untitled h1
untitled h2

!""\#"
$
%&''()
*+",
./012
(3
'%
4
56
7&8'9%% :
;;
82
0<  
=>1?/
@/:  
A0/B
4
!,\#C
,+D"
E>>
=/2>3
F G102/02H
0<
8>I02
;II>00H
B
J00H
KG8;JL &/2
<02
&2
M2:
K&&ML 7/0
&2
;//>/
K7&;L %'
&/2
F2N J>B
%'3
M00I
%97'A
J/:B3
F
'O :0P
9'%Q'Q'' RIP
?>>S/2>T:S0N
,+D",
D,+  
| F2> 7IP   |  K=J''%%9(O&L   |    |
|---|---|----|
| ;7F 7>I12P   | %9)(   |    |
| =U002P   | &/2 <02 &2 M2:3 7&;   |    |
| ></>22P   | RF =2003 ;S   |    |
| =>UU2   | R | =2003 ;S    |  
4"66\#
D,+
",
untitled h1
precis background

Metastatic or refractory/recurrent HPV associated malignancies (cervical, anal,
.  
oropharyngeal cancers etc.) are often incurable and poorly palliated by standard therapies.  
TGF BR1 pathway signaling and overexpression are significantly associated with HPV+
.  
cancers.  
PD-1 inhibitors have produced a 12-20% response rate for these diseases.  
.  
M7824 is a novel bifunctional fusion protein composed of monoclonal antibodies against
.  
human PD-L1 and soluble extracellular domain of human TGF-β receptor II (TGF-βRII),
which functions as a TGF-β "trap."
.  
Early data from a small cohort of patients with HPV associated malignancies in a phase I
trial of M7824 has shown promising activity (NCT02517398). As of May 30, 2017, 4 of 9 patients (44%) with HPV associated malignancies have had preliminary evidence of clinical benefit including:
o Patient with metastatic cervical cancer with a 25% reduction in her disease at 3 months o Patient with metastatic P16+ head and neck cancer with an unconfirmed partial response (PR) at 6 weeks o  
Patient with metastatic anal cancer with a durable PR ongoing 9 months after
starting treatment o Patient with metastatic cervical cancer with a durable complete response (CR)
ongoing 15 months after starting treatment.  
o Notably, the P16+ head and neck cancer patient with unconfirmed PR, anal cancer patient with durable PR and cervical cancer patient with durable CR all have HV+ disease.  
.  
Immune related adverse events with M7824 in the phase I trial to date have been on par with other PD-1/PD-L1 inhibitors, suggesting a manageable safety profile.  
.  
EMD Serono has an ongoing expansion cohort evaluating M7824 in patients with  
HNSCC as well as in cervical cancer excluding neuroendocrine cervical cancer.
untitled h1
objective

.  
To determine the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) in subjects with recurrent or metastatic HPV
associated malignancies.
untitled h1
eligibility

.  
Age > 18 years old
.  
Subjects with cytologically or histologically confirmed locally advanced or metastatic HV associated malignancies including:
o Non-Neuroendocrine Cervical cancers o P16+ Oropharyngeal cancers o Anal cancers o Vulvar, vaginal, penile, squamous cell rectal and neuroendocrine cervical cancers o Other locally advanced or metastatic solid tumors (e.g. lung, esophagus) that are known HPV+
.  
Subjects must have measurable disease.
untitled h1
design

.  
This is a Phase II trial of M7824 in patients with recurrent or metastatic HPV associated malignancies.  
.  
Patients will be scheduled to receive 1,20 mg of M7824 IV every 2 weeks until off treatment criteria are met.  
.  
There will be six cohorts: (1) Patients with anal cancer whose disease is naïve to checkpoint inhibition, (2) Patients with non-neuroendocrine cervical cancer naïve to checkpoint inhibition, (3) Patients with P16+ oropharyngeal cancers naïve to checkpoint inhibition, and (4) Patients with other rare HPV associated tumors (e.g. squamous cell rectal, vulvar, vaginal, penile cancer, neuroendocrine cervical) naïve to checkpoint inhibition, (5) Patients with any HPV associated cancers whose disease is refractory to checkpoint inhibition. Patients who are determined to be HPV negative after enrolling will be taken off of their previously assigned cohort and reassigned to cohort 6 and their slot on their previously assigned cohort will be replaced.  
.  
Cohorts 1-5 of the trial will be conducted using a Simon two-stage phase II trial design.
untitled h1
table of contents

| PRECIS                                                                                                                                                                   | 2                                                                                                                                             |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------|
| TABLE OF CONTENTS...............................................................................................................................4                        |                                                                                                                                               |
| STATEMENT OF COMPLIANCE                                                                                                                                                  |                                                                                                                                               |
| l                                                                                                                                                                        | INTRODUCTION .                                                                                                                                |
| 1.1 STUDY OBJECTIVES ..................................................................................................................................................7 |                                                                                                                                               |
| 1.2 BACKGROUND AND RATIONALE ................................................................................................................8                           |                                                                                                                                               |
| 2                                                                                                                                                                        | ELIGIBILITY ASSESSMENT AND ENROLLMENT ...............................................................18                                       |
| 2.1 E LIGIBILITY C RITERIA  ..................................................................................................................................18         |                                                                                                                                               |
| 2 SCREENING EVALUATION .                                                                                                                                                 |                                                                                                                                               |
| 2.3 P ARTICIPANT R EGISTRATION AND S TATUS U PDATE P ROCEDURES                                                                                                           |                                                                                                                                               |
| 23 BASELINE EVALUATION .                                                                                                                                                 |                                                                                                                                               |
| 3                                                                                                                                                                        | STUDY IMPLEMENTATION .                                                                                                                        |
| 3.1 S TUDY D ESIGN .                                                                                                                                                     |                                                                                                                                               |
| 3.2 DRUG ADMINISTRATION                                                                                                                                                  |                                                                                                                                               |
| 3.3 DOSE MODIFICATIONS .                                                                                                                                                 |                                                                                                                                               |
| 3.4 ASSESSMENTS ON TREATMENT .........................................................................................................35                                 |                                                                                                                                               |
| 3.5 STUDY CALENDAR .                                                                                                                                                     |                                                                                                                                               |
| 38 COST AND COMPENSATION ..............................................................................................................38                                |                                                                                                                                               |
| 3.7 Criteria for Removal from Protocol Therapy and Off Study Criteria ............38                                                                                     |                                                                                                                                               |
| 4                                                                                                                                                                        | CONCOMITANT MEDICATIONS/MEASURES                                                                                                              |
| 4.1 THE FOLLOWING TREATMENTS SHOULD NOT BE ADMINISTERED DURING THE TRIAL: .........39                                                                                    |                                                                                                                                               |
| 4.2 OTHER MEDICATIONS ...................................................................................................................39                              |                                                                                                                                               |
| 5                                                                                                                                                                        | CORRELATIVE STUDIES FOR RESEARCH / PHARMACOKINETICS STUDIES ......40                                                                          |
| 5.1 BIOSPECIMEN COLLECTION ...........................................................................................................40                                 |                                                                                                                                               |
| 5.2 SAMPLE COLLECTION ....................................................................................................................42                             |                                                                                                                                               |
| 5.3 R ESEARCH A NALYSIS P ERFORMED A T NIH                                                                                                                               |                                                                                                                                               |
| 5.4  SAMPLE STORAGE, TRACKING AND DISPOSITION ......................................................................43                                                   |                                                                                                                                               |
| 5.5 SAMPLES FOR GENETIC/GENOMIC ANALYSIS ..........................................................................46                                                    |                                                                                                                                               |
| DATA COLLECTION AND EVALUATION ............................................................................46                                                            |                                                                                                                                               |
| 6                                                                                                                                                                        | 6.1 DATA COLLECTION .......................................................................................................................46 |
| 6.2 DATA SHARING PLANS .................................................................................................................47                               |                                                                                                                                               |
| 6.3 R ESPONSE C RITERIA .................................................................................................................48                              |                                                                                                                                               |  
| 6.4  TOXICITY CRITERIA .                                                                                                                                   |                                                                   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|
| 7                                                                                                                                                          | NIHREPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN......53 |
| 7.1 DEFINITIONS                                                                                                                                            |                                                                   |
| 7.2 OHSRP OFFICE OF COMPLIANCE AND TRAINING /IRB REPORTING .........................................53                                                     |                                                                   |
| 7.3   NCI CLINICAL DIRECTOR REPORTING                                                                                                                      |                                                                   |
| 7.4 NIH REQUIRED DATA AND SAFETY MONITORING PLAN .......................................................53                                                 |                                                                   |
| 8                                                                                                                                                          | SPONSOR PROTOCOL / SAFETY REPORTING                               |
| 8.1 D EFINITIONS .                                                                                                                                         |                                                                   |
| 8.2 ASSESSMENT OF SAFETY EVENTS                                                                                                                            |                                                                   |
| 8.3 R EPORTING OF S ERIOUS A VERSE E VENTS                                                                                                                 |                                                                   |
| 8.4   W AIVER OF EXPEDITED REPORTING TO CCR                                                                                                                |                                                                   |
| 8.5 SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS .....................56                                                                  |                                                                   |
| 8.6 R EPORTING P REGNANCY                                                                                                                                  |                                                                   |
| 8.7 REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND ......57                                                                            |                                                                   |
| 9                                                                                                                                                          | CLINICAL MONITORING                                               |
| 10 STATISTICAL CONSIDERATIONS                                                                                                                              |                                                                   |
| 10.1 S TATISTICAL H YPOTHESIS                                                                                                                              |                                                                   |
| 10.2 S AMPLE S IZE D ETERMINATION                                                                                                                          |                                                                   |
| 10.3 P OPULATION FOR A NALYSES .                                                                                                                           |                                                                   |
| 10.4 S TATISTICAL A NALYSES ............................................................................................................................60 |                                                                   |
| 1 COLLABORATIVE AGREEMENTS ...........................................................................................................62                   |                                                                   |
| 1.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) .................................62                                                             |                                                                   |
| 1.2PATENT                                                                                                                                                  |                                                                   |
| 12 HUMAN SUBJECTS PROTECTIONS ....................................................................................................62                       |                                                                   |
| 12.1 R ATIONALE FOR S UBJECT S ELECTION ...................................................................................................62              |                                                                   |
| 12.2P ARTICIPATION OF C HILDREN                                                                                                                            |                                                                   |
| 12.3P ARTICIPATION OF S UBJECTS U NABLE TO G IVE C ONSENT ............................................................62                                   |                                                                   |
| 12.4EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS                                                                                                           |                                                                   |
| 12.5R ISK /B ENEFIT A NALYSIS ..............................................................................................................63             |                                                                   |
| 12.6C ONSENT P ROCESS AND D OCUMENTATION .......................................................................................64                         |                                                                   |
| 13 REGULATORY AND OPERATIONAL CONSIDERATIONS ................................................65                                                            |                                                                   |
| 13.1 S TUDY D ISCONTINUATION AND C LOSURE .....................................................................................65                          |                                                                   |
| 13.2QUALITY ASSURANCE AND QUALITY CONTROL ........................................................................66                                       |                                                                   |  
|            |
|---|
|                                       |
untitled h1
statement of compliance

The trial will be carried out in accordance with International Conference 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.
untitled h1
introduction 1 1.1 study objectives

.  
To determine the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) in subjects with recurrent or metastatic HPV
associated malignancies.  
1.1.2  
Secondary Objectives
.  
To determine the safety and tolerability of M7824.  
.  
To determine disease control rate (DCR) - confirmed response or stable disease (SD)
lasting for at least 6 months.  
.  
To assess progression-free survival time (PFS) according to RECIST 1.1.
.  
To assess overall survival (OS) time.  
.  
To assess duration of response.  
.  
To combine checkpoint inhibitor naïve subjects if permitted based on adequate similarity
of results in cohorts 1, 2, 3, and 4.  
.  
To determine the ratio of patients that are hospitalized because of adverse events attributed to disease progression
1.1.3  
Exploratory Objectives
.  
To conduct exploratory immunologic studies to understand and improve the administered treatment, including:
peripheral immune subset analysis before and on treatment; o soluble factors circulation (e.g., sCD27 and sCD40 ligand) before and on o treatment; antigen specific T cell responses to E6/E7 oncoproteins before and on treatment; o tumor tissue immune infiltration before and after treatment.  
o
.  
To assess circulating tumor DNA before and after treatment.  
.  
To perform HPV typing.  
.  
To assess responses to M7824 in patients with HPV associated tumors using (iRECIST).  
.  
To assess responses to M7824 in patients with HPV negative tumors by RECIST 1.1 and iRECIST.  
.  
To assess response rate to M7824 by RESIST 1.1 and iRESIST in two sub populations:
(1) patients who have previously received lymphodepleting chemotherapy regimens (e.g.  
fludarabine/ cyclophosphamide) and (2) patients who have not previously received lymphodepleting chemotherapy regimens.
untitled h1
1.2 background and rationale 1.2.1

In the United States, there are more than 30,000 cases of HPV associated cancer annually[1]
(Table 1).  Metastatic HPV associated malignancies (cervical, anal, oropharyngeal cancers etc.) are often incurable and poorly palliated by standard therapies.  Responses to chemotherapy are variable but generally short-lived with median PFS around 3 to 7 months[2-5] .  In a Gynecologic Oncology Group randomized trial comparing four cisplatin-based doublets as first line therapy for cervical cancer the response rates were 22-29% and median PFS was 4 to 6 months with median OS 10 to 13 months [ 6 ].  The addition of bevacizumab to combination chemotherapy has been reported to increase OS by 3.7 months, but virtually all patients die of their disease within 2 years [ 7 ].  Randomized trials of second line therapy are lacking but response rates for single agents are generally reported to be less than 20% [ 8 ]. Early evidence suggests that immune checkpoint therapy also has a low response rate in this disease with a phase 1b trial
(KEYSTONE 028) showing a 12.5% response rate (3/24 patients) to pembrolizumab in patients with recurrent or metastatic cervical cancer [ 9 ]. For oropharyngeal cancer, the best estimates of the chemotherapy responsiveness are inferred from looking at the oropharyngeal site in subset analyses from clinical trials for head and neck cancers.  In a pivotal clinical trial that established platinum, 5-fluorouracil (5-FU), plus cetuximab as first line therapy in head and neck cancer, patients with oropharyngeal tumors experienced PFS of 4 to 6 months and OS of 8 to 11 months [ 3 ].  Immune checkpoint therapy has become the standard second line therapy for metastatic oropharyngeal cancer but response rates are still low with this therapy. As an example, the phase 1b trial (KEYNOTE-012) of pembrolizumab which led to its FDA approval for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) as second line therapy had a 17.7% response rate (34/192 patients). Response rates were slightly better in HPV positive HNSCC (21.9%) [10] , but still occurred in only a minority of the patients. In regards 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,  
-  
!  
"
\#$  
- !
%
&  
$$
$  
'(  
)(  
""  
*+  
,-(..  
/  
0  
0  
/  
-  
0  
"1  
22  
0!  
300  
"$  
4\#\#  
25
678-)971":  
!;0!  
"1  
4"  
*$$+  
0
/  
&
0  
0
/  
,'<
-  
0  
0  
300  
0  
-  
| UGFA   | VJLGIAJLA MN OPQ >EEMLG>FAI L>JLARE   | W>EAE >FFRG?KFAI FM OPQ XYZ   |
|--------|---------------------------------------|-------------------------------|
| )/         | $#:                                       | $$111 1$                               |
| .&        | $$$                                       | $111 [1\                               |
| <0        | #                                       | "11 \::                               |
| <         | :1"                                   | \11                                |
| '         | $$\:                                  | 11 \##                               |
| ] 300   1        | 11 [$$                                       |                               |
|  0        | 1$1                                       | \11 [$$                               |
| 9        | #:[#                                       | #111 [$                               |
untitled h1
=>?@a

Bc  
Defgh>Fai
>Jjk>@
Gjlgiajla
Mn
Opq
>Eemlg>Fai
L>Jlare
Gj
Fsa
Tu $"" ^:"  
9  
_
`abcd_e  
/  
2  
00  
0
0  
,  
-  
abcd_  
0  
0
-  
*  +
abcd_
]
$
`abc_fgh
/  
&  
!
0  
!  
/  
,'<%  
* + 5  
0
ij(  
0-  
k
"1[$  
k\$  
:\#\#  
$" /  
0  
/  
0  
-  
/  
l  
&  
/  
/
-
/
0  
/  
/  
/  
9/
0  
abc_fg  
/
&  
,'<%  
2  
/
!  
mno_pq
/  
/  
,'<%  
* +
9  
abcd_  
9  
0  
;/  
-
(  
0  
0
"r
-6i"r
2  
-6i"r
s
!/
&
^,.  
2
/
30  
^2.  
0
-6  
* +
7  
abcd_  
!
0  
-
outcomes in many different human cancers [16, 17] [18, 19] . Prompted by these observations, antibodies (e.g., fresolimumab) and small-molecule inhibitors (e.g., galunisertib) targeting the TGF- β pathway have entered clinical development, where they have demonstrated initial signs of efficacy in hepatocellular carcinoma, pancreatic cancer, and melanoma [20].  
Programmed death ligand 1 (PD-L1) expression on tumor cells has also been associated strongly with poor prognosis in a variety of human cancers [21-24] . In recent years, a number of agents targeting the programmed death 1 (PD-1)/PD-L1 pathway have received regulatory approval, demonstrating impressive durations of response for multiple tumor types, including melanoma, non-small cell lung cancer, renal cell cancer, and head and neck cancer [ 25 -33 ]. Notably, atezolizumab, durvalumab and avelumab are all anti–PD-L1 antibodies with proven efficacy and regulatory approval [34-36] . Unfortunately, not all cancer types seem to respond to these agents, and, even among susceptible cancer types, the percentage of responding patients is usually <
20% [37].  
In an effort to increase the rate of response to these therapies, many ongoing trials are evaluating anti-PD-1/PD-L1 agents in combination with other immunotherapies [38] . Importantly, combined inhibition of PD-L1 and TGF-ß is a promising therapeutic strategy because these key pathways have independent and complementary immunosuppressive functions; therefore, their dual inhibition may result in synergistic antitumor activity.  
M7824 is a novel bifunctional fusion protein composed of a fully human IgG1 monoclonal antibody against human PD-L1 fused, via a flexible glycine-serine linker, to the soluble extracellular domain of human TGF-β receptor II (TGF-βRII), which functions as a TGF-β "trap." The anti-D-L1 moiety of M7824 is based on avelumab (MSB0010718C), which is currently in Phase III clinical trials in multiple tumor types and was recently FDA approved for metastatic Merkel cell carcinoma and urothelial carcinoma [35, 36] . Preclinical studies have shown its ability to simultaneously bind PD-L1 and TGF-β, as well as appropriately block PD-
L1 signaling and TGF-β signaling in vitro. M7824 was shown to have better antitumor efficacy than anti-PD-L1 or TGF-β trap control (a mutated antibody that doesn't bind to PD-L1, linked with the TGF-β trap) in both MC38 and EMT-6 tumor models in both wild-type mice and B cell deficient mice Because M7824 is very immunogenic in mice, due to the fully human antibody and its immune stimulatory mechanism of action, host anti-drug antibodies preclude continued dosing. In an orthotopic EMT-6 breast cancer model using B cell-deficient Jh mice M7824 showed much better activity than either anti-PD-L1 antibody alone or TGF-β trap control (Figure 1). At tumor re-challenge, 13/13 mice previously cured with M7824 treatment had complete protection (resistance to tumor; Figure 2). Furthermore, M7824 therapy extended survival in a dose dependent manner. Similar results were also observed in the MC38 colorectal carcinoma model. Furthermore, depletion studies in MC38 model demonstrated that both CD8+
cytotoxic T cells and NK cells are required for tumor rejection (Figure 3).  
EMT-6 Breast Cancer  
  
Figure 1: Preclinical studies using B cell-deficient Jh mice with subcutaneous EMT-6 breast cancer tumors showing significantly reduced tumor volume with M7824 (anti-PD-L1/TGFβ) compared with either anti-PDL1 antibody or TGF-β trap alone.  
  
Figure 2: Mice previously cleared of their EMT-6 breast cancer tumors after treatment with M7824 were resistant to tumor re-challenge with EMT-6 cells.  
  
!"\#$%&'()*+
, -./0123"4'5 6787989:;<=>8?;@7:<:7AB>8>CDEFG>?HI?J;?KLMNO87<P?;?I=QJ7>R87>STUVW8<P87<P? <=Q:I@8<JA;:;=R;<J7<8JAAB87HI?J;?>XTEYZ[H?AAJ7>\]H?AA87^8A<IJ<8:7W8<P87<P?<=Q:I@ WP8A?>?HI?J;87_QB?A:8>[>?I89?>;=``I?;;:IH?AAaCTbXc87^8A<IJ<8:7@H:Q`JI?>W8<PJ7J7<8d ST[UVJ7<8R:>BH:7<I:Ae fJ;?>:7<P?;?`I?HA878HJA>J<J@JSPJ;?6gYg>:;?[?;HJAJ<8:7;<=>BWJ;H:Q`A?<?><:?9JA=J<? <P?`PJIQJH:h87?<8H;aS]c@;J^?<B@<:A?IJR8A8<B@J7>R8:A:_8HJAJ7>HA878HJAJH<898<B:^CDEFG87 `J<8?7<;W8<PJ>9J7H?>;:A8><=Q:I;a\XZiFjVDgkEce b8l<??7P?J98AB`I?<I?J<?>`J<8?7<;I?H?89?>CDEFGJ<V@g@Vi@:IFiQ_mh_:7H?[?9?IB[F[W??h;e CDEFGWJ;;P:W7<:;J<=IJ<?`?I8`P?IJAST[UVJ<>:;?;ngQ_mh_a*cJ7>;?o=?;<?I `AJ;QJKLMNOpqNOrqJ7>NOsatc<PI:=_P:=<<P?>:;87_`?I8:>J<npQ_mh_eZP?:7AB TUZ:R;?I9?>WJ;H:A8<8;W8<PJ;;:H8J<?>J7?Q8JaFiQ_mh_ce\:CZTWJ;I?JHP?>euIJ>?g <I?J<Q?7<[I?AJ<?>J>9?I;??9?7<;:HH=II?>87g`J<8?7<;a;h8787^?H<8:7;?H:7>JIB<:A:HJA8v?> R=AA:=;`?Q`P8_:8>agQ_mh_c@J;BQ`<:QJ<8HA8`J;?87HI?J;?aFiQ_mh_c@J7>H:A8<8;aFiQ_mh_c W8<PJ;;:H8J<?>J7?Q8JceZP?;?<:l8H8<8?;JI?:7`JIW8<P:<P?IST[VmST[UV87P8R8<:I;eZP?:7AB J>>?><:l8H8<B;??7:9?I<IJ>8<8:7JAST[VmST[UV87P8R8<:I;WJ;<P?:HH=II?7H?:^ h?IJ<:JHJ7<P:QJ;WP8HPPJ9?R??7>?;HI8R?>`I?98:=;ABW8<PKLMO87P8R8<:I;wgkxeZP?I?W?I? 7:<I?J<Q?7<[I?AJ<?>_IJ>?Gdj?9?7<;e  
  
  
ean TGF-βββββ
Figure 5 : Total TGF-β1, -β2, and -β3 plasma concentrations following intravenous administration In addition, in the ongoing Phase I study of M7824 (NCT02517398), substantial clinical evidence has been seen in 4 of 9 patients (44%) with HPV associated malignancies, including 2 of 5 patients (40%) with metastatic cervical cancer, 1 of 2 patients (50%) with metastatic anal cancer and 1 of 2 patients (50%) with metastatic P16+ head and neck cancer have had substantial clinical benefit. This includes a patient with metastatic cervical cancer with a 25% reduction (by long axis measurement) in her disease at 3 months (Figure 6), a patient with metastatic P16+ head and neck cancer with an unconfirmed partial response 6 weeks after starting treatment (Figure 7), a patient with metastatic anal cancer with normalization of tumor markers (Figure 8)
and an ongoing durable partial response 9 months after starting treatment (Figure 9) and a patient with metastatic cervical cancer with normalization of tumor markers (Figure 10) and an ongoing durable complete response for more than a year ( Figure 11 ).  
  
  
Figure 7: This 72-year-old man with metastatic HPV+ head and neck cancer s/p cisplatin/RT for initially local disease with multiple disease recurrences in neck s/p modified radical neck dissection and Erbitux/RT (to neck) who developed mets to lungs, back and knee s/p multiple rounds of surgery + Erbitux/RT (to knee) with metastatic right groin mass (arrow in left side of figure) who received M7824 at 20 mg/kg every other week. Restaging scan at 6 weeks showed an unconfirmed PR (right side of figure).  
  
  
Figure 9 : This 57-year-old female with metastatic HPV+ anal cancer to liver, retroperitoneal and periportal nodes s/p definitive chemoradiation with 5-FU + mitomycin in the locally advanced setting followed by cisplatin + xeloda for recurrent metastatic disease had progressive disease at enrollment (arrows in left side of figure). She received a single dose of M7824 at 0.3 mg/kg followed by M7824 at 10 mg/kg every other week. Restaging scans at 3 months showed a PR which has been  
  
  
-
!"\#$
%  
&  
'
()*+,-./01-2-3.45-+5-//64)4.2437-2*,82+9*2):;<-++46*-2,15-/*=8-86*,+*82)*+7)-+,> 2.*-/43?@ABC+D==,+2+2)-22)*+-=,82E9)*6)2-.=,2+F42);GHI>-81JKLM7-2)9-0+E5-0 7.41D6,.,+748+,+-2-)*=),..-2,-+6457-.,19*2)42),.+*8=/,-=,82;GH>N;GHI>*8)*F*24.+*8 2)*+7-2*,82747D/-2*48OP3842,2),-F4Q,;>RS),-1-818,6T6-86,.7-2*,829*2)D86483*.5,1 ;UE-8-/6-86,.7-2*,829*2)1D.-F/,;U-816,.Q*6-/6-86,.7-2*,829*2)1D.-F/,VU-//)-Q, :;<S1*+,-+,O
W?GX,.484)-++,Q,.-/2D54.+7,6*3*6,Y7-8+*4864)4.2+48=4*8=,Q-/D-2*8=?@ABC*86/D1*8= ,Y7-8+*4864)4.2+*87-2*,82+9*2):ZXVV-+9,//-+6,.Q*6-/6-86,.,Y6/D1*8=8,D.4,8146.*8, 6,.Q*6-/6-86,.O(),.,-.,842.*-/+,Q-/D-2*8=?@ABC*87-2*,82+9*2).-.,.:;<-++46*-2,1 5-/*=8-86*,+*86/D1*8=-8-/EQD/Q-.EQ-=*8-/E7,8*/,E8,D.4,8146.*8,6,.Q*6-/4.+[D-54D+6,// .,62-/6-86,.O(),.,34.,E9,7.474+,2)*+7)-+,\\2.*-/9)*6)9*//*86/D1,2),,Q-/D-2*4843 ?@ABC,33*6-60*82),+,.-.,.2D54.207,+O
V/*8*6-/F,8,3*29-+4F+,.Q,1*8-+5-//64)4.2437-2*,82+9*2):;<-++46*-2,15-/*=8-86*,+*8 -;)-+,\2.*-/43?@ABCO()*+;)-+,\\+2D109*//3D.2),.*8Q,+2*=-2,2),6/*8*6-/,33*6-6043 ?@ABC*8:;<-++46*-2,12D54.+O
untitled h1
] ^!!'!^!#ab""""cd#bdedf^^cd# ] ^!!'!^!#a !#!b

] \86/D+*48V.*2,.*-  
g h=,i>A0,-.+O
F*/*2043+DFj,6224D81,.+2-81-812),9*//*8=8,++24+*=8-9.*22,8*834.5,1648+,82 146D5,82O
g XDFj,62+9*2)6024/4=*6-//04.)*+24/4=*6-//06483*.5,1/46-//0-1Q-86,14.5,2-+2-2*6 :;<-++46*-2,15-/*=8-86*,+*86/D1*8=k l Z48HZ,D.4,8146.*8,V,.Q*6-/6-86,.+
;>RSP.47)-.08=,-/6-86,.+ h8-/6-86,.+ <D/Q-.EQ-=*8-/E7,8*/,E+[D-54D+6,//.,62-/-818,D.4,8146.*8,6,.Q*6-/6-86,.+
P2),./46-//0-1Q-86,14.5,2-+2-2*6+4/*12D54.+m,O=O/D8=E,+47)-=D+n2)-2-., T8498:;<S
g ;-2*,82+5D+2)-Q,1*+,-+,2)-2*+842-5,8-F/,24742,82*-//06D.-2*Q,.,+,62*48
g XDFj,62+5D+2)-Q,5,-+D.-F/,1*+,-+,mX,62*48o%%nO g WVPp7,.34.5-86,+2-2D+qBmbbnO g h1,[D-2,),5-24/4=*63D862*48-2+6.,,8*8=E-+34//49+k  
l hF+4/D2,8,D2.47)*/64D82mhZVnirY>stNI
A
untitled h1
hemoglobin >= 9 g/dl

A
Platelets ≥ 75,000/microliter.  
.  
Adequate renal and hepatic function at screening, as follows:
A
Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl)
≥ 40 mL/min per institutional standard.  
A
Bilirubin ≤ 1.5 x ULN OR in subjects with Gilbert's syndrome, a total bilirubin ≤ 3.0 x ULN
A
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN,
uless liver metastases are present, then values must be < 3 x ULN)
.  
The effects of M7824 on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and up to 60 days after the last dose of the drug. 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.  
.  
Patients serologically positive for HIV, Hep B, Hep C are eligible as long as the viral loads are undetectable by quantitative PCR. HIV positive patients must have CD4 count
> 300 cells per cubic millimeter at enrollment, be on stable antiretroviral therapy and have no reported opportunistic infections within 12 months prior to enrollment.  
2.1.2 Exclusion Criteria
.  
.  
Pregnant women are excluded from this study because this drug has 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 M7824, breastfeeding should be discontinued if the mother is treated with M7824.  
Patients with prior investigational drug, chemotherapy, immunotherapy or any prior radiotherapy (except for palliative bone directed therapy) within the past 28 days prior to the first drug administration except if the investigator has assessed that all residual treatment-related toxicities have resolved or are minimal and feel the patient is otherwise suitable for enrollment. Patients may continue adjuvant hormonal therapy in the setting of a definitively treated cancer (e.g., breast).  
.  
Major surgery within 28 days prior to the first drug administration(minimally invasive procedures such as diagnostic biopsies are permitted).  
.  
Known intolerance to or life threatening side effects resulting from prior checkpoint inhibitor therapy.  
.  
Known active brain or central nervous system metastasis (less than 1 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 patients must have repeat CNS imaging at least one month after definitive treatment showing stable CNS disease. Patients 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.  
.  
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; A
Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses
::: 10 mg of prednisone or equivalent per day; A
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; A
Subjects on systemic intravenous or oral corticosteroid therapy with the exception of physiologic doses of corticosteroids ( < the equivalent of prednisone 10 mg/day) or other immunosuppressives such as azathioprine or cyclosporin A are excluded on the basis of potential immune suppression. For these subjects these excluded treatments must be discontinued at least 1 weeks prior to enrollment for recent short course use
(   14 days) or discontinued at least 4 weeks prior to enrollment for long term use ( > 14 days). In addition, the use of corticosteroids as premedication for contrastenhanced studies is allowed prior to enrollment and on study.  
.  
Subjects with a history of serious intercurrent chronic or acute illness, such as cardiac or pulmonary disease, hepatic disease, bleeding diathesis or recent (within 3 months)
clinically significant bleeding events, or other illness considered by the Investigator as high risk for investigational drug treatment. History of non-HPV associated second malignancy within 3 years of enrollment except localized malignancy which has been adequately treated or malignancy which does not require active systemic treatment (e.g., low risk CLL).  
.  
Known severe hypersensitivity reactions to monoclonal antibodies (Grade > 3 NCI-
CTCAE v5.0)
.  
Receipt of any organ transplantation requiring ongoing immunosuppression.  
.  
Patients with vulvar cancer originating from differentiated vulvar intraepithelial neoplasia
(d-VIN), as opposed to vulvar intraepithelial neoplasia of usual type, are excluded.  
Vulvar squamous cell carcinoma originating from differentiated VIN (d-VIN) is HPV negative; however, rare cases of HPV positive d-VIN can occur.  Patients are not excluded if their tumor has tested positive for HPV or there is no documentation of prior VIN type.  
.  
Patients with known HPV negative malignancies based on comprehensive laboratory testing (e.g. PCR based assay evaluating for HPV 16, 18, 31, 33, 35, 39, 51, 52, 56, 58, 59, 66, 68). Patients with HPV associated malignancies and unknown HPV status prior to enrollment are eligible.
untitled h1
2.1.3 recruitment strategies

This study will be listed on available websites (www.clinicaltrials.gov) and participants will be recruited from the current patient population at NIH.
untitled h1
2.2 s creening e valuation

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
A waiver of consent for these activities has been requested in section 12.6.2.  
For Patients not-requiring HPV testing:
Note:  Screening evaluation testing/procedures are conducted under the separate screening protocol, 01-C-0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural Research Program Clinical Protocols).
untitled h1
2.2.2

Screening activities performed after a consent for screening has been signed
untitled h1
for patients requiring hpv testing

The following activities will be performed only after the subject has signed the consent for this study for screening. Assessments performed at outside facilities or on another NIH protocol within the timeframes below may also be used to determine eligibility once a patient has signed the consent.
untitled h1
for patients not-requiring hpv testing

The following activities will be performed only after the subject has signed the consent for study \# 01C0129 on which screening activities will be performed. Assessments performed at outside facilities or on another NIH protocol within the timeframes below may also be used to determine eligibility once a patient has signed the consent.  
All screening tests and procedures must be performed within 28 days prior to the first drug administration:
.  
Complete medical history and physical examination (including height, weight, vital  
signs, and ECOG performance status).  
.  
CT of chest, abdomen and pelvis or MRI
.  
A brain CT / MRI scan if clinically indicated
.  
Nuclear bone scan if clinically indicated  
!"\#!$\#%  
&  
''  
()'  
$
*+,-./0'
'
'1
23  
'  
4 &5&5&657
'
8  
4  
&  
'  
46'
7  
'  
'  
4
untitled h1
9 <=>?@a@<=b?>cd@e?>=?@fb=bge?=?heh<g=?c<>facgh>ce

I
44%
''  
%
''1
%I$JK!(I13IK L$'
4 3484 \#!K  
| AMNMOPQ BRSTUO   | BVSU   | GUQWOXYPXMZ   |
|------------------|--------|---------------|
|                   |           | $[ \7 %                  |
| 3                |   3        | $[ 1  7\7  %                 |
| 8                |   8        | $[K]   \7 %                  |
| )                |   )        | $[ &K5  44^  777   7 \7 %                 |
| _                |   _        | $[ &K5   '   %                 |
|                   |           | K  &K57'  % '' '7                   |  
| reassigned to cohort 6 and their slot on their previously assigned   |
|----------------------------------------------------------------------|
| cohort will be replaced.                                             |  
Arms  
| Number   | Name                                                   | Description   |
|----------|--------------------------------------------------------|---------------|
| l        | M7824 at a flat dose of 1,200 mg IV once every 2 weeks |               |
| Arm 1    |                                                        |               |
untitled h1
arm assignment

Patients in Cohort 1-6 will be directly assigned to treatment Arm 1.
untitled h1
baseline evaluation 2.4

All subjects are required to complete baseline evaluations within one week prior to the first planned dosing of the study drug (any screening evaluation done within this time period can also serve for the baseline evaluation):
.  
Physical exam including weight, ECOG performance status and vital signs.  
.  
Concomitant Medications and Baseline Signs and Symptoms evaluation.  
•
EKG
.  
Serum pregnancy test ( β -HCG) for females of childbearing-potential and women
< 12 months since the onset of menopause.  
.  
Chemistry: sodium, potassium, chloride, bicarbonate, calcium, glucose, BUN,
creatinine, ALT, AST, alkaline phosphatase, total protein, albumin, and total and direct bilirubin.
.  
ACTH, TSH, free T4, lipase, amylase
.  
Hematology: CBC with differential and platelets
.  
Coagulation panel: PT, INR, and PTT
.  
Sedimentation Rate (ESR), CRP
.  
Urinalysis
untitled h1
3 study implementation 3.1 study

This is a Phase II trial of M7824 in patients with recurrent or metastatic HPV associated malignancies.  
Subjects will be treated with 26 doses of M7824 and at this point the drug will be withheld.  
These subjects will be followed with surveillance scans every 6-12 weeks. Patients with evidence of disease progression will be allowed retreatment with M7824 using the same dosing regimen.  
Retreatment will restart after repeat of baseline evaluation.  Participants will not be re-treated unless willing to accept blood products as medically indicated 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 in order to minimize the risks of receiving M7824.  
The second course of treatment will continue for 26 doses of M7824 and at this point the drug will be withheld. These subjects will be followed with surveillance scans every 6-12 weeks.  
Patients with evidence of disease progression will be allowed additional treatment courses with M7824 using the same dosing regimen. These additional treatment courses will restart after repeat of baseline evaluations.  
Patents might be taken off treatment for disease progression during 26 doses period, 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 for unacceptable toxicity.  
Although positive HPV testing will not be required prior to enrolling, HPV testing will be offered as an exploratory endpoint and patients testing negative for HPV after enrolling or whose HPV status cannot be confirmed may be replaced with other patients for the primary efficacy analysis. Patients testing negative for HPV after enrolling or whose HPV status cannot be confirmed may continue to receive treatment on study. The response rate of M7824 in patients who are HPV negative will be assessed as an exploratory endpoint.  
In addition, early data from the phase I trial suggests that patients with HPV associated malignancies who have previously received lymphodepleting chemotherapy regimens (i.e.  
fludarabine/cyclophosphamide) may not respond as well to M7824 as standard patients. Of the initial 9 patients with HPV associated malignancy enrolled three had received prior lymphodepleting chemotherapy regimens and all three had no evidence of clinical benefit whereas six patients did not receive prior lymphodepleting chemotherapy and of these four had evidence of clinical benefit. Therefore given this early data and the possibility that patients receiving prior lymphodepleting chemotherapy may not respond as well to M7824 as standard patients, patients previously receiving lymphodepleting chemotherapy regimens may be replaced with other patients for the first stage of the Simon two -stage assessment as well as the primary efficacy analysis. The response rate of M7824 in patients previously receiving  lymphodepleting chemotherapy regimens will be assessed as an exploratory endpoint.  
In addition, early data from the phase I/II trial suggest that older patients with HPV associated malignancies may respond more frequently to M7824. The observation that older patients may respond more often to checkpoint therapy has also been described in the literature with other checkpoint inhibitors and malignancies[ 40 ]. Of the initial 10 patients over the age of 65 with HPV associated malignancies enrolled who received M7824, 5 patients responded per RECIST
1.1 including 3/6 patients with checkpoint naïve disease and 2/4 patients with checkpoint refractory disease. A 4 th patient with checkpoint naïve disease had 27% reduction in her disease. No patients with checkpoint refractory disease less than 65 years of age have responded to date.  
As clinical trial options for patients > 65 years of age are limited due to their general exclusion from adoptive T cell protocols it is worth evaluating the efficacy signal of M7824 specifically in this older patient population. Therefore given this data and rationale patients < 65 years of age may be replaced with patients ≥ 65 years of age for the first stage of the Simon two -stage assessment as well as the primary efficacy analysis. All Cohorts 1-5 of the trial (see section 2.3.1) will be conducted using a Simon two-stage Phase I trial design.  
.  
For Cohorts 1, 2, 3, and 4: 8 evaluable patients will be enrolled on each cohort in the first stage and if 2 or more of the 8 on an individual cohort have an objective response (see section 6.3) within 1 year of starting treatment, then accrual would continue on that individual cohort until a total of 13 evaluable patients have been treated. If there are 4 or more of 13 (30.8%) who experience a response on an individual cohort, this would be sufficiently interesting to warrant further study in later trials.  
.  
For Cohort 5: 13 evaluable patients will be enrolled in the first stage, and if 1 or more of the 13 have an objective response (see section 6.3) within 1 year of starting treatment, then accrual would continue until a total of 20 evaluable patients have been treated. If there are 3 or more of 20 (15.0%) who experience a response, this would be sufficiently interesting to warrant further study in later trials. To assure a mixture of tumor types in Cohort 3: no more than 8 evaluable patients with cervical cancer, 8 evaluable patients with anal cancer and 8 evaluable patients with head and neck cancer will enroll on this cohort.  
.  
A total of 45 evaluable subjects (8, 8, 8, 13 in Cohorts 1, 2, 3, 4, 5 respectively) will be enrolled in the first stage of the trial. Depending upon the number of objective responses seen in the first stage of the trial up to another 27 evaluable subjects may be enrolled in the second stage for up to a total of 72 evaluable subjects.  
.  
In the event that a patient develops a response (>30% decrease in target lesions as compared with baseline scan) following initial progression of disease attributed to pseudo-progression, this response will be considered as an objective response in the determination to expand a given cohort.
untitled h1
3.2 drug administration

Bintrafusp alfa 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.  
Subjects will be scheduled to receive M7824 at a flat dose of 1,200 mg IV once every 2 weeks.  
M7824 may be administered through a peripherally inserted intravenous catheter including a peripherally inserted central catheter. It may also be administered through an implanted access device (i.e. port) when the reservoir of the device is made of titanium.  
In the phase I trial, M7824 was evaluated at a dose of 1, 3, 10 and 20 mg/kg IV once every 2 weeks and only one DLT was observed (colitis) at a dose of 20 mg/kg. No MTD was found.  
Based upon this safety data the decision was made to continue with a flat dose of 1,200 mg  IV
once every 2 weeks in nearly all phase Ib expansion cohorts. To align with these cohorts this phase II trial will also evaluate M7824 at a flat dose of 1,200 mg IV once every 2 weeks.  
Subjects will receive IV infusion of M7824 over 1 hour (-10 minutes / +20 minutes, that is, 50 to 80 minutes). As a routine precaution, subjects enrolled in this trial must be observed for 60 minutes' post end of infusion, in an area with resuscitation equipment and emergency agents.
untitled h1
3.2.1 premedication

Current experience revealed that infusion related reactions (IRRs) to M7824 seldom occur and are generally mild to moderate in severity. Therefore, administration of a premedication is generally not required.  
If an Investigator deems it necessary to administer a premedication, an antihistamine (for example, 25-50 mg diphenhydramine) and acetaminophen 500-650 mg intravenously or equivalent oral dose is recommended approximately 30 to 60 minutes prior to each dose of M7824. If Grade ≥ 2 infusion reactions are seen during the first two infusions, premedication should not be stopped. Steroids as premedication are not permitted.  
Management of symptoms should follow the guidelines shown in Table 2.
untitled h1
3.2.1.1 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
untitled h1
3.2.1.2 flu-like symptoms

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.
untitled h1
dose modifications 3.3 3.3.1 discontinuation

M7824 treatment will be discontinued in case of:
.  
Any Grade 4 adverse drug reactions (ADRs), as defined by CTCAE v5.0 and assessed as related to M7824 by the Investigator, except for laboratory values that are determined to not be clinically significant or single laboratory valued that resolve to Grade ≤ 1 or baseline grade within 7 days with adequate medical management.  
.  
Any Grade 3 ADRs except for any of the following:
o Transient (≤ 48 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical management.  
o  
Transient (≤ 48 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis which is controlled with medical management.  
o Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or suspected tumor.  
!"\#$  
%
&
%  
'  
(  
(  
(  
'  
$
)*)*+ ,
,
-. /0  
/,1  
23 ,1  
(  
(  
'  
4  
(
/,1 0  
'5  
(  
-. /0  
(
6  
5  
/7  
5  
'
untitled h1

-  
8
9
8  
-. /05  
"' 3!"'  
$3"'7  
5  
-. /0  
3/!!
33!"'  
(
:  
'  
;:  
(  
(  
,1  
3/!!
$
0 <;-
untitled h1
=>?@a+b=ca>deafdghijkjl>djhfmnji>flakhcopeqdherhksfknrjhftua@>daiua>ldjhfr jfl@nijfvseeaij>dawpqacrafrjdjxjdp

8  
5  
Y  
(  
8
1  
1
811$
'-. /0  
| NCI-CTCAE Grade                                                                            | Treatment Modification for M7824                    |                                                    |    |     |
|--------------------------------------------------------------------------------------------|-----------------------------------------------------|----------------------------------------------------|----|-----|
| Grade 1 - mild                                                                             | .                                                   | Increase monitoring of vital signs as medically    |    |     |
| indicated as participants are deemed medically                                             |                                                     |                                                    |    |     |
| Mild transient reaction; in general,                                                       | stable by the attending Investigator.               |                                                    |    |     |
| infusion interruption not indicated;                                                       |                                                     |                                                    |    |     |
| intervention not indicated.                                                                | .                                                   | Hold infusion if deemed necessary                  | by | the |
| investigator.                                                                              |                                                     |                                                    |    |     |
| Grade 2 - moderate                                                                         | .                                                   | Stop the infusion of the study intervention.       |    |     |
| Therapy or infusion interruption                                                           | .                                                   | Increase monitoring of vital signs as medically    |    |     |
| indicated but responds promptly to                                                         | indicated as participants are deemed medically      |                                                    |    |     |
| symptomatic treatment (for example,                                                        | stable by the attending Investigator.               |                                                    |    |     |
| antihistamines, nonsteroidal anti                                                          | .                                                   | If symptoms resolve quickly, resume infusion at    |    |     |
| inflammatory drugs, narcotics, IV                                                          | 50% of original rate with close monitoring of any   |                                                    |    |     |
| fluids); prophylactic medications                                                          | worsening signs and symptoms, otherwise dosing      |                                                    |    |     |
| indicated for ≤ 24 h.                                                                      | 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                                                             | Stop the infusion of study intervention immediately |                                                    |    |     |
| .                                                                                          |                                                     |                                                    |    |     |
| life-threatening                                                                           | and disconnect infusion tubing from the participant |                                                    |    |     |
| with additional appropriate medical measures and                                           |                                                     |                                                    |    |     |
| Grade 3: Prolonged (for example,                                                           | closely monitor until deemed medically stable by    |                                                    |    |     |
| nt rapidly responsive to                                                                   | the attending Investigator. Hospitalization and/or  |                                                    |    |     |
| symptomatic medication and/or brief                                                        | close monitoring is recommended.                    |                                                    |    |     |
| interruption of infusion); recurrence                                                      |                                                     |                                                    |    |     |
| of symptoms following initial                                                              | .                                                   | Administration of glucocorticoids may be required. |    |     |
| improvement; hospitalization                                                               | .                                                   | For Grade 3 or 4 IRRs, permanent discontinuation   |    |     |
| indicated for clinical sequelae.                                                           | of study intervention is mandated.                  |                                                    |    |     |
| Grade 4: Life-threatening                                                                  |                                                     |                                                    |    |     |
| consequences; urgent intervention                                                          |                                                     |                                                    |    |     |
| indicated.                                                                                 |                                                     |                                                    |    |     |
| 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.              |                                                     |                                                    |    |     |  
NCI-CTCAE Grade
untitled h1
treatment modification for m7824

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.
untitled h1
table 3 immune-related adverse events

Immune-related AEs are specific to immunotherapies and vary by organ system.  
The 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)
.  
The following immune-related AEs are important potential risks for M7824:
.  
.  
.  
.  
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 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 Guillain-Barré syndrome Uveitis  
-  
-  
-  
!"  
- \#  
\#
$  
- \#
%  
\#-
&'  
-  
-  
(  
&)*+  
&)*+
,  
-  
&)*+
D!  
!EFG%'  ,!-  H
-  I  
"  
JDIIK  L
-  M
!- 3.4.516147  N  
"  
I  
-  
-  O
-  N  
- -  P  
Q
R D  
\#
- R E  
\#
E  
- S  
-
I  
-  
!  
$
-
untitled h1
-./0123.4.516147893<261=>.71=?@>4a1.b7>84c

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.
untitled h1
table 5 management of treatment-related

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
untitled h1
basic anemia evaluation

.  
.  
CBC with emphasis on red cell indices If indicated and at clinical discretion, the following should be considered:
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 o Further Recommendation Based on Suspected Etiology (in Addition to Basic Anemia Testing)
.  
Suspected Hemolysis obilirubin, 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:
Hematology consultation o o Consider bone marrow aspiration/morphologic evaluation Additional consideration:
In general, blood transfusions and erythroid growth factors are permitted as clinically indicated.  
| 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                                                                          |                                       |
| Hemoptysis                                                                  |                                                                                    |                                       |
| o                                                                           |                                                                                    |                                       |
| 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     |
| uless 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                                                 |                                                                                    |                                       |
| .                                                                           | Permanently discontinue treatment if the                                           |                                       |
| Investigator considers the participant to                                   |                                                                                    |                                       |
| be at risk for additional severe bleeding.                                  |                                                                                    |                                       |
untitled h1
table 6 management of bleeding

Table 7 Impaired Wound Healing
.  
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.
untitled h1
"# %&&'&&(')&

+)
*,'%*(')*  
-./
01121132451
.4
5/20532456
7820126
122
95:;<
=0824;0/
"\#>  
| "#$                                       | %&'() *+,-.(+/   | ,279  &41M  H2>>2K  6LN   |               |      |    |
|-------------------------------------------|------------------|---------------------------|---------------|------|----|
| %<H4IJ  H2>>2K  6L$                       |                  |                           |               |      |    |
| 012345614                                 | %31447879:       | ;<=4>874 ?  @44A :B       | @44A  CB.D:E" | -F&G |    |
| OPQRSP                                    | T                | T                         |               |      |    |
| UVW XYZ[\]^ _`a^]b`Z^c deafQ              | T                |                           |               |      |    |
| O^Y`][g W`cbeah                           | T                |                           |               |      |    |
| W^`ijb                                    | T                |                           |               |      |    |
| kjhc`][g ^l[fm n^`ijbm Z`b[g  c`i\cm opqr | T                | T                         | T             | T    | T  |
| WVsm Wpsm W^tu                            | T                |                           |               |      |    |
| ovr                                       | T                | T                         | T             |      |    |
| pup n`bj Y`ww^a^\b`[gm tg[b^g^bc          | T                | T                         | T             | T    | T  |
| u`e]j^f`][g taew`g^x                      | T                | T                         | T             | T    | T  |
| p_S yR                                    | T                |                           |               |      |    |
| oz{m p{k                                  | T                | T                         |               |      |    |
| Xp|Wm |zWm da^^ |Sm g`t[c^m  [fhg[c^      | T                | Ty}                       |               |      |    |
| ~a`\[ghc`c                                | T                |                           |               |      |    |
| z^af ta^i\[\]h b^cb`\i `\  nef^\ ew ]j`gY€^[a`\i teb^\b`[g  CB#B                                           | T                | T                         | T             |      |    |
| k|m VU{m [k||                             | T                |                           |               |      |    |
| |fea ^Z[g[b`e\ 'p| z][\ ƒ  O{V yy                                           | T                | T                         | T             |      |    |
| ua[`\ p|ƒO{V yR                                           | T                |                           |               |      |    |
| U]g^[a €e\^ c][\ yR pe\]ef`b[\b O^Y`][b`e\c                                           | T                | T                         | T             | T    |    |
| XYZ^ac^ ^Z^\bc                            | T                | T                         | T             | T    |    |
| qtb`e\[g €`etch wea `ff\^  [\[ghc`c [\Y Wks b^cb`\i y                                           | T                | T                         |               |      |    |
| {^c^[a]j ugeeY  'kuOpcƒc^afƒtg[cf[ yS                                           | T                | T                         | T             |      |    |
| |^g^tje\^ deggen ~t                       | T                | T                         |               |      |    |  
"\#$%&''()(*
'+,-.,/)0(1
2'&30&4'5
6)/7)(
89
5,:1
2&)0&
/0
/7'
3)&1/
5&.*
,54)()1/&,/)0(;
.(-'11 12'%)3)'5
)(
$'%/)0(
<=<=
8\#>,1'-)('
'+,-.,/)0(1
2'&30&4'5
6)/7)(
"
6''?
03
3)&1/
5&.*
,54)()1/&,/)0(\#
\#@+'&:
055
(.4A'&'5
6''?
30&
.2
/0
B"
6''?1\#
CD98E
,54)()1/&,/)0(
,(5
)(5)%,/'5 '+,-.,/)0(1
%,(
A'
50('
.2
/0  
5,:1
',&-)'&
0&
5'-,:'5
.2
/0
"E
5,:1
5.'
/0
70-)5,:1; )(%-'4'(/
6',/7'&;
%0(3-)%/1;
0&
1)4)-,&
&',10(1\#
F7'
/)4)(*
03
1.A1'G.'(/
,54)()1/&,/)0(1
)1 /7'(
,5H.1/'5
/0
4,)(/,)(
,
8
6''?I)(/'&+,-\#
J(
/7'
'+'(/
03
,
5.&,A-'
KL
0&
ML
,3/'&
0('
:',& 0(
/&),3.&/7'&
/&',/4'(/
4,:
A'
7'-5
N'+'(
)3
,
/0/,03
8!
501'1
7,+'
(0/
A''(
*)+'(O
,(5 1%7'5.-'5
,11'114'(/1
4,:
A'
2'&30&4'5
,/
'+'&:  
40(/71
NPQI
8
6''?1O
)(/'&+,-1
,/
/7' 5)1%&'/)0(
03
/7'
)(+'1/)*,/0&\#  
E\#@RF
S
@(5
03
/&',/4'(/
+)1)/T
U7'&'
3',1)A-';
0(
/7'
5,:
03
0&
6)/7)(
D
5,:1
03
/7'
5'%)1)0( /0
5)1%0(/)(.'
/&',/4'(/
2&'4,/.&'-:
A'30&'
%042-'/)0(
03
8!
501'1\#
V0'1
(0/
(''5
/0
A' %042-'/'5
)3
5&.*
)1
6)/77'-5
,3/'&
8!
501'1\#
B\#89
5,:1
NPQI
D
5,:1O
,3/'&
-,1/
/&',/4'(/\#
J3
1.AH'%/1
,&'
(0/
6)--)(*
/0
%04'
/0
WJX
/0
YZ +)1)/;
/7':
6)-A'
%0(/,%/'5
A:
270('
/0
,11'11
,5+'&1'
'+'(/1\#
!\#K,/)'(/1
670
7,+'
%04'
033
/&',/4'(/
30&
5)1',1'
2&0*&'11)0(
6)-A'
30--06'5
A:
270(' ,((.,--:
30&
1.&+)+,-\#
K,/)'(/1
670
7,+'
(0/
2&0*&'11'5
0(
/&',/4'(/
6)-%0(/)(.'
/0
A' 30--06'5
,(5
1%,(('5
2'&
)(+'1/)*,/0&
5)1%&'/)0(
.(/)2&0*&'11)0(\#
F701'
/7,/
%042-'/'5
0(' :',&
03
/&',/4'(/
6)-A'
)(+)/'5
30&
,(
,55)/)0(,:',&
03
/&',/4'(/
,/
/7'
/)4'
03 2&0*&'11)0(\#
J()/),,(5
30--06
.2
%0.&1'1
03
/&',/4'(/
4,:
'[/'(5
A':0(5
,
:',&
2'& )(+'1/)*,/0&
5)1%&'/)0(\#
D\#CD98E
,54)()1/'&'5
J\
,/
3-,/
501'
03
";8]]
4*\#
9\#^1
)(5)%,/'5
)(
$'%/)0(
_<=`;
,-1.AH'%/1
6)-A'
033'&'5
/7'
0220&/.()/:
/0
%042-'/'
,(
WJX ,5+,(%'5
5)&'%/)+'1
30&4\#
F7)1
170.-5
A'
50('
2&'3'&,A-:
,/
A,1'-)('
A./
%,(
A'
50('
,/
,(: /)4'
5.&)(*
/7'
1/.5:
,1
-0(*
,1
/7'
%,2,%)/:
/0
50
10
)1
&'/,)('5\#
F7'
%042-'/)0(
03
/7'
30&4 )1
1/&0(*-:
&'%044'(5'5;
A./
)1
(0/
&'G.)&'5  
a\#>)0%7'4)%,2&03)-'T
105).4;
20/,11).4;
%7-0&)5';
A)%,&A0(,/';
%,-%).4;
*-.%01';
>ZW; %&',/)()(';
^bF;
^$F;
,-?,-)('
270127,/,1';
/0/,2&0/')(;
,-A.4)(;
,(5
/0/,,(5
5)&'%/ A)-)&.A)(
"]\#@+'&:
!
6''?1
""\#@+'&:
1)[
6''?1
NPQI
"
6''?O\#
J(
/7'
'+'(/
03
,
KL
0&
ML
/.40&
)4,*)(*
,11'114'(/1
4,:
A' 2'&30&4'5
'+'&:  
40(/71
NPQI
8
6''?1O
,/
/7'
5)1%&'/)0(
03
/7'
)(+'1/)*,/0&\#
F.40&
,11'114'(/
170.-5
A'
%0(/)(.'5
A':0(5
'(5
03
/&',/4'(/
)(
2,/)'(/1
670
7,+'
(0/ '[2'&)'(%'5
KV
.(/)/7':
'[2'&)'(%'
KV
)(
0&5'&
/0
,11'11
KY$\#  
"8\#J3
%-)()%,--:
)(5)%,/'5 " \#R2/)0(,A)021)'1
,/
A,1'-)('
,(5
6)/7)(
0('
6''?
03
3)&1/
)4,*)(*
&'1/,*)(*\#
"E\#U7'&'
3',1)A-';
&'1',&%7
A-005
NK>CM1;
1'&.4;
2-,14,O
30&
,-1/.5:
,11'114'(/1
N1'' $'%/)0(
cddedf
ghihdhjkh
lemdkh
jen
iemjo=O
6)-A'
%0--'%/'5
,/
6''?1
";
;
D
,(5
'+'&:
!
6''?1 /7'&',3/'&
)(
1'-'%/'5
2,/)'(/1
2'&
KJ
5)1%&'/)0(\#
untitled h1
"#v %w/(.w/)

X&W
W.,&Y)Z
Xw&,
-W&(&%&Z
([.W)-\
)*+
&Xx
'(]+\
%W/(.W/)  
P;MAC:?;55
4G
C;A54<
G4C
C;E4IA?
GC4E
56B:H
6@;CAFHJ
FA6>;<65
L>??
=;
A5^;:
64
@AI;
A
N_
:AH
G4??4L BF
5AG;6H
I>5>60
OA6>;<65
L@4
C;GB5;
64
C;6BC<
G4C
6@>5
I>5>6
L>??
=;
A5^;:
64
C;I>;L
A<H
5AG;6H D4<D;C<5
=H
F@4<;
L>6@><
6@>5
6>E;
F;C>4:0 0!02 3C>6;C>A
G4C
P;E4IA?
GC4E
OC464D4?
Q@;CAFH  
` 3?><>DA?
4C
CA:>4MCAF@>D
FC4MC;55>4<
4G
:>5;A5;
;RD;F6
L@;<
6@;
><I;56>MA64C
G;;?5
6@; 5B=a;D6
>5
56>??
=;<;G>6><M
GC4E
6C;A6E;<60
b86
>5
M;<;CA??H
FC;G;CA=?;
G4C
FA6>;<65
64 C;EA><
4<
6C;A6E;<6
FA56
><>6>A?
CA:>4MCAF@>D
FC4MC;55>4<
><
DA5;
6@;C;
>5
F5;B:4
c FC4MC;55>4<J
;RD;F6
L@;<
6@;
><I;56>MA64C
G;;?5
6@A6
6@;
D?><>DA?
F>D6BC;
LACCA<65 D@A<M><M
6@;CAFH
A6
><>6>A?
FC4MC;55>4<d0
` e<ADD;F6A=?;
Q4R>D>6H
bA5
:;G><;:
><
"\#"\#fd
OAC6>D>FA<6
C;gB;565
64
=;
L>6@:CAL<
GC4E
AD6>I;
6@;CAFH
S6AC6
4G
A<46@;C
5H56;E>D
A<6>DA<D;C
6C;A6E;<6
4C
FAC6>D>FA6>4<
><
A<46@;C ><I;56>MA6>4<A?
6@;CAF;B6>D
6C>A?0
h4DA?
FA??>A6>I;
CA:>46@;CAFHJ
A=?A6>4<J
4C
5BCM;CH
64
A 5>6;
4G
:>5;A5;
L>??
<46
<;D;55>6A6;
C;E4IA?
GC4E
FC464D4?
6@;CAFH0  
` 8<I;56>MA64C
:>5DC;6>4<
O45>6>I;
FC;M<A<DH
6;56 0!0N iGGcS6B:H
3C>6;C>A
` SDC;;<
GA>?BC;
O8
:;D>5>4<
64
;<:
6@;
56B:H  
` OAC6>D>FA<6
C;gB;565
64
=;
L>6@:CAL<
GC4E
56B:H0 AC6>D>FA<6
?456
64
G4??4L
BF
` 8<I;56>MA64C
:>5DC;6>4<
untitled h1
" #%&' ()( +&

&+
-+..+/012  
3
2%4&5652%7&
/5..
8$
6+7,59$4$9
.+,&
&+
:+..+/012
5:
'$
+4
,'$
:%5.,
&+
4$&147
:+4
;
,6'$91.$9
<5,5&, %79
5,
17%8.$
&+
8$
6+7&%6&$9
8=
&'$
,&19=
,5&$
,&%::( >'$
:+..+/57?
%6&5+7,
@1,&
8$
&%A$7
5:
%
2%4&5652%7&
:%5.,
&+
4$&147
&+
&'$
6.5756
:+4
%
4$B154$9 ,&19=
<5,5&C
" >'$
,5&$
/5..
%&&$@2&
&+
6+7&%6&
&'$
2%4&5652%7&
%79
4$,6'$91.$
&'$
@5,,$9
<5,5&
/5&'57
&'$ 7$D&
&/+
/$$A,
%79
6+17,$.
&'$
2%4&5652%7&
+7
&'$
5@2+4&%76$
+:
@%57&%5757?
&'$
%,,5?7$9 <5,5&
,6'$91.$
%79
%,6$4&%57
5:
&'$
2%4&5652%7&
/5,'$,
&+
%79E+4
,'+1.9
6+7&571$
57
&'$ ,&19=( " F$:+4$
%
2%4&5652%7&
5,
9$$@$9
.+,&
&+
:+..+/012G
&'$
57<$,&5?%&+4
+4
9$,5?7$$
/5..
@%A$ $<$4=
$::+4&
&+
4$?%57
6+7&%6&
/5&'
&'$
2%4&5652%7&
H/'$4$
2+,,58.$G  
&$.$2'+7$
6%..,
%79G 5:
7$6$,,%4=G
%7
IJF0%224+<$9
6$4&5:5$9
.$&&$4
&+
&'$
2%4&5652%7&K,
.%,&
A7+/7
@%5.57? %994$,,
+4
.+6%.
$B15<%.$7&
@$&'+9,L(
>'$,$
6+7&%6&
%&&$@2&,
,'+1.9
8$
9+61@$7&$9
57 &'$
2%4&5652%7&K,
@$956%.
4$6+49
+4
,&19=
:5.$( " M'+1.9
&'$
2%4&5652%7&
6+7&571$
&+
8$
174$%6'%8.$G
'$
+4
,'$
/5..
8$
6+7,59$4$9
&+
'%<$ /5&'94%/7
:4+@
&'$
,&19=
/5&'
%
245@%4=
4$%,+7
+:
.+,&
&+
:+..+/012(
untitled h1
n opqoprstuqt

Rvwsoutspqx
Y
Rvuxz[Vx  
37=
@$956%&5+7,
H+&'$4
&'%7
&'+,$
$D6.19$9
8=
&'$
6.5756%.
&45%.
24+&+6+.L
&'%&
%4$
6+7,59$4$9 7$6$,,%4=
&+
24+&$6&
,18\$6&
/$.:%4$
+4
%..$<5%&$
,=@2&+@,
%79
/5..
7+&
57&$4:$4$
/5&'
&'$
&45%. @$956%&5+7
@%=
8$
?5<$7
%&
&'$
I7<$,&5?%&+4K,
95,64$&5+7( ]%..5%&5<$
4%95+&'$4%2=
9$.5<$4$9
57
%
7+4@%.
+4?%70,2$%457?
&$6'75B1$
@%=
8$
%9@575,&$4$9 91457?
&'$
&45%.(
>'$
%,,$,,@$7&
+:
]\#
/5..
7+&
8$
8%,$9
+7
&'$
7$6$,,5&=
:+4
2%..5%&5<$ 4%95+&'$4%2=(
N^_ T`V
aPbbPcSQd
T[VUTRVQTX
X`PZbW
QPT
eV
UWRSQSXTV[VW
WZ[SQd
T`V
T[SUbf  
" g&'$4
5@@17+&'$4%25$,
+4
5@@17+,1224$,,5<$
941?,
H:+4
$D%@2.$G
6'$@+&'$4%2=
+4 ,=,&$@56
6+4&56+,&$4+59,
hijhkl
:+4
24+2'=.%D5,
+4
&4$%&@$7&
+:
%..$4?56
4$%6&5+7,G $79+6457$
4$2.%6$@$7&
&'$4%2=
%&
.+/
9+,$
24$975,+7$
mn
op
@?
9%5.=q
+4
$B15<%.$7&G
:+4 &'$
&4$%&@$7&
+:
543r,G
+4
:+4
,'+4&
6+14,$,
sn
o;
9%=,L
%,
%224+245%&$
@$956%.
&'$4%2=
:+4 174$.%&$9
@$956%.
6+795&5+7,
H$(?(
%,&'@%L(  
M&$4+59,
/5&'
7+
+4
@575@%.
,=,&$@56
$::$6& H&+256%.G
57'%.%&5+7L
%4$
%..+/$9(
" ]4+2'=.%6&56
1,$
+:
6+4&56+,&$4+59,
:+4
57:1,5+7
4$.%&$9
4$%6&5+7,
" 37=
.5<$
<%6657$
&'$4%25$,
:+4
&'$
24$<$7&5+7
+:
57:$6&5+1,
95,$%,$(
39@575,&4%&5+7
+: 57%6&5<%&$9
<%6657$,
5,
%..+/$9
H:+4
$D%@2.$G
57%6&5<%&$9
57:.1$7t%
<%6657$,
+4
.+6%..= %224+<$9
ugvI\#
<%6657$,L(
" M=,&$@56
%7&56%76$4
&4$%&@$7&(
untitled h1
n^w pt'v[

Rvwsoutspqx  
M18\$6&,
@1,&
8$
57,&416&$9
&+
57:+4@
&'$
57<$,&5?%&+4,
+:
&'$
6144$7&
+4
2.%77$9
1,$
+4
%..
+&'$4 @$956%&5+7,
91457?
&'$
,&19=
H576.1957?
24$,6452&5+7
@$956%&5+7,G
+<$40&'$06+17&$4
@$956%&5+7,G <5&%@57,
%79
'$48%.
%79
71&45&5+7%.
,122.$@$7&,L(
F5,2'+,2'+7%&$,
,&%4&$9
245+4
&+
,64$$757?  
activities or initiated during the course of the study to control bone pain may be used with caution.
untitled h1
correlative studies for research /

Exploratory immunologic studies will be conducted to evaluate the study drug's effect on the immune response before and after treatment and help improve the administered therapy. This will include functional and quantitative analyses of immune cell types (CD4 and CD8 T cells, natural killer [NK] cells, regulatory T cells [Tregs], myeloid-derived suppressor cells [MDSCs],
and dendritic cells) pre and post therapy as well as soluble factors which have been both positively and negatively associated with T cell activation and anti-tumor immunity (e.g., sCD27 and sCD40 ligand). In addition, T cell clonality and antigen specific T cell responses to E6/E7 oncoproteins before and after treatment will also be assessed. These assessments will help us evaluate the effect of treatment on the peripheral immune system. In addition to evaluate the effect of treatment on the tumor microenvironment, tumor immune infiltration as well as PD-L1 expression will be evaluated on optional biopsies pre and post treatment. Finally, TGF beta levels pre and post treatment will also be assessed to evaluate any correlation between changes in these values and response to treatment.
untitled h1
5.1.2 hv status

As the primary efficacy analysis, we will try to focus on HPV positive malignancies, it will be important to determine the HPV status of patients' tumors.  Therefore, where at all possible HPV testing will be done on archived tissue or optional biopsies. In addition to evaluate the correlation between peripheral HPV DNA testing and HPV testing on tumor tissue, circulating tumor DNA (e.g., HPV DNA) will also be assessed in the peripheral blood.
untitled h1
5.1.3 rna analysis

Where possible, RNA analysis will be done on the peripheral blood as well as archived tumor tissue or optional biopsies to help further evaluate changes in immune pathways with treatment as well as to determine tumor 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 in combination with M7824.  
| Test/assay       | Volume            | Type of tube   | Collection point   | Location of   |
|------------------|-------------------|----------------|--------------------|---------------|
| (pprox.)         | specimen analysis |                |                    |               |
| Standard and 123 | PBMC              | Sodium         | See study calendar | LTIB          |
| immune cell      | heparin           | 3.5            |                    |               |
| subsets by FACS  | (green top)       |                |                    |               |
| tubes            |                   |                |                    |               |  
| "#$%&'$$'(                                                          | )*+,-# .'//0*123                     | "(/# *4 %,5#                        | 6*++#7%8*9 /*89%                               | :*7'%8*9 *4  $/#78-#9 '9'+($8$                 |
|---------------------------------------------------------------------|--------------------------------------|-------------------------------------|------------------------------------------------|------------------------------------------------|
| ;<=>?@A=BC  D=BCEF@F AG  @HH<=I >ICC  F<JFI?F JE ;DKL               | MNOK                                 | LAP@<H  QIRBS@=  TUSII= ?ARV  ?<JIF | LII F?<PE >BCI=PBS  W2X                        | YZ[N                                           |
| D=?@UI= LRI>@G@>  [HH<=I \IFRA=FI  JE >E?A]@=I  F?B@=@=U BFFBE MNOK | LAP@<H  QIRBS@=  TUSII= ?ARV  ?<JIF  | LII F?<PE >BCI=PBS  W2X             | YZ[N                                           |                                                |
| FK^_` B=P FK^ !  C@UB=P JE aY[LD  LIS<H                             | LLZ                                  | LII F?<PE >BCI=PBS  W2X             | YZ[N                                           |                                                |
| bcdefg CIhICF JE  aY[LD AS JIBP  JBFIP H<C?@RCIi  BFFBEF MCBFHB     | a^ZD  TCBhI=PIS  ?ARV                | LII F?<PE >BCI=PBS  W2X             | YZ[N AS ^Sj Y@B=U  KBAkF YBJ                   |                                                |
| [HH<=I OBS]ISF  JE [lK                                              | Z<HAS  FBHRCIF                       | mnD                                 | LII F?<PE >BCI=PBS  W2X                        | oON Z[Oa YBJ                                   |
| \mD IiRSIFF@A=  CIhIC AG ``! UI=IF                                  | pQACI  JCAAP                         | LAP@<H  QIRBS@=  TUSII= ?ARV  ?<JIF | LII F?<PE >BCI=PBS  W2X                        | YZ[N B=P mK[  ;SIPIS@>] oI=AH@>  KASI ;B>@C@?E |
| \mD IiRSIFF@A=  CIhIC AG ``! UI=IF                                  | Z<HAS  FBHRCIF                       | mnD                                 | LII F?<PE >BCI=PBS  W2X                        | YZ[N B=P mK[  ;SIPIS@>] oI=AH@>  KASI ;B>@C@?E |
| lMq F?B?<F JE  MK\ AG ^mD                                           | Z<HAS  FBHRCIF                       | mnD                                 | LII F?<PE >BCI=PBS  W2X                        | ^Sj l@=S@>QkF YBJ                              |
| K@S><CB?@=U GSII  ?<HAS ^mD  T>G?^mDV JE MK\  FEF?IH MCBFHB         | a^ZD  TCBhI=PIS  ?ARV                | LII F?<PE >BCI=PBS  W2X             | ^Sj Y@B=U KBA YBJ                              |                                                |
| Z >ICC >CA=BC@?E JE  @HH<=FIr  RCB?GASH Z<HAS  FBHRCIF              | mnD                                  | LII F?<PE >BCI=PBS  W2X             | YZ[N B=P mK[  ;SIPIS@>] oI=AH@>  KASI ;B>@C@?E |                                                |
| Z >ICC >CA=BC@?E JE  @HH<=FIr  RCB?GASH MNOK                        | LAP@<H  QIRBS@=  TUSII= ?ARV  ?<JIFs | LII F?<PE >BCI=PBS  W2X             | YZ[N B=P mK[  ;SIPIS@>] oI=AH@>  KASI ;B>@C@?E |                                                |  
Patients will undergo blood and tissue sampling for research purposes on the time points outlined in the Study Calendar 3.5.  
Tissue samples will be sent to Laboratory of Pathology for disease evaluation first, leftover samples will be used for research.
untitled h1
5.2 sample collection 5.2.1 peripheral

Subjects will have approximately 100 mL of peripheral blood drawn at each time point specified in  Study Calendar 3.5 (five to six, 10-mL green top sodium heparin tubes for PBMC samples, two 8-mL serum-separating tube for serum samples, two 10-mL lavender EDTA tubes.
untitled h1
5.2.2 tissue samples

Where available archival tumor samples will be requested. For patients with lesions amenable to biopsy, two optional biopsies may be performed at baseline and at first restaging. CT or other imaging guidance will be used as appropriate. Tumor samples will be sent to the Laboratory of Pathology for disease evaluation and storage.
untitled h1
5.3 research analysis performed at

Unless otherwise specified, assessments will be performed at the Laboratory of Tumor Immunology and Biology at the NCI's Center for Cancer Research (CCR) and include:
untitled h1
5.3.1 standard and 123 immune

Per PI discrection, PBMCs, separated by Ficoll-Hypaque density gradient centrifugation, will be analyzed for changes in standard immune cell types (CD4 and CD8 T cells, natural killer [NK]
cells, regulatory T cells [Tregs], myeloid-derived suppressor cells [MDSCs], and dendritic cells)
as well as 123 immune cell subsets, using multi-color flow cytometry [ 41 ].
untitled h1
5.3.2

Functional Analysis of immune cell subsets from blood This analysis may include phenotypic and functional analysis of immune-cell subsets (such as CD4 and CD8 T cells, NK cells, Tregs, and MDSCs) including proliferation, cytokine production, lysis, and suppression using flow based assays.
untitled h1
5.3.3 pbmc antigen specific immune

Per PI discretion, PBMCs may be analyzed for antigen-specific immune responses to the oncoproteins E6 and E7 using an intracellular cytokine staining assay. PBMCs will be stimulated in vitro with overlapping 15-mer peptide pools encoding E6 and E7.  Control peptide pools will include evaluation of the use of human leukocyte antigens (HLA) 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-y, IL-2, tumor necrosis factor, and CD107a. If sufficient PBMCs are available, assays may also be performed for the development of T cells to other tumorassociated antigens.
untitled h1
5.3.4

Serum analyses of soluble factors Per PI discrection, sera will be analyzed pre- and post-therapy for the following soluble factors:
sCD27 and sCD40 ligand using commercial ELISAs.  
"\#$\#" %&'()'
'*'&+(,(
-./
012345
&676&(
%6/
%8
9,(:/6:;,.*<
=&'()'
>,&&
?6
'*'&+@69
=/6A
'*9
=.(;A;B6/'=+
-./
012345
&676&(
CD(,*E FG8HI
./
?6'9
?'(69
)D&;,=&6J
'(('+(
,*
;B6
GK8L
./
M/\#
G,'*E
N'.O(
G'?P\#
"\#$\#Q I*'&+(6(
.KD)./
K,((D6
-./
8))D*6
R'/S6/(
?+
8TNU
H;D9+
.,))D*6
,*-,&;/';,.*
'(
>6&&
'(
%MAGV
(;';D(
?+
8TN
>,;B,*
;B6
;D)./
),:/.6*7,/.*)6*; =/6
7(\#
=.(;
;/6';)6*;
)'+
?6
=6/-./)69
C:.&&'?./';,.*
>,;B
;B6
WRL
K8RF
G'?P\#
"\#$\#X YZI
'*'&+(,(
.?&..9
'*9
;D)./
;,((D6
%6/,=B6/'&
?&..9
(')=&6(
'*9
;D)./
(')=&6(
)'+
?6
'*'&+@69
;.
67'&D';6
,))D*6
/6&';69 =';B>'+(
/6&';69
;.
:'*:6/
./
'
=/.;.:.&
;B6/'=+
)6:B'*,()
.':;,.*\# YZI
6J=/6((,.*
&676&
.XX[
E6*6(
>,&&
?6
9.*6  
D(,*E
*'*.(;/,*E
=&';-./)
CGK8L
'*9
ZN8 \/696/,:S
W6*.),:
N./6
\':,&,;+P\#
\/69/,:S
E6*.),:
:./6
-':,&,;+U G6,9.(
L,.)69,:'&
Y6(6'/:B<
8*:U M/\#
],'.&,*
^D
IKY\<
Y)
N$[VQ _"Q[
%/.E/6((
M/,76 \/696/,:S<
RM
!VX[V %B\#
$[VA_ QAXQXX
untitled h1
'ab cdefgh

Cijkdlhm
Ikdnopql
Dqr
Rpcfjcpipjq  
"\# \#V H')=&6
K/':S,*E<
'*9
M,(=.(,;,.*
H')=&6(
>,&&
?6
./96/69
,*
NY8H
'*9
;/':S69
;B/.DEB
'
N&,*,:'&
K/,'&
M';'
R'*'E6)6*;
(+(;6)\# HB.D&9
'
NY8H
(:/66*
*.;
?6
'7',&'?&6<
;B6
NY8H
9.>*;,)6
=/.:69D/6(
>,&&
?6
-.&&.>69\# H')=&6(
>,&&
*.;
?6
(6*;
.D;(,96
;B6
Z';,.*'&
8*(;,;D;6(
-./
T6'&;B
CZ8TP
>,;B.D;
'==/.=/,';6 '==/.7'&(
'*9s./
'E/66)6*;(<
,/6tD,/69\#
KB6
%8
>,&&
/6:./9
'*+
&.((
./
D*'*;,:,=';69
96(;/D:;,.*
.(')=&6(
'(
'
967,';,.*\#
Y6=./;,*E
>,&& ?6
=6/
;B6
/6tD,/6)6*;(
.H6:;,.*
uav\#
"\# \#! H')=&6
R'*'E6)6*;
'*9
H;./'E6
';
N&,*,:'&
H6/7,:6(
%/.E/')
w
G6,9.(
L,.)69,:'& Y6(6'/:B<
8*:\#
CNH%P
L&..9
(')=&6(
>,&&
?6
=/.:6((69
';U
G6,9.(
L,.)69,:'&
Y6(6'/:B I;;*U
KB6/6('
LD/S( V["[
L.+&6(
H;/66; L&9E\#
xQsY..)
V!V \/696/,:S<
RM
!VX[!  
y*
9'+(
(')=&6(
'/6
9/'>*<
z6*
L'*EB
';
NH%
C='/;
.ZN8
\/696/,:S
N6*;/'&
Y6=.(,;./,6(P
(B.D&9 ?6
*.;,-,69
C=B.*6U
{$[V|
_ QA"_x$}
-'J
{$[V|
_ QAQ!!!P\#
HB6
>,&&
'//'*E6
(')6A9'+
:.D/,6/ 96&,76/+
.;B6
(=6:,)6*(\#
I&&
9';'
'((.:,';69
>,;B
;B6
=';,6*;
(')=&6(
,(
=/.;6:;69
?+
D(,*E
'
(6:D/6
9';'?'(6\#
I&&
N&,*,:'& HD==./;
G'?./';./+
H;'-/6:6,76
'**D'&
;/',*,*E
,*
)',*;',*,*E
/6:./9(O
:.*-,96*;,'&,;+\#
I&&
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. Samples will be tracked and managed by Central Repository database, where there is no link to personal identifiable information. All samples will be stored in either a -80°C 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 patient 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. The subcontractor's IRB reviews policies and procedures for labeling, data collection and storage, access, and security. The IRB will review protection of privacy issues prior to acceptance of any new work and in the event of change impacting privacy issues in existing work.  
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.  
!" "\# $%&'()*
+%,%-).
/0
12"
34--5*
6(77.
8279)**4,:72)
;68:< !" "\#"= 68:
97,>%9>
4,?72&%>47, 8()%*)
)@&%4(
A:B6(77.972)C&%4(",4D"-7E
%>
()%*>
F
D7G2*
/)?72)
>2%,*'72>4,*%&'()*
;>D) 324.%0
/)?72)
4*
'2)?)22).<"
372
*%&'()
'49HG'I
'%-)
=JF@==KL "
372
4&&).4%>)
D)('I
9%((
F J@MLJ@L=NJ
;&%4,
/(77.
'279)**4,972)
,G&/)2<
72I
4?
,7
%,*O)2I F J@MLJ@L=KJ
;&%4,
9(4,49%(
'D%2&%97(7-0
(%/
,G&/)2<"
372
PG)*>47,*
2)-%2.4,*%&'()
'279)**4,-I
97,>%9>
A:B6(77.972)C&%4(",4D"-7E"
untitled h1
!" "#"f %&'()

1%>%
:7(()9>47,  
Q((
*%&'()*
*),>
>7
>D)
6(77.
8279)**4,:72)
;68:<
O4((
/)
/%297.).I
O4>D
.%>%
),>)2).
%,. *>72).
4,
>D)
R%/&%>24S
G>4(4T).
/0
>D)
68:"
UD4*
4*
%
*)9G2)
'27-2%&I
O4>D
%99)**
>7
R%/&%>24S (4&4>).
>7
.)?4,).
34-(%/
')2*7,,)(I
OD7
%2)
4**G).
4,.4E4.G%(
G*)2
%997G,>*"
B,*>%((%>47,
7? R%/&%>24S
4*
(4&4>).
>7
97&'G>)2*
*')94?4).
/0
12"
34--"
UD)*)
97&'G>)2*
%((
D%E)
%
'%**O72. 2)*>249>).
(7-4,
*92)),"
R%/&%>24S
92)%>)*
%
G,4PG)
/%297.)
B1
?72
)E)20
*%&'()
%,.
*%&'()
/7SI
OD49D
9%,,7>
/)
>2%9). /%9H
>7
'%>4),>*
O4>D7G>
R%/&%>24S
%99)**"
UD)
.%>%
2)972.).
?72
)%9D
*%&'()
4,9(G.)*
>D) '%>4),>
B1I
,%&)I
>24%(
,%&)V'27>797(
,G&/)2I
>4&)
.2%O,I
909()
>4&)
'74,>I
.7*)I
&%>)24%(
>0')I %*
O)((
%*
/7S
%,.
?2))T)2
(79%>47,"
8%>4),>
.)&7-2%'D49*
%**794%>).
O4>D
>D)
9(4,49%(
9),>)2 '%>4),>
,G&/)2
%2)
'27E4.).
4,
>D)
*0*>)&"
372
)%9D
*%&'()I
>D)2)
%2)
,7>)*
%**794%>).
O4>D
>D) '279)**4,&)>D7.
;.)(%0
4,
*%&'()
'279)**4,-I
*>72%-)
97,.4>47,*
7,
>D)
O%2.I
)>9"<"
untitled h1
!" "#"# %&'()

$>72%-)  
6%297.).
*%&'()*
%2)
*>72).
4,
/%297.).
/7S)*
4,
%
(79H).
?2))T)2
%>
)4>D)2
@FJ
72
@NJW:
%9972.4,>7
*>%/4(4>0
2)PG42)&),>*"
UD)*)
?2))T)2*
%2)
(79%>).
7,*4>)
4,
>D)
68:
%,.
7??*4>)
%> A:B
32).)249H
:),>2%(
X)'7*4>720
$)2E49)*
4,
32).)249HI
+1"
Y4*4>72*
>7
>D)
(%/72%>720
%2) 2)PG42).
>7
/)
%997&'%,4).
/0
(%/72%>720
*>%??
%>
%((
>4&)*"
Q99)**
>7
*>72).
9(4,49%(
*%&'()*
4*
2)*>249>)."
$%&'()*
O4((
/)
*>72).
G,>4(
2)PG)*>).
/0
% 2)*)%29D)2
,%&).
7,
>D)
'27>797("
Q((
2)PG)*>*
%2)
&7,4>72).
%,.
>2%9H).
4,
R%/&%>24S"
Q(( 2)*)%29D)2*
%2)
2)PG42).
>7
*4-,
%
?72&
*>%>4,>D%>
>D)
*%&'()*
%2)
7,(0
>7
/)
G*).
?72
2)*)%29D 'G2'7*)*
%**794%>).
O4>D
>D4*
>24%(
;%*
')2
>D)
BX6
%''27E).
'27>797(<
%,.
>D%>
%,0
G,G*). *%&'()*
&G*>
/)
2)>G2,).
>7
>D)
68:"
B>
4*
>D)
2)*'7,*4/4(4>0
7?
>D)
A:B
824,94'%(
B,E)*>4-%>72
>7 ),*G2)
>D%>
>D)
*%&'()*
2)PG)*>).
%2)
/)4,G*).
4,
%
&%,,)2
97,*4*>),>
O4>D
BX6
%''27E%("
!" " 8279).G2)*
?72
$>72%-)
7?
U4**G)
$')94&),*
4,
>D)
R%/72%>720
7?
8%>D7(7-0 U4**G)*
.)*4-,%>).
?72
9(4,49%(
.4%-,7*>49*
%2)
>2%,*'72>).
>7
>D)
R%/72%>720
7?
8%>D7(7-0
;R8< OD)2)
>D)0
%2)
)S%&4,).
-27**(0
%,.
2)()E%,>
'72>47,*
%2)
?4S).I
)&/)..).
4,
'%2%??4,
%,. *)9>47,).
%,.
*>%4,).
?72
.4%-,7*>49
4,>)2'2)>%>47,"
Z,G>4(4T).
)S9)**
>4**G)*
%2)
*>72).
?72
G'
>7 >D2))
&7,>D*I
4,
%9972.%,9)
O4>D
:7(()-)
7?
Q&)249%,
8%>D7(7-4*>*V[74,>
:7&&4**47,
7, Q992).4>%>47,
7?
\)%(>D9%2)
]2-%,4T%>47,*
;:Q8V[:Q\]<
-G4.)(4,)*I
%,.
>D),
.4*9%2.)." 37((7O4,97&'()>47,
7?
>D)
.4%-,7*>49
O72HG'I
>D)
*(4.)*
%,.
>4**G)
/(79H*
%2)
*>72). 4,.)?4,4>)(0
4,
>D)
R85*
9(4,49%(
%29D4E)*"
Q((
*')94&),*
%2)
9%>%(7-G).
%,.
2)>24)E).
G>4(4T4,>D) 9(4,49%(
(%/72%>720
4,?72&%>47,
*0*>)&*I
4,
%9972.%,9)
O4>D
:Q8V[:Q\]
2)-G(%>47,*"
UD)
G*)
7? %,0
*>72).
*')94&),*
?72
2)*)%29D
'G2'7*)*
4*
7,(0
%((7O).
OD),
>D)
%''27'24%>)
BX6
%''27E%(
has been obtained. In some cases, this approval has been obtained via the original protocol on which the patient was enrolled.
untitled h1
5.4.5

Protocol Completion/Sample Destruction All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are remaining at the completion of the protocol will be stored in the conditions described above. The study will remain open so long as sample or data analysis continues. Samples from consenting subjects will be stored until they are no longer of scientific value or if a subject withdraws consent for their continued use, at which time they will be destroyed.  
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will be per the requirements of section 7.2.1.
untitled h1
5.5 s amples for g

In patients with available tumor tissue (either archival or by optional biopsy), HPV testing will be performed using the Roche Cobas or Becton Dickinson HPV PCR based DNA assay, if no prior HPV testing of the tumor has been performed. This will be done through collaboration with Dr. Hinrich's Lab.
untitled h1
5.5.2 circulating tumor dna

If sufficient plasma is available, select patient samples may be analyzed for circulating tumor DNA (Collaboration with Dr. Liang Cao).  Plasma DNA will be isolated with an automated purification system by Promega Corp using a system-attached bar-code reader to track samples and DNA products.  The circulating tumor/HPV DNA will be quantified with a digital droplet PCR system from Bio-Rad to obtain precise quantification. This is just quantification by PCR.  
There is no DNA sequencing.
untitled h1
5.5.3 t cell clonality at

Tumor tissue and blood from selected patients may be tested for T cell clonality using immunseq platform of adaptive biotechnologies (LTIB lab and Fredrick genomic core facility). V, D, and J genes of T cell receptors will be sequenced.
untitled h1
5.5.4 management of results

All samples will be coded as described in Section 7.2.1. None of the assays are expected to generate incidental findings as they're not broad enough in scope and we are not returning research results.
untitled h1
data collection and evaluation 6

The PI will be responsible for overseeing entry of data into an in-house password protected electronic system (C3D) 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 intervention, Study Day 1 through 28 days after removal from study treatment or until off-study, whichever comes first. Adverse events that are serious ned to be recorded through 28 days after the last intervention. Beyond 28 days after the last intervention and through long term follow up (survival of subject), only adverse events which are serious and related to the study intervention need to be recorded. An abnormal laboratory value will be recorded in the database as an AE only if the laboratory abnormality is characterized by any of the following:
.  
Results in discontinuation from the study  
.
Is associated with clinical signs or symptoms  
.
Requires treatment or any other therapeutic intervention  
.
Is associated with death or another serious adverse event, including hospitalization.  
.
Is judged by the Investigator to be of significant clinical impact  
.  
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 patient's outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect subject confidentiality and trial data has occurred, this will be reported expeditiously per requirements in Section 7.2.1.  
6.1.1 Exceptions to Data Collection and/or Reporting
untitled h1
events that do not meet

Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (e.g., an overnight stay to facilitate chemotherapy and related hydration therapy application) are not considered as SAEs. However, all events leading to unplanned hospitalizations or unplanned prolongation of an elective hospitalization (e.g., undesirable effects of any administered treatment) must be documented and reported as SAEs.
untitled h1
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)
Coded, linked or identified data with approved outside collaborators under appropriate agreements. Data will be shared through:
" \#$
%&'()*$+,+
-.
/00.-1,+
0*2345
.,0-647-.89
534$45/37.4/36:;-1: " <=>&?
@/*7-A/745
)-.
/5741474,6
4$
7B,
C34$45/3
C,$7,.D
" \#00.-1,+
-*764+,
5-33/2-./7-.6
*$+,.
/00.-0.4/7,
4$+414+*/3
/;.,,A,$76:
" E*2345/74-$
/$+F-.
0*2345
0.,6,$7/74-$6: G/7/
H433
2,
6B/.,+9 " <,)-.,
0*2345/74-$: \#7
7B,
74A,
-)
0*2345/74-$
-.
6B-.738
7B,.,/)7,.: I:J:J K,$-A45
G/7/
?B/.4$;
E3/$ L$34$M,+
;,$-A45
+/7/
H433
2,
+,0-647,+
4$
0*2345
;,$-A45
+/7/2/6,6
6*5B
/6
+2K/E
4$
5-A034/$5,
H47B
7B,
%&'
K,$-A45
G/7/
?B/.4$;
E-3458
untitled h1
nop qrstuvsr

Wqxyrqxz I:[:\ #$747*A-.
>,60-$6,  
=*A-.
/66,66A,$76
A/8
4$53*+,
7B,
)-33-H4$;
,1/3*/74-$69
0B8645/3
,]/A4$/74-$
@H47B 0B-7-;./0B
/$+
A,/6*.,A,$7
-)
6M4$
3,64-$6^
/6
/00345/23,D_
5.-66(6,574-$/3
4A/;4$;
*64$; 5-A0*7,+
7-A-;./0B8
@C=D
-.
A/;$,745
.,6-$/$5,
4A/;4$;
@`>&D
65/$
-)
7B,
5B,67^
/2+-A,$^ /$+
0,3146
@0,3146
65/$
46
-074-$/3
*$3,66
M$-H$
0,3145
+46,/6,
46
0.,6,$7
/7
2/6,34$,D_
$*53,/. 2-$,
65/$
)-.
6*2a,576
H47B
M$-H$F6*60,57,+
2-$,
3,64-$6_
/$+
C=
-.
`>&
65/$
-)
7B,
2./4$ @-$38
/6
534$45/338
H/../$7,+
2/6,+
-$
68A07-A6F)4$+4$;6D:
=B,
0.,),..,+
A,7B-+
-)
+46,/6, /66,66A,$7
46
C=
H47B
5-$7./67:
&)
C=
H47B
5-$7./67
46
5-$7./4$+45/7,+^
C=
-)
7B,
5B,67
H47B-*7 5-$7./67
/$+
`>&
65/$
-)
7B,
/2+-A,$F0,3146
46
0.,),..,+:
\#7
2/6,34$,^
7*A-.
3,64-$6
H433
2,
6,3,57,+
/$+
5/7,;-.4b,+
/6
7/.;,7
-.
$-$(7/.;,7
3,64-$6:
=/.;,7 3,64-$6
4$53*+,
7B-6,
3,64-$6
7B/7
/.,
A,/6*.,/23,
0,.
?,574-$
NOPOc:
`/34;$/$7
38A0B
$-+,6
H47B /
6B-.7
/]46
+4/A,7,.
d
\e
AA
5/$
2,
5-$64+,.,+
7/.;,7
3,64-$6:
L0
7/
A/]4A*A
-)
J
7/.;,7 3,64-$6
0,.
-.;/$
/$+
e
7/.;,7
3,64-$6
4$
7-7/3
H433
2,
4+,$74)4,+
/7
2/6,34$,:
=B,6,
3,64-$6
6B-*3+ 2,
.,0.,6,$7/741,
-)
/33
4$1-31,+
-.;/$6
/$+
6,3,57,+
2/6,+
-$
7B,4.
64b,
@7B-6,
H47B
7B,
3-$;,67 +4/A,7,.D
/$+
7B,4.
6*47/243478
)-.
/55*./7,
.,0,/7,+
A,/6*.,A,$76:
\#
6*A
-)
7B,
3-$;,67
3,64-$ +4/A,7,.
@ffGD
)-.
/33
7/.;,7
3,64-$6
H433
2,
5/35*3/7,+
/$+
.,0-.7,+
/6
7B,
2/6,34$,
6*A
ffG:
g-. A/34;$/$7
38A0B
$-+,6
4+,$74)4,+
/6
7/.;,7
3,64-$6^
7B,
6B-.7
/]46
+4/A,7,.
H433
2,
*6,+
4$
7B,
6*A -)
ffG
5/35*3/74-$:
\#33
-7B,.
3,64-$6
@-.
647,6
-)
+46,/6,D
6B-*3+
2,
4+,$74)4,+
/6
$-$(7/.;,7 3,64-$6
@4$53*+4$;
2-$,
3,64-$6D:
\#33
0-67(2/6,34$,
.,60-$6,
/66,66A,$76
6B-*3+
)-33-H
7B,
6/A,
3,64-$6
4+,$74)4,+
/7
2/6,34$,:
=B, 6/A,
A-+,
-)
/66,66A,$7
@,:;:^
C=D
*6,+
74+,$74)8F,1/3*/7,
3,64-$6
/7
2/6,34$,
6B-*3+
2,
*6,+ 7B.-*;B-*7
7B,
5-*.6,
-)
7B,
67*+8
*$3,66
6*2a,57
6/),78
$,5,6647/7,6
/
5B/$;,
@,:;:^
/33,.;45 .,/574-$
75-$7./67
A,+4/D:
g-.
7B,
0.4A/.8
,$+0-4$7
/$747*A-.
/5741478
H433
2,
,1/3*/7,+
H47B
7/.;,7
/$+F-.
$-$(7/.;,7 3,64-$6
/55-.+4$;
7>hC&?=
i,.64-$
\:\
untitled h1
i[j g46/6

E/./A,7,.6  
`,/6*./23,
+46,/6,9
`,/6*./23,
3,64-$6
/.,
+,)4$,+
/6
7B-6,
7B/7
5/$
2,
/55*./7,38
A,/6*.,+
4$ /7
3,/67
-$,
+4A,$64-$
@3-$;,67
+4/A,7,.
72,
.,5-.+,+D9
.  
By chest x-ray >20 mm;  
.  
By CT scan:
o Scan slice thickness 5mm or under: as >10 mm; Scan slice thickness >5 mm: double the slice thickness o
.  
With calipers by 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 patient, these are preferred for selection as target lesions.  
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease.  
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up.  
6.3.3 Methods for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and nver 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.
untitled h1
response criteria 6.3.4

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 Prinicpal Investigator. For each subject, the Investigator will designate 1 or more of the following measures of tumor status to follow for determining response: CT or MRI images of primary and / or metastatic tumor masses, physical examination findings, and the results of other assessments. All available images collected during the trial period will be considered. The most appropriate measures to evaluate the tumor status of a subject should be used. The measure(s) to be chosen for sequential evaluation during the trial have to correspond to the measures used to document the progressive tumor status that qualifies the subject for enrollment. The tumor response assessment will be assessed and listed according to the Study Calendar 3.5.  
The foreseen treatment duration is until disease progression verified by a scan subsequent to the initial documentation of PD, unacceptable toxicity, or any criterion for withdrawal from the trial occurs (see Section 3.6). Before stopping the treatment, progressive disease should be confirmed
"\#
$%&'$('
)
*+
,
-../0
123.4.3&"5\#
,
-../06
"7*
(+*
5&*.38
&4*.3
23+'3.00$+(
9&0
"..(
:$&'(+0.: &;;+3:$('
*+
<=>?@A
BCB
D)E6
)FGC
?4
23+'3.00$+(
$0
"&0.:
+(
*9.
+;;733.(;.
+4
&
(.5.0$+(
$( &(
&3.&
(+*
0;&((.:
&*
H&0.5$(.6
&
473*9.3
+(I0*7:\#
0;&(
,
-../0
5&*.3
09+75:
".
;+(0$:.3.: ".4+3.
2.34+3%$('
*9.
EJIK&\#
@&4.*\#
L+55+-I72
M$0$*C
A3.&*%.(*
%&\#
".
;+(*$(7.:
:.02$*. 23+'3.00$+(
&;;+3:$('
*+
<=>?@A
BCB
&*
&(\#
*$%.
$4N
O A9.3.
&3.
(+
(.+3
;+(;.3($('
0\#%2*+%0C  
O A9.3.
$0
(+
:.;3.&0.
$(
=>PQ
R@C
.
?(M.0*$'&*+3
:+.0
(+*
;+(0$:.3
$*
(.;.00&3\#
*+
&:%$($0*.3
&
0&5M&'.
*9.3&2\#C
A9.
*3.&*%.(*
09+75:
".
0*+22.:
$%%.:$&*.5\#6
$4
*9.
07"S.;*
:+.0
(+*
*+5.3&*.
TUJE)
+3
$4 *9.3&2.7*$;
4&$573.
+;;7306
-9$;9
3.V7$3.0
73'.(*
*3.&*%.(*
-$*9
&(
&::$*$+(&5
:37'
+3
3.075*0
$( ;5$($;&55\#
0$'($4$;&(*
23+'3.00$+(
W
:.*.3$+3&*$+(C
A7%+3
3.02+(0.0
*+
*3.&*%.(*
-$55
".
&00$'(.:
"&0.:
+(
*9.
.M&57&*$+(
+4
*9.
3.02+(0.
+4
*&3'.*6 (+(I*&3'.*6
&(:
(.5.0$+(0
&;;+3:$('
*+
<=>?@A
BCB
1&55
%.&073.%.(*0
09+75:
".
3.;+3:.:
$( %.*3$;
(+*&*$+(8C O A+
&00.00
+"S.;*$M.
3.02+(0.6
*9.
*7%+3
"73:.(
&*
"&0.5$(.
-$55
".
.0*$%&*.:
&(:
70.:
4+3 ;+%2&3$0+(
-$*9
07"0.V7.(*
%.&073.%.(*0C
X*
"&0.5$(.6
*7%+3
5.0$+(0
-$55
".
;&*.'+3$Y.:
$( *&3'.*
&(:
(+(I*&3'.*
5.0$+(0
&;;+3:$('
*+
<=>?@A
BCBC
<.075*0
4+3
*9.0.
.M&57&*$+(0
-$55
".
3.;+3:.:
-$*9
&0
%7;9
02.;$4$;$*\#
&0
2+00$"5.
0+
*9&*
23. &(:
2+0*I*3.&*%.(*
3.075*0
-$55
23+M$:.
*9.
".0*
+22+3*7($*\#
4+3
.M&57&*$('
*7%+3
3.02+(0.C
X(\#
><
+3
R<
09+75:
".
;+(4$3%.:
&;;+3:$('
*+
<=>?@A
BCB
1Z[\]^
_8C
?(
*9.
;&0.
+4
&
R<
+3 ><6
&
;+(4$3%&*+3\#
>A
+3
T<?
0;&(
09+75:
".
:+(.
(+
0++(.3
*9&(
)
-../0
123.4.3&"5\#
&*
*9. 0;9.:75.:
,I-../
$(*.3M&58C
A9.
?(M.0*$'&*+3
%&\#
2.34+3%
0;&(0
$(
&::$*$+(
*+
&
0;9.:75.:
*3$&5
0;&(
4+3
%.:$;&5
3.&0+(0
+3
$4 *9.
?(M.0*$'&*+3
0702.;*0
RKC
Z[\]^
_`
a^bcdeb^
fghi^gh[
jdg
k[ih^eib
lhim
n^[bog[\]^
phb^[b^
qh`^`r
Z[gs^i
phb^[b^t  
| Z[gs^i  x^bhdeb   | ydezZ[gs^i  x^bhdeb y^l  x^bhdeb {|^g[]]  a^bcdeb^ }^bi {|^g[]] a^bcdeb^ lm^e  fdejhg~[ihde hb a^ohg^€                                |    |    |    |
|-------------------|--------------------------------|----|----|----|
| ><                | ><                             | v+ | >< | ') -/0C >+(4$3%&*$+(ww    |
| ><                | v+(I ><Wv+(IRK                 | v+ | R< |    |
| ><                | v+*  .M&57&*.:                 | v+ | R< |    |
| R<                | v+(I ><Wv+(I RKW(+*  .M&57&*.: | v+ | R< | ') -/0C >+(4$3%&*$+(ww    |
| @K                | v+(I ><Wv+(I                   | v+ | @K | K+;7%.(*.: &* 5.&0* +(;. ')  -/0C 43+% "&0.5$(.ww    |  
A&3'.*
u.0$+(0v+(IA&3'.*
u.0$+(0 v.u.0$+(0PM.3&55
<.02+(0. H.0*
PM.3&55
<.02+(0.
-9.(
>+(4$3%&*$+(
$0
<.V7$3.:w  
| "#$%&'  ()*+,*'(-   |                                                                                                                      |               |    |                       |
|---------------------|----------------------------------------------------------------------------------------------------------------------|---------------|----|-----------------------|
| "#                  | .%/                                                                                                                  | 0(1 &2  3& "# |    |                       |
| .%/                 | "#444                                                                                                                | 0(1 &2  3& "# |    |                       |
| .%/                 | .%/                                                                                                                  | 0(1           | "# | %& 526&2 7#8 "9 &2 :9 |
| 4                   | 7(( 9;:<7= !>! ?*%,1@265' A&2 A,2'B(2 -('*6+1 &% CB*' 61 ()6-(%@( &A * %(C +(16&%>                                   |               |    |                       |
| 4                   | D%+/ A&2 %&%E2*%-&?6F(- '26*+1 C6'B 2(15&%1( *1 526?*2/ (%-5&6%'>                                                    |               |    |                       |
| 444                 | <% (G@(5'6&%*+ @62@,?1'*%@(18 ,%(H,6)&@*+ 52&I2(116&% 6% %&%E'*2I(' +(16&%1 ?*/ J( *@@(5'(- *1  -61(*1( 52&I2(116&%> |               |    |                       |
| 3&'(K               | "*'6(%'1 C6'B * I+&J*+ -('(26&2*'6&% &A B(*+'B 1'*',1 2(H,626%I -61@&%'6%,*'6&% &A '2(*'?(%' C6'B&,'  &JL(@'6)( ()6-(%@( &A -61(*1( 52&I2(116&% *' 'B*' '6?( 1B&,+- J( 2(5&2'(- *1 MNOPO  Q ;)(2/ (AA&2' 1B&,+- J( ?*-( '& -&@,?(%' 'B( &JL(@'6)( 52&I2(116&% ()(% *A'(2  -61@&%'6%,*'6&% &A '2(*'?(%'>                                                                                                                      |               |    |                       |  
.1
*%
(G5+&2*'&2/
(%-5&6%'
*%'6',?&2
*@'6)6'/
C6++
*+1&
J(
()*+,*'(*@@&2-6%I
'&
69;:<7=
RSSTK U16%I
69;:<7=
@26'(26*
'B(
A&++&C6%I
C6++
J(
6%@&25&2*'(6%'&
*11(11?(%'K
!>.%
6%@2(*1(
6%
'B(
1,?
&A
'*2I('
+(16&%1
&A
?&2(
'B*%
VWX8
,%(H,6)&@*+
6%@2(*1(
6%
%&%E '*2I('
+(16&%1
&2
%(C
+(16&%1
2(1,+'
6%
6U"\#
Y,%@&%A62?(52&I2(116)(
-61(*1(Z[
6U"\#
@*% J(
*116I%(?,+'65+(
'6?(1
*1
+&%I
*1
6:"\#
Y@&%A62?(52&I2(116)(
-61(*1(Z
61
%&' @&%A62?(*'
'B(
%(G'
*11(11?(%'>  
V>"2&I2(116&%
61
@&%A62?(6%
'B(
'*2I('
+(16&%
@*'(I&2/
6A
'B(
%(G'
6?*I6%I
*11(11?(%'
*A'(2 6U"\#
YS\]
C((^1
+*'(2Z
@&%A62?1
*
A,2'B(2
6%@2(*1(
6%
1,?
&A
?(*1,2(1
&A
'*2I('
-61(*1( A2&?
6U"\#8
C6'B
*%
6%@2(*1(
&A
*'
+(*1'  
??>
"2&I2(116&%
61
@&%A62?(6%
'B(
%&%E'*2I(' +(16&%
@*'(I&2/
6A
1,J1(H,(%'
6?*I6%I8
-&%(
S\]
C((^1
*A'(2
6U"\#8
1B&C1
*
A,2'B(2 ,%(H,6)&@*+
6%@2(*1(
6%
%&%
'*2I('
+(16&%1>
"2&I2(116&%
61
@&%A62?(6%
'B(
%(C
+(16&%1 @*'(I&2/
6A
*'
%(G'
*11(11?(%'
*--6'6&%*+
%(C
+(16&%1
*55(*2
&2
*%
6%@2(*1(
6%
16F(
&A 52()6&,1+/
1((%
%(C
+(16&%1
61
1((%
_`a
??
A&2
1,?
&A
%(C
+(16&%
'*2I('Z>
b>c&C()(28
'B(
@26'(26*
A&2
6:"\#
Y*A'(2
6U"\#Z
*2(
%&'
@&%16-(2('&
B*)(
J((%
?('
6A @&?5+('(
2(15&%1(8
5*2'6*+
2(15&%1(8
&2  
1'*J+(
-61(*1(
@26'(26*
Y@&?5*2(C6'B
J*1(+6%( *%*1
-(A6%(J/
9;:<7=
!>!Z
*2(
?('
*'
'B(
%(G'
*11(11?(%'
*A'(2
6U"\#>
=B(
1'*',1
61 2(1('
Y,%+6^(
9;:<7=
!>!8
6%
CB6@B
*%/
52&I2(116&%
52(@+,-(1
+*'(2
@&?5+('(
2(15&%1(8 5*2'6*+
2(15&%1(8
&2
1'*J+(
-61(*1(Z>
6:98
6"98
&2
67\#
1B&,+'B(%
J(
*116I%(-[
*%6A
%& @B*%I(
61
-('(@'(-8
'B(%
'B(
'6?(5&6%'
2(15&%1(
61
6U"\#>
d>b> \#,2*'6&%
&A
9(15&%1(
\#,2*'6&%
&A
&)(2*++
2(15&%1(K  
=B(
-,2*'6&%
&A
&)(2*++
2(15&%1(
61
?(*1,2(A2&?
'B(
'6?( ?(*1,2(?(%'
@26'(26*
*2(
?('
A&2
:9
&2
"9
YCB6@B()(2
61
A621'
2(@&2-(-Z
,%'6+
'B(
A621'
-*'(
'B*' 2(@,22(%'
&2
52&I2(116)(
-61(*1(
61
&JL(@'6)(+/
-&@,?(%'(->
\#,2*'6&%
&A
1'*J+(
-61(*1(K  
7'*J+(
-61(*1(
61
?(*1,2(A2&?
'B(
1'*2'
&A
'B(
'2(*'?(%'
,%'6+
'B( @26'(26*
A&2
52&I2(116&%
*2(
?('>
"\#$\#" %&'(&)**+',-.&))
/0&1+123
4%./5
%./
+*
6)7+,)6
2*
89)
60&28+',
'7
8+:)
7&':
*82&8
'7
8&)28:),8
8'
8+:)
'7
;&'(&)**+',
'&
6)289< =9+>9)1)&
'>>0&*
7+&*8\#
untitled h1
?@a bcdefebg

Fhebihej  
K9)
7'33'=+,(
261)&*)
)1),8
:2,2():),8
(0+6)3+,)*
2&)
+,8),6)6
8'
),*0&)
89)
*27)8L
'7
)2>9 ;28+),8
=9+3)
',
89)
*806L\#  
K9)
6)*>&+;8+',*
2,6
(&26+,(
*>23)*
7'0,6
+,
89)
&)1+*)6
MNO N'::',
K)&:+,'3'(L
N&+8)&+2
7'&
P61)&*)
Q1),8*
4NKNPQ5
1)&*+',  
=+33
R)
08+3+S)6
7'&
PQ &);'&8+,(\#  
P33
2;;&';&+28)
8&)28:),8
2&)2*
*9'036
921)
2>>)**
8'
2
>';L
'7
89)
NKNPQ
1)&*+',
\#  
4988;*TUU>8);\#>2,>)&\#('1U;&'8'>'36)1)3';:),8U)3)>8&',+>V2;;3+>28+',*U>8>\#98:5
untitled h1
w@s xfe

Fcexefjc
Aehifbch
Hizchbex[  
%&'R3):*
)l;)6+8+'0*3L
&);'&8)6
8'
89)
pn/h%
+,
+hO/
=+33
23*'
R)
&);'&8)6
8'
89)
MNO
N3+,+>23 q+&)>8'&\#  
P
*);2&28)
*0R:+**+',
+*
,'8
,)>)**2&L
2*
&);'&8*
+,
+hO/
=+33
R)
212+32R3)
8'
89) N3+,+>23
q+&)>8'&\# O,
266+8+',
8'
89'*)
&);'&8*<
233
6)289*
8928
'>>0&
=+89+,
$f
62L*
278)&
&)>)+1+,(
2
&)*)2&>9 +,8)&1),8+',
t9'036
R)
&);'&8)6
1+2
):2+3
8'
89)
N3+,+>23
q+&)>8'&
0,3)**
89)L
2&)
60)
8' ;&'(&)**+1)
6+*)2*)\# K'
&);'&8
89)*)
6)289*<
;3)2*)
*),6
2,
):2+3
6)*>&+R+,(
89)
>+&>0:*82,>)*
'7
89)
6)289
8'
q&\# q2908
28
MNONNhuPv:2+3\#,+9\#('1
=+89+,
',)
R0*+,)**
62L
'7
3)2&,+,(
'7
89)
6)289
untitled h1
w@a xey

Hi\]Ehia
Ajbj
Jxa
_Jbibg
^Cxebchex[
Zcjx K#W#G %&+,>+;23
O,1)*8+(28'&Uh)*)2&>9
K)2:  
K9)
>3+,+>23
&)*)2&>9
8)2:
=+33
:))8
',
2
&)(032&
R2*+*
42;;&'l+:28)3L
=))x3L5
=9),
;28+),8*
2&) R)+,(
2>8+1)3L
8&)28)6
',
89)
8&+23
8'
6+*>0**
)2>9
;28+),8<
),&'33:),8
2,6
6282
:2,2():),8 +**0)*\#
q)>+*+',*
2R'08
6'*)
3)1)3
),&'33:),8
2,6
6'*)
)*>2328+',
=+33
R)
:26)
R2*)6
',
89) 8'l+>+8L
6282
7&':
;&+'&
;28+),8*\#
P33
6282
=+33
R)
>'33)>8)6
+,
2
8+:)3L
:2,,)&
2,6
&)1+)=)6
RL
89)
;&+,>+;23
+,1)*8+(28'&
'&
2
3)26 2**'>+28)
+,1)*8+(28'&\#
Q1),8*
:))8+,(
&)m0+&):),8*
7'&
)l;)6+8)6
&);'&8+,(
2*
6)*>&+R)6
+, /)>8+',
W@i@d
=+33
R)
*0R:+88)6
=+89+,
89)
2;;&';&+28)
8+:)3+,)*\#
\#
The principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff.
untitled h1
7.4.2

Data Safety Monitoring Board (DSMB)
The DSMB is an independent group of at least 3 experts that monitors participant safety and advises The Sponsor. DSMB members will be separate and independent of study staff participating in this trial and should not have scientific, financial, or other conflicts of interest related to this trial. The DSMB will consist of members with appropriate expertise to contribute to the interpretation of data from this trial. A quorum will consist of a simple majority.  
The DSMB will review cumulative safety data from this trial at least annually.  
The DSMB will meet when requested by the sponsor or PI. The DSMB will have a final review meeting at the end of the study.  
Procedures for DSMB reviews/meetings will be defined in the DSMB charter. The DSMB will review applicable data, including, but not limited to, enrollment, demographics, dosing data, clinical laboratory data, and safety data, at scheduled timepoints during this trial as defined in the DSMB charter. The DSMB will review blinded aggregate data in the open session of the DSMB
metings.  
Additional data may be requested by the DSMB, and interim statistical reports may be generated as deemed necessary and appropriate by the Sponsor. As an outcome of each review/meeting, the DSMB will make a recommendation as to the advisability of proceeding with study product administration, and to continue, modify, or terminate this trial.
untitled h1
sponsor safety reporting 8 8.1

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)).
untitled h1
8.1.2

Adverse Event of Special Interest (AESI)
Mucosal bleeding events which are at least possibly related to study drug (M7824) will be captured as AESIs. These events will not require expedited reporting to the study sponsor unless they also meet SAE criteria.
untitled h1
8.1.3

Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following:
.  
Death,
" \#
$%&'()*+',)'-%-.
,/0'+1'
'0'-)
21''
3'4)%567879:  
;-<,)%'-)
*51<%),$%=,)%55+
<+5$5-.,)%55&
'>%1)%-.
*51<%),$%=,)%5-
? \#
*51<%),$%=,)%5-@,/A%11%5)*,)
%1
<+'(<$,--'/
2%B'BC
'$'4)%0'
5+
14*'/D$'/
1D+.'+E ,++,-.'/
<+%5+
)5
)*'
1),+)
5&
)*'
1)D/E:C
,
<$,--'/
*51<%),$%=,)%5&5+
<+'('>%1)%-. 45-/%)%5-C
5+
,
<+54'/D+'
+'FD%+'/
GE
)*'
<+5)545$C
H%)*5D)
,
1'+%5D1
/')'+%5+,)%5%- *',$)*C
%1
-5)
45-1%/'+'/
,
1'+%5D1
,/0'+1'
'0'-)B
? \#
*51<%),$%=,)%5-@,/A%11%5)*,)
%1
15$'$E
/+%0'GE
-5-(A'/%4,$
+',15-1
2'B.BC *51<%),$%=,)%5&5+
<,)%'-)
5+
1DGI'4)
45-0'-%'-4':
%1
-5)
45-1%/'+'/
,
1'+%5D1
,/0'+1' '0'-)B ? JA'+.'-4E
+55A
0%1%)1
5+
1),E1
%5G1'+0,)%5D-%)1
)*,)
/5
-5)
+'1D$)
%,/A%11%5)5 )*'
*51<%),$
H5D$/
-5)
G'
45-1%/'+'/
,
1'+%5D1
,/0'+1'
'0'-)B
K*'
+',15&5+
1''L%-. A'/%4,$
4,+'
1*5D$/
G'
'0,$D,)'/
&5+
A'')%-.
5-'
5&
)*'
5)*'+
1'+%5D1
4+%)'+%,B
" M'+1%1)'-)
5+
1%.-%&%4,-)
%-4,<,4%)E
5+
1DG1),-)%,$
/%1+D<)%55&
)*'
,G%$%)E
)5
45-/D4) -5+A,$
$%&'
&D-4)%5-1
" \#
45-.'-%),$
,-5A,$E@G%+)*
/'&'4)
;A<5+),-)
A'/%4,$
'0'-)1
)*,)
A,E
-5)
+'1D$)
%/',)*C
G'
$%&'()*+',)'-%-.C
5+
+'FD%+' *51<%),$%=,)%5A,E
G'
45-1%/'+'/
,
1'+%5D1
,/0'+1'
/+D.
'><'+%'-4'
H*'-C
G,1'/
D<5- ,<<+5<+%,)'
A'/%4,$
ID/.A'-)C
)*'E
A,E
I'5<,+/%='
)*'
<,)%'-)
5+
1DGI'4)
,-/
A,E
+'FD%+' A'/%4,$
5+
1D+.%4,$
%-)'+0'-)%5)5
<+'0'-)
5-'
5&
)*'
5D)45A'1
$%1)'/
%)*%1
/'&%-%)%5-B
NBOB! P%&'()*+',)'-%-. \#,/0'+1'
'0'-)
5+
1D1<'4)'/
,/0'+1'
+',4)%5%1
45-1%/'+'/
Q$%&'()*+',)'-%-.Q
%&C
%)*'
0%'H
5& '%)*'+
)*'
%-0'1)%.,)5+
5+
1<5-15+C
%)1
544D++'-4'
<$,4'1
)*'
<,)%'-)
5+
1DGI'4)
,)
%AA'/%,)'
+%1L
5& /',)*B
;)
/5'1
-5)
%-4$D/'
,,/0'+1'
'0'-)
5+
1D1<'4)'/
,/0'+1'
+',4)%5)*,)C
*,/
%)
544D++'/
%, A5+'
1'0'+'
&5+AC
A%.*)
*,0'
4,D1'/
/',)*B
2ROSTUVORBVR:
NBOB 3'0'+%)E K*'
1'0'+%)E
5&
',4*
\#/0'+1'
J0'-)
H%$$
G'
,11'11'/
D)%$%=%-.
)*'
SKS\#J
0'+1%5 BWB
untitled h1
nbobx u')%5-1%<

)5
3)D/E
M+5/D4)  
\#$$
\#J1
H%$$
*,0'
)*'%+
+'$,)%5-1*%<
)5
1)D/E
<+5/D4)
,11'11'/
D1%-.
)*'
)'+A1Y  
+'$,)'/
5+
-5) +'$,)'/B " U'$,)'/
Z
K*'+'
%1
,
+',15-,G$'
<511%G%$%)E
)*,)
)*'
1)D/E
<+5/D4)
4,D1'/
)*'
,/0'+1' '0'-)B
U',15-,G$'
<511%G%$%)E
A',-1
)*,)
)*'+'
%1
'0%/'-4'
)5
1D..'1)
,
4,D1,$
+'$,)%5-1*%< G')H'')*'
1)D/E
<+5/D4)
,-/
)*'
,/0'+1'
'0'-)B  
" [5)
U'$,)'/
Z
K*'+'
%1
-5)
,
+',15-,G$'
<511%G%$%)E
)*,)
)*'
,/A%-%1)+,)%55&
)*'
1)D/E <+5/D4)
4,D1'/
)*'
'0'-)B
untitled h1
67 ]^^^^'ab

Cd
^]D_Be
_F_Ab^  
\#J
%-&5+A,)%545$$'4)'/
H%$$
%-4$D/'
'0'-)
/'14+%<)%5-C
/,)'
5&
5-1')C
,11'11A'-)
5&
1'0'+%)E ,-/
+'$,)%5-1*%<
)5
1)D/E
<+5/D4)
,-/
,$)'+-,)'
')%5$5.E
2%&
-5)
+'$,)'/
)5
1)D/E
<+5/D4):C
/,)'
5& +'15$D)%55&
)*'
'0'-)C
1'+%5D1-'11
,-/
5D)45A'B
K*'
,11'11A'-)
5&
1'0'+%)E
,-/
+'$,)%5-1*%<
)5 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 7.2.1. 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.
untitled h1
8.3 reporting of serious adverse

Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of Special Interest that require expedited reporting must be submitted immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report form.  Any exceptions to the expedited reporting requirements are found in Section 8.4.  
All SAE reporting must include the elements described in Section 8.2.  
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.
untitled h1
w w aiver of expedited

As overall survival, which includes death due to disease progression and hospitalization due to disease progression are part of the study objectives, and captured as an endpoint in this study, death/hospitalization due to disease progression will not be reported in expedited manner to the sponsor. However, if there is evidence suggesting a causal relationship between the study drug and the event, report the event in an expedited manner according to Section 7.2.1.
untitled h1
8.5 safety reporting criteria to

To be sent by Office of Sponsor and Regulatory Oversight, CCR, NCI/NIH:
The following reportable events must be submitted to EMD Serono within 2 business days or 3 calendar days (whichever comes first) using the applicable safety report form provided. The Sponsor will assume responsibility for submitting the reportable event(s) to EMD Serono as well as ensuring that any local reporting requirements are completed in parallel.  
.  
Serious Adverse Events  
.  
Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse event)
.  
Occupational exposure (even if not associated with an adverse event)
.  
Potential drug-induced liver injury (Hy's Law cases): These events are considered important medical events and should be reported as SAEs.  
.  
In addition, all aggregated AEs including periodicity will be collected in tabulated form and reported to EMD Serono as outlined in the Collaborative Agreement.
untitled h1
to be sent by study

.  
An overdose is defined as any dose twice the recommended single dose. Any overdose must be recorded in the trial medication section of the eCRF.  
For monitoring purposes, any case of overdose, whether or not associated with an AE
.  
(serious or non-serious), must be reported to the sponsor.  
There are no known symptoms of M7824 overdose to date. The Investigator should monitor closely for AEs should an overdose occur and use his or her clinical judgment in providing symptomatic / supportive care as medically indicated. There is no known antidote for M7824.
untitled h1
contact information for submission of

Fax: +49 6151 72 6914 O
E-mail: GlobalDrugSafety@merckgroup.com Specifying:
PROTOCOL Number and/or Title EMD Serono assigned Study Number SUBJECT Number SITE Number/PI Name SAE/ONSET DATE
untitled h1
reporting pregnancy 8.6

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 cn be found here:
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
"\#$\#% &'()*+',
)-./01*) 23
'
.'(4)+(
5)6/7)0
.*)8+'+(
91*4+8
(:)
6/1*0)
/3
(:)
0(19;<
(:)
0(19;
(*)'(7)+(
0:/1,9
5) 9406/+(4+1)9
477)94'(),;<
'+9
(:)
.*)8+'+6;
*)./*()9
(/
(:)
=./+0/*
+/
,'()*
(:'+
>?
:/1*0
/3 @:)+
(:)
2+A)0(48'(/*
5)6/7)0
'@'*)
/3
4(\#
B:)
2+A)0(48'(/*
0:/1,9
+/(43;
(:)
=./+0/*
+/
,'()* (:'+
>?
:/1*0
/3
@:)+
(:)
/1(6/7)
/3
(:)
C*)8+'+6;
5)6/7)0
D+/@+< C*)8+'+6;
4(0),3
40
+/(
*)8'*9)9
'0
'+
=EF\#
G/@)A)*<
6/+8)+4(',
'5+/*7',4(4)0
/*
54*(:
9)3)6(0 '+9
0./+('+)/10
7406'**4'8)0
(:'(
7))(
0)*4/10
6*4()*4'
H=)6(4/+
IJKJLM
0:/1,9
5)
*)./*()9
'0 =EF0\# B:)
/1(6/7)
/3
',,
.*)8+'+64)0
H0./+('+)/10
7406'**4'8)<
),)6(4A)
()*74+'(4/+<
)6(/.46 .*)8+'+6;<
+/*7',
54*(:<
/*
6/+8)+4(',
'5+/*7',4(;M
0:/1,9
5)
3/,,/@)9
1.
'+9
9/617)+()9\#
"\#$\#> C'()*+',
)-./01*) &',)
.'(4)+(0
0:/1,9
*)3*'4+
3*/7
3'(:)*4+8
'
6:4,9
/*
9/+'(4+8
0.)*7
91*4+8
(:)
0(19;
'+9
3/*
> 7/+(:0
'3()*
(:)
,'0(
9/0)
/3
&!">?\#
C*)8+'+6;
/3
(:)
.'(4)+(N0
.'*(+)*
40
+/(
6/+049)*)9
(/
5)
'+
EF\#
G/@)A)*<
(:)
/1(6/7)
/3
',, .*)8+'+64)0
H0./+('+)/10
7406'**4'8)<
),)6(4A)
()*74+'(4/+<
)6(/.46
.*)8+'+6;<
+/*7',
54*(:<
/* 6/+8)+4(',
'5+/*7',4(;M
/661**4+8
3*/7
(:)
9'()
/3
(:)
34*0(
9/0)
1+(4,
>
7/+(:0
'3()*
(:)
,'0( 9/0)
0:/1,9<
43
./0045,)<
5)
3/,,/@)9
1.
'+9
9/617)+()9\#
untitled h1
ijo pqrstuvwpx

Pqywpvz[R
\Wp
]Vs^Zq]
_W[^S_Vq^
S[^Qp
__P`]Yw[]Wpq^
Z[^  
a/,,/@4+8
+/(4346'(4/+
3*/7
(:)
4+A)0(48'(/*<
bbc<
(:)
2de
0./+0/*<
@4,,
*)./*(
'+;
010.)6()9 '9A)*0)
*)'6(4/+
(:'(
40
5/(:
0)*4/10
'+9
1+)-.)6()9\#
bbc
@4,,
*)./*(
'+
EF
'0
'
010.)6()9 '6(4/+
/+,;
43
(:)*)
40
)A49)+6)
(/
0188)0(
'
6'10',
*),'(4/+0:4.
5)(@))+
(:)
0(19; .*/916(
'+9
(:)
'9A)*0)
)A)+(\#  
bbc
@4,,
+/(43;
aeE
'+9
',,
.'*(464.'(4+8
4+A)0(48'(/*0
H4\#)\#<
',, 4+A)0(48'(/*0
(/
@:/7
(:)
0./+0/*
40
.*/A494+8
9*18
1+9)*
4(0
2de0
/*
1+9)*
'+;
4+A)0(48'(/*N0 2deM
4+
'+
2de
0'3)(;
*)./*(
/3
./()+(4',
0)*4/10
*40D0
3*/7
6,4+46',
(*4',0
/*
'+;
/(:)*
0/1*6)<
'0 0//+
'0
./0045,)<
4+
'66/*9'+6)
(/
>%
bac
C'*(
f%>\#f>\#
E,,
0)*4/10
)A)+(0
@4,,
5)
*)./*()9
(/
(:)
aeE
'(
,)'0(
'++1',,;
4+
'
0177'*;
3/*7'(\#
untitled h1
g tz[zut

Hw[Zvwpz[R  
E0
'
0./+0/*
3/*
6,4+46',
(*4',0<
aeE
*)81,'(4/+0
*)i14*)
(:)
bbc
(/
7'4+('4+
'
7/+4(/*4+8 .*/8*'7\#
B:)
bbcN0
.*/8*'7
',,/@0
3/*
6/+34*7'(4/+
/3j
0(19;
9'('<
0.)64346',,;
9'('
(:'(
6/1,9 '33)6(
(:)
4+()*.*)('(4/+
/3
.*47'*;
'+9
0)6/+9'*;
0(19;
)+9./4+(0k
'9:)*)+6)
(/
(:)
.*/(/6/,< *)81,'(4/+0<
2bG
F$<
'+9
=lC0k
'+9
:17'+
015m)6(0
.*/()6(4/+\#
B:40
40
9/+)
(:*/18: 4+9).)+9)+(
A)*4346'(4/+
/3
0(19;
9'('
@4(:
0/1*6)
9/617)+('(4/+
3/6104+8
/+j n 2+3/*7)9
6/+0)+(
.*/6)00  
n F,48454,4(;
6/+34*7'(4/+ n e*18
'974+40(*'(4/+
'+9
'66/1+('54,4(; n E9A)*0)
)A)+(0
7/+4(/*4+8 n c)0./+0)
'00)007)+(\#
B:)
7/+4(/*4+8
.*/8*'7
',0/
)-()+90
(/
71,(4o04()
*)0)'*6:
@:)+
(:)
bbc
40
(:)
6//*94+'(4+8 6)+()*\#
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified by training and experience to monitor the progress of clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial conduct.
untitled h1
10 statistical considerations 10.1 statistical

This is a Phase II trial of M7824 in patients with recurrent or metastatic HPV associated malignancies. Patients will receive 1200 mg flat dose of M7824 IV every 2 weeks until PD or toxicity.  
The primary objective of this trial is to determine the objective response rate to a combined anti PD-L1/TGF beta inhibitor in patients with HPV associated cancers. Patients will be enrolled into five cohorts: (1) Patients with anal cancer whose disease is naïve to checkpoint inhibition, (2) Patients with non-neuroendocrine cervical cancer naïve to checkpoint inhibition, (3) Patients with P16+ oropharyngeal cancer naïve to checkpoint inhibition, (4) Patients with rare HPV associated tumors (e.g., squamous cell rectal, vulvar, vaginal, penile cancer, neuroendocrine cervical) naïve to checkpoint inhibition, and (5) Patients with any HPV associated cancer whose disease is refractory to checkpoint inhibition. A secondary hypothesis (objective) will be to obtain preliminary data on DCR, duration of response, PFS, and OS in treated subjects. An exploratory hypothesis (objective) will be to evaluate exploratory immunologic studies to understand and improve the administered treatment.
untitled h1
10.2 s ample s ize

Data from the literature suggest that a response rate for HPV associated cancers including anal, cervical and oropharyngeal cancers  receiving PD-1/PD-L1 treatment may be approximately 15%. This trial will try to demonstrate if the proposed therapy may be associated with an improved response rate. In order to establish the efficacy of this treatment in patients naïve to therapy, the primary objective in cohorts 1-4 would be to determine if using the proposed agent would rule out a 15% response rate and result in a response rate consistent with 40%. As such, cohort 1-4 will be conducted using a Simon minimax two-stage phase II trial design (Simon R, Controlled Clinical Trials 10:1-10, 1989) in order to rule out an unacceptably low PR+CR rate of 15% (p0=0.15) in favor of an improved response rate of 40% (p1=0.40). Aiming to keep the cohorts deliberately small, with alpha=0.15 (probability of accepting a poor treatment=0.15) and beta = 0.20
(probability of rejecting a good treatment=0.20), the first stage of each cohort will enroll 8 evaluable patients, and if 0 to 1 of the 8 have a clinical response, then no further patients will be accrued. If 2 or more of the first 8 patients have a response in an individual cohort, then accrual would continue until a total of 13 evaluable patients have been treated in that cohort. As it may take up to several months to determine if a patient has experienced a response, a temporary pause in the accrual may be necessary to ensure that enrollment to the second stage is warranted. Only HV positive patients will be included in the first stage when determining if adequate responses have occurred. If any patients in the first stage are determined to be HPV negative, they will be replaced by additional patients until the first stage contains the intended number of HPV positive patients. If there are 2 to 3 patients with a response out of 13 patients, this would be an uninterestingly low response rate. If there were 4 or more of 13 (30.8%) who experienced a response, this would be sufficiently interesting to warrant further study in later trials. Under the null hypothesis (15% response rate), the probability of early termination of each cohort is 65.7%.  
10.2.2  Checkpoint Refractory Cohort (Cohort 5)
There is limited information in the published literature regarding potential response rates in this population, but it is expected to be low. A response rate clearly exceeding 5% would be of interest to obtain.  
In order to establish the efficacy of this treatment in patients who are refractory to immune checkpoint therapy, the primary objective in this cohort would be to determine if using the proposed agent would rule out a 5% response rate and result in a response rate consistent with 2%. As such, this cohort of the trial will be conducted using a Simon minimax two-stage phase I trial design (Simon R, Controlled Clinical Trials 10:1-10, 1989) in order to rule out an unacceptably low PR+CR rate of 5% (p0=0.05) in favor of an improved response rate of 25% (p1=0.25). With alpha=0.10 (probability of accepting a poor treatment=0.10) and beta = 0.10
(probability of rejecting a good treatment=0.10), the first stage will enroll 13 evaluable patients, and if 0 of the 13 have a clinical response, then no further patients will be accrued in this cohort. If 1 or more of the first 13 patients have a response, then accrual would continue until a total of 20 evaluable patients who are refractory to therapy have been treated. As it may take up to several months to determine if a patient has experienced a response, a temporary pause in the accrual may be necessary to ensure that enrollment to the second stage is warranted. Only HPV positive patients will be included in the first stage when determining if adequate responses have occurred. If any patients in the first stage are determined to be HPV negative, they will be replaced by additional patients until the first stage contains the intended number of HPV positive patients. If there are 1 to 2 patients with a response out of 20 patients, this would be an uninterestingly low response rate. If there were 3 or more of 20 (15.0%) who experienced a response, this would be sufficiently interesting to warrant further study in later trials. Under the null hypothesis (5% response rate), the probability of early termination is 51.3%.  
It is expected that approximately 3 patients per month may enroll onto this trial. Thus, it is expected that 2 years may be required in order to enroll up to 72 evaluable patients. In order to allow for replacement of patients with HPV negative tumors or patients whom have previously received lymphodepleting chemotherapy as well as a small number of inevaluable patients in addition to screen failures the accrual ceiling will be set at 120 patients.
untitled h1
10.3 p opulation for a

A Modified Intention-to-Treat Analysis Dataset will be used. Only those patients who have measurable disease present at baseline and have had their disease re-evaluated at first restaging will be considered evaluable for response. (Note: Patients who exhibit objective disease progression prior to first restaging will also be considered evaluable.) Evaluable participants will be evaluable for the primary efficacy analysis unless they are replaced due to negative HPV testing, inability to confirm HPV status, or prior lymphodepleting chemotherapy. (Efficacy of the study drug in patients who test negative for HPV as well as in patients whom previously received lymphodepleting chemotherapy will be assessed as correlative exploratory endpoints.) Evaluable patients for objective response will have their response classified according to the definitions stated below.  
"\#$%&$'%(
)*+
,*-./.,01
2%%
3$,.(4,5
6.%%
'(
(\#$%&$'%(
)*+
,*-./.,0
)+*7
,8(
,.7(
*)
,8(.+
).+5, ,+($,7(4,
6.,8
9:;<=>
untitled h1
?@abcdedfcdfgeh

Eiehjckc  
L!>=>LM(4(+$%
233+*$/8 N8(
3%$44(O
$4$%05(5
)*+
($/8
*'P(/,.\#(
.5
O(5/+.'(O
.4
,8(
5&'5(/,.*45
'(%*6> L!>=><24$%05.5
*)
Q+.7$+0
"))./$/0
"4O3*.4,R5S
N8(
3(+/(4,$T(
*)
5&'P(/,5
,8$,
$/8.(\#(
$4
*'P(/,.\#(
/*4).+7(O
/*73%(,(
*+
3$+,.$%
*\#(+$%%
,&7*+ +(53*45(
&5.4T
U"VWXN
Y(+5.*4
L>L
6.%%
'(
(\#$%&$,(O
3(+
/*8*+,
RV*8*+,
LZ[S>
W)
$4,.Z,&7*+ +(53*45(5
$+(
*'5(+\#(O\
,8(
][^
/*4).O(4/(
.4,(+\#$%
*)
,8(
+(53*45(
+$,(
6.%%
'(
(\#$%&$,(O>
L!>=>_24$%05(5
*)
X(/*4O$+0
"))./$/0
"4O3*.4,5
`.5($5(
/*4,+*%
R/*4).+7(O
+(53*45(
*+
X`
%$5,.4T
)*+
$,
%($5,  
7*4,85S
6.%%
'(
$4$%0a(O
.4
$ 5.7.%$+
7$44(+
$5
,8(
3+.7$+0
(4O3*.4,>
`$,$
6.%%
'(
*',$.4(O
*4
O&+$,.*4
*)
+(53*45(\
QbX
$4O
cX>
2,
,8(
/*4/%&5.*4
*)
,8(
,+.$%\
,8(
+(53*45(
+$,(5
)+*7
/*8*+,5
LZ=  
6.%%
'(
/*73$+(O
6.,8
$
4*4Z 3$+$7(,+./
,6*Z5.O(O
,(5,\
9(8,$d5
7*O.)./$,.*4
,*
b.58(+d5
(-$/,
,(5,>
W)
,8(
+(53*45(
+$,(5
$+( 5&))./.(4,%0
5.7.%$+
R3e!><!
'0
b.58(+d5
(-$/,
,(5,S\
.4
$OO.,.*4
,*
+(3*+,.4T
,8(.+
+(5&%,5 .4O.\#.O&$%%0
'0
/*8*+,\
$
5(/*4O$+0
$4$%05.5
6.%%
'(
,*
+(3*+,
$
/*7'.4(O
+(53*45(
+$,(
'$5(O
*4 ,*,$%
+(53*45(5
.4
/*8*+,5
LZ=
*&,
*)
,8(
,*,$%
4&7'(+
*)
(\#$%&$'%(
5&'P(/,5
.4
/*8*+,5
LZ=>
N8.5 +(53*45(
)+$/,.*4
6.%%
'(
+(3*+,(O
$%*4T
6.,8
$
][^
,6*Z5.O(O
/*4).O(4/(
.4,(+\#$%>
untitled h1
l!>=>>l'&+.4

*)
U(53*45(  
N8(
O&+$,.*4
*)
*\#(+$%%
+(53*45(
6.%%
'(
(\#$%&$,(O
'0
/*8*+,>
N8(
O&+$,.*4
*)
*\#(+$%%
+(53*45(
.5 7($5&+(O
)+*7
,8(
,.7(
7($5&+(7(4,
/+.,(+.$
$+(
7(,
)*+
VU
*+
QU
R68./8(\#(+
.5
).+5,
+(/*+O(OS &4,.%
,8(
).+5,
O$,(
,8$,
+(/&++(4,
*+
Q`
.5
*'P(/,.\#(%0
O*/&7(4,(O\
$4O
.5
(\#$%&$,(O
&5.4T
,8( f$3%$4Z9(.(+
7(,8*O>
L!>=>_><Q+*T+(55.*4Zb+((
X&+\#.\#$%
QbX
6.%%
'(
(\#$%&$,(O
'0
/*8*+,
$4O
*\#(+$%%
&5.4T
f$3%$4Z9(.(+
7(,8*O5>
QbX
6.%%
'(
O().4(O
$5 ,8(
,.7(
)+*7
,8(
O$,(
*)
).+5,
,+($,7(4,
,*
,8(
O$,(
*)
O.5($5(
3+*T+(55.*4
*+
O($,8
R$40
/$&5(S 68./8(\#(+
*//&+5
).+5,>
X&'P(/,5
68*
O*
4*,
8$\#(
O.5($5(
3+*T+(55.*4
*+
8$\#(
4*,
O.(O
$,
,8(
(4O *)
)*%%*6
&3
6.%%
'(
/(45*+(O
$,
,8(
%$5,
g4*64
O$,(
,8(
5&'P(/,
6$5
3+*T+(55.*4
)+((>
L!>=>_>_c'P(/,.\#(
+(53*45( c'P(/,.\#(
+(53*45(
.5
$
/*73%(,(
*+
3$+,.$%
+$O.*T+$38./
+(53*45(
$5
O().4(O
'0
U"VWXN
L>L> L!>=>_>=
`.5($5(
/*4,+*%
+$,(
R`VUS
`VU
.5
,8(
3(+/(4,$T(
*)
3$,.(4,5
68*
$/8.(\#(
$
/*73%(,(
+(53*45(\
3$+,.$%
+(53*45(
$4O
5,$'%( O.5($5(
$5
O().4(O
'0
U"VWXN
L>L>
untitled h1
!"##%&'()

+,&-*./.  
%&'()*
(,012/,).
3/-4(
&,&-*5(0
&.
.677&8*
.)&)/.)/9.
068/,:
)8(&)7(,)
&,0;28
&.
9<&,:(
.928(. '827
4&.(-/,(
&..(..7(,).\#  
+=.
3/-4(
920(0
&.
0('/,(0
/,
)<(
>(0/9&?/9)/2,&8*
'28 @(:6-&)28*
+9)/A/)/(.
B>(0?@+C\#
+-+=.
3/-4(
8(9280(0
&,0
)&46-&)(0
'2--23/,:
(&9< )8(&)7(,)\#
+=.
3/-4(
8(9280(0
4*
.(A(8/)*D
'8(E6(,9*D
&,0
8(-&)/2,.</1
)2
)<(
.)60*
/,)(8A(,)/2, &,0
3/-4(
18(.(,)(0
4*
%*.)(7
F8:&,
G-&..
B%FGC
0(./:,&)/2,.
&,0
18('(88(0
)(87
:8261/,:.\# H,'287&)/2,
2,
(&9<
+=
3/-/,9-60(
.)&8)
0&)(D
.)21
0&)(D
.(A(8/)*D
8(-&)/2,.</1D
(I1(9)(0,(..D 26)927(D
&,0
068&)/2,\#
+0A(8.(
(A(,).
-(&0/,:
)2
18(7&)68(
0/.92,)/,6&)/2,
'827
)<(
.)60* /,)(8A(,)/2,
&,0
.(8/26.
)8(&)7(,)J(7(8:(,)
+=.
3/-4(
18(.(,)(0
(/)<(8
/,
&
K&4-(
28
&
L/.)/,:\#
H,
&00/)/2,D
2A(8&-.&'()*
3/-4(
&..(..(0
4*
0(.98/1)/A(
&,&-*.(.
6./,:
)&46-&)(0
'8(E6(,9/(.
2' +=.
4*
:8&0(
6./,:
GKG+=
M(8./2,
N\#"
3/)</,
02.(
92<28).
&,0
'28
)<(
2A(8&-.)60*
1216-&)/2, /,
)(87.
2'
)8(&)7(,)J(7(8:(,)
+=.D
%+=.D
&,0
9-/,/9&--*
./:,/'/9&,)
9<&,:(.
/,
.&'()* -&428&)28*
)(.).D
1<*./9&(I&7/,&)/2,.D
=GO.D
&,0
A/)&./:,.\#
!"\#$\#NP&.(-/,(
?(.98/1)/A(
%)&)/.)/9. P&.(-/,(
G<&8&9)(8/.)/9.
3/-4(
0(.98/4(0\# !"\#$\# Q-&,,(0
H,)(8/7
+,&-*.(.  
H,)(8/7
&..(..7(,)
2'
(''/9&9*
3/-4(
7&0(
&99280/,:
)2
)<(
%/72,
)32
.)&:(
1<&.(
HH
0(./:,.
2' (&9<
92<28)
0(.98/4(0
/,
%(9)/2,
RSTU\#
untitled h1
!"##v%64jo8261

+,&-*.(.  
=&9<
2'
)<(
'/A(
92<28).
3/-4(
(A&-6&)(0
/,0(1(,0(,)-*\#
H'
'(&./4-(
26)927(.
3/-4(
(A&-6&)(0 4&.(0
612,
.1(9/'/9
)6728
)*1(
&,0;28
WQM
)*1(\#  
F6)927(.
7&*
&-.2
4(
(A&-6&)(0
3/)<
8(.1(9) )2
)8(&)7(,)
3/)<
18/28
-*71<20(1-()/,:
9<(72)<(8&1*
8(:/7(,.
28
WHM
.)&)6.\#
X/,&--*
26)927(. 7&*
4(
(A&-6&)(0
3/)<
8(.1(9)
)2
</.)2-2:/9
.64)*1(.
B&0(,29&89/,27&D
.E6&726.D
1228-* 0/''(8(,)/&)(0
()9C\#
!"\#$\#YK&46-&)/2,
2'
H,0/A/06&Q&8)/9/1&,)
?&)&
H,0/A/06&8(.12,.(.
/,
&
92<28)
7&*
4(
0(1/9)(0
3/)</,
&
-&8:(8
:8261
6./,:
&
3&)(8'&-1-2)
28 .1/0(8
0/&:8&7\#
!"\#$\#Z=I1-28&)28*
+,&-*.(.
BH776,(
@(.12,.(.C
=I1-28&)28*
/776,(
&,&-*.(.
3/-4(
92,069)(0
)2
(A&-6&)(
&,)/J)6728
/776,(
8(.12,.(. /,069(0
4*
>VY[$\#
H776,(
8(.12,.(
3/-4(
&..(..(0
&72,:
&-.64\(9).
)8(&)(0
/,
(&9<
92<28)\# K<(
7&:,/)60(
2'
/776,(
8(.12,.(.
3/-4(
0(.98/4(0\#
+
.64\(9)
3/-4(
92,./0(8(0
(A&-6&4-( '28
/776,(
8(.12,.(
/'
)<(*
8(9(/A(
&)
-(&.)
2,(
02.(
2'
)8(&)7(,)\#
K<(
1(89(,)&:(
2'
.64\(9). 3/)<
&
12./)/A(
/776,(
8(.12,.(
3/-4(
(A&-6&)(0
4*
92<28)\#
X28
'-23
9*)27()8*
&,&-*.(.
2, QP>G
.&71-(.D
%)60(,)
K
)(.).
28
]86.^&-J_&--/.
&,0
_/-92I2,
8&,^
.67
)(.).
&.
&118218/&)( 3/-4(
1(8'287(0
2,
1(89(,)&:(.
2'
K`XJa
&,0;28
HX`Jb
(I18(../,:
9(--.
&72,:
)<(
0/''(8(,) 92<28).
)2
0()(87/,(
&,*
./:,/'/9&,)
0/''(8(,9(.
/,
9(-1216-&)/2,.\#
X28
&,)/:(,
.1(9/'/9
K
9(-- 8(.12,.(.
&
12./)/A(
/776,(
8(.12,.(
/.
0('/,(0
4*
G>H
8(&9)/A/)*
/,
c  
.)/76-&)/2,
6./,:
& '-23
9*)27()8/9
8(&026)
B9*)2^/,(
182069)/2,
28
G?!"V
(I18(../2,C\#
+,)/:(,J.1(9/'/9
1(1)/0( 9<&--(,:(
&..&*.
8(E6/8(
&
8(&026)
2'
d[N"
8(&9)/A(
KJ9(--.;7/--/2,
9(--.
&42A(
)<(
4&9^:826,0 efgh\#
untitled h1
"1r2&()#2&)/

$P
0N'O,#)0
N/&'%,
)$
-*+,
#$/0,/)  
7TPBG?
P@CFBE
GK
S>`E
DK@?E@G
CLE
EqDBPTET
NLKQ
E@LKBB>@S
>@
GIE
ALKGKDKB^  
eKHE`ELV
LEjDK@?E@G QCM
FE
@EDE??CLM
C@T
GIELE
>?
C
AK??>F>B>GMV
GIKPSI
P@B>iEBMV
GICG
?PFhEDG?
DKPBT
FEDKQE
TED>?>K@CBBM
>QAC>LET^
mKL
GI>?
LEC?K@
C@T
FEDCP?E
GIELE
>?
C
ALK?AEDG
KN
T>LEDG
FE@EN>G
NLKQ LE?ECLDI
ACLG>D>ACG>K@
;ZEDG>K@
"_1s=^
7BB
?PFhEDG?
t
CSE
k\  
H>BB
FE
KNNELET
GIE
KAAKLGP@>GM
GK
N>BB >@
GIE>L
H>?IE?
NKL
LE?ECLDI
C@T
DCLEV
C@T
C??>S@
C
?PF?G>GPGE
TED>?>K@
QCiEL
K@
GIE
uWRe 7T`C@DE
:>LEDG>`E
NKL
eECBGI
8CLE
C@T
YET>DCB
9E?ECLDI
fCLG>D>ACG>K@v
NKLQ
?K
GICG
C@KGIEL AEL?K@
DC@
QCiE
TED>?>K@?
CFKPG
GIE>L
QET>DCB
DCLE
>@
GIE
E`E@G
GICG
GIEM
FEDKQE
>@DCACD>GCGET KL
DKS@>G>`EBM
>QAC>LET
TPL>@S
GIE
DKPL?E
KN
GIE
?GPTM^
WKGEw
OIE
fR
KL
7R
H>BB
DK@GCDG
GIE
WRe
7F>B>GM
GK
8K@?E@G
7??E??QE@G
OECQ
;787O=
NKL E`CBPCG>K@
GK
C??E??
K@SK>@S
DCACD>GM
KN
GIE
?PFhEDG?
C@T
GK
>TE@G>NM
C@
J79V
C?
@EETET^
fBEC?E
?EE
ZEDG>K@
"_1x1"
NKL
DK@?E@G
ALKDETPLE^
untitled h1
"1s+&%n&)/

$P
',/,P*)0
&/4
(*0Y0Z4*0#$.P$()0  
fCG>E@G?
H>BB
LEDE>`E
E`CBPCG>K@
KN
GIE>L
T>?EC?E
CG
GIE
WCG>K@CB
8C@DEL
R@?G>GPGE{?
8B>@>DCB
8E@GEL^ OIE
AKGE@G>CB
FE@EN>G
GK
C
ACG>E@G
GICG
SKE?
K@GK
?GPTM
>?
C
LETPDG>K@
>@
GIE
FPBi
KN
GIE>L
GPQKL HI>DI
QCM
KL
QCM
@KG
IC`E
NC`KLCFBE
>QACDG
K@
?MQAGKQ?
C@TbKL
?PL`>`CB^
fKGE@G>CB
CT`EL?E
LECDG>K@?
CGGL>FPGCFBE
GK
GIE
CTQ>@>?GLCG>K@
KN
GIE
?GPTM
TLPS
PG>B>|ET
>@
GI>?
GL>CB CLE
T>?DP??ET
>@
ZEDG>K@
"r^
7BB
DCLE
H>BB
FE
GCiE@
GK
Q>@>Q>|E
?>TE
ENNEDG?V
FPG
GIEM
DC@
FE P@ALET>DGCFBE
>@
@CGPLE
C@T
?E`EL>GM^
fCG>E@G?
H>BB
FE
EqCQ>@ET
C@T
E`CBPCGET
AL>KL
GK
E@LKBBQE@G^ 7BB
E`CBPCG>K@?
GK
QK@>GKL
GIE
GLECGQE@G
KN
ACG>E@G?
H>BB
FE
LEDKLTET
>@
GIE
ACG>E@G
DICLG^
RN
patients suffer any physical injury as a result of the participation in this study, immediate medical treatment is available at the Clinical Center, National Cancer Institute, Bethesda, Maryland.  
The potential benefits to patients may include improvement of their condition or temporary relief of symptoms.  
Although no compensation is available, any injury will be evaluated and treated in keeping with the benefits or care to which patients are entitled under applicable regulations. In all publications and presentations resulting from this trial, patients' anonymity will be protected to the maximum extent possible. Authorized personnel from the National Cancer Institute (NCI) and Food and Drug Administration (FDA) or other regulatory authorities may have access to research files in order to verify that patients' rights have been safeguarded. In addition, patient names will be given to the Central Registration to register and verify patients' eligibility.
untitled h1
12.5 r isk / b

12.5.1.1 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.  
12.5.1.2 Potential Risks Associated with M7824 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.  
12.5.1.3 Risk of Optional Biopsies All care will be taken to minimize risks that may be incurred by tumor sampling. However, there are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained fully during informed consent.  
12.5.1.4 Risks of exposure to ionizing radiation This research study involves the possibility of 8 CT CAP scans and 2 CT guided biopsies collected for research purposes. The amount of radiation exposure you will receive from these procedures is equal to approximately 10.4 rem. The CT scans and CT guided biopsies in this study will expose the research participant to 34.7 years' worth of background radiation. This level of exposure results in an increased risk of cancer.  
Subjects undergoing two optional biopsies collections will be exposed to 1.6 rem.  
12.5.1.5 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.
untitled h1
"#%"e&'()

*+
F2=*1'5'79
G5:25@/=
,&-  
B:/
;2=*1'5'79
'5+7('*5
928
@27(/
9'1=
(8904*9(
(7@:
2(
@*1=5/((
'5
4:/
239
=73'5;
4:/ '56/@4'*5C
2
9/4211'@
42(4/C
:/2=2@:/C
25=
527(/2$
B:/3/
23/
3'()(
*+
25
-H
@24:/4/3
'5@17=/
>1//='5;C '5+/@4'*5C
*3
'5+129924'*5
*+
4:/
()'5
25=
</'5
?'4:
02'5
25=
(?/11'5;$
.3*@/=73/D3/124/=
3'()(
+3*9
,&25=
;2=*1'5'79
/5:25@/=
,&?'11
>/
/A012'5/=
+7118
=73'5; '5+*39/=
@*5(/54$
"\#$%$"$I&/(/23@:
J1**=
K*11/@4'*5
&'()( &'()(
*+
>1**=
=32?(
'5@17=/
02'5
25=
>37'('5;
'5
4:/
23/2
?:/3/
4:/
5//=1/
'(
012@/=C 1';:4:/2=/=5/((C
25=
323/18C
+2'54'5;$
L:/5
123;/
29*754(
*+
>1**=
23/
@*11/@4/=C
1*?
3/=
>1**= @/11
@*754
M25/9'2N
@25
=/</1*0$ "\#$%$"$OP4:/3
&'()( &'()(
'5@17=/
4:/
0*(('>1/
*@@733/5@/
*+
258
*+
2
325;/
*+
('=/
/++/@4(
?:'@:
23/
1'(4/=
'5
4:/ K*5(/54
Q*@79/54
*3
4:'(
03*4*@*1
=*@79/54$
R3/S7/54
9*5'4*3'5;
+*3
2=</3(/
/++/@4(
?'11
:/10 4*
9'5'9'T/
4:/
3'()(
2((*@'24/=
?'4:
2=9'5'(4324'*5
*+
4:/
(47=8
2;/54($
untitled h1
vwxyz[]^

`A[Z^]]
B\C
C[Zde^\_B_F[\  
B:/
'5+*39/=
@*5(/54
=*@79/54
?'11
>/
03*<'=/=
2(
2
0:8('@21
*3
/1/@43*5'@
=*@79/54
4*
4:/ 0234'@'0254
*3
@*5(/54
=/(';5//M(N
2(
2001'@2>1/
+*3
3/<'/?
03'*3
4*
@*5(/54'5;$  
g
=/(';524/=
(47=8 '5</(4';24*3
?'11
@23/+7118
/A012'5
4:/
03*@/=73/(
25=
4/(4(
'5<*1</=
'5
4:'(
(47=8C
25=
4:/ 2((*@'24/=
3'()(C
='(@*9+*34(
25=
>/5/+'4($
-5
*3=/3
4*
9'5'9'T/
0*4/54'21
@*/3@'*5C
2(
97@:
4'9/
2(
'(
5//=/=
4*
3/<'/?
4:/
=*@79/54
?'11
>/
;'</5C
'5@17='5;
25
*00*3475'48
4*
='(@7((
'4
?'4: +3'/5=(C
+29'18
9/9>/3(
25=U*3
*4:/3
2=<'(*3(C
25=
4*
2()
S7/(4'*5(
*+
258
=/(';524/=
(47=8 '5</(4';24*3$
g
(';5/=
'5+*39/=
@*5(/54
=*@79/54
?'11
>/
*>42'5/=
03'*3
4*
/5438
*54*
4:/
(47=8$
B:/
'5'4'21
@*5(/54
03*@/((
2(
?/11
2(
3/D@*5(/54C
?:/5
3/S7'3/=C
928
42)/
012@/
'5
0/3(*5
*3 3/9*4/18
M/$;$C
<'2
4/1/0:*5/
*3
*4:/3
h-i
2003*</=
3/9*4/
0124+*39(
7(/=
'5
@*901'25@/
?'4: 0*1'@8C
'5@17='5;
i&..
.*1'@8
jkjN
0/3
='(@3/4'*5
*+
4:/
=/(';524/=
(47=8
'5</(4';24*3
25=
?'4: 4:/
2;3//9/54
*+
4:/
0234'@'0254U@*5(/54
=/(';5//M(N$  
L:/4:/3
'5
0/3(*5
*3
3/9*4/C
4:/
03'<2@8
*+ 4:/
(7>6/@4
?'11
>/
92'542'5/=$
K*5(/54'5;
'5</(4';24*3(
M25=
0234'@'0254U@*5(/54
=/(';5//C
?:/5 '5
0/3(*5N
?'11
>/
1*@24/=
'5
2
03'<24/
23/2
M/$;$C
@1'5'@
@*5(714
3**9N$
L:/5
@*5(/54
'(
@*5=7@4/= 3/9*4/18C
4:/
0234'@'0254U@*5(/54
=/(';5//
?'11
>/
'5+*39/=
*+
4:/
03'<24/
52473/
*+
4:/
='(@7(('*5 25=
?'11
>/
/5@*732;/=
4*
3/1*@24/
4*
2
9*3/
03'<24/
(/44'5;
'+
5//=/=$
K*5(/54
?'11
>/
=*@79/54/=
?'4:
3/S7'3/=
(';52473/(
*5
4:/
0:8('@21
=*@79/54
M?:'@:
'5@17=/( 4:/
03'54*74
*+
25
/1/@43*5'@
=*@79/54
(/54
4*
0234'@'0254N
*3
2(
=/(@3'>/=
>/1*?C
?'4:
2
925721
(non-electronic) signature on the electronic document.  When required, witness signature will be obtained similarly as described for the investigator and participant.
untitled h1
manual (non-electronic) signature on electronic

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 participant 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 here.  
12.6.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation For participants addressed in Section Error! Reference source not found., an LAR will be identified consistent with Policy 403 and informed consent obtained from the LAR, as described in Section Error! Reference source not found..  
12.6.2 Request for Waiver of Consent for Screening Activities Prior to the subject signing the consent for this study pre-screening activities listed in Section 2.2.1 may be performed. We request a waiver of consent for these activities as they involve only minimal risk to the subjects.  A waiver will not adversely affect the rights and welfare of the subjects given that the activities are only intended to determine suitability for screening for participation in research protocols.  These activities could not practicably be carried out without the wavier as central recruiting services, utilized in the NIH Clinical Center, perform pre-screening activities for multiple studies and obtaining consent for each one is beyond their resources.  The subjects will be provided with additional pertinent information after participation as they will be informed whether or not they are eligible to sign a consent for additional screening.
untitled h1
13 regulatory and operational considerations

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:  
.  
.
.  
.  
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).
untitled h1
13.2 quality assurance and quality

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 Conference 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.
untitled h1
13.3 conflict of interest policy

The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation in the design and conduct of this trial. The study leadership in conjunction with the National Cancer Institute has established policies and procedures for all study group members to disclose all conflicts of interest and will establish a mechanism for the management of all reported dualities of interest.
untitled h1
13.4 c onfidentiality and p

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.  
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and records required to be maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit access to such records.  
The study participant's contact information will be securely stored at the clinical site for internal use during the study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements.  
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be stored at the NCI CCR. This will not include the participant's contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by the clinical site and by NCI CCR research staff will be secured and password protected. At the end of the study, all study databases will be archived at the NIH.  
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued by the National Institutes of Health (NIH). This certificate protects identifiable research information from forced disclosure. It allows the investigator and others who have access to research records to refuse to disclose identifying information on research participation in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from being compelled to disclose information that would identify research participants, Certificates of Confidentiality help achieve the research objectives and promote participation in studies by helping assure confidentiality and privacy to participants.
untitled h1
14 pharmaceutical information 14.1 d

M7824 will be supplied by EMD Serono as a sterile liquid formulation. Each vial of Powder for Concentrate for Solution for Infusion (freeze-dried formulation) is packaged in United States Pharmacopeia (USP) and European Pharmacopeia (Ph Eur) type I glass vials. Each vial is filled with 45 mg of M7824 (45 mg/vial) as preservative-free powder containing histidine, trehalose dihydrate, sodium chloride, L-methionine and polysorbate 20 (Tween 20). The vials are closed with a rubber stopper in lyophilization format complying with USP and Ph Eur and sealed with an aluminum plastic crimping cap. Only excipients that conform to the current USP and / or Ph Eur are used for M7824 drug product.  
The Concentrate for Solution for Infusion (liquid formulation) is packaged at a 10 mg/mL
concentration in USP / Ph Eur type I 50R vials that are filled with drug product solution to allowan extractable volume of 60 mL (600 mg/60 mL). The liquid formulation contains histidine, trehalose dihydrate, sodium chloride, L-methionine and polysorbate 20 (Tween 20). The vials are closed with rubber stoppers within serum format complying with USP and Ph Eur with an aluminum crimp seal closure.  
For applications in clinical studies, the liquid formulation is diluted directly with 0.9% NaCl solution (sodium chloride injection) supplied in an infusion bag.  
"\#$
$%&'()&$*
+,-.($%
,/
*$-'+$01
)0$
)2&'3'4)&$*
&,
5$
2,
(,0$
&\#)2
678
(9:
;\#'3\#
)0$ 3-'2'3)--1
)33$4&)5-$<
untitled h1
=>?@abcdedaf

"\#$
'((.2,G-,5.-'2
4,0&',2
,/
HI!6J
(,-$3.-$
'%
'*$2&'3)&,
)+$-.()5
KL)+$23',M<
N$%4$3&'+$ ;)02'2G%
)2*
40$3).&',2%
/,0
G0)*$
6
,0
\#'G\#$0
'((.2$O($*')&$*
42$.(,2'&'%:
'((.2$O($*')&$* 3,-'&'%:
'((.2$O($*')&$*
$2*,30'2,4)&\#'$%:
'((.2$O($*')&$*
\#$4)&'&'%M
)2*
'2/.%',2
0$)3&',2% )0$
'23-.*$*
'2
&\#$
40$%30'5'2G
/,0
L)+$23',
K5)+$23',<3,(M<
P)0&'3'4)2&%
;'-5$
40$O($*'3)&$*
&, 40,4\#1-)Q
)G)'2%&
'2/.%',2%
0$)3&',2%<
"\#$
/,--,;'2G
)**'&',2)--1
%'G2'/'3)2&
'((.2$O($*')&$* )*+$0%$
0$)3&',2%
\#)+$
,33.00$*
'2
-$%%
&\#)2
RS
,/
RIT!
4)0&'3'4)2&%
&0$)&$*
;'&\#
LUVWXYZ[\ (1,3)0*'&'%
;'&\#
/)&)3)%$%:
(1,%'&'%:
4%,0')%'%:
)0&\#0'&'%:
$Q/,-')&'+$
*$0()&'&'%:
$01&\#$()
(.-&'/,0($:
4$(4\#'G,'*:
\#14,4'&.'&)0'%(:
.+$'&'%:
].'--)'2OL)00^
%12*0,($:
)2*
%1%&$('3 '2/-)(()&,01
0$%4,2%$<
"\#$
)5,+$
'0UW%
)0$
)-3,2%'*$0$*
)2
)2&'3'4)&$*
0'%_
,/
&0$)&($2&
;'&\# HI!6J
)2*
&\#.%
;'-2,&
5$
3,2%'*$0$*
`9"%<
Z2
)
4\#)%$
R:
,4$2O-)5$TaT
*,%$O$%3)-)&',2
%&.*1
,/
HI!6J
'2
R
4)0&'3'4)2&%:
T
4)0&'3'4)2&% $Q4$0'$23$*
G0)*$
T
*0.GO0$-)&$*
)*+$0%$
$+$2&%
'23-.*'2G
%_'2
'2/$3&',2
%$3,2*)01
&,
G0)*$
6 5.--,.%
4$(4\#'G,'*:
-'4)%$
'230$)%$*:
)2*
3,-'&'%
;'&\#
)%%,3')&$*
)2$(')<
"\#$0$
;$0$
2,
G0)*$
J
b 7
&0$)&($2&
0$-)&$*
)*+$0%$
$+$2&%<
P-$)%$
%$$
&)5-$
5$-,;
/,0
*$&)'-%<  
| Acdefgdhficdjefdk ekldcmd dldhfm n opq r s  nt  opq r s nt  opq r s t                                |  r s ut            |          |            |          |            |          |
|--------------------------------|------------|----------|------------|----------|------------|----------|
| U21  ]0)*$ ]0)*$  T            | U21  ]0)*$ | ]0)*$  T | U21  ]0)*$ | ]0)*$  T | U21  ]0)*$ | ]0)*$  T |
| vecfwxwyehfm zwf{  eh| dldhf}} | @          |          |            |          |            |          |
| ~?€                                | =          |          |            |          |            |          |
| ~''?'                                | =          |          |            |          |            |          |
| ~''?'                                | ƒ ~ƒ?ƒ            | >        |            |          |            |          |
| ~"€?=                                | @          |          |            |          |            |          |
| ~@…?                                | €            |          |            |          |            |          |
| ~>'?…                                | '            |          |            |          |            |          |
| ~=…?…                                |            |          |            |          |            |          |
| U2$(')                         | R          |          |            |          |            |          |
| KRJ<TM                         | R          |          |            |          |            |          |
| KRJ<TM                         | R K <TM    | R K <TM  |            |          |            |          |
| L.--,.%  4$(4#'G,'*            | R          |          |            |          |            |          |
| KTT<TM                         | R K <TM    |          |            |          |            |          |
| Y,-'&'%                        | R          |          |            |          |            |          |
| KRJ<TM                         | R          |          |            |          |            |          |
| KRJ<TM                         | R K <TM    | R K <TM  |            |          |            |          |
| `$0()&'&'%  )32$'/,0(          | R          |          |            |          |            |          |
| KTT<TM                         | R K <TM    |          |            |          |            |          |
| `1%42$)  $Q$0&',2)-†††                                | R          |          |            |          |            |          |
| KRJ<TM                         | R K <TM    |          |            |          |            |          |
| ‡14$0&#10,'*'%( ‡14,4#,%4#)&$(')                                | R          |          |            |          |            |          |
| KRJ<TM                         | R K <TM    |          |            |          |            |          |
| ‡14,&#10,'*'%(                                | R          |          |            |          |            |          |
| KTT<TM                         | R          |          |            |          |            |          |
| KRJ<TM                         | 6          |          |            |          |            |          |
| KR6<7M                         |            |          |            |          |            |          |
| Z2/.%',2O0$-)&$*  0$)3&',2     | R          |          |            |          |            |          |
| KRJ<TM                         | R K <TM    |          |            |          |            |          |
| ˆ$0)&,)3)2&#,()                                |            |          |            |          |            |          |  
| " #$% & '  "(  #$% & ' "(  #$% & ' (                               |  & ' )(         |         |
|-------------------------------|---------|---------|
| *+,-./ +012/-./               | 3       |         |
| 435678                        | 3       |         |
| 435678                        | 3 4 678 | 3 4 678 |
| 9-:./-                        | 3       |         |
| 477678                        | 3 4 678 |         |
| ;2:2+<:. =-.> ?-1:@AB ,-,:@-2 | 3       |         |
| 477678                        | 3       |         |
| 477678                        | C       |         |
| 43C6D8                        |         |         |
| EF+0 +0G/1<+A0                | 3       |         |
| 477678                        | 3       |         |
| 477678                        | 3 4 678 | 3 4 678 |
| HA?+<+0I                      | 3       |         |
| 477678                        | 3 4 678 |         |  
JJK>/2/
L/2/
0A
<2/-<?/0<B2/@-</M
NO.
+0
<>/
7
,-2<+1+,-0<.
<2/-</M
L+<>
3
?IPFI
QRSC56 JJJK>/
M+GG/2/0<+-@
GA2
<>+.
MT.,0/L-.
,0/:?A0+<+.
U.6
@T?,>-0I+<+1
.,2/-M
AG
M+./-./
4M+./-./ ,2AI2/..+A086 N.
AG
N:I:.<
CV3RW
X
DVV
,-2<+1+,-0<.
>-U/
Y//0
<2/-</M
L+<>
QRSC5
-12A..
?:@<+,@/
.A@+M
<:?A2 /Z,-0.+A0
1A>A2<.6
K>/
.-G/<T
,2AG+@/
+.
1A0.+.</0<
L+<>
A<>/2
?A0A<>/2-,T
1>/1F,A+0<
+0>+Y+<A2.W L+<>
<>/
/Z1/,<+A0
AG
F/2-<A-1-0<>A?-.
-0M
1:<-0/A:.
.[:-?A:.
1/@@
1-21+0A?-.
L>+1>
>-U/ A11:22/M
+0
-,,2AZ+?-</@T
7BD\
AG
,-2<+1+,-0<.W
-0M
-2/
L/@@
?-0-I/M
L+<>
.:2I+1-@
/Z1+.+A06 K>/./
@/.+A0.
>-U/
0A<
Y//0
12+</2+A0
GA2
<2/-<?/0<
M+.1A0<+0:-<+A0W
Y:<
<>:.
G-2
>-U/
-@@ .,A0<-0/A:.@T
2/I2/../M
GA@@AL+0I
<2/-<?/0<
M+.1A0<+0:-<+A06
]0
-MM+<+A0W
-G</2
M+.1:..+A0
-?A0I
9^]
+0U/.<+I-<A2.
A0
?:@<+,@/
,2A<A1A@.
:.+0I
QRSC5W
?:@<+,@/ Y@//M+0I
/U/0<.
2-0I+0I
G2A?
@AL
I2-M/
I+0I+U-@
Y@//M+0I
-0M
/,+.<-Z+.
<A
?A2/
./2+A:. >/?A,<T.+.W
_]
Y@//M+0I
-0M
>/?-<:2+>-U/
Y//0
AY./2U/M6
EA?/
AG
<>/./
/U/0<.
1-0
Y/
-<<2+Y:</M <A
Y@//M+0I
/U/0<.
2/@-</M
<A
1-01/2
M+2/1<@T
-0M
A<>/2.
Y@//M+0I
/U/0<.
1-0
Y/
-<<2+Y:</M
<A
1A@+<+. A2
1T.<+<+.
L>+1>
+.
F0AL0
<AZ+1+<T
AG
-0<+B;`B*3
-I/0<.
+01@:M+0I
QRSC56
aAL/U/2W
<>/2/ 2/?-+0.
<>/
,A..+Y+@+<T
<>-<
QRSC5
?-T
+012/-./
<>/
AU/2-@@
2+.F
AG
Y@//M+0I
+0
L-T.
<>-<
?-T
0A< Y/
M+2/1<@T
2/@-</M
<A
M+2/1<
<:?A2
Y@//M+0I
A2
+0G@-??-<A2T
Y@//M+0I
/U/0<.
M/.12+Y/M
L+<> 1>/1F,A+0<
+0>+Y+<A2.
@+F/
QRSC56
]<
+.
>T,A<>/.+b/M
<>-<
<>+.
,A..+Y@/
+012/-./M
Y@//M+0I
2+.F
?-T Y/
M:/
<A
K_c
Y/<+0>+Y+<+A0
L>+1>
>-.
-0
/GG/1<
A0
-0I+AI/0/.+.d
Y@//M+0I
>-.
-@.A
Y//0
AY./2U/M +0
,-2<+1+,-0<.
2/1/+U+0I
QRSC5
-0M
?-T
Y/
M2:IB2/@-</M
4/6I6W
I:?
Y@//M+0IW
0A./
Y@//M.W 1A:I>+0I
:,
Y@AAMW
Y@AAM
+0
<>/+2
:2+0/W
A2
Y@AAM
+0
<>/
.<AA@86
N11A2M+0I@TW
,-2<+1+,-0<.
L+@@
Y/ 0A<+G+/M
AG
<>/
.-?/
,A..+Y@/
2+.F
+0
<>/
+0GA2?/M
1A0./0<
MA1:?/0<
GA2
<>+.
.<:MT
4/6I6W
I:? Y@//M+0IW
0A./
Y@//M.W
1A:I>+0I
:,
Y@AAMW
Y@AAM
+0
<>/+2
:2+0/W
A2
Y@AAM
+0
<>/
.<AA@86 N<
@/-.<
C
+0.<-01/.
AG
0AM:@-2
2/I/0/2-<+U/
>T,/2,@-.+>-U/
Y//0
AY./2U/M
L+<>
<>/
:./
AG
<>+. -I/0<6
untitled h1
efghijkiljlmnopq

Rlpstnpuq
Lps
Vmojluk  
QRSC5
M2:I
,2AM:1<
?:.<
Y/
.<A2/M
-<
Cw^
<A
Sw^
:0<+@
:./6
K>/
.<A2-I/
1A0M+<+A0
+.
Y-./M
A0 M-<G2A?
A0IA+0I
@A0I
</2?
.<-Y+@+<T
.<:M+/.
L+<>
QRSC56  
" \#$%
&'()
*'+&(,.-+'/&
0'++1
2$345
-+
$ 456
+'
78)7/'
-/1*/'0-('/.
9+'
/:-/;&/&
*/'8+&. +9
-81/
18)7</
.(<=/,-+
&/)'0&0-8+;>
" \#$%
1(.;+</
9'+?/;>
@+()7
.70A8;)
+9
-7/ '/,+;.-8-(-/&
.+B(-8+;
1(.</
0C+8&/&>
" \#$%
1(.;+</
(./&
9+'
0;D
*('*+./
+-7/'
-70;
-7/
.-(&D>
E7/
,+;-/;-.
+9
-7/
" \#$%
C80B.
0'/
.-/'8B/
0;&
;+;*D'+)/;8,F
0;&
&+
;+,+;-08;
<0,-/'8+.-0-8, *'/./'C0-8C/.>
G;D
.*8BB.
-70+,,('
.7+(B&
</
,B/0;/&
(*
(.8;)
-7/
90,8B8-DH.
.-0;&0'&
,B/0;(* *'+,/&('/.
9+'
<8+B+)8,
*'+&(,-.>
G;D
(;(./&
*+'-8+;
+9
-7/
.+B(-8+;
.7+(B&
</
&8.,0'&/&
8;
<8+70?0'&
I0.-/
&8.*+.0B
I8-7
98;0B &8.*+.0B
<D
0,,/*-/&
B+,0B
0;&
;0-8+;0B
.-0;&0'&.
+9
8;,8;/'0-8+;>
JKLKMNOPQR
PSM
PMTUSUOVWPVUNS X//
X/,-8+;
YLZ
untitled h1
"# %&%%'(%)

!* +,-./0
1*2*0
-3
45*0
67
8769
:
9
;
<=
9
>>?@
>ABC
>AB345
?D5E
@-F0
GH!I*
J\#KGILM
F*
II!NI* G* 1A.O0
P*2*0
QBR0
-3
45*0
S7T
8U
VVV  
W
8
XU  
XU6
8
7
W
U
6
Y  
Z[
\[
Z68
<6[
2
]5,.
^._A50 GHH`*
abKG!LM
F*
cIGINQQ* Q* +-BdABD-.0
2*e*0
-3
45*0
679
U7U8[
86
6Y7  
U  
f
g
h.O5
2
>-R0
GHHi*
b\#jK!!LM
F*
!!!ING * c* 1A.O0
P*2*0
QBR0
7
W
7  
X
W
U
6
2 ]5,.
^._A50
GHH *
a\#KGHLM
F*
GkIIN c* `* h.O0
]*0
-3
45*0
U  
W
[7
U7U8[  
768[
77 78
U  
6
W
8
XU
7
l676  
7
W
U  
^._A34BO-30
GH!c*
\#KGGLM
F*
!!!QQNcG* I* >A.D0
e*2*0
-3
45*0
U
VVV  
W
W6
89
6
7-
Vm=
6=  
8  
7  
Z[
\[
Z68 6[
2
]5,.
^._A50
GHHk*
anKGiLM
F*
cIckN``* * o-p4B,0
q*r*0
-3
45*0
V78
6
XU
T67  
g h.O5
2
>-R0
GH!c*
bnsKiLM
F*
QcNcQ* i* >A.D0
e*2*0
-3
45*0
U
VV  
W
T67  
U
7
W
8 6
l676  
7
W
U
Y  
[
[
68
6[
2 ]5,.
^._A50
GHHk*
anK LM
F*
!HIkN c* k* t4.
P-BF-.0
]*>*0
-3
45*0
V67
UVu9
7  
U  
f l676  
7
8
6
m  
v.3
2
]4._-B0
GHHi*
"abK!HLM F*
GQ`cNI!* !H* wBAxd4..0
y*0
-3
45*0
Vu9  
[  
:  
87
6
T
W
z{9 f88m  
87
:
W
Vu9
86
vdd|.,3E0
!kki*
jKQLM
F*
Q!`NGQ* !!* }-5
+-__x,A0
>*0
-3
45*0
V6f9  
88  
88 ]5,.
]4._-B
@-/0
GHH *
"bK!ILM
F*
cI Ni`* !G* }-BE._D0
@*0
@*2*
~Dx|B/30
4.R
~*
e45d4,.0
Z{9  
67
688  
8
g43
w-.-30
GHH!*
ajKGLM
F*
!! NGk* !Q* 24DAp5-p0
r*e*0
W7
XU
W9  
7
]4._-B >-34/34/,/
@-t0
GHHI*
a\#KQLM
F*
cQ`N` * !c* 1-tAt,30
]*0
-3
45*0
Z{
8  
776
68[  
9  
]4._-B
@-/0
GH!c*
nKGQLM
F*
IiQQNcc* !`* >4//4O|-0
2*0
Z{  
:
]-550
GHHi*
"bKGLM
F*
G!`NQH* !I* o-,_x-B0
e*~*0
W7
XU
W9  
U
776
8  
7
]5,.
]4._-B
@-/0
GHH *
"bKG!LM
F*
IGc N`!* ! * @-,/0
r*o*0
-3
45*0
W9
Y8  
7f
W
8
8  
8
]5,.,_/
Kr4A
4|5AL0
GH!!*
JJK LM
F*
!!cQN * !i* eB|.40
~*0
-3
45*0
U
Z{9<7
[
W
8
8  
7
8
87  
8W
8  
U
7U[
W
U
Z{9m ]4._-B
]-550
GHH *
""KGLM
F*
!c NIH* !k* w4A0
g*0
-3
45*0
:
V78
W
SVV
Y8  
m
:
1Ar ^.-0
GH!`*
"sK!!LM
F*
-H!c!c!G*
!"\# $%&'()
*\#
'+,
-\#
./+
012(/)  
345
6  
7
.8/+,9
$'+:/8) !"; \#
<=;>?
@\#
ABC ;\# !;\# -D'+)
E\#)
/F
'&\#)
6GG  
HI  
JI
K  
I5 J
L++
$'8,1%FD%8':
*M8N)
!";A\#
O=!>?
@\#
;""C;;\# !! P%)
Q\#*\#)
R\#
E'+N)
'+,
Q\#S\#
E1T)  
U
5V  
I  
GI I5J
W+F
Q
X1%&
Y'8(/89)
!"; \#
<Z=;>?
@\#
/B[C/ \\# !]\# ^M)
S\#R\#)
S\#_\#
*D/+)
'+,
S\#
`1)
aUU
U  
b
cG  
HUd I  
J
U  
74
Q
^M'eD%+N
f+1g *:1
./:D+%&%N
Y/,
*:1)
!";A\#
<h=\>?
@\#
A];C\\# !\\# iM)
-\#)
/F
'&\#)
5V  
6G  
6
GI  
5J
-`%*
j+/)
!";A\# kl=B>?
@\#
/";];\"]\# !A\# i/m/8)
Q\#*\#)
/F
'&\#)
nGI
G
bIbHJ  
H
Kb  
II Kb
H
U
57V5
I
o7bp
qr  
Id d
H5d
Hb
q  
`'+:/F
j+:%&)
!";A\#
ks=\>?
@\#
] AC[\\# !B\# -%9F%t)
Y\#L\#)
/F
'&\#)
nGI  
HIGI
G
HIGI  
G
II
u
v+N&
Q
Y/,)
!";A\#
<wZ=!;>?
@\#
!""BC; \# ! \# x%m/8F)
$\#)
/F
'&\#)
IyGI
G
zHIGI  
I
u
v+N&
Q Y/,)
!";A\#
<wZ=!B>?
@\#
!A!;C]!\# ![\# X%8ND'/1)
^\#)
/F
'&\#)
nGI
G
{  
n|GIG
n56I5 7
VG
7
u
v+N&
Q
Y/,)
!";A\#
<w<=; >?
@\#
;B! C]}\# !}\# ^/8m9F)
x\#*\#)
/F
'&\#)
IyGI
G
{
U
HGJ
d
5V5 Hd  
5I5
G  
o~ana5r  
I  
`'+:/F)
!";B\#
<w=;""! >?
@\#
;A\"CA"\# ]"\# Y%Fe/8)
x\#Q\#)
/F
'&\#)
nGI
G
aIG  
57
7I
u v+N&
Q
Y/,)
!";A\#
<w<=;}>?
@\#
;["]C;]\# ];\# */1t/8F)
.\#S\#)
/F
'&\#)
6UJ  
J
U
HIyGI
U
I
U G  
I
|GIG  
I
U
b
b  
p
o~ana5r
H5d
IGd
Hb  
`'+:/F
j+:%&)
!";B\#
kw= >?
@\#
}ABCBA\#
]!\# $D%t)
`\#\#)
/F
'&\#)
GI
J
U
IyGI  
Ip5
b
G  
np
6|GIG
7
7I G
4I
b
b
z
~ana5
a{H
7b
Q
$&1+
j+:%&)
!";B\# ]]\# _/8819)
x\#`\#)
/F
'&\#)
nGI
U
G
6|GIG57
7I
U
b  
np
u
v+N&
Q
Y/,)
!";B\#
<wh=;}>?
@\#
;[ABC;[B \# ]\\# XM9D)
L\#Y\#)
Q\#i\#
^%&91+N/8)
Q8\#)
'+,
`\#0\#
-8Pm1&)
aIHJ
b
GJ
H
aG
b  
U
a57
_8%+F
-Mm&1:
^/'&FD)
!";B\#
O?
@\#
A\# ]A\# E'MT'+)
^\#`\#)
/F
'&\#)
GI  
H
Kb
bIbHJ5UJ
I p  
I  
IGd
5GHd
H5d
Hb  
`'+:/F j+:%&)
!";B\#
kw=;">?
@\#
;] \C;][A\# ]B\# Y'99'8,)
$\#)
/F
'&\#)
6UJ  
aUUJ
U
GGI
oazqrd  
5 II
7
b
V5
zIIG
7bpH
zbd  
b
b  
7
Q
$&1+
j+:%&)
!";B\#
<O=!B>?
@\#
];;}C!A\# ] \# *F8'M99)
Q\#)
x\#L\#
Y','+)
'+,
Q\#`\#
RM&&/P)
7
U
b
I
U  
IIG
bpH
b
v@/8F
j@1+
X1%&
.D/8)
!";B\# ks= >?
@\#
[}AC}";\# ][\# Y/&/8%)
W\#)
/F
'&\#)
a
J
I
U  
IIGbH I  
u'F
x/g
$'+:/8)
!";A\#
kh=[>?
@\#
\A C !\#
!"\# $%&'()(*+,
-\#.\#,
+)
%/\#,
011
23456141  
4
73
18
9
94
73
9  
:
3
4 :
9414
;<0=
>%?&+*
@AA(?'/
@AA(?')B+*,
CDEF\#
GHIJKL
M\#
J! NJO\# JD\# P(Q+/,
>\#R\#,
!*S,
+)
%/\#,  
0
73
TU  
VW
T9
V T
99  
X14
Y99  
T1:
V0
U1
>/Z? >%?&+*
[+\,
CDE]\#
^HICEKL
M\#
F!J NF!FO\# JE\# $+M'?+
$-,
_\#[\#,
`*+?Q%
@,
-+)+?'(
a,
[Z&B%*S\
b,
R++*c
>[,
`(//+c
b$,
a&B/'A b\#  
d?%/c\Z\
'e
EC!
M+*ZMB+*%/
B(A%?
ZAA(?+
&+//
\(f\+)\L
S+eZ?Z?Q
SZee+*+?&+\
gZ)B
%Q+ %?S
f+)g++?
B+%/)Bc
S'?'*\
%?S
&%?&+*
M%)Z+?)\
?')
S+)+&)+S
Z?
%?%/c\Z\
'e
\)%?S%*S ZAA(?+
&+//
)cM+\\#
b
>Z*&
hZ'A%*i\#
CDEOj
FLF
@
S'ZL
ED\#F CkOC!CC\# JC\# .Z\+?B%(+*,
.\#d\#,
+)
%/\#,
l7
U
1  
141
TY0Xm
1
;
=
.(*
b
>%?&+*,
CDD"\#
HnICKL
M\#
CC]NJ \# J!\# oB+\)Z%?Zi'p,
q\#_\#,
`\#.\#
a%p+/r+p%,
%?S
q\#$\#
P%/Z?Z?,
s3
U
U
44:
0
tU1  
3
3:UV
41
Y33  
<4u v\Z)'/'QZZ%,
E""E\#
wwIEKL
M\#
]]N"O\# JJ\# a+cA'(*,
$\#,
+)
%/\#,
TY0Xm
1
9
U  
9
1  
4413U1
$%?&+)
x?&'/,
CDE \#
yzI!KL
M\#
+EJ!N+EFC\# JF\# R++*c,
>\#[\#,
+)
%/\#,
3
X  
9  
{V|
3U1
0  
;<XV }~=  
3
U  
|3:1:
>%?&+*
@AA(?'/
[+\,
CDEF\#
wIEEKL M\#
ECJ]NFO\#
untitled h1
"# %%&'()&+ "#"%%&'()

%&./0.1$'*&
+2$23+
*.)2&.)$  
| 4567 89:;<:=>?@9 AB>BCD A@>E9                                                                            | F>:?<;DGH 89:;<:=>?@9 A@>E9                                                                                                                                                                |                           |                                                                            |
|----------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------|----------------------------------------------------------------------------|
| 7:>I9                                                                                                    | J9D@:KLBK<?D                                                                                                                                                                               | 89:@9?B                   | J9D@:KLBK<?                                                                |
| MNN                                                                                                      | O<:=>EP ?< @<=LE>K?BDP ?<  9QKI9?@9 <; IKD9>D9R                                                                                                                                            |                           |                                                                            |
| N                                                                                                        | O<:=>E >@BKQKBHR SCEEH >@BKQ9P  >TE9 B< @>::H <? >EE L:9UIKD9>D9  L9:;<:=>?@9 VKBW<CB :9DB:K@BK<?R                                                                                         | XN                        | YTE9 B< @>::H <? ?<:=>E >@BKQKBHZ  =K?<: DK[?D <: DH=LB<=D <;  IKD9>D9R    |
| \N                                                                                                       | O<:=>E >@BKQKBH VKBW 9;;<:BZ  D<=9 DK[?D <: DH=LB<=D <;  IKD9>D9R                                                                                                                          |                           |                                                                            |
| M                                                                                                        | AH=LB<=DP TCB >=TCE>B<:HR  ]9DB:K@B9I K? LWHDK@>EEH DB:9?C<CD  >@BKQKBHP TCB >=TCE>B<:H >?I >TE9  B< @>::H <CB V<:G <; > EK[WB <:  D9I9?B>:H ?>BC:9 ^9R[RP EK[WB  W<CD9V<:GP <;;K@9 V<:G_R | N                         | 5>:9D ;<: D9E;P C?>TE9 B< @>::H <?  ?<:=>E >@BKQKBH <: B< I< >@BKQ9  V<:GR |
| `N                                                                                                       | ]9aCK:9D <@@>DK<?>E >DDKDB>?@9P  TCB KD >TE9 B< @>:9 ;<: =<DB <;  WKDbW9: ?99IDR                                                                                                           |                           |                                                                            |
| c                                                                                                        | d? T9I efNg <; BW9 BK=9R  Y=TCE>B<:H >?I @>L>TE9 <; >EE  D9E;U@>:9P TCB C?>TE9 B< @>::H <CB  >?H V<:G >@BKQKBK9DR hL >?I  >T<CB =<:9 BW>? fNg <; V>GK?[  W<C:DR                            | fN                        | ]9aCK:9D @<?DKI9:>TE9 >DDKDB>?@9  >?I ;:9aC9?B =9IK@>E @>:9R               |
| !N                                                                                                       | JKD>TE9IP :9aCK:9D DL9@K>E @>:9  >?I >DDKDB>?@9R                                                                                                                                           |                           |                                                                            |
| i                                                                                                        | d? T9I jfNg <; BW9 BK=9R  5>L>TE9 <; <?EH EK=KB9I D9E;U@>:9P  @<?;K?9I B< T9I <: @W>K: =<:9  BW>? fNg <; V>GK?[ W<C:DR                                                                     | iN                        | A9Q9:9EH IKD>TE9IP  W<DLKB>EKk>BK<? K?IK@>B9IR J9>BW  ?<B K==K?9?BR        |
| MNNg T9I:KII9?R 5<=LE9B9EH  IKD>TE9IR 5>??<B @>::H <? >?H  D9E;U@>:9R m<B>EEH @<?;K?9I B< T9I  <: @W>K:R | MN                                                                                                                                                                                         | n<:KTC?IP ;>B>E L:<@9DD9D |                                                                            |
| cN                                                                                                       | l9:H DK@GP W<DLKB>EKk>BK<? K?IK@>B9IR J9>BW ?<B K==K?9?BR                                                                                                                                  |                           |                                                                            |
| !                                                                                                        | L:<[:9DDK?[ :>LKIEHR                                                                                                                                                                       |                           |                                                                            |
| f                                                                                                        | J9>IR                                                                                                                                                                                      | N                         | J9>IR                                                                      |