consequently, while the prognosis for Stage I patients is better than Stage II and III, 
there is a need for de-intensification of treatment in Stage I T1-2 N1 disease. 
In this clinical trial, we are studying immunotherapy consisting of PRGN-2009, an investigational 
HPV vaccine with therapeutic intent with or without M7824, a dual PD-L1 and TGF beta inhibitor, 
first as a phase I study to assess safety and tolerability, then as a phase II induction “window of 
opportunity” study with treatment before and after definitive therapy for patients with newly 
diagnosed stage I (T1,2 N1)/II/III HPV-positive OPSCC. 
1.2.2
Sinonasal Squamous Cell Cancer 
Sinonasal Squamous Cell Cancer (SNSCC) comprises 3-5% of all head and neck squamous cell 
cancers. Approximately 50% arise in the nasal cavity and the rest in the paranasal sinuses, and are 
usually not accompanied by nodal metastases at diagnosis (~10-20%). Emerging evidence 
supports a potential role for HPV in a subset of SNSCC, with studies reporting ~30% of SNSCC 
having HPV present, more often so in the nonkeratinizing SCC subtype, with HPV-16 the most 
common genotype, and less commonly genotypes HPV-18, 31 and 33. Contrary to HPV-OPC it 
has been reported that is more common in patients who are smoking or were smokers. Importantly, 
similarly to HPV-OPC, HPV positivity appears to be associated with improved prognosis, with a 
5-year OS for HPV-SNSCC ranging 68.1-80.0% vs. 31-51.5% in HPV negative SNSCC. 
Treatment for newly diagnosed tumors consists of surgical resection with postoperative 
radiotherapy, but in the case of advanced stage tumors treatment is not well defined, and induction 
approaches are promising. For incurable tumors treatment follows the paradigm of HNSCC. In 
this trial we are planning to test an induction strategy in a small number of newly diagnosed HPV-
SNSCC patients, following the design utilized for the HPV-OPC patient cohort. 

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Figure 1: Stage-specific overall survival based upon AJCC 8th Edition Classification 
1.2.3
T cell dysfunction in HPV-positive OPSCC
HPV-positive OPSCCs are infiltrated by exhausted and functionally suppressed HPV-specific T 
cells (19-21). This demonstrates that although an adaptive immune response against one or more 
HPV antigens develops, these T cells are ineffective at controlling the growth of antigen-
expressing tumors. This also suggests that reversing exhaustion in or the suppression of existing 
HPV-specific T cells may induce HPV antigen-specific anti-tumor immunity. When ligated by 
programmed death-ligand 1 (PD-L1), signaling through programmed death-receptor 1 (PD-1) on 
T cells is a significant mechanism of T cell exhaustion (22). 
1.2.4
M7824
M7824 is a novel bifunctional fusion protein composed of a fully human IgG1 mAb against PD-
L1 fused to the soluble extracellular domain of human transforming growth factor-beta (TGF)-
receptor II which functions as a TGF “trap”. Functionally, M7824 both blocks PD-L1 and 
neutralizes TGF within the tumor microenvironment (TME). Expression of PD-1/PD-L1 pathway 
components is present in approximately two-thirds of HPV-positive OPSCCs (23, 24). Immune 
checkpoint blockade of the PD-1/PD-L1 pathway with pembrolizumab is currently FDA-approved 
for the first-line treatment of recurrent/metastatic HPV-positive or -negative head and neck SCC 
in patients with a combined positive score (CPS) of >1 (24, 25) (NCT02358031). TGF is a major 
driver of local suppression of both T cell and NK cell function and is overexpressed in HPV-
associated malignancies (26, 27). Through dual PD-L1 blockade and neutralization of TGF, 
M7824 induced superior tumor growth inhibition in multiple pre-clinical, syngeneic models of 
cancer (28, 29). 
1.2.5
Clinical Experience with M7824 in HPV associated malignancies
The first in human dose escalation study of M7824 in patients with advanced solid tumors was 
conducted in the CCR (29). This work demonstrated on-target PD-L1 saturation and reduction of 

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circulating TGF, early evidence of clinical efficacy including in a number of patients with HPV 
associated malignancies, and an acceptable safety profile. Continuation of this work in patients 
Figure 2: Waterfall plot of confirmed best overall responses in patients with immune checkpoint 
inhibitor-naïve, recurrent/metastatic HPV-positive OPSCC (orange).
with metastatic HPV-associated cancers which was presented at AACR 2019 revealed a 35% 
response rate in 43 patients including a 43% response rate in 14 patients with p16+ OPSCC 
(Figure 2). These response rates are notably higher than the 12-24% response rate seen with 
blockade of PD-1 or PD-L1 alone for HPV-associated malignancies (e.g., cervical, anal, P16+ 
oropharyngeal) in the literature (25, 30-35). In addition, the median survival of the 43 enrolled 
patients with HPV-associated malignancies was 16.2 months and the median survival of the 36 
enrolled patients with HPV positive malignancies was not reached after 16.8 months of follow-up. 
It should be noted that both of these median survivals are substantially longer than the median 
survival reported for similar populations receiving PD-1 or PD-L1 inhibitors alone (7.5-11.5 
months) in the literature (25, 32, 33, 35-37) .   
Adverse events for M7824 were similar to those experienced with pembrolizumab or nivolumab, 
with the addition of the development of low-grade mucosal bleeding and keratoacanthomas (21%) 
known to be associated with systemic TGF blockade. Treatment with M7824 induced the 
expansion of peripheral blood HPV 16 antigen-specific T cells to a greater degree in patients with 
a best overall response of CR, PR or SD compared to patients that had a best overall response of 
PD (Figure 3). These data suggested that M7824 could reverse suppression of HPV antigen-
specific immunity in patients harboring HPV-positive malignancies refractory to standard 
treatments.

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Figure 3: PBMC from patients treated with M7824 were assayed for HPV 16 antigen-specific 
cytokine production or CD107a positivity  
1.2.6
HPV 16/18 gorilla adenovirus vaccine
In addition to reversing exhaustion and local immunosuppression of existing antigen-specific T 
cells, a complimentary approach to induce anti-cancer immunity is to induce de novo T cell 
responses with therapeutic vaccines (38). The use of a therapeutic vaccine may be ideal for virally-
induced cancers as viral oncogenes required for malignant transformation are known (E6 and E7 
for high-risk HPV). Human adenoviral vaccine platforms are effective at delivering nucleic acid 
payload to dendritic cells and can induce antigen-specific T cell immunity following as few as two 
treatments but can be limited by the presence of pre-existing immunity to the vaccine platform 
itself. Gorilla adenovirus vaccine platforms retain the advantages of human adenoviruses including 
the ability to delete genetic regions to ensure replication incompetence and allow for insertion of 
transgenes of interest, but are not recognized by human sera from healthy donors (39). Whole 
genes or long synthetic peptides of interest can be inserted into adenoviral constructs to allow the 
processing of naturally processed and presented T cell antigens by antigen presenting cells. This 
allows for treatment of all patients with HPV-positive malignancy without HLA restriction. In 
collaboration with Precigen, Inc., a gorilla adenovirus vaccine that encodes HPV T cell antigen 
epitopes from HPV 16 and 18 (hereto referred to as PRGN-2009) has been developed. 
PRGN-2009 was developed from the base gorilla adenoviral vector GC46. The adenovirus from 
which the GC46 adenovector is built was originally isolated from a healthy African gorilla. The 
wild type adenovirus was fully sequenced and, the adenovector genome, was isolated and inserted 
into plasmid DNA. Therefore, the GC46 adenovector is completely separated from the virus 
isolation process.  The GC46 adenovirus vector is closely related to and clusters phylogenetically 
with the human species C adenovirus based on hexon, DNA polymerase and E4 ORF6 protein 
sequence comparisons (40) .
The seroprevalence of GC46 is less than 6% in the USA and the seropositive titers were low (below 
100 IC90). In comparison, the seroprevalence of Ad5 is 57% with most of the seropositive 

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individuals having high titers (above 200 IC90; (41)). In addition, comparative studies from human 
sera samples from Sub-Saharan Africa also confirmed the rare and weak pre-existing neutralizing 
activity in the human population.  High level pre-existing seroprevalence to Ad5 has been shown 
to limit the effectiveness of Ad5 based adenovectors in clinical studies. Therefore, the rare and 
weak pre-existing neutralizing activity to GC46 provides an advantage for GC46 based 
adenovector use in clinical applications. 
The cloned GC46 genome was engineered to have deletions of two essential regions of the 
adenovector, E1 and E4. Deletion of these regions removes several essential elements necessary 
for GC46 replication. Therefore, PRGN-2009 is not replication competent. PRGN-2009, as well 
as other GC46 adenovectors with E1 and E4 deletions have been evaluated for growth in human 
cell lines and were found to only replicate in Precigen’s complementing manufacturing cell lines, 
ORF6 and M2A. The multi-deleted, replication incompetent adenovector platform technology was 
first developed using Ad5 based adenovectors. These similarly deleted, constructed and 
manufactured Ad5 adenovectors were used for clinical development of multiple molecular vaccine 
and gene therapy molecules administered to over 3,000 clinical study participants.
HPV-16 and HPV-18 are the genotypes of HPV most frequently associated with cervical, head 
and neck, and other cancers and, as such, infections with either genotype are considered “high 
risk” for the development of cancer.  In HPV-16 and HPV-18, two primary oncoproteins, E6 and 
E7, are constitutively expressed by HPV-associated tumors and are critical for the induction and 
maintenance of cellular transformation in HPV-infected cells. Recent evidence suggests the E5 
protein also affects viral transformation. The HPV antigen expressed in PRGN-2009 was designed 
for optimum immunogenicity. Guided by bioinformatics analysis and in silico protein engineering, 
32 key immunogenic peptides were selected which included CTL specific peptides from E6 (HPV-
16/-18), E7 (HPV-16/-18), and E5 (HPV16) and 3 unique agonist peptides (40) for this multi-
epitope antigen design. These 35 CTL peptide sequences were grafted to a human ankyrin repeat 
protein scaffold enabling protein linker sequences embedded between the peptides wherein this 
scaffold retains it tertiary structure displaying the HPV epitopes. Designed shuffling of the 
peptides prevents any reformation of E6 and E7 oncogenic protein potential and HPV protein viral 
function. 
PRGN-2009 Drug Substance (DS) is manufactured at Advanced Bioscience Laboratories (ABL) 
utilizing a standardized Adenoviral vector manufacturing process that was developed at Precigen 
and transferred to ABL. The production cell line is Precigen’s proprietary 293-ORF6 cell line, 
which complements for both adenoviral E1 and E4 ORF6 to enable efficient production of the 
replication incompetent GC46 adenoviral vector. The 293-ORF6 cells are cultured in serum free 
suspension in shaker flasks and infected with PRGN-2009 Master Virus Bank (MVB) at a 
multiplicity of infection (MOI) of 100 PU/cell. The PRGN-2009 culture harvest is downstream 
processed and purified using three rounds of cesium chloride (CsCl) density gradient 
ultracentrifugation to yield a highly purified PRGN-2009 DS material. Manufacture of the PRGN-
2009 DP commences with the thaw of frozen PRGN-2009 DS, which is then sterile-filtered and 
filled into Diakyo Crystal Zenith (CZ) vials to create the DP, which is stored in freezer boxes in a 
secure freezer at -60ºC to -90ºC. PRGN-2009 has been tested in three independent in vitro analyses 
to assess oncogenic potential in mammalian cells. PRGN-2009 did not induce an oncogenic profile 
in any assay.

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Figure 4: Peripheral PBMC from WT B6 mice bearing TC-1 tumors were assessed for HPV 16 E6 
antigen-specific responses following exposure to overlapping peptide. HPV4 = PRGN-2009.
Figure 5: (A) NSG B2M-/- mice bearing SiHa tumors were immune humanized with HLA matched 
PBMC and mice were treated with PRGN-2009. (B) Following the second vaccine administration, 
SiHa tumors were assessed for CD8+ T cell infiltration by flow cytometry.   
              PBS vs Ad-HPV: P<0.0001                                    Empty vector vs HPV: P = 0.09
Pre-clinically, PRGN-2009 induced the formation of peripheral blood HPV 16 E6 antigen-specific 
responses in wild-type C57BL/6 mice bearing HPV 16 E6/E7 positive lung SCCs (TC-1 tumors). 
No HPV 16 E6 antigen-specific T cell responses were measurable in the absence of PRGN-2009 
(Figure 4). Additionally, mice bearing HPV 16-positive SiHa cervical cancers were immune 
humanized with HLA-matched human PBMC and treated with PRGN-2009 (Figure 5). Treatment 

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resulted in tumor growth inhibition and increased tumor infiltration of CD8+ T cells. These data 
demonstrated that PRGN-2009 is capable of inducing HPV antigen-specific immune responses 
and anti-tumor immunity sufficient to inhibit tumor growth. 
1.2.7
Rationale for combination of PRGN-2009 and M7824
The rationale for combination therapy includes induction of antigen-specific T cell responses with 
vaccine that can then be fully activated with the addition of immune checkpoint blockade. In a 
phase II trial, ISA101, a synthetic long-HPV 16 E6/E7 peptide vaccine, was combined with 
nivolumab in patients with incurable HPV 16-positive cancer (12). This study demonstrated an 
objective response rate of 33% and an acceptable safety profile. Two phase I studies have 
demonstrated the safety and feasibility of combining therapeutic vaccines targeting different 
antigens with PD-1 mAb treatment, along with correlative immunologic responses, in patients with 
melanoma (42, 43). In addition, there is an ongoing clinical trial at CCR evaluating an adenoviral 
vaccine targeting CEA (ETBX-011) in combination with Avelumab and standard of care 
chemotherapy (FOLFOX) for patients with metastatic colorectal cancer (NCT03050814). To date 
23 patients have been enrolled on this study of which 15 patients have received the combination 
of all study agents including the adenoviral vaccine and Avelumab. One patient had grade 2 
arthritis which was managed with a steroid taper. Otherwise no notable immune related toxicities 
have been observed in the 15 patients receiving vaccine and Avelumab.
The specific combination of PRGN-2009 and M7824 was tested in wild-type C57BL/6 mice 
bearing TC-1 tumors (Figure 6). The addition of M7824 further enhanced tumor growth inhibition 
observed with PRGN-2009 alone. Cumulatively, these results indicate that the addition of M7824 
to potentially therapeutic vaccination is both safe and feasible in the clinical setting as well as 
induces tumor growth inhibition in pre-clinical models of HPV-positive malignancy.  
Figure 6: C57BL/6 mice bearing TC-1 tumors were treated with PRGN-2009 alone or in combination 
with M7824 and assessed for primary tumor growth.   
PBS vs Ad-HPV: P<0.0001          PBS vs Ad-HPV + M7824: P<0.0001
1.2.8
Phase I study for participants with advanced HPV associated malignancies 
To first assess the safety and feasibility of treatment with PRGN-2009 alone or in combination 
with M7824, we plan to implement a sequential phase I study of dose-escalating PRGN-2009 (two 
dose levels) alone or in combination with a fixed-dose of M7824. Participants with 

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recurrent/metastatic HPV-positive malignancy will receive two dose levels (1x1011 and 5x1011 
VP) of PRGN-2009, followed by an evaluation of the RP2D dose of PRGN-2009 in combination 
with 1200 mg (RP2D) of M7824.until progression or unacceptable toxicity. This design will allow 
the determination of safety and tolerability of PRGN-2009 alone and in combination with M7824 
and allow each participant the opportunity to benefit from combination treatment. The phase I 
portion of this study will allow immune checkpoint naïve or refractory participants. 
1.2.9
Phase II window of opportunity study for participants with newly diagnosed stage I (T1,2 
N1)/II/III p16-positive OPSCC
Once the safety and tolerability of PRGN-2009 alone or in combination with M7824 is established 
in the phase I portion of the study, we plan to implement a two arm induction, Phase II window-
of-opportunity study of PRGN-2009 (Arm 2A) or PRGN-2009 plus M7824 (Arm 2B) in 
participants with newly diagnosed, previously untreated stage I (T1,2 N1)/II/III p16-positive 
OPSCC who plan to receive definitive therapy. Induction or neoadjuvant immunotherapy for 
newly diagnosed, OPSCC is an area of active study in an attempt to decrease locoregional failure 
and the development of distant metastasis after completion of definitive treatment. Participants 
will receive PRGN-2009 or PRGN-2009 plus M7824 before therapy. Upon completion of the 
neoadjuvant or induction immunotherapy treatment participants will be referred back to their 
referring providers for standard of care definitive therapy. 
Participants diagnosed with a new stage II/III p16-positive OPSCC with planned definitive therapy 
typically wait 4-6 weeks for initiation of treatment due to radiation mapping and simulation and 
scheduling for chemotherapy (44). During this “window of opportunity” participants receive no 
treatment for their cancer. The phase II portion of this study would take advantage of this 
opportunity and offer the participant the chance to benefit from immunotherapy. 
Note: In September of 2021 we received a report by EMD Serono, the manufacturer of M7824, 
that three randomized clinical trials (two in non-small cell lung cancer and one in biliary tract 
cancer) had been terminated due to futility and the suggestion of increased toxicity in some 
subjects, or increased progression in a subset of subjects. This was reported to the Sponsor and the 
IRB and following review of submitted data it was decided to allow Phase I to proceed and Phase 
II Arm 2A (vaccine only) but to close Arm 2B (vaccine plus bintrafusp alfa) before enrollment 
started. The Phase II portion of this study will only consist of only Arm 2A PRGN-2009 alone. 
Studies that were to be conducted under Arm 2B will be removed from the rest of the protocol; 
however, will remain here (and in Section 2.3.2) for background and informational purposes.
1.2.10 Rationale summary

Clinical outcomes for recurrent/metastatic HPV-positive malignancy and newly diagnosed 
stage II/III p16-positive OPSCC are poor, and while they are better for I (T1,2 N1) p16-
positive OPSCC de-intensification is needed to reduce long-term toxicity.

Participants with advanced p16-positive OPSCC have tumors infiltrated with exhausted 
and dysfunctional HPV antigen-specific T cells.

Treatment with a vaccine targeting HPV oncogenes to induce antigen-specific immunity 
(PRGN-2009) combined with immune checkpoint blockade to fully activate new and 
existing antigen-specific T cells (M7824) is a rational combination treatment strategy.

Investigators at the NIH Clinical Center have significant clinical experience with M7824.

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
1200 mg flat dose of M7824 has been chosen based on a phase I dose escalation trial of 
M7824 in solid tumors done at the NCI and PK/ PD data from that trial (NCT02517398). 

DL1 and DL2 of PRGN-2009 has been chosen based on the dose used for other adenovirus 
vaccines.

The phase I portion of the study will offer participants with immune checkpoint refractory 
recurrent/metastatic HPV-positive malignancy a chance to benefit from combination 
PRGN-2009 and M7824 treatment.

The phase II portion of the study will offer participants the opportunity to benefit from 
immunotherapy during a period of time when they are normally scheduling and awaiting 
definitive therapy for their newly diagnosed HPV-positive OPSCC.

Pre-treatment and post-treatment tumor biopsies before definitive therapy can provide 
tissue for studies aimed at interrogating the effects of single agent or combination immuno-
oncologic treatments on the tumor microenvironment and correlating those effects with 
clinical activity.
1.2.11 Rationale and background for performing 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 where multiple samples can be analyzed over the 
course of a given therapy vs. pre-therapy. The LTIB has now developed and employed (45-48) 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 of where these assays have been employed involves an ongoing first-in-human trial of 
the NHS-IL12 tumor-targeting immunocytokine (NCT01417546). 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 infiltration of p16-positive HNSCC with tumor infiltrating lymphocytes (TIL) tends to be 
greater than that observed in p16-negative HNSCC (49), possibly related to the presence of strong 
viral antigens. Supporting that these TIL are active and possess anti-tumor function, greater 
numbers of TIL present within p16-postive HNSCCs is positively correlated with increased 
survival after standard anti-cancer treatment and associated with an increased type I immune 
profile within the tumor (20). A meta-analysis of all published papers exploring TIL infiltration 
into p16-positive HNSCC demonstrated a strong, significant, positive correlation (50). Thus, 
changes in TIL infiltration into p16-positive HNSCCs after immunotherapy will be used for the 
primary outcome of the phase II portion of this study.  
In addition, 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.

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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 not amenable to 
potentially curative local therapies or metastatic HPV associated malignancies (Phase I 
only):

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 with cytologically or histologically confirmed newly diagnosed stage I (T1,2 
N1), II or III p16-positive oropharyngeal squamous cell carcinoma planned for definitive 
therapy or with newly diagnosed stage II or III or IVA or IVB HPV-positive sinonasal 
squamous carcinoma (HPV-SNSCC) eligible for primary surgery (Phase II only).
2.1.1.3
Subjects must have measurable disease, per RECIST 1.1. See Section 6.3 for the 
evaluation of measurable disease (Phase 1 only).
2.1.1.4
Phase I only: Participants must have received one prior line of systemic chemotherapy in 
the recurrent/metastatic setting as well as checkpoint blockade therapy in tumors with 
FDA approval (head and neck squamous cell cancer and PDL1+ cervical cancer). 
Exceptions to this include participants not eligible to receive standard therapy.
2.1.1.5
Men or Women; Age >18 years. 
2.1.1.6
ECOG performance status < 2 (see APPENDIX A: Performance Status Criteria).
2.1.1.7
Adequate hematologic function at screening, as follows:

Absolute neutrophil count (ANC) ≥1 x 109/L; 

Hemoglobin ≥ 9 g/dL; 

Platelets ≥ 75,000/microliter. 
2.1.1.8
 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).
2.1.1.9
The effects of the immunotherapies (PRGN-2009 vaccine and M7824) on the developing 
human fetus are unknown. For this reason and because M7824 and PRGN-2009 used in 
this trial are possibly teratogenic, women of child-bearing potential and men must agree 
to use highly effective contraception (hormonal or barrier method of birth control; 

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abstinence) prior to study entry and up to 2 months following the last dose of M7824 
study treatment. Should a woman become pregnant or suspect she is pregnant while she 
or her partner is participating in this study, she should inform her treating physician 
immediately.
2.1.1.10 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.
2.1.2
Exclusion Criteria
2.1.2.1
Participants with prior investigational drug, live vaccine, 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).
2.1.2.2
Major surgery within 28 days prior to the first drug administration (minimally invasive 
procedures such as diagnostic biopsies are permitted). 
2.1.2.3
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 repeated 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.    
2.1.2.4
Pregnant women are excluded from this study because M7824 and PRGN-2009 vaccine 
have not been tested in pregnant women 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, 
breastfeeding should be discontinued if the mother is treated on this protocol.
2.1.2.5
Only for Phase I, Arm 1B: 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; 

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 immunosuppressors 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 (> 

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14 days). In addition, the use of corticosteroids as premedication for contrast-enhanced 
studies is allowed prior to enrollment and on study.
2.1.2.6
Only for Phase I: 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, known left ventricular ejection fraction 
<50% (confirmation of EF > 50% is not required for eligibility), history of myocarditis, 
or recent myocardial infarction (within 6 months), or other illness considered by the 
Investigator as high risk for M7824 drug treatment. 
2.1.2.7
Only for Phase I: Subjects refusing to accept blood products as medically indicated.
2.1.2.8
History of second malignancy within 3 years of enrollment except for the following: 
adequately treated localized skin cancer, cervical carcinoma in situ, superficial bladder 
cancer, other localized malignancy which has been adequately treated or malignancy 
which does not require active systemic treatment (e.g., low risk CLL).  For participants 
enrolled on the phase I portion of the protocol a second HPV driven malignancy is 
allowed. 
2.1.2.9
Only for Phase I, Arm 1B: Subjects with a known severe hypersensitivity reaction to 
monoclonal antibodies or its excipients (grade >/= 3 NCI-CTCAE v5) will be evaluated 
by the allergy/immunology team prior to enrollment. 
2.1.2.10 Prior allogenic tissue/solid organ transplant. 
2.1.2.11 For participants who may receive M7824: previous life-threatening side effects resulting 
from prior checkpoint inhibitor therapy. 
2.1.2.12 Participants with pulse oximetry < 92% on room air at screening.
2.1.2.13 Participants unable to provide informed consent.
2.1.2.14 Participants whose inclusion in the trial would in the judgement of the PI lead to time 
from diagnosis to initiation of curative treatment of >70 days (Arm 2A only).
2.1.3
Recruitment Strategies
This protocol may be abstracted into a plain language announcement posted on NIH websites and 
on NIH social media platforms. 
This study will be listed on www.clinicaltrials.gov. 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. Recruitment flyers may be used to advertise this study 
in the future after IRB approval.   
Participants for the Phase I portion of the study will be recruited from the current participant 
population at NIH. participants with HPV related cancers are currently being treated on another 
trial through LTIB, 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. Norberg’s 
group, Experimental Transplantation and Immunology Branch, CCR, NIH) who also have a large 
referral base for HPV related cancers. Participants on the phase II portion of the study will be 
recruited from locoregional hospital including the Johns Hopkin’s community network of which 
Clint Allen, MD, an AI on this protocol, is also a part.

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2.2
SCREENING EVALUATION
2.2.1
Screening activities performed prior to 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. 

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 procedures are permitted on that study) on which 
screening activities will be performed within 28 days prior to enrollment unless otherwise 
indicated. 
Assessments performed at outside facilities or on another NIH protocol within the timeframes 
below may also be used to determine eligibility once a participant has signed the consent.
Complete medical history and physical examination (including height, weight, vital signs, 
and ECOG performance status).

Imaging for Phase I:

CT of chest, abdomen and pelvis or MRI, if clinically indicated.

A brain CT scan in participants with known CNS disease as described in Section 
2.1.2.3/ MRI scan if clinically indicated.

Imaging for Phase II:

CT of the neck and chest+, or MRI, if clinically indicated, for participants with 
oropharyngeal cancer. 

CT of skull, neck and chest+, or MRI, if clinically indicated, for participants with 
sinonasal SCC.
+Imaging of chest and neck ± skull is preferred but not required if a PET/CT is available 
from within the screening timeframe.

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):
o
Acute care panel (Na+, K+, Cl-, total CO2, creatinine, glucose, blood urea nitrogen).
o
Hepatic panel (AST/GOT, ALT/GPT, total bilirubin, direct bilirubin).

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o
Mineral panel (albumin, calcium total, magnesium total, phosphorus).
o
Urine or serum pregnancy test (β-HCG) for females of childbearing-potential and 
women < 12 months since the onset of menopause (within 5 days prior to enrollment).
o
Hematology: complete blood count (CBC) with differential.
o
Urinalysis.

HBV, HCV, HIV testing including viral load for HCV, HBV and HIV if clinically 
indicated (within 3 months prior to enrollment). CD4 testing may also be required for 
HIV+ participants.

Participants with a history of ≥ grade 3 hypersensitivity reaction to monoclonal antibodies 
or M7824 will be evaluated by immunologist prior to enrollment.
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://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825. 
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
2.3.2.1
Cohorts
Number
Name
Description
1
Cohort 1
Subjects with advanced or metastatic HPV associated 
malignancies (Phase I)
2
Cohort 2
Subjects with newly diagnosed p16+ oropharyngeal 
cancer (Phase II):
Arm 2A: Stage I (T1,T2 N1)/II/III
Arm 2B: Stage II/III Note: Closed, Will Not Enroll
3
Cohort 3
Subjects with newly diagnosed stage II/III/IVA/IVB 
HPV+ sinonasal squamous cell cancer (Phase II)

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2.3.2.2
Arms
Number
Name
Description
1
Arm 1A
HPV vaccine at 1x1011 Viral Particles (VP) (DL1) and 
at 5x1011 VP (DL2) 
Note: Closed, Enrollment Completed
2
Arm 1B
HPV vaccine at RP2D plus M7824 at 1200 mg 
3
Arm 2A
HPV vaccine at RP2D given as neoadjuvant or 
induction therapy
4
Arm 2B
HPV vaccine at RP2D plus M7824 at 1200 mg given as 
neoadjuvant or induction therapy 
Note: Closed, Will Not Enroll
2.3.2.3
Arm Assignment
Participants in Cohort 1 will be sequentially assigned to Arm 1A, to determine RP2D of PRGN-
2009, and then Arm 1B, evaluating the combination of RP2D of PRGN plus M7824. Participants 
will be enrolled to these arms based upon a 3+3 dose escalation schema. In addition, Arm 1B will 
be expanded to a total of 10 evaluable participants to gauge the preliminary efficacy of the 
combination of PRGN-2009 and M7824 in participants with advanced disease.
Once the RP2D of HPV vaccine has been determined, p16+ oropharyngeal cancer participants in 
Cohort 2 and HPV-SNSCC participants in Cohort 3 will be assigned to Arm 2A (20 evaluable 
participants for Cohort 2, up to 2 for Cohort 3). 
2.4
BASELINE EVALUATION
All subjects are required to complete baseline evaluations within two weeks (four weeks for Phase 
II imaging) prior to the first dose of the study drug (any screening evaluation done within this time 
period can also serve for the baseline evaluation unless otherwise indicated):

Physical exam including weight, ECOG performance status and vital signs. 

Skin assessment. 

Medical history (Concomitant Medications and Baseline Signs and Symptoms 
evaluation).

Imaging for Phase I*:

CT of chest, abdomen and pelvis or MRI, if clinically indicated.

A brain CT scan in participants with known CNS disease as described in Section 
2.1.2.3/ MRI scan if clinically indicated.

Imaging for Phase II*:

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
CT of the neck† and chest+, or MRI, if clinically indicated, for participants with 
oropharyngeal cancer. 

CT of skull†, neck† and chest+, or MRI, if clinically indicated, for participants 
with sinonasal SCC.
*Imaging for baseline should be within 2 weeks (for Phase I) or 4 weeks (for Phase II) 
prior to the first dose of study drug and is not required if available within the baseline 
timeframe. Imaging performed at outside facilities within the timeframe may also be 
used for baseline.
+Imaging of chest is not required if a PET/CT is available within the baseline 
timeframe. 
†The CT component of a PET/CT obtained within the baseline timeframe may be 
used as CT of the neck ± skull per PI discretion.

Urine or serum pregnancy test (β-HCG) for females of childbearing-potential and 
women < 12 months since the onset of menopause (within 5 days prior to study 
therapy).

Acute care panel (Na+, K+, Cl-, total CO2, creatinine, glucose, blood urea nitrogen).

Hepatic panel (AST/GOT, ALT/GPT, total bilirubin, direct bilirubin).

Mineral panel (albumin, calcium total, magnesium total, phosphorus). 

Thyroid tests (TSH and reflex free T3 & T4), lipase, amylase, C-Reactive Protein 
(CRP).

Hematology: CBC with differential. 

Coagulation panel: PT, INR, and PTT.

HLA typing (any time prior to study treatment initiation - may be deferred if it has 
been previously performed at the NIH).  (For Phase II only)

Urinalysis.

For correlative studies: Blood and tissue sample will be collected. Please refer to 
Section 5.1 for details regarding samples to be collected and refer to the Study 
Calendar for collection timepoints.

Creatinine phosphokinase (CPK).

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3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
Phase I: Recurrent/metastatic HPV associated cancer

A 3+3 dose escalation design will be used which will evaluate PRGN-2009 (HPV vaccine) 
at two dose levels (1x1011 and 5x1011 VP) given as monotherapy followed by an evaluation 
of the RP2D dose of PRGN-2009 in combination with 1200 mg (RP2D) of M7824.

Dose escalation will follow the rules as outlined:
o
After completion of enrollment on DL1 of Arm 1A, enrollment to DL2 of Arm 1A 
will proceed if 0 out of 3 or 1 out of 6 participants in DL1 of Arm 1A experience a 
DLT.
o
After completion of enrollment on DL2 of Arm 1A, enrollment to Arm 1B will 
proceed if   out of 3 or 1 out of 6 participants in DL2 of Arm 1A experience a DLT.
o
If 2 participants in a given dose level of Arm 1A or Arm 1B experience a DLT, accrual 
to that arm will be halted.

There will be a 4-week DLT evaluation period for each dose level.

There will be a 1-week delay between the first three participants treated on a given dose 
level. 

All other participants will be enrolled a minimum of six days apart on the phase I portion 
of the protocol except between the last participant in one dose level and the first participant 
in the next dose level in which case the DLT period of 4 weeks will be the minimum wait 
time.  

In addition, Arm 1B will be expanded to a total of 10 evaluable participants to gauge the 
preliminary efficacy of the combination of PRGN-2009 and M7824 in participants with 
advanced disease.
Schema for Phase I

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Phase II: Newly diagnosed stage I (T1,T2 N1)/II/III HPV-positive oropharyngeal cancer 
and newly diagnosed stage II/III/IVA/IVB HPV-positive sinonasal squamous carcinoma:

Evaluation of HPV vaccine alone (Arm 2A) as neoadjuvant or induction therapy in HPV-
positive oropharyngeal cancer (20 participants), and HPV-SNSCC participants (2 
participants). 

After completion of induction immunotherapy participants will be referred back to their 
home institution for definitive standard of care therapy. At outside institutions, standard of 
care treatment will be performed and chosen solely by outside providers. NCI investigators 
will have no role in treatments received at outside institutions.
Schema for Phase II
Although positive HPV testing will not be required for the phase I or II portion of the protocol 
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. 
3.1.1
Dose Limiting Toxicity (for first 3-6 participants enrolled on Arms 1A and 1B; phase I 
part of the study): 
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 HPV vaccine monotherapy or 28 days 
of starting the HPV vaccine + M7824 combination therapy:

Any Grade 3 or higher bleeding episode requiring blood transfusion(s).

Any Grade 4 or higher adverse drug reactions (ADRs) as defined by CTCAE v5.0 and 
assessed as possibly related to any 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 any agent except for any of the following:

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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 7 days without medical intervention.
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 participants (e.g., placement of a pleural catheter for recurrent 
inflammatory pleural effusions) and resolves to at least grade one or baseline 
grade within 72 hours. 
Where clinically appropriate subjects enrolled on Arm 1 will receive one year of treatment during 
which subjects will be followed with surveillance scans using CT/MRI (as appropriate) every 6-
12 weeks. On a case by case basis treatment beyond a year is allowed per investigator discretion. 
Subjects with evidence of disease progression after completing a year of treatment will be allowed 
retreatment. Patients 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.  
3.2
DRUG ADMINISTRATION
General Rule 
For participants enrolled on the phase I portion of the protocol 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). For participants enrolled on the phase II portion of the protocol a window of 
+/- 7 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 PRGN-2009 should be administered first, followed by M7824 (when 
given). 
3.2.1
PRGN-2009
On the phase I portion of the protocol PRGN-2009 will be administered on D1, D15, D29 followed 
by booster vaccines every 4 weeks for up to a year. The dose level given as booster will be the 
same dose participants will be receiving for D1, D15 and D29. On the phase II portion of the 
protocol PRGN-2009 will be administered on just D1 and D15. 
3.2.1.1
Refer to Sections 14.1.4 Pharmacy Preparation and 14.1.5 Vaccine Preparation
3.2.1.2
Administration Procedures

Injection Volume – The injection volume for both doses is 1.0 ml.  

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
Injection Route – The route of injection is by subcutaneous injection using a 1.0 ml syringe.
Follow your standard institutional clinical procedures for preparation of the subject’s injection site, 
subcutaneous injection and post-injection bandaging of the injection site. PRGN-2009 is a non-
replicating, non-integrating adenoviral vector. Since the parental adenovirus is classified as 
biosafety level 2 (BSL2), PRGN-2009 should be handled as BSL2 material for disposal of all 
materials that were used in the dose administration. Spills of PRGN-2009 should be 
decontaminated using a solution of 10% bleach. 
3.2.2
M7824
Subjects enrolled to Arm 1B will receive M7824 via IV infusion over 1 hour (-10 minutes / +20 
minutes, that is, over 50 to 80 minutes) once every 2 weeks for up to a year (Arm 1B). M7824 
will be administered as a "flat" dose of 1,200 mg independent of body weight. M7824 is 
administered as an intravenous infusion with a mandatory 0.2 micron in-line filter. Infusion of 
M7824 can be administered through a PIV or CVAD or port with titanium as the main material.
Current experience revealed that IRRs to M7824 occur seldomly and are generally mild to 
moderate in severity. Therefore, administration of a premedication is generally not required.
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.
Management of symptoms should follow the guidelines shown in Table 2.
3.2.2.1
Immediate Hypersensitivity Reaction
Hypersensitivity reactions may require immediate intensive care. M7824 should be administered 
in a setting that allows for immediate access to an intensive care unit or equivalent environment 
and administration of therapy for anaphylaxis, such as the ability to implement immediate 
resuscitation measures. Steroids (dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy 
medications (IV antihistamines), bronchodilators, or equivalents, and oxygen should be available 
for immediate access.
A complete guideline for the emergency treatment of anaphylactic reactions according to the 
Working Group of the Resuscitation Council United Kingdom and can be found at 
https://www.resus.org.uk/pages/reaction.pdf.
3.2.2.2
Flu-Like Symptoms
Treatment is based on clinical assessment and at the discretion of the Investigator. For prophylaxis 
of flu like symptoms, a nonsteroidal anti-inflammatory drug (NSAID), e.g., ibuprofen 400 mg or 
comparable NSAID dose, may be administered 2 hours before and 8 hours after the start of each 
IV infusion.
3.3
DOSE MODIFICATIONS
3.3.1
Discontinuation
Phase 1 and Phase 2: 

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Treatment with individual agents (PRGN-2009 alone or in combination with M7824) will be 
discontinued in participants experiencing specific adverse events; subjects will however still 
remain on study for follow up of survival. Treatment discontinuation will occur in any 
participant experiencing a DLT-defining toxicity and 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 any of the following: 
o
Laboratory values that are asymptomatic or resolve to Grade ≤ 1 or baseline grade within 
7 days without medical intervention.
o
Any endocrinopathy that can be medically managed with hormone replacement. 

Any Grade 3 ADRs possibly attributed to that 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. 
o
Grade 3 laboratory values that are asymptomatic or resolve to Grade ≤ 1 or baseline 
grade within 7 days with medical management. 
o
Keratoacanthoma and squamous cell carcinoma of the skin. 
o
Any endocrinopathy that can be medically managed with hormone replacement.
o
Any other grade 3 adverse drug reaction that resolves to grade <1 or baseline grade 
within 72 hours. 
3.3.2
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. 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.
3.3.3
Study Accrual Halting Rules 
Accrual will be halted if: 

Phase 1 and Phase 2: 
o
There is an occurrence of any death (other than death related to progressive disease 
or accidental death) that occurs within 30 days of administration of study agents 
(PRGN-2009 and M7824) for both Phase 1 and Phase 2.     

Phase 2 only: 
o
There is a delay in initiation of definitive standard of care therapy of 4 weeks or 
more beyond the planned start date due to treatment-related toxicities from HPV 
vaccine in two participants.

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o
There is occurrence of treatment-related ADRs from HPV vaccine of either Grade 
4 (except for laboratory values that are asymptomatic or resolve to Grade ≤1 or 
baseline within 7 days) or of Grade 3 not resolving to Grade ≤1 or baseline within 
7 days in two participants.
The IRB and the sponsor will be notified if one of the study accrual halting rules has been reached. 
The accrual halt will be lifted once the data has been reviewed and there has been a reassessment 
of available safety information prior to reopening the study to accrual and allowing the study to 
proceed.  
3.3.4
Dose Modification 
During DLT period dose modifications are not allowed. 
HPV vaccine: Vaccine doses will not be modified for an individual participant but doses may be 
skipped per investigator discretion. Once a dose is given to a participant that will always be the 
dose of vaccine they receive during this trial. 
M7824: Dose reductions are not allowed but doses may be skipped per investigator discretion. 
3.3.5
Toxicity Management 
Table 2 Treatment Modification Guidance for Symptoms of Infusion-Related Reactions 
including Immediate Hypersensitivity
Infusion-Related Reactions (IRR) are an important risk for M7824.
NCI-CTCAE Grade
Treatment Modification 
Grade 1 - mild
Mild transient reaction; in general, infusion 
interruption not indicated; intervention not 
indicated

Increase monitoring of vital signs as 
medically indicated as participants are 
deemed medically stable by the attending 
Investigator.

Hold infusion if deemed necessary by the 
investigator.

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NCI-CTCAE Grade
Treatment Modification 
Grade 2 – moderate
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(for example, antihistamines, nonsteroidal 
anti-inflammatory drugs, narcotics, IV fluids); 
prophylactic medications indicated for  24 h.

Stop the infusion of the study 
intervention. 

Increase monitoring of vital signs as 
medically indicated as participants are 
deemed medically stable by the attending 
Investigator.

If symptoms resolve quickly, resume 
infusion at 50% of original rate with close 
monitoring of any worsening signs and 
symptoms, otherwise dosing held until 
resolution of symptoms with mandated 
premedication for the next scheduled visit.

If not improving, consider administration 
of glucocorticoids and stop the infusion 
for that day.

If the participant has a second IRR Grade 
≥ 2 on the slower infusion rate despite 
premedication, the infusion should be 
stopped, and the investigator may 
consider withdrawal of this participant 
from the study.
Grade 3 or Grade 4 – severe or 
life-threatening
o
Grade 3: Prolonged (for example, not 
rapidly responsive to symptomatic 
medication and/or brief interruption of 
infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for clinical 
sequelae.
o
Grade 4: Life-threatening consequences; 
urgent intervention indicated.

Stop the infusion of study intervention 
immediately and disconnect infusion 
tubing from the participant with additional 
appropriate medical measures and closely 
monitor until deemed medically stable by 
the attending Investigator. Hospitalization 
and/or close monitoring is recommended
 Administration of glucocorticoids may be 
required

For Grade 3 or 4 IRRs, permanent 
discontinuation of study intervention is 
mandated.

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NCI-CTCAE Grade
Treatment Modification 
Once the infusion is interrupted or rate reduced to 50% of previous infusion rate, it must 
remain decreased for all subsequent infusions. 
For all types and grades of infusion reactions, details about drug physical constitution, 
method of preparation, and infusion must be recorded.
Participants should be instructed to report any delayed reaction immediately.
Once the infusion is interrupted or rate reduced to 50% of previous infusion rate, it must 
remain decreased for all subsequent infusions. 
For all types and grades of infusion reactions, details about drug physical constitution, 
method of preparation, and infusion must be recorded.
Participants should be instructed to report any delayed reaction immediately.
Table 3 Immune-related adverse events (irAEs)
Immune-related AEs are specific to immunotherapies and vary by organ system. 
Following immune-related AEs are important identified risks for M7824: 

Immune-related pneumonitis

Immune-related hepatitis

Immune-related colitis

Immune-related nephritis and renal dysfunction

Immune-related endocrinopathies 

(thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus, pituitary disorders)

Immune related rash

Other immune-related events (myositis, myocarditis, encephalitis)
Following immune-related AEs are important potential risks for M7824:

Guillain-Barré syndrome

Uveitis

Pancreatitis

Myasthenia gravis/myasthenic syndrome
Recommended guidance and management for specific irAEs are provided in the current 
NCCN (guideline available at http://www.nccn.org).
Requirements in addition to NCCN guidelines:

Permanent treatment discontinuation is required in case of immune-related Grade 4 
rash/inflammatory dermatitis, nephritis, autoimmune hemolytic anemia, hemolytic 
uremic syndrome, aplastic anemia, immune thrombocytopenia, acquired thrombotic 

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thrombocytopenic purpura inflammatory arthritis, myositis and polymyalgia-like 
syndrome.

For Grade 4 immune-related lymphopenia, permanent treatment discontinuation will be 
required, if lymphopenia is considered immune-related in nature, no clear alternative 
explanation exists for the event, and it does not resolve within 14 days. Permanent 
treatment discontinuation is not required when the AE is manifested by a single 
laboratory value out of normal range without any clinical correlates. In this case, 
treatment should be held until the etiology is determined. If the event is not considered 
immune-related and resolves to Grade ≤ 1, restarting treatment may be considered.

For Grade 1 immune-related pneumonitis: continue treatment. If clinically indicated, 
monitor participants weekly or more frequently as needed with history, physical 
examination and pulse oximetry. If symptoms appear and/or changes in the physical 
exam are noted, treat as Grade 2.

For myositis: in case of management with rituximab, treatment should be discontinued.

For Grade 3 or 4 endocrinopathies: withhold until clinically stable or permanently 
discontinue depending on severity.

For hepatitis with no tumor involvement of the liver: withhold if total bilirubin 
increases to more than 1.5 and up to 3 times ULN, permanently discontinue if more 
than 3 times ULN.

Hepatitis with tumor involvement of the liver: permanently discontinue if total 
bilirubin increases to more than 3 times ULN.
Table 4 Management of M7824 mediated Skin Reactions
Skin reactions are considered important identified risk for M7824.

Hyperkeratosis

Keratoacanthoma

Cutaneous squamous cell carcinoma (cSCC)

Basal cell carcinoma

Actinic keratosis
Management

Discontinuation or termination not required in most cases. Continuation of treatment 
should be evaluated by the Investigator.

Emollients may be used

Develop diagnostic and treatment plan in collaboration with Investigator and 
dermatologist

Treatment follow-up will depend on number and localization of lesions.
o
Single lesion: full excision may be recommended

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o
Multiple lesion or location not suitable for full excision: Mohrs surgery, 
cryotherapy or other standard treatment options depending on pathology. 
Retinoids may be used after discussion with Investigator.

Close clinical follow-up for re-evaluation, resolution and potential recurrence should be 
implemented

In general, treatment of skin lesions should be based on local guidelines/standard of 
care.
Additional consideration: Keratoacanthoma lesions may resolve spontaneously without 
surgical intervention within weeks after discontinuing M7824.
Consult with Medical Monitor as needed for management of skin lesions.
Table 5 Management of Anemia

Anemia is considered an important identified risk for M7824.

All relevant hematological testing for treatment-related anemias should be done prior to 
a blood transfusion, if clinically feasible
Basic Anemia Evaluation

CBC with emphasis on red cell indices

If indicated and at clinical discretion, the following should be considered:
o
Iron studies
o
Serum Folate and Vit B12 values
o
Coagulation factors
o
Fecal occult blood
o
Urinalysis
o
Hormone panel: TSH, Erythropoietin
o
Peripheral blood smear
Further Recommendation Based on Suspected Etiology (in Addition to Basic Anemia 
Testing)

Suspected Hemolysis
o
bilirubin, LDH, Coombs test, haptoglobin

Suspected bleeding: 
o
Consider imaging/interventional radiology consultation as indicated
o
Consider imaging and/or endoscopy as clinically indicated

Suspected aplastic anemia:
o
Hematology consultation
o
Consider bone marrow aspiration/morphologic evaluation

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Additional consideration: 
In general, blood transfusions and erythroid growth factors are permitted as clinically 
indicated.
Table 6 Management of Bleeding Adverse Events
Bleeding Adverse Events

Bleeding adverse events are considered important identified risk for M7824.

In general, mild and moderate mucosal bleedings resolve without discontinuation of 
treatment.

These events may include, but are not limited to the following:
o
Epistaxis
o
Hemoptysis 
o
Gingival bleeding
o
Hematuria
Non-tumor Bleeding
Grading
Management
Grade 2

If resolves to Grade ≤ 1 by the day 
before the next infusion, study 
intervention may be continued

If not resolved to Grade ≤ 1 by the day 
before the next infusion, but is 
manageable and /or not clinically 
relevant, assessment if clinically 
reasonable to administer the following 
infusion will be per PI discretion.
Grade 3

Permanently discontinue treatment 
unless an alternative explanation can be 
identified (such as concomitant use of 
antithrombotic agents, traumatic events, 
etc.) 

In case of alternative explanations, hold 
study treatment until the event recovers 
to Grade ≤ 1
Grade 4

Treatment must be permanently 
discontinued if no alternative 
explanation is identified.
Tumor Bleeding
Grade ≥ 2

Study treatment must be held till the 
event recovers to Grade ≤ 1

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
Permanently discontinue treatment if the 
Investigator considers the participant to 
be at risk for additional severe bleeding.
Table 7 Impaired Wound Healing

Impaired wound healing is considered important potential risk for M7824

Elective surgery on study will be allowed per PI discretion

It is recommended to hold study intervention for approximately 4 weeks post major 
surgery for observation.
Post-operative wound healing should be closely monitored

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3.4
STUDY CALENDAR
3.4.1
Study Calendar for Phase I
Procedure
Screening1
Baseline / 
Day 12
Odd numbered 
Weeks (W1, 
W3, W5, W7 
onwards)3
EOT4
Safety 
follow 
up5
Long 
Term 
follow up6
Treatment3 
X
X
NIH Advance Directives Form 7
X
Medical History 17
X
Height
X
Physical exam, weight, vital signs, 
ECOG 16
X
X
X
X
X
Skin assessment 18
X
X
X
X
HIV, HCV, HepB
X
EKG
X
X
X
CBC with differential
X
X
X
X
X
Biochemical profile 8
X
X
X
X
X
Tumor Markers 9
X
X
X
CD4 10
X
TSH with reflex Free T3 and T4, 
lipase, amylase, CRP
X
X11
Urinalysis 
X
Urine or serum pregnancy testing in 
women of childbearing potential 
X
X
X
PT, INR, PTT
X
Tumor evaluation (CT Scan / MRI) 
X
X
X12
X
Brain CT/MRI 13
X
Concomitant Medications
X
X
X
X
Adverse events
X
X
X
X
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 2 weeks prior to first drug administration. 
Note: Baseline Labs will not be redrawn if done already as screening within the 2 weeks prior to drug 
administration.  
3.  Treatment: 
•
Trial treatment will be given with either HPV vaccine monotherapy (Arm 1A) or the combination 
of HPV vaccine + M7824 (Arm 1B) for a year. 
•
HPV vaccine will be given on D1, D15 and D29 followed by every 4 weeks thereafter and M7824 
will be given every 2 weeks. 
•
Both of these agents may be discontinued early for unacceptable toxicity or disease progression. 
Treatment beyond a year may be given per PI discretion.
•
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.  
5. Approximately 28 days (+/- 7 days) after last treatment. If subjects are not willing to come to NIH for 
FU visit, they will be contacted by phone to assess adverse events and for such participants no labs will be 
needed at FU. 
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 
directive 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: Acute care, hepatic and mineral panel as described in Sections 2.2 and 2.4.
9. Evaluate CEA, CA19-9, CA125 and CA15-3 at baseline and follow elevated values thereafter (for 
participants enrolled on the phase I portion of the protocol). 
10. In HIV positive participants. 
11. Every 8 weeks for participants.
12. Imaging will be performed 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 (with gadolinium) will be used when CT scan is not an option to follow 
the disease. Bone scans and other imaging assessments may also be performed as clinically indicated.

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13. In participants with known CNS disease as described in Section 2.1.2.3; MRIs may be performed as 
clinically indicated in this population.
14. Where feasible, optional biopsies may be done at baseline and at week 9 and will likely be CT guided. 
If a recent (≤ 6 months preferred) outside biopsy has been performed that specimen may be used in lieu of 
a baseline biopsy for both phase I and II participants. 
15. Where feasible, research blood (see Section 5.1) will be collected at the following time points: 

PKs and ADAs – performed only on Arm 1B (bintrafusp alfa plus vaccine) 
o
Samples for PK analysis will be taken prior to infusion and following infusion on W1 
and W5 and prior to infusion on W3 and W11 or with end of treatment labs if 
patients comes off treatment prior to any of those timepoints; and 
o
Samples for ADA analysis will be taken prior to infusion on W1, W5, and W11 or 
with end of treatment labs if participants come off treatment prior to any of those 
timepoints. 

Samples for AVA analysis will be taken prior to infusion on W1, W3, W5, W11, and 
restaging visits or with end of treatment labs if participants come off treatment prior to any of 
those timepoints.

All other blood samples
o
Baseline, Week 3, and Week 5; restaging visits per PI discretion.

Note: Samples may be sent to Precigen, Inc for additional analyses (see Section 5.1.9).
16. Vital signs at screening should include pulse oximetry on room air.
17. Medical history will include monitoring for signs of bleeding.
18. Skin assessment must be performed at baseline and at least every 6 weeks, starting on week 5 during 
treatment and at the end of treatment or at the 28 (±7 days) day safety follow-up (if not performed in the 
previous 6 weeks). 
3.4.2
Study Calendar for Phase II
Procedure
Screen
ing1
Baseli
ne2
Week 
1
Week 
3
Week 
4-518
EOT4
Safety 
follow 
up5
Long 
Term 
follow up6
Treatment 3 
X
X
X
NIH Advance Directives Form 7
X
Medical History 14
X
Height
X
Physical exam, weight, vital signs, 
ECOG 13
X
X
X
X
X
X
X
Skin assessment 16
X
X
X
X
X
X
HIV, HCV, HepB
X
EKG
X
X
X
CBC with differential
X
X
X
X
X
X
X

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Procedure
Screen
ing1
Baseli
ne2
Week 
1
Week 
3
Week 
4-518
EOT4
Safety 
follow 
up5
Long 
Term 
follow up6
Biochemical profile 8
X
X
X
X
X
X
X
CD4 9
X
TSH with reflex Free T3 and T4, 
lipase, amylase, CRP
X
X
X
X
Urinalysis 
X
Urine or serum pregnancy testing in 
women of childbearing potential 
X
X
X
X
HLA typing 17
X
PT, INR, PTT
X
Tumor evaluation (CT Scan / MRI)10 
X
X
X
Concomitant Medications
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
Biopsy for immune analysis 11
X
X
Research Blood 12
X
X
X
X
X
Saliva sample 15
X
X
X
X
X
X
Taken off treatment for definitive 
treatment 19
X
Telephone/email Follow Up
X
X
1. Screening evaluations performed within 28 days prior to the first drug administration, unless specified 
in Section 2.2.
2. Baseline evaluations performed within 2 weeks prior to first drug administration. 
Note: Baseline Labs will not be redrawn if done already as screening within the 2 weeks prior to drug 
administration. 
Note: Imaging within 4 weeks prior to drug administration.
3.  Therapeutic agents administered will be as outlined in Section 3.1: 
•
Participants will be planned to receive two doses of treatment (HPV vaccine alone in Arm 2A) 
before definitive standard of care therapy.
•
Administration of study agents and indicated evaluations can be done up to 3 days earlier or delayed 
up to 3 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. 

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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 prematurely or one month of neoadjuvant 
or induction treatment. Note: Does not need to be completed if drug is withheld after these timepoints and 
such participants will be considered off-treatment.
5. Approximately 28 days (+/- 7 days) after last treatment. If subjects are not willing to come to NIH for 
FU visit, they will be contacted by phone to assess adverse events and for such participants no labs will be 
needed at FU. 
6. Participants who have completed neoadjuvant or induction immunotherapy on the phase II portion of the 
protocol will be followed by phone or email for recurrence, adverse events and survival starting 2 months 
(+/- 2 weeks) after safety visit and then annually (+/- 1 month) until the patient is 5 years out from surgery 
or completion of chemoradiotherapy.
7. As indicated in Section 12.3, all subjects will be offered the opportunity to complete an NIH advanced 
directive 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: Acute care, hepatic and mineral panel as described in Sections 2.2 and 2.4. 
9. In HIV positive participants. 
10. Imaging (CT of neck and chest/ MRI, if indicated, for oropharyngeal cancer participants; CT of skull, 
neck and chest/ MRI, if indicated, for sinonasal SCC; no CT chest required if PET/CT available) at 
baseline/screening, and at Week 4-5 (CT of neck/ MRI, if indicated, for oropharyngeal cancer participants; 
CT of skull, neck/ MRI, if indicated, for sinonasal SCC). MRI (with gadolinium) will be used when CT 
scan is not an option to follow the disease. Bone scans and other imaging assessments may also be 
performed as clinically indicated. Post-treatment imaging is to be strongly pursued but is not required and 
may be waived at the discretion of the PI.
11. Where feasible, biopsies will be done at baseline as well as at week 4-5. Biopsies will be done by ENT 
under direct visualization. Where feasible at least 2 cores will be obtained. If a recent (≤ 6 months preferred) 
outside biopsy has been performed that specimen may be used in lieu of a baseline biopsy. For patients that 
have surgery as definitive treatment, Week 4-5 biopsy may be omitted: in this case tumor biospecimens 
will be obtained from the institution where the patient underwent surgery after the patient signs that 
institution’s release document. 
12. Where feasible, research blood (see Section 5.1) will be collected at baseline, week 3 and week 45 
with the following exceptions: 

Samples for AVA analysis will be taken prior to infusion on W1, W3, with research labs on 
4-5 or with end of treatment labs if participants come off treatment prior to any of those 
timepoints.

Note: Samples may be sent to Precigen, Inc for additional analyses (see Section 5.1.9).
13. Vital signs at screening should include pulse oximetry on room air.
14. Medical history will include monitoring for signs of bleeding.
15. Only for p16+ oropharyngeal cancer patients: Collection of saliva by mouth rinse and gargle with 15-
20 mL 0.9% NaCl for 30 seconds and spitting into the collection tube. Where possible, saliva samples will 
be analyzed for HPV DNA detection and quantification.  
16. Skin assessment must be performed at baseline and at least every 6 weeks starting on week 5 during 
treatment and at the end of treatment or at the 28 (±7 days) day safety follow-up (if not performed in the 
previous 6 weeks). 

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17. HLA A, B, C and DR, DQ and NGS A, B, C and DR, DQ, at any time prior to treatment start. Patients 
who have had HLA typing previously performed at NIH do not require retesting.
18. Preferably scheduled for Week 5, with Week 4 an option to not interfere with activities required for 
arrangements for definitive treatment. An earlier timepoint may also be used to avoid interfering with 
definitive treatment, but should be at least a day after the second vaccination.
19. Upon completion of induction or neoadjuvant immunotherapy participants on the phase II portion of 
the protocol will be taken off treatment and referred back to their home institutions for definitive standard 
of care therapy and follow up will be performed per superscript # 6 above.

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3.5
COST AND COMPENSATION 
3.5.1
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.    
3.5.2
Compensation
Subjects will not receive compensation for participation in this study.
3.5.3
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.   
3.6
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 are unable or unwilling to return for this visit will be asked 
to review any safety concerns by phone within this time period.  
3.6.1
Criteria for Removal from Protocol Therapy

Completion of 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 (see Section 3.3). 

Participant requests to be withdrawn from active therapy.

Start of another systemic anticancer treatment or participation in another 
investigational therapeutic trial (except for standard of care therapy for phase II 
participants). For participants enrolled in the phase I portion of the protocol, focal 
palliative radiotherapy, ablation, or surgery to a site of disease will not necessitate 
removal from protocol therapy.  

Investigator discretion.

Positive pregnancy test.

Intercurrent illness that prevents further administration of treatment, in the judgement 
of the investigator.

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3.6.2
Off-Study Criteria

Failure to maintain eligibility criteria prior to starting treatment.

Screen failure.

PI decision to end the study.

Participant requests to be withdrawn from study. 

Participant lost to follow-up.

Investigator discretion. 

Death.

Completion of 5-year follow up period. (Only for Phase II)
3.6.3
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 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
4.1
PERMITTED MEDICATIONS
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-sparing technique may be administered during 
the trial. The assessment of PD will not be based on the necessity for palliative radiotherapy.
4.2
PROHIBITED MEDICATIONS
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 

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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 (except standard of care therapy for phase II participants).

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5
CORRELATIVE STUDIES FOR RESEARCH
5.1
BIOSPECIMEN COLLECTION
Test/assay
Volume 
(approx.) per 
Timepoint
Type of 
tube a
Collection 
point
Location of specimen analysis
Standard and 123 
immune cell subsets 
by FACS
LTIB
[Storage at Clinical Services 
Program (CSP)]
Functional Analysis 
of immune cell 
subsets by FACS
LTIB
(Storage at CSP)
Antigen Specific 
Immune Response 
by cytokine staining 
assay
LTIB
(Storage at CSP)
T cell clonality by 
immuno-seq 
platform
LTIB and NCI Frederick Genomic 
Core Facility
(Storage at CSP)
RNA expression 
level of 770 genes
60-80 mL 
blood for 
PBMCs
Sodium 
heparin 
(green top) 
tubes
LTIB and NCI Frederick Genomic 
Core Facility
Soluble Factors (to 
include sCD27 and 
sCD40 ligand) by 
ELISA 
8 mL blood 
for serum
SST
LTIB
(Storage at CSP)
M7824 
Pharmacokinetics
4 mL blood 
for serum
SST
EMD Serono (Storage at BPC)
ADA by ELISA
4 mL blood 
for serum
SST
EMD Serono (Storage at BPC)
AVA by ELISA
1 mL blood 
for serum
SST
Precigen (Storage at BPC)
Immune Markers 
by IHC
Tumor 
samples
N/A
GMB TIME LAB
(Storage at LP, CSP)
Single-cell 
Proteomic analysis
Tumor 
samples
N/A
See Study 
Calendar
Precigen (Storage at LP, CSP)

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Test/assay
Volume 
(approx.) per 
Timepoint
Type of 
tube a
Collection 
point
Location of specimen analysis
Immune 
transcriptomic 
analysis 
Tumor 
samples
N/A
Precigen (Storage at LP, CSP)
RNA expression 
level of 770 genes
Tumor 
samples
N/A
LTIB and NCI Frederick Genomic 
Core Facility (Storage at LP, CSP)
HPV status by PCR 
of DNA
Tumor 
samples
N/A
Dr. Norberg’s Team
(Storage at LP, CSP)
Circulating free 
tumor DNA 
(cftDNA) by PCR 
system
Plasma
EDTA 
(lavender 
top)
LTIB and NCI Frederick Genomic 
Core Facility
(Storage at CSP)
T cell clonality by 
immunoseq 
platform
Tumor 
samples
N/A
LTIB and NCI Frederick Genomic 
Core Facility 
(Storage at LP, CSP)
Salivary HPV DNA
15-20 mL 
0.9% NaCl 
rinse
50 mL 
conical 
tube
LTIB and NCI Frederick Genomic 
Core Facility
(Storage at CSP)
a Please note that tubes and media may be substituted based on availability with the 
permission of the PI or laboratory investigator.
Research blood samples will be sent either to the Clinical Services Program – Leidos 
Biomedical Research, Inc. (CSP) (Section 5.2.1) or the Blood Processing Core (BPC) (Section 
5.2.2) for barcoding, initial processing and storage. Tissue will be sent to the Laboratory of 
Pathology as described in Section 5.2.3. Additional tissue for research may also be stored in 
CSP (Section 5.2.1). From these facilities, coded, linked samples will be sent to the designated 
labs for analysis upon request.
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 the Study Calendar. The 
following immune assays may be performed at the Laboratory of Tumor Immunology and Biology 
(LTIB) 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 

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[MDSCs], and dendritic cells) as well as 123 immune cell subsets, using multi-color flow 
cytometry.
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 HPV 16 E6 and E7 and 
HPV18 E6 and E7; 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 the Study Calendar. 
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).
5.1.3
AVA
Anti-vector antibodies (AVA) are one mechanism of neutralization and inefficacy of viral vectors. 
Longitudinal detection and titer measurement of AVA to the vaccine adenoviral vector will assist 
in characterizing cases of loss of efficacy.
5.1.4
M7824 Pharmacokinetics
PK measurements of M7824 will be taken in Arm 1B only to collect data which will provide 
insight into population PKs of M7824 in participants receiving these novel combinations.
The schedule is in the Study Calendar. Serum M7824 PK measurements will be done at EMD 
Serono.
5.1.5
ADA
Anti-Drug Antibody (ADA) development is an accepted mechanism of loss of efficacy of 
administered human monoclonal antibodies. Measuring titers will ensure that lack of efficacy of 
M7824 is not due to ADA development.
The schedule is in the Study Calendar – samples will be collected in Arm 1B only. The 
investigation will be done by EMD Serono using ELISA. 

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5.1.6
Tumor Tissue Analyses for Immune Markers
Analyses may be performed in pre-treatment vs. post-treatment (at Week 4-5 for phase II 
participants) tumor tissue. Where available, archival tumor samples may be requested for pre-
treatment analysis (preferably tissue samples from the last 6 months). For participants with lesions 
amenable to biopsy, two biopsies may be performed at baseline and at Week 4-5 (phase II 
participants) or Week 9 (phase I participants). 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 5.2.1. 
Where available, 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 Laboratory.
5.1.7
Single-cell proteomic analysis
Where available, tumor tissue single-cell proteomic analysis of immune and signaling pathways 
may be performed with the Isoplexis Single Cell Functional proteomic platform by Precigen. 
5.1.8
Immune transcriptomic analysis
Where available, tumor tissue immune transcriptomic analysis may be performed with the 
Nanostring platform by Precigen.
5.1.9
Additional Biomarker Studies
De-identified, coded blood (PBMC, plasma, and/or serum) or tissue samples may be sent to 
Precigen Inc., the manufacturer of PRGN-2009, to further investigate HPV 16/18 -specific immune 
responses, activation status of the immune system (e.g., leukocyte subsets, exhaustion, cytokines 
profile), antigen cascade, anti-tumor specific immune responses induced by the exposure to 
PRGN-2009, and potential predictive/prognostic biomarker candidates related to the drug and/or 
cancer (e.g., specificity of tumor infiltrating cells), and results of these analyses will be shared with 
the NCI. These analyses are exploratory and dependent on the quality and availability of sufficient 
materials. The panel of biomarkers might be adjusted based on results from ongoing research; 
therefore, any remaining samples can be stored at Precigen and can be used for future exploratory 
research on the drug and/or disease-related aspects. Only remaining samples will be used to this 
purpose, no additional samples will be collected. 
5.1.10 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. Norberg’s Team.
5.1.11 Circulating tumor DNA 
If sufficient plasma is available, select participant samples may be analyzed for circulating tumor 
DNA (LTIB and NCI Frederick Genomic Core Facility). Plasma DNA will be isolated with an 
automated purification system. 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.

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5.1.12 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 
(LTIB and NCI Frederick Genomic Core Facility).
NCI Fredrick Genomic Core Facility:
Leidos Biomedical Research, Inc:
ATRF, Rm C3016
8560 Progress Drive
Frederick, MD 21701
Ph. 301-846-7677
5.1.13 Salivary HPV DNA
Participants in Phase 2 Cohort 2 with p16-positive oropharyngeal cancer will have collection of 
saliva by mouth rinse and gargle with 15-20 mL 0.9% NaCl for 30 seconds and spitting into the 
collection tube (timepoints per Study Calendar). Where possible, saliva samples will be analyzed 
for HPV DNA detection and quantification (LTIB and NCI Frederick Genomic Core Facility). 
Salivary HPV DNA will be quantified with digital droplet PCR; no sequencing is involved. 
5.2
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) without appropriate approvals 
and/or agreements, if required.
5.2.1
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 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 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 patient-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.
5.2.2
Samples Managed by Dr. Figg’s Blood Processing Core (BPC) 
5.2.2.1
BPC contact information 
Please email NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).

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For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.
5.2.2.2
Sample Data Collection
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the Labmatrix utilized by the BPC. This is a secure program, with access to Labmatrix 
limited to defined Figg lab personnel, who are issued individual user accounts. Installation of 
Labmatrix is limited to computers specified by Dr. Figg. These computers all have a password 
restricted login screen. All Figg lab personnel with access to participant information are required 
to complete the Human Subjects Research course. 
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to participants without Labmatrix access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Participant demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.).
5.2.2.3
Sample Storage 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80C 
according to stability requirements. These freezers are located onsite in the BPC and offsite at NCI 
Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are required to 
be accompanied by laboratory staff at all times. 
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused samples 
must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that 
the samples requested are being used in a manner consistent with IRB approval.
5.2.3
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 
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.
5.2.4
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 

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subjects will be stored until they are no longer of scientific value. If, at any time, a participant 
withdraws from the study and does not wish for their existing samples to be utilized, the individual 
must provide a written request. Following receipt of this request, the samples will be destroyed (or 
returned to the participant, if so requested). The PI will report any loss or unanticipated destruction 
of samples per Section 7.2.1. If the participants 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.
Sample barcodes are linked to participant demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to participant information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables.
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 treatment, study day 1, through 28 days after the subject received the last 
product administration. After 28 days, only adverse events which are serious and related to the 
study investigational agent need to be recorded. For participants enrolled on the phase II portion 
of the protocol adverse events which occur while participant is being treated with standard 
chemoradiation and which are not attributed to immunotherapy need not be captured. 
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; and/or

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. 

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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 
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 

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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.
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 

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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 
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.

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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.
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 (51). 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).
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). 

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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 (52).
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).
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 
participant to be considered in complete clinical response.

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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 >6 
wks. from baseline**
PD
Any
Yes or 
No
PD
Any
PD***
Yes or 
No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

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Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
*
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.
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).
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.
6.3.6
Immune Response Evaluation
6.3.6.1 Tumor Biopsies: Biopsies obtained will be stained for multiple immune cell markers 
(CD4, CD8, CD3, PD-1, PD-L1) as well as tumor cell markers (pancytokeratin) using an 
automated multiplex immunofluorescence (MxIF) staining protocol (Opal™ method). This 
method explained below uses tissue sparingly and ensures simultaneous staining of different 
markers in the same tissue plain. An average of 5 consecutive biopsy recuts (4-5-micron thick 
formalin fixed paraffin embedded tissue sections (FFPE) mounted on 25 x 75mm, charged glass 
slides) or unstained slides (US) per each biopsy time point is needed for this analysis. 
Hematoxylin and Eosin (H&E) staining (done on last or deepest recut level) will be examined by 
a research pathologist (GMB TIME Laboratory), for presence of tumor and tissue integrity.
6.3.6.2 Staining Protocol: Formalin-fixed paraffin-embedded (FFPE) tumor sections (US) will be 
immuno-stained using Opal Multiplex Automation IHC Detection Kits on the BOND RX from 
Leica Biosystems' BOND RX. First, sections will be subjected to deparaffinization and antigen 
retrieval (HIER). Subsequent Opal staining of each antigen occurs as follows: slides will be 

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blocked with blocking buffer (Akoya/Leica) for 10 min then incubated with primary antibodies 
at optimized concentrations (GMB TIME Laboratory) followed by Opal HRP polymer (or 
secondary antibody) and one of the Opal fluorophores. Individual antibody complexes will be 
stripped after each round of antigen detection. After the final stripping step, DAPI (4',6-
diamidino-2- phenylindole) counterstain will be applied and slides will be removed from the 
BOND RX for cover slipping.
The Opal method is based on PerkinElmer’s TSA® (Tyramide Signal Amplification) Plus 
reagents and offers many advantages compared to conventional indirect 
immunofluorescence labeling, including brighter signals for faster scanning, balanced 
signals for higher level multiplexing, signals that do not photobleach, and freedom from 
species-based interference. The Opal method is explained in more details in the attachment 
(Opal_Assay_Development_Guide_Aug2017).
6.3.6.3 Digital Imaging Protocol: Once all antigens of interest are stained, a multiplex scanning 
protocol will be created on Vectra Polaris scanner (Akoya/Perkinelmer), to allow for whole slide 
imaging at 10-20X. This is followed by higher resolution scan of regions of interest (ROIs) 
picked (5 on average) or whole slide analysis (if feasible) by research pathologist (GMB TIME 
Laboratory). The scans generated at high resolution are called multispectral images (MSIs) and 
are available in .im3 format. These can only be analyzed using inform software (available in 
GMB TIME Laboratory). The software allows for spectral unmixing based on a spectral library 
(built based on single reference stains) and artificial intelligence based unmixing algorithm. 
Individual ROIs will be segmented based on nuclear counterstain DAPI, and cells will be 
counted based on expression of various markers (CD3, CD4, CD8) in a binary fashion allowing 
for objective measurements of density, absolute counts, and percentages of each cell type. 
Averages of representative ROIs or whole areas of interest (if feasible) for each time point will 
be generated for statistical analysis.
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
participant 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: 

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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 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.
7.3
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.
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.
7.4
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA
7.4.1
Serious Adverse Event Reports to IBC
The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life-threatening 
experience associated with the use of PRGN-2009 as soon as possible but in no event later than 7 
calendar days of initial receipt of the information. Serious adverse events that are unexpected and 
associated with the use of the PRGN-2009, but are not fatal or life-threatening, must be reported 
to the NIH IBC as soon as possible, but not later than 15 calendar days after the investigator’s 
initial receipt of the information. Adverse events may be reported by using the FDA Form 3500a.
7.4.2
Annual Reports to IBC
Within 60 days after the one-year anniversary of the date on which the IBC approved the initial 
protocol, and after each subsequent anniversary until the trial is completed, the Principal 
Investigator (or delegate) shall submit the information described below. Alternatively, the IRB 
continuing review report can be sent to the IBC in lieu of a separate report. Please include the IBC 
protocol number on the report.
7.4.3
Clinical Trial Information 
A brief summary of the status of the trial in progress or completed during the previous year. The 
summary is required to include the following information: 

the title and purpose of the trial; 

clinical site;

the Principal Investigator;

clinical protocol identifiers; 

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
participant population (such as disease indication and general age group, e.g., adult or 
pediatric); 

the total number of participants planned for inclusion in the trial; the number entered into 
the trial to date whose participation in the trial was completed; and the number who 
dropped out of the trial with a brief description of the reasons; 

the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, 
or fully completed; and 

if the trial has been completed, a brief description of any study results. 
7.4.4
Progress Report and Data Analysis 
Information obtained during the previous year's clinical and non-clinical investigations, 
including: 

a narrative or tabular summary showing the most frequent and most serious adverse 
experiences by body system;

a summary of all serious adverse events submitted during the past year;

a summary of serious adverse events that were expected or considered to have causes not 
associated with the use of the gene transfer product such as disease progression or 
concurrent medications;

if any deaths have occurred, the number of participants who died during participation in 
the investigation and causes of death; and

a brief description of any information obtained that is pertinent to an understanding of the 
gene transfer product’s actions, including, for example, information about dose-response, 
information from controlled trials, and information about bioavailability. 
7.5
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.5.1
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 
7.2.1 will be submitted within the appropriate timelines. 
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 
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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
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 8.1.3);

Inpatient hospitalization or prolongation of existing hospitalization;
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 participant 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.
8.1.3
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).
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0.

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8.1.5
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.
8.1.6
Adverse Events of Special Interest (AESI)
Adverse events of special interest (AESIs) are serious or nonserious AEs that are of clinical 
interest and should be closely followed.
AESIs include following:

Infusion-related reactions including immediate hypersensitivity.

Immune-related adverse events.

TGFβ inhibition mediated skin reactions.

Anemia.

Bleeding AEs.
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 from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in Section 8.4. 

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8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets a protocol-defined serious criterion 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.
Hospitalizations related to adverse events attributed to disease progression will not need to be 
reported expeditiously as these events will be captured as a separate study endpoint.
All SAE reporting must include the elements described in Section 8.1.6.
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://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions 
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.
In addition, the Sponsor is responsible for reporting adverse events to the FDA in compliance with 
21 CFR 312.32. The Sponsor must report all serious, unexpected and related or possibly related 
adverse events within 15 calendar days after the study team receives knowledge of the event, and 
all life-threatening and/or fatal unexpected events related or possibly related to the use of the 
investigational agent within 7 calendar days after the study team receives knowledge of the event. 
8.4
WAIVER OF EXPEDITED REPORTING TO CCR  
As death/hospitalization due to disease progression is/are part of the study objectives, and captured 
as an endpoint in this study, they 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
As M7824 is known to result in immune related toxicities as well as an increased risk of mucosal 
bleeding as documented in the informed consent and protocol and shared with the FDA, only those 
SAEs that are unexpected will be reported to the Sponsor in an expedited manner.
The PI will submit a summary table of all grade 3-5 events, whether or not considered related to 
the product, every 6 months. The report shall include the number of participants treated in the 
timeframe, the number of events per AE term per grade which occurred in the 6-month timeframe 
and in total since the start of the study, attribution, and type/category of serious. 
Reports will be submitted to the Center for Cancer Research (CCR) at OSROSafety@mail.nih.gov.
The Sponsor might request case summaries for those events if, upon review, the Sponsor 
determines that an aggregate safety report is required (21CFR312.32(c)(1)(iv)).
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 

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can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
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 no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy becomes known.
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (Section 8.1.2) should be reported as SAEs. 
The outcome of all pregnancies should be followed up and documented.
8.6.2
Paternal Exposure
Male participants should refrain from fathering a child or donating sperm during the study and for 
two 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. 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 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 

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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.
9
CLINICAL MONITORING
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 

that 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 before the study starts is 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 take place at the study 
site(s). Monitoring visit reports will describe visit activities, observations, findings of protocol 
non-adherence and associated action items or follow-up required for resolution of findings.  
Monitoring reports will be distributed to the study PI, NCI CCR QA, 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. 
10 STATISTICAL CONSIDERATIONS
10.1 STATISTICAL HYPOTHESIS
10.1.1 Primary Endpoints
10.1.1.1 Phase I:
The primary endpoint of the phase I portion of the study is to determine the recommended phase 
II dose (RP2D) of PRGN-2009 (HPV vaccine) alone and in combination with M7824. 

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10.1.1.2 Phase II:
The primary endpoint of the phase II portion of the study is to determine if HPV vaccine alone 
(Arm 2A) is able to result in a  2-fold increase in CD3+ tumor infiltrating T cells post treatment 
compared with pre-treatment in participants with p16+ oropharyngeal cancer. 
10.1.2 Secondary Endpoints
10.1.2.1 Phase I:
The secondary endpoint of the phase I portion of the study are to determine overall response rate 
(ORR), progression-free survival time (PFS), overall survival (OS), ratio of participants that are 
hospitalized because of adverse events attributed to disease progression, and duration of response 
of the combination therapy in participants with advanced disease. 
10.1.2.2 Phase II:
The secondary endpoints of the phase II portion of the study are:

To determine if the use of HPV vaccine alone results in potentially prolonged survival as 
compared to the expected 80% three-year historical survival for this population. 

To determine the 3-year overall and relapse-free survival rate for HPV vaccine alone (Arm 
2A) in combination with standard of care chemoradiation in participants with p16+ 
oropharyngeal cancer. 
10.1.3 Exploratory Endpoints
The exploratory endpoints of the Phase II portion of the study are: 

To determine if the use of HPV vaccine alone results in potentially prolonged survival 
as compared to the expected 80% three-year historical survival for this population. 

To determine the 3-year overall and relapse-free survival rate for HPV vaccine alone 
(Arm 2A) in combination with standard of care chemoradiation in HPV-SNSCC 
participants. 
10.2 SAMPLE SIZE DETERMINATION
The phase I portion of the trial will be conducted using 3+3 dose escalation design evaluating the 
safety of PRGN-2009 at two dose levels as monotherapy and at the RP2D of PRGN-2009 in 
combination with a fixed dose of M7824. Using this design up to 22 participants may be enrolled 
on the phase I portion of the study. 
In arm 2A, phase II, 20 participants with p16+ oropharyngeal cancer will be enrolled based on the 
following reasoning. Assume that a success for any individual participant will be defined as that 
participant experiencing a two-fold increase in CD3+ tumor infiltrating T cells post treatment 
compared with pre-treatment. With 20 participants, there would be 80.4% power to detect a 
difference between 50% and 80% of participants experiencing a success in arm 2A, with an exact 
binomial test using a one-sided 0.05 significance level. As an illustration, with 20 participants, if 
15 participants were able to have a two-fold increase, the lower two-sided 90% confidence bound 
on 15/20 is 54.4% and the upper two-sided 90% confidence bound is 89.6%. Thus, 15/20 
participants would demonstrate the intended magnitude of effect. If 14/20 had this outcome, the 
lower 90% two-sided bound is 49.2% and the upper two-sided 90% bound is 86.0%, essentially 
demonstrating nearly the same result.

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Expecting that up to 22 evaluable participants will enroll on the phase I portion of the study, that 
20 evaluable p16+ oropharyngeal cancer participants will enroll on phase II 2A, and that up to 2 
evaluable HPV-SNSCC participants may enroll on phase II 2A, a total of up to 44 evaluable 
participants will be planned to enroll on this protocol. To allow for a few inevaluable participants 
the accrual ceiling for this protocol will be set at 50 participants. 
10.3 POPULATIONS FOR ANALYSES
All participants who receive any investigational treatment will be evaluable for safety and toxicity 
evaluations. 
For phase II, only HPV-OPC participants will be evaluable for primary and secondary objective 
endpoints. HPV-SNSCC participants will be evaluable only for exploratory objectives. 
For phase II, participants who receive at least two doses of therapy and have an adequate 
pretreatment and posttreatment biopsy will be evaluable for immune infiltration assessments. For 
phase II, participants who receive at least two doses of immunotherapy and go on to receive 
standard definitive therapy will be evaluable for relapse free survival and overall survival 
assessments. 
For phase I and II participants, 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
The phase I portion of the study will be conducted as a safety assessment using a 3+3 dose 
escalation design. In addition, Arm 1B will be expanded to a total of 10 evaluable participants to 
gauge the preliminary efficacy of the combination of PRGN-2009 and M7824 in participants with 
advanced disease. The phase II portion of the study will be conducted to evaluate for a potentially 
significant increase in CD3+ tumor infiltrating lymphocytes with immunotherapy induction.  
10.4.2 Analysis of the Primary Endpoints
Regarding the phase I portion of the study, participants will be evaluated with respect to the grades 
and types of toxicities obtained. The results will be presented descriptively and tabled if 
appropriate. Regarding the phase II portion of the study the rate of doubling of baseline CD3+ 
tumor infiltrating lymphocytes will be provided as well as the 95% confidence interval. 
10.4.3 Analysis of the Secondary Endpoints
For the phase I portion of the study data will be obtained on ORR, duration of response, PFS, OS, 
and ratio of participants that are hospitalized because of adverse events attributed to disease 
progression.
10.4.4 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.

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10.4.4.1 Progression-Free Survival and Relapse-Free survival 
PFS and RFS 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. RFS will be defined as the time from completion of standard chemoradiation to the date of 
disease recurrence or death (any cause) whichever occurs first. Subjects who do not have disease 
progression, disease recurrence or have not died at the end of follow up will be censored at the last 
known date the subject was progression or relapse free.
10.4.4.2 Objective Response
Objective response is a complete or partial radiographic response as defined by RECIST 1.1 
(Section 6.3.5).
10.4.4.3 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.
10.4.5 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.
10.4.6 Baseline Descriptive Statistics
Baseline Characteristics will be described. 
10.4.7 Planned Interim Analyses
Interim assessment of safety will be made based on DLT assessments according to the 3+3 dose 
escalation design in the phase I portion of the study and the first six participants enrolled on the 
phase II portion of the study. 
10.4.8 Tabulation of Individual Participant Data
Individual responses in a cohort may be depicted within a larger group using a waterfall plot or 
spider diagram. 
10.4.9 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 

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magnitude of immune responses will be described. A subject will be considered evaluable for 
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 
(53).  
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 (03209) is in place with Precigen for the supply of PRGN-2009.
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, participants with poorly controlled HIV as 
well as patents with detectable viral loads of hepatitis B and C will be excluded. 
Patients 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. 
In addition, these patients could compromise the scientific validity of the study. For example, 
death from blood loss could make it difficult to assess other aspects of the investigational 
immunotherapy’s safety—a primary scientific goal in this early-phase immunotherapy trial, 
which are carried out in small numbers of participants. 
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 give consent are excluded from enrolling in the protocol. However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (Section 12.4.2), all subjects ≥ age 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.

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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 RISK/BENEFIT ASSESSMENT
12.4.1 Known Potential 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 Risks Associated with Study Drugs
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 Institutes of Health, 
Bethesda, Maryland.
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 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.
12.4.1.3 Risks of Exposure to Ionizing Radiation 
12.4.1.3.1 Phase I
This research study involves the possibility of 8 CT CAP scans, 2 brain CT scan, and 2 CT guided 
biopsies collected for research purposes for Phase I participants. 
The amount of radiation exposure is equal to approximately 10.6 rem. This level of exposure 
results in an increased risk of cancer.
12.4.1.3.2 Phase II
This research study involves the possibility of 3 CT neck and chest scans for research purposes for 
Phase II participants with oropharyngeal cancer and 3 CT neck, chest, and skull scans for research 
purposes for Phase II participants with SNSCC.

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The amount of radiation exposure is equal to approximately 0.99 rem and 1.29 rem for Phase II 
participants with oropharyngeal cancer and SNSCC, respectively. This level of exposure could 
result in an increased risk of cancer.
12.4.1.4 CT Scan Risk 
CT scans create low levels of radiation, which has a small potential to cause cancer and other 
defects. However, the risk associated with scan is small. 
12.4.1.5 Risks Due to Contrast Agents for CT 
Contrast agents can cause allergic reactions and kidney damage. Allergic reactions can include 
mild itching associated with hives but can also result in a serious life-threatening emergency from 
difficulty breathing. If this occurs, it is treatable. 
12.4.1.6 Risk of MRI
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body. 
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the scanner 
is loud enough to damage hearing, especially in people who already have hearing loss. 
There are no known long-term risks of MRI scans.
12.4.1.7 Risk of Gadolinium Enhanced MRI
The gadolinium infusion may cause mild symptoms such as coldness in the arm during the 
injection, a metallic taste, headache, and nausea. There are risks of an IV catheter include bleeding, 
infection, or inflammation of the skin and vein with pain and swelling.  
Procedure-related risks from MRI and gadolinium enhanced MRI will be explained fully during 
informed consent.
12.4.1.8 Risks of Clinical Endoscopy and Nasopharyngo-laryngoscopy
In this procedure, a physician gently places a small, thin, flexible endoscope with a camera through 
participant’s nose to view their upper airway anatomy above the vocal cords. This procedure takes 
only a few minutes, is painless and does not require any sedation. It is a normal part of an ENT 
exam. Risks of clinic endoscopy include epistaxis or vasovagal syncope, each of which occur in 
<1% of all participants. 
If participant’s tumors are not accessible in the clinic or a biopsy in the clinic is deemed unsafe by 
the study doctor, biopsies may be performed in the operating room under general anesthesia. Side 
effects of general anesthesia may include temporary confusion, difficulty passing urine, bruising 
or soreness from the IV drip, nausea and vomiting, shivering and feeling cold, and sore throat. 
Risks of operative biopsies include post-op bleeding (<1% of all participants), dental damage from 
laryngoscopy 
instrumentation 
(<1% 
of 
all 
participants) 
and 
temporary 
tongue 
paresthesia/dysgeusia (<10% of all participants) that resolves within a few days. 
12.4.1.9 Risk from Saliva Collection
Saliva collection is not known to be associated with risk. There may be some discomfort from 
the oral rinse and gargle with saline. 

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12.4.1.10
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. 
12.4.1.11
Risks of Delaying Potentially Curative Treatment 
Side effects of this investigational treatment may cause delay in scheduled curative therapy. A 
prior study has shown that people with oropharyngeal cancer who received treatment more than 
10 weeks after their initial diagnosis did significantly worse than those who received treatment 
sooner.
12.4.1.12
Other Risks
Risks include the possible occurrence of any of a range of side effects which are listed in the 
Consent Document and this protocol document. Frequent monitoring for adverse effects will help 
to minimize the risks associated with administration of the study agents.
12.4.2 Known Potential Benefits
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 favorable impact on symptoms and/or survival.
12.4.3 Assessment of Potential Risks and Benefits
Locally advanced, metastatic or refractory/recurrent HPV associated malignancies (cervical, anal, 
oropharyngeal cancers, etc.) need improved therapy options. Preclinical studies suggest that the 
use of a combination of multiple immunotherapy agents may improve anti-tumor efficacy. 
Therefore, PRGN-2009 alone or in combination with M7824 may improve clinical outcome of 
participants with HPV associated malignancies. A number of clinically appropriate strategies to 
minimize risk to participants have been built into the protocol through the means of 
inclusion/exclusion criteria, monitoring strategies, and management guidelines. Overall, the 
potential benefits of PRGN-2009 alone or in combination with M7824 for this group of 
participants outweigh the risks associated with the proposed entry into this protocol with PRGN-
2009 alone or in combination with M7824.
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) 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 
local 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 

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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 as described below. 
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 in 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://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
As there is an optional biopsy for research in this protocol, the participant/consent designee will 
be asked to sign a separate consent at the time of the procedure. If the participant/consent designee 
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 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. 
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, funding agency, the Investigational New Drug (IND) sponsor and regulatory 
authorities. If the study is 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:

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
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
The 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 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 on 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 NCI 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 
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.

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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 sites 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
14.1 PRGN-2009 (IND #19628)
14.1.1 Source / Acquisition and Accountability
PRGN-2009 will be provided by Precigen through a CRADA with NCI to Pharmacy. All study 
interventions will be given at NIH Clinical Center and documented in the electronic medical 
record. 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.
14.1.2 Toxicity 
PRGN-2009 has not been tested in humans. PRGN-2009 antigen was successfully evaluated in 
three different types of in vitro analyses designed to identify potential oncogenicity of novel DNA 
in mammalian cells. The HPV PRGN-2009 antigen did not induce an oncogenic profile in the host 
cells in any assay, whereas cells transformed with wild type HPV oncogene versions 
unambiguously displayed morphological and phenotypic changes consistent with oncogenesis, 
both qualitatively and quantitatively. This data provides confidence that the HPV PRGN-2009 

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molecular vaccine candidate is safe for use in mammalian cells and will not induce aberrant growth 
consistent with carcinogenesis. 
PRGN-2009 is a non-replicating, non-integrating adenoviral vector.  Since the parental adenovirus 
is classified as biosafety level 2 (BSL2), PRGN-2009 should be handled as BSL2 material for 
disposal of all materials that were used in the dose preparation.  Avoid generation of aerosols.  
Spills of PRGN-2009 should be decontaminated using a solution of 10% bleach. 
This is a first in human study with PRGN-2009. Possible side effects may include injection side 
reaction, fever, flu like symptoms (e.g., fatigue, headache, muscle aches), poor appetite, increase 
in blood sugar, and skin rash. 
Table 8: Summary of Treatment-Emergent Adverse Events in Phase 1/2 Study in Patients 
with HPV+ Malignancies (NCT04432597) (Reference: Table 7 in PRGN-2009 IB 
Version 3)

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Table 9: Adverse Events Related to PRGN-2009 Treatment by System-Organ Class in Phase 
1/2 Study in Patients with HPV+ Malignancies (NCT04432597) (Reference: Table 8 
in PRGN-2009 IB Version 3)

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14.1.3 Formulation and Preparation 
o
Precigen will provide the following materials:
o
The concentration of the PRGN-2009 in supplied vials is 5 x 10E11 PU/ml;
o
PRGN-2009 vials (manufactured by ABL) – 1.0 ml/vial (extractable 
volume; frozen);

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o
Final formulation buffer (FFB) Diluent vials (manufactured by ABL) – 4.0 
ml/vial (frozen); and 
o
Sterile empty glass vials (manufactured by ALK) for preparing dilutions (if 
required).
14.1.3.1 Stability and Storage 
PRGN-2009 (manufactured by ABL) is provided as a sterile, frozen, injectable liquid that has been 
aseptically filled into crystal zenith (CZ) vials fitted with a butyl rubber stopper and an aluminum 
flip-cap seal. PRGN-2009 must be stored in an ultracold freezer in the temperature range of -60 to 
-90°C. Each vial contains 1.0 ml (extractable volume) of PRGN-2009 at a target concentration of 
5 x 1011 PU/ml. Therefore, each vial contains approximately 5 x 1011 PU.  
14.1.3.2 Diluent
Final formulation buffer (FFB; manufactured by ABL) will be used as the diluent for PRGN-2009 
and will be supplied by Precigen. Diluent is provided as a sterile, frozen, injectable liquid that has 
been aseptically filled into crystal zenith (CZ) vials fitted with a butyl rubber stopper and an 
aluminum flip-cap seal. Each vial contains 4.0 ml (extractable volume) of PRGN-2009. NOTE: no 
other diluents other than FFB should be used with PRGN-2009.
Two different doses of PRGN-2009 will be evaluated during the phase I dose escalation phase of 
the trial:

Initial dose: 1 x 1011 PU – A single vial of PRGN-2009 and a single vial of Diluent will be 
used for dilution and administration of the initial dose of 1 x 1011 PU. See instructions 
below for preparation of the initial dose.

Maximum dose: 5 x 1011 PU – A single vial will be used for administration of the maximum 
dose of 5 x 1011 PU. No pooling of vials will be required. A Diluent vial will not be needed 
for the 5 x 1011 PU dose.
14.1.4 Pharmacy Preparation 
Follow institutional procedures for handling of a BSL-2 organism. Since the PRGN-2009, is 
provided with a butyl rubber stopper with aluminum flip-tear seal, these materials do not required 
handling within a biological safety cabinet. Care should be taken to avoid creation of aerosols 
during syringe withdrawals through the butyl rubber stopper. If institutional policies dictate, the 
steps involving a syringe transfer should be conducted within a biological safety cabinet.  Spills 
of PRGN-2009 should be decontaminated using a solution of 10% bleach.  All materials should 
be disposed of according to institutional procedures for a BSL-2 organism.  
14.1.5 Vaccine Preparation
Thawing – For each subject, a single vial of PRGN-2009 should be removed from the ultracold 
freezer and rapidly thawed in a 37C water bath until the contents are just thawed (avoid prolonged 
exposure of the thawed vial to the 37C water bath). Once thawed, do not refreeze.  After thawing, 
vials should be wiped down with 70% IPA. Thawed vials of PRGN-2009 can be stored for up to 
2 hours at ambient temperature prior to administration. Do not store thawed vials on wet ice or in 
contact with a cold pack or inside a refrigerator.  

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Dilution of PRGN-2009 and storage of the diluted product at ambient temperature is addressed in 
the pharmacy manual, which should be referenced if dilution is required.
Visually inspect the vialed products before use. If the appearance does not match the appearance 
listed below, contact the manufacturer (Precigen) and quarantine the vial(s) until further guidance 
is provided. Do not use the product if they appear to be damaged in any way.
o
PRGN-2009 should appear to be a clear to slightly opalescent, colorless liquid and 
should be free of visible particulates.
o
FFB should appear to be a clear, colorless liquid and should be free of visible 
particulates.
Two different doses of PRGN-2009 will be evaluated during the dose escalation phase of the trial: 

Preparation of the 1 x 1011 PU dose - A single vial of PRGN-2009 will be thawed and 
diluted 1:5 using the Diluent provided by Precigen, prior to administration to a subject as 
follows. After thawing, 0.4 ml of PRGN-2009 should be aseptically withdrawn from the 
vial and transferred into an empty sterile glass vial (provided by Precigen) using an 
appropriately sized sterile syringe. It is permissible to push air into the vial before 
withdrawing the specified volumes, as long as aerosols are not created. Next, 1.6 ml of 
thawed Diluent will be aseptically withdrawn from the Diluent vial using an appropriately 
sized sterile syringe and this volume will be transferred into the glass vial into which the 
0.4 ml of PRGN-2009 has been transferred in the previous step. The contents should be 
gently swirled to thoroughly mix (do not vigorously shake). A volume of 1.0 ml of the 
diluted PRGN-2009 will then be aseptically withdrawn using an appropriately sized sterile 
syringe and administered for the initial dose of 1 x 1011 PU. The remaining contents of the 
PRGN-2009 vial, the remaining contents of the Diluent vial, the glass dilution vial, and 
used syringes should be discarded as biohazardous waste. The syringe containing PRGN-
2009 can be stored at ambient temperature after preparation. The total time for exposure of 
PRGN-2009 to ambient temperature after thawing the vial is 2 hours, including dilution, 
syringe filling and administration. Do not store prepared PRGN-2009 syringe on wet ice 
or in a refrigerator.  Also, do not share vials of PRGN-2009 or Diluent between subjects.

Preparation of the 5 x 1011 PU dose - The top dose of 5 x 1011 PU will be obtained by 
aseptically withdrawing 1.0 ml of PRGN-2009 from a single thawed vial using an 
appropriately sized sterile syringe. One ml of the undiluted PRGN-2009 will be 
administered for the top dose of 5 x 1011 PU. The empty PRGN-2009 vial should be 
discarded as biohazardous waste. The total time for exposure of PRGN-2009 to ambient 
temperature after thawing the vial is 2 hours, including syringe filling and administration.  
Do not store on wet ice or in a refrigerator.
14.1.6 Stability and Storage 
PRGN-2009 and Diluent are provided in cardboard cartons containing 10 vials of frozen 
liquid. Each 10-pack carton is provided within a sealed, labeled Mylar pouch. The sealed pouch is 
shipped inside a cardboard box that contains dry ice so that the contents will remain frozen during 

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shipment. This Mylar pouch protects the vials from direct exposure to dry ice vapors.  PRGN-2009 
and Diluent will be shipped to the clinical site from SriSai Biopharmaceutical Solutions, Frederick, 
MD.  

After receipt, the package should be opened and the contents inspected to confirm 
that a quantity of dry ice remains and that the Mylar pouch is intact. (Report to 
Precigen any issues observed when receiving and opening a package). The Mylar-
enclosed carton of 10 vials should be immediately transferred to an ultracold freezer 
and stored in the range of -60 to -90C. This freezer should be appropriately 
monitored for temperature excursions. Any excursions that occur outside the 
recommended storage temperature range for PRGN-2009 should be documented 
and reported to the Sponsor.
The carton can remain within the Mylar pouch until a vial of PRGN-2009 is required for 
administration to a subject. After the Mylar pouch is opened, the carton should be quickly returned 
to the ultracold freezer to avoid exposure of PRGN-2009 to ambient temperature. After the pouch 
is opened it can be disposed of and the cardboard carton can be stored directly within the ultracold 
freezer. Do not expose unprotected vials (without Mylar pouch) directly to dry ice vapors after 
opening and removing the pouch.
14.1.7 Incompatibilities
Not available. 
14.2 M7824 (IND #19628 )
14.2.1 Source / Acquisition and Accountability 
M7824 is manufactured and supplied for the trial by EMD Serono Research and Development 
Institute to Pharmacy. All study interventions will be given at NIH Clinical Center and documented 
in the electronic medical record. 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.

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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.
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.

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***The differential for this dyspnea was pneumonitis vs. lymphangitic spread of disease (disease 
progression).
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 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 directly. 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. 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).
Potential risks include anemia, alterations in wound, healing or repair of tissue damage, and 
embryofetal toxicity. 
In addition, at least 2 instances of nodular regenerative hyperplasia have been observed with the 
use of this agent.
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 LHistidine 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 
intended to be stored unless dilution has taken place in controlled and validated aseptic conditions. 

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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 3.2.2. 
14.2.6 Incompatibilities
Not available. 

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16  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.